{ "$schema_version": "5.3", "review_mode": "fresh", "claim_restatement": { "index_wording": "Gut Microbiome as Master Regulator of Health", "entry_form": "phenomenon", "gradeable_restatement": "The gut microbiome operates as an autonomous upstream master regulator of human health across metabolic, oncological, psychiatric and immunological systems.", "restatement_required": true, "split_into": [], "parent_claim": null, "scope_qualifiers": [ { "qualifier": "Species, genotype, baseline disease, diet, dose and timing", "determinable_before_outcome": true, "determined_from": "Enrollment and experimental design, before results; no responder-defined scope.", "action": "retained" } ] }, "hypothesis": { "name": "Gut Microbiome as Master Regulator of Health", "central_claim": "The gut microbiome operates as an autonomous upstream master regulator of human health across metabolic, oncological, psychiatric and immunological systems.", "proposed_mechanism": "The gut microbiome operates as an autonomous upstream master regulator of human health across metabolic, oncological, psychiatric and immunological systems.", "claimed_scope": "multi-system human health", "claimed_level": [ "progression" ], "is_conjunctive": true, "conjunctive_note": "SC4 matches the broad central claim; recipient-animal and depleted-CDI-niche results remain separate. SC3 wording tests causal restoration rather than incorrectly presuming every intact microbiome is necessary." }, "rubric_routing": { "primary_rubric": "04-microbiome-systemic.md", "secondary_rubrics": [], "index_notes_applied": [ "SC4 matches the broad central claim; recipient-animal and depleted-CDI-niche results remain separate. SC3 wording tests causal restoration rather than incorrectly presuming every intact microbiome is necessary." ], "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 reproducibly between health and disease across systemic conditions.", "subclaim_type": "existence", "scope": "human observational disease cohorts", "claimed_scope": "human observational disease cohorts", "governing_rubric": "04-microbiome-systemic.md", "key_evidence_anchor": "Confounder-controlled reproducible composition/function differences", "hsef_level": "Β", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "SC1 is reproducible association. Medication, stool consistency, diet and disease-state adjustment change the signature; observational replication cannot identify causal direction [42–46]." }, { "id": "SC2", "statement": "Defined microbial manipulation causally moves phenotype in rodents.", "subclaim_type": "sufficiency", "scope": "specified gnotobiotic and conventional rodent settings", "claimed_scope": "specified gnotobiotic and conventional rodent settings", "governing_rubric": "04-microbiome-systemic.md", "key_evidence_anchor": "Defined strains, transfer, subtraction and rescue", "hsef_level": "Ζ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "SC2 reaches Ζ within specified rodent contexts. Defined bacteria/metabolites, transfer and rescue converge with host receptor/enhancer or immune-cell epistasis; diet and species-negative controls map limits [22,23,25,47,49,53,58]. This is causal modulation, not endogenous human primacy." }, { "id": "SC3", "statement": "Microbiota restoration causally restores colonization resistance in recurrent C. difficile infection.", "subclaim_type": "mechanism", "scope": "humans with recurrent CDI following antibiotics", "claimed_scope": "humans with recurrent CDI following antibiotics", "governing_rubric": "04-microbiome-systemic.md", "key_evidence_anchor": "Clinical recurrence outcomes, community restoration and defined product trials", "hsef_level": "Ζ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "SC3 reaches Ζ for recurrent post-antibiotic CDI restoration. Randomized spore/defined-consortium clinical outcomes, live-versus-filtered component discrimination, and a distinct strain/bile-acid rescue route converge [1,3,7,59]. The human precise mediator and universally required strain remain unresolved." }, { "id": "SC4", "statement": "The microbiome is an autonomous upstream driver of systemic human health.", "subclaim_type": "primacy", "scope": "human metabolic, oncological, psychiatric and immunological systems", "claimed_scope": "human metabolic, oncological, psychiatric and immunological systems", "governing_rubric": "04-microbiome-systemic.md", "key_evidence_anchor": "Defined microbial manipulation with clinical phenotypes, mediation and diet/host/medication controls", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "SC4 remains Γ for autonomous upstream multi-system primacy. UC treatment causality and context-specific model pathways are real, but no selective intervention demonstrates independence from substrate, host physiology or concurrent drugs across the claimed systems [9–15,26–32,55–60]." } ], "aggregation_rule": "scope-matched", "aggregation_preregistered": true, "aggregation_rationale": "SC4 matches the broad central claim; recipient-animal and depleted-CDI-niche results remain separate. SC3 wording tests causal restoration rather than incorrectly presuming every intact microbiome is necessary.", "primary_subclaim_id": "SC4", "aggregation_derivation": "The preregistered scope-matched SC4 gate returns Γ. Positive recurrent-CDI restoration reaches Ζ and selected UC packages establish bounded human causal benefit; neither demonstrates autonomous multi-system primacy. Weakest-link would return Β because SC1 deliberately asks an observational existence question.", "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": "M3", "is_nominal": false, "name": "Niche-depletion-specific causality", "core_claim": "Microbial restoration repairs a depleted colonization-resistance niche; level refers to recurrent CDI.", "explains_what_nominal_does_not": "Microbial restoration repairs a depleted colonization-resistance niche; level refers to recurrent CDI.", "strongest_supporting_evidence": [ "SER-109, VE303 and strain rescue support this defined scope [1,3,59]." ], "strongest_contradictory_evidence": [ "UC benefits show that this model is not an exhaustive account of all microbial effects [26–31]." ], "hsef_level_for_this_model": "Ζ", "rationale": "SER-109, VE303 and strain rescue support this defined scope [1,3,59]. UC benefits show that this model is not an exhaustive account of all microbial effects [26–31]." }, { "rank_in_tournament": 2, "model_id": "M2", "is_nominal": false, "name": "Diet/substrate regulation", "core_claim": "Diet changes substrate availability and host/microbial outputs.", "explains_what_nominal_does_not": "Diet changes substrate availability and host/microbial outputs.", "strongest_supporting_evidence": [ "Dietary interventions and diet-dependent twin-community rescue demonstrate conditions [11,13,49,60]." ], "strongest_contradictory_evidence": [ "A direct diet effect does not prove that microbes mediate every dietary health benefit." ], "hsef_level_for_this_model": "Ε", "rationale": "Dietary interventions and diet-dependent twin-community rescue demonstrate conditions [11,13,49,60]. A direct diet effect does not prove that microbes mediate every dietary health benefit." }, { "rank_in_tournament": 3, "model_id": "M4", "is_nominal": false, "name": "Host-genome/physiology gating", "core_claim": "Host receptors, immune cells and physiological niches determine microbial effects in models.", "explains_what_nominal_does_not": "Host receptors, immune cells and physiological niches determine microbial effects in models.", "strongest_supporting_evidence": [ "RGMb, Tfh, eosinophil and CNS1 contrasts demonstrate host gating [25,51,53,58]." ], "strongest_contradictory_evidence": [ "No single host pathway explains all human systemic conditions." ], "hsef_level_for_this_model": "Ε", "rationale": "RGMb, Tfh, eosinophil and CNS1 contrasts demonstrate host gating [25,51,53,58]. No single host pathway explains all human systemic conditions." }, { "rank_in_tournament": 4, "model_id": "M5", "is_nominal": false, "name": "Disease/medication-to-microbiome reverse causation", "core_claim": "Disease, diet selection and drugs can create diagnostic signatures.", "explains_what_nominal_does_not": "Disease, diet selection and drugs can create diagnostic signatures.", "strongest_supporting_evidence": [ "Medication stratification and ASD dietary associations support this direction [43,44,46]." ], "strongest_contradictory_evidence": [ "Observational direction remains imperfectly identified; reverse causation cannot explain controlled microbial rescue." ], "hsef_level_for_this_model": "Β", "rationale": "Medication stratification and ASD dietary associations support this direction [43,44,46]. Observational direction remains imperfectly identified; reverse causation cannot explain controlled microbial rescue." }, { "rank_in_tournament": 5, "model_id": "M1", "is_nominal": true, "name": "Autonomous microbial master regulator", "core_claim": "One autonomous microbial system sits upstream of human systemic health.", "explains_what_nominal_does_not": "One autonomous microbial system sits upstream of human systemic health.", "strongest_supporting_evidence": [ "Transferability, human treatment benefits and defined pathways make microbial causation plausible." ], "strongest_contradictory_evidence": [ "Diet-dependent rescue, pasteurized products, host epistasis, null primary endpoints and treatment dependence do not support autonomy [9,25,49,55–58]." ], "hsef_level_for_this_model": "Γ", "rationale": "Transferability, human treatment benefits and defined pathways make microbial causation plausible. Diet-dependent rescue, pasteurized products, host epistasis, null primary endpoints and treatment dependence do not support autonomy [9,25,49,55–58]." } ], "tournament_summary": "Descriptive comparison; does not modify the nominal score. Factorially manipulate a defined microbial function and substrate supply with matched host strata; a substrate-dependent effect favors conditional regulation over autonomy. Ranking of a narrow CDI model is not a claim that CDI explains systemic health.", "study_separating_rank1_from_rank2": "Factorially manipulate a defined microbial function and substrate supply with matched host strata; a substrate-dependent effect favors conditional regulation over autonomy. Ranking of a narrow CDI model is not a claim that CDI explains systemic health.", "nominal_wins_only_by_funding_artifact": false, "level_unchanged_by_tournament": true }, "evidence_inventory": [ { "n": 1, "pmid": "35045228", "title": "SER-109, an Oral Microbiome Therapy for Recurrent Clostridioides difficile Infection.", "citation": "Feuerstadt P, Louie TJ, Lashner B et al. SER-109, an Oral Microbiome Therapy for Recurrent Clostridioides difficile Infection. The New England journal of medicine. 2022.", "doi": "10.1056/NEJMoa2106516", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/35045228/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35045228/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "NCT03183128", "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": [ "M1" ], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Post-antibiotic SER-109 reduced recurrent CDI at 8 weeks in the randomized trial.", "what_it_does_not_show": "Restoration in a depleted niche does not establish autonomous regulation of systemic health.", "confounders_present": [ "Restoration in a depleted niche does not establish autonomous regulation of systemic health." ], "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": [] } }, { "n": 2, "pmid": "40523286", "title": "Fecal Microbiota Transplantation Versus Vancomycin for Primary Clostridioides difficile Infection : A Randomized Controlled Trial.", "citation": "Juul FE, Bretthauer M, Johnsen PH et al. Fecal Microbiota Transplantation Versus Vancomycin for Primary Clostridioides difficile Infection : A Randomized Controlled Trial. Annals of internal medicine. 2025.", "doi": "10.7326/ANNALS-24-03285", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/40523286/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40523286/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID40523286", "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": "mixed", "what_it_shows": "Primary-CDI FMT met the specified noninferiority comparison against vancomycin.", "what_it_does_not_show": "The 25-point margin and rescue therapy limit claims of superiority; this is primary CDI rather than the exact recurrent-CDI subclaim.", "confounders_present": [ "The 25-point margin and rescue therapy limit claims of superiority; this is primary CDI rather than the exact recurrent-CDI subclaim." ], "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": [] } }, { "n": 3, "pmid": "37060545", "title": "VE303, a Defined Bacterial Consortium, for Prevention of Recurrent Clostridioides difficile Infection: A Randomized Clinical Trial.", "citation": "Louie T, Golan Y, Khanna S et al. VE303, a Defined Bacterial Consortium, for Prevention of Recurrent Clostridioides difficile Infection: A Randomized Clinical Trial. JAMA. 2023.", "doi": "10.1001/jama.2023.4314", "pmcid": "PMC10105904", "url": "https://pubmed.ncbi.nlm.nih.gov/37060545/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37060545/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "NCT03788434", "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" ], "favors_models": [ "M1" ], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "A defined eight-strain VE303 consortium reduced recurrence at the high dose in the phase 2 trial.", "what_it_does_not_show": "Small groups and recurrence definitions require confirmation; the exact mediator was not randomized.", "confounders_present": [ "Small groups and recurrence definitions require confirmation; the exact mediator was not randomized." ], "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": [] } }, { "n": 4, "pmid": "36287379", "title": "Efficacy and Safety of RBX2660 in PUNCH CD3, a Phase III, Randomized, Double-Blind, Placebo-Controlled Trial with a Bayesian Primary Analysis for the Prevention of Recurrent Clostridioides difficile Infection.", "citation": "Khanna S, Assi M, Lee C et al. Efficacy and Safety of RBX2660 in PUNCH CD3, a Phase III, Randomized, Double-Blind, Placebo-Controlled Trial with a Bayesian Primary Analysis for the Prevention of Recurrent Clostridioides difficile Infection. Drugs. 2022.", "doi": "10.1007/s40265-022-01797-x", "pmcid": "PMC9607700", "url": "https://pubmed.ncbi.nlm.nih.gov/36287379/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36287379/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "ErratumIn: PMID36342618" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "RBX-phase2b+PUNCH-CD3-Bayesian", "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" ], "favors_models": [ "M1" ], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "RBX2660 had higher modeled treatment success than placebo following antibiotics.", "what_it_does_not_show": "The Bayesian estimate borrows the phase 2 study and is not an independent replication of that report; linked correction remains attached.", "confounders_present": [ "The Bayesian estimate borrows the phase 2 study and is not an independent replication of that report; linked correction 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": [] } }, { "n": 5, "pmid": "36152636", "title": "Faecal microbiota transplantation for first or second Clostridioides difficile infection (EarlyFMT): a randomised, double-blind, placebo-controlled trial.", "citation": "Baunwall SMD, Andreasen SE, Hansen MM et al. Faecal microbiota transplantation for first or second Clostridioides difficile infection (EarlyFMT): a randomised, double-blind, placebo-controlled trial. The lancet. Gastroenterology & hepatology. 2022.", "doi": "10.1016/S2468-1253(22)00276-X", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/36152636/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36152636/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID36152636", "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" ], "favors_models": [ "M1" ], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Early FMT improved resolution after antibiotics in first or second CDI.", "what_it_does_not_show": "Early stopping and disease-stage differences limit magnitude and recurrent-CDI generalization.", "confounders_present": [ "Early stopping and disease-stage differences limit magnitude and recurrent-CDI generalization." ], "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": [] } }, { "n": 6, "pmid": "29183074", "title": "Effect of Oral Capsule- vs Colonoscopy-Delivered Fecal Microbiota Transplantation on Recurrent Clostridium difficile Infection: A Randomized Clinical Trial.", "citation": "Kao D, Roach B, Silva M et al. Effect of Oral Capsule- vs Colonoscopy-Delivered Fecal Microbiota Transplantation on Recurrent Clostridium difficile Infection: A Randomized Clinical Trial. JAMA. 2017.", "doi": "10.1001/jama.2017.17077", "pmcid": "PMC5820695", "url": "https://pubmed.ncbi.nlm.nih.gov/29183074/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29183074/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID29183074", "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" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "Capsule FMT was noninferior to colonoscopic FMT for preventing recurrence.", "what_it_does_not_show": "Both groups received FMT; the route contrast does not isolate efficacy against no FMT.", "confounders_present": [ "Both groups received FMT; the route contrast does not isolate efficacy against no FMT." ], "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": [] } }, { "n": 7, "pmid": "40997843", "title": "Effects of lyophilised faecal filtrate compared with lyophilised donor stool on Clostridioides difficile recurrence: a multicentre, randomised, double-blinded, non-inferiority trial.", "citation": "Kao D, Wong K, Lee C et al. Effects of lyophilised faecal filtrate compared with lyophilised donor stool on Clostridioides difficile recurrence: a multicentre, randomised, double-blinded, non-inferiority trial. The lancet. Gastroenterology & hepatology. 2025.", "doi": "10.1016/S2468-1253(25)00190-6", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/40997843/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40997843/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID40997843", "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" ], "favors_models": [ "M1" ], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Sterile filtrate failed noninferiority to live donor stool, with lower recurrence-free proportions.", "what_it_does_not_show": "Filtration changes multiple components; failure of noninferiority is not proof that every live organism is necessary.", "confounders_present": [ "Filtration changes multiple components; failure of noninferiority is not proof that every live organism is necessary." ], "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": [] } }, { "n": 8, "pmid": "29617739", "title": "Results From a Randomized, Placebo-Controlled Clinical Trial of a RBX2660-A Microbiota-Based Drug for the Prevention of Recurrent Clostridium difficile Infection.", "citation": "Dubberke ER, Lee CH, Orenstein R et al. Results From a Randomized, Placebo-Controlled Clinical Trial of a RBX2660-A Microbiota-Based Drug for the Prevention of Recurrent Clostridium difficile Infection. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2018.", "doi": "10.1093/cid/ciy259", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/29617739/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29617739/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "RBX-phase2b+PUNCH-CD3-Bayesian", "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" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "The two-dose RBX2660 primary contrast did not meet significance; a one-dose secondary contrast favored treatment.", "what_it_does_not_show": "Secondary and open-label rescue outcomes cannot replace the null primary comparison; this cohort informs the phase 3 Bayesian estimate.", "confounders_present": [ "Secondary and open-label rescue outcomes cannot replace the null primary comparison; this cohort informs the phase 3 Bayesian estimate." ], "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": [] } }, { "n": 9, "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": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID31263284", "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": true, "endogenous": true, "direction": "mixed", "what_it_shows": "Pasteurized Akkermansia improved insulin sensitivity and some metabolic measures in a small human pilot.", "what_it_does_not_show": "Weight and fat changes were not significant; a pasteurized product effect does not establish live-community autonomy.", "confounders_present": [ "Weight and fat changes were not significant; a pasteurized product effect does not establish live-community autonomy." ], "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": [] } }, { "n": 10, "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": "2026-10-04", "status_checked_on": "2026-10-04", "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", "SC4" ], "favors_models": [ "M1" ], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Pasteurized Akkermansia and its membrane protein partially reproduced metabolic benefits in mice.", "what_it_does_not_show": "Human observations in this report concern safety; a protein/TLR2 pathway depends on host machinery.", "confounders_present": [ "Human observations in this report concern safety; a protein/TLR2 pathway depends on host machinery." ], "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": [] } }, { "n": 11, "pmid": "39454570", "title": "Effects of healthy low-carbohydrate diet and time-restricted eating on weight and gut microbiome in adults with overweight or obesity: Feeding RCT.", "citation": "Li L, Li R, Tian Q et al. Effects of healthy low-carbohydrate diet and time-restricted eating on weight and gut microbiome in adults with overweight or obesity: Feeding RCT. Cell reports. Medicine. 2024.", "doi": "10.1016/j.xcrm.2024.101801", "pmcid": "PMC11604488", "url": "https://pubmed.ncbi.nlm.nih.gov/39454570/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39454570/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID39454570", "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 interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "Controlled dietary restriction and timing changed weight and microbial measures.", "what_it_does_not_show": "Diet was manipulated directly; parallel changes do not isolate microbial mediation.", "confounders_present": [ "Diet was manipulated directly; parallel changes do not isolate microbial mediation." ], "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": [] } }, { "n": 12, "pmid": "36948576", "title": "A mechanism by which gut microbiota elevates permeability and inflammation in obese/diabetic mice and human gut.", "citation": "Mishra SP, Wang B, Jain S et al. A mechanism by which gut microbiota elevates permeability and inflammation in obese/diabetic mice and human gut. Gut. 2023.", "doi": "10.1136/gutjnl-2022-327365", "pmcid": "PMC10512000", "url": "https://pubmed.ncbi.nlm.nih.gov/36948576/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36948576/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID36948576", "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": [ "M1" ], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Transfer, ethanolamine metabolism and probiotic rescue linked microbial function to barrier and metabolic phenotypes.", "what_it_does_not_show": "Model rescue supports a defined pathway, not autonomous human multi-system primacy.", "confounders_present": [ "Model rescue supports a defined pathway, not autonomous human multi-system 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": [] } }, { "n": 13, "pmid": "32075887", "title": "Mediterranean diet intervention in overweight and obese subjects lowers plasma cholesterol and causes changes in the gut microbiome and metabolome independently of energy intake.", "citation": "Meslier V, Laiola M, Roager HM et al. Mediterranean diet intervention in overweight and obese subjects lowers plasma cholesterol and causes changes in the gut microbiome and metabolome independently of energy intake. Gut. 2020.", "doi": "10.1136/gutjnl-2019-320438", "pmcid": "PMC7306983", "url": "https://pubmed.ncbi.nlm.nih.gov/32075887/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32075887/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID32075887", "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 interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "An isocaloric Mediterranean dietary intervention changed cholesterol and microbial/metabolic profiles.", "what_it_does_not_show": "Direct dietary effects and correlated microbiome changes do not identify the mediator.", "confounders_present": [ "Direct dietary effects and correlated microbiome changes do not identify the mediator." ], "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": [] } }, { "n": 14, "pmid": "39879980", "title": "Akkermansia muciniphila supplementation in patients with overweight/obese type 2 diabetes: Efficacy depends on its baseline levels in the gut.", "citation": "Zhang Y, Liu R, Chen Y et al. Akkermansia muciniphila supplementation in patients with overweight/obese type 2 diabetes: Efficacy depends on its baseline levels in the gut. Cell metabolism. 2025.", "doi": "10.1016/j.cmet.2024.12.010", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/39879980/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39879980/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID39879980", "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": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "The Akkermansia T2D trial had overall null between-group weight/HbA1c contrasts, with benefits in a low-baseline-abundance subgroup and accompanying mouse work.", "what_it_does_not_show": "Subgroup findings require prospective confirmation; baseline community dependence contradicts simple universal response.", "confounders_present": [ "Subgroup findings require prospective confirmation; baseline community dependence contradicts simple universal response." ], "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": [] } }, { "n": 15, "pmid": "36704100", "title": "Fecal microbiota transplantation reverses insulin resistance in type 2 diabetes: A randomized, controlled, prospective study.", "citation": "Wu Z, Zhang B, Chen F et al. Fecal microbiota transplantation reverses insulin resistance in type 2 diabetes: A randomized, controlled, prospective study. Frontiers in cellular and infection microbiology. 2022.", "doi": "10.3389/fcimb.2022.1089991", "pmcid": "PMC9872724", "url": "https://pubmed.ncbi.nlm.nih.gov/36704100/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36704100/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID36704100", "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": [ "M1" ], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "A small short-term FMT/metformin comparison reported improvements in metabolic indices.", "what_it_does_not_show": "Limited size, duration and comparator structure do not establish durable broad human health benefit.", "confounders_present": [ "Limited size, duration and comparator structure do not establish durable broad human health 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": [] } }, { "n": 16, "pmid": "29097494", "title": "Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors.", "citation": "Routy B, Le Chatelier E, Derosa L et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science (New York, N.Y.). 2018.", "doi": "10.1126/science.aan3706", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/29097494/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29097494/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID29097494", "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": [ "M1" ], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Responder transfer and Akkermansia rescue enhanced PD-1 effects in mice with an IL-12-dependent route.", "what_it_does_not_show": "Human antibiotic and taxon associations remain confounded; active anticancer treatment and host immunity gate the effect.", "confounders_present": [ "Human antibiotic and taxon associations remain confounded; active anticancer treatment and host immunity gate the 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": [] } }, { "n": 17, "pmid": "29097493", "title": "Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients.", "citation": "Gopalakrishnan V, Spencer CN, Nezi L et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science (New York, N.Y.). 2018.", "doi": "10.1126/science.aan4236", "pmcid": "PMC5827966", "url": "https://pubmed.ncbi.nlm.nih.gov/29097493/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29097493/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID29097493", "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": [ "M1" ], "evidence_class": "Moderate", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Melanoma responder communities were associated with response and transferred favorable immune/tumor phenotypes into mice.", "what_it_does_not_show": "The human observational comparison does not establish the microbial cause of patient benefit.", "confounders_present": [ "The human observational comparison does not establish the microbial cause of patient 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": [] } }, { "n": 18, "pmid": "34941392", "title": "Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response.", "citation": "Spencer CN, McQuade JL, Gopalakrishnan V et al. Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response. Science (New York, N.Y.). 2021.", "doi": "10.1126/science.aaz7015", "pmcid": "PMC8970537", "url": "https://pubmed.ncbi.nlm.nih.gov/34941392/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34941392/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID34941392", "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", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Dietary fiber associated with human progression-free survival; low fiber or probiotics impaired ICI response in models.", "what_it_does_not_show": "The human diet comparison is observational and the model effect depends on diet and immunotherapy.", "confounders_present": [ "The human diet comparison is observational and the model effect depends on diet and immunotherapy." ], "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": [] } }, { "n": 19, "pmid": "40639377", "title": "Exercise-induced microbiota metabolite enhances CD8 T cell antitumor immunity promoting immunotherapy efficacy.", "citation": "Phelps CM, Willis NB, Duan T et al. Exercise-induced microbiota metabolite enhances CD8 T cell antitumor immunity promoting immunotherapy efficacy. Cell. 2025.", "doi": "10.1016/j.cell.2025.06.018", "pmcid": "PMC12258965", "url": "https://pubmed.ncbi.nlm.nih.gov/40639377/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40639377/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID40639377", "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": [ "M1" ], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Exercise-associated microbial formate was tested as a required/sufficient contributor to antitumor Tc1 phenotypes, with Nrf2 mediation.", "what_it_does_not_show": "Human formate is a biomarker candidate; exercise and host transcriptional gating remain upstream conditions.", "confounders_present": [ "Human formate is a biomarker candidate; exercise and host transcriptional gating remain upstream conditions." ], "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": [] } }, { "n": 20, "pmid": "33542131", "title": "Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients.", "citation": "Davar D, Dzutsev AK, McCulloch JA et al. Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients. Science (New York, N.Y.). 2021.", "doi": "10.1126/science.abf3363", "pmcid": "PMC8097968", "url": "https://pubmed.ncbi.nlm.nih.gov/33542131/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33542131/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "Davar-FMT-antiPD1", "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": [ "M1" ], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Responder-derived FMT plus anti-PD-1 produced clinical benefit in six of fifteen refractory melanoma patients.", "what_it_does_not_show": "Single-arm drug rechallenge does not isolate the incremental FMT effect or human mediator necessity.", "confounders_present": [ "Single-arm drug rechallenge does not isolate the incremental FMT effect or human mediator 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": [] } }, { "n": 21, "pmid": "33303685", "title": "Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients.", "citation": "Baruch EN, Youngster I, Ben-Betzalel G et al. Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients. Science (New York, N.Y.). 2021.", "doi": "10.1126/science.abb5920", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/33303685/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33303685/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "Baruch-FMT-antiPD1", "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": [ "M1" ], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "FMT with PD-1 reinduction produced responses in three of ten refractory melanoma patients.", "what_it_does_not_show": "The phase 1 single-arm design establishes feasibility and signals, not a controlled causal efficacy estimate.", "confounders_present": [ "The phase 1 single-arm design establishes feasibility and signals, not a controlled causal efficacy estimate." ], "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": [] } }, { "n": 22, "pmid": "26541606", "title": "Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy.", "citation": "Sivan A, Corrales L, Hubert N et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science (New York, N.Y.). 2015.", "doi": "10.1126/science.aac4255", "pmcid": "PMC4873287", "url": "https://pubmed.ncbi.nlm.nih.gov/26541606/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26541606/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID26541606", "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": [ "M1" ], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Cohousing, transfer and Bifidobacterium administration improved mouse tumor immunity and checkpoint efficacy.", "what_it_does_not_show": "Mouse facility/community and immune context limit human generalization.", "confounders_present": [ "Mouse facility/community and immune context limit human generalization." ], "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": [] } }, { "n": 23, "pmid": "32792462", "title": "Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy.", "citation": "Mager LF, Burkhard R, Pett N et al. Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy. Science (New York, N.Y.). 2020.", "doi": "10.1126/science.abc3421", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/32792462/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32792462/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID32792462", "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": [ "M1" ], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Defined bacterial isolates and inosine enhanced checkpoint efficacy in several mouse cancer models through a costimulation-dependent A2A receptor route.", "what_it_does_not_show": "The metabolite requires treatment/barrier and host immune context; it is not an autonomous human master switch.", "confounders_present": [ "The metabolite requires treatment/barrier and host immune context; it is not an autonomous human master switch." ], "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": [] } }, { "n": 24, "pmid": "29302014", "title": "The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients.", "citation": "Matson V, Fessler J, Bao R et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science (New York, N.Y.). 2018.", "doi": "10.1126/science.aao3290", "pmcid": "PMC6707353", "url": "https://pubmed.ncbi.nlm.nih.gov/29302014/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29302014/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID29302014", "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" ], "favors_models": [ "M1" ], "evidence_class": "Moderate", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Baseline melanoma taxa associated with response; responder-derived microbiota improved tumor control in mice.", "what_it_does_not_show": "Human association and recipient sufficiency do not identify endogenous human necessity.", "confounders_present": [ "Human association and recipient sufficiency do not identify endogenous human 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": [] } }, { "n": 25, "pmid": "37138075", "title": "Targeting PD-L2-RGMb overcomes microbiome-related immunotherapy resistance.", "citation": "Park JS, Gazzaniga FS, Wu M et al. Targeting PD-L2-RGMb overcomes microbiome-related immunotherapy resistance. Nature. 2023.", "doi": "10.1038/s41586-023-06026-3", "pmcid": "PMC10219577", "url": "https://pubmed.ncbi.nlm.nih.gov/37138075/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37138075/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID37264079" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID37138075", "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": [ "M1" ], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "PD-L2/RGMb blockade or conditional T-cell RGMb deletion overcame microbial-context ICI resistance in mouse tumors.", "what_it_does_not_show": "The host immune intervention can bypass microbial resistance; correction-body details were not examined.", "confounders_present": [ "The host immune intervention can bypass microbial resistance; correction-body details were not examined." ], "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": [] } }, { "n": 26, "pmid": "28214091", "title": "Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial.", "citation": "Paramsothy S, Kamm MA, Kaakoush NO et al. Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet (London, England). 2017.", "doi": "10.1016/S0140-6736(17)30182-4", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/28214091/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28214091/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID28214091", "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": [ "M1" ], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Intensive multidonor FMT improved the prespecified steroid-free clinical/endoscopic outcome in UC versus placebo.", "what_it_does_not_show": "Crude-community benefit supports a UC treatment package, not strain-specific or autonomous systemic causation.", "confounders_present": [ "Crude-community benefit supports a UC treatment package, not strain-specific or autonomous systemic 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": [] } }, { "n": 27, "pmid": "34863330", "title": "Lyophilised oral faecal microbiota transplantation for ulcerative colitis (LOTUS): a randomised, double-blind, placebo-controlled trial.", "citation": "Haifer C, Paramsothy S, Kaakoush NO et al. Lyophilised oral faecal microbiota transplantation for ulcerative colitis (LOTUS): a randomised, double-blind, placebo-controlled trial. The lancet. Gastroenterology & hepatology. 2022.", "doi": "10.1016/S2468-1253(21)00400-3", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/34863330/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34863330/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID34863330", "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": [ "M1" ], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Oral FMT after antibiotics improved the week-8 UC outcome; a very small maintenance randomization favored continuation.", "what_it_does_not_show": "Early pandemic termination, pretreatment and tiny maintenance groups limit generalization and mechanism.", "confounders_present": [ "Early pandemic termination, pretreatment and tiny maintenance groups limit generalization and 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": [] } }, { "n": 28, "pmid": "25857665", "title": "Fecal Microbiota Transplantation Induces Remission in Patients With Active Ulcerative Colitis in a Randomized Controlled Trial.", "citation": "Moayyedi P, Surette MG, Kim PT et al. Fecal Microbiota Transplantation Induces Remission in Patients With Active Ulcerative Colitis in a Randomized Controlled Trial. Gastroenterology. 2015.", "doi": "10.1053/j.gastro.2015.04.001", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/25857665/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25857665/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID25857665", "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": [ "M1" ], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Weekly donor FMT improved remission versus water enema in active UC.", "what_it_does_not_show": "Donor dependence and early futility stopping complicate precision; the result does not establish universal microbiome primacy.", "confounders_present": [ "Donor dependence and early futility stopping complicate precision; the result does not establish universal microbiome 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": [] } }, { "n": 29, "pmid": "31586453", "title": "Effects of Low FODMAP Diet on Symptoms, Fecal Microbiome, and Markers of Inflammation in Patients With Quiescent Inflammatory Bowel Disease in a Randomized Trial.", "citation": "Cox SR, Lindsay JO, Fromentin S et al. Effects of Low FODMAP Diet on Symptoms, Fecal Microbiome, and Markers of Inflammation in Patients With Quiescent Inflammatory Bowel Disease in a Randomized Trial. Gastroenterology. 2020.", "doi": "10.1053/j.gastro.2019.09.024", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/31586453/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31586453/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID31586453", "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 interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "Low FODMAP diet improved reported adequate symptom relief while reducing some putatively beneficial taxa.", "what_it_does_not_show": "Inflammatory markers and diversity did not differ; health cannot be inferred from a universal favorable-diversity metric.", "confounders_present": [ "Inflammatory markers and diversity did not differ; health cannot be inferred from a universal favorable-diversity metric." ], "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": [] } }, { "n": 30, "pmid": "35973787", "title": "Faecal microbiota transplantation with anti-inflammatory diet (FMT-AID) followed by anti-inflammatory diet alone is effective in inducing and maintaining remission over 1 year in mild to moderate ulcerative colitis: a randomised controlled trial.", "citation": "Kedia S, Virmani S, K Vuyyuru S et al. Faecal microbiota transplantation with anti-inflammatory diet (FMT-AID) followed by anti-inflammatory diet alone is effective in inducing and maintaining remission over 1 year in mild to moderate ulcerative colitis: a randomised controlled trial. Gut. 2022.", "doi": "10.1136/gutjnl-2022-327811", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/35973787/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35973787/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID35973787", "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": [ "M1" ], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "FMT plus anti-inflammatory diet improved UC outcomes versus optimized standard therapy.", "what_it_does_not_show": "The bundled unblinded intervention and continued diet do not isolate FMT or a universal microbial mechanism.", "confounders_present": [ "The bundled unblinded intervention and continued diet do not isolate FMT or a universal microbial 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": [] } }, { "n": 31, "pmid": "30644982", "title": "Effect of Fecal Microbiota Transplantation on 8-Week Remission in Patients With Ulcerative Colitis: A Randomized Clinical Trial.", "citation": "Costello SP, Hughes PA, Waters O et al. Effect of Fecal Microbiota Transplantation on 8-Week Remission in Patients With Ulcerative Colitis: A Randomized Clinical Trial. JAMA. 2019.", "doi": "10.1001/jama.2018.20046", "pmcid": "PMC6439766", "url": "https://pubmed.ncbi.nlm.nih.gov/30644982/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30644982/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID30644982", "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": [ "M1" ], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Anaerobic pooled donor FMT improved week-8 steroid-free UC remission versus autologous FMT.", "what_it_does_not_show": "Most initial responders did not retain remission at twelve months; the mediator is not selectively identified.", "confounders_present": [ "Most initial responders did not retain remission at twelve months; the mediator is not selectively identified." ], "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": [] } }, { "n": 32, "pmid": "32445952", "title": "Low-Fat, High-Fiber Diet Reduces Markers of Inflammation and Dysbiosis and Improves Quality of Life in Patients With Ulcerative Colitis.", "citation": "Fritsch J, Garces L, Quintero MA et al. Low-Fat, High-Fiber Diet Reduces Markers of Inflammation and Dysbiosis and Improves Quality of Life in Patients With Ulcerative Colitis. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2021.", "doi": "10.1016/j.cgh.2020.05.026", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/32445952/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32445952/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID32445952", "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 interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "Catered diets improved quality of life in a small UC crossover with microbial/metabolite changes.", "what_it_does_not_show": "Some inflammatory contrasts were only significant versus baseline; diet-microbiome mediation was not isolated.", "confounders_present": [ "Some inflammatory contrasts were only significant versus baseline; diet-microbiome mediation was 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": [] } }, { "n": 33, "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": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID31150625", "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": [ "M1" ], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "ASD donor transfer induced mouse behavioral features; candidate metabolites improved model phenotypes.", "what_it_does_not_show": "Recipient mouse behaviors are not human ASD causation or remission, and donor phenotypes include diet-related differences.", "confounders_present": [ "Recipient mouse behaviors are not human ASD causation or remission, and donor phenotypes include diet-related differences." ], "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": [] } }, { "n": 34, "pmid": "32300799", "title": "Probiotic Supplementation Improves Cognitive Function and Mood with Changes in Gut Microbiota in Community-Dwelling Older Adults: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial.", "citation": "Kim CS, Cha L, Sim M et al. Probiotic Supplementation Improves Cognitive Function and Mood with Changes in Gut Microbiota in Community-Dwelling Older Adults: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial. The journals of gerontology. Series A, Biological sciences and medical sciences. 2021.", "doi": "10.1093/gerona/glaa090", "pmcid": "PMC7861012", "url": "https://pubmed.ncbi.nlm.nih.gov/32300799/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32300799/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID32300799", "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": [ "M1" ], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "A small probiotic RCT improved selected flexibility/stress measures in healthy older adults.", "what_it_does_not_show": "Multiple outcomes and short follow-up limit general clinical interpretation; BDNF correlation is not manipulated mediation.", "confounders_present": [ "Multiple outcomes and short follow-up limit general clinical interpretation; BDNF correlation is not manipulated mediation." ], "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": [] } }, { "n": 35, "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": "2026-10-04", "status_checked_on": "2026-10-04", "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": [ "M1" ], "evidence_class": "Moderate", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Depression-associated donor stool induced anhedonia/anxiety and metabolic features in depleted rats.", "what_it_does_not_show": "Recipient effects establish capacity in a model, not primary causation of endogenous human depression.", "confounders_present": [ "Recipient effects establish capacity in a model, not primary causation of endogenous human depression." ], "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": [] } }, { "n": 36, "pmid": "28122648", "title": "Microbiota Transfer Therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study.", "citation": "Kang DW, Adams JB, Gregory AC et al. Microbiota Transfer Therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study. Microbiome. 2017.", "doi": "10.1186/s40168-016-0225-7", "pmcid": "PMC5264285", "url": "https://pubmed.ncbi.nlm.nih.gov/28122648/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28122648/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID28122648", "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": [ "M1" ], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "A bundled antibiotic/cleanse/FMT open-label ASD study reported persistent GI and behavioral improvement.", "what_it_does_not_show": "Eighteen participants without randomized masking cannot separate expectation, co-interventions or natural trajectory.", "confounders_present": [ "Eighteen participants without randomized masking cannot separate expectation, co-interventions or natural trajectory." ], "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": [] } }, { "n": 37, "pmid": "35508109", "title": "Microbiota alterations in proline metabolism impact depression.", "citation": "Mayneris-Perxachs J, Castells-Nobau A, Arnoriaga-Rodríguez M et al. Microbiota alterations in proline metabolism impact depression. Cell metabolism. 2022.", "doi": "10.1016/j.cmet.2022.04.001", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/35508109/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35508109/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID35508109", "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" ], "favors_models": [ "M1" ], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Multi-cohort proline associations were combined with supplementation, transfer and transporter/RNAi or bacterial manipulations in models.", "what_it_does_not_show": "Human dietary and depression relationships remain observational; cross-species behaviors do not establish clinical efficacy.", "confounders_present": [ "Human dietary and depression relationships remain observational; cross-species behaviors do not establish clinical 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": [] } }, { "n": 38, "pmid": "37033942", "title": "Psychobiotic Lactobacillus plantarum JYLP-326 relieves anxiety, depression, and insomnia symptoms in test anxious college via modulating the gut microbiota and its metabolism.", "citation": "Zhu R, Fang Y, Li H et al. Psychobiotic Lactobacillus plantarum JYLP-326 relieves anxiety, depression, and insomnia symptoms in test anxious college via modulating the gut microbiota and its metabolism. Frontiers in immunology. 2023.", "doi": "10.3389/fimmu.2023.1158137", "pmcid": "PMC10077425", "url": "https://pubmed.ncbi.nlm.nih.gov/37033942/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37033942/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID37033942", "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": [ "M1" ], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "A short probiotic/placebo comparison in test-anxious students reported improved symptom questionnaires.", "what_it_does_not_show": "Short, selected student symptoms are not durable clinical psychiatric remission or established microbial mediation.", "confounders_present": [ "Short, selected student symptoms are not durable clinical psychiatric remission or established microbial mediation." ], "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": [] } }, { "n": 39, "pmid": "35143877", "title": "Bacteroides species differentially modulate depression-like behavior via gut-brain metabolic signaling.", "citation": "Zhang Y, Fan Q, Hou Y et al. Bacteroides species differentially modulate depression-like behavior via gut-brain metabolic signaling. Brain, behavior, and immunity. 2022.", "doi": "10.1016/j.bbi.2022.02.007", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/35143877/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35143877/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID35143877", "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": [ "M1" ], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Selected Bacteroides species reproduced behavioral/neurogenesis effects in antibiotic-treated mice whereas another species did not.", "what_it_does_not_show": "Species and host-metabolite specificity constrain the result; the exact human primary pathway is not established.", "confounders_present": [ "Species and host-metabolite specificity constrain the result; the exact human primary pathway is not 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": [] } }, { "n": 40, "pmid": "37386523", "title": "Microbiome and tryptophan metabolomics analysis in adolescent depression: roles of the gut microbiota in the regulation of tryptophan-derived neurotransmitters and behaviors in human and mice.", "citation": "Zhou M, Fan Y, Xu L et al. Microbiome and tryptophan metabolomics analysis in adolescent depression: roles of the gut microbiota in the regulation of tryptophan-derived neurotransmitters and behaviors in human and mice. Microbiome. 2023.", "doi": "10.1186/s40168-023-01589-9", "pmcid": "PMC10311725", "url": "https://pubmed.ncbi.nlm.nih.gov/37386523/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37386523/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID37386523", "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" ], "favors_models": [ "M1" ], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Human adolescent signatures and Roseburia/healthy-transfer rescue linked tryptophan pathways to stressed-mouse phenotypes.", "what_it_does_not_show": "Sertraline alters human signatures; model rescue is not a randomized human mediator test.", "confounders_present": [ "Sertraline alters human signatures; model rescue is not a randomized human mediator test." ], "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": [] } }, { "n": 41, "pmid": "38367621", "title": "Donor-recipient intermicrobial interactions impact transfer of subspecies and fecal microbiota transplantation outcome.", "citation": "Chen Q, Wu C, Xu J et al. Donor-recipient intermicrobial interactions impact transfer of subspecies and fecal microbiota transplantation outcome. Cell host & microbe. 2024.", "doi": "10.1016/j.chom.2024.01.013", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/38367621/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38367621/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "ASD-2100043906+external-FMT-reanalysis", "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": [ "M1" ], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Donor-recipient subspecies interactions associated with transfer and outcomes across FMT datasets.", "what_it_does_not_show": "Reanalysis of shared datasets does not create independent clinical intervention lines or establish outcome mediation.", "confounders_present": [ "Reanalysis of shared datasets does not create independent clinical intervention lines or establish outcome mediation." ], "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": [] } }, { "n": 42, "pmid": "30531976", "title": "Gut microbiome structure and metabolic activity in inflammatory bowel disease.", "citation": "Franzosa EA, Sirota-Madi A, Avila-Pacheco J et al. Gut microbiome structure and metabolic activity in inflammatory bowel disease. Nature microbiology. 2019.", "doi": "10.1038/s41564-018-0306-4", "pmcid": "PMC6342642", "url": "https://pubmed.ncbi.nlm.nih.gov/30531976/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30531976/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID30971771" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID30531976", "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": [ "M1" ], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "IBD microbiome/metabolome differences and classifiers replicated across discovery/validation cohorts.", "what_it_does_not_show": "Inflammatory state and reverse causation remain possible; linked erratum-body impact is unresolved.", "confounders_present": [ "Inflammatory state and reverse causation remain possible; linked erratum-body impact is 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": [] } }, { "n": 43, "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": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID27126039", "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 observational", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Population cohorts linked microbial composition to numerous covariates, especially stool consistency and medications.", "what_it_does_not_show": "Associations identify confounders, not causal direction or autonomous regulation.", "confounders_present": [ "Associations identify confounders, not causal direction or autonomous regulation." ], "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": [] } }, { "n": 44, "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": "2026-10-04", "status_checked_on": "2026-10-04", "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": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "The ASD cohort showed negligible direct diagnostic associations and supported diet/stool-mediated signatures.", "what_it_does_not_show": "Observational mediation does not prove all ASD microbial findings are reactive; correction impact is not fully examined.", "confounders_present": [ "Observational mediation does not prove all ASD microbial findings are reactive; correction impact is not fully examined." ], "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": [] } }, { "n": 45, "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": "2026-10-04", "status_checked_on": "2026-10-04", "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": [ "M1" ], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Neuroactive taxonomic/function potential associated with depression and quality of life in population cohorts.", "what_it_does_not_show": "Covariate adjustment cannot exclude reverse causation or demonstrate pathway activity and necessity.", "confounders_present": [ "Covariate adjustment cannot exclude reverse causation or demonstrate pathway activity and 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": [] } }, { "n": 46, "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": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID26633628", "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 observational", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Stratification distinguished metformin-associated microbial signatures from untreated T2D signatures.", "what_it_does_not_show": "Medication confounding is material; associations do not prove the microbial fraction of drug efficacy; correction remains attached.", "confounders_present": [ "Medication confounding is material; associations do not prove the microbial fraction of drug efficacy; correction 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": [] } }, { "n": 47, "pmid": "35051369", "title": "Genetic manipulation of gut microbes enables single-gene interrogation in a complex microbiome.", "citation": "Jin WB, Li TT, Huo D et al. Genetic manipulation of gut microbes enables single-gene interrogation in a complex microbiome. Cell. 2022.", "doi": "10.1016/j.cell.2021.12.035", "pmcid": "PMC8919858", "url": "https://pubmed.ncbi.nlm.nih.gov/35051369/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35051369/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID35051369", "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": [ "M1" ], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "A targeted commensal bile-acid gene deletion in a complex community altered host colon inflammation.", "what_it_does_not_show": "Gene-level specificity is stronger than dysbiosis association but does not establish a universal human regulator.", "confounders_present": [ "Gene-level specificity is stronger than dysbiosis association but does not establish a universal human regulator." ], "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": [] } }, { "n": 48, "pmid": "38840170", "title": "Colorectal cancer microbiome programs DNA methylation of host cells by affecting methyl donor metabolism.", "citation": "Liu Z, Zhang Q, Zhang H et al. Colorectal cancer microbiome programs DNA methylation of host cells by affecting methyl donor metabolism. Genome medicine. 2024.", "doi": "10.1186/s13073-024-01344-1", "pmcid": "PMC11151592", "url": "https://pubmed.ncbi.nlm.nih.gov/38840170/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38840170/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID38840170", "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": [ "M1" ], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "New CRC tissue/fecal profiling linked microbial methyl-donor features to host methylation patterns.", "what_it_does_not_show": "Original observational data are admitted; the accompanying meta-analysis is not an additional primary source or causal perturbation.", "confounders_present": [ "Original observational data are admitted; the accompanying meta-analysis is not an additional primary source or causal perturbation." ], "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": [] } }, { "n": 49, "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": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID24009397", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: S2, S4, S8. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [ "M1" ], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Obese/lean twin communities and cultured collections transferred adiposity; cohousing rescue succeeded or failed depending on diet.", "what_it_does_not_show": "Food intake contrasts do not explain adiposity here, but dietary dependence directly limits microbial autonomy; mild glucose changes are not established insulin resistance.", "confounders_present": [ "Food intake contrasts do not explain adiposity here, but dietary dependence directly limits microbial autonomy; mild glucose changes are not established insulin resistance." ], "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": [] } }, { "n": 50, "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": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID24315484", "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": [ "M1" ], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "B. fragilis improved barrier and selected behaviors in maternal-immune-activation offspring; a candidate metabolite induced behavioral abnormalities.", "what_it_does_not_show": "Developmental immune injury precedes the microbial intervention; model modulation does not establish human ASD initiation.", "confounders_present": [ "Developmental immune injury precedes the microbial intervention; model modulation does not establish 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": [] } }, { "n": 51, "pmid": "35709757", "title": "Small intestinal resident eosinophils maintain gut homeostasis following microbial colonization.", "citation": "Ignacio A, Shah K, Bernier-Latmani J et al. Small intestinal resident eosinophils maintain gut homeostasis following microbial colonization. Immunity. 2022.", "doi": "10.1016/j.immuni.2022.05.014", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/35709757/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35709757/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID35709757", "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": [ "M1" ], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Eosinophil-deficient/colonization contrasts linked microbial IL-33 responses to gut physiological homeostasis.", "what_it_does_not_show": "Host immune cells gate the microbial effect; the pathway is mutualistic rather than autonomous.", "confounders_present": [ "Host immune cells gate the microbial effect; the pathway is mutualistic rather than autonomous." ], "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": [] } }, { "n": 52, "pmid": "32408110", "title": "A dysregulated bile acid-gut microbiota axis contributes to obesity susceptibility.", "citation": "Wei M, Huang F, Zhao L et al. A dysregulated bile acid-gut microbiota axis contributes to obesity susceptibility. EBioMedicine. 2020.", "doi": "10.1016/j.ebiom.2020.102766", "pmcid": "PMC7225614", "url": "https://pubmed.ncbi.nlm.nih.gov/32408110/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32408110/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID33845237" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID32408110", "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" ], "favors_models": [ "M1" ], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "C. scindens or bile-acid administration altered metabolic/obesity phenotypes in mice alongside human associations.", "what_it_does_not_show": "Host bile-acid substrate and diet are required context; correction details remain unexamined.", "confounders_present": [ "Host bile-acid substrate and diet are required context; correction details remain unexamined." ], "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": [] } }, { "n": 53, "pmid": "34861182", "title": "Microbiota-specific T follicular helper cells drive tertiary lymphoid structures and anti-tumor immunity against colorectal cancer.", "citation": "Overacre-Delgoffe AE, Bumgarner HJ, Cillo AR et al. Microbiota-specific T follicular helper cells drive tertiary lymphoid structures and anti-tumor immunity against colorectal cancer. Immunity. 2021.", "doi": "10.1016/j.immuni.2021.11.003", "pmcid": "PMC8865366", "url": "https://pubmed.ncbi.nlm.nih.gov/34861182/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34861182/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID34861182", "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": [ "M1" ], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "H. hepaticus-induced tumor control depended on Tfh cells, with host-cell rescue in a deficient mouse setting.", "what_it_does_not_show": "Host immune epistasis supplies a specific causal route; it does not prove broad human cancer benefit.", "confounders_present": [ "Host immune epistasis supplies a specific causal route; it does not prove broad human cancer 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": [] } }, { "n": 54, "pmid": "36473468", "title": "Gut microbiota promotes stem cell differentiation through macrophage and mesenchymal niches in early postnatal development.", "citation": "Kim JE, Li B, Fei L et al. Gut microbiota promotes stem cell differentiation through macrophage and mesenchymal niches in early postnatal development. Immunity. 2022.", "doi": "10.1016/j.immuni.2022.11.003", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/36473468/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36473468/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID37703832" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID36473468", "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": [ "M1" ], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Antibiotic, mouse genetic and Lactobacillus/macrophage rescue contrasts linked microbes to postnatal niches and NEC severity.", "what_it_does_not_show": "Developmental host-cell dependence and antibiotic pleiotropy limit autonomy; erratum-body details were not examined.", "confounders_present": [ "Developmental host-cell dependence and antibiotic pleiotropy limit autonomy; erratum-body details were not examined." ], "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": [] } }, { "n": 55, "pmid": "41606119", "title": "Fecal microbiota transplantation plus pembrolizumab and axitinib in metastatic renal cell carcinoma: the randomized phase 2 TACITO trial.", "citation": "Porcari S, Ciccarese C, Heidrich V et al. Fecal microbiota transplantation plus pembrolizumab and axitinib in metastatic renal cell carcinoma: the randomized phase 2 TACITO trial. Nature medicine. 2026.", "doi": "10.1038/s41591-025-04189-2", "pmcid": "PMC13099650", "url": "https://pubmed.ncbi.nlm.nih.gov/41606119/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41606119/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "NCT04758507", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: Sec5, Sec17, Sec29, Sec30. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "TACITO primary 12-month PFS was 70% versus 41%, P=.053; secondary median PFS favored FMT.", "what_it_does_not_show": "The primary superiority threshold was not met; secondary nominal signals, small groups and concurrent cancer drugs do not prove autonomous regulation.", "confounders_present": [ "The primary superiority threshold was not met; secondary nominal signals, small groups and concurrent cancer drugs do not prove autonomous regulation." ], "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": [] } }, { "n": 56, "pmid": "41606121", "title": "Fecal microbiota transplantation plus immunotherapy in non-small cell lung cancer and melanoma: the phase 2 FMT-LUMINate trial.", "citation": "Duttagupta S, Messaoudene M, Hunter S et al. Fecal microbiota transplantation plus immunotherapy in non-small cell lung cancer and melanoma: the phase 2 FMT-LUMINate trial. Nature medicine. 2026.", "doi": "10.1038/s41591-025-04186-5", "pmcid": "PMC13099432", "url": "https://pubmed.ncbi.nlm.nih.gov/41606121/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41606121/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "LUMINate-new-cohorts+prior-FMT-reanalysis", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: Sec7, Sec41. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC4" ], "favors_models": [ "M1" ], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "LUMINate reported single-arm clinical response signals; reintroducing lost baseline bacterial cocktails impaired ICI efficacy in mouse recipients.", "what_it_does_not_show": "Clinical FMT benefit lacks a randomized counterfactual; the controlled mouse add-back establishes only recipient/treatment-context mediation.", "confounders_present": [ "Clinical FMT benefit lacks a randomized counterfactual; the controlled mouse add-back establishes only recipient/treatment-context mediation." ], "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": [] } }, { "n": 57, "pmid": "42309058", "title": "Adjunctive fecal microbiota transplantation for major depressive disorder: A randomized, double-blind, placebo-controlled trial.", "citation": "Li J, Wang Y, Li R et al. Adjunctive fecal microbiota transplantation for major depressive disorder: A randomized, double-blind, placebo-controlled trial. Cell host & microbe. 2026.", "doi": "10.1016/j.chom.2026.05.017", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/42309058/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42309058/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID42309058", "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": true, "endogenous": true, "direction": "mixed", "what_it_shows": "Adjunct FMT improved selected depression scores but not week-8 remission versus placebo with escitalopram.", "what_it_does_not_show": "Statistical bile-acid mediation is not selective causal manipulation; durable remission and autonomous monotherapy are not shown.", "confounders_present": [ "Statistical bile-acid mediation is not selective causal manipulation; durable remission and autonomous monotherapy are not shown." ], "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": [] } }, { "n": 58, "pmid": "24226773", "title": "Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation.", "citation": "Arpaia N, Campbell C, Fan X et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature. 2013.", "doi": "10.1038/nature12726", "pmcid": "PMC3869884", "url": "https://pubmed.ncbi.nlm.nih.gov/24226773/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24226773/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID24226773", "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": [ "M1" ], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Butyrate/propionate promoted peripheral Treg generation with CNS1 dependence; acetate lacked the corresponding activity.", "what_it_does_not_show": "Defined metabolite/host enhancer logic supports communication, not a universal human master regulator.", "confounders_present": [ "Defined metabolite/host enhancer logic supports communication, not a universal human master regulator." ], "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": [] } }, { "n": 59, "pmid": "25337874", "title": "Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile.", "citation": "Buffie CG, Bucci V, Stein RR et al. Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile. Nature. 2015.", "doi": "10.1038/nature13828", "pmcid": "PMC4354891", "url": "https://pubmed.ncbi.nlm.nih.gov/25337874/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25337874/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID25337874", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: BODY, S4, S5. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [ "M1" ], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "C. scindens/consortium transfer reduced CDI illness in mice; bile-salt sequestration neutralized inhibition ex vivo.", "what_it_does_not_show": "The human cohort is observational and the bile-acid blockade is ex vivo, not in vivo gene-specific necessity or human mediation.", "confounders_present": [ "The human cohort is observational and the bile-acid blockade is ex vivo, not in vivo gene-specific necessity or human mediation." ], "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": [] } }, { "n": 60, "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": "2026-10-04", "status_checked_on": "2026-10-04", "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": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "Short animal/plant diets rapidly altered human microbial structure and expression.", "what_it_does_not_show": "This demonstrates diet-to-microbiome direction; downstream health mediation was not isolated.", "confounders_present": [ "This demonstrates diet-to-microbiome direction; downstream health mediation was 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": [] } } ], "verification_summary": { "load_bearing_claims_checked": 65, "verified": 65, "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": "SC1 is reproducible association. Medication, stool consistency, diet and disease-state adjustment change the signature; observational replication cannot identify causal direction [42–46].", "resulting_ceiling": "Β" }, { "subclaim_id": "SC4", "cap": "Γ", "cap_source": "rubric", "triggered": true, "trigger_text_quoted": "Association plus mechanistic in vitro support, or host-pathway plausibility, caps at Γ.", "specific_trigger": "SC4 remains Γ for autonomous upstream multi-system primacy. UC treatment causality and context-specific model pathways are real, but no selective intervention demonstrates independence from substrate, host physiology or concurrent drugs across the claimed systems [9–15,26–32,55–60].", "resulting_ceiling": "Γ" } ], "cap_precedence_resolutions": [ { "collision": "Perturbation in a defined setting versus broader inference", "subclaim_scope_cap_binds_on": "The gut microbiome operates as an autonomous upstream master regulator of human health across metabolic, oncological, psychiatric and immunological systems.", "subclaim_scope_threshold_binds_on": "The precise experimentally tested subclaim scope", "resolution": "The microbiome rubric permits transfer to cross Δ in recipient animals and defined rescue/epistasis to support Ζ. Universal forced-transfer limits govern inference to endogenous human primacy, not the actual model result. Human randomized clinical recurrence and UC functional outcomes are assessed separately from biomarker associations. Convergent restoration evidence is not re-capped as merely crude FMT.", "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": "unclear", "qualifying_evidence_citation": "PMID39454570, PMID32075887, PMID29097494, PMID29097493, PMID34941392, PMID33542131, PMID33303685, PMID29302014, PMID31586453, PMID32445952, PMID27491067, PMID35508109, PMID37386523, PMID32408110, PMID41606119, PMID41606121, PMID24336217", "gamma_hard_rules_triggered": [ "“Association plus cell-culture metabolite assays” and “Association plus in vitro immune readouts” constrain isolated associative inferences.", "“Any framework that has not crossed the transfer/rescue threshold in vivo” does not describe the complete corpus; SC2 crosses it. Forced transfer alone remains insufficient for endogenous human primacy." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "SC1 is reproducible association. Medication, stool consistency, diet and disease-state adjustment change the signature; observational replication cannot identify causal direction [42–46].", "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": "PMID27892954, PMID36948576, PMID39879980, PMID29097494, PMID29097493, PMID34941392, PMID40639377, PMID26541606, PMID32792462, PMID29302014, PMID37138075, PMID31150625, PMID27491067, PMID35508109, PMID35143877, PMID37386523, PMID35051369, PMID24009397, PMID24315484, PMID35709757, PMID32408110, PMID34861182, PMID36473468, PMID41606121, PMID24226773, PMID25337874", "gamma_hard_rules_triggered": [ "“Association plus cell-culture metabolite assays” and “Association plus in vitro immune readouts” constrain isolated associative inferences.", "“Any framework that has not crossed the transfer/rescue threshold in vivo” does not describe the complete corpus; SC2 crosses it. Forced transfer alone remains insufficient for endogenous human primacy." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "SC2 reaches Ζ within specified rodent contexts. Defined bacteria/metabolites, transfer and rescue converge with host receptor/enhancer or immune-cell epistasis; diet and species-negative controls map limits [22,23,25,47,49,53,58]. This is causal modulation, not endogenous human primacy.", "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": "PMID35045228, PMID40523286, PMID37060545, PMID36287379, PMID36152636, PMID29183074, PMID40997843, PMID29617739, PMID25337874", "gamma_hard_rules_triggered": [ "“Association plus cell-culture metabolite assays” and “Association plus in vitro immune readouts” constrain isolated associative inferences.", "“Any framework that has not crossed the transfer/rescue threshold in vivo” does not describe the complete corpus; SC2 crosses it. Forced transfer alone remains insufficient for endogenous human primacy." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "SC3 reaches Ζ for recurrent post-antibiotic CDI restoration. Randomized spore/defined-consortium clinical outcomes, live-versus-filtered component discrimination, and a distinct strain/bile-acid rescue route converge [1,3,7,59]. The human precise mediator and universally required strain remain unresolved.", "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": "unclear", "qualifying_evidence_citation": "PMID35045228, PMID40523286, PMID31263284, PMID27892954, PMID39454570, PMID36948576, PMID32075887, PMID39879980, PMID36704100, PMID29097494, PMID29097493, PMID34941392, PMID40639377, PMID33542131, PMID33303685, PMID28214091, PMID34863330, PMID25857665, PMID31586453, PMID35973787, PMID30644982, PMID32445952, PMID31150625, PMID32300799, PMID27491067, PMID28122648, PMID37033942, PMID24009397, PMID35709757, PMID41606119, PMID41606121, PMID42309058, PMID24336217", "gamma_hard_rules_triggered": [ "“Association plus cell-culture metabolite assays” and “Association plus in vitro immune readouts” constrain isolated associative inferences.", "“Any framework that has not crossed the transfer/rescue threshold in vivo” does not describe the complete corpus; SC2 crosses it. Forced transfer alone remains insufficient for endogenous human primacy." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "SC4 remains Γ for autonomous upstream multi-system primacy. UC treatment causality and context-specific model pathways are real, but no selective intervention demonstrates independence from substrate, host physiology or concurrent drugs across the claimed systems [9–15,26–32,55–60].", "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": [ "[11] Controlled dietary restriction and timing changed weight and microbial measures.", "[13] An isocaloric Mediterranean dietary intervention changed cholesterol and microbial/metabolic profiles.", "[16] Responder transfer and Akkermansia rescue enhanced PD-1 effects in mice with an IL-12-dependent route.", "[17] Melanoma responder communities were associated with response and transferred favorable immune/tumor phenotypes into mice.", "[18] Dietary fiber associated with human progression-free survival; low fiber or probiotics impaired ICI response in models.", "[20] Responder-derived FMT plus anti-PD-1 produced clinical benefit in six of fifteen refractory melanoma patients.", "[21] FMT with PD-1 reinduction produced responses in three of ten refractory melanoma patients.", "[24] Baseline melanoma taxa associated with response; responder-derived microbiota improved tumor control in mice.", "[29] Low FODMAP diet improved reported adequate symptom relief while reducing some putatively beneficial taxa.", "[32] Catered diets improved quality of life in a small UC crossover with microbial/metabolite changes.", "[35] Depression-associated donor stool induced anhedonia/anxiety and metabolic features in depleted rats.", "[37] Multi-cohort proline associations were combined with supplementation, transfer and transporter/RNAi or bacterial manipulations in models.", "[40] Human adolescent signatures and Roseburia/healthy-transfer rescue linked tryptophan pathways to stressed-mouse phenotypes.", "[52] C. scindens or bile-acid administration altered metabolic/obesity phenotypes in mice alongside human associations.", "[55] TACITO primary 12-month PFS was 70% versus 41%, P=.053; secondary median PFS favored FMT.", "[56] LUMINate reported single-arm clinical response signals; reintroducing lost baseline bacterial cocktails impaired ICI efficacy in mouse recipients.", "[60] Short animal/plant diets rapidly altered human microbial structure and expression." ], "what_would_cross_it": "A prospective selectively microbial intervention linked to the same functional disease phenotype, beyond composition association." }, { "subclaim_id": "SC2", "threshold": "Δ", "requirement_quoted": "Requires a transfer paradigm or causal perturbation in vivo.", "satisfied": "yes", "supporting_evidence": [ "[10] Pasteurized Akkermansia and its membrane protein partially reproduced metabolic benefits in mice.", "[12] Transfer, ethanolamine metabolism and probiotic rescue linked microbial function to barrier and metabolic phenotypes.", "[14] The Akkermansia T2D trial had overall null between-group weight/HbA1c contrasts, with benefits in a low-baseline-abundance subgroup and accompanying mouse work.", "[16] Responder transfer and Akkermansia rescue enhanced PD-1 effects in mice with an IL-12-dependent route.", "[17] Melanoma responder communities were associated with response and transferred favorable immune/tumor phenotypes into mice.", "[18] Dietary fiber associated with human progression-free survival; low fiber or probiotics impaired ICI response in models.", "[19] Exercise-associated microbial formate was tested as a required/sufficient contributor to antitumor Tc1 phenotypes, with Nrf2 mediation.", "[22] Cohousing, transfer and Bifidobacterium administration improved mouse tumor immunity and checkpoint efficacy.", "[23] Defined bacterial isolates and inosine enhanced checkpoint efficacy in several mouse cancer models through a costimulation-dependent A2A receptor route.", "[24] Baseline melanoma taxa associated with response; responder-derived microbiota improved tumor control in mice.", "[25] PD-L2/RGMb blockade or conditional T-cell RGMb deletion overcame microbial-context ICI resistance in mouse tumors.", "[33] ASD donor transfer induced mouse behavioral features; candidate metabolites improved model phenotypes.", "[35] Depression-associated donor stool induced anhedonia/anxiety and metabolic features in depleted rats.", "[37] Multi-cohort proline associations were combined with supplementation, transfer and transporter/RNAi or bacterial manipulations in models.", "[39] Selected Bacteroides species reproduced behavioral/neurogenesis effects in antibiotic-treated mice whereas another species did not.", "[40] Human adolescent signatures and Roseburia/healthy-transfer rescue linked tryptophan pathways to stressed-mouse phenotypes.", "[47] A targeted commensal bile-acid gene deletion in a complex community altered host colon inflammation.", "[49] Obese/lean twin communities and cultured collections transferred adiposity; cohousing rescue succeeded or failed depending on diet.", "[50] B. fragilis improved barrier and selected behaviors in maternal-immune-activation offspring; a candidate metabolite induced behavioral abnormalities.", "[51] Eosinophil-deficient/colonization contrasts linked microbial IL-33 responses to gut physiological homeostasis.", "[52] C. scindens or bile-acid administration altered metabolic/obesity phenotypes in mice alongside human associations.", "[53] H. hepaticus-induced tumor control depended on Tfh cells, with host-cell rescue in a deficient mouse setting.", "[54] Antibiotic, mouse genetic and Lactobacillus/macrophage rescue contrasts linked microbes to postnatal niches and NEC severity.", "[56] LUMINate reported single-arm clinical response signals; reintroducing lost baseline bacterial cocktails impaired ICI efficacy in mouse recipients.", "[58] Butyrate/propionate promoted peripheral Treg generation with CNS1 dependence; acetate lacked the corresponding activity.", "[59] C. scindens/consortium transfer reduced CDI illness in mice; bile-salt sequestration neutralized inhibition ex vivo." ], "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] Pasteurized Akkermansia and its membrane protein partially reproduced metabolic benefits in mice.", "[12] Transfer, ethanolamine metabolism and probiotic rescue linked microbial function to barrier and metabolic phenotypes.", "[14] The Akkermansia T2D trial had overall null between-group weight/HbA1c contrasts, with benefits in a low-baseline-abundance subgroup and accompanying mouse work.", "[16] Responder transfer and Akkermansia rescue enhanced PD-1 effects in mice with an IL-12-dependent route.", "[17] Melanoma responder communities were associated with response and transferred favorable immune/tumor phenotypes into mice.", "[18] Dietary fiber associated with human progression-free survival; low fiber or probiotics impaired ICI response in models.", "[19] Exercise-associated microbial formate was tested as a required/sufficient contributor to antitumor Tc1 phenotypes, with Nrf2 mediation.", "[22] Cohousing, transfer and Bifidobacterium administration improved mouse tumor immunity and checkpoint efficacy.", "[23] Defined bacterial isolates and inosine enhanced checkpoint efficacy in several mouse cancer models through a costimulation-dependent A2A receptor route.", "[24] Baseline melanoma taxa associated with response; responder-derived microbiota improved tumor control in mice.", "[25] PD-L2/RGMb blockade or conditional T-cell RGMb deletion overcame microbial-context ICI resistance in mouse tumors.", "[33] ASD donor transfer induced mouse behavioral features; candidate metabolites improved model phenotypes.", "[35] Depression-associated donor stool induced anhedonia/anxiety and metabolic features in depleted rats.", "[37] Multi-cohort proline associations were combined with supplementation, transfer and transporter/RNAi or bacterial manipulations in models.", "[39] Selected Bacteroides species reproduced behavioral/neurogenesis effects in antibiotic-treated mice whereas another species did not.", "[40] Human adolescent signatures and Roseburia/healthy-transfer rescue linked tryptophan pathways to stressed-mouse phenotypes.", "[47] A targeted commensal bile-acid gene deletion in a complex community altered host colon inflammation.", "[49] Obese/lean twin communities and cultured collections transferred adiposity; cohousing rescue succeeded or failed depending on diet.", "[50] B. fragilis improved barrier and selected behaviors in maternal-immune-activation offspring; a candidate metabolite induced behavioral abnormalities.", "[51] Eosinophil-deficient/colonization contrasts linked microbial IL-33 responses to gut physiological homeostasis.", "[52] C. scindens or bile-acid administration altered metabolic/obesity phenotypes in mice alongside human associations.", "[53] H. hepaticus-induced tumor control depended on Tfh cells, with host-cell rescue in a deficient mouse setting.", "[54] Antibiotic, mouse genetic and Lactobacillus/macrophage rescue contrasts linked microbes to postnatal niches and NEC severity.", "[56] LUMINate reported single-arm clinical response signals; reintroducing lost baseline bacterial cocktails impaired ICI efficacy in mouse recipients.", "[58] Butyrate/propionate promoted peripheral Treg generation with CNS1 dependence; acetate lacked the corresponding activity.", "[59] C. scindens/consortium transfer reduced CDI illness in mice; bile-salt sequestration neutralized inhibition ex vivo." ], "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] Pasteurized Akkermansia and its membrane protein partially reproduced metabolic benefits in mice.", "[12] Transfer, ethanolamine metabolism and probiotic rescue linked microbial function to barrier and metabolic phenotypes.", "[14] The Akkermansia T2D trial had overall null between-group weight/HbA1c contrasts, with benefits in a low-baseline-abundance subgroup and accompanying mouse work.", "[16] Responder transfer and Akkermansia rescue enhanced PD-1 effects in mice with an IL-12-dependent route.", "[17] Melanoma responder communities were associated with response and transferred favorable immune/tumor phenotypes into mice.", "[18] Dietary fiber associated with human progression-free survival; low fiber or probiotics impaired ICI response in models.", "[19] Exercise-associated microbial formate was tested as a required/sufficient contributor to antitumor Tc1 phenotypes, with Nrf2 mediation.", "[22] Cohousing, transfer and Bifidobacterium administration improved mouse tumor immunity and checkpoint efficacy.", "[23] Defined bacterial isolates and inosine enhanced checkpoint efficacy in several mouse cancer models through a costimulation-dependent A2A receptor route.", "[24] Baseline melanoma taxa associated with response; responder-derived microbiota improved tumor control in mice.", "[25] PD-L2/RGMb blockade or conditional T-cell RGMb deletion overcame microbial-context ICI resistance in mouse tumors.", "[33] ASD donor transfer induced mouse behavioral features; candidate metabolites improved model phenotypes.", "[35] Depression-associated donor stool induced anhedonia/anxiety and metabolic features in depleted rats.", "[37] Multi-cohort proline associations were combined with supplementation, transfer and transporter/RNAi or bacterial manipulations in models.", "[39] Selected Bacteroides species reproduced behavioral/neurogenesis effects in antibiotic-treated mice whereas another species did not.", "[40] Human adolescent signatures and Roseburia/healthy-transfer rescue linked tryptophan pathways to stressed-mouse phenotypes.", "[47] A targeted commensal bile-acid gene deletion in a complex community altered host colon inflammation.", "[49] Obese/lean twin communities and cultured collections transferred adiposity; cohousing rescue succeeded or failed depending on diet.", "[50] B. fragilis improved barrier and selected behaviors in maternal-immune-activation offspring; a candidate metabolite induced behavioral abnormalities.", "[51] Eosinophil-deficient/colonization contrasts linked microbial IL-33 responses to gut physiological homeostasis.", "[52] C. scindens or bile-acid administration altered metabolic/obesity phenotypes in mice alongside human associations.", "[53] H. hepaticus-induced tumor control depended on Tfh cells, with host-cell rescue in a deficient mouse setting.", "[54] Antibiotic, mouse genetic and Lactobacillus/macrophage rescue contrasts linked microbes to postnatal niches and NEC severity.", "[56] LUMINate reported single-arm clinical response signals; reintroducing lost baseline bacterial cocktails impaired ICI efficacy in mouse recipients.", "[58] Butyrate/propionate promoted peripheral Treg generation with CNS1 dependence; acetate lacked the corresponding activity.", "[59] C. scindens/consortium transfer reduced CDI illness in mice; bile-salt sequestration neutralized inhibition ex vivo." ], "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] Pasteurized Akkermansia and its membrane protein partially reproduced metabolic benefits in mice.", "[12] Transfer, ethanolamine metabolism and probiotic rescue linked microbial function to barrier and metabolic phenotypes.", "[14] The Akkermansia T2D trial had overall null between-group weight/HbA1c contrasts, with benefits in a low-baseline-abundance subgroup and accompanying mouse work.", "[16] Responder transfer and Akkermansia rescue enhanced PD-1 effects in mice with an IL-12-dependent route.", "[17] Melanoma responder communities were associated with response and transferred favorable immune/tumor phenotypes into mice.", "[18] Dietary fiber associated with human progression-free survival; low fiber or probiotics impaired ICI response in models.", "[19] Exercise-associated microbial formate was tested as a required/sufficient contributor to antitumor Tc1 phenotypes, with Nrf2 mediation.", "[22] Cohousing, transfer and Bifidobacterium administration improved mouse tumor immunity and checkpoint efficacy.", "[23] Defined bacterial isolates and inosine enhanced checkpoint efficacy in several mouse cancer models through a costimulation-dependent A2A receptor route.", "[24] Baseline melanoma taxa associated with response; responder-derived microbiota improved tumor control in mice.", "[25] PD-L2/RGMb blockade or conditional T-cell RGMb deletion overcame microbial-context ICI resistance in mouse tumors.", "[33] ASD donor transfer induced mouse behavioral features; candidate metabolites improved model phenotypes.", "[35] Depression-associated donor stool induced anhedonia/anxiety and metabolic features in depleted rats.", "[37] Multi-cohort proline associations were combined with supplementation, transfer and transporter/RNAi or bacterial manipulations in models.", "[39] Selected Bacteroides species reproduced behavioral/neurogenesis effects in antibiotic-treated mice whereas another species did not.", "[40] Human adolescent signatures and Roseburia/healthy-transfer rescue linked tryptophan pathways to stressed-mouse phenotypes.", "[47] A targeted commensal bile-acid gene deletion in a complex community altered host colon inflammation.", "[49] Obese/lean twin communities and cultured collections transferred adiposity; cohousing rescue succeeded or failed depending on diet.", "[50] B. fragilis improved barrier and selected behaviors in maternal-immune-activation offspring; a candidate metabolite induced behavioral abnormalities.", "[51] Eosinophil-deficient/colonization contrasts linked microbial IL-33 responses to gut physiological homeostasis.", "[52] C. scindens or bile-acid administration altered metabolic/obesity phenotypes in mice alongside human associations.", "[53] H. hepaticus-induced tumor control depended on Tfh cells, with host-cell rescue in a deficient mouse setting.", "[54] Antibiotic, mouse genetic and Lactobacillus/macrophage rescue contrasts linked microbes to postnatal niches and NEC severity.", "[56] LUMINate reported single-arm clinical response signals; reintroducing lost baseline bacterial cocktails impaired ICI efficacy in mouse recipients.", "[58] Butyrate/propionate promoted peripheral Treg generation with CNS1 dependence; acetate lacked the corresponding activity.", "[59] C. scindens/consortium transfer reduced CDI illness in mice; bile-salt sequestration neutralized inhibition ex vivo." ], "what_would_cross_it": "Repeat narrowed causal routes across independent facilities with diet, handling, cage and host genetic controls sufficient for Η." }, { "subclaim_id": "SC3", "threshold": "Δ", "requirement_quoted": "Requires a transfer paradigm or causal perturbation in vivo.", "satisfied": "yes", "supporting_evidence": [ "[1] Post-antibiotic SER-109 reduced recurrent CDI at 8 weeks in the randomized trial.", "[2] Primary-CDI FMT met the specified noninferiority comparison against vancomycin.", "[3] A defined eight-strain VE303 consortium reduced recurrence at the high dose in the phase 2 trial.", "[4] RBX2660 had higher modeled treatment success than placebo following antibiotics.", "[5] Early FMT improved resolution after antibiotics in first or second CDI.", "[6] Capsule FMT was noninferior to colonoscopic FMT for preventing recurrence.", "[7] Sterile filtrate failed noninferiority to live donor stool, with lower recurrence-free proportions.", "[8] The two-dose RBX2660 primary contrast did not meet significance; a one-dose secondary contrast favored treatment.", "[59] C. scindens/consortium transfer reduced CDI illness in mice; bile-salt sequestration neutralized inhibition ex vivo." ], "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": [ "[1] Post-antibiotic SER-109 reduced recurrent CDI at 8 weeks in the randomized trial.", "[2] Primary-CDI FMT met the specified noninferiority comparison against vancomycin.", "[3] A defined eight-strain VE303 consortium reduced recurrence at the high dose in the phase 2 trial.", "[4] RBX2660 had higher modeled treatment success than placebo following antibiotics.", "[5] Early FMT improved resolution after antibiotics in first or second CDI.", "[6] Capsule FMT was noninferior to colonoscopic FMT for preventing recurrence.", "[7] Sterile filtrate failed noninferiority to live donor stool, with lower recurrence-free proportions.", "[8] The two-dose RBX2660 primary contrast did not meet significance; a one-dose secondary contrast favored treatment.", "[59] C. scindens/consortium transfer reduced CDI illness in mice; bile-salt sequestration neutralized inhibition ex vivo." ], "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": "yes", "supporting_evidence": [ "[1] Post-antibiotic SER-109 reduced recurrent CDI at 8 weeks in the randomized trial.", "[2] Primary-CDI FMT met the specified noninferiority comparison against vancomycin.", "[3] A defined eight-strain VE303 consortium reduced recurrence at the high dose in the phase 2 trial.", "[4] RBX2660 had higher modeled treatment success than placebo following antibiotics.", "[5] Early FMT improved resolution after antibiotics in first or second CDI.", "[6] Capsule FMT was noninferior to colonoscopic FMT for preventing recurrence.", "[7] Sterile filtrate failed noninferiority to live donor stool, with lower recurrence-free proportions.", "[8] The two-dose RBX2660 primary contrast did not meet significance; a one-dose secondary contrast favored treatment.", "[59] C. scindens/consortium transfer reduced CDI illness in mice; bile-salt sequestration neutralized inhibition ex vivo." ], "what_would_cross_it": "" }, { "subclaim_id": "SC3", "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": [ "[1] Post-antibiotic SER-109 reduced recurrent CDI at 8 weeks in the randomized trial.", "[2] Primary-CDI FMT met the specified noninferiority comparison against vancomycin.", "[3] A defined eight-strain VE303 consortium reduced recurrence at the high dose in the phase 2 trial.", "[4] RBX2660 had higher modeled treatment success than placebo following antibiotics.", "[5] Early FMT improved resolution after antibiotics in first or second CDI.", "[6] Capsule FMT was noninferior to colonoscopic FMT for preventing recurrence.", "[7] Sterile filtrate failed noninferiority to live donor stool, with lower recurrence-free proportions.", "[8] The two-dose RBX2660 primary contrast did not meet significance; a one-dose secondary contrast favored treatment.", "[59] C. scindens/consortium transfer reduced CDI illness in mice; bile-salt sequestration neutralized inhibition ex vivo." ], "what_would_cross_it": "Selective human mediator manipulation or an independently discriminating defined-factor rescue with matched delivery and substrate controls for Η." }, { "subclaim_id": "SC4", "threshold": "Δ", "requirement_quoted": "Requires a transfer paradigm or causal perturbation in vivo.", "satisfied": "no", "supporting_evidence": [ "[1] Post-antibiotic SER-109 reduced recurrent CDI at 8 weeks in the randomized trial.", "[2] Primary-CDI FMT met the specified noninferiority comparison against vancomycin.", "[9] Pasteurized Akkermansia improved insulin sensitivity and some metabolic measures in a small human pilot.", "[10] Pasteurized Akkermansia and its membrane protein partially reproduced metabolic benefits in mice.", "[11] Controlled dietary restriction and timing changed weight and microbial measures.", "[12] Transfer, ethanolamine metabolism and probiotic rescue linked microbial function to barrier and metabolic phenotypes.", "[13] An isocaloric Mediterranean dietary intervention changed cholesterol and microbial/metabolic profiles.", "[14] The Akkermansia T2D trial had overall null between-group weight/HbA1c contrasts, with benefits in a low-baseline-abundance subgroup and accompanying mouse work.", "[15] A small short-term FMT/metformin comparison reported improvements in metabolic indices.", "[16] Responder transfer and Akkermansia rescue enhanced PD-1 effects in mice with an IL-12-dependent route.", "[17] Melanoma responder communities were associated with response and transferred favorable immune/tumor phenotypes into mice.", "[18] Dietary fiber associated with human progression-free survival; low fiber or probiotics impaired ICI response in models.", "[19] Exercise-associated microbial formate was tested as a required/sufficient contributor to antitumor Tc1 phenotypes, with Nrf2 mediation.", "[20] Responder-derived FMT plus anti-PD-1 produced clinical benefit in six of fifteen refractory melanoma patients.", "[21] FMT with PD-1 reinduction produced responses in three of ten refractory melanoma patients.", "[26] Intensive multidonor FMT improved the prespecified steroid-free clinical/endoscopic outcome in UC versus placebo.", "[27] Oral FMT after antibiotics improved the week-8 UC outcome; a very small maintenance randomization favored continuation.", "[28] Weekly donor FMT improved remission versus water enema in active UC.", "[29] Low FODMAP diet improved reported adequate symptom relief while reducing some putatively beneficial taxa.", "[30] FMT plus anti-inflammatory diet improved UC outcomes versus optimized standard therapy.", "[31] Anaerobic pooled donor FMT improved week-8 steroid-free UC remission versus autologous FMT.", "[32] Catered diets improved quality of life in a small UC crossover with microbial/metabolite changes.", "[33] ASD donor transfer induced mouse behavioral features; candidate metabolites improved model phenotypes.", "[34] A small probiotic RCT improved selected flexibility/stress measures in healthy older adults.", "[35] Depression-associated donor stool induced anhedonia/anxiety and metabolic features in depleted rats.", "[36] A bundled antibiotic/cleanse/FMT open-label ASD study reported persistent GI and behavioral improvement.", "[38] A short probiotic/placebo comparison in test-anxious students reported improved symptom questionnaires.", "[49] Obese/lean twin communities and cultured collections transferred adiposity; cohousing rescue succeeded or failed depending on diet.", "[51] Eosinophil-deficient/colonization contrasts linked microbial IL-33 responses to gut physiological homeostasis.", "[55] TACITO primary 12-month PFS was 70% versus 41%, P=.053; secondary median PFS favored FMT.", "[56] LUMINate reported single-arm clinical response signals; reintroducing lost baseline bacterial cocktails impaired ICI efficacy in mouse recipients.", "[57] Adjunct FMT improved selected depression scores but not week-8 remission versus placebo with escitalopram.", "[60] Short animal/plant diets rapidly altered human microbial structure and expression." ], "what_would_cross_it": "Demonstrate a positive selectively microbial human clinical perturbation identifying autonomous upstream action in the registered systemic scope." } ], "generalization_check": { "generalization_tested": "yes", "context_boundary_mapped": "yes", "internal_negative_controls": [ "Twin-community rescue fails under the high saturated-fat/low fruit-vegetable diet [49].", "Live versus sterile-filtered stool favors live treatment but does not establish universal microbial necessity [7].", "Akkermansia overall metabolic contrasts and TACITO primary superiority were null [14,55]." ], "note": "Mapped dependence on diet, strain, host pathways and treatment supports bounded causal contexts; it does not by itself rescue the distinct assertion of autonomy." }, "falsification_patterns_met": [ { "subclaim_id": "SC4", "pattern": "Host phenotype persists after removing the claimed microbial driver", "evidence": "Host immune blockade can bypass microbiome-linked resistance [25]; dietary and drug context are material. This limits universal necessity without denying causal routes.", "downgrade_applied": false }, { "subclaim_id": "SC4", "pattern": "Rescue fails despite reinstating the proposed taxa", "evidence": "Community rescue depends on diet and colonization [49]; this is a mapped limit already reflected in the nominal scope score.", "downgrade_applied": false } ], "pitfalls_flagged": [ { "subclaim_id": "SC4", "pitfall": "1. Correlation promoted to mechanism", "where": "Dysbiosis, engraftment and statistical mediation are distinguished from selective causal mediation." }, { "subclaim_id": "SC4", "pitfall": "13. Therapeutic effect misread as mechanistic proof", "where": "FMT packages and concurrent ICI/escitalopram are not proof of autonomous microbial primacy." }, { "subclaim_id": "SC2", "pitfall": "16. Untested generalization confused with mapped boundaries", "where": "Diet/species-negative controls define Ε or higher within actually tested rodent scopes." }, { "subclaim_id": "SC4", "pitfall": "22. Scope fitted to the result", "where": "Baseline abundance is a possible predictive context; post-treatment responders do not define the claim." } ], "causal_tally_audit": { "tally_claimed_by_document": 53, "tally_after_audit": 53, "items_rejected": [ "Null and negative contrasts are discriminators, not positive threshold crossings. Reports and replications are not independent causal lines.", "A decisive flag denotes an intervention discriminator, including dietary and negative contrasts; it does not count positive nominal autonomy tests.", "CRC methylation report [48] contributes original observational measurements only; its meta-analysis is not an extra primary study." ] }, "steelman": { "case_one_rung_higher": "The strongest Δ case is that several human randomized microbial interventions produce clinical benefit and model routes are unusually specific. This is persuasive for microbial contribution. It does not identify the extra autonomous upstream action across all four human systems, which is the registered SC4 target.", "case_one_rung_lower": "The strongest Β case is that most human multi-system signatures are observational and confounded. It understates demonstrated model pathways, clinical recurrence restoration and UC treatment contrasts. Those findings provide biological causal support beyond a signature-only hypothesis, while leaving the nominal autonomous scope unresolved.", "which_rejected": "Reject nominal Δ because the selectively identifying full-scope autonomy experiment is missing; reject Β because verified clinical/model contributions supply mechanistic support. Narrow SC2/SC3 remain Ζ rather than being dragged down by SC4.", "blocking_cap_threshold_or_missing_experiment": "Missing experiment: Randomize a defined microbial metabolic function against an otherwise matched inactive consortium in predeclared human metabolic and psychiatric or oncological settings, factorially controlling substrate and usual treatment, with equal contact, blinded outcomes, engraftment and longitudinal mediator measurements. Pair human contrasts with microbial-gene deletion and matched metabolite rescue in conventional animals." }, "final_score": { "hsef_level": "Γ", "hsef_descriptor": "Mechanistically plausible, partial system support", "confidence": "Moderate", "confidence_rationale": "60 primary reports with 4 selected partial-body examinations; density, heterogeneous controls and incomplete access set the confidence, not correctness.", "rests_on_non_peer_reviewed_work": false, "rationale": "The preregistered scope-matched SC4 gate returns Γ. Positive recurrent-CDI restoration reaches Ζ and selected UC packages establish bounded human causal benefit; neither demonstrates autonomous multi-system primacy. Weakest-link would return Β because SC1 deliberately asks an observational existence question." }, "role_of_mechanism": { "classification": "reinforcing / stabilizing factor", "derivation_step_matched": "5", "derivation": "Apply causal-direction steps in order: some signatures are downstream, but controlled microbial effects preclude classifying the whole mechanism as downstream (step 1) or epiphenomenal (step 2). Autonomous initiation and rate limitation are not demonstrated (step 3); a uniformly necessary prerequisite is not established across systems (step 4). Microbial functions amplify or stabilize host, diet and treatment-dependent phenotypes, matching step 5. This broad classification does not erase a narrower primary causal role in restoration of depleted CDI resistance.", "tournament_used_as_tiebreaker": false, "note": "Derived from causal direction, not tournament rank." }, "extended_scoring_MSD": { "momentum": { "value": "Mechanistic only", "artifact": "Named causal developments include microbial single-gene interrogation [47], exercise/formate/Nrf2 experiments [19] and LUMINate bacterial add-back [56]. Completed TACITO and depression trials are outcomes, not work still underway; none selectively tests the next autonomy boundary.", "justification": "Named causal developments include microbial single-gene interrogation [47], exercise/formate/Nrf2 experiments [19] and LUMINate bacterial add-back [56]. Completed TACITO and depression trials are outcomes, not work still underway; none selectively tests the next autonomy boundary." }, "stability": { "value": "Stable", "trigger": "No specifically verified pending trial selectively identifying autonomous multi-system primacy was found in this bounded search. Completed 2026 trials are not a pending stability trigger.", "justification": "No specifically verified pending trial selectively identifying autonomous multi-system primacy was found in this bounded search. Completed 2026 trials are not a pending stability trigger." }, "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": "Randomize a defined microbial metabolic function against an otherwise matched inactive consortium in predeclared human metabolic and psychiatric or oncological settings, factorially controlling substrate and usual treatment, with equal contact, blinded outcomes, engraftment and longitudinal mediator measurements. Pair human contrasts with microbial-gene deletion and matched metabolite rescue in conventional animals.", "readout": "Prespecified clinical phenotype or durable remission and adverse effects, alongside function-specific metabolite flux", "critical_control": "Identical donor matrix/delivery and antibiotic exposure; baseline diet, medication and host strata; active versus function-inactive consortium", "supporting_result": "Reproducible clinical and mediator effects attributable to the defined microbial function across the prespecified systems, including substrate-independent contrasts required for autonomy", "falsifying_result": "Adequate function engagement without clinical change, benefits attributable to host/substrate treatment, or failure of the matched rescue" } ], "knowledge_gaps": [ { "name": "Gap 1", "statement": "Precisely which live factors are necessary for human recurrent-CDI restoration?", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 2", "statement": "Which UC treatment components cause sustained benefit and how durable is the effect?", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 3", "statement": "Are the newer cancer and depression signals replicated on primary endpoints with clinically meaningful durability?", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 4", "statement": "Do baseline abundance predictors prospectively identify treatment response rather than post hoc subgroups?", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 5", "statement": "Can human selective mediation distinguish metabolite products, ecological remodeling and host immune effects?", "relevance": "Limits mechanism identification or scope." } ], "review_metadata": { "review_date": "2026-10-04", "reviewer": "Codex", "evidence_base_note": "60 primary reports; cutoff 2026-10-04; bounded critical review, not exhaustive systematic review.", "literature_tools_available": true, "literature_tools_note": "Life Sciences Literature PubMed/PMC; SciSpace and authenticated Consensus discovery; primary-source verification. No API credential handled.", "skill_version": "5.3", "validator_run": "Archived validator run; receipt and logs accompany this pair.", "validator_warnings_addressed": "Claim-form warning is justified: the popularity-list topic is explicitly restated as a causal proposition. The steelman specifies the missing experiment.", "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": "Randomized clinical recurrence, UC remission, live/filter component contrast, host epistasis and strain/metabolite rescue are eligible causal equivalents. Together they carry narrow SC2/SC3 to Ζ. Missing precise human mediation and matched cross-context autonomy keep the nominal claim below Ζ; no blanket RCT-only requirement or weakest-leg re-cap is imposed." }, { "kind": "natural_experiment", "available": true, "why_not_sufficient": "Randomized clinical recurrence, UC remission, live/filter component contrast, host epistasis and strain/metabolite rescue are eligible causal equivalents. Together they carry narrow SC2/SC3 to Ζ. Missing precise human mediation and matched cross-context autonomy keep the nominal claim below Ζ; no blanket RCT-only requirement or weakest-leg re-cap is imposed." }, { "kind": "dose_response_across_populations", "available": false, "why_not_sufficient": "Randomized clinical recurrence, UC remission, live/filter component contrast, host epistasis and strain/metabolite rescue are eligible causal equivalents. Together they carry narrow SC2/SC3 to Ζ. Missing precise human mediation and matched cross-context autonomy keep the nominal claim below Ζ; no blanket RCT-only requirement or weakest-leg re-cap is imposed." }, { "kind": "withdrawal_rechallenge", "available": true, "why_not_sufficient": "Randomized clinical recurrence, UC remission, live/filter component contrast, host epistasis and strain/metabolite rescue are eligible causal equivalents. Together they carry narrow SC2/SC3 to Ζ. Missing precise human mediation and matched cross-context autonomy keep the nominal claim below Ζ; no blanket RCT-only requirement or weakest-leg re-cap is imposed." }, { "kind": "therapeutic_perturbation_hard_endpoint", "available": true, "why_not_sufficient": "Randomized clinical recurrence, UC remission, live/filter component contrast, host epistasis and strain/metabolite rescue are eligible causal equivalents. Together they carry narrow SC2/SC3 to Ζ. Missing precise human mediation and matched cross-context autonomy keep the nominal claim below Ζ; no blanket RCT-only requirement or weakest-leg re-cap is imposed." } ], "convergence_present": true, "cap_reapplied_to_convergent_set": false }, "provenance_header": { "sources_total": 60, "claims_total": 65, "claims_verified": 65, "claims_unverified": 0, "claims_contradicted": 0, "tier_a_sources": 60, "generated_by": "Codex; HSEF v5.3", "gate_passed": true }, "claims": [ { "id": "C1", "text": "Post-antibiotic SER-109 reduced recurrent CDI at 8 weeks in the randomized trial. Restoration in a depleted niche does not establish autonomous regulation of systemic health.", "carries_number": true, "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": "2026-10-04", "note": "" }, { "id": "C2", "text": "Primary-CDI FMT met the specified noninferiority comparison against vancomycin. The 25-point margin and rescue therapy limit claims of superiority; this is primary CDI rather than the exact recurrent-CDI subclaim.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 2 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C3", "text": "A defined eight-strain VE303 consortium reduced recurrence at the high dose in the phase 2 trial. Small groups and recurrence definitions require confirmation; the exact mediator was not randomized.", "carries_number": true, "load_bearing_for": [ "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": "2026-10-04", "note": "" }, { "id": "C4", "text": "RBX2660 had higher modeled treatment success than placebo following antibiotics. The Bayesian estimate borrows the phase 2 study and is not an independent replication of that report; linked correction remains attached.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 4 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C5", "text": "Early FMT improved resolution after antibiotics in first or second CDI. Early stopping and disease-stage differences limit magnitude and recurrent-CDI generalization.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 5 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C6", "text": "Capsule FMT was noninferior to colonoscopic FMT for preventing recurrence. Both groups received FMT; the route contrast does not isolate efficacy against no FMT.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 6 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C7", "text": "Sterile filtrate failed noninferiority to live donor stool, with lower recurrence-free proportions. Filtration changes multiple components; failure of noninferiority is not proof that every live organism is necessary.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 7 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C8", "text": "The two-dose RBX2660 primary contrast did not meet significance; a one-dose secondary contrast favored treatment. Secondary and open-label rescue outcomes cannot replace the null primary comparison; this cohort informs the phase 3 Bayesian estimate.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 8 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C9", "text": "Pasteurized Akkermansia improved insulin sensitivity and some metabolic measures in a small human pilot. Weight and fat changes were not significant; a pasteurized product effect does not establish live-community autonomy.", "carries_number": false, "load_bearing_for": [ "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": "2026-10-04", "note": "" }, { "id": "C10", "text": "Pasteurized Akkermansia and its membrane protein partially reproduced metabolic benefits in mice. Human observations in this report concern safety; a protein/TLR2 pathway depends on host machinery.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 10 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C11", "text": "Controlled dietary restriction and timing changed weight and microbial measures. Diet was manipulated directly; parallel changes do not isolate microbial mediation.", "carries_number": false, "load_bearing_for": [ "SC1", "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": "2026-10-04", "note": "" }, { "id": "C12", "text": "Transfer, ethanolamine metabolism and probiotic rescue linked microbial function to barrier and metabolic phenotypes. Model rescue supports a defined pathway, not autonomous human multi-system primacy.", "carries_number": false, "load_bearing_for": [ "SC2", "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": "2026-10-04", "note": "" }, { "id": "C13", "text": "An isocaloric Mediterranean dietary intervention changed cholesterol and microbial/metabolic profiles. Direct dietary effects and correlated microbiome changes do not identify the mediator.", "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": "2026-10-04", "note": "" }, { "id": "C14", "text": "The Akkermansia T2D trial had overall null between-group weight/HbA1c contrasts, with benefits in a low-baseline-abundance subgroup and accompanying mouse work. Subgroup findings require prospective confirmation; baseline community dependence contradicts simple universal response.", "carries_number": true, "load_bearing_for": [ "SC2", "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": "2026-10-04", "note": "" }, { "id": "C15", "text": "A small short-term FMT/metformin comparison reported improvements in metabolic indices. Limited size, duration and comparator structure do not establish durable broad human health benefit.", "carries_number": false, "load_bearing_for": [ "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": "2026-10-04", "note": "" }, { "id": "C16", "text": "Responder transfer and Akkermansia rescue enhanced PD-1 effects in mice with an IL-12-dependent route. Human antibiotic and taxon associations remain confounded; active anticancer treatment and host immunity gate the effect.", "carries_number": true, "load_bearing_for": [ "SC1", "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": "2026-10-04", "note": "" }, { "id": "C17", "text": "Melanoma responder communities were associated with response and transferred favorable immune/tumor phenotypes into mice. The human observational comparison does not establish the microbial cause of patient benefit.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC4" ], "source_ns": [ 17 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C18", "text": "Dietary fiber associated with human progression-free survival; low fiber or probiotics impaired ICI response in models. The human diet comparison is observational and the model effect depends on diet and immunotherapy.", "carries_number": false, "load_bearing_for": [ "SC1", "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": "2026-10-04", "note": "" }, { "id": "C19", "text": "Exercise-associated microbial formate was tested as a required/sufficient contributor to antitumor Tc1 phenotypes, with Nrf2 mediation. Human formate is a biomarker candidate; exercise and host transcriptional gating remain upstream conditions.", "carries_number": true, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 19 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C20", "text": "Responder-derived FMT plus anti-PD-1 produced clinical benefit in six of fifteen refractory melanoma patients. Single-arm drug rechallenge does not isolate the incremental FMT effect or human mediator necessity.", "carries_number": true, "load_bearing_for": [ "SC1", "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": "2026-10-04", "note": "" }, { "id": "C21", "text": "FMT with PD-1 reinduction produced responses in three of ten refractory melanoma patients. The phase 1 single-arm design establishes feasibility and signals, not a controlled causal efficacy estimate.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 21 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C22", "text": "Cohousing, transfer and Bifidobacterium administration improved mouse tumor immunity and checkpoint efficacy. Mouse facility/community and immune context limit human generalization.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 22 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C23", "text": "Defined bacterial isolates and inosine enhanced checkpoint efficacy in several mouse cancer models through a costimulation-dependent A2A receptor route. The metabolite requires treatment/barrier and host immune context; it is not an autonomous human master switch.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 23 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C24", "text": "Baseline melanoma taxa associated with response; responder-derived microbiota improved tumor control in mice. Human association and recipient sufficiency do not identify endogenous human necessity.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 24 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C25", "text": "PD-L2/RGMb blockade or conditional T-cell RGMb deletion overcame microbial-context ICI resistance in mouse tumors. The host immune intervention can bypass microbial resistance; correction-body details were not examined.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 25 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C26", "text": "Intensive multidonor FMT improved the prespecified steroid-free clinical/endoscopic outcome in UC versus placebo. Crude-community benefit supports a UC treatment package, not strain-specific or autonomous systemic causation.", "carries_number": false, "load_bearing_for": [ "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": "2026-10-04", "note": "" }, { "id": "C27", "text": "Oral FMT after antibiotics improved the week-8 UC outcome; a very small maintenance randomization favored continuation. Early pandemic termination, pretreatment and tiny maintenance groups limit generalization and mechanism.", "carries_number": true, "load_bearing_for": [ "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": "2026-10-04", "note": "" }, { "id": "C28", "text": "Weekly donor FMT improved remission versus water enema in active UC. Donor dependence and early futility stopping complicate precision; the result does not establish universal microbiome primacy.", "carries_number": false, "load_bearing_for": [ "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": "2026-10-04", "note": "" }, { "id": "C29", "text": "Low FODMAP diet improved reported adequate symptom relief while reducing some putatively beneficial taxa. Inflammatory markers and diversity did not differ; health cannot be inferred from a universal favorable-diversity metric.", "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": "2026-10-04", "note": "" }, { "id": "C30", "text": "FMT plus anti-inflammatory diet improved UC outcomes versus optimized standard therapy. The bundled unblinded intervention and continued diet do not isolate FMT or a universal microbial mechanism.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 30 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C31", "text": "Anaerobic pooled donor FMT improved week-8 steroid-free UC remission versus autologous FMT. Most initial responders did not retain remission at twelve months; the mediator is not selectively identified.", "carries_number": true, "load_bearing_for": [ "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": "2026-10-04", "note": "" }, { "id": "C32", "text": "Catered diets improved quality of life in a small UC crossover with microbial/metabolite changes. Some inflammatory contrasts were only significant versus baseline; diet-microbiome mediation was not isolated.", "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": "2026-10-04", "note": "" }, { "id": "C33", "text": "ASD donor transfer induced mouse behavioral features; candidate metabolites improved model phenotypes. Recipient mouse behaviors are not human ASD causation or remission, and donor phenotypes include diet-related differences.", "carries_number": false, "load_bearing_for": [ "SC2", "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": "2026-10-04", "note": "" }, { "id": "C34", "text": "A small probiotic RCT improved selected flexibility/stress measures in healthy older adults. Multiple outcomes and short follow-up limit general clinical interpretation; BDNF correlation is not manipulated mediation.", "carries_number": false, "load_bearing_for": [ "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": "2026-10-04", "note": "" }, { "id": "C35", "text": "Depression-associated donor stool induced anhedonia/anxiety and metabolic features in depleted rats. Recipient effects establish capacity in a model, not primary causation of endogenous human depression.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "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": "2026-10-04", "note": "" }, { "id": "C36", "text": "A bundled antibiotic/cleanse/FMT open-label ASD study reported persistent GI and behavioral improvement. Eighteen participants without randomized masking cannot separate expectation, co-interventions or natural trajectory.", "carries_number": false, "load_bearing_for": [ "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": "2026-10-04", "note": "" }, { "id": "C37", "text": "Multi-cohort proline associations were combined with supplementation, transfer and transporter/RNAi or bacterial manipulations in models. Human dietary and depression relationships remain observational; cross-species behaviors do not establish clinical efficacy.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 37 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C38", "text": "A short probiotic/placebo comparison in test-anxious students reported improved symptom questionnaires. Short, selected student symptoms are not durable clinical psychiatric remission or established microbial mediation.", "carries_number": false, "load_bearing_for": [ "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": "2026-10-04", "note": "" }, { "id": "C39", "text": "Selected Bacteroides species reproduced behavioral/neurogenesis effects in antibiotic-treated mice whereas another species did not. Species and host-metabolite specificity constrain the result; the exact human primary pathway is not established.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 39 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C40", "text": "Human adolescent signatures and Roseburia/healthy-transfer rescue linked tryptophan pathways to stressed-mouse phenotypes. Sertraline alters human signatures; model rescue is not a randomized human mediator test.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 40 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C41", "text": "Donor-recipient subspecies interactions associated with transfer and outcomes across FMT datasets. Reanalysis of shared datasets does not create independent clinical intervention lines or establish outcome mediation.", "carries_number": false, "load_bearing_for": [ "SC1", "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": "2026-10-04", "note": "" }, { "id": "C42", "text": "IBD microbiome/metabolome differences and classifiers replicated across discovery/validation cohorts. Inflammatory state and reverse causation remain possible; linked erratum-body impact is unresolved.", "carries_number": false, "load_bearing_for": [ "SC1", "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": "2026-10-04", "note": "" }, { "id": "C43", "text": "Population cohorts linked microbial composition to numerous covariates, especially stool consistency and medications. Associations identify confounders, not causal direction or autonomous regulation.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 43 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C44", "text": "The ASD cohort showed negligible direct diagnostic associations and supported diet/stool-mediated signatures. Observational mediation does not prove all ASD microbial findings are reactive; correction impact is not fully examined.", "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": "2026-10-04", "note": "" }, { "id": "C45", "text": "Neuroactive taxonomic/function potential associated with depression and quality of life in population cohorts. Covariate adjustment cannot exclude reverse causation or demonstrate pathway activity and necessity.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 45 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C46", "text": "Stratification distinguished metformin-associated microbial signatures from untreated T2D signatures. Medication confounding is material; associations do not prove the microbial fraction of drug efficacy; correction remains attached.", "carries_number": true, "load_bearing_for": [ "SC1", "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": "2026-10-04", "note": "" }, { "id": "C47", "text": "A targeted commensal bile-acid gene deletion in a complex community altered host colon inflammation. Gene-level specificity is stronger than dysbiosis association but does not establish a universal human regulator.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 47 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C48", "text": "New CRC tissue/fecal profiling linked microbial methyl-donor features to host methylation patterns. Original observational data are admitted; the accompanying meta-analysis is not an additional primary source or causal perturbation.", "carries_number": false, "load_bearing_for": [ "SC1", "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": "2026-10-04", "note": "" }, { "id": "C49", "text": "Obese/lean twin communities and cultured collections transferred adiposity; cohousing rescue succeeded or failed depending on diet. Food intake contrasts do not explain adiposity here, but dietary dependence directly limits microbial autonomy; mild glucose changes are not established insulin resistance.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 49 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: S2, S4, S8. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C50", "text": "B. fragilis improved barrier and selected behaviors in maternal-immune-activation offspring; a candidate metabolite induced behavioral abnormalities. Developmental immune injury precedes the microbial intervention; model modulation does not establish human ASD initiation.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 50 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C51", "text": "Eosinophil-deficient/colonization contrasts linked microbial IL-33 responses to gut physiological homeostasis. Host immune cells gate the microbial effect; the pathway is mutualistic rather than autonomous.", "carries_number": true, "load_bearing_for": [ "SC2", "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": "2026-10-04", "note": "" }, { "id": "C52", "text": "C. scindens or bile-acid administration altered metabolic/obesity phenotypes in mice alongside human associations. Host bile-acid substrate and diet are required context; correction details remain unexamined.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 52 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C53", "text": "H. hepaticus-induced tumor control depended on Tfh cells, with host-cell rescue in a deficient mouse setting. Host immune epistasis supplies a specific causal route; it does not prove broad human cancer benefit.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 53 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C54", "text": "Antibiotic, mouse genetic and Lactobacillus/macrophage rescue contrasts linked microbes to postnatal niches and NEC severity. Developmental host-cell dependence and antibiotic pleiotropy limit autonomy; erratum-body details were not examined.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 54 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C55", "text": "TACITO primary 12-month PFS was 70% versus 41%, P=.053; secondary median PFS favored FMT. The primary superiority threshold was not met; secondary nominal signals, small groups and concurrent cancer drugs do not prove autonomous regulation.", "carries_number": true, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 55 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: Sec5, Sec17, Sec29, Sec30. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C56", "text": "LUMINate reported single-arm clinical response signals; reintroducing lost baseline bacterial cocktails impaired ICI efficacy in mouse recipients. Clinical FMT benefit lacks a randomized counterfactual; the controlled mouse add-back establishes only recipient/treatment-context mediation.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC4" ], "source_ns": [ 56 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: Sec7, Sec41. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C57", "text": "Adjunct FMT improved selected depression scores but not week-8 remission versus placebo with escitalopram. Statistical bile-acid mediation is not selective causal manipulation; durable remission and autonomous monotherapy are not shown.", "carries_number": true, "load_bearing_for": [ "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": "2026-10-04", "note": "" }, { "id": "C58", "text": "Butyrate/propionate promoted peripheral Treg generation with CNS1 dependence; acetate lacked the corresponding activity. Defined metabolite/host enhancer logic supports communication, not a universal human master regulator.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 58 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C59", "text": "C. scindens/consortium transfer reduced CDI illness in mice; bile-salt sequestration neutralized inhibition ex vivo. The human cohort is observational and the bile-acid blockade is ex vivo, not in vivo gene-specific necessity or human mediation.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 59 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: BODY, S4, S5. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C60", "text": "Short animal/plant diets rapidly altered human microbial structure and expression. This demonstrates diet-to-microbiome direction; downstream health mediation was not isolated.", "carries_number": false, "load_bearing_for": [ "SC1", "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": "2026-10-04", "note": "" }, { "id": "CSC1", "text": "SC1 is reproducible association. Medication, stool consistency, diet and disease-state adjustment change the signature; observational replication cannot identify causal direction [42–46].", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 11, 13, 16, 17, 18, 20, 21, 24, 29, 32, 35, 37, 40, 41, 42, 43, 44, 45, 46, 48, 52, 55, 56, 60 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-04", "note": "" }, { "id": "CSC2", "text": "SC2 reaches Ζ within specified rodent contexts. Defined bacteria/metabolites, transfer and rescue converge with host receptor/enhancer or immune-cell epistasis; diet and species-negative controls map limits [22,23,25,47,49,53,58]. This is causal modulation, not endogenous human primacy.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 10, 12, 14, 16, 17, 18, 19, 22, 23, 24, 25, 33, 35, 37, 39, 40, 47, 49, 50, 51, 52, 53, 54, 56, 58, 59 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-04", "note": "" }, { "id": "CSC3", "text": "SC3 reaches Ζ for recurrent post-antibiotic CDI restoration. Randomized spore/defined-consortium clinical outcomes, live-versus-filtered component discrimination, and a distinct strain/bile-acid rescue route converge [1,3,7,59]. The human precise mediator and universally required strain remain unresolved.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 1, 2, 3, 4, 5, 6, 7, 8, 59 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-04", "note": "" }, { "id": "CSC4", "text": "SC4 remains Γ for autonomous upstream multi-system primacy. UC treatment causality and context-specific model pathways are real, but no selective intervention demonstrates independence from substrate, host physiology or concurrent drugs across the claimed systems [9–15,26–32,55–60].", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 1, 2, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 38, 41, 42, 43, 44, 45, 46, 48, 49, 51, 55, 56, 57, 60 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-04", "note": "" }, { "id": "CH", "text": "Defined microbial functions causally alter phenotypes and recurrent-CDI restoration is strongly supported; autonomous upstream control of systemic human health remains Γ.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 1, 3, 7, 26, 49, 55, 57 ], "verification": "verified", "verified_against": "Bounded synthesis of examined sources; score is adjudication.", "verified_on": "2026-10-04", "note": "" } ], "citation_ledger": [ { "n": 1, "citation": "Feuerstadt P, Louie TJ, Lashner B et al. 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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": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID31263284", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C9", "CSC4" ] }, { "n": 10, "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": "2026-10-04", "status_checked_on": "2026-10-04", "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": [ "C10", "CSC2", "CSC4" ] }, { "n": 11, "citation": "Li L, Li R, Tian Q et al. Effects of healthy low-carbohydrate diet and time-restricted eating on weight and gut microbiome in adults with overweight or obesity: Feeding RCT. Cell reports. Medicine. 2024.", "tier": "A", "kind": "rct", "pmid": "39454570", "doi": "10.1016/j.xcrm.2024.101801", "url": "https://pubmed.ncbi.nlm.nih.gov/39454570/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID39454570", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C11", "CSC1", "CSC4" ] }, { "n": 12, "citation": "Mishra SP, Wang B, Jain S et al. A mechanism by which gut microbiota elevates permeability and inflammation in obese/diabetic mice and human gut. Gut. 2023.", "tier": "A", "kind": "primary", "pmid": "36948576", "doi": "10.1136/gutjnl-2022-327365", "url": "https://pubmed.ncbi.nlm.nih.gov/36948576/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID36948576", "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", "CSC4" ] }, { "n": 13, "citation": "Meslier V, Laiola M, Roager HM et al. Mediterranean diet intervention in overweight and obese subjects lowers plasma cholesterol and causes changes in the gut microbiome and metabolome independently of energy intake. Gut. 2020.", "tier": "A", "kind": "rct", "pmid": "32075887", "doi": "10.1136/gutjnl-2019-320438", "url": "https://pubmed.ncbi.nlm.nih.gov/32075887/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID32075887", "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": "Zhang Y, Liu R, Chen Y et al. Akkermansia muciniphila supplementation in patients with overweight/obese type 2 diabetes: Efficacy depends on its baseline levels in the gut. Cell metabolism. 2025.", "tier": "A", "kind": "rct", "pmid": "39879980", "doi": "10.1016/j.cmet.2024.12.010", "url": "https://pubmed.ncbi.nlm.nih.gov/39879980/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID39879980", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C14", "CSC2", "CSC4" ] }, { "n": 15, "citation": "Wu Z, Zhang B, Chen F et al. Fecal microbiota transplantation reverses insulin resistance in type 2 diabetes: A randomized, controlled, prospective study. Frontiers in cellular and infection microbiology. 2022.", "tier": "A", "kind": "rct", "pmid": "36704100", "doi": "10.3389/fcimb.2022.1089991", "url": "https://pubmed.ncbi.nlm.nih.gov/36704100/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID36704100", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C15", "CSC4" ] }, { "n": 16, "citation": "Routy B, Le Chatelier E, Derosa L et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science (New York, N.Y.). 2018.", "tier": "A", "kind": "primary", "pmid": "29097494", "doi": "10.1126/science.aan3706", "url": "https://pubmed.ncbi.nlm.nih.gov/29097494/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID29097494", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C16", "CSC1", "CSC2", "CSC4" ] }, { "n": 17, "citation": "Gopalakrishnan V, Spencer CN, Nezi L et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science (New York, N.Y.). 2018.", "tier": "A", "kind": "primary", "pmid": "29097493", "doi": "10.1126/science.aan4236", "url": "https://pubmed.ncbi.nlm.nih.gov/29097493/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID29097493", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C17", "CSC1", "CSC2", "CSC4" ] }, { "n": 18, "citation": "Spencer CN, McQuade JL, Gopalakrishnan V et al. Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response. Science (New York, N.Y.). 2021.", "tier": "A", "kind": "primary", "pmid": "34941392", "doi": "10.1126/science.aaz7015", "url": "https://pubmed.ncbi.nlm.nih.gov/34941392/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID34941392", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C18", "CSC1", "CSC2", "CSC4" ] }, { "n": 19, "citation": "Phelps CM, Willis NB, Duan T et al. Exercise-induced microbiota metabolite enhances CD8 T cell antitumor immunity promoting immunotherapy efficacy. Cell. 2025.", "tier": "A", "kind": "primary", "pmid": "40639377", "doi": "10.1016/j.cell.2025.06.018", "url": "https://pubmed.ncbi.nlm.nih.gov/40639377/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID40639377", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C19", "CSC2", "CSC4" ] }, { "n": 20, "citation": "Davar D, Dzutsev AK, McCulloch JA et al. Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients. Science (New York, N.Y.). 2021.", "tier": "A", "kind": "primary", "pmid": "33542131", "doi": "10.1126/science.abf3363", "url": "https://pubmed.ncbi.nlm.nih.gov/33542131/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "Davar-FMT-antiPD1", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C20", "CSC1", "CSC4" ] }, { "n": 21, "citation": "Baruch EN, Youngster I, Ben-Betzalel G et al. Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients. Science (New York, N.Y.). 2021.", "tier": "A", "kind": "primary", "pmid": "33303685", "doi": "10.1126/science.abb5920", "url": "https://pubmed.ncbi.nlm.nih.gov/33303685/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "Baruch-FMT-antiPD1", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C21", "CSC1", "CSC4" ] }, { "n": 22, "citation": "Sivan A, Corrales L, Hubert N et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science (New York, N.Y.). 2015.", "tier": "A", "kind": "primary", "pmid": "26541606", "doi": "10.1126/science.aac4255", "url": "https://pubmed.ncbi.nlm.nih.gov/26541606/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID26541606", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C22", "CSC2" ] }, { "n": 23, "citation": "Mager LF, Burkhard R, Pett N et al. Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy. Science (New York, N.Y.). 2020.", "tier": "A", "kind": "primary", "pmid": "32792462", "doi": "10.1126/science.abc3421", "url": "https://pubmed.ncbi.nlm.nih.gov/32792462/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID32792462", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C23", "CSC2" ] }, { "n": 24, "citation": "Matson V, Fessler J, Bao R et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science (New York, N.Y.). 2018.", "tier": "A", "kind": "primary", "pmid": "29302014", "doi": "10.1126/science.aao3290", "url": "https://pubmed.ncbi.nlm.nih.gov/29302014/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID29302014", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C24", "CSC1", "CSC2" ] }, { "n": 25, "citation": "Park JS, Gazzaniga FS, Wu M et al. Targeting PD-L2-RGMb overcomes microbiome-related immunotherapy resistance. Nature. 2023.", "tier": "A", "kind": "primary", "pmid": "37138075", "doi": "10.1038/s41586-023-06026-3", "url": "https://pubmed.ncbi.nlm.nih.gov/37138075/", "status_flags": [ "ErratumIn: PMID37264079" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID37138075", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C25", "CSC2" ] }, { "n": 26, "citation": "Paramsothy S, Kamm MA, Kaakoush NO et al. Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet (London, England). 2017.", "tier": "A", "kind": "rct", "pmid": "28214091", "doi": "10.1016/S0140-6736(17)30182-4", "url": "https://pubmed.ncbi.nlm.nih.gov/28214091/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID28214091", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C26", "CSC4", "CH" ] }, { "n": 27, "citation": "Haifer C, Paramsothy S, Kaakoush NO et al. Lyophilised oral faecal microbiota transplantation for ulcerative colitis (LOTUS): a randomised, double-blind, placebo-controlled trial. The lancet. 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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": "2026-10-04", "status_checked_on": "2026-10-04", "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": [ "C60", "CSC1", "CSC4" ] } ], "independence_basis": { "required": true, "lines": [ { "label": "SC3 defined microbial clinical product", "sources": [ 1, 3 ], "excludes_error": "Defined/spore randomized recurrence benefit reduces expectation/natural-resolution explanations and crude nonmicrobial donor-matrix confounding; the two products remain one clinical intervention family, not two orthogonal lines." }, { "label": "SC3 live-versus-filter component discriminator", "sources": [ 7 ], "excludes_error": "A randomized contrast changes the live component while retaining donor-derived material; it challenges a purely soluble-product explanation. Processing also changes components, so it is supporting discrimination rather than absolute necessity." }, { "label": "SC2/SC3 strain and biochemical rescue", "sources": [ 59 ], "excludes_error": "Controlled specific-strain transfer with illness and ex vivo bile-salt sequestration addresses taxonomic-signature correlation and supplies a pathway distinct from human expectation. Ex vivo mediation is not human in vivo necessity." }, { "label": "SC2 host genetic/immune epistasis", "sources": [ 25, 53, 58 ], "excludes_error": "Host receptor, Tfh and enhancer perturbations distinguish an actual host-microbe route from merely transferring stool contents or recipient housing artifacts." }, { "label": "SC2 cultured community and diet discriminator", "sources": [ 49 ], "excludes_error": "Cultured collections recapitulate adiposity and diet-switch rescue maps substrate dependence, addressing nonbacterial donor components and simple food-intake confounding." } ], "shared_failure_mode_checked": true, "note": "At Ζ, independence is assigned to distinct failure modes, not paper counts. Human product trials share modality; RBX2b is borrowed by phase3 and is one family. LUMINate reanalyses Davar/Baruch and counts no new independent patient cohorts. Clinical controls, defined microbial precision and host/biochemical epistasis cover different weaknesses; no one expectation, crude-matrix or sequencing error explains them all. Cross-system success remains narrower than autonomous human primacy." }, "consensus_validation": { "completed": true, "status": "documented_historical_discovery_and_reconciliation", "provider": "Consensus", "provider_mode": "Historical browser/connector use as recorded in the source artifacts", "local_audit_date": "2026-10-09", "primary_comparison_count": null, "reported_usage": [], "grade_changed": false, "score_before": { "hsef_level": "Γ", "hsef_descriptor": "Mechanistically plausible, partial system support", "confidence": "Moderate", "confidence_rationale": "60 primary reports with 4 selected partial-body examinations; density, heterogeneous controls and incomplete access set the confidence, not correctness.", "rests_on_non_peer_reviewed_work": false, "rationale": "The preregistered scope-matched SC4 gate returns Γ. Positive recurrent-CDI restoration reaches Ζ and selected UC packages establish bounded human causal benefit; neither demonstrates autonomous multi-system primacy. Weakest-link would return Β because SC1 deliberately asks an observational existence question." }, "score_after": { "hsef_level": "Γ", "hsef_descriptor": "Mechanistically plausible, partial system support", "confidence": "Moderate", "confidence_rationale": "60 primary reports with 4 selected partial-body examinations; density, heterogeneous controls and incomplete access set the confidence, not correctness.", "rests_on_non_peer_reviewed_work": false, "rationale": "The preregistered scope-matched SC4 gate returns Γ. Positive recurrent-CDI restoration reaches Ζ and selected UC packages establish bounded human causal benefit; neither demonstrates autonomous multi-system primacy. Weakest-link would return Β because SC1 deliberately asks an observational existence question." }, "independent_blinded_audit": false, "raw_receipts": [ { "path": "deliverables\\hsef_v53_popularity_batch_2026-10-04\\microbiome-master-regulator\\consensus\\evidence-cards.json", "sha256": "762c69ef9fd1bae72aab2c99c61fa65704f9ba46886b0be666e3d4fbed647fe6" }, { "path": "deliverables\\hsef_v53_popularity_batch_2026-10-04\\microbiome-master-regulator\\consensus\\evidence-cards.md", "sha256": "74f7a37ba22e6bcd109cd4e2f0bd5006a251a031e3338c1986d51c34607b9887" }, { "path": "deliverables\\hsef_v53_popularity_batch_2026-10-04\\microbiome-master-regulator\\discovery\\consensus-targeted.json", "sha256": "b204877e31b4d36ddccb60f0ffb75dfd6628d543d4b9de032daf231e40090873" } ], "limitations": "This verifies documented historical use and links the record to the final edition. It adds no primary-source, full-text, independence or verification credit. 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