{ "$schema_version": "5.3", "review_mode": "fresh", "claim_restatement": { "index_wording": "Leaky Gut Syndrome", "entry_form": "phenomenon", "gradeable_restatement": "Increased intestinal epithelial permeability is a primary initiating cause of human autoimmune, inflammatory and metabolic disease through translocation of microbial products.", "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": "Leaky Gut Syndrome", "central_claim": "Increased intestinal epithelial permeability is a primary initiating cause of human autoimmune, inflammatory and metabolic disease through translocation of microbial products.", "proposed_mechanism": "Increased intestinal epithelial permeability is a primary initiating cause of human autoimmune, inflammatory and metabolic disease through translocation of microbial products.", "claimed_scope": "Human T1D, rheumatoid arthritis and metabolic disease; animal mechanisms are separate supporting scopes.", "claimed_level": [ "initiation", "necessity", "generalization" ], "is_conjunctive": true, "conjunctive_note": "The index specifies scope-matched assessment. SC6 carries the broad cross-disease initiating claim; SC3–SC5 retain separate disease applications. Disease-specific therapeutic effects cannot carry general initiation." }, "rubric_routing": { "primary_rubric": "04-microbiome-systemic.md", "secondary_rubrics": [ "05-immunology-inflammation.md", "06-metabolism-aging.md" ], "index_notes_applied": [ "The index specifies scope-matched assessment. SC6 carries the broad cross-disease initiating claim; SC3–SC5 retain separate disease applications. Disease-specific therapeutic effects cannot carry general initiation." ], "rubric_fit_note": "Exact archived v5.3 framework. Any stale index empirical framing is rechecked against primary results." }, "subclaim_matrix": { "subclaims": [ { "id": "SC1", "statement": "Intestinal epithelial permeability is elevated in the assessed human disease states.", "subclaim_type": "existence", "scope": "human type 1 diabetes, rheumatoid arthritis and metabolic disease", "claimed_scope": "human type 1 diabetes, rheumatoid arthritis and metabolic disease", "governing_rubric": "04-microbiome-systemic.md", "key_evidence_anchor": "Validated permeability measures, with assay identity and baseline disease controls", "hsef_level": "Β", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Functional measures support abnormalities in some cohorts, with normal ratios or fasting permeability elsewhere; kit signals alone do not establish permeability [7–11,32,68]." }, { "id": "SC2", "statement": "Increased epithelial permeability permits microbial-product translocation that causally worsens systemic pathology.", "subclaim_type": "mechanism", "scope": "defined experimental barrier perturbations and human inference kept separate", "claimed_scope": "defined experimental barrier perturbations and human inference kept separate", "governing_rubric": "04-microbiome-systemic.md", "key_evidence_anchor": "Selective barrier perturbation, translocation measures, disease outcomes and rescue", "hsef_level": "Ε", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Selective MLCK intervention and stage-specific deletion, plus defined gut-joint and alcohol pathways, establish bounded causal contributions. DSS, forced LPS and vascular-only manipulations are not counted as isolated epithelial causation [1,13–16,23–24,63]." }, { "id": "SC3", "statement": "Increased epithelial permeability initiates human type 1 diabetes.", "subclaim_type": "primacy", "scope": "human type 1 diabetes before diagnosis", "claimed_scope": "human type 1 diabetes before diagnosis", "governing_rubric": "04-microbiome-systemic.md", "key_evidence_anchor": "Prospective antecedence and barrier-selective prevention with clinical outcomes", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Preclinical human associations and animal perturbations support plausibility, but no examined barrier-selective human prevention result establishes initiation. Bosi compares disease stages after autoimmunity is already present [44,64]." }, { "id": "SC4", "statement": "Increased epithelial permeability initiates human rheumatoid arthritis.", "subclaim_type": "primacy", "scope": "human rheumatoid arthritis before diagnosis", "claimed_scope": "human rheumatoid arthritis before diagnosis", "governing_rubric": "04-microbiome-systemic.md", "key_evidence_anchor": "Prediagnostic measurements and disease prevention after barrier-selective intervention", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Tajik combines human risk associations with post-immunization mouse rescue; the commercial serum assay has specificity limitations and there is no human prevention randomization [1,10,43,46,61,67]." }, { "id": "SC5", "statement": "Increased epithelial permeability initiates human metabolic disease.", "subclaim_type": "primacy", "scope": "human obesity, insulin resistance and metabolic liver disease", "claimed_scope": "human obesity, insulin resistance and metabolic liver disease", "governing_rubric": "04-microbiome-systemic.md", "key_evidence_anchor": "Selective barrier manipulation with adiposity/metabolic disease outcomes and diet controls", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Mouse endotoxin biology is causal but does not isolate human epithelial initiation. Human carrageenan permeability changed with null primary metabolic endpoints, and obesity can occur without measured barrier failure [20–22,25,27,30,50,68]." }, { "id": "SC6", "statement": "The same epithelial leak mechanism is the primary initiating explanation across these human disease classes.", "subclaim_type": "generalization", "scope": "human autoimmune, inflammatory and metabolic disease", "claimed_scope": "human autoimmune, inflammatory and metabolic disease", "governing_rubric": "04-microbiome-systemic.md", "key_evidence_anchor": "Convergent selective causal evidence across the prespecified disease classes", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "The animal and ex vivo mechanisms make cross-disease leak biologically plausible; distinct upstream triggers, barriers and null endpoints prevent a shared initiating claim in humans [1,20,25,27,51–52,63,66]." } ], "aggregation_rule": "scope-matched", "aggregation_preregistered": true, "aggregation_rationale": "The index specifies scope-matched assessment. SC6 carries the broad cross-disease initiating claim; SC3–SC5 retain separate disease applications. Disease-specific therapeutic effects cannot carry general initiation.", "primary_subclaim_id": "SC6", "aggregation_derivation": "Scope-matched SC6 returns Γ. The preregistered human cross-disease initiator has partial experimental support but lacks a selective causal test in its claimed scope. SC2 reaches Ε for mapped experimental contributions; it cannot carry the human initiation claims. Weakest-link would return Β because the descriptive association subclaim is Β; primary-subclaim and scope-matched return Γ.", "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": "M2", "is_nominal": false, "name": "Permissive second-hit amplifier", "core_claim": "An antecedent immune, dietary or toxic process makes barrier changes disease-modifying.", "explains_what_nominal_does_not": "An antecedent immune, dietary or toxic process makes barrier changes disease-modifying.", "strongest_supporting_evidence": [ "No spontaneous colitis despite CA-MLCK leak, followed by accelerated transfer colitis, and stage-specific MLCK deletion distinguish contribution from sufficiency [62–63]." ], "strongest_contradictory_evidence": [ "Human incidence mediation remains untested; some barrier perturbations are pleiotropic." ], "hsef_level_for_this_model": "Ε", "rationale": "No spontaneous colitis despite CA-MLCK leak, followed by accelerated transfer colitis, and stage-specific MLCK deletion distinguish contribution from sufficiency [62–63]. Human incidence mediation remains untested; some barrier perturbations are pleiotropic." }, { "rank_in_tournament": 2, "model_id": "M3", "is_nominal": false, "name": "Multi-tier epithelial/vascular/hepatic firewall", "core_claim": "Systemic exposure depends on successive containment and clearance layers.", "explains_what_nominal_does_not": "Systemic exposure depends on successive containment and clearance layers.", "strongest_supporting_evidence": [ "Endothelial beta-catenin preservation limited NASH despite epithelial bacterial translocation, and Kupffer-cell clearance studies identify a separate hepatic barrier [51–52,66]." ], "strongest_contradictory_evidence": [ "Layer-specific experiments are mouse-dominant, and the vascular GOF experiment was not blinded or randomized." ], "hsef_level_for_this_model": "Ε", "rationale": "Endothelial beta-catenin preservation limited NASH despite epithelial bacterial translocation, and Kupffer-cell clearance studies identify a separate hepatic barrier [51–52,66]. Layer-specific experiments are mouse-dominant, and the vascular GOF experiment was not blinded or randomized." }, { "rank_in_tournament": 3, "model_id": "M5", "is_nominal": false, "name": "Reactive permeability and shared diet/immune causes", "core_claim": "Disease, glycemia or inflammation can cause leak and establish feedback loops.", "explains_what_nominal_does_not": "Disease, glycemia or inflammation can cause leak and establish feedback loops.", "strongest_supporting_evidence": [ "Epithelial GLUT2 and glucose-control interventions demonstrate the hyperglycemia-to-leak arrow; arthritis disrupts gut resolving mediators [20,43]." ], "strongest_contradictory_evidence": [ "Selective barrier rescue also helps in defined contexts, so reaction alone cannot explain the entire literature." ], "hsef_level_for_this_model": "Ε", "rationale": "Epithelial GLUT2 and glucose-control interventions demonstrate the hyperglycemia-to-leak arrow; arthritis disrupts gut resolving mediators [20,43]. Selective barrier rescue also helps in defined contexts, so reaction alone cannot explain the entire literature." }, { "rank_in_tournament": 4, "model_id": "M4", "is_nominal": false, "name": "Assay artifact in zonulin epidemiology", "core_claim": "Some serum associations measure an unvalidated protein proxy rather than epithelial flux.", "explains_what_nominal_does_not": "Some serum associations measure an unvalidated protein proxy rather than epithelial flux.", "strongest_supporting_evidence": [ "Recombinant-protein, immunocapture, genotype and Ussing-chamber checks undermine named commercial kits [32,61,67]." ], "strongest_contradictory_evidence": [ "Sugar permeability and direct biopsy results persist independently of zonulin kits; artifact cannot explain all real barrier defects." ], "hsef_level_for_this_model": "Ε", "rationale": "Recombinant-protein, immunocapture, genotype and Ussing-chamber checks undermine named commercial kits [32,61,67]. Sugar permeability and direct biopsy results persist independently of zonulin kits; artifact cannot explain all real barrier defects." }, { "rank_in_tournament": 5, "model_id": "M1", "is_nominal": true, "name": "Permeability as primary systemic initiator", "core_claim": "A common epithelial leak starts the assessed human diseases.", "explains_what_nominal_does_not": "A common epithelial leak starts the assessed human diseases.", "strongest_supporting_evidence": [ "Prediagnostic associations and mouse gut-joint rescue are the strongest supporting case [1,44,60,64]." ], "strongest_contradictory_evidence": [ "Immune priming precedes rescue, leak alone can lack disease, metabolic endpoints can be null and vascular/liver mechanisms cannot substitute for epithelial initiation [25,27,52,62–63]." ], "hsef_level_for_this_model": "Γ", "rationale": "Prediagnostic associations and mouse gut-joint rescue are the strongest supporting case [1,44,60,64]. Immune priming precedes rescue, leak alone can lack disease, metabolic endpoints can be null and vascular/liver mechanisms cannot substitute for epithelial initiation [25,27,52,62–63]." } ], "tournament_summary": "Descriptive comparison; does not modify the nominal score. PMID31419514 distinguishes the top amplifier model from a purely epithelial explanation: endothelial protection left epithelial translocation possible while limiting later disease. PMID19027740 provides the clearest second-hit versus standalone comparison. Neither is a human prevention trial.", "study_separating_rank1_from_rank2": "PMID31419514 distinguishes the top amplifier model from a purely epithelial explanation: endothelial protection left epithelial translocation possible while limiting later disease. PMID19027740 provides the clearest second-hit versus standalone comparison. Neither is a human prevention trial.", "nominal_wins_only_by_funding_artifact": false, "level_unchanged_by_tournament": true }, "evidence_inventory": [ { "n": 1, "pmid": "32332732", "title": "Targeting zonulin and intestinal epithelial barrier function to prevent onset of arthritis.", "citation": "Tajik N, Frech M, Schulz O et al. Targeting zonulin and intestinal epithelial barrier function to prevent onset of arthritis. Nature communications. 2020.", "doi": "10.1038/s41467-020-15831-7", "pmcid": "PMC7181728", "url": "https://pubmed.ncbi.nlm.nih.gov/32332732/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32332732/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "GUT-JOINT-TAJIK-2020", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph1, 1:Results:paragraph3, 1:Results:paragraph5, 1:Results:paragraph6, 1:Results:paragraph7, 1:Results:paragraph8, 1:Results:paragraph9, 1:Results:paragraph10, 1:Results:paragraph12, 1:Results:paragraph13, 1:Results:paragraph14, 1:Results:paragraph15, 2:Discussion:paragraph1, 2:Discussion:paragraph3, 3:Methods:paragraph0, 3:Methods:paragraph1, 3:Methods:paragraph8, 3:Methods:paragraph24. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC4", "SC6" ], "favors_models": [], "evidence_class": "Strong", "system": "animal plus human observational", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Larazotide reduced CIA severity and cell trafficking after collagen/adjuvant immunization; pre-RA serum signals predicted transition.", "what_it_does_not_show": "The human arm was observational and used Cusabio; immunization preceded leak. This establishes a checkpoint in induced arthritis, not human disease initiation.", "confounders_present": [ "The human arm was observational and used Cusabio; immunization preceded leak. This establishes a checkpoint in induced arthritis, not human disease 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": 2, "pmid": "28761156", "title": "Aggravation of collagen-induced arthritis by orally administered Porphyromonas gingivalis through modulation of the gut microbiota and gut immune system.", "citation": "Sato K, Takahashi N, Kato T et al. Aggravation of collagen-induced arthritis by orally administered Porphyromonas gingivalis through modulation of the gut microbiota and gut immune system. Scientific reports. 2017.", "doi": "10.1038/s41598-017-07196-7", "pmcid": "PMC5537233", "url": "https://pubmed.ncbi.nlm.nih.gov/28761156/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28761156/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID28761156", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "Oral P. gingivalis aggravated induced arthritis and altered gut immunity and microbiota.", "what_it_does_not_show": "Multiple bacterial functions and prior collagen induction prevent assigning the effect specifically to barrier leak.", "confounders_present": [ "Multiple bacterial functions and prior collagen induction prevent assigning the effect specifically to barrier leak." ], "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": "38493812", "title": "Irisin delays the onset of type 1 diabetes in NOD mice by enhancing intestinal barrier.", "citation": "Sun Y, Wang Y, Lin Z et al. Irisin delays the onset of type 1 diabetes in NOD mice by enhancing intestinal barrier. International journal of biological macromolecules. 2024.", "doi": "10.1016/j.ijbiomac.2024.130857", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/38493812/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38493812/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID38493812", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal plus human observational", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "Irisin treatment delayed NOD diabetes with improved barrier and islet inflammation.", "what_it_does_not_show": "Exercise-hormone effects on energy expenditure and immunity confound barrier-specific mediation; human samples were from new-onset disease.", "confounders_present": [ "Exercise-hormone effects on energy expenditure and immunity confound barrier-specific mediation; human samples were from new-onset disease." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 4, "pmid": "33912174", "title": "Aberrant Gut Microbiome Contributes to Intestinal Oxidative Stress, Barrier Dysfunction, Inflammation and Systemic Autoimmune Responses in MRL/lpr Mice.", "citation": "Wang H, Wang G, Banerjee N et al. Aberrant Gut Microbiome Contributes to Intestinal Oxidative Stress, Barrier Dysfunction, Inflammation and Systemic Autoimmune Responses in MRL/lpr Mice. Frontiers in immunology. 2021.", "doi": "10.3389/fimmu.2021.651191", "pmcid": "PMC8071869", "url": "https://pubmed.ncbi.nlm.nih.gov/33912174/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33912174/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID33912174", "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", "SC6" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "N-acetylcysteine attenuated systemic autoimmunity alongside microbial and barrier changes in MRL/lpr mice.", "what_it_does_not_show": "Antioxidant pleiotropy and lupus genotype prevent a selective test of spontaneous human barrier initiation.", "confounders_present": [ "Antioxidant pleiotropy and lupus genotype prevent a selective test of spontaneous human barrier 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": 5, "pmid": "12489925", "title": "Mucosal inflammation in a genetic model of spontaneous type I diabetes mellitus.", "citation": "Hardin JA, Donegan L, Woodman RC et al. Mucosal inflammation in a genetic model of spontaneous type I diabetes mellitus. Canadian journal of physiology and pharmacology. 2002.", "doi": "10.1139/y02-138", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/12489925/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/12489925/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID12489925", "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": "Weak", "system": "animal observational", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "Diabetes-prone BB rats showed intestinal inflammatory activity before and after diabetes.", "what_it_does_not_show": "Genotype, inflammation and barrier changes were not separated by a selective manipulation.", "confounders_present": [ "Genotype, inflammation and barrier changes were not separated by a selective manipulation." ], "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": "31182588", "title": "Loss of gut barrier integrity triggers activation of islet-reactive T cells and autoimmune diabetes.", "citation": "Sorini C, Cosorich I, Lo Conte M et al. Loss of gut barrier integrity triggers activation of islet-reactive T cells and autoimmune diabetes. Proceedings of the National Academy of Sciences of the United States of America. 2019.", "doi": "10.1073/pnas.1814558116", "pmcid": "PMC6660755", "url": "https://pubmed.ncbi.nlm.nih.gov/31182588/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31182588/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID31182588", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Results:paragraph2, 0:Results:paragraph3, 0:Results:paragraph4, 0:Results:paragraph5. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "DSS colitis activated islet-reactive T cells and diabetes in BDC2.5 NOD mice; antibiotics prevented activation.", "what_it_does_not_show": "DSS injury and a transgenic diabetogenic T-cell repertoire are combined perturbations, not isolated endogenous epithelial leak in humans.", "confounders_present": [ "DSS injury and a transgenic diabetogenic T-cell repertoire are combined perturbations, not isolated endogenous epithelial leak in humans." ], "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": "10067726", "title": "Altered intestinal permeability to mannitol in diabetes mellitus type I.", "citation": "Carratù R, Secondulfo M, de Magistris L et al. Altered intestinal permeability to mannitol in diabetes mellitus type I. Journal of pediatric gastroenterology and nutrition. 1999.", "doi": "10.1097/00005176-199903000-00010", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/10067726/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/10067726/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID10067726", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Mannitol recovery increased in established type 1 diabetes while the cellobiose/mannitol ratio remained normal.", "what_it_does_not_show": "Probe absorption is not interchangeable with a selective macromolecular leak; disease duration can confound direction.", "confounders_present": [ "Probe absorption is not interchangeable with a selective macromolecular leak; disease duration can confound direction." ], "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": "3519337", "title": "Abnormal intestinal permeability to sugars in diabetes mellitus.", "citation": "Mooradian AD, Morley JE, Levine AS et al. Abnormal intestinal permeability to sugars in diabetes mellitus. Diabetologia. 1986.", "doi": "10.1007/BF00454879", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/3519337/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/3519337/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID3519337", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Both sugar recoveries increased in diabetic patients without a group difference in their ratio.", "what_it_does_not_show": "Raw recovery and differential permeability diverged; established disease cannot establish initiation.", "confounders_present": [ "Raw recovery and differential permeability diverged; established disease cannot establish 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": 9, "pmid": "1906938", "title": "Intestinal mucosal permeability in inflammatory rheumatic diseases. I. Role of antiinflammatory drugs.", "citation": "Mielants H, Goemaere S, De Vos M et al. Intestinal mucosal permeability in inflammatory rheumatic diseases. I. Role of antiinflammatory drugs. The Journal of rheumatology. 1991.", "doi": "", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/1906938/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/1906938/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID1906938", "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": "Antiinflammatory medication altered permeability in control subjects, complicating arthritis comparisons.", "what_it_does_not_show": "NSAID and steroid exposure are potential common causes of measured leak and disease treatment status.", "confounders_present": [ "NSAID and steroid exposure are potential common causes of measured leak and disease treatment status." ], "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": "38503474", "title": "Expression of HIF1α in intestinal epithelium restricts arthritis inflammation by inhibiting RIPK3-induced cell death machinery.", "citation": "Lyu P, Wen J, Zhang W et al. Expression of HIF1α in intestinal epithelium restricts arthritis inflammation by inhibiting RIPK3-induced cell death machinery. Annals of the rheumatic diseases. 2024.", "doi": "10.1136/ard-2023-224491", "pmcid": "PMC11287550", "url": "https://pubmed.ncbi.nlm.nih.gov/38503474/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38503474/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "GUT-JOINT-HIF2024-shared-human-biopsies", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Methods:paragraph0, 1:Methods:paragraph1, 1:Methods:paragraph2. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal plus human observational", "decisive_perturbation": true, "endogenous": true, "direction": "positive", "what_it_shows": "IEC Hif1a deletion exacerbated CIA and RIPK3-directed rescue suppressed necroptosis and arthritis.", "what_it_does_not_show": "Collagen induction remains upstream; HIF1a has effects beyond permeability. Human ileal biopsy material overlaps the earlier gut-joint study.", "confounders_present": [ "Collagen induction remains upstream; HIF1a has effects beyond permeability. Human ileal biopsy material overlaps the earlier gut-joint study." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "shared_components": [ "Human ileal biopsy material described in PMID32332732; not independent human replication. Separate mouse manipulation." ] }, { "n": 11, "pmid": "3769195", "title": "Studies of intestinal permeability in inflammatory diseases using polyethylene glycol 400.", "citation": "Jenkins RT, Goodacre RL, Rooney PJ et al. Studies of intestinal permeability in inflammatory diseases using polyethylene glycol 400. Clinical biochemistry. 1986.", "doi": "10.1016/s0009-9120(86)80045-5", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/3769195/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/3769195/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID3769195", "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": "negative", "what_it_shows": "PEG400 urinary recovery did not identify increased permeability in active inflammatory disease.", "what_it_does_not_show": "Different probe size and absorption kinetics limit direct comparison with lactulose or FITC-dextran results.", "confounders_present": [ "Different probe size and absorption kinetics limit direct comparison with lactulose or FITC-dextran results." ], "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": "33473182", "title": "Early-life fingolimod treatment improves intestinal homeostasis and pancreatic immune tolerance in non-obese diabetic mice.", "citation": "Jia LL, Zhang M, Liu H et al. Early-life fingolimod treatment improves intestinal homeostasis and pancreatic immune tolerance in non-obese diabetic mice. Acta pharmacologica Sinica. 2021.", "doi": "10.1038/s41401-020-00590-4", "pmcid": "PMC8463616", "url": "https://pubmed.ncbi.nlm.nih.gov/33473182/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33473182/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID33473182", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "Early fingolimod improved gut and pancreatic immune tolerance and reduced NOD diabetes incidence.", "what_it_does_not_show": "Systemic lymphocyte trafficking effects make barrier restoration an unisolated mediator.", "confounders_present": [ "Systemic lymphocyte trafficking effects make barrier restoration an unisolated 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": 13, "pmid": "38412124", "title": "Claudin-2 upregulation enhances intestinal permeability, immune activation, dysbiosis, and mortality in sepsis.", "citation": "Oami T, Abtahi S, Shimazui T et al. Claudin-2 upregulation enhances intestinal permeability, immune activation, dysbiosis, and mortality in sepsis. Proceedings of the National Academy of Sciences of the United States of America. 2024.", "doi": "10.1073/pnas.2217877121", "pmcid": "PMC10927519", "url": "https://pubmed.ncbi.nlm.nih.gov/38412124/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38412124/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID38412124", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "animal plus human observational", "decisive_perturbation": true, "endogenous": true, "direction": "positive", "what_it_shows": "Claudin-2 deletion improved septic mouse survival alongside reduced pore permeability and immune activation.", "what_it_does_not_show": "Sepsis was induced; developmental deletion and altered microbial virulence require caution about isolated barrier mediation and other diseases.", "confounders_present": [ "Sepsis was induced; developmental deletion and altered microbial virulence require caution about isolated barrier mediation and other diseases." ], "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": "41494803", "title": "Targeting MLCK1 uncouples immune checkpoint inhibitor-induced colitis from antitumour immunity.", "citation": "Xiong L, Huang J, Dong Y et al. Targeting MLCK1 uncouples immune checkpoint inhibitor-induced colitis from antitumour immunity. Gut. 2026.", "doi": "10.1136/gutjnl-2025-337780", "pmcid": "PMC13227545", "url": "https://pubmed.ncbi.nlm.nih.gov/41494803/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41494803/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID41494803", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "animal plus human observational", "decisive_perturbation": true, "endogenous": true, "direction": "positive", "what_it_shows": "MLCK deletion preserved junctions and ameliorated checkpoint-inhibitor colitis; an interaction blocker retained antitumour efficacy.", "what_it_does_not_show": "Abstract-only access; ICI exposure and wild microbiota define context, and systemic human disease initiation was not tested.", "confounders_present": [ "Abstract-only access; ICI exposure and wild microbiota define context, and systemic human disease initiation was not tested." ], "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": "30936544", "title": "Intracellular MLCK1 diversion reverses barrier loss to restore mucosal homeostasis.", "citation": "Graham WV, He W, Marchiando AM et al. Intracellular MLCK1 diversion reverses barrier loss to restore mucosal homeostasis. Nature medicine. 2019.", "doi": "10.1038/s41591-019-0393-7", "pmcid": "PMC6461392", "url": "https://pubmed.ncbi.nlm.nih.gov/30936544/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30936544/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID30936544", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph2, 1:RESULTS:paragraph16, 1:RESULTS:paragraph18, 1:RESULTS:paragraph19. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": true, "direction": "positive", "what_it_shows": "Divertin blocked MLCK1 recruitment, delayed transfer-colitis symptoms and improved established experimental disease.", "what_it_does_not_show": "Transfer colitis and IL10 deficiency supply upstream immune abnormalities; human prevention was not tested.", "confounders_present": [ "Transfer colitis and IL10 deficiency supply upstream immune abnormalities; human prevention was not tested." ], "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": "41654223", "title": "Macrophage-derived cathepsin B disrupts intestinal tight junctions through occludin degradation and promotes alcohol-associated liver disease.", "citation": "Fondevila MF, Kreimeyer H, Hsu CL et al. Macrophage-derived cathepsin B disrupts intestinal tight junctions through occludin degradation and promotes alcohol-associated liver disease. Journal of hepatology. 2026.", "doi": "10.1016/j.jhep.2026.01.013", "pmcid": "PMC13197211", "url": "https://pubmed.ncbi.nlm.nih.gov/41654223/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41654223/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID41654223", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "animal plus human observational", "decisive_perturbation": true, "endogenous": true, "direction": "positive", "what_it_shows": "Myeloid cathepsin B deletion or gut-restricted inhibition preserved occludin and attenuated ethanol steatohepatitis.", "what_it_does_not_show": "Abstract-only access; alcohol is an antecedent and myeloid protease effects are broader than a pure epithelial perturbation.", "confounders_present": [ "Abstract-only access; alcohol is an antecedent and myeloid protease effects are broader than a pure epithelial 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": 17, "pmid": "40095977", "title": "Enteroendocrine cells regulate intestinal barrier permeability.", "citation": "Nwako JG, Patel SD, Roach TJ et al. Enteroendocrine cells regulate intestinal barrier permeability. American journal of physiology. Cell physiology. 2025.", "doi": "10.1152/ajpcell.01077.2024", "pmcid": "PMC12054964", "url": "https://pubmed.ncbi.nlm.nih.gov/40095977/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40095977/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID40161779" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID40095977", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human organoid", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "Enteroendocrine-cell loss impaired enteroid barrier function and PYY or somatostatin supplementation rescued it.", "what_it_does_not_show": "Organoid barrier physiology is not organismal systemic disease or proof of human initiation.", "confounders_present": [ "Organoid barrier physiology is not organismal systemic disease or proof of human 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": 18, "pmid": "35537812", "title": "Tacrolimus-binding protein FKBP8 directs myosin light chain kinase-dependent barrier regulation and is a potential therapeutic target in Crohn's disease.", "citation": "Zuo L, Kuo WT, Cao F et al. Tacrolimus-binding protein FKBP8 directs myosin light chain kinase-dependent barrier regulation and is a potential therapeutic target in Crohn's disease. Gut. 2023.", "doi": "10.1136/gutjnl-2021-326534", "pmcid": "PMC9977574", "url": "https://pubmed.ncbi.nlm.nih.gov/35537812/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35537812/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID35537812", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "animal plus human organoid", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "FKBP8 disruption blocked TNF-dependent MLCK recruitment and barrier loss; interactions were elevated in Crohn biopsies.", "what_it_does_not_show": "Tacrolimus is immunosuppressive; barrier rescue without a disease-incidence endpoint cannot establish systemic primacy.", "confounders_present": [ "Tacrolimus is immunosuppressive; barrier rescue without a disease-incidence endpoint cannot establish systemic 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": 19, "pmid": "23671105", "title": "Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity.", "citation": "Everard A, Belzer C, Geurts L et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proceedings of the National Academy of Sciences of the United States of America. 2013.", "doi": "10.1073/pnas.1219451110", "pmcid": "PMC3670398", "url": "https://pubmed.ncbi.nlm.nih.gov/23671105/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23671105/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID23671105", "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", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "Viable A. muciniphila reduced high-fat-diet fat gain, endotoxemia and insulin resistance while restoring mucus.", "what_it_does_not_show": "Microbial treatment changes several metabolites and endocrine signals; barrier mediation and human causality were not isolated.", "confounders_present": [ "Microbial treatment changes several metabolites and endocrine signals; barrier mediation and human causality were 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": 20, "pmid": "29519916", "title": "Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection.", "citation": "Thaiss CA, Levy M, Grosheva I et al. Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection. Science (New York, N.Y.). 2018.", "doi": "10.1126/science.aar3318", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/29519916/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29519916/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID29519916", "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", "SC5", "SC6" ], "favors_models": [], "evidence_class": "Strong", "system": "animal plus human observational", "decisive_perturbation": false, "endogenous": false, "direction": "negative", "what_it_shows": "Hyperglycemia drove barrier disruption; epithelial GLUT2 deletion or glucose control restored containment.", "what_it_does_not_show": "This is causal evidence for the reverse arrow and infection susceptibility, not barrier-first metabolic disease.", "confounders_present": [ "This is causal evidence for the reverse arrow and infection susceptibility, not barrier-first metabolic disease." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 21, "pmid": "18305141", "title": "Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice.", "citation": "Cani PD, Bibiloni R, Knauf C et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes. 2008.", "doi": "10.2337/db07-1403", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/18305141/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/18305141/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID18305141", "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", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "Antibiotics and CD14 deletion reduced HFD-associated endotoxemia and metabolic abnormalities.", "what_it_does_not_show": "Antibiotics and immune receptor deletion do not isolate epithelial permeability as the initiating mediator.", "confounders_present": [ "Antibiotics and immune receptor deletion do not isolate epithelial permeability as the initiating 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": 22, "pmid": "34525353", "title": "Metabolic endotoxemia is dictated by the type of lipopolysaccharide.", "citation": "Anhê FF, Barra NG, Cavallari JF et al. Metabolic endotoxemia is dictated by the type of lipopolysaccharide. Cell reports. 2021.", "doi": "10.1016/j.celrep.2021.109691", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/34525353/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34525353/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID34525353", "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", "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Equal endotoxin-unit doses from different bacterial LPS sources produced opposing glycemic effects.", "what_it_does_not_show": "LPS structure and TLR4 activity matter; total measured endotoxin is not a uniform pathogenic exposure.", "confounders_present": [ "LPS structure and TLR4 activity matter; total measured endotoxin is not a uniform pathogenic exposure." ], "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": "35705057", "title": "TRPV6 channel mediates alcohol-induced gut barrier dysfunction and systemic response.", "citation": "Meena AS, Shukla PK, Bell B et al. TRPV6 channel mediates alcohol-induced gut barrier dysfunction and systemic response. Cell reports. 2022.", "doi": "10.1016/j.celrep.2022.110937", "pmcid": "PMC9250449", "url": "https://pubmed.ncbi.nlm.nih.gov/35705057/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35705057/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID35705057", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "animal plus cell culture", "decisive_perturbation": true, "endogenous": true, "direction": "positive", "what_it_shows": "TRPV6 loss or inhibition blocked ethanol-induced calcium influx, barrier disruption and inflammatory response.", "what_it_does_not_show": "Alcohol remains upstream and TRPV6 expression is not exclusively epithelial; inference is restricted to alcohol exposure.", "confounders_present": [ "Alcohol remains upstream and TRPV6 expression is not exclusively epithelial; inference is restricted to alcohol exposure." ], "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": "19240062", "title": "Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability.", "citation": "Cani PD, Possemiers S, Van de Wiele T et al. Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut. 2009.", "doi": "10.1136/gut.2008.165886", "pmcid": "PMC2702831", "url": "https://pubmed.ncbi.nlm.nih.gov/19240062/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/19240062/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID19240062", "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", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "positive", "what_it_shows": "GLP2 antagonism abolished much of prebiotic barrier benefit and GLP2 agonism improved permeability and inflammation.", "what_it_does_not_show": "ob/ob biology and GLP2 trophic effects bound inference; it does not demonstrate human metabolic disease initiation.", "confounders_present": [ "ob/ob biology and GLP2 trophic effects bound inference; it does not demonstrate human metabolic disease 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": 25, "pmid": "39593091", "title": "Carrageenan and insulin resistance in humans: a randomised double-blind cross-over trial.", "citation": "Wagner R, Buettner J, Heni M et al. Carrageenan and insulin resistance in humans: a randomised double-blind cross-over trial. BMC medicine. 2024.", "doi": "10.1186/s12916-024-03771-8", "pmcid": "PMC11590543", "url": "https://pubmed.ncbi.nlm.nih.gov/39593091/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39593091/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID39593091", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Methods:paragraph0, 1:Methods:paragraph2, 1:Methods:paragraph5, 1:Methods:paragraph6, 1:Methods:paragraph14, 2:Results:paragraph0, 2:Results:paragraph1, 2:Results:paragraph2, 2:Results:paragraph6. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "Randomized carrageenan exposure increased lactulose/mannitol permeability but primary and co-primary insulin-sensitivity endpoints were null.", "what_it_does_not_show": "BMI interactions were ancillary, not proof of the nominal primary endpoint or mediation by permeability.", "confounders_present": [ "BMI interactions were ancillary, not proof of the nominal primary endpoint or mediation by permeability." ], "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": "36528936", "title": "ALDH2 deficiency increases susceptibility to binge alcohol-induced gut leakiness, endotoxemia, and acute liver injury in mice through the gut-liver axis.", "citation": "Rungratanawanich W, Lin Y, Wang X et al. ALDH2 deficiency increases susceptibility to binge alcohol-induced gut leakiness, endotoxemia, and acute liver injury in mice through the gut-liver axis. Redox biology. 2023.", "doi": "10.1016/j.redox.2022.102577", "pmcid": "PMC9792909", "url": "https://pubmed.ncbi.nlm.nih.gov/36528936/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36528936/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID36528936", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "ALDH2 loss increased ethanol leak and liver injury, with complementary cell inhibition and activation.", "what_it_does_not_show": "Acetaldehyde metabolism, cell injury and liver toxicity are pleiotropic; this is alcohol-context susceptibility.", "confounders_present": [ "Acetaldehyde metabolism, cell injury and liver toxicity are pleiotropic; this is alcohol-context susceptibility." ], "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": "25676872", "title": "Diet-induced obesity causes metabolic impairment independent of alterations in gut barrier integrity.", "citation": "Kless C, Müller VM, Schüppel VL et al. Diet-induced obesity causes metabolic impairment independent of alterations in gut barrier integrity. Molecular nutrition & food research. 2015.", "doi": "10.1002/mnfr.201400840", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/25676872/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25676872/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID25676872", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC5", "SC6" ], "favors_models": [], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": false, "endogenous": false, "direction": "negative", "what_it_shows": "Diet-induced impaired glucose tolerance occurred across tested mouse backgrounds without detectable barrier loss.", "what_it_does_not_show": "Assay sensitivity and diets limit universal absence claims, but leak was not necessary in these tested metabolic models.", "confounders_present": [ "Assay sensitivity and diets limit universal absence claims, but leak was not necessary in these tested metabolic models." ], "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": "39875729", "title": "Intestinal neutrophil extracellular traps promote gut barrier damage exacerbating endotoxaemia, systemic inflammation and progression of diabetic retinopathy in type 2 diabetes.", "citation": "Floyd JL, Prasad R, Dupont MD et al. Intestinal neutrophil extracellular traps promote gut barrier damage exacerbating endotoxaemia, systemic inflammation and progression of diabetic retinopathy in type 2 diabetes. Diabetologia. 2025.", "doi": "10.1007/s00125-024-06349-4", "pmcid": "PMC11950064", "url": "https://pubmed.ncbi.nlm.nih.gov/39875729/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39875729/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID39875729", "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", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal plus human observational", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "PAD4 inhibition reduced intestinal NETs, endotoxemia and progression of diabetic retinopathy.", "what_it_does_not_show": "Late diabetes and direct retinal or marrow effects prevent interpreting benefit as barrier-first diabetes initiation.", "confounders_present": [ "Late diabetes and direct retinal or marrow effects prevent interpreting benefit as barrier-first diabetes 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": 29, "pmid": "34170951", "title": "Could serum zonulin be an intestinal permeability marker in diabetes kidney disease?", "citation": "Carpes LS, Nicoletto BB, Canani LH et al. Could serum zonulin be an intestinal permeability marker in diabetes kidney disease? PloS one. 2021.", "doi": "10.1371/journal.pone.0253501", "pmcid": "PMC8232531", "url": "https://pubmed.ncbi.nlm.nih.gov/34170951/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34170951/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID34170951", "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", "SC5" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Serum zonulin-kit signals differed across diabetic kidney disease stages and predicted renal outcomes.", "what_it_does_not_show": "Renal clearance, adiposity and assay identity confound interpreting a serum signal as intestinal permeability.", "confounders_present": [ "Renal clearance, adiposity and assay identity confound interpreting a serum signal as intestinal permeability." ], "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": "27810310", "title": "Probiotic With or Without Fiber Controls Body Fat Mass, Associated With Serum Zonulin, in Overweight and Obese Adults-Randomized Controlled Trial.", "citation": "Stenman LK, Lehtinen MJ, Meland N et al. Probiotic With or Without Fiber Controls Body Fat Mass, Associated With Serum Zonulin, in Overweight and Obese Adults-Randomized Controlled Trial. EBioMedicine. 2016.", "doi": "10.1016/j.ebiom.2016.10.036", "pmcid": "PMC5264483", "url": "https://pubmed.ncbi.nlm.nih.gov/27810310/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27810310/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID27810310", "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", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "The probiotic/fibre trial had no significant body-fat difference in ITT; PP and post-hoc analyses were more favorable.", "what_it_does_not_show": "Attrition, compliance restriction, reduced energy intake and zonulin association do not establish barrier-mediated fat loss.", "confounders_present": [ "Attrition, compliance restriction, reduced energy intake and zonulin association do not establish barrier-mediated fat loss." ], "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": "34032635", "title": "Multisystem inflammatory syndrome in children is driven by zonulin-dependent loss of gut mucosal barrier.", "citation": "Yonker LM, Gilboa T, Ogata AF et al. Multisystem inflammatory syndrome in children is driven by zonulin-dependent loss of gut mucosal barrier. The Journal of clinical investigation. 2021.", "doi": "10.1172/JCI149633", "pmcid": "PMC8279585", "url": "https://pubmed.ncbi.nlm.nih.gov/34032635/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34032635/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID34032635", "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", "SC6" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "MIS-C biospecimens showed antigenemia and barrier-associated signals; one larazotide-treated patient improved.", "what_it_does_not_show": "An uncontrolled treated case and postinfectious disease cannot prove mediation, efficacy or a universal epithelial initiator.", "confounders_present": [ "An uncontrolled treated case and postinfectious disease cannot prove mediation, efficacy or a universal epithelial initiator." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 32, "pmid": "33535002", "title": "Colonic paracellular permeability and circulating zonulin-related proteins.", "citation": "Meira de-Faria F, Bednarska O, Ström M et al. Colonic paracellular permeability and circulating zonulin-related proteins. Scandinavian journal of gastroenterology. 2021.", "doi": "10.1080/00365521.2021.1879247", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/33535002/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33535002/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID33535002", "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", "SC6" ], "favors_models": [], "evidence_class": "Strong", "system": "human biopsy and assay validation", "decisive_perturbation": false, "endogenous": false, "direction": "negative", "what_it_shows": "Circulating zonulin did not mirror colonic permeability or pre-HP2; pre-HP2 non-producers still had kit signals.", "what_it_does_not_show": "Local biopsy relationships differ from plasma; the result invalidates a proxy in the tested setting, not all barrier biology.", "confounders_present": [ "Local biopsy relationships differ from plasma; the result invalidates a proxy in the tested setting, not all barrier biology." ], "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": "25493023", "title": "Increased circulating zonulin in children with biopsy-proven nonalcoholic fatty liver disease.", "citation": "Pacifico L, Bonci E, Marandola L et al. Increased circulating zonulin in children with biopsy-proven nonalcoholic fatty liver disease. World journal of gastroenterology. 2014.", "doi": "10.3748/wjg.v20.i45.17107", "pmcid": "PMC4258579", "url": "https://pubmed.ncbi.nlm.nih.gov/25493023/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25493023/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID25493023", "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", "SC5" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "A serum zonulin signal tracked steatosis but not histological inflammation, ballooning or fibrosis in obese children.", "what_it_does_not_show": "Cross-sectional case-control design and commercial-marker uncertainty prevent initiation or liver-injury causality.", "confounders_present": [ "Cross-sectional case-control design and commercial-marker uncertainty prevent initiation or liver-injury causality." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 34, "pmid": "39340210", "title": "Changes in intestinal permeability and gut microbiota following diet-induced weight loss in patients with metabolic dysfunction-associated steatohepatitis and liver fibrosis.", "citation": "Koutoukidis DA, Yen S, Gomez Castro P et al. Changes in intestinal permeability and gut microbiota following diet-induced weight loss in patients with metabolic dysfunction-associated steatohepatitis and liver fibrosis. Gut microbes. 2024.", "doi": "10.1080/19490976.2024.2392864", "pmcid": "PMC11444513", "url": "https://pubmed.ncbi.nlm.nih.gov/39340210/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39340210/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID39340210", "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", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "positive", "what_it_shows": "Diet-induced weight loss improved MASH markers with falling serum zonulin; microbial changes were not sustained.", "what_it_does_not_show": "No control arm or barrier-selective perturbation; caloric restriction and weight loss are plausible upstream causes.", "confounders_present": [ "No control arm or barrier-selective perturbation; caloric restriction and weight loss are plausible upstream causes." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 35, "pmid": "11082037", "title": "Human zonulin, a potential modulator of intestinal tight junctions.", "citation": "Wang W, Uzzau S, Goldblum SE et al. Human zonulin, a potential modulator of intestinal tight junctions. Journal of cell science. 2000.", "doi": "10.1242/jcs.113.24.4435", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/11082037/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/11082037/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID11082037", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "ex vivo tissue", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "An immunologically identified zonulin preparation reversibly disrupted primate epithelial junctions ex vivo.", "what_it_does_not_show": "Early protein identity and purified exposure do not demonstrate necessity in endogenous human disease.", "confounders_present": [ "Early protein identity and purified exposure do not demonstrate necessity in endogenous human disease." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 36, "pmid": "32764250", "title": "Effects of Probiotic Strains on Disease Activity and Enteric Permeability in Psoriatic Arthritis-A Pilot Open-Label Study.", "citation": "Haidmayer A, Bosch P, Lackner A et al. Effects of Probiotic Strains on Disease Activity and Enteric Permeability in Psoriatic Arthritis-A Pilot Open-Label Study. Nutrients. 2020.", "doi": "10.3390/nu12082337", "pmcid": "PMC7468965", "url": "https://pubmed.ncbi.nlm.nih.gov/32764250/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32764250/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID32764250", "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": "Weak", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "positive", "what_it_shows": "A small open-label PsA probiotic study reported transient improvement in symptoms and permeability markers.", "what_it_does_not_show": "No placebo control, different arthritis disease and fecal-marker identity limit inference to rheumatoid arthritis.", "confounders_present": [ "No placebo control, different arthritis disease and fecal-marker identity limit inference to rheumatoid arthritis." ], "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": "31608059", "title": "Exploiting the Zonulin Mouse Model to Establish the Role of Primary Impaired Gut Barrier Function on Microbiota Composition and Immune Profiles.", "citation": "Miranda-Ribera A, Ennamorati M, Serena G et al. Exploiting the Zonulin Mouse Model to Establish the Role of Primary Impaired Gut Barrier Function on Microbiota Composition and Immune Profiles. Frontiers in immunology. 2019.", "doi": "10.3389/fimmu.2019.02233", "pmcid": "PMC6761304", "url": "https://pubmed.ncbi.nlm.nih.gov/31608059/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31608059/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "ZONULIN-TG-2019", "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", "SC6" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal overexpression", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Zonulin-transgenic mice showed immune skew and dysbiosis; wildtype microbiota did not normalize immune profiles.", "what_it_does_not_show": "Overexpression and latent inflammation need an environmental hit and do not establish spontaneous cross-disease causality.", "confounders_present": [ "Overexpression and latent inflammation need an environmental hit and do not establish spontaneous cross-disease causality." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 38, "pmid": "30108163", "title": "Randomised placebo-controlled trial of dietary glutamine supplements for postinfectious irritable bowel syndrome.", "citation": "Zhou Q, Verne ML, Fields JZ et al. Randomised placebo-controlled trial of dietary glutamine supplements for postinfectious irritable bowel syndrome. Gut. 2019.", "doi": "10.1136/gutjnl-2017-315136", "pmcid": "PMC9549483", "url": "https://pubmed.ncbi.nlm.nih.gov/30108163/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30108163/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID30108163", "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", "SC6" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "positive", "what_it_shows": "Glutamine improved symptoms and permeability in postinfectious IBS-D selected for high permeability.", "what_it_does_not_show": "Glutamine has multiple actions; the population and symptom endpoint do not establish autoimmune or metabolic disease prevention.", "confounders_present": [ "Glutamine has multiple actions; the population and symptom endpoint do not establish autoimmune or metabolic disease prevention." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 39, "pmid": "10233193", "title": "Effect of glutamine on the intestinal permeability changes induced by indomethacin in humans.", "citation": "Hond ED, Peeters M, Hiele M et al. Effect of glutamine on the intestinal permeability changes induced by indomethacin in humans. Alimentary pharmacology & therapeutics. 1999.", "doi": "10.1046/j.1365-2036.1999.00523.x", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/10233193/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/10233193/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID10233193", "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": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "Glutamine effects on indomethacin permeability depended on dose timing; pretreatment alone failed.", "what_it_does_not_show": "Drug-induced barrier damage is a different initiating exposure and there was no systemic disease endpoint.", "confounders_present": [ "Drug-induced barrier damage is a different initiating exposure and there was no systemic disease endpoint." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 40, "pmid": "31423661", "title": "Low Methoxyl Pectin Protects against Autoimmune Diabetes and Associated Caecal Dysfunction.", "citation": "Wu C, Pan LL, Luo Y et al. Low Methoxyl Pectin Protects against Autoimmune Diabetes and Associated Caecal Dysfunction. Molecular nutrition & food research. 2019.", "doi": "10.1002/mnfr.201900307", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/31423661/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31423661/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID31423661", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "Low-methoxyl pectin delayed NOD diabetes with caecal, SCFA and immune changes.", "what_it_does_not_show": "Dietary fibre changes microbial and immune pathways simultaneously; permeability is not an isolated mediator.", "confounders_present": [ "Dietary fibre changes microbial and immune pathways simultaneously; permeability is not an isolated 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": 41, "pmid": "30776371", "title": "Ameliorating gut microenvironment through staphylococcal nuclease-mediated intestinal NETs degradation for prevention of type 1 diabetes in NOD mice.", "citation": "Liang Y, Wang X, He D et al. Ameliorating gut microenvironment through staphylococcal nuclease-mediated intestinal NETs degradation for prevention of type 1 diabetes in NOD mice. Life sciences. 2019.", "doi": "10.1016/j.lfs.2019.02.034", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/30776371/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30776371/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID30776371", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "Engineered L. lactis delivering nuclease reduced NET markers and improved NOD glycemia and inflammation.", "what_it_does_not_show": "Microbial engineering, immune effects and commercial leak markers permit several alternative mediators.", "confounders_present": [ "Microbial engineering, immune effects and commercial leak markers permit several alternative mediators." ], "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": "39471704", "title": "Effects of probiotics and fibers on markers of nephropathy, inflammation, intestinal barrier dysfunction and endothelial dysfunction in individuals with type 1 diabetes and albuminuria. The ProFOS Study.", "citation": "Stougaard EB, Tougaard NH, Sivalingam S et al. Effects of probiotics and fibers on markers of nephropathy, inflammation, intestinal barrier dysfunction and endothelial dysfunction in individuals with type 1 diabetes and albuminuria. The ProFOS Study. Journal of diabetes and its complications. 2024.", "doi": "10.1016/j.jdiacomp.2024.108892", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/39471704/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39471704/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID39471704", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "negative", "what_it_shows": "ProFOS synbiotics did not improve albuminuria or measured secondary outcomes in type 1 diabetes.", "what_it_does_not_show": "Established kidney disease and nonspecific microbiota treatment do not falsify a selective barrier prevention hypothesis.", "confounders_present": [ "Established kidney disease and nonspecific microbiota treatment do not falsify a selective barrier prevention hypothesis." ], "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": "31292292", "title": "Inflammatory arthritis disrupts gut resolution mechanisms, promoting barrier breakdown by Porphyromonas gingivalis.", "citation": "Flak MB, Colas RA, Muñoz-Atienza E et al. Inflammatory arthritis disrupts gut resolution mechanisms, promoting barrier breakdown by Porphyromonas gingivalis. JCI insight. 2019.", "doi": "10.1172/jci.insight.125191", "pmcid": "PMC6629160", "url": "https://pubmed.ncbi.nlm.nih.gov/31292292/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31292292/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID36278492" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID31292292", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Arthritis disrupted intestinal resolving mediators; resolvin restored barrier and reduced joint inflammation after P. gingivalis.", "what_it_does_not_show": "The reverse arrow is supported; pleiotropic immunoresolution is not epithelial-specific. Linked erratum must remain attached.", "confounders_present": [ "The reverse arrow is supported; pleiotropic immunoresolution is not epithelial-specific. Linked erratum must remain 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": 44, "pmid": "17028899", "title": "Increased intestinal permeability precedes clinical onset of type 1 diabetes.", "citation": "Bosi E, Molteni L, Radaelli MG et al. Increased intestinal permeability precedes clinical onset of type 1 diabetes. Diabetologia. 2006.", "doi": "10.1007/s00125-006-0465-3", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/17028899/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17028899/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID17028899", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "Lactulose/mannitol abnormality was present in autoantibody-positive preclinical as well as clinical diabetes groups.", "what_it_does_not_show": "Stage comparison is not a prospective prevention experiment and cannot exclude autoimmunity already causing leak.", "confounders_present": [ "Stage comparison is not a prospective prevention experiment and cannot exclude autoimmunity already causing leak." ], "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": "20012858", "title": "Gut barrier disruption by an enteric bacterial pathogen accelerates insulitis in NOD mice.", "citation": "Lee AS, Gibson DL, Zhang Y et al. Gut barrier disruption by an enteric bacterial pathogen accelerates insulitis in NOD mice. Diabetologia. 2010.", "doi": "10.1007/s00125-009-1626-y", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/20012858/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/20012858/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID20012858", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "Barrier-disrupting Citrobacter accelerated NOD insulitis; an espF-deficient strain did not.", "what_it_does_not_show": "Virulence differences and infection immune effects complicate a pure permeability mediator interpretation.", "confounders_present": [ "Virulence differences and infection immune effects complicate a pure permeability mediator interpretation." ], "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": "37242269", "title": "Assessment of Intestinal Permeability and Inflammation Bio-Markers in Patients with Rheumatoid Arthritis.", "citation": "Heidt C, Kämmerer U, Fobker M et al. Assessment of Intestinal Permeability and Inflammation Bio-Markers in Patients with Rheumatoid Arthritis. Nutrients. 2023.", "doi": "10.3390/nu15102386", "pmcid": "PMC10221762", "url": "https://pubmed.ncbi.nlm.nih.gov/37242269/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37242269/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID37242269", "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": "RA marker relationships differed by sex and disease duration in a proof-of-principle cohort.", "what_it_does_not_show": "No healthy control group and unvalidated zonulin assays prevent defining a disease-specific barrier abnormality.", "confounders_present": [ "No healthy control group and unvalidated zonulin assays prevent defining a disease-specific barrier abnormality." ], "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": "30707717", "title": "A single alcohol binge impacts on neutrophil function without changes in gut barrier function and gut microbiome composition in healthy volunteers.", "citation": "Stadlbauer V, Horvath A, Komarova I et al. A single alcohol binge impacts on neutrophil function without changes in gut barrier function and gut microbiome composition in healthy volunteers. PloS one. 2019.", "doi": "10.1371/journal.pone.0211703", "pmcid": "PMC6358085", "url": "https://pubmed.ncbi.nlm.nih.gov/30707717/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30707717/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID30707717", "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", "SC6" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "negative", "what_it_shows": "A single alcohol binge altered neutrophil function without detected barrier or translocation changes in healthy volunteers.", "what_it_does_not_show": "Small cohort and short sampling window constrain null inference; immune effects need not require detectable leak.", "confounders_present": [ "Small cohort and short sampling window constrain null inference; immune effects need not require detectable leak." ], "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": "27353603", "title": "Zonulin Regulates Intestinal Permeability and Facilitates Enteric Bacteria Permeation in Coronary Artery Disease.", "citation": "Li C, Gao M, Zhang W et al. Zonulin Regulates Intestinal Permeability and Facilitates Enteric Bacteria Permeation in Coronary Artery Disease. Scientific reports. 2016.", "doi": "10.1038/srep29142", "pmcid": "PMC4926221", "url": "https://pubmed.ncbi.nlm.nih.gov/27353603/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27353603/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID27353603", "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", "SC6" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational plus cell culture", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "CAD blood bacterial sequences and zonulin-kit signals were accompanied by cell-culture junction changes.", "what_it_does_not_show": "Low-biomass contamination, assay specificity and established CAD prevent assigning endogenous systemic causality.", "confounders_present": [ "Low-biomass contamination, assay specificity and established CAD prevent assigning endogenous systemic causality." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 49, "pmid": "28138755", "title": "Epithelial barrier dysfunction in lymphocytic colitis through cytokine-dependent internalization of claudin-5 and -8.", "citation": "Barmeyer C, Erko I, Awad K et al. Epithelial barrier dysfunction in lymphocytic colitis through cytokine-dependent internalization of claudin-5 and -8. Journal of gastroenterology. 2017.", "doi": "10.1007/s00535-017-1309-2", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/28138755/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28138755/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID28138755", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human biopsy plus cell culture", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "Lymphocytic-colitis biopsies had barrier defects; TNF/IFNg reproduced claudin redistribution without MLCK dependence.", "what_it_does_not_show": "Cytokines can lie upstream and different junction pathways prevent a single universal leak mechanism.", "confounders_present": [ "Cytokines can lie upstream and different junction pathways prevent a single universal leak 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": 50, "pmid": "17456850", "title": "Metabolic endotoxemia initiates obesity and insulin resistance.", "citation": "Cani PD, Amar J, Iglesias MA et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007.", "doi": "10.2337/db06-1491", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/17456850/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17456850/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID17456850", "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", "SC5" ], "favors_models": [], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "Chronic subcutaneous LPS infusion induced weight and hepatic metabolic abnormalities and CD14 mutants were protected.", "what_it_does_not_show": "Infusion bypasses epithelium and hepatic versus whole-body insulin effects differ; it is not proof of gut leak initiation.", "confounders_present": [ "Infusion bypasses epithelium and hepatic versus whole-body insulin effects differ; it is not proof of gut leak 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": "26564856", "title": "A gut-vascular barrier controls the systemic dissemination of bacteria.", "citation": "Spadoni I, Zagato E, Bertocchi A et al. A gut-vascular barrier controls the systemic dissemination of bacteria. Science (New York, N.Y.). 2015.", "doi": "10.1126/science.aad0135", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/26564856/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26564856/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID26564856", "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", "SC6" ], "favors_models": [], "evidence_class": "Strong", "system": "animal plus human observational", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "Gut endothelium formed a second barrier to bacteria; Salmonella penetrated through virulence-dependent beta-catenin disruption.", "what_it_does_not_show": "Vascular escape is distinct from epithelial permeability; infection paradigms cannot prove all chronic systemic disease.", "confounders_present": [ "Vascular escape is distinct from epithelial permeability; infection paradigms cannot prove all chronic systemic disease." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 52, "pmid": "31419514", "title": "Microbiota-driven gut vascular barrier disruption is a prerequisite for non-alcoholic steatohepatitis development.", "citation": "Mouries J, Brescia P, Silvestri A et al. Microbiota-driven gut vascular barrier disruption is a prerequisite for non-alcoholic steatohepatitis development. Journal of hepatology. 2019.", "doi": "10.1016/j.jhep.2019.08.005", "pmcid": "PMC6880766", "url": "https://pubmed.ncbi.nlm.nih.gov/31419514/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31419514/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID31419514", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Materials and methods:paragraph0, 1:Materials and methods:paragraph1, 2:Results:paragraph0, 2:Results:paragraph9, 2:Results:paragraph11. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal plus human observational", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "Endothelial beta-catenin activation prevented vascular escape and diet-induced NASH despite epithelial translocation.", "what_it_does_not_show": "The manipulated layer was vascular, not epithelial; gain-of-function, nonrandomized and unblinded mouse work limits attribution.", "confounders_present": [ "The manipulated layer was vascular, not epithelial; gain-of-function, nonrandomized and unblinded mouse work limits attribution." ], "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": "28183447", "title": "Acute low-dose endotoxin treatment results in improved whole-body glucose homeostasis in mice.", "citation": "Stevens JR, McMillan RP, Resendes JT et al. Acute low-dose endotoxin treatment results in improved whole-body glucose homeostasis in mice. Metabolism: clinical and experimental. 2017.", "doi": "10.1016/j.metabol.2016.12.008", "pmcid": "PMC5319723", "url": "https://pubmed.ncbi.nlm.nih.gov/28183447/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28183447/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID28183447", "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", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal plus cell culture", "decisive_perturbation": false, "endogenous": false, "direction": "negative", "what_it_shows": "Acute low-dose LPS improved mouse glucose homeostasis while long exposure reduced cell glycogen synthesis.", "what_it_does_not_show": "Exposure duration and direct liver effects rebut treating endotoxin concentration as a monotonic metabolic toxin.", "confounders_present": [ "Exposure duration and direct liver effects rebut treating endotoxin concentration as a monotonic metabolic toxin." ], "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": "33886649", "title": "Larazotide acetate induces recovery of ischemia-injured porcine jejunum via repair of tight junctions.", "citation": "Slifer ZM, Hernandez L, Pridgen TA et al. Larazotide acetate induces recovery of ischemia-injured porcine jejunum via repair of tight junctions. PloS one. 2021.", "doi": "10.1371/journal.pone.0250165", "pmcid": "PMC8061941", "url": "https://pubmed.ncbi.nlm.nih.gov/33886649/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33886649/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID33886649", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "ex vivo pig intestine", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "Larazotide improved ischemia-injured jejunal barrier at an intermediate dose, with fragment-dependent loss of efficacy.", "what_it_does_not_show": "Ex vivo repair and nonmonotonic dosing are not systemic disease prevention or unambiguous target identity.", "confounders_present": [ "Ex vivo repair and nonmonotonic dosing are not systemic disease prevention or unambiguous target identity." ], "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": "22825365", "title": "A randomized, double-blind study of larazotide acetate to prevent the activation of celiac disease during gluten challenge.", "citation": "Leffler DA, Kelly CP, Abdallah HZ et al. A randomized, double-blind study of larazotide acetate to prevent the activation of celiac disease during gluten challenge. The American journal of gastroenterology. 2012.", "doi": "10.1038/ajg.2012.211", "pmcid": "PMC3463856", "url": "https://pubmed.ncbi.nlm.nih.gov/22825365/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22825365/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID22825365", "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", "SC6" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "Larazotide gluten-challenge trial showed variable permeability assays, null between-group permeability and lower-dose symptom signals.", "what_it_does_not_show": "Null primary permeability results and induced gluten exposure prevent claiming barrier-mediated systemic disease initiation.", "confounders_present": [ "Null primary permeability results and induced gluten exposure prevent claiming barrier-mediated systemic disease 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": 56, "pmid": "22401908", "title": "Larazotide acetate regulates epithelial tight junctions in vitro and in vivo.", "citation": "Gopalakrishnan S, Durai M, Kitchens K et al. Larazotide acetate regulates epithelial tight junctions in vitro and in vivo. Peptides. 2012.", "doi": "10.1016/j.peptides.2012.02.015", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/22401908/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22401908/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID22401908", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal plus cell culture", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "Larazotide limited gliadin/cytokine junction changes and preserved gut junctions in sensitized transgenic mice.", "what_it_does_not_show": "Experimental sensitization and junction readouts do not establish endogenous human autoimmune disease initiation.", "confounders_present": [ "Experimental sensitization and junction readouts do not establish endogenous human autoimmune disease 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": 57, "pmid": "22401910", "title": "Larazotide acetate promotes tight junction assembly in epithelial cells.", "citation": "Gopalakrishnan S, Tripathi A, Tamiz AP et al. Larazotide acetate promotes tight junction assembly in epithelial cells. Peptides. 2012.", "doi": "10.1016/j.peptides.2012.02.016", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/22401910/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22401910/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID22401910", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "cell culture", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "Larazotide promoted junction assembly in calcium-switch MDCK and leaky Caco2 models.", "what_it_does_not_show": "Assembly physiology in vitro is capped at plausibility for organismal disease.", "confounders_present": [ "Assembly physiology in vitro is capped at plausibility for organismal disease." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 58, "pmid": "25683116", "title": "Larazotide acetate for persistent symptoms of celiac disease despite a gluten-free diet: a randomized controlled trial.", "citation": "Leffler DA, Kelly CP, Green PH et al. Larazotide acetate for persistent symptoms of celiac disease despite a gluten-free diet: a randomized controlled trial. Gastroenterology. 2015.", "doi": "10.1053/j.gastro.2015.02.008", "pmcid": "PMC4446229", "url": "https://pubmed.ncbi.nlm.nih.gov/25683116/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25683116/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID25683116", "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", "SC6" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "Low-dose larazotide improved persistent celiac symptoms; higher doses did not differ from placebo.", "what_it_does_not_show": "Symptom treatment in established celiac disease is not prevention or proven mediation by reduced epithelial flux.", "confounders_present": [ "Symptom treatment in established celiac disease is not prevention or proven mediation by reduced epithelial flux." ], "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": "23163616", "title": "Larazotide acetate in patients with coeliac disease undergoing a gluten challenge: a randomised placebo-controlled study.", "citation": "Kelly CP, Green PH, Murray JA et al. Larazotide acetate in patients with coeliac disease undergoing a gluten challenge: a randomised placebo-controlled study. Alimentary pharmacology & therapeutics. 2013.", "doi": "10.1111/apt.12147", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/23163616/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23163616/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID23163616", "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", "SC6" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "Larazotide reduced gluten immune/symptom responses but did not significantly change lactulose/mannitol ratios.", "what_it_does_not_show": "Clinical and biomarker effects cannot be assigned to permeability when the permeability endpoint was null.", "confounders_present": [ "Clinical and biomarker effects cannot be assigned to permeability when the permeability endpoint was null." ], "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": "32791132", "title": "Increased Intestinal Permeability Is Associated With Later Development of Crohn's Disease.", "citation": "Turpin W, Lee SH, Raygoza Garay JA et al. Increased Intestinal Permeability Is Associated With Later Development of Crohn's Disease. Gastroenterology. 2020.", "doi": "10.1053/j.gastro.2020.08.005", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/32791132/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32791132/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID32791132", "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", "SC6" ], "favors_models": [], "evidence_class": "Weak", "system": "human prospective", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "Baseline permeability in asymptomatic Crohn relatives predicted later Crohn diagnosis over years.", "what_it_does_not_show": "Prospective association reduces clinical reverse causation but does not eliminate latent inflammation, inherited risk or common exposures.", "confounders_present": [ "Prospective association reduces clinical reverse causation but does not eliminate latent inflammation, inherited risk or common exposures." ], "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": 61, "pmid": "30640940", "title": "Serum zonulin as a marker of intestinal mucosal barrier function: May not be what it seems.", "citation": "Ajamian M, Steer D, Rosella G et al. Serum zonulin as a marker of intestinal mucosal barrier function: May not be what it seems. PloS one. 2019.", "doi": "10.1371/journal.pone.0210728", "pmcid": "PMC6331146", "url": "https://pubmed.ncbi.nlm.nih.gov/30640940/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30640940/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID30640940", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Materials and methods:paragraph2, 1:Materials and methods:paragraph3, 1:Materials and methods:paragraph4, 1:Materials and methods:paragraph5, 1:Materials and methods:paragraph6, 2:Results:paragraph13, 2:Results:paragraph14, 2:Results:paragraph15, 2:Results:paragraph16, 3:Discussion:paragraph0. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC6" ], "favors_models": [], "evidence_class": "Strong", "system": "assay validation", "decisive_perturbation": false, "endogenous": false, "direction": "negative", "what_it_shows": "CUSABIO and Immundiagnostik assays failed recombinant pre-HP2 detection; immunocaptured proteins included C3 or haptoglobin.", "what_it_does_not_show": "Captured abundant proteins did not prove a unique reactive antigen; conclusions are kit-specific, not a denial of permeability.", "confounders_present": [ "Captured abundant proteins did not prove a unique reactive antigen; conclusions are kit-specific, not a denial of permeability." ], "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": 62, "pmid": "19027740", "title": "Targeted epithelial tight junction dysfunction causes immune activation and contributes to development of experimental colitis.", "citation": "Su L, Shen L, Clayburgh DR et al. Targeted epithelial tight junction dysfunction causes immune activation and contributes to development of experimental colitis. Gastroenterology. 2009.", "doi": "10.1053/j.gastro.2008.10.081", "pmcid": "PMC2712351", "url": "https://pubmed.ncbi.nlm.nih.gov/19027740/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/19027740/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID19027740", "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", "SC6" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal overexpression", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Constitutively active epithelial MLCK caused immune activation and accelerated transfer colitis without spontaneous disease.", "what_it_does_not_show": "Overexpression sufficiency for leak does not establish endogenous necessity and the negative spontaneous-disease result argues for a second hit.", "confounders_present": [ "Overexpression sufficiency for leak does not establish endogenous necessity and the negative spontaneous-disease result argues for a second hit." ], "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": 63, "pmid": "23619146", "title": "TNFR2 activates MLCK-dependent tight junction dysregulation to cause apoptosis-mediated barrier loss and experimental colitis.", "citation": "Su L, Nalle SC, Shen L et al. TNFR2 activates MLCK-dependent tight junction dysregulation to cause apoptosis-mediated barrier loss and experimental colitis. Gastroenterology. 2013.", "doi": "10.1053/j.gastro.2013.04.011", "pmcid": "PMC3722284", "url": "https://pubmed.ncbi.nlm.nih.gov/23619146/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23619146/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID23619146", "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", "SC6" ], "favors_models": [], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "TNFR2 or long-MLCK deletion delayed transfer colitis, but apoptosis and DSS injury bypassed protection.", "what_it_does_not_show": "This maps a stage-specific pathway and its failure boundary, not a universal epithelial or systemic initiator.", "confounders_present": [ "This maps a stage-specific pathway and its failure boundary, not a universal epithelial or systemic initiator." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 64, "pmid": "16644703", "title": "Zonulin upregulation is associated with increased gut permeability in subjects with type 1 diabetes and their relatives.", "citation": "Sapone A, de Magistris L, Pietzak M et al. Zonulin upregulation is associated with increased gut permeability in subjects with type 1 diabetes and their relatives. Diabetes. 2006.", "doi": "10.2337/db05-1593", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/16644703/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/16644703/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID16644703", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "Elevated serum signals and permeability occurred in a subset of T1D; stored prediagnostic sera showed earlier elevations.", "what_it_does_not_show": "Archived precursor-marker association is not randomized prevention; exact historical assay identity must not be equated automatically with later commercial kits.", "confounders_present": [ "Archived precursor-marker association is not randomized prevention; exact historical assay identity must not be equated automatically with later commercial kits." ], "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": 65, "pmid": "28423466", "title": "Zonulin transgenic mice show altered gut permeability and increased morbidity/mortality in the DSS colitis model.", "citation": "Sturgeon C, Lan J, Fasano A et al. Zonulin transgenic mice show altered gut permeability and increased morbidity/mortality in the DSS colitis model. Annals of the New York Academy of Sciences. 2017.", "doi": "10.1111/nyas.13343", "pmcid": "PMC5479715", "url": "https://pubmed.ncbi.nlm.nih.gov/28423466/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28423466/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "ZONULIN-TG-2017", "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", "SC6" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal overexpression", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Zonulin-transgenic mice had greater DSS morbidity and antagonist rescue.", "what_it_does_not_show": "DSS and overexpression define a sensitization experiment; neither demonstrates spontaneous human cross-disease initiation.", "confounders_present": [ "DSS and overexpression define a sensitization experiment; neither demonstrates spontaneous human cross-disease 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": 66, "pmid": "24848256", "title": "The liver may act as a firewall mediating mutualism between the host and its gut commensal microbiota.", "citation": "Balmer ML, Slack E, de Gottardi A et al. The liver may act as a firewall mediating mutualism between the host and its gut commensal microbiota. Science translational medicine. 2014.", "doi": "10.1126/scitranslmed.3008618", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/24848256/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24848256/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID24848256", "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", "SC6" ], "favors_models": [], "evidence_class": "Strong", "system": "animal plus human observational", "decisive_perturbation": false, "endogenous": false, "direction": "positive", "what_it_shows": "Kupffer-cell clearance and liver damage experiments support a hepatic firewall to circulating gut commensals.", "what_it_does_not_show": "Clearance failure can raise systemic exposure independently of epithelial leak and does not identify the first human disease event.", "confounders_present": [ "Clearance failure can raise systemic exposure independently of epithelial leak and does not identify the first human disease event." ], "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": 67, "pmid": "29459849", "title": "Widely Used Commercial ELISA Does Not Detect Precursor of Haptoglobin2, but Recognizes Properdin as a Potential Second Member of the Zonulin Family.", "citation": "Scheffler L, Crane A, Heyne H et al. Widely Used Commercial ELISA Does Not Detect Precursor of Haptoglobin2, but Recognizes Properdin as a Potential Second Member of the Zonulin Family. Frontiers in endocrinology. 2018.", "doi": "10.3389/fendo.2018.00022", "pmcid": "PMC5807381", "url": "https://pubmed.ncbi.nlm.nih.gov/29459849/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29459849/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID29459849", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Materials and Methods:paragraph1, 1:Materials and Methods:paragraph9, 1:Materials and Methods:paragraph10, 1:Materials and Methods:paragraph11, 1:Materials and Methods:paragraph15, 1:Materials and Methods:paragraph16, 2:Results:paragraph0, 2:Results:paragraph1, 2:Results:paragraph2, 2:Results:paragraph4. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC6" ], "favors_models": [], "evidence_class": "Strong", "system": "assay validation", "decisive_perturbation": false, "endogenous": false, "direction": "negative", "what_it_shows": "ELISA signals failed to reflect HP genotype and did not detect recombinant pre-HP2; properdin was a candidate target.", "what_it_does_not_show": "Properdin identity and pathogenic function are not settled by immunocapture alone; correlated kit signals are not validated epithelial flux.", "confounders_present": [ "Properdin identity and pathogenic function are not settled by immunocapture alone; correlated kit signals are not validated epithelial flux." ], "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": 68, "pmid": "29984492", "title": "Increased jejunal permeability in human obesity is revealed by a lipid challenge and is linked to inflammation and type 2 diabetes.", "citation": "Genser L, Aguanno D, Soula HA et al. Increased jejunal permeability in human obesity is revealed by a lipid challenge and is linked to inflammation and type 2 diabetes. The Journal of pathology. 2018.", "doi": "10.1002/path.5134", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/29984492/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29984492/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID29984492", "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", "SC5" ], "favors_models": [], "evidence_class": "Moderate", "system": "human biopsy observational", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Fasting permeability was similar between obese and controls, while lipid challenge increased ex vivo macromolecular flux more in obesity.", "what_it_does_not_show": "Diet challenge, established obesity, inflammation and ex vivo assays do not establish human metabolic initiation.", "confounders_present": [ "Diet challenge, established obesity, inflammation and ex vivo assays do not establish human metabolic 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": [] } } ], "verification_summary": { "load_bearing_claims_checked": 75, "verified": 75, "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": "Functional measures support abnormalities in some cohorts, with normal ratios or fasting permeability elsewhere; kit signals alone do not establish permeability [7–11,32,68].", "resulting_ceiling": "Β" } ], "cap_precedence_resolutions": [ { "collision": "Perturbation in a defined setting versus broader inference", "subclaim_scope_cap_binds_on": "Increased intestinal epithelial permeability is a primary initiating cause of human autoimmune, inflammatory and metabolic disease through translocation of microbial products.", "subclaim_scope_threshold_binds_on": "The precise experimentally tested subclaim scope", "resolution": "\"A perturbation crosses a threshold within the system it was actually run in. A universal cap governs the inference from that system to the hypothesis’s claimed scope.\" SC2 receives animal-context credit. Forced LPS infusion, DSS colitis and transgenic overexpression cannot establish endogenous human epithelial initiation; the convergent set is assessed without re-capping its observational leg. Rubric06 lifespan language is not used as an obesity endpoint requirement; functional metabolic outcomes remain distinct from permeability biomarkers.", "note": "Convergent lines are assessed as a set; one weak leg is not re-capped over the assembled case." } ], "boundary_check_BGD": [ { "subclaim_id": "SC1", "field_valid_perturbation_quote": "\n- Gnotobiotic or transfer experiment showing phenotype movement, at minimum\n- Even without defined-consortium precision or robust rescue, a transfer paradigm in vivo is the minimum that crosses this threshold\n\nPer **Cap precedence** above, a gnotobiotic or forced-transfer experiment crosses Δ for the recipient-animal subclaim it was actually run in, while universal cap 5 (seeding or forced-transfer paradigms cap at Γ) still blocks the inference from that result to endogenous human biology — score the two scopes separately rather than choosing between the rules.", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "PMID32332732", "gamma_hard_rules_triggered": [], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Functional measures support abnormalities in some cohorts, with normal ratios or fasting permeability elsewhere; kit signals alone do not establish permeability [7–11,32,68].", "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": "PMID32332732, PMID38503474, PMID38412124, PMID41494803, PMID30936544, PMID41654223, PMID35705057, PMID19240062, PMID23619146", "gamma_hard_rules_triggered": [], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Selective MLCK intervention and stage-specific deletion, plus defined gut-joint and alcohol pathways, establish bounded causal contributions. DSS, forced LPS and vascular-only manipulations are not counted as isolated epithelial causation [1,13–16,23–24,63].", "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": "no", "qualifying_evidence_citation": "", "gamma_hard_rules_triggered": [ "Human initiating scope is not established by the selective animal perturbations; the complete convergent set is assessed without a blanket in vitro cap.", "Biomarker-only improvement without organismal benefit does not count as clinical disease causation." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Preclinical human associations and animal perturbations support plausibility, but no examined barrier-selective human prevention result establishes initiation. Bosi compares disease stages after autoimmunity is already present [44,64].", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC4", "field_valid_perturbation_quote": "\n- Gnotobiotic or transfer experiment showing phenotype movement, at minimum\n- Even without defined-consortium precision or robust rescue, a transfer paradigm in vivo is the minimum that crosses this threshold\n\nPer **Cap precedence** above, a gnotobiotic or forced-transfer experiment crosses Δ for the recipient-animal subclaim it was actually run in, while universal cap 5 (seeding or forced-transfer paradigms cap at Γ) still blocks the inference from that result to endogenous human biology — score the two scopes separately rather than choosing between the rules.", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "PMID32332732, PMID38503474", "gamma_hard_rules_triggered": [ "Human initiating scope is not established by the selective animal perturbations; the complete convergent set is assessed without a blanket in vitro cap.", "Biomarker-only improvement without organismal benefit does not count as clinical disease causation." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Tajik combines human risk associations with post-immunization mouse rescue; the commercial serum assay has specificity limitations and there is no human prevention randomization [1,10,43,46,61,67].", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC5", "field_valid_perturbation_quote": "\n- Gnotobiotic or transfer experiment showing phenotype movement, at minimum\n- Even without defined-consortium precision or robust rescue, a transfer paradigm in vivo is the minimum that crosses this threshold\n\nPer **Cap precedence** above, a gnotobiotic or forced-transfer experiment crosses Δ for the recipient-animal subclaim it was actually run in, while universal cap 5 (seeding or forced-transfer paradigms cap at Γ) still blocks the inference from that result to endogenous human biology — score the two scopes separately rather than choosing between the rules.", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "PMID19240062", "gamma_hard_rules_triggered": [ "Human initiating scope is not established by the selective animal perturbations; the complete convergent set is assessed without a blanket in vitro cap.", "Biomarker-only improvement without organismal benefit does not count as clinical disease causation." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Mouse endotoxin biology is causal but does not isolate human epithelial initiation. Human carrageenan permeability changed with null primary metabolic endpoints, and obesity can occur without measured barrier failure [20–22,25,27,30,50,68].", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC6", "field_valid_perturbation_quote": "\n- Gnotobiotic or transfer experiment showing phenotype movement, at minimum\n- Even without defined-consortium precision or robust rescue, a transfer paradigm in vivo is the minimum that crosses this threshold\n\nPer **Cap precedence** above, a gnotobiotic or forced-transfer experiment crosses Δ for the recipient-animal subclaim it was actually run in, while universal cap 5 (seeding or forced-transfer paradigms cap at Γ) still blocks the inference from that result to endogenous human biology — score the two scopes separately rather than choosing between the rules.", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "PMID32332732, PMID23619146", "gamma_hard_rules_triggered": [ "Human initiating scope is not established by the selective animal perturbations; the complete convergent set is assessed without a blanket in vitro cap.", "Biomarker-only improvement without organismal benefit does not count as clinical disease causation." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "The animal and ex vivo mechanisms make cross-disease leak biologically plausible; distinct upstream triggers, barriers and null endpoints prevent a shared initiating claim in humans [1,20,25,27,51–52,63,66].", "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": [ "[1] Larazotide reduced CIA severity and cell trafficking after collagen/adjuvant immunization; pre-RA serum signals predicted transition." ], "what_would_cross_it": "A barrier-selective intervention with validated flux/translocation, prespecified incident disease or functional endpoint, and mediator specificity in the stated scope; replicate with orthogonal genetic or pharmacologic instruments." }, { "subclaim_id": "SC2", "threshold": "Δ", "requirement_quoted": "Requires a transfer paradigm or causal perturbation in vivo.", "satisfied": "yes", "supporting_evidence": [ "[1] Larazotide reduced CIA severity and cell trafficking after collagen/adjuvant immunization; pre-RA serum signals predicted transition.", "[10] IEC Hif1a deletion exacerbated CIA and RIPK3-directed rescue suppressed necroptosis and arthritis.", "[13] Claudin-2 deletion improved septic mouse survival alongside reduced pore permeability and immune activation.", "[14] MLCK deletion preserved junctions and ameliorated checkpoint-inhibitor colitis; an interaction blocker retained antitumour efficacy.", "[15] Divertin blocked MLCK1 recruitment, delayed transfer-colitis symptoms and improved established experimental disease.", "[16] Myeloid cathepsin B deletion or gut-restricted inhibition preserved occludin and attenuated ethanol steatohepatitis.", "[23] TRPV6 loss or inhibition blocked ethanol-induced calcium influx, barrier disruption and inflammatory response.", "[24] GLP2 antagonism abolished much of prebiotic barrier benefit and GLP2 agonism improved permeability and inflammation.", "[63] TNFR2 or long-MLCK deletion delayed transfer colitis, but apoptosis and DSS injury bypassed protection." ], "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": [ "[1] Larazotide reduced CIA severity and cell trafficking after collagen/adjuvant immunization; pre-RA serum signals predicted transition.", "[10] IEC Hif1a deletion exacerbated CIA and RIPK3-directed rescue suppressed necroptosis and arthritis.", "[13] Claudin-2 deletion improved septic mouse survival alongside reduced pore permeability and immune activation.", "[14] MLCK deletion preserved junctions and ameliorated checkpoint-inhibitor colitis; an interaction blocker retained antitumour efficacy.", "[15] Divertin blocked MLCK1 recruitment, delayed transfer-colitis symptoms and improved established experimental disease.", "[16] Myeloid cathepsin B deletion or gut-restricted inhibition preserved occludin and attenuated ethanol steatohepatitis.", "[23] TRPV6 loss or inhibition blocked ethanol-induced calcium influx, barrier disruption and inflammatory response.", "[24] GLP2 antagonism abolished much of prebiotic barrier benefit and GLP2 agonism improved permeability and inflammation.", "[63] TNFR2 or long-MLCK deletion delayed transfer colitis, but apoptosis and DSS injury bypassed protection." ], "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": "no", "supporting_evidence": [ "[1] Larazotide reduced CIA severity and cell trafficking after collagen/adjuvant immunization; pre-RA serum signals predicted transition.", "[10] IEC Hif1a deletion exacerbated CIA and RIPK3-directed rescue suppressed necroptosis and arthritis.", "[13] Claudin-2 deletion improved septic mouse survival alongside reduced pore permeability and immune activation.", "[14] MLCK deletion preserved junctions and ameliorated checkpoint-inhibitor colitis; an interaction blocker retained antitumour efficacy.", "[15] Divertin blocked MLCK1 recruitment, delayed transfer-colitis symptoms and improved established experimental disease.", "[16] Myeloid cathepsin B deletion or gut-restricted inhibition preserved occludin and attenuated ethanol steatohepatitis.", "[23] TRPV6 loss or inhibition blocked ethanol-induced calcium influx, barrier disruption and inflammatory response.", "[24] GLP2 antagonism abolished much of prebiotic barrier benefit and GLP2 agonism improved permeability and inflammation.", "[63] TNFR2 or long-MLCK deletion delayed transfer colitis, but apoptosis and DSS injury bypassed protection." ], "what_would_cross_it": "A barrier-selective intervention with validated flux/translocation, prespecified incident disease or functional endpoint, and mediator specificity in the stated scope; replicate with orthogonal genetic or pharmacologic instruments." }, { "subclaim_id": "SC3", "threshold": "Δ", "requirement_quoted": "Requires a transfer paradigm or causal perturbation in vivo.", "satisfied": "no", "supporting_evidence": [], "what_would_cross_it": "A barrier-selective intervention with validated flux/translocation, prespecified incident disease or functional endpoint, and mediator specificity in the stated scope; replicate with orthogonal genetic or pharmacologic instruments." }, { "subclaim_id": "SC4", "threshold": "Δ", "requirement_quoted": "Requires a transfer paradigm or causal perturbation in vivo.", "satisfied": "no", "supporting_evidence": [ "[1] Larazotide reduced CIA severity and cell trafficking after collagen/adjuvant immunization; pre-RA serum signals predicted transition.", "[10] IEC Hif1a deletion exacerbated CIA and RIPK3-directed rescue suppressed necroptosis and arthritis." ], "what_would_cross_it": "A barrier-selective intervention with validated flux/translocation, prespecified incident disease or functional endpoint, and mediator specificity in the stated scope; replicate with orthogonal genetic or pharmacologic instruments." }, { "subclaim_id": "SC5", "threshold": "Δ", "requirement_quoted": "Requires a transfer paradigm or causal perturbation in vivo.", "satisfied": "no", "supporting_evidence": [ "[24] GLP2 antagonism abolished much of prebiotic barrier benefit and GLP2 agonism improved permeability and inflammation." ], "what_would_cross_it": "A barrier-selective intervention with validated flux/translocation, prespecified incident disease or functional endpoint, and mediator specificity in the stated scope; replicate with orthogonal genetic or pharmacologic instruments." }, { "subclaim_id": "SC6", "threshold": "Δ", "requirement_quoted": "Requires a transfer paradigm or causal perturbation in vivo.", "satisfied": "no", "supporting_evidence": [ "[1] Larazotide reduced CIA severity and cell trafficking after collagen/adjuvant immunization; pre-RA serum signals predicted transition.", "[63] TNFR2 or long-MLCK deletion delayed transfer colitis, but apoptosis and DSS injury bypassed protection." ], "what_would_cross_it": "A barrier-selective intervention with validated flux/translocation, prespecified incident disease or functional endpoint, and mediator specificity in the stated scope; replicate with orthogonal genetic or pharmacologic instruments." } ], "generalization_check": { "generalization_tested": "yes", "context_boundary_mapped": "yes", "internal_negative_controls": [ "CA-MLCK leak without spontaneous disease [62]", "MLCK knockout bypass by apoptosis and DSS [63]", "Metabolic impairment without measured leak [27]", "Carrageenan permeability change with null primary insulin-sensitivity endpoints [25]" ], "note": "Internal negatives map animal pathway and stage boundaries; the human initiating generalization is tested indirectly and remains unestablished, rather than being rescued by post hoc responder scope." }, "falsification_patterns_met": [ { "pattern": "Leak is not sufficient for spontaneous disease", "evidence": "CA-MLCK mice lacked spontaneous colitis despite leak [62].", "downgrade_applied": false }, { "pattern": "Disease can bypass the nominated pathway", "evidence": "MLCK loss delayed transfer disease but not late apoptosis or DSS colitis; metabolic impairment occurred without detected leak [27,63].", "downgrade_applied": false }, { "pattern": "Biomarker and phenotype dissociate", "evidence": "Carrageenan changed permeability with null metabolic primary endpoints; larazotide symptoms changed with null permeability comparisons [25,55,59].", "downgrade_applied": false } ], "pitfalls_flagged": [ { "pitfall": "Mistaking presence for primacy", "where": "Serum markers in established disease [29,33,46]." }, { "pitfall": "Temporal order inferred rather than demonstrated", "where": "Bosi stage comparison precedes clinical diagnosis but not already-present islet autoimmunity [44]." }, { "pitfall": "Therapeutic effect misread as mechanistic proof", "where": "Fingolimod, irisin, antioxidants and probiotics have alternative mediators [3–4,12,30,38]." }, { "pitfall": "Scope fitted to the result", "where": "No subgroup defined as susceptible solely because it became ill; genotype, baseline autoantibody status and exposure are antecedent facts." } ], "causal_tally_audit": { "tally_claimed_by_document": 9, "tally_after_audit": 9, "items_rejected": [ "Null and negative contrasts are discriminators, not positive threshold crossings. Reports and replications are not independent causal lines.", "Only positive selective in vivo contributions carry the decisive flag; negative contrasts, overexpression, forced microbial/LPS exposure and surrogate-only experiments do not. The count is reports, not independent lines." ] }, "steelman": { "case_one_rung_higher": "The case for Δ is that several gut-directed interventions prevent model disease, human leak can precede diagnosis, and local larazotide is closer to barrier specificity than broad immunosuppression [1,15,44,60]. If an incident human endpoint plus verified epithelial mediator were present, the full-scope boundary could be crossed.", "case_one_rung_lower": "The case for Β is that human initiation remains associational and commercial zonulin evidence is unreliable [32,61,67]. It is strongest if animal and organoid work are excluded entirely from plausibility rather than treated as partial system support.", "which_rejected": "Reject Δ for the full human initiating claim because model rescue does not carry that scope and the human clinical/permeability dissociations are material. Reject Β as the scope-matched level because experimentally grounded mechanisms supply more than association. Preserve Β as the preregistered weakest-link sensitivity.", "blocking_cap_threshold_or_missing_experiment": "Missing experiment: Randomize objectively defined islet-autoantibody-positive participants or ACPA-positive pre-RA participants to a gut-restricted, selective barrier intervention versus matched control before clinical disease. Preregister flux and translocation mediation, disease incidence, follow-up and effect size; validate the agent’s target and independent off-target profile." }, "final_score": { "hsef_level": "Γ", "hsef_descriptor": "Mechanistically plausible, partial system support", "confidence": "Moderate", "confidence_rationale": "68 primary reports with 8 selected partial-body examinations; density, heterogeneous controls and incomplete access set the confidence, not correctness.", "rests_on_non_peer_reviewed_work": false, "rationale": "Scope-matched SC6 returns Γ. The preregistered human cross-disease initiator has partial experimental support but lacks a selective causal test in its claimed scope. SC2 reaches Ε for mapped experimental contributions; it cannot carry the human initiation claims. Weakest-link would return Β because the descriptive association subclaim is Β; primary-subclaim and scope-matched return Γ." }, "role_of_mechanism": { "classification": "reinforcing / stabilizing factor", "derivation_step_matched": 5, "derivation": "The assessed causal contribution is amplification in defined models: barrier rescue changes trajectory after collagen immunization, immune-cell transfer, alcohol or other triggers. Initiation, rate limitation and necessity across the human scope are not jointly demonstrated. Hyperglycemia and arthritis also produce leak, so causal direction is bidirectional and context-dependent rather than exclusively downstream.", "tournament_used_as_tiebreaker": false, "note": "Derived from causal direction, not tournament rank." }, "extended_scoring_MSD": { "momentum": { "value": "Mechanistic only", "artifact": "2026 MLCK1 ICI-colitis and cathepsin-B alcohol-liver experiments attempt selective mechanism narrowing [14,16]. The examined human carrageenan, larazotide and synbiotic studies do not test prevention of T1D or RA [25,42,55,58–59]. No pending prevention trial is claimed without a verified registration.", "justification": "2026 MLCK1 ICI-colitis and cathepsin-B alcohol-liver experiments attempt selective mechanism narrowing [14,16]. The examined human carrageenan, larazotide and synbiotic studies do not test prevention of T1D or RA [25,42,55,58–59]. No pending prevention trial is claimed without a verified registration." }, "stability": { "value": "Stable", "trigger": "No verified pending barrier-selective human disease-incidence result was identified. A positive independently replicated prevention result would raise the human subclaim; an assay-corrected null prospective study would narrow it, but these are proposed tests, not named pending results.", "justification": "No verified pending barrier-selective human disease-incidence result was identified. A positive independently replicated prevention result would raise the human subclaim; an assay-corrected null prospective study would narrow it, but these are proposed tests, not named pending results." }, "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 objectively defined islet-autoantibody-positive participants or ACPA-positive pre-RA participants to a gut-restricted, selective barrier intervention versus matched control before clinical disease. Preregister flux and translocation mediation, disease incidence, follow-up and effect size; validate the agent’s target and independent off-target profile.", "readout": "Incident clinical T1D or synovitis alongside validated size-selective permeability, microbial-product identity and longitudinal immune activation", "critical_control": "Equal diet and systemic immune therapy, blinded incidence adjudication, target engagement, an orthogonal barrier assay and prespecified baseline genotype/autoantibody strata", "supporting_result": "Target-specific restoration precedes lower incident disease and mediation survives orthogonal perturbation and exposure controls", "falsifying_result": "Verified restoration with adequate power leaves incident disease unchanged, or benefit is fully accounted for by systemic immunomodulation" } ], "knowledge_gaps": [ { "name": "Gap 1", "statement": "Barrier-selective prevention with incident T1D or RA, rather than symptoms or serum proxies. Consensus proposed this gap; the examined human studies do not resolve it.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 2", "statement": "Determine the actual antigens detected by each serum kit and prospectively validate them against size-selective epithelial flux.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 3", "statement": "Measure epithelial passage, vascular escape and hepatic clearance together, so increased circulating material is assigned to the correct layer.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 4", "statement": "Prespecify exposure duration, LPS molecular structure, glycemic status and diet to test where endotoxemia is metabolically harmful or neutral.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 5", "statement": "Replicate the gut-joint intervention with independent human material and blinded randomized animal designs; shared biopsies should not count twice.", "relevance": "Limits mechanism identification or scope." } ], "review_metadata": { "review_date": "2026-10-05", "reviewer": "Codex", "evidence_base_note": "68 primary reports; cutoff 2026-10-05; bounded critical review, not exhaustive systematic review.", "literature_tools_available": true, "literature_tools_note": "Life Sciences Literature PubMed/Europe PMC; signed-in Consensus browser discovery and indexed full-text extraction; independent checks against original sections. Zero Consensus API calls.", "skill_version": "5.3", "validator_run": "exact archived v5.3 validator 2.3; see validator.txt", "validator_warnings_addressed": "Phenomenon entry was restated as the preregistered causal claim. No real phenomenon is labelled refuted; warning is explicitly justified.", "consensus_consistency_audit": "2026-10-09; supplementary provenance/source reconciliation; original grading retained; prior grades visible." }, "is_calibration_entry": { "value": false, "entry_role": "not_calibration", "blind_graded": null, "completed_blinded_calibration": false, "expected_band_sealed_at": "", "target_sha256": "", "target_authorship": "not applicable", "target_author_saw_review": null, "future_run_status": "not prepared", "unblinded_reason": "Ranking categorical verdict and index guidance were visible. No completed blinded calibration claimed." }, "upper_ladder_check": { "final_level_below_zeta": true, "equivalents_considered": [ { "kind": "mendelian_randomization", "available": false, "why_not_sufficient": "Human prevention and valid natural experiments could reach Η–Ω without demanding an unethical disease induction trial. Examined treatments do not isolate epithelial leak with incident human disease. HP genotype helps assess assay identity, not barrier causation. MR on an invalid serum proxy would not solve the problem." }, { "kind": "natural_experiment", "available": true, "why_not_sufficient": "Human prevention and valid natural experiments could reach Η–Ω without demanding an unethical disease induction trial. Examined treatments do not isolate epithelial leak with incident human disease. HP genotype helps assess assay identity, not barrier causation. MR on an invalid serum proxy would not solve the problem." }, { "kind": "dose_response_across_populations", "available": false, "why_not_sufficient": "Human prevention and valid natural experiments could reach Η–Ω without demanding an unethical disease induction trial. Examined treatments do not isolate epithelial leak with incident human disease. HP genotype helps assess assay identity, not barrier causation. MR on an invalid serum proxy would not solve the problem." }, { "kind": "withdrawal_rechallenge", "available": false, "why_not_sufficient": "Human prevention and valid natural experiments could reach Η–Ω without demanding an unethical disease induction trial. Examined treatments do not isolate epithelial leak with incident human disease. HP genotype helps assess assay identity, not barrier causation. MR on an invalid serum proxy would not solve the problem." }, { "kind": "therapeutic_perturbation_hard_endpoint", "available": true, "why_not_sufficient": "Human prevention and valid natural experiments could reach Η–Ω without demanding an unethical disease induction trial. Examined treatments do not isolate epithelial leak with incident human disease. HP genotype helps assess assay identity, not barrier causation. MR on an invalid serum proxy would not solve the problem." } ], "convergence_present": true, "cap_reapplied_to_convergent_set": false }, "provenance_header": { "sources_total": 68, "claims_total": 75, "claims_verified": 75, "claims_unverified": 0, "claims_contradicted": 0, "tier_a_sources": 68, "generated_by": "Codex; HSEF v5.3", "gate_passed": true }, "claims": [ { "id": "C1", "text": "Larazotide reduced CIA severity and cell trafficking after collagen/adjuvant immunization; pre-RA serum signals predicted transition. The human arm was observational and used Cusabio; immunization preceded leak. This establishes a checkpoint in induced arthritis, not human disease initiation.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC4", "SC6" ], "source_ns": [ 1 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph1, 1:Results:paragraph3, 1:Results:paragraph5, 1:Results:paragraph6, 1:Results:paragraph7, 1:Results:paragraph8, 1:Results:paragraph9, 1:Results:paragraph10, 1:Results:paragraph12, 1:Results:paragraph13, 1:Results:paragraph14, 1:Results:paragraph15, 2:Discussion:paragraph1, 2:Discussion:paragraph3, 3:Methods:paragraph0, 3:Methods:paragraph1, 3:Methods:paragraph8, 3:Methods:paragraph24. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C2", "text": "Oral P. gingivalis aggravated induced arthritis and altered gut immunity and microbiota. Multiple bacterial functions and prior collagen induction prevent assigning the effect specifically to barrier leak.", "carries_number": false, "load_bearing_for": [ "SC2", "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": "2026-10-05", "note": "" }, { "id": "C3", "text": "Irisin treatment delayed NOD diabetes with improved barrier and islet inflammation. Exercise-hormone effects on energy expenditure and immunity confound barrier-specific mediation; human samples were from new-onset disease.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 3 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C4", "text": "N-acetylcysteine attenuated systemic autoimmunity alongside microbial and barrier changes in MRL/lpr mice. Antioxidant pleiotropy and lupus genotype prevent a selective test of spontaneous human barrier initiation.", "carries_number": false, "load_bearing_for": [ "SC2", "SC6" ], "source_ns": [ 4 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C5", "text": "Diabetes-prone BB rats showed intestinal inflammatory activity before and after diabetes. Genotype, inflammation and barrier changes were not separated by a selective manipulation.", "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": "2026-10-05", "note": "" }, { "id": "C6", "text": "DSS colitis activated islet-reactive T cells and diabetes in BDC2.5 NOD mice; antibiotics prevented activation. DSS injury and a transgenic diabetogenic T-cell repertoire are combined perturbations, not isolated endogenous epithelial leak in humans.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 6 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Results:paragraph2, 0:Results:paragraph3, 0:Results:paragraph4, 0:Results:paragraph5. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C7", "text": "Mannitol recovery increased in established type 1 diabetes while the cellobiose/mannitol ratio remained normal. Probe absorption is not interchangeable with a selective macromolecular leak; disease duration can confound direction.", "carries_number": true, "load_bearing_for": [ "SC1", "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": "2026-10-05", "note": "" }, { "id": "C8", "text": "Both sugar recoveries increased in diabetic patients without a group difference in their ratio. Raw recovery and differential permeability diverged; established disease cannot establish initiation.", "carries_number": false, "load_bearing_for": [ "SC1", "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": "2026-10-05", "note": "" }, { "id": "C9", "text": "Antiinflammatory medication altered permeability in control subjects, complicating arthritis comparisons. NSAID and steroid exposure are potential common causes of measured leak and disease treatment status.", "carries_number": false, "load_bearing_for": [ "SC1", "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": "2026-10-05", "note": "" }, { "id": "C10", "text": "IEC Hif1a deletion exacerbated CIA and RIPK3-directed rescue suppressed necroptosis and arthritis. Collagen induction remains upstream; HIF1a has effects beyond permeability. Human ileal biopsy material overlaps the earlier gut-joint study.", "carries_number": true, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 10 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Methods:paragraph0, 1:Methods:paragraph1, 1:Methods:paragraph2. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C11", "text": "PEG400 urinary recovery did not identify increased permeability in active inflammatory disease. Different probe size and absorption kinetics limit direct comparison with lactulose or FITC-dextran results.", "carries_number": true, "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": "2026-10-05", "note": "" }, { "id": "C12", "text": "Early fingolimod improved gut and pancreatic immune tolerance and reduced NOD diabetes incidence. Systemic lymphocyte trafficking effects make barrier restoration an unisolated mediator.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 12 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C13", "text": "Claudin-2 deletion improved septic mouse survival alongside reduced pore permeability and immune activation. Sepsis was induced; developmental deletion and altered microbial virulence require caution about isolated barrier mediation and other diseases.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 13 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C14", "text": "MLCK deletion preserved junctions and ameliorated checkpoint-inhibitor colitis; an interaction blocker retained antitumour efficacy. Abstract-only access; ICI exposure and wild microbiota define context, and systemic human disease initiation was not tested.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 14 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C15", "text": "Divertin blocked MLCK1 recruitment, delayed transfer-colitis symptoms and improved established experimental disease. Transfer colitis and IL10 deficiency supply upstream immune abnormalities; human prevention was not tested.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 15 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph2, 1:RESULTS:paragraph16, 1:RESULTS:paragraph18, 1:RESULTS:paragraph19. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C16", "text": "Myeloid cathepsin B deletion or gut-restricted inhibition preserved occludin and attenuated ethanol steatohepatitis. Abstract-only access; alcohol is an antecedent and myeloid protease effects are broader than a pure epithelial perturbation.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 16 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C17", "text": "Enteroendocrine-cell loss impaired enteroid barrier function and PYY or somatostatin supplementation rescued it. Organoid barrier physiology is not organismal systemic disease or proof of human initiation.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 17 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C18", "text": "FKBP8 disruption blocked TNF-dependent MLCK recruitment and barrier loss; interactions were elevated in Crohn biopsies. Tacrolimus is immunosuppressive; barrier rescue without a disease-incidence endpoint cannot establish systemic primacy.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 18 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C19", "text": "Viable A. muciniphila reduced high-fat-diet fat gain, endotoxemia and insulin resistance while restoring mucus. Microbial treatment changes several metabolites and endocrine signals; barrier mediation and human causality were not isolated.", "carries_number": false, "load_bearing_for": [ "SC2", "SC5" ], "source_ns": [ 19 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C20", "text": "Hyperglycemia drove barrier disruption; epithelial GLUT2 deletion or glucose control restored containment. This is causal evidence for the reverse arrow and infection susceptibility, not barrier-first metabolic disease.", "carries_number": true, "load_bearing_for": [ "SC2", "SC5", "SC6" ], "source_ns": [ 20 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C21", "text": "Antibiotics and CD14 deletion reduced HFD-associated endotoxemia and metabolic abnormalities. Antibiotics and immune receptor deletion do not isolate epithelial permeability as the initiating mediator.", "carries_number": true, "load_bearing_for": [ "SC2", "SC5" ], "source_ns": [ 21 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C22", "text": "Equal endotoxin-unit doses from different bacterial LPS sources produced opposing glycemic effects. LPS structure and TLR4 activity matter; total measured endotoxin is not a uniform pathogenic exposure.", "carries_number": false, "load_bearing_for": [ "SC2", "SC5" ], "source_ns": [ 22 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C23", "text": "TRPV6 loss or inhibition blocked ethanol-induced calcium influx, barrier disruption and inflammatory response. Alcohol remains upstream and TRPV6 expression is not exclusively epithelial; inference is restricted to alcohol exposure.", "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": "2026-10-05", "note": "" }, { "id": "C24", "text": "GLP2 antagonism abolished much of prebiotic barrier benefit and GLP2 agonism improved permeability and inflammation. ob/ob biology and GLP2 trophic effects bound inference; it does not demonstrate human metabolic disease initiation.", "carries_number": true, "load_bearing_for": [ "SC2", "SC5" ], "source_ns": [ 24 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C25", "text": "Randomized carrageenan exposure increased lactulose/mannitol permeability but primary and co-primary insulin-sensitivity endpoints were null. BMI interactions were ancillary, not proof of the nominal primary endpoint or mediation by permeability.", "carries_number": false, "load_bearing_for": [ "SC1", "SC5" ], "source_ns": [ 25 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Methods:paragraph0, 1:Methods:paragraph2, 1:Methods:paragraph5, 1:Methods:paragraph6, 1:Methods:paragraph14, 2:Results:paragraph0, 2:Results:paragraph1, 2:Results:paragraph2, 2:Results:paragraph6. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C26", "text": "ALDH2 loss increased ethanol leak and liver injury, with complementary cell inhibition and activation. Acetaldehyde metabolism, cell injury and liver toxicity are pleiotropic; this is alcohol-context susceptibility.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 26 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C27", "text": "Diet-induced impaired glucose tolerance occurred across tested mouse backgrounds without detectable barrier loss. Assay sensitivity and diets limit universal absence claims, but leak was not necessary in these tested metabolic models.", "carries_number": false, "load_bearing_for": [ "SC5", "SC6" ], "source_ns": [ 27 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C28", "text": "PAD4 inhibition reduced intestinal NETs, endotoxemia and progression of diabetic retinopathy. Late diabetes and direct retinal or marrow effects prevent interpreting benefit as barrier-first diabetes initiation.", "carries_number": true, "load_bearing_for": [ "SC2", "SC5" ], "source_ns": [ 28 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C29", "text": "Serum zonulin-kit signals differed across diabetic kidney disease stages and predicted renal outcomes. Renal clearance, adiposity and assay identity confound interpreting a serum signal as intestinal permeability.", "carries_number": false, "load_bearing_for": [ "SC1", "SC5" ], "source_ns": [ 29 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C30", "text": "The probiotic/fibre trial had no significant body-fat difference in ITT; PP and post-hoc analyses were more favorable. Attrition, compliance restriction, reduced energy intake and zonulin association do not establish barrier-mediated fat loss.", "carries_number": false, "load_bearing_for": [ "SC2", "SC5" ], "source_ns": [ 30 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C31", "text": "MIS-C biospecimens showed antigenemia and barrier-associated signals; one larazotide-treated patient improved. An uncontrolled treated case and postinfectious disease cannot prove mediation, efficacy or a universal epithelial initiator.", "carries_number": false, "load_bearing_for": [ "SC2", "SC6" ], "source_ns": [ 31 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C32", "text": "Circulating zonulin did not mirror colonic permeability or pre-HP2; pre-HP2 non-producers still had kit signals. Local biopsy relationships differ from plasma; the result invalidates a proxy in the tested setting, not all barrier biology.", "carries_number": true, "load_bearing_for": [ "SC1", "SC6" ], "source_ns": [ 32 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C33", "text": "A serum zonulin signal tracked steatosis but not histological inflammation, ballooning or fibrosis in obese children. Cross-sectional case-control design and commercial-marker uncertainty prevent initiation or liver-injury causality.", "carries_number": false, "load_bearing_for": [ "SC1", "SC5" ], "source_ns": [ 33 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C34", "text": "Diet-induced weight loss improved MASH markers with falling serum zonulin; microbial changes were not sustained. No control arm or barrier-selective perturbation; caloric restriction and weight loss are plausible upstream causes.", "carries_number": false, "load_bearing_for": [ "SC1", "SC5" ], "source_ns": [ 34 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C35", "text": "An immunologically identified zonulin preparation reversibly disrupted primate epithelial junctions ex vivo. Early protein identity and purified exposure do not demonstrate necessity in endogenous human disease.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 35 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C36", "text": "A small open-label PsA probiotic study reported transient improvement in symptoms and permeability markers. No placebo control, different arthritis disease and fecal-marker identity limit inference to rheumatoid arthritis.", "carries_number": false, "load_bearing_for": [ "SC2", "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": "2026-10-05", "note": "" }, { "id": "C37", "text": "Zonulin-transgenic mice showed immune skew and dysbiosis; wildtype microbiota did not normalize immune profiles. Overexpression and latent inflammation need an environmental hit and do not establish spontaneous cross-disease causality.", "carries_number": false, "load_bearing_for": [ "SC2", "SC6" ], "source_ns": [ 37 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C38", "text": "Glutamine improved symptoms and permeability in postinfectious IBS-D selected for high permeability. Glutamine has multiple actions; the population and symptom endpoint do not establish autoimmune or metabolic disease prevention.", "carries_number": false, "load_bearing_for": [ "SC2", "SC6" ], "source_ns": [ 38 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C39", "text": "Glutamine effects on indomethacin permeability depended on dose timing; pretreatment alone failed. Drug-induced barrier damage is a different initiating exposure and there was no systemic disease endpoint.", "carries_number": false, "load_bearing_for": [ "SC1", "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": "2026-10-05", "note": "" }, { "id": "C40", "text": "Low-methoxyl pectin delayed NOD diabetes with caecal, SCFA and immune changes. Dietary fibre changes microbial and immune pathways simultaneously; permeability is not an isolated mediator.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 40 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C41", "text": "Engineered L. lactis delivering nuclease reduced NET markers and improved NOD glycemia and inflammation. Microbial engineering, immune effects and commercial leak markers permit several alternative mediators.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 41 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C42", "text": "ProFOS synbiotics did not improve albuminuria or measured secondary outcomes in type 1 diabetes. Established kidney disease and nonspecific microbiota treatment do not falsify a selective barrier prevention hypothesis.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 42 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C43", "text": "Arthritis disrupted intestinal resolving mediators; resolvin restored barrier and reduced joint inflammation after P. gingivalis. The reverse arrow is supported; pleiotropic immunoresolution is not epithelial-specific. Linked erratum must remain attached.", "carries_number": false, "load_bearing_for": [ "SC2", "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": "2026-10-05", "note": "" }, { "id": "C44", "text": "Lactulose/mannitol abnormality was present in autoantibody-positive preclinical as well as clinical diabetes groups. Stage comparison is not a prospective prevention experiment and cannot exclude autoimmunity already causing leak.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 44 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C45", "text": "Barrier-disrupting Citrobacter accelerated NOD insulitis; an espF-deficient strain did not. Virulence differences and infection immune effects complicate a pure permeability mediator interpretation.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 45 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C46", "text": "RA marker relationships differed by sex and disease duration in a proof-of-principle cohort. No healthy control group and unvalidated zonulin assays prevent defining a disease-specific barrier abnormality.", "carries_number": false, "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": "2026-10-05", "note": "" }, { "id": "C47", "text": "A single alcohol binge altered neutrophil function without detected barrier or translocation changes in healthy volunteers. Small cohort and short sampling window constrain null inference; immune effects need not require detectable leak.", "carries_number": false, "load_bearing_for": [ "SC1", "SC6" ], "source_ns": [ 47 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C48", "text": "CAD blood bacterial sequences and zonulin-kit signals were accompanied by cell-culture junction changes. Low-biomass contamination, assay specificity and established CAD prevent assigning endogenous systemic causality.", "carries_number": false, "load_bearing_for": [ "SC2", "SC6" ], "source_ns": [ 48 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C49", "text": "Lymphocytic-colitis biopsies had barrier defects; TNF/IFNg reproduced claudin redistribution without MLCK dependence. Cytokines can lie upstream and different junction pathways prevent a single universal leak mechanism.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 49 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C50", "text": "Chronic subcutaneous LPS infusion induced weight and hepatic metabolic abnormalities and CD14 mutants were protected. Infusion bypasses epithelium and hepatic versus whole-body insulin effects differ; it is not proof of gut leak initiation.", "carries_number": true, "load_bearing_for": [ "SC2", "SC5" ], "source_ns": [ 50 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C51", "text": "Gut endothelium formed a second barrier to bacteria; Salmonella penetrated through virulence-dependent beta-catenin disruption. Vascular escape is distinct from epithelial permeability; infection paradigms cannot prove all chronic systemic disease.", "carries_number": false, "load_bearing_for": [ "SC2", "SC6" ], "source_ns": [ 51 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C52", "text": "Endothelial beta-catenin activation prevented vascular escape and diet-induced NASH despite epithelial translocation. The manipulated layer was vascular, not epithelial; gain-of-function, nonrandomized and unblinded mouse work limits attribution.", "carries_number": false, "load_bearing_for": [ "SC2", "SC5" ], "source_ns": [ 52 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Materials and methods:paragraph0, 1:Materials and methods:paragraph1, 2:Results:paragraph0, 2:Results:paragraph9, 2:Results:paragraph11. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C53", "text": "Acute low-dose LPS improved mouse glucose homeostasis while long exposure reduced cell glycogen synthesis. Exposure duration and direct liver effects rebut treating endotoxin concentration as a monotonic metabolic toxin.", "carries_number": false, "load_bearing_for": [ "SC2", "SC5" ], "source_ns": [ 53 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C54", "text": "Larazotide improved ischemia-injured jejunal barrier at an intermediate dose, with fragment-dependent loss of efficacy. Ex vivo repair and nonmonotonic dosing are not systemic disease prevention or unambiguous target identity.", "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": "2026-10-05", "note": "" }, { "id": "C55", "text": "Larazotide gluten-challenge trial showed variable permeability assays, null between-group permeability and lower-dose symptom signals. Null primary permeability results and induced gluten exposure prevent claiming barrier-mediated systemic disease initiation.", "carries_number": false, "load_bearing_for": [ "SC2", "SC6" ], "source_ns": [ 55 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C56", "text": "Larazotide limited gliadin/cytokine junction changes and preserved gut junctions in sensitized transgenic mice. Experimental sensitization and junction readouts do not establish endogenous human autoimmune disease initiation.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 56 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C57", "text": "Larazotide promoted junction assembly in calcium-switch MDCK and leaky Caco2 models. Assembly physiology in vitro is capped at plausibility for organismal disease.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 57 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C58", "text": "Low-dose larazotide improved persistent celiac symptoms; higher doses did not differ from placebo. Symptom treatment in established celiac disease is not prevention or proven mediation by reduced epithelial flux.", "carries_number": false, "load_bearing_for": [ "SC2", "SC6" ], "source_ns": [ 58 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C59", "text": "Larazotide reduced gluten immune/symptom responses but did not significantly change lactulose/mannitol ratios. Clinical and biomarker effects cannot be assigned to permeability when the permeability endpoint was null.", "carries_number": false, "load_bearing_for": [ "SC2", "SC6" ], "source_ns": [ 59 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C60", "text": "Baseline permeability in asymptomatic Crohn relatives predicted later Crohn diagnosis over years. Prospective association reduces clinical reverse causation but does not eliminate latent inflammation, inherited risk or common exposures.", "carries_number": false, "load_bearing_for": [ "SC1", "SC6" ], "source_ns": [ 60 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C61", "text": "CUSABIO and Immundiagnostik assays failed recombinant pre-HP2 detection; immunocaptured proteins included C3 or haptoglobin. Captured abundant proteins did not prove a unique reactive antigen; conclusions are kit-specific, not a denial of permeability.", "carries_number": true, "load_bearing_for": [ "SC1", "SC6" ], "source_ns": [ 61 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Materials and methods:paragraph2, 1:Materials and methods:paragraph3, 1:Materials and methods:paragraph4, 1:Materials and methods:paragraph5, 1:Materials and methods:paragraph6, 2:Results:paragraph13, 2:Results:paragraph14, 2:Results:paragraph15, 2:Results:paragraph16, 3:Discussion:paragraph0. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C62", "text": "Constitutively active epithelial MLCK caused immune activation and accelerated transfer colitis without spontaneous disease. Overexpression sufficiency for leak does not establish endogenous necessity and the negative spontaneous-disease result argues for a second hit.", "carries_number": false, "load_bearing_for": [ "SC2", "SC6" ], "source_ns": [ 62 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C63", "text": "TNFR2 or long-MLCK deletion delayed transfer colitis, but apoptosis and DSS injury bypassed protection. This maps a stage-specific pathway and its failure boundary, not a universal epithelial or systemic initiator.", "carries_number": true, "load_bearing_for": [ "SC2", "SC6" ], "source_ns": [ 63 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C64", "text": "Elevated serum signals and permeability occurred in a subset of T1D; stored prediagnostic sera showed earlier elevations. Archived precursor-marker association is not randomized prevention; exact historical assay identity must not be equated automatically with later commercial kits.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 64 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C65", "text": "Zonulin-transgenic mice had greater DSS morbidity and antagonist rescue. DSS and overexpression define a sensitization experiment; neither demonstrates spontaneous human cross-disease initiation.", "carries_number": false, "load_bearing_for": [ "SC2", "SC6" ], "source_ns": [ 65 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C66", "text": "Kupffer-cell clearance and liver damage experiments support a hepatic firewall to circulating gut commensals. Clearance failure can raise systemic exposure independently of epithelial leak and does not identify the first human disease event.", "carries_number": false, "load_bearing_for": [ "SC2", "SC6" ], "source_ns": [ 66 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C67", "text": "ELISA signals failed to reflect HP genotype and did not detect recombinant pre-HP2; properdin was a candidate target. Properdin identity and pathogenic function are not settled by immunocapture alone; correlated kit signals are not validated epithelial flux.", "carries_number": true, "load_bearing_for": [ "SC1", "SC6" ], "source_ns": [ 67 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Materials and Methods:paragraph1, 1:Materials and Methods:paragraph9, 1:Materials and Methods:paragraph10, 1:Materials and Methods:paragraph11, 1:Materials and Methods:paragraph15, 1:Materials and Methods:paragraph16, 2:Results:paragraph0, 2:Results:paragraph1, 2:Results:paragraph2, 2:Results:paragraph4. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "C68", "text": "Fasting permeability was similar between obese and controls, while lipid challenge increased ex vivo macromolecular flux more in obesity. Diet challenge, established obesity, inflammation and ex vivo assays do not establish human metabolic initiation.", "carries_number": false, "load_bearing_for": [ "SC1", "SC5" ], "source_ns": [ 68 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-05", "note": "" }, { "id": "CSC1", "text": "Functional measures support abnormalities in some cohorts, with normal ratios or fasting permeability elsewhere; kit signals alone do not establish permeability [7–11,32,68].", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 1, 7, 8, 9, 11, 25, 29, 32, 33, 34, 39, 44, 46, 47, 60, 61, 64, 67, 68 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-05", "note": "" }, { "id": "CSC2", "text": "Selective MLCK intervention and stage-specific deletion, plus defined gut-joint and alcohol pathways, establish bounded causal contributions. DSS, forced LPS and vascular-only manipulations are not counted as isolated epithelial causation [1,13–16,23–24,63].", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 1, 2, 3, 4, 6, 10, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 31, 35, 36, 37, 38, 39, 40, 41, 42, 43, 45, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 62, 63, 65, 66 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-05", "note": "" }, { "id": "CSC3", "text": "Preclinical human associations and animal perturbations support plausibility, but no examined barrier-selective human prevention result establishes initiation. Bosi compares disease stages after autoimmunity is already present [44,64].", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 3, 5, 6, 7, 8, 12, 40, 41, 42, 44, 45, 64 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-05", "note": "" }, { "id": "CSC4", "text": "Tajik combines human risk associations with post-immunization mouse rescue; the commercial serum assay has specificity limitations and there is no human prevention randomization [1,10,43,46,61,67].", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 1, 2, 9, 10, 11, 36, 43, 46 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-05", "note": "" }, { "id": "CSC5", "text": "Mouse endotoxin biology is causal but does not isolate human epithelial initiation. Human carrageenan permeability changed with null primary metabolic endpoints, and obesity can occur without measured barrier failure [20–22,25,27,30,50,68].", "carries_number": false, "load_bearing_for": [ "SC5" ], "source_ns": [ 19, 20, 21, 22, 24, 25, 27, 28, 29, 30, 33, 34, 50, 52, 53, 68 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-05", "note": "" }, { "id": "CSC6", "text": "The animal and ex vivo mechanisms make cross-disease leak biologically plausible; distinct upstream triggers, barriers and null endpoints prevent a shared initiating claim in humans [1,20,25,27,51–52,63,66].", "carries_number": false, "load_bearing_for": [ "SC6" ], "source_ns": [ 1, 4, 20, 27, 31, 32, 37, 38, 47, 48, 51, 55, 58, 59, 60, 61, 62, 63, 65, 66, 67 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-05", "note": "" }, { "id": "CH", "text": "Barrier dysfunction can causally amplify disease in defined experimental settings; a common epithelial-leak initiator of human autoimmune and metabolic disease is not established.", "carries_number": false, "load_bearing_for": [ "SC6" ], "source_ns": [ 1, 63, 25, 61, 27 ], "verification": "verified", "verified_against": "Bounded synthesis of examined sources; score is adjudication.", "verified_on": "2026-10-05", "note": "" } ], "citation_ledger": [ { "n": 1, "citation": "Tajik N, Frech M, Schulz O et al. Targeting zonulin and intestinal epithelial barrier function to prevent onset of arthritis. Nature communications. 2020.", "tier": "A", "kind": "primary", "pmid": "32332732", "doi": "10.1038/s41467-020-15831-7", "url": "https://pubmed.ncbi.nlm.nih.gov/32332732/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "GUT-JOINT-TAJIK-2020", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph1, 1:Results:paragraph3, 1:Results:paragraph5, 1:Results:paragraph6, 1:Results:paragraph7, 1:Results:paragraph8, 1:Results:paragraph9, 1:Results:paragraph10, 1:Results:paragraph12, 1:Results:paragraph13, 1:Results:paragraph14, 1:Results:paragraph15, 2:Discussion:paragraph1, 2:Discussion:paragraph3, 3:Methods:paragraph0, 3:Methods:paragraph1, 3:Methods:paragraph8, 3:Methods:paragraph24. 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International journal of biological macromolecules. 2024.", "tier": "A", "kind": "primary", "pmid": "38493812", "doi": "10.1016/j.ijbiomac.2024.130857", "url": "https://pubmed.ncbi.nlm.nih.gov/38493812/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID38493812", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C3", "CSC2", "CSC3" ] }, { "n": 4, "citation": "Wang H, Wang G, Banerjee N et al. Aberrant Gut Microbiome Contributes to Intestinal Oxidative Stress, Barrier Dysfunction, Inflammation and Systemic Autoimmune Responses in MRL/lpr Mice. Frontiers in immunology. 2021.", "tier": "A", "kind": "primary", "pmid": "33912174", "doi": "10.3389/fimmu.2021.651191", "url": "https://pubmed.ncbi.nlm.nih.gov/33912174/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID33912174", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C4", "CSC2", "CSC6" ] }, { "n": 5, "citation": "Hardin JA, Donegan L, Woodman RC et al. Mucosal inflammation in a genetic model of spontaneous type I diabetes mellitus. Canadian journal of physiology and pharmacology. 2002.", "tier": "A", "kind": "primary", "pmid": "12489925", "doi": "10.1139/y02-138", "url": "https://pubmed.ncbi.nlm.nih.gov/12489925/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID12489925", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C5", "CSC3" ] }, { "n": 6, "citation": "Sorini C, Cosorich I, Lo Conte M et al. Loss of gut barrier integrity triggers activation of islet-reactive T cells and autoimmune diabetes. Proceedings of the National Academy of Sciences of the United States of America. 2019.", "tier": "A", "kind": "primary", "pmid": "31182588", "doi": "10.1073/pnas.1814558116", "url": "https://pubmed.ncbi.nlm.nih.gov/31182588/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID31182588", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 0:Results:paragraph2, 0:Results:paragraph3, 0:Results:paragraph4, 0:Results:paragraph5. No complete-paper or supplement audit claimed.", "carries_claims": [ "C6", "CSC2", "CSC3" ] }, { "n": 7, "citation": "Carratù R, Secondulfo M, de Magistris L et al. Altered intestinal permeability to mannitol in diabetes mellitus type I. Journal of pediatric gastroenterology and nutrition. 1999.", "tier": "A", "kind": "primary", "pmid": "10067726", "doi": "10.1097/00005176-199903000-00010", "url": "https://pubmed.ncbi.nlm.nih.gov/10067726/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID10067726", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C7", "CSC1", "CSC3" ] }, { "n": 8, "citation": "Mooradian AD, Morley JE, Levine AS et al. Abnormal intestinal permeability to sugars in diabetes mellitus. Diabetologia. 1986.", "tier": "A", "kind": "primary", "pmid": "3519337", "doi": "10.1007/BF00454879", "url": "https://pubmed.ncbi.nlm.nih.gov/3519337/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID3519337", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C8", "CSC1", "CSC3" ] }, { "n": 9, "citation": "Mielants H, Goemaere S, De Vos M et al. Intestinal mucosal permeability in inflammatory rheumatic diseases. I. Role of antiinflammatory drugs. The Journal of rheumatology. 1991.", "tier": "A", "kind": "primary", "pmid": "1906938", "doi": "", "url": "https://pubmed.ncbi.nlm.nih.gov/1906938/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID1906938", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C9", "CSC1", "CSC4" ] }, { "n": 10, "citation": "Lyu P, Wen J, Zhang W et al. Expression of HIF1α in intestinal epithelium restricts arthritis inflammation by inhibiting RIPK3-induced cell death machinery. Annals of the rheumatic diseases. 2024.", "tier": "A", "kind": "primary", "pmid": "38503474", "doi": "10.1136/ard-2023-224491", "url": "https://pubmed.ncbi.nlm.nih.gov/38503474/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "GUT-JOINT-HIF2024-shared-human-biopsies", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Methods:paragraph0, 1:Methods:paragraph1, 1:Methods:paragraph2. No complete-paper or supplement audit claimed.", "carries_claims": [ "C10", "CSC2", "CSC4" ] }, { "n": 11, "citation": "Jenkins RT, Goodacre RL, Rooney PJ et al. Studies of intestinal permeability in inflammatory diseases using polyethylene glycol 400. Clinical biochemistry. 1986.", "tier": "A", "kind": "primary", "pmid": "3769195", "doi": "10.1016/s0009-9120(86)80045-5", "url": "https://pubmed.ncbi.nlm.nih.gov/3769195/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID3769195", "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": "Jia LL, Zhang M, Liu H et al. Early-life fingolimod treatment improves intestinal homeostasis and pancreatic immune tolerance in non-obese diabetic mice. Acta pharmacologica Sinica. 2021.", "tier": "A", "kind": "primary", "pmid": "33473182", "doi": "10.1038/s41401-020-00590-4", "url": "https://pubmed.ncbi.nlm.nih.gov/33473182/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID33473182", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C12", "CSC2", "CSC3" ] }, { "n": 13, "citation": "Oami T, Abtahi S, Shimazui T et al. Claudin-2 upregulation enhances intestinal permeability, immune activation, dysbiosis, and mortality in sepsis. Proceedings of the National Academy of Sciences of the United States of America. 2024.", "tier": "A", "kind": "primary", "pmid": "38412124", "doi": "10.1073/pnas.2217877121", "url": "https://pubmed.ncbi.nlm.nih.gov/38412124/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID38412124", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C13", "CSC2" ] }, { "n": 14, "citation": "Xiong L, Huang J, Dong Y et al. Targeting MLCK1 uncouples immune checkpoint inhibitor-induced colitis from antitumour immunity. Gut. 2026.", "tier": "A", "kind": "primary", "pmid": "41494803", "doi": "10.1136/gutjnl-2025-337780", "url": "https://pubmed.ncbi.nlm.nih.gov/41494803/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID41494803", "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" ] }, { "n": 15, "citation": "Graham WV, He W, Marchiando AM et al. Intracellular MLCK1 diversion reverses barrier loss to restore mucosal homeostasis. Nature medicine. 2019.", "tier": "A", "kind": "primary", "pmid": "30936544", "doi": "10.1038/s41591-019-0393-7", "url": "https://pubmed.ncbi.nlm.nih.gov/30936544/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-05", "status_checked_on": "2026-10-05", "study_id": "PMID30936544", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:RESULTS:paragraph2, 1:RESULTS:paragraph16, 1:RESULTS:paragraph18, 1:RESULTS:paragraph19. No complete-paper or supplement audit claimed.", "carries_claims": [ "C15", "CSC2" ] }, { "n": 16, "citation": "Fondevila MF, Kreimeyer H, Hsu CL et al. Macrophage-derived cathepsin B disrupts intestinal tight junctions through occludin degradation and promotes alcohol-associated liver disease. 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