{ "$schema_version": "5.3", "review_mode": "fresh", "claim_restatement": { "index_wording": "Microbiome Causality vs Correlation Problem", "entry_form": "methodological_critique", "gradeable_restatement": "The composition of the human gut microbiome is a primary, targetable causal driver of systemic and neurobehavioural disease.", "restatement_required": true, "split_into": [], "parent_claim": null, "scope_qualifiers": [ { "qualifier": "Human cardiometabolic, hepatic, autoimmune and neurobehavioural conditions defined at baseline; rodent genotypes/diets and timing are scored separately", "determinable_before_outcome": true, "determined_from": "Enrollment and experimental design, before results; no responder-defined scope.", "action": "retained" } ] }, "hypothesis": { "name": "Microbiome Causality vs Correlation Problem", "central_claim": "The composition of the human gut microbiome is a primary, targetable causal driver of systemic and neurobehavioural disease.", "proposed_mechanism": "The composition of the human gut microbiome is a primary, targetable causal driver of systemic and neurobehavioural disease.", "claimed_scope": "The composition of the human gut microbiome is a primary, targetable causal driver of systemic and neurobehavioural disease.", "claimed_level": [ "initiation", "maintenance", "response" ], "is_conjunctive": true, "conjunctive_note": "The ranking title is a methodological problem; grade the index causal-primacy proposition, not the existence of the microbiome or the methodological critique. Human systemic and neurobehavioural disease scope is gated by SC4; rodent causality and human contribution are distinct scopes. C. difficile eradication is an out-of-scope calibration comparator, not support for systemic primacy." }, "rubric_routing": { "primary_rubric": "04-microbiome-systemic.md", "secondary_rubrics": [], "index_notes_applied": [ "The ranking title is a methodological problem; grade the index causal-primacy proposition, not the existence of the microbiome or the methodological critique. Human systemic and neurobehavioural disease scope is gated by SC4; rodent causality and human contribution are distinct scopes. C. difficile eradication is an out-of-scope calibration comparator, not support for systemic primacy." ], "rubric_fit_note": "Exact archived v5.3 framework. Any stale index empirical framing is rechecked against primary results." }, "subclaim_matrix": { "subclaims": [ { "id": "SC1", "statement": "Microbiome composition differs between healthy and diseased humans.", "subclaim_type": "existence", "scope": "baseline diagnosis, diet, medication and transit measured independently", "claimed_scope": "baseline diagnosis, diet, medication and transit measured independently", "governing_rubric": "04-microbiome-systemic.md", "key_evidence_anchor": "Confounder-controlled human composition studies", "hsef_level": "Β", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Disease-associated community features recur, but stool consistency, medication and quantitative measurement substantially alter interpretation; association alone is Β." }, { "id": "SC2", "statement": "Defined microbes or microbial factors are causal in rodent systemic or behavioural phenotypes.", "subclaim_type": "mechanism", "scope": "defined strain, recipient genotype, housing and substrate", "claimed_scope": "defined strain, recipient genotype, housing and substrate", "governing_rubric": "04-microbiome-systemic.md", "key_evidence_anchor": "Strain subtraction/addition, transfer and mechanistic rescue", "hsef_level": "Ζ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Defined microbial addition/rescue, host-pathway interruption and nonlethal microbial-enzyme inhibition converge on functional rodent effects with distinct failure modes. Genotype, diet and developmental timing remain prespecified boundaries." }, { "id": "SC3", "statement": "A microbiome mechanism contributes causally to human systemic or neurobehavioural disease.", "subclaim_type": "mechanism", "scope": "prespecified cardiometabolic, hepatic, autoimmune or neurobehavioural diagnosis and intervention", "claimed_scope": "prespecified cardiometabolic, hepatic, autoimmune or neurobehavioural diagnosis and intervention", "governing_rubric": "04-microbiome-systemic.md", "key_evidence_anchor": "Target-specific human intervention with functional endpoint", "hsef_level": "Ε", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Human FMT in treated cirrhosis alters recurrence/cognition, with phase2 placebo-controlled evidence and weaker earlier studies. Metabolic and PD trials are heterogeneous and ALS is negative; a context-specific contribution is supported, not one mechanism across disorders." }, { "id": "SC4", "statement": "Microbiome composition is a primary targetable upstream driver across that human disease scope.", "subclaim_type": "primacy", "scope": "baseline diet, transit, drugs, host genotype and diagnosis; nonresponders remain enrolled", "claimed_scope": "baseline diet, transit, drugs, host genotype and diagnosis; nonresponders remain enrolled", "governing_rubric": "04-microbiome-systemic.md", "key_evidence_anchor": "Temporal ordering plus mechanism-specific human correction and matched confounder controls", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Diet, host genotype, treatment and transit can precede microbial changes. Community engraftment or changed abundance can occur without functional benefit; targeted products can benefit without changing overall composition. No broad human upstream-primacy contrast closes these alternatives." } ], "aggregation_rule": "scope-matched", "aggregation_preregistered": true, "aggregation_rationale": "The ranking title is a methodological problem; grade the index causal-primacy proposition, not the existence of the microbiome or the methodological critique. Human systemic and neurobehavioural disease scope is gated by SC4; rodent causality and human contribution are distinct scopes. C. difficile eradication is an out-of-scope calibration comparator, not support for systemic primacy.", "primary_subclaim_id": "SC4", "aggregation_derivation": "SC4 is the preregistered human-primacy gate. Transfers, defined strains and microbial products show real bounded contributions, and HE intervention crosses human contribution thresholds, but none establishes composition as the primary upstream target across systemic and neurobehavioural disease. SC1 association is Β, bounded rodent causality SC2 Ζ, human contribution SC3 Ε, broad primacy SC4 Γ. These are different scopes, not a refutation of the microbiome.", "aggregation_alternatives": { "weakest_link_would_return": "Β", "primary_subclaim_would_return": "Γ", "scope_matched_would_return": "Γ", "note": "Separate narrow successes do not replace the preregistered gate." }, "index_rule_deviation": "" }, "competing_models": { "models_evaluated": [ { "rank_in_tournament": 1, "model_id": "M4", "is_nominal": false, "name": "Diet/substrate-dependent microbial contribution", "core_claim": "Host diet and microbial function interact; neither alone is a universal primary switch.", "explains_what_nominal_does_not": "Host diet and microbial function interact; neither alone is a universal primary switch.", "strongest_supporting_evidence": [ "Ridaura diet-dependent rescue and carbohydrate/SCFA/host-pathway experiments directly discriminate substrate conditions (PMID24009397,24412651,36041436)." ], "strongest_contradictory_evidence": [ "Defined host contexts and human factor trials are incomplete; a flexible interaction model must make factor-specific predictions." ], "hsef_level_for_this_model": "Ε", "rationale": "Ridaura diet-dependent rescue and carbohydrate/SCFA/host-pathway experiments directly discriminate substrate conditions (PMID24009397,24412651,36041436). Defined host contexts and human factor trials are incomplete; a flexible interaction model must make factor-specific predictions." }, { "rank_in_tournament": 2, "model_id": "M2", "is_nominal": false, "name": "Disease/transit/medication-dependent microbiome", "core_claim": "Disease features, treatment and transit reshape community signatures.", "explains_what_nominal_does_not": "Disease features, treatment and transit reshape community signatures.", "strongest_supporting_evidence": [ "Metformin stratification, dietary intervention and stool-consistency studies explain important signature variance (PMID26633628,24336217,26069274,34767757)." ], "strongest_contradictory_evidence": [ "FMT/defined-factor functional effects prevent reducing every microbial feature to a passive consequence (PMID39800192,20620945)." ], "hsef_level_for_this_model": "Β", "rationale": "Metformin stratification, dietary intervention and stool-consistency studies explain important signature variance (PMID26633628,24336217,26069274,34767757). FMT/defined-factor functional effects prevent reducing every microbial feature to a passive consequence (PMID39800192,20620945)." }, { "rank_in_tournament": 3, "model_id": "M3", "is_nominal": false, "name": "Rodent-context microbial causality", "core_claim": "Specific microbial factors can be causal inside predefined genotypes and diets.", "explains_what_nominal_does_not": "Specific microbial factors can be causal inside predefined genotypes and diets.", "strongest_supporting_evidence": [ "SFB arthritis, ketogenic diet colonization and targeted TMA inhibition cross defined functional boundaries (PMID20620945,29804833,26687352)." ], "strongest_contradictory_evidence": [ "Human trials and developmental/context differences limit translation (PMID39073834,32150549)." ], "hsef_level_for_this_model": "Ζ", "rationale": "SFB arthritis, ketogenic diet colonization and targeted TMA inhibition cross defined functional boundaries (PMID20620945,29804833,26687352). Human trials and developmental/context differences limit translation (PMID39073834,32150549)." }, { "rank_in_tournament": 4, "model_id": "M5", "is_nominal": false, "name": "Host-genetic and immune-state common causes", "core_claim": "Host traits influence both disease and microbial ecology.", "explains_what_nominal_does_not": "Host traits influence both disease and microbial ecology.", "strongest_supporting_evidence": [ "Leptin-null ecology, host-autoantigen dependence and host-genetic association provide plausible common causes (PMID16033867,22031325,33462485)." ], "strongest_contradictory_evidence": [ "Host-genetic association alone cannot exclude controlled microbial contribution." ], "hsef_level_for_this_model": "Β", "rationale": "Leptin-null ecology, host-autoantigen dependence and host-genetic association provide plausible common causes (PMID16033867,22031325,33462485). Host-genetic association alone cannot exclude controlled microbial contribution." }, { "rank_in_tournament": 5, "model_id": "M1", "is_nominal": true, "name": "Primary gut-microbiome driver", "core_claim": "Composition is the broad primary upstream, targetable human disease cause.", "explains_what_nominal_does_not": "Composition is the broad primary upstream, targetable human disease cause.", "strongest_supporting_evidence": [ "Transfer and human HE recurrence evidence supply a strong case for component causality (PMID24009397,39800192)." ], "strongest_contradictory_evidence": [ "Broad primacy fails to account for host/diet dependence, null functional trials and product effects without global community change (PMID32150549,34767757,31263284)." ], "hsef_level_for_this_model": "Γ", "rationale": "Transfer and human HE recurrence evidence supply a strong case for component causality (PMID24009397,39800192). Broad primacy fails to account for host/diet dependence, null functional trials and product effects without global community change (PMID32150549,34767757,31263284)." } ], "tournament_summary": "Descriptive comparison; does not modify the nominal score. Factorial diet-by-defined-community human trials, with transit/medication held stable and host pathways measured, separate an active microbial contribution from host-driven signature change. No complete pan-disease separating study is in this corpus.", "study_separating_rank1_from_rank2": "Factorial diet-by-defined-community human trials, with transit/medication held stable and host pathways measured, separate an active microbial contribution from host-driven signature change. No complete pan-disease separating study is in this corpus.", "nominal_wins_only_by_funding_artifact": false, "level_unchanged_by_tournament": true }, "evidence_inventory": [ { "n": 1, "pmid": "30535398", "title": "Impact of chronic dietary red meat, white meat, or non-meat protein on trimethylamine N-oxide metabolism and renal excretion in healthy men and women.", "citation": "Wang Z, Bergeron N, Levison BS et al. Impact of chronic dietary red meat, white meat, or non-meat protein on trimethylamine N-oxide metabolism and renal excretion in healthy men and women. European heart journal. 2019.", "doi": "10.1093/eurheartj/ehy799", "pmcid": "PMC6374688", "url": "https://pubmed.ncbi.nlm.nih.gov/30535398/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30535398/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID30535398", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "contradicts", "what_it_shows": "Controlled dietary crossover changes TMAO production and renal excretion; withdrawal reduces circulating TMAO.", "what_it_does_not_show": "Diet and kidney handling determine the readout; no cardiovascular disease prevention endpoint.", "confounders_present": [ "Diet and kidney handling determine the readout; no cardiovascular disease prevention endpoint." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 2, "pmid": "31263284", "title": "Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study.", "citation": "Depommier C, Everard A, Druart C et al. Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study. Nature medicine. 2019.", "doi": "10.1038/s41591-019-0495-2", "pmcid": "PMC6699990", "url": "https://pubmed.ncbi.nlm.nih.gov/31263284/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31263284/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID31263284", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Main text:paragraph1, 2:Main text:paragraph3, 2:Main text:paragraph5, 2:Main text:paragraph12, 2:Main text:paragraph13, 2:Main text:paragraph14. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Placebo-controlled pasteurized Akkermansia supplementation improves insulin sensitivity and circulating lipids in insulin-resistant overweight adults.", "what_it_does_not_show": "HOMA-based indices, baseline insulin imbalance, small exploratory sample and unchanged HbA1c/overall community structure restrict inference; weight/fat changes are not significant.", "confounders_present": [ "HOMA-based indices, baseline insulin imbalance, small exploratory sample and unchanged HbA1c/overall community structure restrict inference; weight/fat changes are not significant." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 3, "pmid": "27892954", "title": "A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice.", "citation": "Plovier H, Everard A, Druart C et al. A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice. Nature medicine. 2017.", "doi": "10.1038/nm.4236", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/27892954/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27892954/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID27892954", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "animal perturbation", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Pasteurized Akkermansia and its outer-membrane protein partly reproduce metabolic benefits in obese/diabetic mice.", "what_it_does_not_show": "Administration demonstrates bounded sufficiency and host-receptor plausibility, not endogenous necessity or human disease prevention.", "confounders_present": [ "Administration demonstrates bounded sufficiency and host-receptor plausibility, not endogenous necessity or human disease prevention." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 4, "pmid": "39800192", "title": "Microbiota transplant for hepatic encephalopathy in cirrhosis: The THEMATIC trial.", "citation": "Bajaj JS, Fagan A, Gavis EA et al. Microbiota transplant for hepatic encephalopathy in cirrhosis: The THEMATIC trial. Journal of hepatology. 2025.", "doi": "10.1016/j.jhep.2024.12.047", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/39800192/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39800192/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "THEMATIC-NCT03796598", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "THEMATIC compares placebo with capsule/enema FMT in treated cirrhosis and reports lower HE recurrence in a post hoc any-FMT comparison.", "what_it_does_not_show": "Safety is primary; recurrence is secondary and its pooled contrast post hoc. Underlying cirrhosis and concurrent drugs remain upstream.", "confounders_present": [ "Safety is primary; recurrence is secondary and its pooled contrast post hoc. Underlying cirrhosis and concurrent drugs remain upstream." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": true, "supporting_count": 1, "mentioning_count": 22, "contrasting_count": 0, "notable_contrasting_statements": [], "note": "Provider-indexed aggregate citation counts and selected outgoing references, not an incoming contradiction-body audit or quality score." }, "shared_components": [] }, { "n": 5, "pmid": "28586116", "title": "Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: A randomized clinical trial.", "citation": "Bajaj JS, Kassam Z, Fagan A et al. Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: A randomized clinical trial. Hepatology (Baltimore, Md.). 2017.", "doi": "10.1002/hep.29306", "pmcid": "PMC6102730", "url": "https://pubmed.ncbi.nlm.nih.gov/28586116/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28586116/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID28586116", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:EXPERIMENTAL PROCEDURES:paragraph1, 0:EXPERIMENTAL PROCEDURES:paragraph4, 2:RESULTS::paragraph0, 2:RESULTS::paragraph1, 2:RESULTS::paragraph3, 2:RESULTS::paragraph4. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Randomized open-label FMT with antibiotic pretreatment improves cognition and recurrent HE compared with standard care.", "what_it_does_not_show": "Small male cohort and unmatched antibiotic pretreatment; crude donor community does not identify the microbial causal factor.", "confounders_present": [ "Small male cohort and unmatched antibiotic pretreatment; crude donor community does not identify the microbial causal factor." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 6, "pmid": "41503571", "title": "The multi-omic basis for hepatic encephalopathy recurrence: Analysis of the THEMATIC trial.", "citation": "Bajaj JS, Fagan A, Sterling RK et al. The multi-omic basis for hepatic encephalopathy recurrence: Analysis of the THEMATIC trial. JHEP reports : innovation in hepatology. 2026.", "doi": "10.1016/j.jhepr.2025.101634", "pmcid": "PMC12769789", "url": "https://pubmed.ncbi.nlm.nih.gov/41503571/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41503571/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "THEMATIC-NCT03796598", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "human association", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "THEMATIC secondary multi-omics links HE recurrence with microbial, metabolite and inflammatory signatures.", "what_it_does_not_show": "Same trial as PMID39800192; outcome-selected molecular associations are not new causal lines or proof of individual taxa necessity.", "confounders_present": [ "Same trial as PMID39800192; outcome-selected molecular associations are not new causal lines or proof of individual taxa necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 7, "pmid": "31038755", "title": "Fecal Microbial Transplant Capsules Are Safe in Hepatic Encephalopathy: A Phase 1, Randomized, Placebo-Controlled Trial.", "citation": "Bajaj JS, Salzman NH, Acharya C et al. Fecal Microbial Transplant Capsules Are Safe in Hepatic Encephalopathy: A Phase 1, Randomized, Placebo-Controlled Trial. Hepatology (Baltimore, Md.). 2019.", "doi": "10.1002/hep.30690", "pmcid": "PMC6819208", "url": "https://pubmed.ncbi.nlm.nih.gov/31038755/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31038755/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "ErratumIn: PMID33464567" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID31038755", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Placebo-controlled FMT capsules improve cognitive testing and mucosal measures without antibiotic pretreatment in cirrhosis.", "what_it_does_not_show": "Phase1 safety focus; infection/HE episodes are similar and efficacy remains provisional. Linked erratum is attached and not separately counted.", "confounders_present": [ "Phase1 safety focus; infection/HE episodes are similar and efficacy remains provisional. Linked erratum is attached and not separately counted." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 8, "pmid": "24336217", "title": "Diet rapidly and reproducibly alters the human gut microbiome.", "citation": "David LA, Maurice CF, Carmody RN et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014.", "doi": "10.1038/nature12820", "pmcid": "PMC3957428", "url": "https://pubmed.ncbi.nlm.nih.gov/24336217/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24336217/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID24336217", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "contradicts", "what_it_shows": "Short-term animal versus plant diets rapidly change microbial structure and activity.", "what_it_does_not_show": "Shows diet-to-microbiome direction rather than proving microbes irrelevant to downstream disease.", "confounders_present": [ "Shows diet-to-microbiome direction rather than proving microbes irrelevant to downstream disease." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 9, "pmid": "30401435", "title": "Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1.", "citation": "Koh A, Molinaro A, Ståhlman M et al. Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1. Cell. 2018.", "doi": "10.1016/j.cell.2018.09.055", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/30401435/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30401435/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID30401435", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal perturbation", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Microbial imidazole propionate impairs mouse glucose tolerance and activates a p38gamma-p62-mTORC1 signaling route.", "what_it_does_not_show": "Administered metabolite and human associations do not establish endogenous human contribution or broad compositional primacy.", "confounders_present": [ "Administered metabolite and human associations do not establish endogenous human contribution or broad compositional primacy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 10, "pmid": "24009397", "title": "Gut microbiota from twins discordant for obesity modulate metabolism in mice.", "citation": "Ridaura VK, Faith JJ, Rey FE et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science (New York, N.Y.). 2013.", "doi": "10.1126/science.1241214", "pmcid": "PMC3829625", "url": "https://pubmed.ncbi.nlm.nih.gov/24009397/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24009397/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID24009397", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 3:Phenotypes produced by bacterial culture collections, 7:Diet-specific effects. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal transfer", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Discordant-twin communities and culture collections transmit body-fat phenotypes; lean-community cohousing rescue depends on diet.", "what_it_does_not_show": "Rescue fails on high-saturated-fat/low-fruit-vegetable diet. Early glucose contrast does not establish full insulin resistance; transfer remains recipient-mouse causality.", "confounders_present": [ "Rescue fails on high-saturated-fat/low-fruit-vegetable diet. Early glucose contrast does not establish full insulin resistance; transfer remains recipient-mouse causality." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": true, "supporting_count": 107, "mentioning_count": 2816, "contrasting_count": 5, "notable_contrasting_statements": [], "note": "Provider-indexed aggregate citation counts and selected outgoing references, not an incoming contradiction-body audit or quality score." }, "shared_components": [] }, { "n": 11, "pmid": "17183312", "title": "An obesity-associated gut microbiome with increased capacity for energy harvest.", "citation": "Turnbaugh PJ, Ley RE, Mahowald MA et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006.", "doi": "10.1038/nature05414", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/17183312/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17183312/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID17183312", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal transfer", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Obese-donor mouse microbiota increases energy-harvest potential and fat gain in germ-free recipients.", "what_it_does_not_show": "Crude transfer and genetically obese donors do not isolate strains or establish general human obesity primacy.", "confounders_present": [ "Crude transfer and genetically obese donors do not isolate strains or establish general human obesity primacy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 12, "pmid": "28530702", "title": "Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug.", "citation": "Wu H, Esteve E, Tremaroli V et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nature medicine. 2017.", "doi": "10.1038/nm.4345", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/28530702/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28530702/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID28530702", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Randomized metformin changes human microbiota; post-treatment donor microbiota improves glucose tolerance after mouse transfer.", "what_it_does_not_show": "Drug has host effects; recipient transfer supports a contribution but does not measure microbiome-specific mediation of human glycemic benefit.", "confounders_present": [ "Drug has host effects; recipient transfer supports a contribution but does not measure microbiome-specific mediation of human glycemic benefit." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 13, "pmid": "16033867", "title": "Obesity alters gut microbial ecology.", "citation": "Ley RE, Bäckhed F, Turnbaugh P et al. Obesity alters gut microbial ecology. Proceedings of the National Academy of Sciences of the United States of America. 2005.", "doi": "10.1073/pnas.0504978102", "pmcid": "PMC1176910", "url": "https://pubmed.ncbi.nlm.nih.gov/16033867/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/16033867/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID16033867", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "animal association", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Leptin-deficient obese mice differ in broad bacterial divisions from related lean mice on the same diet.", "what_it_does_not_show": "Genetic host phenotype can reshape ecology; division-level signatures are not a causal mechanism.", "confounders_present": [ "Genetic host phenotype can reshape ecology; division-level signatures are not a causal mechanism." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 14, "pmid": "36216942", "title": "Microbiome-derived ethanol in nonalcoholic fatty liver disease.", "citation": "Meijnikman AS, Davids M, Herrema H et al. Microbiome-derived ethanol in nonalcoholic fatty liver disease. Nature medicine. 2022.", "doi": "10.1038/s41591-022-02016-6", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/36216942/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36216942/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID36216942", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Portal sampling and ADH inhibition reveal microbial ethanol production in NAFLD, abolished after antibiotics.", "what_it_does_not_show": "Intervention changes an exposure biomarker; no demonstrated liver disease trajectory change or strain-specific causality.", "confounders_present": [ "Intervention changes an exposure biomarker; no demonstrated liver disease trajectory change or strain-specific causality." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 15, "pmid": "37730687", "title": "Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamine N-oxide.", "citation": "Andrikopoulos P, Aron-Wisnewsky J, Chakaroun R et al. Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamine N-oxide. Nature communications. 2023.", "doi": "10.1038/s41467-023-39824-4", "pmcid": "PMC10511707", "url": "https://pubmed.ncbi.nlm.nih.gov/37730687/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37730687/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID37730687", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human association", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Kidney function predicts circulating TMAO more strongly than diet/community composition; mouse exposure supports bidirectional renal injury.", "what_it_does_not_show": "Mediation and propensity matching are not randomized human mechanism tests; concentration alone cannot identify microbial primacy.", "confounders_present": [ "Mediation and propensity matching are not randomized human mechanism tests; concentration alone cannot identify microbial primacy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 16, "pmid": "24412651", "title": "Microbiota-generated metabolites promote metabolic benefits via gut-brain neural circuits.", "citation": "De Vadder F, Kovatcheva-Datchary P, Goncalves D et al. Microbiota-generated metabolites promote metabolic benefits via gut-brain neural circuits. Cell. 2014.", "doi": "10.1016/j.cell.2013.12.016", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/24412651/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24412651/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID24412651", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal perturbation", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "SCFA/fiber metabolic benefits disappear in intestinal-gluconeogenesis-deficient mice despite similar microbiota changes.", "what_it_does_not_show": "Host pathway dependence and administered metabolites establish conditional benefit; endogenous strain necessity remains unspecified.", "confounders_present": [ "Host pathway dependence and administered metabolites establish conditional benefit; endogenous strain necessity remains unspecified." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 17, "pmid": "20040631", "title": "The gut microbiota modulates host energy and lipid metabolism in mice.", "citation": "Velagapudi VR, Hezaveh R, Reigstad CS et al. The gut microbiota modulates host energy and lipid metabolism in mice. Journal of lipid research. 2010.", "doi": "10.1194/jlr.M002774", "pmcid": "PMC2853437", "url": "https://pubmed.ncbi.nlm.nih.gov/20040631/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/20040631/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID20040631", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal perturbation", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Germ-free versus conventionally raised mice differ in energy metabolites and tissue lipid distributions.", "what_it_does_not_show": "Developmental/immune differences accompany germ-free status; molecular profiles do not establish a disease phenotype.", "confounders_present": [ "Developmental/immune differences accompany germ-free status; molecular profiles do not establish a disease phenotype." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 18, "pmid": "31196984", "title": "Discovery and inhibition of an interspecies gut bacterial pathway for Levodopa metabolism.", "citation": "Maini Rekdal V, Bess EN, Bisanz JE et al. Discovery and inhibition of an interspecies gut bacterial pathway for Levodopa metabolism. Science (New York, N.Y.). 2019.", "doi": "10.1126/science.aau6323", "pmcid": "PMC7745125", "url": "https://pubmed.ncbi.nlm.nih.gov/31196984/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31196984/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID31196984", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal perturbation", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Defined bacterial enzymes metabolize levodopa and pathway inhibition raises mouse drug bioavailability.", "what_it_does_not_show": "Functional pharmacokinetic effect is distinct from initiating Parkinson disease or changing neurodegeneration.", "confounders_present": [ "Functional pharmacokinetic effect is distinct from initiating Parkinson disease or changing neurodegeneration." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 19, "pmid": "27912057", "title": "Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson's Disease.", "citation": "Sampson TR, Debelius JW, Thron T et al. Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson's Disease. Cell. 2016.", "doi": "10.1016/j.cell.2016.11.018", "pmcid": "PMC5718049", "url": "https://pubmed.ncbi.nlm.nih.gov/27912057/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27912057/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID27912057", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph5, 1:Results:paragraph8, 1:Results:paragraph12. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal perturbation", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Microbial depletion/recolonization and SCFA challenge change motor deficits and microglia in alpha-synuclein-overexpressing mice.", "what_it_does_not_show": "Host transgene establishes vulnerability; forced human-donor transfer cannot show endogenous human PD primacy.", "confounders_present": [ "Host transgene establishes vulnerability; forced human-donor transfer cannot show endogenous human PD primacy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 20, "pmid": "25860609", "title": "Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis.", "citation": "Yano JM, Yu K, Donaldson GP et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell. 2015.", "doi": "10.1016/j.cell.2015.02.047", "pmcid": "PMC4393509", "url": "https://pubmed.ncbi.nlm.nih.gov/25860609/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25860609/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID25860609", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal perturbation", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Spore-forming bacteria regulate host peripheral serotonin, GI motility and platelet function.", "what_it_does_not_show": "Peripheral serotonin is not demonstrated brain neurotransmission; linked erratum with no PMID supplied remains explicit.", "confounders_present": [ "Peripheral serotonin is not demonstrated brain neurotransmission; linked erratum with no PMID supplied remains explicit." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 21, "pmid": "24315484", "title": "Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders.", "citation": "Hsiao EY, McBride SW, Hsien S et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell. 2013.", "doi": "10.1016/j.cell.2013.11.024", "pmcid": "PMC3897394", "url": "https://pubmed.ncbi.nlm.nih.gov/24315484/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24315484/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID24315484", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 5:B. fragilis Treatment Corrects ASD-Related Behavioral Abnormalities, 7:B. fragilis Treatment Corrects Levels of MIA-Induced Serum Metabolites, 8:A Serum Metabolite Induces ASD-Related Behavior. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal perturbation", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Bacteroides fragilis improves gut permeability and selected behaviors after maternal immune activation; a metabolite challenge induces some abnormalities.", "what_it_does_not_show": "Social deficits persist; 4EPS induces anxiety/startle changes but not repetitive or communicative deficits. Maternal immune activation is upstream and human ASD causality is untested.", "confounders_present": [ "Social deficits persist; 4EPS induces anxiety/startle changes but not repetitive or communicative deficits. Maternal immune activation is upstream and human ASD causality is untested." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": true, "supporting_count": 68, "mentioning_count": 2702, "contrasting_count": 5, "notable_contrasting_statements": [], "note": "Provider-indexed aggregate citation counts and selected outgoing references, not an incoming contradiction-body audit or quality score." }, "shared_components": [] }, { "n": 22, "pmid": "31150625", "title": "Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice.", "citation": "Sharon G, Cruz NJ, Kang DW et al. Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice. Cell. 2019.", "doi": "10.1016/j.cell.2019.05.004", "pmcid": "PMC6993574", "url": "https://pubmed.ncbi.nlm.nih.gov/31150625/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31150625/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID31150625", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph1, 1:RESULTS:paragraph12, 1:RESULTS:paragraph13, 1:RESULTS:paragraph14, 3:STAR Methods:paragraph28, 3:STAR Methods:paragraph29, 3:STAR Methods:paragraph38. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal transfer", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Human ASD-donor microbiota induces altered mouse behavior and splicing; candidate metabolites improve a mouse model.", "what_it_does_not_show": "Donor, sex and age affect recipient behavior. High-dose taurine/5AV rescue depends on prenatal/weaning exposure; juvenile-only treatment fails in BTBR. Mouse phenotype is distinct from human ASD initiation.", "confounders_present": [ "Donor, sex and age affect recipient behavior. High-dose taurine/5AV rescue depends on prenatal/weaning exposure; juvenile-only treatment fails in BTBR. Mouse phenotype is distinct from human ASD initiation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 23, "pmid": "34194038", "title": "Microbiota regulate social behaviour via stress response neurons in the brain.", "citation": "Wu WL, Adame MD, Liou CW et al. Microbiota regulate social behaviour via stress response neurons in the brain. Nature. 2021.", "doi": "10.1038/s41586-021-03669-y", "pmcid": "PMC8346519", "url": "https://pubmed.ncbi.nlm.nih.gov/34194038/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34194038/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID34194038", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal perturbation", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Microbial depletion changes male mouse social behavior; host HPA/neuronal interruption and Enterococcus faecalis reverse defined defects.", "what_it_does_not_show": "Circuit specificity is conditional on stress and depletion; mouse social activity is not a human disease endpoint.", "confounders_present": [ "Circuit specificity is conditional on stress and depletion; mouse social activity is not a human disease endpoint." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 24, "pmid": "29804833", "title": "The Gut Microbiota Mediates the Anti-Seizure Effects of the Ketogenic Diet.", "citation": "Olson CA, Vuong HE, Yano JM et al. The Gut Microbiota Mediates the Anti-Seizure Effects of the Ketogenic Diet. Cell. 2018.", "doi": "10.1016/j.cell.2018.04.027", "pmcid": "PMC6003870", "url": "https://pubmed.ncbi.nlm.nih.gov/29804833/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29804833/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID30007420" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID29804833", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal perturbation", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Defined Akkermansia/Parabacteroides colonization restores ketogenic-diet seizure protection and transfers protection under control diet.", "what_it_does_not_show": "Two mouse seizure contexts support treatment mediation, not universal epilepsy causation. Linked erratum remains attached.", "confounders_present": [ "Two mouse seizure contexts support treatment mediation, not universal epilepsy causation. Linked erratum remains attached." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 25, "pmid": "32968276", "title": "The maternal microbiome modulates fetal neurodevelopment in mice.", "citation": "Vuong HE, Pronovost GN, Williams DW et al. The maternal microbiome modulates fetal neurodevelopment in mice. Nature. 2020.", "doi": "10.1038/s41586-020-2745-3", "pmcid": "PMC7554197", "url": "https://pubmed.ncbi.nlm.nih.gov/32968276/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32968276/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID32968276", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal perturbation", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Maternal microbial depletion impairs fetal thalamocortical axons; defined consortium/metabolites rescue and alter later tactile behavior.", "what_it_does_not_show": "Prenatal physiological development and specific behavioral tasks do not demonstrate human neurodevelopmental disease primacy.", "confounders_present": [ "Prenatal physiological development and specific behavioral tasks do not demonstrate human neurodevelopmental disease primacy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 26, "pmid": "36376318", "title": "Metagenomics of Parkinson's disease implicates the gut microbiome in multiple disease mechanisms.", "citation": "Wallen ZD, Demirkan A, Twa G et al. Metagenomics of Parkinson's disease implicates the gut microbiome in multiple disease mechanisms. Nature communications. 2022.", "doi": "10.1038/s41467-022-34667-x", "pmcid": "PMC9663292", "url": "https://pubmed.ncbi.nlm.nih.gov/36376318/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36376318/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID36376318", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "human association", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Deep metagenomics identifies broad PD-associated species, genes and pathway shifts.", "what_it_does_not_show": "Calling predicted pathways disease permissive does not demonstrate human causal dependency; medication, transit and disease remain alternatives.", "confounders_present": [ "Calling predicted pathways disease permissive does not demonstrate human causal dependency; medication, transit and disease remain alternatives." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 27, "pmid": "27126039", "title": "Population-level analysis of gut microbiome variation.", "citation": "Falony G, Joossens M, Vieira-Silva S et al. Population-level analysis of gut microbiome variation. Science (New York, N.Y.). 2016.", "doi": "10.1126/science.aad3503", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/27126039/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27126039/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "FGFP-and-LifeLines-DEEP-shared-component", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "human association", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Population cohorts identify stool consistency and medication as major microbiome covariates.", "what_it_does_not_show": "Covariate association warns about confounding but does not prove all disease associations disappear.", "confounders_present": [ "Covariate association warns about confounding but does not prove all disease associations disappear." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "LifeLines-DEEP participants also described by PMID27126040." ] }, { "n": 28, "pmid": "32374853", "title": "Quantifying technical confounders in microbiome studies.", "citation": "Bartolomaeus TUP, Birkner T, Bartolomaeus H et al. Quantifying technical confounders in microbiome studies. Cardiovascular research. 2021.", "doi": "10.1093/cvr/cvaa128", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/32374853/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32374853/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID32374853", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "method validation", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Comparative sample-processing experiments show extraction methods can mimic biological microbiome differences.", "what_it_does_not_show": "Technical measurement artifact is not a direct test of disease mechanism.", "confounders_present": [ "Technical measurement artifact is not a direct test of disease mechanism." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 29, "pmid": "23023125", "title": "A metagenome-wide association study of gut microbiota in type 2 diabetes.", "citation": "Qin J, Li Y, Cai Z et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature. 2012.", "doi": "10.1038/nature11450", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/23023125/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23023125/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "T2D-metagenomes-reanalysed-in-Forslund", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "human association", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Two-stage human metagenomics identifies diabetes-associated microbial markers and functions.", "what_it_does_not_show": "Diagnostic classification and abundance association do not establish direction or microbial necessity.", "confounders_present": [ "Diagnostic classification and abundance association do not establish direction or microbial necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 30, "pmid": "26633628", "title": "Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota.", "citation": "Forslund K, Hildebrand F, Nielsen T et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature. 2015.", "doi": "10.1038/nature15766", "pmcid": "PMC4681099", "url": "https://pubmed.ncbi.nlm.nih.gov/26633628/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26633628/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID28470190" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "Forslund-pooled-T2D-metagenomes", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 3:Main text:paragraph0, 3:Main text:paragraph2, 3:Main text:paragraph4, 3:Main text:paragraph5, 3:Main text:paragraph6. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "human association", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Medication-stratified metagenomics separates metformin-associated features from untreated diabetes signatures.", "what_it_does_not_show": "Residual untreated-disease association remains; inferred therapeutic mediation is not isolated by human intervention. Linked erratum is retained.", "confounders_present": [ "Residual untreated-disease association remains; inferred therapeutic mediation is not isolated by human intervention. Linked erratum is retained." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Reanalysis includes earlier T2D metagenomics; not an independent new replication of all constituent cohorts." ] }, { "n": 31, "pmid": "29143816", "title": "Quantitative microbiome profiling links gut community variation to microbial load.", "citation": "Vandeputte D, Kathagen G, D'hoe K et al. Quantitative microbiome profiling links gut community variation to microbial load. Nature. 2017.", "doi": "10.1038/nature24460", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/29143816/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29143816/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID29143816", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "method validation", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Flow-cytometry plus sequencing reveals variable microbial loads and compositional artifacts of relative profiling.", "what_it_does_not_show": "Counts improve measurement; they do not determine whether a disease signature is causal.", "confounders_present": [ "Counts improve measurement; they do not determine whether a disease signature is causal." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 32, "pmid": "33462485", "title": "Large-scale association analyses identify host factors influencing human gut microbiome composition.", "citation": "Kurilshikov A, Medina-Gomez C, Bacigalupe R et al. Large-scale association analyses identify host factors influencing human gut microbiome composition. Nature genetics. 2021.", "doi": "10.1038/s41588-020-00763-1", "pmcid": "PMC8515199", "url": "https://pubmed.ncbi.nlm.nih.gov/33462485/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33462485/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID33462485", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human genetics", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "MiBioGen links host loci with taxa and reports suggestive MR disease relationships.", "what_it_does_not_show": "Low taxonomic instrument coverage, dietary pathways and pleiotropy constrain a broad human causal-primacy inference.", "confounders_present": [ "Low taxonomic instrument coverage, dietary pathways and pleiotropy constrain a broad human causal-primacy inference." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 33, "pmid": "30718848", "title": "The neuroactive potential of the human gut microbiota in quality of life and depression.", "citation": "Valles-Colomer M, Falony G, Darzi Y et al. The neuroactive potential of the human gut microbiota in quality of life and depression. Nature microbiology. 2019.", "doi": "10.1038/s41564-018-0337-x", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/30718848/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30718848/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID30718848", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "human association", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Replicated population microbiome features correlate with depression and quality of life after antidepressant adjustment.", "what_it_does_not_show": "Neuroactive pathway potential and adjusted association do not establish microbial brain activity or human disease causation.", "confounders_present": [ "Neuroactive pathway potential and adjusted association do not establish microbial brain activity or human disease causation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 34, "pmid": "32160527", "title": "Propionic Acid Shapes the Multiple Sclerosis Disease Course by an Immunomodulatory Mechanism.", "citation": "Duscha A, Gisevius B, Hirschberg S et al. Propionic Acid Shapes the Multiple Sclerosis Disease Course by an Immunomodulatory Mechanism. Cell. 2020.", "doi": "10.1016/j.cell.2020.02.035", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/32160527/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32160527/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID32160527", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Propionate supplementation changes Treg function; post hoc long-term analyses associate supplementation with improved MS course.", "what_it_does_not_show": "Nonrandomized proof-of-concept/add-on treatment and post hoc endpoints do not isolate microbial source or clinical causal effect.", "confounders_present": [ "Nonrandomized proof-of-concept/add-on treatment and post hoc endpoints do not isolate microbial source or clinical causal effect." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 35, "pmid": "27126040", "title": "Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity.", "citation": "Zhernakova A, Kurilshikov A, Bonder MJ et al. Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity. Science (New York, N.Y.). 2016.", "doi": "10.1126/science.aad3369", "pmcid": "PMC5240844", "url": "https://pubmed.ncbi.nlm.nih.gov/27126040/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27126040/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "LifeLines-DEEP-shared-component", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "human association", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Dutch population metagenomics links community variation with diet, drugs and intrinsic host factors.", "what_it_does_not_show": "Shares LifeLines-DEEP material with PMID27126039; not an independent replication line.", "confounders_present": [ "Shares LifeLines-DEEP material with PMID27126039; not an independent replication line." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "LifeLines-DEEP participants also analysed within PMID27126039." ] }, { "n": 36, "pmid": "23985870", "title": "Richness of human gut microbiome correlates with metabolic markers.", "citation": "Le Chatelier E, Nielsen T, Qin J et al. Richness of human gut microbiome correlates with metabolic markers. Nature. 2013.", "doi": "10.1038/nature12506", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/23985870/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23985870/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID23985870", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "human association", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Low microbial gene richness tracks adiposity, metabolic abnormalities and later weight gain.", "what_it_does_not_show": "Prospective weight association still permits diet, medication and host-state causes.", "confounders_present": [ "Prospective weight association still permits diet, medication and host-state causes." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 37, "pmid": "26972052", "title": "Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk.", "citation": "Zhu W, Gregory JC, Org E et al. Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk. Cell. 2016.", "doi": "10.1016/j.cell.2016.02.011", "pmcid": "PMC4862743", "url": "https://pubmed.ncbi.nlm.nih.gov/26972052/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26972052/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "Hazen-angiography-shared-component", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal perturbation", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Diet/TMAO exposure and microbial transfer affect platelet reactivity and experimental thrombosis, paired with human event prediction.", "what_it_does_not_show": "Human event risk is observational; overlapping angiography/platform material and administered metabolite are not independent clinical causality.", "confounders_present": [ "Human event risk is observational; overlapping angiography/platform material and administered metabolite are not independent clinical causality." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Clinical angiography material overlaps the TMAO research programme; mouse platelet work is separate." ] }, { "n": 38, "pmid": "26687352", "title": "Non-lethal Inhibition of Gut Microbial Trimethylamine Production for the Treatment of Atherosclerosis.", "citation": "Wang Z, Roberts AB, Buffa JA et al. Non-lethal Inhibition of Gut Microbial Trimethylamine Production for the Treatment of Atherosclerosis. Cell. 2015.", "doi": "10.1016/j.cell.2015.11.055", "pmcid": "PMC4871610", "url": "https://pubmed.ncbi.nlm.nih.gov/26687352/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26687352/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID26687352", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal perturbation", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "DMB inhibits microbial TMA generation and decreases diet-enhanced atherosclerotic lesions in ApoE-deficient mice.", "what_it_does_not_show": "Chemical specificity and selected diet/genotype need controls; no human hard-endpoint trial establishes broad primacy.", "confounders_present": [ "Chemical specificity and selected diet/genotype need controls; no human hard-endpoint trial establishes broad primacy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 39, "pmid": "29018189", "title": "The gut microbiome in atherosclerotic cardiovascular disease.", "citation": "Jie Z, Xia H, Zhong SL et al. The gut microbiome in atherosclerotic cardiovascular disease. Nature communications. 2017.", "doi": "10.1038/s41467-017-00900-1", "pmcid": "PMC5635030", "url": "https://pubmed.ncbi.nlm.nih.gov/29018189/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29018189/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID29018189", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "human association", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Human ACVD metagenomics identifies taxa and functions associated with disease after drug analyses.", "what_it_does_not_show": "Case-control disease status remains susceptible to reverse causation and residual confounding.", "confounders_present": [ "Case-control disease status remains susceptible to reverse causation and residual confounding." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 40, "pmid": "23614584", "title": "Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk.", "citation": "Tang WH, Wang Z, Levison BS et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. The New England journal of medicine. 2013.", "doi": "10.1056/NEJMoa1109400", "pmcid": "PMC3701945", "url": "https://pubmed.ncbi.nlm.nih.gov/23614584/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23614584/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "Hazen-angiography-4007-shared-component", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Antibiotics suppress isotope-labeled choline-derived TMAO with recovery after withdrawal; higher TMAO predicts cardiovascular events.", "what_it_does_not_show": "Production causality is established; cardiovascular disease causality is not tested by the biomarker intervention.", "confounders_present": [ "Production causality is established; cardiovascular disease causality is not tested by the biomarker intervention." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 41, "pmid": "23563705", "title": "Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis.", "citation": "Koeth RA, Wang Z, Levison BS et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nature medicine. 2013.", "doi": "10.1038/nm.3145", "pmcid": "PMC3650111", "url": "https://pubmed.ncbi.nlm.nih.gov/23563705/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23563705/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID23563705", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal perturbation", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Carnitine feeding increases microbial TMAO and mouse atherosclerosis, attenuated by microbial suppression; human challenge is diet-dependent.", "what_it_does_not_show": "Broad antibiotics and administered substrates do not isolate endogenous human cardiovascular dependency.", "confounders_present": [ "Broad antibiotics and administered substrates do not isolate endogenous human cardiovascular dependency." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 42, "pmid": "36041436", "title": "Microbiota imbalance induced by dietary sugar disrupts immune-mediated protection from metabolic syndrome.", "citation": "Kawano Y, Edwards M, Huang Y et al. Microbiota imbalance induced by dietary sugar disrupts immune-mediated protection from metabolic syndrome. Cell. 2022.", "doi": "10.1016/j.cell.2022.08.005", "pmcid": "PMC9556172", "url": "https://pubmed.ncbi.nlm.nih.gov/36041436/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36041436/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID36041436", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal perturbation", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Dietary sugar displaces Th17-inducing microbes; microbial/immune restoration protects against mouse metabolic syndrome.", "what_it_does_not_show": "Diet, microbes and host immunity interact; no autonomous microbial initiator or general human implication is established.", "confounders_present": [ "Diet, microbes and host immunity interact; no autonomous microbial initiator or general human implication is established." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 43, "pmid": "21205640", "title": "Induction of colonic regulatory T cells by indigenous Clostridium species.", "citation": "Atarashi K, Tanoue T, Shima T et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science (New York, N.Y.). 2011.", "doi": "10.1126/science.1198469", "pmcid": "PMC3969237", "url": "https://pubmed.ncbi.nlm.nih.gov/21205640/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21205640/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID21205640", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "animal perturbation", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Defined Clostridium strains induce colonic Tregs and protect against experimental colitis and systemic IgE responses.", "what_it_does_not_show": "Selected mouse immune contexts do not establish primary human autoimmune disease causes.", "confounders_present": [ "Selected mouse immune contexts do not establish primary human autoimmune disease causes." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 44, "pmid": "30568995", "title": "Disease-modifying therapies alter gut microbial composition in MS.", "citation": "Katz Sand I, Zhu Y, Ntranos A et al. Disease-modifying therapies alter gut microbial composition in MS. Neurology(R) neuroimmunology & neuroinflammation. 2019.", "doi": "10.1212/NXI.0000000000000517", "pmcid": "PMC6278850", "url": "https://pubmed.ncbi.nlm.nih.gov/30568995/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30568995/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID30568995", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "human association", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "MS disease-modifying treatment groups have distinct microbial composition and predicted functions.", "what_it_does_not_show": "Treatment is not randomized here; warns about medication effects without proving microbial irrelevance.", "confounders_present": [ "Treatment is not randomized here; warns about medication effects without proving microbial irrelevance." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 45, "pmid": "19836068", "title": "Induction of intestinal Th17 cells by segmented filamentous bacteria.", "citation": "Ivanov II, Atarashi K, Manel N et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell. 2009.", "doi": "10.1016/j.cell.2009.09.033", "pmcid": "PMC2796826", "url": "https://pubmed.ncbi.nlm.nih.gov/19836068/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/19836068/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID19836068", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "animal perturbation", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Single segmented filamentous bacterium induces mucosal Th17 cells and pathogen resistance.", "what_it_does_not_show": "Mucosal physiology is distinct from systemic disease initiation; disease relevance is tested separately.", "confounders_present": [ "Mucosal physiology is distinct from systemic disease initiation; disease relevance is tested separately." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 46, "pmid": "28893978", "title": "Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models.", "citation": "Cekanaviciute E, Yoo BB, Runia TF et al. Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models. Proceedings of the National Academy of Sciences of the United States of America. 2017.", "doi": "10.1073/pnas.1711235114", "pmcid": "PMC5635915", "url": "https://pubmed.ncbi.nlm.nih.gov/28893978/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28893978/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID29073033" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID28893978", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal transfer", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "MS-associated strains alter T-cell responses and patient-donor transfer exacerbates induced mouse autoimmune encephalomyelitis.", "what_it_does_not_show": "Challenge-induced recipient disease and ex vivo human cells do not establish human MS initiation. Linked erratum attached.", "confounders_present": [ "Challenge-induced recipient disease and ex vivo human cells do not establish human MS initiation. Linked erratum attached." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 47, "pmid": "39073834", "title": "Fecal Microbiota Transplantation for Treatment of Parkinson Disease: A Randomized Clinical Trial.", "citation": "Scheperjans F, Levo R, Bosch B et al. Fecal Microbiota Transplantation for Treatment of Parkinson Disease: A Randomized Clinical Trial. JAMA neurology. 2024.", "doi": "10.1001/jamaneurol.2024.2305", "pmcid": "PMC11287445", "url": "https://pubmed.ncbi.nlm.nih.gov/39073834/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39073834/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID39073834", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "contradicts", "what_it_shows": "Placebo-controlled PD FMT trial finds no primary clinical benefit despite stronger donor-dependent microbiota changes.", "what_it_does_not_show": "Negative regimen-specific test is not a positive threshold crossing and does not exclude every strain or intervention.", "confounders_present": [ "Negative regimen-specific test is not a positive threshold crossing and does not exclude every strain or intervention." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 48, "pmid": "39617896", "title": "Effect of fecal microbiota transplantation on patients with sporadic amyotrophic lateral sclerosis: a randomized, double-blind, placebo-controlled trial.", "citation": "Feng R, Zhu Q, Wang A et al. Effect of fecal microbiota transplantation on patients with sporadic amyotrophic lateral sclerosis: a randomized, double-blind, placebo-controlled trial. BMC medicine. 2024.", "doi": "10.1186/s12916-024-03781-6", "pmcid": "PMC11610222", "url": "https://pubmed.ncbi.nlm.nih.gov/39617896/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39617896/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID39617896", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "contradicts", "what_it_shows": "Placebo-controlled sporadic ALS FMT changes community features without slowing ALSFRS-R decline.", "what_it_does_not_show": "Small trial cannot exclude modest effects; constipation or mood improvements do not establish neurodegeneration modification.", "confounders_present": [ "Small trial cannot exclude modest effects; constipation or mood improvements do not establish neurodegeneration modification." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 49, "pmid": "38057970", "title": "Efficacy of fecal microbiota transplantation in patients with Parkinson's disease: clinical trial results from a randomized, placebo-controlled design.", "citation": "Cheng Y, Tan G, Zhu Q et al. Efficacy of fecal microbiota transplantation in patients with Parkinson's disease: clinical trial results from a randomized, placebo-controlled design. Gut microbes. 2023.", "doi": "10.1080/19490976.2023.2284247", "pmcid": "PMC10841011", "url": "https://pubmed.ncbi.nlm.nih.gov/38057970/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38057970/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID38057970", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Randomized PD oral FMT reports improved symptom scores and GI measures compared with placebo.", "what_it_does_not_show": "Small trial and medication interactions require replication; symptomatic change is distinct from disease initiation or neuron preservation.", "confounders_present": [ "Small trial and medication interactions require replication; symptomatic change is distinct from disease initiation or neuron preservation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 50, "pmid": "38113884", "title": "Precision microbial intervention improves social behavior but not autism severity: A pilot double-blind randomized placebo-controlled trial.", "citation": "Mazzone L, Dooling SW, Volpe E et al. Precision microbial intervention improves social behavior but not autism severity: A pilot double-blind randomized placebo-controlled trial. Cell host & microbe. 2024.", "doi": "10.1016/j.chom.2023.11.021", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/38113884/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38113884/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID38113884", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Defined L. reuteri combination improves social functioning in ASD while overall autism severity and community composition do not change.", "what_it_does_not_show": "Pilot selected-domain benefit does not establish overall ASD treatment, microbial-composition primacy or strain-specific human efficacy.", "confounders_present": [ "Pilot selected-domain benefit does not establish overall ASD treatment, microbial-composition primacy or strain-specific human efficacy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 51, "pmid": "40848995", "title": "Colonoscopic fecal microbiota transplantation for Mild-to-Moderate Parkinson's Disease: A randomized controlled trial.", "citation": "Wang J, Xue L, Zhang M et al. Colonoscopic fecal microbiota transplantation for Mild-to-Moderate Parkinson's Disease: A randomized controlled trial. Brain, behavior, and immunity. 2025.", "doi": "10.1016/j.bbi.2025.106086", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/40848995/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40848995/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID40848995", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Small blinded fresh-colonoscopic FMT trial reports improved PD motor, nonmotor and constipation scores over short follow-up.", "what_it_does_not_show": "Multiple symptom measures and small single-center sample do not establish neuroprotection or broad microbial primacy.", "confounders_present": [ "Multiple symptom measures and small single-center sample do not establish neuroprotection or broad microbial primacy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 52, "pmid": "38686220", "title": "Safety and efficacy of faecal microbiota transplantation in patients with mild to moderate Parkinson's disease (GUT-PARFECT): a double-blind, placebo-controlled, randomised, phase 2 trial.", "citation": "Bruggeman A, Vandendriessche C, Hamerlinck H et al. Safety and efficacy of faecal microbiota transplantation in patients with mild to moderate Parkinson's disease (GUT-PARFECT): a double-blind, placebo-controlled, randomised, phase 2 trial. EClinicalMedicine. 2024.", "doi": "10.1016/j.eclinm.2024.102563", "pmcid": "PMC11056595", "url": "https://pubmed.ncbi.nlm.nih.gov/38686220/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38686220/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID38686220", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Methods:paragraph3, 1:Methods:paragraph9, 1:Methods:paragraph11, 2:Results:paragraph2, 2:Results:paragraph5, 2:Results:paragraph12. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "GUT-PARFECT compares donor with autologous FMT and reports mild off-medication motor benefit over twelve months.", "what_it_does_not_show": "Small stage-defined cohort, baseline imbalance and comparator effects constrain generalization; symptomatic benefit is not neuron-preservation proof.", "confounders_present": [ "Small stage-defined cohort, baseline imbalance and comparator effects constrain generalization; symptomatic benefit is not neuron-preservation proof." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 53, "pmid": "27491067", "title": "Transferring the blues: Depression-associated gut microbiota induces neurobehavioural changes in the rat.", "citation": "Kelly JR, Borre Y, O' Brien C et al. Transferring the blues: Depression-associated gut microbiota induces neurobehavioural changes in the rat. Journal of psychiatric research. 2016.", "doi": "10.1016/j.jpsychires.2016.07.019", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/27491067/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27491067/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID27491067", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal transfer", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Depression-donor communities induce anhedonia/anxiety-like behavior and altered tryptophan metabolism in depleted rats.", "what_it_does_not_show": "Recipient behavior is not human depressive illness; crude community transfer leaves diet/drug and strain identity unresolved.", "confounders_present": [ "Recipient behavior is not human depressive illness; crude community transfer leaves diet/drug and strain identity unresolved." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 54, "pmid": "27067014", "title": "Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host's metabolism.", "citation": "Zheng P, Zeng B, Zhou C et al. Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host's metabolism. Molecular psychiatry. 2016.", "doi": "10.1038/mp.2016.44", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/27067014/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27067014/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID27067014", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal transfer", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "MDD-donor microbiota induces mouse depression-like behavior with metabolic changes.", "what_it_does_not_show": "Germ-free recipient physiology and donor confounding restrict inference to human disease primacy.", "confounders_present": [ "Germ-free recipient physiology and donor confounding restrict inference to human disease primacy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 55, "pmid": "27865949", "title": "Lost in translation? The potential psychobiotic Lactobacillus rhamnosus (JB-1) fails to modulate stress or cognitive performance in healthy male subjects.", "citation": "Kelly JR, Allen AP, Temko A et al. Lost in translation? The potential psychobiotic Lactobacillus rhamnosus (JB-1) fails to modulate stress or cognitive performance in healthy male subjects. Brain, behavior, and immunity. 2017.", "doi": "10.1016/j.bbi.2016.11.018", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/27865949/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27865949/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID27865949", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "contradicts", "what_it_shows": "Randomized JB-1 crossover finds no stress, cognitive, inflammatory or HPA benefit in healthy men.", "what_it_does_not_show": "Healthy men are a translational comparator, not a disease-cohort test; null does not exclude effects in prospectively defined disorders.", "confounders_present": [ "Healthy men are a translational comparator, not a disease-cohort test; null does not exclude effects in prospectively defined disorders." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 56, "pmid": "22728514", "title": "Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome.", "citation": "Vrieze A, Van Nood E, Holleman F et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology. 2012.", "doi": "10.1053/j.gastro.2012.06.031", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/22728514/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22728514/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID22728514", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Randomized lean-donor versus autologous FMT improves short-term clamp insulin sensitivity in metabolic syndrome.", "what_it_does_not_show": "Small short-term physiology endpoint does not show durable prevention, strain identity or broad primacy. Linked erratum without supplied PMID retained.", "confounders_present": [ "Small short-term physiology endpoint does not show durable prevention, strain identity or broad primacy. Linked erratum without supplied PMID retained." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 57, "pmid": "24316517", "title": "Impact of oral vancomycin on gut microbiota, bile acid metabolism, and insulin sensitivity.", "citation": "Vrieze A, Out C, Fuentes S et al. Impact of oral vancomycin on gut microbiota, bile acid metabolism, and insulin sensitivity. Journal of hepatology. 2014.", "doi": "10.1016/j.jhep.2013.11.034", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/24316517/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24316517/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID24316517", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Randomized vancomycin versus amoxicillin changes microbiota/bile acids and lowers clamp insulin sensitivity.", "what_it_does_not_show": "No placebo and broad drug actions constrain microbial specificity; not a hard disease-trajectory endpoint.", "confounders_present": [ "No placebo and broad drug actions constrain microbial specificity; not a hard disease-trajectory endpoint." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 58, "pmid": "27411009", "title": "Effects of Gut Microbiota Manipulation by Antibiotics on Host Metabolism in Obese Humans: A Randomized Double-Blind Placebo-Controlled Trial.", "citation": "Reijnders D, Goossens GH, Hermes GD et al. Effects of Gut Microbiota Manipulation by Antibiotics on Host Metabolism in Obese Humans: A Randomized Double-Blind Placebo-Controlled Trial. Cell metabolism. 2016.", "doi": "10.1016/j.cmet.2016.06.016", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/27411009/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27411009/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "ErratumIn: PMID27508877" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID27411009", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "contradicts", "what_it_shows": "Placebo-controlled antibiotics substantially alter microbiota/metabolites without changing measured metabolic health or later insulin sensitivity.", "what_it_does_not_show": "Regimen-specific null despite community change; no claim that every microbial factor is dispensable. Search-linked erratum is attached.", "confounders_present": [ "Regimen-specific null despite community change; no claim that every microbial factor is dispensable. Search-linked erratum is attached." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 59, "pmid": "28978426", "title": "Improvement of Insulin Sensitivity after Lean Donor Feces in Metabolic Syndrome Is Driven by Baseline Intestinal Microbiota Composition.", "citation": "Kootte RS, Levin E, Salojärvi J et al. Improvement of Insulin Sensitivity after Lean Donor Feces in Metabolic Syndrome Is Driven by Baseline Intestinal Microbiota Composition. Cell metabolism. 2017.", "doi": "10.1016/j.cmet.2017.09.008", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/28978426/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28978426/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID28978426", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Lean-donor FMT improves insulin sensitivity at six weeks but not eighteen weeks; baseline composition predicts response.", "what_it_does_not_show": "Predictor must be validated prospectively; responders cannot define the claimed scope after outcomes.", "confounders_present": [ "Predictor must be validated prospectively; responders cannot define the claimed scope after outcomes." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 60, "pmid": "29581220", "title": "Effect of Vegan Fecal Microbiota Transplantation on Carnitine- and Choline-Derived Trimethylamine-N-Oxide Production and Vascular Inflammation in Patients With Metabolic Syndrome.", "citation": "Smits LP, Kootte RS, Levin E et al. Effect of Vegan Fecal Microbiota Transplantation on Carnitine- and Choline-Derived Trimethylamine-N-Oxide Production and Vascular Inflammation in Patients With Metabolic Syndrome. Journal of the American Heart Association. 2018.", "doi": "10.1161/JAHA.117.008342", "pmcid": "PMC5907601", "url": "https://pubmed.ncbi.nlm.nih.gov/29581220/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29581220/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID29581220", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "contradicts", "what_it_shows": "Vegan-donor FMT changes community toward donor profile in some recipients without changing TMAO production or vascular-inflammation measures.", "what_it_does_not_show": "Small short follow-up trial; altered composition without functional change does not establish systemic causality.", "confounders_present": [ "Small short follow-up trial; altered composition without functional change does not establish systemic causality." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 61, "pmid": "32150549", "title": "Fecal microbiota transplantation for the improvement of metabolism in obesity: The FMT-TRIM double-blind placebo-controlled pilot trial.", "citation": "Yu EW, Gao L, Stastka P et al. Fecal microbiota transplantation for the improvement of metabolism in obesity: The FMT-TRIM double-blind placebo-controlled pilot trial. PLoS medicine. 2020.", "doi": "10.1371/journal.pmed.1003051", "pmcid": "PMC7062239", "url": "https://pubmed.ncbi.nlm.nih.gov/32150549/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32150549/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID32150549", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "contradicts", "what_it_shows": "FMT-TRIM achieves persistent donor engraftment without significant clamp insulin-sensitivity or body-composition benefit.", "what_it_does_not_show": "Small pilot with mild insulin resistance and no paired dietary intervention; does not exclude modest or substrate-dependent effects.", "confounders_present": [ "Small pilot with mild insulin resistance and no paired dietary intervention; does not exclude modest or substrate-dependent effects." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 62, "pmid": "34767757", "title": "Autism-related dietary preferences mediate autism-gut microbiome associations.", "citation": "Yap CX, Henders AK, Alvares GA et al. Autism-related dietary preferences mediate autism-gut microbiome associations. Cell. 2021.", "doi": "10.1016/j.cell.2021.10.015", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/34767757/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34767757/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID38242089" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID34767757", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human association", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Australian autism study detects little direct diagnostic microbiome association while diet/stool traits account for observed relationships.", "what_it_does_not_show": "Cross-sectional mediation does not prove all gut-brain contributions absent; linked correction retained.", "confounders_present": [ "Cross-sectional mediation does not prove all gut-brain contributions absent; linked correction retained." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 63, "pmid": "26069274", "title": "Stool consistency is strongly associated with gut microbiota richness and composition, enterotypes and bacterial growth rates.", "citation": "Vandeputte D, Falony G, Vieira-Silva S et al. Stool consistency is strongly associated with gut microbiota richness and composition, enterotypes and bacterial growth rates. Gut. 2016.", "doi": "10.1136/gutjnl-2015-309618", "pmcid": "PMC4717365", "url": "https://pubmed.ncbi.nlm.nih.gov/26069274/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26069274/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID26069274", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "human association", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Stool consistency correlates with richness, enterotypes and taxa including Akkermansia.", "what_it_does_not_show": "Bristol score is a proxy; direct temporal transit-to-community causation is not isolated.", "confounders_present": [ "Bristol score is a proxy; direct temporal transit-to-community causation is not isolated." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 64, "pmid": "28893994", "title": "Gut microbiota from multiple sclerosis patients enables spontaneous autoimmune encephalomyelitis in mice.", "citation": "Berer K, Gerdes LA, Cekanaviciute E et al. Gut microbiota from multiple sclerosis patients enables spontaneous autoimmune encephalomyelitis in mice. Proceedings of the National Academy of Sciences of the United States of America. 2017.", "doi": "10.1073/pnas.1711233114", "pmcid": "PMC5635914", "url": "https://pubmed.ncbi.nlm.nih.gov/28893994/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28893994/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID28893994", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal transfer", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "MS-discordant twin transfer increases spontaneous autoimmunity in transgenic recipients; IL-10 interruption changes protected recipients.", "what_it_does_not_show": "Host autoreactive genotype is essential context; transfer is not endogenous human MS initiation.", "confounders_present": [ "Host autoreactive genotype is essential context; transfer is not endogenous human MS initiation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 65, "pmid": "22031325", "title": "Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination.", "citation": "Berer K, Mues M, Koutrolos M et al. Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature. 2011.", "doi": "10.1038/nature10554", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/22031325/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22031325/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID22031325", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal perturbation", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Commensal flora and host myelin autoantigen cooperate in spontaneous autoimmune demyelination in a defined mouse model.", "what_it_does_not_show": "Host autoreactive repertoire and antigen context constrain generalization; microbiota is not an autonomous human initiator.", "confounders_present": [ "Host autoreactive repertoire and antigen context constrain generalization; microbiota is not an autonomous human initiator." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 66, "pmid": "21475195", "title": "Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease.", "citation": "Wang Z, Klipfell E, Bennett BJ et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011.", "doi": "10.1038/nature09922", "pmcid": "PMC3086762", "url": "https://pubmed.ncbi.nlm.nih.gov/21475195/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21475195/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID21475195", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal perturbation", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Dietary choline/TMAO and microbial suppression alter mouse foam-cell accumulation and atherosclerosis, with human metabolite-risk association.", "what_it_does_not_show": "Hyperlipidemic mouse genotype and dietary exposure define scope; observational clinical metabolite risk is distinct from causal prevention.", "confounders_present": [ "Hyperlipidemic mouse genotype and dietary exposure define scope; observational clinical metabolite risk is distinct from causal prevention." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] }, { "n": 67, "pmid": "20620945", "title": "Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells.", "citation": "Wu HJ, Ivanov II, Darce J et al. Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity. 2010.", "doi": "10.1016/j.immuni.2010.06.001", "pmcid": "PMC2904693", "url": "https://pubmed.ncbi.nlm.nih.gov/20620945/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/20620945/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID20620945", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal perturbation", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Single SFB colonization reinstates Th17/autoantibody responses and arthritis in germ-free K/BxN mice; IL-17 neutralization prevents disease.", "what_it_does_not_show": "Autoreactive host genotype is prerequisite; single strain is causal within this mouse context, not across human autoimmunity.", "confounders_present": [ "Autoreactive host genotype is prerequisite; single strain is causal within this mouse context, not across human autoimmunity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [] } ], "verification_summary": { "load_bearing_claims_checked": 72, "verified": 72, "unverified": 0, "contradicted": 0, "note": "Verified attribution is distinct from mechanism truth or complete body access." }, "factual_issues_found": [], "cap_rules_applied": [ { "subclaim_id": "SC1", "cap": "Β", "cap_source": "universal", "triggered": true, "trigger_text_quoted": "Pure association evidence — however large, however replicated — cannot exceed Β.", "specific_trigger": "Disease-associated community features recur, but stool consistency, medication and quantitative measurement substantially alter interpretation; association alone is Β.", "resulting_ceiling": "Β" }, { "subclaim_id": "SC4", "cap": "Γ", "cap_source": "universal", "triggered": true, "trigger_text_quoted": "Seeding or forced-transfer paradigms cap at Γ for endogenous propagation claims. Forced spread is not observed spread.", "specific_trigger": "Diet, host genotype, treatment and transit can precede microbial changes. Community engraftment or changed abundance can occur without functional benefit; targeted products can benefit without changing overall composition. No broad human upstream-primacy contrast closes these alternatives.", "resulting_ceiling": "Γ" } ], "cap_precedence_resolutions": [ { "collision": "Perturbation in a defined setting versus broader inference", "subclaim_scope_cap_binds_on": "The composition of the human gut microbiome is a primary, targetable causal driver of systemic and neurobehavioural disease.", "subclaim_scope_threshold_binds_on": "The precise experimentally tested subclaim scope", "resolution": "Gnotobiotic transfer/addition crosses the microbiome perturbation threshold for recipient rodent SC2. Universal cap5 blocks transferring that result to endogenous human SC4. FMT with a human functional disease endpoint can cross SC3 within baseline cirrhosis; the cap does not erase this clinical contribution, but treatment benefit does not prove autonomous initiation. Biomarker-only TMAO/ethanol/HOMA results do not alone cross clinical trajectory thresholds.", "note": "Convergent lines are assessed as a set; one weak leg is not re-capped over the assembled case." } ], "boundary_check_BGD": [ { "subclaim_id": "SC1", "field_valid_perturbation_quote": "\n- Gnotobiotic or transfer experiment showing phenotype movement, at minimum\n- Even without defined-consortium precision or robust rescue, a transfer paradigm in vivo is the minimum that crosses this threshold\n\nPer **Cap precedence** above, a gnotobiotic or forced-transfer experiment crosses Δ for the recipient-animal subclaim it was actually run in, while universal cap 5 (seeding or forced-transfer paradigms cap at Γ) still blocks the inference from that result to endogenous human biology — score the two scopes separately rather than choosing between the rules.", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "", "gamma_hard_rules_triggered": [ "Association plus cell-culture metabolite assays: cannot carry SC4 beyond Γ.", "Association plus in vitro immune readouts: cannot carry SC4 beyond Γ.", "Any framework that has not crossed the transfer/rescue threshold in vivo: not triggered for bounded rodent SC2; human primacy is still separately unproved.", "Microbial production biomarkers without disease trajectory change do not cross human clinical dependency." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Disease-associated community features recur, but stool consistency, medication and quantitative measurement substantially alter interpretation; association alone is Β.", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC2", "field_valid_perturbation_quote": "\n- Gnotobiotic or transfer experiment showing phenotype movement, at minimum\n- Even without defined-consortium precision or robust rescue, a transfer paradigm in vivo is the minimum that crosses this threshold\n\nPer **Cap precedence** above, a gnotobiotic or forced-transfer experiment crosses Δ for the recipient-animal subclaim it was actually run in, while universal cap 5 (seeding or forced-transfer paradigms cap at Γ) still blocks the inference from that result to endogenous human biology — score the two scopes separately rather than choosing between the rules.", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "PMID24009397, PMID24412651, PMID24315484, PMID29804833, PMID26687352, PMID20620945", "gamma_hard_rules_triggered": [ "Association plus cell-culture metabolite assays: cannot carry SC4 beyond Γ.", "Association plus in vitro immune readouts: cannot carry SC4 beyond Γ.", "Any framework that has not crossed the transfer/rescue threshold in vivo: not triggered for bounded rodent SC2; human primacy is still separately unproved.", "Microbial production biomarkers without disease trajectory change do not cross human clinical dependency." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Defined microbial addition/rescue, host-pathway interruption and nonlethal microbial-enzyme inhibition converge on functional rodent effects with distinct failure modes. Genotype, diet and developmental timing remain prespecified boundaries.", "ceiling_from_boundary_check": "Δ or higher" }, { "subclaim_id": "SC3", "field_valid_perturbation_quote": "\n- Gnotobiotic or transfer experiment showing phenotype movement, at minimum\n- Even without defined-consortium precision or robust rescue, a transfer paradigm in vivo is the minimum that crosses this threshold\n\nPer **Cap precedence** above, a gnotobiotic or forced-transfer experiment crosses Δ for the recipient-animal subclaim it was actually run in, while universal cap 5 (seeding or forced-transfer paradigms cap at Γ) still blocks the inference from that result to endogenous human biology — score the two scopes separately rather than choosing between the rules.", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "PMID39800192", "gamma_hard_rules_triggered": [ "Association plus cell-culture metabolite assays: cannot carry SC4 beyond Γ.", "Association plus in vitro immune readouts: cannot carry SC4 beyond Γ.", "Any framework that has not crossed the transfer/rescue threshold in vivo: not triggered for bounded rodent SC2; human primacy is still separately unproved.", "Microbial production biomarkers without disease trajectory change do not cross human clinical dependency." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Human FMT in treated cirrhosis alters recurrence/cognition, with phase2 placebo-controlled evidence and weaker earlier studies. Metabolic and PD trials are heterogeneous and ALS is negative; a context-specific contribution is supported, not one mechanism across disorders.", "ceiling_from_boundary_check": "Δ or higher" }, { "subclaim_id": "SC4", "field_valid_perturbation_quote": "\n- Gnotobiotic or transfer experiment showing phenotype movement, at minimum\n- Even without defined-consortium precision or robust rescue, a transfer paradigm in vivo is the minimum that crosses this threshold\n\nPer **Cap precedence** above, a gnotobiotic or forced-transfer experiment crosses Δ for the recipient-animal subclaim it was actually run in, while universal cap 5 (seeding or forced-transfer paradigms cap at Γ) still blocks the inference from that result to endogenous human biology — score the two scopes separately rather than choosing between the rules.", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "", "gamma_hard_rules_triggered": [ "Association plus cell-culture metabolite assays: cannot carry SC4 beyond Γ.", "Association plus in vitro immune readouts: cannot carry SC4 beyond Γ.", "Any framework that has not crossed the transfer/rescue threshold in vivo: not triggered for bounded rodent SC2; human primacy is still separately unproved.", "Microbial production biomarkers without disease trajectory change do not cross human clinical dependency." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Diet, host genotype, treatment and transit can precede microbial changes. Community engraftment or changed abundance can occur without functional benefit; targeted products can benefit without changing overall composition. No broad human upstream-primacy contrast closes these alternatives.", "ceiling_from_boundary_check": "Γ" } ], "thresholds_tested": [ { "subclaim_id": "SC1", "threshold": "Δ", "requirement_quoted": "Requires a transfer paradigm or causal perturbation in vivo.", "satisfied": "no", "supporting_evidence": [], "what_would_cross_it": "For a causal interpretation of a particular signature, isolate a strain/factor and show a functional human endpoint; association existence remains a separate claim." }, { "subclaim_id": "SC2", "threshold": "Δ", "requirement_quoted": "Requires a transfer paradigm or causal perturbation in vivo.", "satisfied": "yes", "supporting_evidence": [ "[10] Discordant-twin communities and culture collections transmit body-fat phenotypes; lean-community cohousing rescue depends on diet.", "[16] SCFA/fiber metabolic benefits disappear in intestinal-gluconeogenesis-deficient mice despite similar microbiota changes.", "[21] Bacteroides fragilis improves gut permeability and selected behaviors after maternal immune activation; a metabolite challenge induces some abnormalities.", "[24] Defined Akkermansia/Parabacteroides colonization restores ketogenic-diet seizure protection and transfers protection under control diet.", "[38] DMB inhibits microbial TMA generation and decreases diet-enhanced atherosclerotic lesions in ApoE-deficient mice.", "[67] Single SFB colonization reinstates Th17/autoantibody responses and arthritis in germ-free K/BxN mice; IL-17 neutralization prevents disease." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Ε", "requirement_quoted": "Requires context-specific causal effect with defined limits. A transferable phenotype exists, but microbial identity or generalizability remains incomplete.", "satisfied": "yes", "supporting_evidence": [ "[10] Discordant-twin communities and culture collections transmit body-fat phenotypes; lean-community cohousing rescue depends on diet.", "[16] SCFA/fiber metabolic benefits disappear in intestinal-gluconeogenesis-deficient mice despite similar microbiota changes.", "[21] Bacteroides fragilis improves gut permeability and selected behaviors after maternal immune activation; a metabolite challenge induces some abnormalities.", "[24] Defined Akkermansia/Parabacteroides colonization restores ketogenic-diet seizure protection and transfers protection under control diet.", "[38] DMB inhibits microbial TMA generation and decreases diet-enhanced atherosclerotic lesions in ApoE-deficient mice.", "[67] Single SFB colonization reinstates Th17/autoantibody responses and arthritis in germ-free K/BxN mice; IL-17 neutralization prevents disease." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Ζ", "requirement_quoted": "Requires:\n- Defined consortium or strain-level causal evidence\n- Rescue logic\n- Replication across at least two relevant models or cohorts", "satisfied": "yes", "supporting_evidence": [ "[10] Discordant-twin communities and culture collections transmit body-fat phenotypes; lean-community cohousing rescue depends on diet.", "[16] SCFA/fiber metabolic benefits disappear in intestinal-gluconeogenesis-deficient mice despite similar microbiota changes.", "[21] Bacteroides fragilis improves gut permeability and selected behaviors after maternal immune activation; a metabolite challenge induces some abnormalities.", "[24] Defined Akkermansia/Parabacteroides colonization restores ketogenic-diet seizure protection and transfers protection under control diet.", "[38] DMB inhibits microbial TMA generation and decreases diet-enhanced atherosclerotic lesions in ApoE-deficient mice.", "[67] Single SFB colonization reinstates Th17/autoantibody responses and arthritis in germ-free K/BxN mice; IL-17 neutralization prevents disease." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Η", "requirement_quoted": "Requires:\n- Defined consortium or factor rescue in multiple contexts\n- Narrowed mechanism\n- Strong exclusion of diet, housing, batch, and handling confounds", "satisfied": "no", "supporting_evidence": [ "[10] Discordant-twin communities and culture collections transmit body-fat phenotypes; lean-community cohousing rescue depends on diet.", "[16] SCFA/fiber metabolic benefits disappear in intestinal-gluconeogenesis-deficient mice despite similar microbiota changes.", "[21] Bacteroides fragilis improves gut permeability and selected behaviors after maternal immune activation; a metabolite challenge induces some abnormalities.", "[24] Defined Akkermansia/Parabacteroides colonization restores ketogenic-diet seizure protection and transfers protection under control diet.", "[38] DMB inhibits microbial TMA generation and decreases diet-enhanced atherosclerotic lesions in ApoE-deficient mice.", "[67] Single SFB colonization reinstates Th17/autoantibody responses and arthritis in germ-free K/BxN mice; IL-17 neutralization prevents disease." ], "what_would_cross_it": "Replicate strain/factor-rescue mechanisms with native abundance across independently housed genotypes/diets while excluding developmental and chemical-target alternatives." }, { "subclaim_id": "SC3", "threshold": "Δ", "requirement_quoted": "Requires a transfer paradigm or causal perturbation in vivo.", "satisfied": "yes", "supporting_evidence": [ "[4] THEMATIC compares placebo with capsule/enema FMT in treated cirrhosis and reports lower HE recurrence in a post hoc any-FMT comparison." ], "what_would_cross_it": "" }, { "subclaim_id": "SC3", "threshold": "Ε", "requirement_quoted": "Requires context-specific causal effect with defined limits. A transferable phenotype exists, but microbial identity or generalizability remains incomplete.", "satisfied": "yes", "supporting_evidence": [ "[4] THEMATIC compares placebo with capsule/enema FMT in treated cirrhosis and reports lower HE recurrence in a post hoc any-FMT comparison." ], "what_would_cross_it": "" }, { "subclaim_id": "SC3", "threshold": "Ζ", "requirement_quoted": "Requires:\n- Defined consortium or strain-level causal evidence\n- Rescue logic\n- Replication across at least two relevant models or cohorts", "satisfied": "no", "supporting_evidence": [ "[4] THEMATIC compares placebo with capsule/enema FMT in treated cirrhosis and reports lower HE recurrence in a post hoc any-FMT comparison." ], "what_would_cross_it": "Prospective factor-defined placebo-controlled trials with durable disease endpoints and host-pathway rescue logic, rather than repeating crude FMT as if it added a new independent line." }, { "subclaim_id": "SC4", "threshold": "Δ", "requirement_quoted": "Requires a transfer paradigm or causal perturbation in vivo.", "satisfied": "no", "supporting_evidence": [], "what_would_cross_it": "Prospective before-disease microbial factor manipulation with matched diet, transit, medication and host-genotype controls, showing a substantial durable disease effect across the registered diagnoses." } ], "generalization_check": { "generalization_tested": "yes", "context_boundary_mapped": "yes", "internal_negative_controls": [ "High-saturated-fat/low-fruit diet prevents lean-community cohousing rescue (PMID24009397).", "WT recipients lack the ASO genotype-specific motor effect and donor pairs are heterogeneous (PMID27912057).", "B. fragilis leaves social deficits and 4EPS lacks repetitive/USV effects (PMID24315484).", "Juvenile-only metabolites fail BTBR rescue (PMID31150625).", "FMT-TRIM and Finnish PD trial do not deliver the selected functional outcomes (PMID32150549,39073834)." ], "note": "Context boundaries are mapped by genotype, diet, timing, retained behavioral domains, and clinical null trials. Broad human primacy is unestablished; mapped positive contexts retain causal credit. Low-level relative microbiome associations do not identify a conserved intervention target." }, "falsification_patterns_met": [ { "pattern": "Phenotype fails to transfer or change despite community manipulation in defined human regimens", "evidence": "FMT-TRIM, vegan FMT, placebo-controlled antibiotics and Finnish PD FMT show engraftment/compositional or metabolic shifts without the requested clinical/physiological benefit (PMID32150549,29581220,27411009,39073834).", "downgrade_applied": false }, { "pattern": "Host and substrate prerequisites constrain transfer/rescue", "evidence": "Ridaura diet blocks cohousing rescue; Sampson WT animals lack the ASO motor phenotype; human ASD diet links and metformin signatures challenge autonomous primacy (PMID24009397,27912057,34767757,26633628).", "downgrade_applied": false } ], "pitfalls_flagged": [ { "pitfall": "Dysbiosis treated as mechanism", "where": "Abundance, diversity and inferred neuroactive functions are separated from functional factor perturbation." }, { "pitfall": "Transfer generalized to endogenous human initiation", "where": "Recipient mouse disease or behavior cannot establish donor human disease causality." }, { "pitfall": "Biomarker change treated as clinical dependency", "where": "TMAO, ethanol and HOMA changes are not cardiovascular events, liver progression or neuron preservation." }, { "pitfall": "Negative perturbation counted as positive threshold", "where": "Null human trials are discriminators, excluded from the positive tally." }, { "pitfall": "Outcome-fitted scope and report independence", "where": "No responder-defined enrollment; THEMATIC secondary analysis and shared cohort reanalyses remain linked." }, { "pitfall": "Provider gap absence treated as field absence", "where": "Consensus metabolic-trial gap was contradicted by retrieved primary trials; its meter/headline are not evidence." } ], "causal_tally_audit": { "tally_claimed_by_document": 8, "tally_after_audit": 8, "items_rejected": [ "Null and negative contrasts are discriminators, not positive threshold crossings. Reports and replications are not independent causal lines.", "Eight contrasts are flagged as especially discriminating within their precise scopes; other positive interventions may contribute but are not counted as mechanism-isolating decisive tests.", "Crude FMT, broad antibiotics, transgene/recipient transfer, administered metabolites and surrogate outcomes do not establish broad human primacy." ] }, "steelman": { "case_one_rung_higher": "One rung above Γ would be Δ for SC4: human FMT and defined microbial products provide an earnest intervention-based case that the community is an upstream driver. The HE recurrence result is stronger than a diversity association and deserves causal credit.", "case_one_rung_lower": "One rung below Γ would be Β if human microbiome primacy rests only on disease-associated abundance signatures. Diet, drugs, stool consistency and negative transplant trials make that an intellectually serious alternative.", "which_rejected": "Δ for broad primacy is rejected because the human trials treat established host disease and do not isolate a primary compositional initiator. Β understates actual controlled factor/transfer mechanisms that provide partial system support. Scoped contribution retains its separate Ε/Ζ scores.", "blocking_cap_threshold_or_missing_experiment": "Missing experiment: Run preregistered diagnosis-specific factorial trials of a defined strain/enzyme consortium and matched control, crossed with controlled dietary substrate, while measuring bowel transit and fixing baseline drugs. Use baseline factor abundance for enrollment, retain nonresponders, and assess mechanistic mediation and durable clinical endpoints." }, "final_score": { "hsef_level": "Γ", "hsef_descriptor": "Mechanistically plausible, partial system support", "confidence": "Moderate", "confidence_rationale": "Evidence density and reproducibility set the confidence, not correctness and not reviewer access: defined rodent perturbations replicate across distinct mechanisms, while the human record is mixed and the transfer literature shows demonstrated rather than hypothetical reproducibility problems - engraftment without functional effect, and housing- and diet-dependent reversals - with heterogeneous products, comparators and endpoints across the 67 reports. Access depth is recorded per ledger row and is not a determinant of the band.", "rests_on_non_peer_reviewed_work": false, "rationale": "SC4 is the preregistered human-primacy gate. Transfers, defined strains and microbial products show real bounded contributions, and HE intervention crosses human contribution thresholds, but none establishes composition as the primary upstream target across systemic and neurobehavioural disease. SC1 association is Β, bounded rodent causality SC2 Ζ, human contribution SC3 Ε, broad primacy SC4 Γ. These are different scopes, not a refutation of the microbiome." }, "role_of_mechanism": { "classification": "reinforcing / stabilizing factor", "derivation_step_matched": 5, "derivation": "Within documented disease contexts, microbial factors modify a process initiated by diet, immune activation, host autoreactivity, cirrhosis or an alpha-synuclein transgene. They can amplify or maintain phenotype. No universal initiation-plus-removal-plus-rate-limiting demonstration establishes a primary-driver role; this direction judgment is not inferred from tournament rank.", "tournament_used_as_tiebreaker": false, "note": "Derived from causal direction, not tournament rank." }, "extended_scoring_MSD": { "momentum": { "value": "Mechanistic only", "artifact": "Active work is clinical rather than boundary-addressing: THEMATIC and recent placebo-controlled PD/ALS/defined-L.reuteri studies test functional human boundaries in established disease (PMID39800192,39073834,39617896,38113884). No currently recruiting trial is claimed, and none of these designs is the before-disease factor manipulation that SC4's next threshold requires, so the value is Mechanistic only rather than Decisive work underway.", "justification": "Active work is clinical rather than boundary-addressing: THEMATIC and recent placebo-controlled PD/ALS/defined-L.reuteri studies test functional human boundaries in established disease (PMID39800192,39073834,39617896,38113884). No currently recruiting trial is claimed, and none of these designs is the before-disease factor manipulation that SC4's next threshold requires, so the value is Mechanistic only rather than Decisive work underway." }, "stability": { "value": "Stable", "trigger": "No named pending result is claimed likely to change the broad primary-driver gate imminently; specific future human factor trials could raise scoped contribution.", "justification": "No named pending result is claimed likely to change the broad primary-driver gate imminently; specific future human factor trials could raise scoped contribution." }, "divergence": { "implied_level": null, "implied_level_basis": "No single field-implied level is defensible from conflicting framings.", "assessed_level": "Γ", "gap_in_rungs": null, "value": "Contested", "justification": "No manufactured field consensus or arithmetic gap." }, "calibration_note": "M/S/D never modify HSEF level or confidence." }, "change_record": { "applies": false, "prior_level": "Ranking categorical verdict visible; no prior letter used as a target", "prior_confidence": null, "prior_source": null, "derived_before_consulting_prior": false, "new_level": "Γ", "direction": "newly assigned", "what_moved_it": "Fresh primary evidence appraisal; not blinded.", "divergence_from_other_reviewers": null }, "proposed_decisive_experiments": [ { "name": "Registered boundary experiment", "experiment": "Run preregistered diagnosis-specific factorial trials of a defined strain/enzyme consortium and matched control, crossed with controlled dietary substrate, while measuring bowel transit and fixing baseline drugs. Use baseline factor abundance for enrollment, retain nonresponders, and assess mechanistic mediation and durable clinical endpoints.", "readout": "HE recurrence or another prespecified diagnosis-specific clinical trajectory, native microbial-factor activity and host-pathway engagement over a registered horizon", "critical_control": "Inactive factor/strain control, equivalent bowel preparation, substrate matching, stable host drugs, transit measurements, blinded outcomes and dose-matched functional rescue", "supporting_result": "Selective factor correction improves the registered disease endpoint with specific mediation across substrate/genotype strata and persists beyond transient engraftment", "falsifying_result": "Verified factor engagement changes only composition/metabolites, benefit disappears after diet/drug matching, or relevant human functional outcomes remain unchanged" } ], "knowledge_gaps": [ { "name": "Gap 1", "statement": "Identify factor/strain necessity separately from crude donor-community sufficiency.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 2", "statement": "Resolve placebo, bowel-cleansing, antibiotic-pretreatment and autologous-stool effects in PD FMT.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 3", "statement": "Test durable hard-endpoint benefit of microbial enzyme inhibition in humans rather than extrapolating TMAO concentration.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 4", "statement": "Separate host metabolic effects of pasteurized bacteria from correction of community composition.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 5", "statement": "Prospectively validate baseline predictors without selecting responders after outcomes.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 6", "statement": "Test human developmental timing and phenotype domains instead of labeling mouse anxiety as autism.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 7", "statement": "Quantify transit and absolute microbial load alongside drugs, diet and strain function.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 8", "statement": "Partition shared trials and reused metagenomes before claiming independent convergence.", "relevance": "Limits mechanism identification or scope." } ], "review_metadata": { "review_date": "2026-10-08", "reviewer": "Codex", "evidence_base_note": "67 primary reports; literature cutoff 2026-10-08; source examination UTC date 2026-10-09; bounded critical review, not exhaustive systematic review.", "literature_tools_available": true, "literature_tools_note": "Life Sciences Literature PubMed/Entrez; attempted Europe PMC XML and successful public NCBI PMC direct HTTPS access are separately logged. Signed-in Consensus browser discovery and targeted indexed full-text checks are reconciled with original sections; failed matches and source substitutions remain explicit. Zero Consensus API calls. SciSpace discovery was also used; primary leads were resolved to canonical originals before counting. See scispace-leads.json.", "skill_version": "5.3", "validator_run": "exact archived v5.3 validator 2.3; see validator.txt", "validator_warnings_addressed": "The index entry was restated as the preregistered causal claim. No real phenomenon is labelled refuted; warning is explicitly justified.", "consensus_consistency_audit": "2026-10-09; supplementary provenance/source reconciliation; original grading retained; prior grades visible." }, "is_calibration_entry": { "value": false, "entry_role": "not_calibration", "blind_graded": null, "completed_blinded_calibration": false, "expected_band_sealed_at": "", "target_sha256": "", "target_authorship": "not applicable", "target_author_saw_review": null, "future_run_status": "not prepared", "unblinded_reason": "Ranking categorical verdict and index guidance were visible. No completed blinded calibration claimed." }, "upper_ladder_check": { "final_level_below_zeta": true, "equivalents_considered": [ { "kind": "mendelian_randomization", "available": false, "why_not_sufficient": "Strain-resolved rescue, nonlethal enzyme inhibition, human FMT disease recurrence and host-genetic instruments were considered. Independent rodent classes support SC2 Ζ. Human trials establish bounded contribution but crude-community modality replication and metabolic surrogates cannot carry SC4 to Ζ; weak association is not re-capped over genuine convergence." }, { "kind": "natural_experiment", "available": false, "why_not_sufficient": "Strain-resolved rescue, nonlethal enzyme inhibition, human FMT disease recurrence and host-genetic instruments were considered. Independent rodent classes support SC2 Ζ. Human trials establish bounded contribution but crude-community modality replication and metabolic surrogates cannot carry SC4 to Ζ; weak association is not re-capped over genuine convergence." }, { "kind": "dose_response_across_populations", "available": false, "why_not_sufficient": "Strain-resolved rescue, nonlethal enzyme inhibition, human FMT disease recurrence and host-genetic instruments were considered. Independent rodent classes support SC2 Ζ. Human trials establish bounded contribution but crude-community modality replication and metabolic surrogates cannot carry SC4 to Ζ; weak association is not re-capped over genuine convergence." }, { "kind": "withdrawal_rechallenge", "available": false, "why_not_sufficient": "Strain-resolved rescue, nonlethal enzyme inhibition, human FMT disease recurrence and host-genetic instruments were considered. Independent rodent classes support SC2 Ζ. Human trials establish bounded contribution but crude-community modality replication and metabolic surrogates cannot carry SC4 to Ζ; weak association is not re-capped over genuine convergence." }, { "kind": "therapeutic_perturbation_hard_endpoint", "available": false, "why_not_sufficient": "Strain-resolved rescue, nonlethal enzyme inhibition, human FMT disease recurrence and host-genetic instruments were considered. Independent rodent classes support SC2 Ζ. Human trials establish bounded contribution but crude-community modality replication and metabolic surrogates cannot carry SC4 to Ζ; weak association is not re-capped over genuine convergence." } ], "convergence_present": true, "cap_reapplied_to_convergent_set": false }, "provenance_header": { "sources_total": 67, "claims_total": 72, "claims_verified": 72, "claims_unverified": 0, "claims_contradicted": 0, "tier_a_sources": 67, "generated_by": "Codex; HSEF v5.3", "gate_passed": true }, "claims": [ { "id": "C1", "text": "Controlled dietary crossover changes TMAO production and renal excretion; withdrawal reduces circulating TMAO. Diet and kidney handling determine the readout; no cardiovascular disease prevention endpoint.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 1 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C2", "text": "Placebo-controlled pasteurized Akkermansia supplementation improves insulin sensitivity and circulating lipids in insulin-resistant overweight adults. HOMA-based indices, baseline insulin imbalance, small exploratory sample and unchanged HbA1c/overall community structure restrict inference; weight/fat changes are not significant.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 2 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Main text:paragraph1, 2:Main text:paragraph3, 2:Main text:paragraph5, 2:Main text:paragraph12, 2:Main text:paragraph13, 2:Main text:paragraph14. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C3", "text": "Pasteurized Akkermansia and its outer-membrane protein partly reproduce metabolic benefits in obese/diabetic mice. Administration demonstrates bounded sufficiency and host-receptor plausibility, not endogenous necessity or human disease prevention.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 3 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C4", "text": "THEMATIC compares placebo with capsule/enema FMT in treated cirrhosis and reports lower HE recurrence in a post hoc any-FMT comparison. Safety is primary; recurrence is secondary and its pooled contrast post hoc. Underlying cirrhosis and concurrent drugs remain upstream.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 4 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C5", "text": "Randomized open-label FMT with antibiotic pretreatment improves cognition and recurrent HE compared with standard care. Small male cohort and unmatched antibiotic pretreatment; crude donor community does not identify the microbial causal factor.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 5 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:EXPERIMENTAL PROCEDURES:paragraph1, 0:EXPERIMENTAL PROCEDURES:paragraph4, 2:RESULTS::paragraph0, 2:RESULTS::paragraph1, 2:RESULTS::paragraph3, 2:RESULTS::paragraph4. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C6", "text": "THEMATIC secondary multi-omics links HE recurrence with microbial, metabolite and inflammatory signatures. Same trial as PMID39800192; outcome-selected molecular associations are not new causal lines or proof of individual taxa necessity.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 6 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C7", "text": "Placebo-controlled FMT capsules improve cognitive testing and mucosal measures without antibiotic pretreatment in cirrhosis. Phase1 safety focus; infection/HE episodes are similar and efficacy remains provisional. Linked erratum is attached and not separately counted.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 7 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C8", "text": "Short-term animal versus plant diets rapidly change microbial structure and activity. Shows diet-to-microbiome direction rather than proving microbes irrelevant to downstream disease.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 8 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C9", "text": "Microbial imidazole propionate impairs mouse glucose tolerance and activates a p38gamma-p62-mTORC1 signaling route. Administered metabolite and human associations do not establish endogenous human contribution or broad compositional primacy.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC4" ], "source_ns": [ 9 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C10", "text": "Discordant-twin communities and culture collections transmit body-fat phenotypes; lean-community cohousing rescue depends on diet. Rescue fails on high-saturated-fat/low-fruit-vegetable diet. Early glucose contrast does not establish full insulin resistance; transfer remains recipient-mouse causality.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 10 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 3:Phenotypes produced by bacterial culture collections, 7:Diet-specific effects. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C11", "text": "Obese-donor mouse microbiota increases energy-harvest potential and fat gain in germ-free recipients. Crude transfer and genetically obese donors do not isolate strains or establish general human obesity primacy.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 11 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C12", "text": "Randomized metformin changes human microbiota; post-treatment donor microbiota improves glucose tolerance after mouse transfer. Drug has host effects; recipient transfer supports a contribution but does not measure microbiome-specific mediation of human glycemic benefit.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 12 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C13", "text": "Leptin-deficient obese mice differ in broad bacterial divisions from related lean mice on the same diet. Genetic host phenotype can reshape ecology; division-level signatures are not a causal mechanism.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 13 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C14", "text": "Portal sampling and ADH inhibition reveal microbial ethanol production in NAFLD, abolished after antibiotics. Intervention changes an exposure biomarker; no demonstrated liver disease trajectory change or strain-specific causality.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 14 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C15", "text": "Kidney function predicts circulating TMAO more strongly than diet/community composition; mouse exposure supports bidirectional renal injury. Mediation and propensity matching are not randomized human mechanism tests; concentration alone cannot identify microbial primacy.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC4" ], "source_ns": [ 15 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C16", "text": "SCFA/fiber metabolic benefits disappear in intestinal-gluconeogenesis-deficient mice despite similar microbiota changes. Host pathway dependence and administered metabolites establish conditional benefit; endogenous strain necessity remains unspecified.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 16 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C17", "text": "Germ-free versus conventionally raised mice differ in energy metabolites and tissue lipid distributions. Developmental/immune differences accompany germ-free status; molecular profiles do not establish a disease phenotype.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 17 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C18", "text": "Defined bacterial enzymes metabolize levodopa and pathway inhibition raises mouse drug bioavailability. Functional pharmacokinetic effect is distinct from initiating Parkinson disease or changing neurodegeneration.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 18 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C19", "text": "Microbial depletion/recolonization and SCFA challenge change motor deficits and microglia in alpha-synuclein-overexpressing mice. Host transgene establishes vulnerability; forced human-donor transfer cannot show endogenous human PD primacy.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 19 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph5, 1:Results:paragraph8, 1:Results:paragraph12. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C20", "text": "Spore-forming bacteria regulate host peripheral serotonin, GI motility and platelet function. Peripheral serotonin is not demonstrated brain neurotransmission; linked erratum with no PMID supplied remains explicit.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 20 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C21", "text": "Bacteroides fragilis improves gut permeability and selected behaviors after maternal immune activation; a metabolite challenge induces some abnormalities. Social deficits persist; 4EPS induces anxiety/startle changes but not repetitive or communicative deficits. Maternal immune activation is upstream and human ASD causality is untested.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 21 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 5:B. fragilis Treatment Corrects ASD-Related Behavioral Abnormalities, 7:B. fragilis Treatment Corrects Levels of MIA-Induced Serum Metabolites, 8:A Serum Metabolite Induces ASD-Related Behavior. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C22", "text": "Human ASD-donor microbiota induces altered mouse behavior and splicing; candidate metabolites improve a mouse model. Donor, sex and age affect recipient behavior. High-dose taurine/5AV rescue depends on prenatal/weaning exposure; juvenile-only treatment fails in BTBR. Mouse phenotype is distinct from human ASD initiation.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 22 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph1, 1:RESULTS:paragraph12, 1:RESULTS:paragraph13, 1:RESULTS:paragraph14, 3:STAR Methods:paragraph28, 3:STAR Methods:paragraph29, 3:STAR Methods:paragraph38. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C23", "text": "Microbial depletion changes male mouse social behavior; host HPA/neuronal interruption and Enterococcus faecalis reverse defined defects. Circuit specificity is conditional on stress and depletion; mouse social activity is not a human disease endpoint.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 23 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C24", "text": "Defined Akkermansia/Parabacteroides colonization restores ketogenic-diet seizure protection and transfers protection under control diet. Two mouse seizure contexts support treatment mediation, not universal epilepsy causation. Linked erratum remains attached.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 24 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C25", "text": "Maternal microbial depletion impairs fetal thalamocortical axons; defined consortium/metabolites rescue and alter later tactile behavior. Prenatal physiological development and specific behavioral tasks do not demonstrate human neurodevelopmental disease primacy.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 25 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C26", "text": "Deep metagenomics identifies broad PD-associated species, genes and pathway shifts. Calling predicted pathways disease permissive does not demonstrate human causal dependency; medication, transit and disease remain alternatives.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 26 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C27", "text": "Population cohorts identify stool consistency and medication as major microbiome covariates. Covariate association warns about confounding but does not prove all disease associations disappear.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 27 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C28", "text": "Comparative sample-processing experiments show extraction methods can mimic biological microbiome differences. Technical measurement artifact is not a direct test of disease mechanism.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 28 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C29", "text": "Two-stage human metagenomics identifies diabetes-associated microbial markers and functions. Diagnostic classification and abundance association do not establish direction or microbial necessity.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 29 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C30", "text": "Medication-stratified metagenomics separates metformin-associated features from untreated diabetes signatures. Residual untreated-disease association remains; inferred therapeutic mediation is not isolated by human intervention. Linked erratum is retained.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 30 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 3:Main text:paragraph0, 3:Main text:paragraph2, 3:Main text:paragraph4, 3:Main text:paragraph5, 3:Main text:paragraph6. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C31", "text": "Flow-cytometry plus sequencing reveals variable microbial loads and compositional artifacts of relative profiling. Counts improve measurement; they do not determine whether a disease signature is causal.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 31 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C32", "text": "MiBioGen links host loci with taxa and reports suggestive MR disease relationships. Low taxonomic instrument coverage, dietary pathways and pleiotropy constrain a broad human causal-primacy inference.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 32 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C33", "text": "Replicated population microbiome features correlate with depression and quality of life after antidepressant adjustment. Neuroactive pathway potential and adjusted association do not establish microbial brain activity or human disease causation.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 33 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C34", "text": "Propionate supplementation changes Treg function; post hoc long-term analyses associate supplementation with improved MS course. Nonrandomized proof-of-concept/add-on treatment and post hoc endpoints do not isolate microbial source or clinical causal effect.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 34 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C35", "text": "Dutch population metagenomics links community variation with diet, drugs and intrinsic host factors. Shares LifeLines-DEEP material with PMID27126039; not an independent replication line.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 35 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C36", "text": "Low microbial gene richness tracks adiposity, metabolic abnormalities and later weight gain. Prospective weight association still permits diet, medication and host-state causes.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 36 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C37", "text": "Diet/TMAO exposure and microbial transfer affect platelet reactivity and experimental thrombosis, paired with human event prediction. Human event risk is observational; overlapping angiography/platform material and administered metabolite are not independent clinical causality.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 37 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C38", "text": "DMB inhibits microbial TMA generation and decreases diet-enhanced atherosclerotic lesions in ApoE-deficient mice. Chemical specificity and selected diet/genotype need controls; no human hard-endpoint trial establishes broad primacy.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 38 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C39", "text": "Human ACVD metagenomics identifies taxa and functions associated with disease after drug analyses. Case-control disease status remains susceptible to reverse causation and residual confounding.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 39 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C40", "text": "Antibiotics suppress isotope-labeled choline-derived TMAO with recovery after withdrawal; higher TMAO predicts cardiovascular events. Production causality is established; cardiovascular disease causality is not tested by the biomarker intervention.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 40 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C41", "text": "Carnitine feeding increases microbial TMAO and mouse atherosclerosis, attenuated by microbial suppression; human challenge is diet-dependent. Broad antibiotics and administered substrates do not isolate endogenous human cardiovascular dependency.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 41 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C42", "text": "Dietary sugar displaces Th17-inducing microbes; microbial/immune restoration protects against mouse metabolic syndrome. Diet, microbes and host immunity interact; no autonomous microbial initiator or general human implication is established.", "carries_number": true, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 42 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C43", "text": "Defined Clostridium strains induce colonic Tregs and protect against experimental colitis and systemic IgE responses. Selected mouse immune contexts do not establish primary human autoimmune disease causes.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 43 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C44", "text": "MS disease-modifying treatment groups have distinct microbial composition and predicted functions. Treatment is not randomized here; warns about medication effects without proving microbial irrelevance.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 44 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C45", "text": "Single segmented filamentous bacterium induces mucosal Th17 cells and pathogen resistance. Mucosal physiology is distinct from systemic disease initiation; disease relevance is tested separately.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 45 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C46", "text": "MS-associated strains alter T-cell responses and patient-donor transfer exacerbates induced mouse autoimmune encephalomyelitis. Challenge-induced recipient disease and ex vivo human cells do not establish human MS initiation. Linked erratum attached.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC4" ], "source_ns": [ 46 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C47", "text": "Placebo-controlled PD FMT trial finds no primary clinical benefit despite stronger donor-dependent microbiota changes. Negative regimen-specific test is not a positive threshold crossing and does not exclude every strain or intervention.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 47 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C48", "text": "Placebo-controlled sporadic ALS FMT changes community features without slowing ALSFRS-R decline. Small trial cannot exclude modest effects; constipation or mood improvements do not establish neurodegeneration modification.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 48 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C49", "text": "Randomized PD oral FMT reports improved symptom scores and GI measures compared with placebo. Small trial and medication interactions require replication; symptomatic change is distinct from disease initiation or neuron preservation.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 49 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C50", "text": "Defined L. reuteri combination improves social functioning in ASD while overall autism severity and community composition do not change. Pilot selected-domain benefit does not establish overall ASD treatment, microbial-composition primacy or strain-specific human efficacy.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 50 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C51", "text": "Small blinded fresh-colonoscopic FMT trial reports improved PD motor, nonmotor and constipation scores over short follow-up. Multiple symptom measures and small single-center sample do not establish neuroprotection or broad microbial primacy.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 51 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C52", "text": "GUT-PARFECT compares donor with autologous FMT and reports mild off-medication motor benefit over twelve months. Small stage-defined cohort, baseline imbalance and comparator effects constrain generalization; symptomatic benefit is not neuron-preservation proof.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 52 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Methods:paragraph3, 1:Methods:paragraph9, 1:Methods:paragraph11, 2:Results:paragraph2, 2:Results:paragraph5, 2:Results:paragraph12. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C53", "text": "Depression-donor communities induce anhedonia/anxiety-like behavior and altered tryptophan metabolism in depleted rats. Recipient behavior is not human depressive illness; crude community transfer leaves diet/drug and strain identity unresolved.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC4" ], "source_ns": [ 53 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C54", "text": "MDD-donor microbiota induces mouse depression-like behavior with metabolic changes. Germ-free recipient physiology and donor confounding restrict inference to human disease primacy.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC4" ], "source_ns": [ 54 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C55", "text": "Randomized JB-1 crossover finds no stress, cognitive, inflammatory or HPA benefit in healthy men. Healthy men are a translational comparator, not a disease-cohort test; null does not exclude effects in prospectively defined disorders.", "carries_number": true, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 55 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C56", "text": "Randomized lean-donor versus autologous FMT improves short-term clamp insulin sensitivity in metabolic syndrome. Small short-term physiology endpoint does not show durable prevention, strain identity or broad primacy. Linked erratum without supplied PMID retained.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 56 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C57", "text": "Randomized vancomycin versus amoxicillin changes microbiota/bile acids and lowers clamp insulin sensitivity. No placebo and broad drug actions constrain microbial specificity; not a hard disease-trajectory endpoint.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 57 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C58", "text": "Placebo-controlled antibiotics substantially alter microbiota/metabolites without changing measured metabolic health or later insulin sensitivity. Regimen-specific null despite community change; no claim that every microbial factor is dispensable. Search-linked erratum is attached.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 58 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C59", "text": "Lean-donor FMT improves insulin sensitivity at six weeks but not eighteen weeks; baseline composition predicts response. Predictor must be validated prospectively; responders cannot define the claimed scope after outcomes.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 59 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C60", "text": "Vegan-donor FMT changes community toward donor profile in some recipients without changing TMAO production or vascular-inflammation measures. Small short follow-up trial; altered composition without functional change does not establish systemic causality.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 60 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C61", "text": "FMT-TRIM achieves persistent donor engraftment without significant clamp insulin-sensitivity or body-composition benefit. Small pilot with mild insulin resistance and no paired dietary intervention; does not exclude modest or substrate-dependent effects.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 61 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C62", "text": "Australian autism study detects little direct diagnostic microbiome association while diet/stool traits account for observed relationships. Cross-sectional mediation does not prove all gut-brain contributions absent; linked correction retained.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 62 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C63", "text": "Stool consistency correlates with richness, enterotypes and taxa including Akkermansia. Bristol score is a proxy; direct temporal transit-to-community causation is not isolated.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 63 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C64", "text": "MS-discordant twin transfer increases spontaneous autoimmunity in transgenic recipients; IL-10 interruption changes protected recipients. Host autoreactive genotype is essential context; transfer is not endogenous human MS initiation.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC4" ], "source_ns": [ 64 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C65", "text": "Commensal flora and host myelin autoantigen cooperate in spontaneous autoimmune demyelination in a defined mouse model. Host autoreactive repertoire and antigen context constrain generalization; microbiota is not an autonomous human initiator.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 65 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C66", "text": "Dietary choline/TMAO and microbial suppression alter mouse foam-cell accumulation and atherosclerosis, with human metabolite-risk association. Hyperlipidemic mouse genotype and dietary exposure define scope; observational clinical metabolite risk is distinct from causal prevention.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC4" ], "source_ns": [ 66 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "C67", "text": "Single SFB colonization reinstates Th17/autoantibody responses and arthritis in germ-free K/BxN mice; IL-17 neutralization prevents disease. Autoreactive host genotype is prerequisite; single strain is causal within this mouse context, not across human autoimmunity.", "carries_number": true, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 67 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-09", "note": "" }, { "id": "CSC1", "text": "Disease-associated community features recur, but stool consistency, medication and quantitative measurement substantially alter interpretation; association alone is Β.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 6, 9, 13, 15, 26, 27, 28, 29, 30, 31, 32, 33, 35, 36, 39, 44, 46, 53, 54, 62, 63, 64, 66 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-09", "note": "" }, { "id": "CSC2", "text": "Defined microbial addition/rescue, host-pathway interruption and nonlethal microbial-enzyme inhibition converge on functional rodent effects with distinct failure modes. Genotype, diet and developmental timing remain prespecified boundaries.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 3, 9, 10, 11, 12, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 37, 38, 41, 42, 43, 45, 46, 53, 54, 64, 65, 66, 67 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-09", "note": "" }, { "id": "CSC3", "text": "Human FMT in treated cirrhosis alters recurrence/cognition, with phase2 placebo-controlled evidence and weaker earlier studies. Metabolic and PD trials are heterogeneous and ALS is negative; a context-specific contribution is supported, not one mechanism across disorders.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 1, 2, 3, 4, 5, 6, 7, 12, 14, 34, 37, 40, 41, 47, 48, 49, 50, 51, 52, 55, 56, 57, 58, 59, 60, 61 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-09", "note": "" }, { "id": "CSC4", "text": "Diet, host genotype, treatment and transit can precede microbial changes. Community engraftment or changed abundance can occur without functional benefit; targeted products can benefit without changing overall composition. No broad human upstream-primacy contrast closes these alternatives.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 44, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-09", "note": "" }, { "id": "CH", "text": "Microbial causality is established in defined animal contexts and some human interventions; broad human compositional primacy remains unestablished.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 67, 4, 47, 62, 61 ], "verification": "verified", "verified_against": "Bounded synthesis of examined sources; score is adjudication.", "verified_on": "2026-10-09", "note": "" } ], "citation_ledger": [ { "n": 1, "citation": "Wang Z, Bergeron N, Levison BS et al. Impact of chronic dietary red meat, white meat, or non-meat protein on trimethylamine N-oxide metabolism and renal excretion in healthy men and women. European heart journal. 2019.", "tier": "A", "kind": "rct", "pmid": "30535398", "doi": "10.1093/eurheartj/ehy799", "url": "https://pubmed.ncbi.nlm.nih.gov/30535398/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID30535398", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C1", "CSC3", "CSC4" ] }, { "n": 2, "citation": "Depommier C, Everard A, Druart C et al. Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study. Nature medicine. 2019.", "tier": "A", "kind": "rct", "pmid": "31263284", "doi": "10.1038/s41591-019-0495-2", "url": "https://pubmed.ncbi.nlm.nih.gov/31263284/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID31263284", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:Main text:paragraph1, 2:Main text:paragraph3, 2:Main text:paragraph5, 2:Main text:paragraph12, 2:Main text:paragraph13, 2:Main text:paragraph14. No complete-paper or supplement audit claimed.", "carries_claims": [ "C2", "CSC3", "CSC4" ] }, { "n": 3, "citation": "Plovier H, Everard A, Druart C et al. A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice. Nature medicine. 2017.", "tier": "A", "kind": "rct", "pmid": "27892954", "doi": "10.1038/nm.4236", "url": "https://pubmed.ncbi.nlm.nih.gov/27892954/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID27892954", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C3", "CSC2", "CSC3" ] }, { "n": 4, "citation": "Bajaj JS, Fagan A, Gavis EA et al. Microbiota transplant for hepatic encephalopathy in cirrhosis: The THEMATIC trial. Journal of hepatology. 2025.", "tier": "A", "kind": "rct", "pmid": "39800192", "doi": "10.1016/j.jhep.2024.12.047", "url": "https://pubmed.ncbi.nlm.nih.gov/39800192/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "THEMATIC-NCT03796598", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C4", "CSC3", "CSC4", "CH" ] }, { "n": 5, "citation": "Bajaj JS, Kassam Z, Fagan A et al. Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: A randomized clinical trial. Hepatology (Baltimore, Md.). 2017.", "tier": "A", "kind": "rct", "pmid": "28586116", "doi": "10.1002/hep.29306", "url": "https://pubmed.ncbi.nlm.nih.gov/28586116/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID28586116", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:EXPERIMENTAL PROCEDURES:paragraph1, 0:EXPERIMENTAL PROCEDURES:paragraph4, 2:RESULTS::paragraph0, 2:RESULTS::paragraph1, 2:RESULTS::paragraph3, 2:RESULTS::paragraph4. No complete-paper or supplement audit claimed.", "carries_claims": [ "C5", "CSC3", "CSC4" ] }, { "n": 6, "citation": "Bajaj JS, Fagan A, Sterling RK et al. The multi-omic basis for hepatic encephalopathy recurrence: Analysis of the THEMATIC trial. JHEP reports : innovation in hepatology. 2026.", "tier": "A", "kind": "primary", "pmid": "41503571", "doi": "10.1016/j.jhepr.2025.101634", "url": "https://pubmed.ncbi.nlm.nih.gov/41503571/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "THEMATIC-NCT03796598", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C6", "CSC1", "CSC3", "CSC4" ] }, { "n": 7, "citation": "Bajaj JS, Salzman NH, Acharya C et al. Fecal Microbial Transplant Capsules Are Safe in Hepatic Encephalopathy: A Phase 1, Randomized, Placebo-Controlled Trial. Hepatology (Baltimore, Md.). 2019.", "tier": "A", "kind": "rct", "pmid": "31038755", "doi": "10.1002/hep.30690", "url": "https://pubmed.ncbi.nlm.nih.gov/31038755/", "status_flags": [ "ErratumIn: PMID33464567" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID31038755", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C7", "CSC3", "CSC4" ] }, { "n": 8, "citation": "David LA, Maurice CF, Carmody RN et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014.", "tier": "A", "kind": "primary", "pmid": "24336217", "doi": "10.1038/nature12820", "url": "https://pubmed.ncbi.nlm.nih.gov/24336217/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID24336217", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C8", "CSC4" ] }, { "n": 9, "citation": "Koh A, Molinaro A, Ståhlman M et al. Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1. Cell. 2018.", "tier": "A", "kind": "primary", "pmid": "30401435", "doi": "10.1016/j.cell.2018.09.055", "url": "https://pubmed.ncbi.nlm.nih.gov/30401435/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID30401435", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C9", "CSC1", "CSC2", "CSC4" ] }, { "n": 10, "citation": "Ridaura VK, Faith JJ, Rey FE et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science (New York, N.Y.). 2013.", "tier": "A", "kind": "primary", "pmid": "24009397", "doi": "10.1126/science.1241214", "url": "https://pubmed.ncbi.nlm.nih.gov/24009397/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID24009397", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 3:Phenotypes produced by bacterial culture collections, 7:Diet-specific effects. No complete-paper or supplement audit claimed.", "carries_claims": [ "C10", "CSC2", "CSC4" ] }, { "n": 11, "citation": "Turnbaugh PJ, Ley RE, Mahowald MA et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006.", "tier": "A", "kind": "primary", "pmid": "17183312", "doi": "10.1038/nature05414", "url": "https://pubmed.ncbi.nlm.nih.gov/17183312/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID17183312", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C11", "CSC2", "CSC4" ] }, { "n": 12, "citation": "Wu H, Esteve E, Tremaroli V et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nature medicine. 2017.", "tier": "A", "kind": "rct", "pmid": "28530702", "doi": "10.1038/nm.4345", "url": "https://pubmed.ncbi.nlm.nih.gov/28530702/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID28530702", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C12", "CSC2", "CSC3", "CSC4" ] }, { "n": 13, "citation": "Ley RE, Bäckhed F, Turnbaugh P et al. Obesity alters gut microbial ecology. Proceedings of the National Academy of Sciences of the United States of America. 2005.", "tier": "A", "kind": "primary", "pmid": "16033867", "doi": "10.1073/pnas.0504978102", "url": "https://pubmed.ncbi.nlm.nih.gov/16033867/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID16033867", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C13", "CSC1", "CSC4" ] }, { "n": 14, "citation": "Meijnikman AS, Davids M, Herrema H et al. Microbiome-derived ethanol in nonalcoholic fatty liver disease. Nature medicine. 2022.", "tier": "A", "kind": "primary", "pmid": "36216942", "doi": "10.1038/s41591-022-02016-6", "url": "https://pubmed.ncbi.nlm.nih.gov/36216942/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID36216942", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C14", "CSC3", "CSC4" ] }, { "n": 15, "citation": "Andrikopoulos P, Aron-Wisnewsky J, Chakaroun R et al. Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamine N-oxide. Nature communications. 2023.", "tier": "A", "kind": "primary", "pmid": "37730687", "doi": "10.1038/s41467-023-39824-4", "url": "https://pubmed.ncbi.nlm.nih.gov/37730687/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID37730687", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C15", "CSC1", "CSC2", "CSC4" ] }, { "n": 16, "citation": "De Vadder F, Kovatcheva-Datchary P, Goncalves D et al. Microbiota-generated metabolites promote metabolic benefits via gut-brain neural circuits. Cell. 2014.", "tier": "A", "kind": "primary", "pmid": "24412651", "doi": "10.1016/j.cell.2013.12.016", "url": "https://pubmed.ncbi.nlm.nih.gov/24412651/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID24412651", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C16", "CSC2", "CSC4" ] }, { "n": 17, "citation": "Velagapudi VR, Hezaveh R, Reigstad CS et al. The gut microbiota modulates host energy and lipid metabolism in mice. Journal of lipid research. 2010.", "tier": "A", "kind": "primary", "pmid": "20040631", "doi": "10.1194/jlr.M002774", "url": "https://pubmed.ncbi.nlm.nih.gov/20040631/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID20040631", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C17", "CSC2" ] }, { "n": 18, "citation": "Maini Rekdal V, Bess EN, Bisanz JE et al. Discovery and inhibition of an interspecies gut bacterial pathway for Levodopa metabolism. Science (New York, N.Y.). 2019.", "tier": "A", "kind": "primary", "pmid": "31196984", "doi": "10.1126/science.aau6323", "url": "https://pubmed.ncbi.nlm.nih.gov/31196984/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID31196984", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C18", "CSC2", "CSC4" ] }, { "n": 19, "citation": "Sampson TR, Debelius JW, Thron T et al. Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson's Disease. Cell. 2016.", "tier": "A", "kind": "primary", "pmid": "27912057", "doi": "10.1016/j.cell.2016.11.018", "url": "https://pubmed.ncbi.nlm.nih.gov/27912057/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID27912057", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph5, 1:Results:paragraph8, 1:Results:paragraph12. No complete-paper or supplement audit claimed.", "carries_claims": [ "C19", "CSC2", "CSC4" ] }, { "n": 20, "citation": "Yano JM, Yu K, Donaldson GP et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. 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EClinicalMedicine. 2024.", "tier": "A", "kind": "primary", "pmid": "38686220", "doi": "10.1016/j.eclinm.2024.102563", "url": "https://pubmed.ncbi.nlm.nih.gov/38686220/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID38686220", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Methods:paragraph3, 1:Methods:paragraph9, 1:Methods:paragraph11, 2:Results:paragraph2, 2:Results:paragraph5, 2:Results:paragraph12. No complete-paper or supplement audit claimed.", "carries_claims": [ "C52", "CSC3", "CSC4" ] }, { "n": 53, "citation": "Kelly JR, Borre Y, O' Brien C et al. Transferring the blues: Depression-associated gut microbiota induces neurobehavioural changes in the rat. Journal of psychiatric research. 2016.", "tier": "A", "kind": "primary", "pmid": "27491067", "doi": "10.1016/j.jpsychires.2016.07.019", "url": "https://pubmed.ncbi.nlm.nih.gov/27491067/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID27491067", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C53", "CSC1", "CSC2", "CSC4" ] }, { "n": 54, "citation": "Zheng P, Zeng B, Zhou C et al. Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host's metabolism. 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Gastroenterology. 2012.", "tier": "A", "kind": "rct", "pmid": "22728514", "doi": "10.1053/j.gastro.2012.06.031", "url": "https://pubmed.ncbi.nlm.nih.gov/22728514/", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID22728514", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C56", "CSC3", "CSC4" ] }, { "n": 57, "citation": "Vrieze A, Out C, Fuentes S et al. Impact of oral vancomycin on gut microbiota, bile acid metabolism, and insulin sensitivity. 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Journal of the American Heart Association. 2018.", "tier": "A", "kind": "rct", "pmid": "29581220", "doi": "10.1161/JAHA.117.008342", "url": "https://pubmed.ncbi.nlm.nih.gov/29581220/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID29581220", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C60", "CSC3", "CSC4" ] }, { "n": 61, "citation": "Yu EW, Gao L, Stastka P et al. Fecal microbiota transplantation for the improvement of metabolism in obesity: The FMT-TRIM double-blind placebo-controlled pilot trial. 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Gut. 2016.", "tier": "A", "kind": "primary", "pmid": "26069274", "doi": "10.1136/gutjnl-2015-309618", "url": "https://pubmed.ncbi.nlm.nih.gov/26069274/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-09", "status_checked_on": "2026-10-09", "study_id": "PMID26069274", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C63", "CSC1", "CSC4" ] }, { "n": 64, "citation": "Berer K, Gerdes LA, Cekanaviciute E et al. Gut microbiota from multiple sclerosis patients enables spontaneous autoimmune encephalomyelitis in mice. 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These are different scopes, not a refutation of the microbiome." }, "score_after": { "hsef_level": "Γ", "hsef_descriptor": "Mechanistically plausible, partial system support", "confidence": "Moderate", "confidence_rationale": "Evidence density and reproducibility set the confidence, not correctness and not reviewer access: defined rodent perturbations replicate across distinct mechanisms, while the human record is mixed and the transfer literature shows demonstrated rather than hypothetical reproducibility problems - engraftment without functional effect, and housing- and diet-dependent reversals - with heterogeneous products, comparators and endpoints across the 67 reports. Access depth is recorded per ledger row and is not a determinant of the band.", "rests_on_non_peer_reviewed_work": false, "rationale": "SC4 is the preregistered human-primacy gate. Transfers, defined strains and microbial products show real bounded contributions, and HE intervention crosses human contribution thresholds, but none establishes composition as the primary upstream target across systemic and neurobehavioural disease. SC1 association is Β, bounded rodent causality SC2 Ζ, human contribution SC3 Ε, broad primacy SC4 Γ. 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