{ "$schema_version": "5.3", "review_mode": "fresh", "claim_restatement": { "index_wording": "Hygiene Hypothesis", "entry_form": "claim", "gradeable_restatement": "Reduced early-life microbial exposure causally increases the incidence of allergic and autoimmune disease.", "restatement_required": true, "split_into": [], "parent_claim": null, "scope_qualifiers": [ { "qualifier": "Species, genotype, developmental window, exposure, baseline disease and measurement fixed before outcomes", "determinable_before_outcome": true, "determined_from": "Enrollment and experimental design, before results; no responder-defined scope.", "action": "retained" } ] }, "hypothesis": { "name": "Hygiene Hypothesis", "central_claim": "Reduced early-life microbial exposure causally increases the incidence of allergic and autoimmune disease.", "proposed_mechanism": "Reduced early-life microbial exposure causally increases the incidence of allergic and autoimmune disease.", "claimed_scope": "Reduced measured early-life microbial exposure and human allergic/autoimmune disease incidence; exposure identity, timing and disease class fixed before outcome", "claimed_level": [ "initiation", "maintenance", "progression" ], "is_conjunctive": true, "conjunctive_note": "SC3 is the causal claim at the registered human/disease or endogenous scope; narrower physiology, model interventions and associations are reported separately. Primary-subclaim aggregation is fixed before new grading." }, "rubric_routing": { "primary_rubric": "05-immunology-inflammation.md", "secondary_rubrics": [ "04-microbiome-systemic.md" ], "index_notes_applied": [ "SC3 is the causal claim at the registered human/disease or endogenous scope; narrower physiology, model interventions and associations are reported separately. Primary-subclaim aggregation is fixed before new grading." ], "rubric_fit_note": "05 governs immune clinical causality; 04 governs consortium/strain evidence and recipient-to-human inference. Eczema is kept separate from sensitization, wheeze, diagnosed asthma, autoantibodies and clinical autoimmune disease. A narrow microbial-product prevention effect is not relabeled as population-wide loss-of-diversity mediation. The partial full-claim Γ is a scope/boundary adjudication, not an assertion that all included trials are biomarker-only." }, "subclaim_matrix": { "subclaims": [ { "id": "SC1", "statement": "Early microbial exposure patterns predict later allergic or autoimmune disease.", "subclaim_type": "existence", "scope": "Age, exposure setting, medication, disease and assay defined before outcome", "claimed_scope": "Age, exposure setting, medication, disease and assay defined before outcome", "governing_rubric": "05-immunology-inflammation.md", "key_evidence_anchor": "Prospective farm, sibling and birth cohorts", "hsef_level": "Β", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Farm, sibling, infant microbiome and antibiotic data repeatedly predict selected immune outcomes, but signs vary by disease, age and exposure. Familial, dietary, infection and indication effects are not uniformly eliminated. The registered predictive association component is Β, not a negation of specific causal interventions reported separately." }, { "id": "SC2", "statement": "Defined microbial exposures causally alter immune regulation and disease susceptibility.", "subclaim_type": "mechanism", "scope": "Defined strain, microbial factor, developmental window and model", "claimed_scope": "Defined strain, microbial factor, developmental window and model", "governing_rubric": "05-immunology-inflammation.md", "key_evidence_anchor": "Selective exposure/mediator perturbation and rescue in vivo", "hsef_level": "Ε", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "Defined colonization, epithelial A20 and Treg MyD88/RORgamma-t controls establish context-specific immune/disease effects in recipient models. Selected randomized human microbial regimens also modify eczema risk, while others are null or adverse. This supports Ε for specified exposure/host/phenotype contexts, not an interchangeable class of protective microbes." }, { "id": "SC3", "statement": "Reduced early-life microbial exposure causally increases human allergic and autoimmune disease incidence.", "subclaim_type": "generalization", "scope": "Human disease classes and measured early exposure; no post hoc protected subgroup", "claimed_scope": "Human disease classes and measured early exposure; no post hoc protected subgroup", "governing_rubric": "05-immunology-inflammation.md", "key_evidence_anchor": "Randomized microbial interventions, natural experiments and genetically controlled cohorts", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "The complete human allergic-and-autoimmune incidence claim has partial mechanistic support, but no source set isolates a generalized early microbial deficit as the cause across the registered disease classes. Specific eczema prevention is real and retained; overall-null respiratory trials, bidirectional infection associations and harmful commensal mechanisms constrain transfer. Food-antigen tolerance and short-term soil immune markers cannot fill the missing autoimmune clinical branch." } ], "aggregation_rule": "primary-subclaim", "aggregation_preregistered": true, "aggregation_rationale": "SC3 is the causal claim at the registered human/disease or endogenous scope; narrower physiology, model interventions and associations are reported separately. Primary-subclaim aggregation is fixed before new grading.", "primary_subclaim_id": "SC3", "aggregation_derivation": "Overall Γ follows the registered complete human incidence SC3, with SC1 at Β and exposure-specific immune/clinical SC2 at Ε. Positive eczema trials and mechanistic recipient experiments are retained without claiming generalized protection from asthma or autoimmunity. Neither a universal biomarker cap nor a negative-trial veto is imposed on the narrow clinical successes; the broad conjunction has not crossed its own causal boundary.", "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": "Exposure-specific immune education", "core_claim": "Microbial factor, host pathway, dose and developmental window determine beneficial or harmful immune effects.", "explains_what_nominal_does_not": "Microbial factor, host pathway, dose and developmental window determine beneficial or harmful immune effects.", "strongest_supporting_evidence": [ "Strain comparisons, Treg/epithelial necessity, timed colonization and clinical eczema effects define restricted causality." ], "strongest_contradictory_evidence": [ "Does not yet predict every human allergic/autoimmune outcome or a universal optimal microbiome." ], "hsef_level_for_this_model": "Ε", "rationale": "Strain comparisons, Treg/epithelial necessity, timed colonization and clinical eczema effects define restricted causality. Does not yet predict every human allergic/autoimmune outcome or a universal optimal microbiome." }, { "rank_in_tournament": 2, "model_id": "M4", "is_nominal": false, "name": "Barrier and antigen-specific tolerance", "core_claim": "Food antigen timing and barrier/immune pathways can change selected allergy outcomes independently of microbial restoration.", "explains_what_nominal_does_not": "Food antigen timing and barrier/immune pathways can change selected allergy outcomes independently of microbial restoration.", "strongest_supporting_evidence": [ "LEAP demonstrates food-specific clinical prevention; epithelial mechanisms supply a distinct causal route." ], "strongest_contradictory_evidence": [ "Food exposure does not explain every farm association or prove systemic autoimmune protection." ], "hsef_level_for_this_model": "Ε", "rationale": "LEAP demonstrates food-specific clinical prevention; epithelial mechanisms supply a distinct causal route. Food exposure does not explain every farm association or prove systemic autoimmune protection." }, { "rank_in_tournament": 3, "model_id": "M1", "is_nominal": true, "name": "General microbial deprivation", "core_claim": "Reduced early microbial contact broadly causes allergic and autoimmune disease.", "explains_what_nominal_does_not": "Reduced early microbial contact broadly causes allergic and autoimmune disease.", "strongest_supporting_evidence": [ "Farm associations, recipient rescues and some positive prevention trials supply its strongest case." ], "strongest_contradictory_evidence": [ "Clinical nulls, harmful microbial pathways, weak human autoimmune mediation and exposure heterogeneity prevent the registered generalization." ], "hsef_level_for_this_model": "Γ", "rationale": "Farm associations, recipient rescues and some positive prevention trials supply its strongest case. Clinical nulls, harmful microbial pathways, weak human autoimmune mediation and exposure heterogeneity prevent the registered generalization." }, { "rank_in_tournament": 4, "model_id": "M3", "is_nominal": false, "name": "Shared environment and indication effects", "core_claim": "Diet, barrier damage, genetics and infection/antibiotic indications generate part of the exposure-disease association.", "explains_what_nominal_does_not": "Diet, barrier damage, genetics and infection/antibiotic indications generate part of the exposure-disease association.", "strongest_supporting_evidence": [ "Familial/sibling constraints and different disease directions show alternatives that must be tested." ], "strongest_contradictory_evidence": [ "Cannot erase randomized eczema effects or selective model pathway necessity." ], "hsef_level_for_this_model": "Γ", "rationale": "Familial/sibling constraints and different disease directions show alternatives that must be tested. Cannot erase randomized eczema effects or selective model pathway necessity." } ], "tournament_summary": "Descriptive comparison; does not modify the nominal score. The randomized HN001/HN019 comparison (PMID18762327), defined-consortium/Treg necessity (PMID31235962), and the opposite-direction microbial peptidoglycan perturbation (PMID30833732) distinguish exposure-specific effects from a simple protective-quantity claim. ORBEX (PMID42705251) tests a prespecified human respiratory-prevention boundary, while LEAP (PMID25705822) supplies an orthogonal antigen-tolerance explanation.", "study_separating_rank1_from_rank2": "The randomized HN001/HN019 comparison (PMID18762327), defined-consortium/Treg necessity (PMID31235962), and the opposite-direction microbial peptidoglycan perturbation (PMID30833732) distinguish exposure-specific effects from a simple protective-quantity claim. ORBEX (PMID42705251) tests a prespecified human respiratory-prevention boundary, while LEAP (PMID25705822) supplies an orthogonal antigen-tolerance explanation.", "nominal_wins_only_by_funding_artifact": false, "level_unchanged_by_tournament": true }, "evidence_inventory": [ { "n": 1, "pmid": "27518660", "title": "Innate Immunity and Asthma Risk in Amish and Hutterite Farm Children.", "citation": "Stein MM, Hrusch CL, Gozdz J et al. Innate Immunity and Asthma Risk in Amish and Hutterite Farm Children. 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No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "mixed animal/human", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Amish/Hutterite asthma and innate-immune differences accompany different dust exposure; Amish dust protects adult mice via MyD88/TRIF.", "what_it_does_not_show": "Human comparison is nonrandomized; adult dust instillation is not a neonatal deprivation experiment.", "confounders_present": [ "Human comparison is nonrandomized; adult dust instillation is not a neonatal deprivation experiment." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": true, "provider": "Scite", "retrieved_on": "2026-10-11", "tally": { "total": 882, "supporting": 37, "contrasting": 4, "mentioning": 824, "citingPublications": 982 }, "notable_contrasting_statements": [], "note": "Provider tally only. Returned snippets are outgoing references from this anchor, not incoming contrasting evidence. No grade inferred from counts; editorial notices were not returned." }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 2, "pmid": "21345099", "title": "Exposure to environmental microorganisms and childhood asthma.", "citation": "Ege MJ, Mayer M, Normand AC et al. Exposure to environmental microorganisms and childhood asthma. The New England journal of medicine. 2011.", "doi": "10.1056/NEJMoa1007302", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/21345099/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21345099/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID21345099", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Farm microbial diversity associates inversely with asthma in two population studies.", "what_it_does_not_show": "Farm setting has multiple correlated exposures; measured diversity mediation is not selective causal manipulation.", "confounders_present": [ "Farm setting has multiple correlated exposures; measured diversity mediation is not selective causal 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": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 3, "pmid": "11297958", "title": "Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial.", "citation": "Kalliomäki M, Salminen S, Arvilommi H et al. Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial. Lancet (London, England). 2001.", "doi": "10.1016/S0140-6736(00)04259-8", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/11297958/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/11297958/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "FINN_LGG", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Perinatal LGG reduces primary eczema incidence in a high-risk randomized trial.", "what_it_does_not_show": "Specific strain/regimen/phenotype; no proof of general asthma or autoimmune prevention.", "confounders_present": [ "Specific strain/regimen/phenotype; no proof of general asthma or autoimmune 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": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 4, "pmid": "12788576", "title": "Probiotics and prevention of atopic disease: 4-year follow-up of a randomised placebo-controlled trial.", "citation": "Kalliomäki M, Salminen S, Poussa T et al. Probiotics and prevention of atopic disease: 4-year follow-up of a randomised placebo-controlled trial. Lancet (London, England). 2003.", "doi": "10.1016/S0140-6736(03)13490-3", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/12788576/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/12788576/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "FINN_LGG", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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": "mixed", "what_it_shows": "Finnish LGG follow-up retains eczema benefit but not skin-test reactivity difference.", "what_it_does_not_show": "Same parent trial with attrition; not independent replication or broad atopy prevention.", "confounders_present": [ "Same parent trial with attrition; not independent replication or broad atopy 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": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 5, "pmid": "18762327", "title": "A differential effect of 2 probiotics in the prevention of eczema and atopy: a double-blind, randomized, placebo-controlled trial.", "citation": "Wickens K, Black PN, Stanley TV et al. A differential effect of 2 probiotics in the prevention of eczema and atopy: a double-blind, randomized, placebo-controlled trial. The Journal of allergy and clinical immunology. 2008.", "doi": "10.1016/j.jaci.2008.07.011", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/18762327/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/18762327/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "NZ_HN001_HN019", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "HN001 reduces eczema, while HN019 and sensitization comparisons are null.", "what_it_does_not_show": "Strain and endpoint boundaries; probiotic exposure is not interchangeable with environmental diversity.", "confounders_present": [ "Strain and endpoint boundaries; probiotic exposure is not interchangeable with environmental diversity." ], "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": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 6, "pmid": "22702506", "title": "A protective effect of Lactobacillus rhamnosus HN001 against eczema in the first 2 years of life persists to age 4 years.", "citation": "Wickens K, Black P, Stanley TV et al. A protective effect of Lactobacillus rhamnosus HN001 against eczema in the first 2 years of life persists to age 4 years. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 2012.", "doi": "10.1111/j.1365-2222.2012.03975.x", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/22702506/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22702506/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "NZ_HN001_HN019", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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": "mixed", "what_it_shows": "HN001 follow-up retains eczema/rhinoconjunctivitis benefit; HN019 and other endpoints remain null or nonsignificant.", "what_it_does_not_show": "Same randomization as the two-strain study; selected secondary outcomes do not show uniform protection.", "confounders_present": [ "Same randomization as the two-strain study; selected secondary outcomes do not show uniform protection." ], "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": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 7, "pmid": "23083673", "title": "Maternal probiotic supplementation during pregnancy and breast-feeding reduces the risk of eczema in the infant.", "citation": "Rautava S, Kainonen E, Salminen S et al. Maternal probiotic supplementation during pregnancy and breast-feeding reduces the risk of eczema in the infant. The Journal of allergy and clinical immunology. 2012.", "doi": "10.1016/j.jaci.2012.09.003", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/23083673/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23083673/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "FINN_MATERNAL_MIX", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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": "supports", "what_it_shows": "Maternal probiotic mixtures reduce eczema in infants of allergic mothers.", "what_it_does_not_show": "No sensitization benefit; incomplete follow-up and selected maternal eligibility limit generalization.", "confounders_present": [ "No sensitization benefit; incomplete follow-up and selected maternal eligibility limit generalization." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 8, "pmid": "17349686", "title": "Probiotics in prevention of IgE-associated eczema: a double-blind, randomized, placebo-controlled trial.", "citation": "Abrahamsson TR, Jakobsson T, Böttcher MF et al. Probiotics in prevention of IgE-associated eczema: a double-blind, randomized, placebo-controlled trial. The Journal of allergy and clinical immunology. 2007.", "doi": "10.1016/j.jaci.2007.01.007", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/17349686/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17349686/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID17349686", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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": "mixed", "what_it_shows": "L. reuteri trial is null for cumulative eczema but reduces IgE-associated eczema in a subset/time window.", "what_it_does_not_show": "Primary and secondary findings differ; wheeze is not improved.", "confounders_present": [ "Primary and secondary findings differ; wheeze is not improved." ], "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": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 9, "pmid": "17208600", "title": "Probiotic supplementation for the first 6 months of life fails to reduce the risk of atopic dermatitis and increases the risk of allergen sensitization in high-risk children: a randomized controlled trial.", "citation": "Taylor AL, Dunstan JA, Prescott SL. Probiotic supplementation for the first 6 months of life fails to reduce the risk of atopic dermatitis and increases the risk of allergen sensitization in high-risk children: a randomized controlled trial. The Journal of allergy and clinical immunology. 2007.", "doi": "10.1016/j.jaci.2006.08.036", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/17208600/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17208600/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID17208600", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "Early L. acidophilus increases colonization without eczema prevention and with increased sensitization.", "what_it_does_not_show": "Specific regimen; does not prove all microbial exposure harmful, but contradicts blanket benefit.", "confounders_present": [ "Specific regimen; does not prove all microbial exposure harmful, but contradicts blanket benefit." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 10, "pmid": "21121927", "title": "Lactobacillus GG treatment during pregnancy for the prevention of eczema: a randomized controlled trial.", "citation": "Boyle RJ, Ismail IH, Kivivuori S et al. Lactobacillus GG treatment during pregnancy for the prevention of eczema: a randomized controlled trial. Allergy. 2011.", "doi": "10.1111/j.1398-9995.2010.02507.x", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/21121927/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21121927/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID21121927", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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": "null", "what_it_shows": "Prenatal-only LGG does not prevent eczema or change cord immune markers.", "what_it_does_not_show": "Timing/regimen boundary; postnatal benefit cannot be assumed from this null.", "confounders_present": [ "Timing/regimen boundary; postnatal benefit cannot be assumed from this 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": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 11, "pmid": "24947281", "title": "Probiotics in the prevention of eczema: a randomised controlled trial.", "citation": "Allen SJ, Jordan S, Storey M et al. Probiotics in the prevention of eczema: a randomised controlled trial. Archives of disease in childhood. 2014.", "doi": "10.1136/archdischild-2013-305799", "pmcid": "PMC4215350", "url": "https://pubmed.ncbi.nlm.nih.gov/24947281/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24947281/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "WALES_ISRCTN26287422", "access_depth": "full_text_partial", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Methods:paragraph2, 1:Methods:paragraph9. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "Registered multispecies trial is null for primary diagnosed eczema, with selected positive secondary sensitization/atopic-eczema findings.", "what_it_does_not_show": "Original Methods preserve broad recruited risk mix and endpoint hierarchy; secondary benefit is not primary success.", "confounders_present": [ "Original Methods preserve broad recruited risk mix and endpoint hierarchy; secondary benefit is not primary success." ], "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": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 12, "pmid": "29769554", "title": "Long term extension of a randomised controlled trial of probiotics using electronic health records.", "citation": "Davies G, Jordan S, Brooks CJ et al. Long term extension of a randomised controlled trial of probiotics using electronic health records. Scientific reports. 2018.", "doi": "10.1038/s41598-018-25954-z", "pmcid": "PMC5955897", "url": "https://pubmed.ncbi.nlm.nih.gov/29769554/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29769554/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "WALES_ISRCTN26287422", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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": "null", "what_it_shows": "Five-year electronic follow-up of the same trial finds no asthma/eczema protection.", "what_it_does_not_show": "Shared parent trial, retention and routine-record ascertainment; not independent randomization.", "confounders_present": [ "Shared parent trial, retention and routine-record ascertainment; not independent randomization." ], "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": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 13, "pmid": "28784701", "title": "Early Probiotic Supplementation for Eczema and Asthma Prevention: A Randomized Controlled Trial.", "citation": "Cabana MD, McKean M, Caughey AB et al. Early Probiotic Supplementation for Eczema and Asthma Prevention: A Randomized Controlled Trial. Pediatrics. 2017.", "doi": "10.1542/peds.2016-3000", "pmcid": "PMC5574725", "url": "https://pubmed.ncbi.nlm.nih.gov/28784701/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28784701/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID28784701", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "null", "what_it_shows": "Infant LGG/inulin trial shows no significant eczema or asthma prevention.", "what_it_does_not_show": "CI permits some effects; null cannot be discarded because another LGG regimen worked.", "confounders_present": [ "CI permits some effects; null cannot be discarded because another LGG regimen worked." ], "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": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 14, "pmid": "24247661", "title": "Supplementation with probiotics in the first 6 months of life did not protect against eczema and allergy in at-risk Asian infants: a 5-year follow-up.", "citation": "Loo EX, Llanora GV, Lu Q et al. Supplementation with probiotics in the first 6 months of life did not protect against eczema and allergy in at-risk Asian infants: a 5-year follow-up. International archives of allergy and immunology. 2014.", "doi": "10.1159/000356338", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/24247661/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24247661/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID24247661", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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": "null", "what_it_shows": "PROMPT follow-up finds no allergy/asthma/eczema benefit at five years.", "what_it_does_not_show": "Same parent intervention and selected at-risk Asian cohort, with follow-up attrition.", "confounders_present": [ "Same parent intervention and selected at-risk Asian cohort, with follow-up attrition." ], "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": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 15, "pmid": "38104554", "title": "OFFSPRING: A SPRING Follow-Up Study Assessing the Efficacy of Maternal Probiotics and Allergic Disease in the Child.", "citation": "Shipton EV, Foxcroft K, Dekker Nitert M et al. OFFSPRING: A SPRING Follow-Up Study Assessing the Efficacy of Maternal Probiotics and Allergic Disease in the Child. International archives of allergy and immunology. 2024.", "doi": "10.1159/000535179", "pmcid": "PMC10911140", "url": "https://pubmed.ncbi.nlm.nih.gov/38104554/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38104554/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID38104554", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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": "null", "what_it_shows": "SPRING respondent follow-up finds no allergic-disease advantage after maternal probiotics.", "what_it_does_not_show": "Small responding subset and questionnaire outcomes limit precision and independence.", "confounders_present": [ "Small responding subset and questionnaire outcomes limit precision and independence." ], "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": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 16, "pmid": "30472801", "title": "Perinatal probiotic intervention prevented allergic disease in a Caesarean-delivered subgroup at 13-year follow-up.", "citation": "Kallio S, Kukkonen AK, Savilahti E et al. Perinatal probiotic intervention prevented allergic disease in a Caesarean-delivered subgroup at 13-year follow-up. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 2019.", "doi": "10.1111/cea.13321", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/30472801/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30472801/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "FINN_MIX_NCT00298337", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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": "mixed", "what_it_shows": "Whole-cohort long-term allergy comparison is null with higher inhalant sensitization; favorable cesarean finding is post hoc.", "what_it_does_not_show": "Baseline delivery mode is measurable, but subgroup choice after results does not prospectively confirm it; substantial attrition.", "confounders_present": [ "Baseline delivery mode is measurable, but subgroup choice after results does not prospectively confirm it; substantial attrition." ], "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": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 17, "pmid": "39074448", "title": "The Role of Infant Gut Microbiota Modulation by Perinatal Maternal Probiotic Intervention in Atopic Eczema Risk Reduction.", "citation": "Puisto R, Gómez-Gallego C, Collado MC et al. The Role of Infant Gut Microbiota Modulation by Perinatal Maternal Probiotic Intervention in Atopic Eczema Risk Reduction. Neonatology. 2025.", "doi": "10.1159/000540075", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/39074448/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39074448/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "FINN_MATERNAL_MIX", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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": "mixed", "what_it_shows": "Subset analysis does not find diversity/composition mediation of a prior eczema-prevention benefit.", "what_it_does_not_show": "Same maternal-mixture trial and selected full-term vaginal/breastfed subset; microbiome modulation is not established as mediator.", "confounders_present": [ "Same maternal-mixture trial and selected full-term vaginal/breastfed subset; microbiome modulation is not established as 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": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 18, "pmid": "40005000", "title": "Effect of Supplementation with a Specific Probiotic (Bifidobacterium bifidum PRL2010) in Pregnancy for the Prevention of Atopic Dermatitis in Children: Preliminary Results of a Randomized Trial.", "citation": "Anania C, Matys V, Marra S et al. Effect of Supplementation with a Specific Probiotic (Bifidobacterium bifidum PRL2010) in Pregnancy for the Prevention of Atopic Dermatitis in Children: Preliminary Results of a Randomized Trial. Nutrients. 2025.", "doi": "10.3390/nu17040673", "pmcid": "PMC11858544", "url": "https://pubmed.ncbi.nlm.nih.gov/40005000/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40005000/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID40005000", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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": "mixed", "what_it_shows": "Small PRL2010 trial has no significant dermatitis-incidence difference, with favorable severity-course signals.", "what_it_does_not_show": "Preliminary and subgroup/secondary results; no established prevention benefit.", "confounders_present": [ "Preliminary and subgroup/secondary results; no established prevention benefit." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 19, "pmid": "42705251", "title": "Use of the bacterial lysate OM-85 for the primary prevention of wheezing lower respiratory illness in preschool children: a randomised, placebo-controlled trial.", "citation": "Morgan WJ, Mauger DT, Bacharier LB et al. Use of the bacterial lysate OM-85 for the primary prevention of wheezing lower respiratory illness in preschool children: a randomised, placebo-controlled trial. Lancet (London, England). 2026.", "doi": "10.1016/S0140-6736(26)01443-1", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/42705251/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42705251/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "ORBEX_NCT02148796", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "null", "what_it_shows": "ORBEX randomizes 822 children; OM-85 does not improve primary time to first wheezing lower-respiratory illness in the off-drug observation period.", "what_it_does_not_show": "Wheezing endpoint and age/lysate regimen are defined; clinical null does not rule out every exposure, and target engagement was not verified here.", "confounders_present": [ "Wheezing endpoint and age/lysate regimen are defined; clinical null does not rule out every exposure, and target engagement was not verified here." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": true, "provider": "Scite", "retrieved_on": "2026-10-11", "tally": { "total": 0, "supporting": 0, "contrasting": 0, "mentioning": 0, "citingPublications": 1 }, "notable_contrasting_statements": [], "note": "Provider tally only. Returned snippets are outgoing references from this anchor, not incoming contrasting evidence. No grade inferred from counts; editorial notices were not returned." }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 20, "pmid": "11799376", "title": "Probiotics during pregnancy and breast-feeding might confer immunomodulatory protection against atopic disease in the infant.", "citation": "Rautava S, Kalliomäki M, Isolauri E. Probiotics during pregnancy and breast-feeding might confer immunomodulatory protection against atopic disease in the infant. The Journal of allergy and clinical immunology. 2002.", "doi": "10.1067/mai.2002.120273", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/11799376/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/11799376/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "FINN_LGG", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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": "supports", "what_it_shows": "Maternal LGG study relates changed milk TGF-beta2 to lower infant eczema.", "what_it_does_not_show": "Related Finnish LGG program/subset; immune-marker association is not proved mediation.", "confounders_present": [ "Related Finnish LGG program/subset; immune-marker association is not proved mediation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 21, "pmid": "18266878", "title": "Probiotics in infancy induce protective immune profiles that are characteristic for chronic low-grade inflammation.", "citation": "Marschan E, Kuitunen M, Kukkonen K et al. Probiotics in infancy induce protective immune profiles that are characteristic for chronic low-grade inflammation. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 2008.", "doi": "10.1111/j.1365-2222.2008.02942.x", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/18266878/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/18266878/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "FINN_MIX_NCT00298337", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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": "mixed", "what_it_shows": "Probiotic exposure alters infant immune markers, with higher CRP associated with lower later eczema risk.", "what_it_does_not_show": "Secondary immune analyses in a parent trial; biomarkers and association do not prove the clinical mediator.", "confounders_present": [ "Secondary immune analyses in a parent trial; biomarkers and association do not prove the clinical 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": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 22, "pmid": "24439655", "title": "Interaction of NPSR1 genotypes and probiotics in the manifestation of atopic eczema in early childhood.", "citation": "P K, M K, K K et al. Interaction of NPSR1 genotypes and probiotics in the manifestation of atopic eczema in early childhood. Allergologia et immunopathologia. 2014.", "doi": "10.1016/j.aller.2013.10.001", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/24439655/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24439655/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "FINN_MIX_NCT00298337", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Weak", "system": "human genetic association", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "NPSR1 analysis in a probiotic trial finds suggestive eczema associations but no general asthma/sensitization association.", "what_it_does_not_show": "Exploratory genotype analyses and shared trial recruitment do not validate prospective protective subtypes.", "confounders_present": [ "Exploratory genotype analyses and shared trial recruitment do not validate prospective protective subtypes." ], "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": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 23, "pmid": "25779902", "title": "Differential effects of two probiotics on the risks of eczema and atopy associated with single nucleotide polymorphisms to Toll-like receptors.", "citation": "Marlow G, Han DY, Wickens K et al. Differential effects of two probiotics on the risks of eczema and atopy associated with single nucleotide polymorphisms to Toll-like receptors. Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. 2015.", "doi": "10.1111/pai.12371", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/25779902/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25779902/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "NZ_HN001_HN019", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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Effect of probiotic mix (Bifidobacterium bifidum, Bifidobacterium lactis, Lactobacillus acidophilus) in the primary prevention of eczema: a double-blind, randomized, placebo-controlled trial. Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. 2010.", "doi": "10.1111/j.1399-3038.2009.00958.x", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/19840300/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/19840300/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID19840300", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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Probiotics in late infancy reduce the incidence of eczema: A randomized controlled trial. Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. 2019.", "doi": "10.1111/pai.13018", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/30790361/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30790361/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID30790361", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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Early infancy microbial and metabolic alterations affect risk of childhood asthma. Science translational medicine. 2015.", "doi": "10.1126/scitranslmed.aab2271", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/26424567/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26424567/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID26424567", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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Maturation of the gut microbiome during the first year of life contributes to the protective farm effect on childhood asthma. Nature medicine. 2020.", "doi": "10.1038/s41591-020-1095-x", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/33139948/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33139948/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID33139948", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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Gram-Positive Bacteria and the Inverse Association between Farm Exposure and Childhood Asthma. NEJM evidence. 2026.", "doi": "10.1056/EVIDoa2500271", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/42517701/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42517701/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID42517701", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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Higher B-cell activating factor levels at birth are positively associated with maternal dairy farm exposure and negatively related to allergy development. The Journal of allergy and clinical immunology. 2015.", "doi": "10.1016/j.jaci.2015.03.022", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/25936566/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25936566/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID25936566", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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Circulating Dendritic Cells, Farm Exposure and Asthma at Early Age. Scandinavian journal of immunology. 2016.", "doi": "10.1111/sji.12389", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/26368653/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26368653/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID26368653", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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Regulation of TH17 markers early in life through maternal farm exposure. The Journal of allergy and clinical immunology. 2014.", "doi": "10.1016/j.jaci.2013.09.030", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/24275363/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24275363/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID24275363", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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Household siblings and nasal and fecal microbiota in infants. Pediatrics international : official journal of the Japan Pediatric Society. 2017.", "doi": "10.1111/ped.13168", "pmcid": "PMC5354996", "url": "https://pubmed.ncbi.nlm.nih.gov/27638139/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27638139/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID27638139", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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Farm exposure is associated with human breast milk immune profile and microbiome. bioRxiv : the preprint server for biology. 2024.", "doi": "10.1101/2024.10.14.618271", "pmcid": "PMC11507701", "url": "https://pubmed.ncbi.nlm.nih.gov/39464075/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39464075/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID39464075", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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Hay fever, asthma and number of older siblings--a twin study. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 1997.", "doi": "", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/9179425/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/9179425/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID9179425", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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Siblings, day-care attendance, and the risk of asthma and wheezing during childhood. The New England journal of medicine. 2000.", "doi": "10.1056/NEJM200008243430803", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/10954761/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/10954761/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID10954761", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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Early Childhood Antibiotic Treatment for Otitis Media and Other Respiratory Tract Infections Is Associated With Risk of Type 1 Diabetes: A Nationwide Register-Based Study With Sibling Analysis. Diabetes care. 2020.", "doi": "10.2337/dc19-1162", "pmcid": "PMC7171951", "url": "https://pubmed.ncbi.nlm.nih.gov/32132008/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32132008/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID32132008", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Infant antibiotic prescription associates with later T1D, with generally compatible but often nonsignificant sibling results.", "what_it_does_not_show": "Indication, infection and direct drug effects remain; no selective commensal-deprivation causal test.", "confounders_present": [ "Indication, infection and direct drug effects remain; no selective commensal-deprivation causal test." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 51, "pmid": "37607456", "title": "Gastrointestinal Infections Modulate the Risk for Insulin Autoantibodies as the First-Appearing Autoantibody in the TEDDY Study.", "citation": "Lönnrot M, Lynch KF, Rewers M et al. Gastrointestinal Infections Modulate the Risk for Insulin Autoantibodies as the First-Appearing Autoantibody in the TEDDY Study. Diabetes care. 2023.", "doi": "10.2337/dc23-0518", "pmcid": "PMC10620548", "url": "https://pubmed.ncbi.nlm.nih.gov/37607456/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37607456/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "TEDDY", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "TEDDY gastrointestinal infection associations with autoantibodies change direction by age and timing.", "what_it_does_not_show": "Autoantibody endpoints and exposure-specific effects do not show universal clinical autoimmune protection.", "confounders_present": [ "Autoantibody endpoints and exposure-specific effects do not show universal clinical autoimmune protection." ], "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": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 52, "pmid": "31744911", "title": "Metagenomics of the faecal virome indicate a cumulative effect of enterovirus and gluten amount on the risk of coeliac disease autoimmunity in genetically at risk children: the TEDDY study.", "citation": "Lindfors K, Lin J, Lee HS et al. Metagenomics of the faecal virome indicate a cumulative effect of enterovirus and gluten amount on the risk of coeliac disease autoimmunity in genetically at risk children: the TEDDY study. Gut. 2020.", "doi": "10.1136/gutjnl-2019-319809", "pmcid": "PMC7234892", "url": "https://pubmed.ncbi.nlm.nih.gov/31744911/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31744911/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "TEDDY", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Enterovirus exposure and gluten interaction associate with increased celiac autoimmunity.", "what_it_does_not_show": "Genetic-risk nested cohort; combines viral and dietary factors rather than a generalized microbial-deficit mechanism.", "confounders_present": [ "Genetic-risk nested cohort; combines viral and dietary factors rather than a generalized microbial-deficit 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": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 53, "pmid": "22422004", "title": "Early life antibiotic-driven changes in microbiota enhance susceptibility to allergic asthma.", "citation": "Russell SL, Gold MJ, Hartmann M et al. Early life antibiotic-driven changes in microbiota enhance susceptibility to allergic asthma. EMBO reports. 2012.", "doi": "10.1038/embor.2012.32", "pmcid": "PMC3343350", "url": "https://pubmed.ncbi.nlm.nih.gov/22422004/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22422004/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID22422004", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal in vivo", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Neonatal vancomycin but not streptomycin increases experimental asthma; adult treatment is null.", "what_it_does_not_show": "Antibiotic and developmental pleiotropy remain, with explicit drug and age boundaries.", "confounders_present": [ "Antibiotic and developmental pleiotropy remain, with explicit drug and age boundaries." ], "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": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 54, "pmid": "26261989", "title": "Microbial Ligand Costimulation Drives Neutrophilic Steroid-Refractory Asthma.", "citation": "Hadebe S, Kirstein F, Fierens K et al. Microbial Ligand Costimulation Drives Neutrophilic Steroid-Refractory Asthma. PloS one. 2015.", "doi": "10.1371/journal.pone.0134219", "pmcid": "PMC4532492", "url": "https://pubmed.ncbi.nlm.nih.gov/26261989/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26261989/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID26348039" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID26261989", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal in vivo", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Combined LPS/beta-glucan promotes steroid-refractory inflammatory asthma through Dectin-1/TLR4.", "what_it_does_not_show": "Different dose/route/context; genuine contrary direction to blanket microbial protection, with linked correction retained.", "confounders_present": [ "Different dose/route/context; genuine contrary direction to blanket microbial protection, with linked correction retained." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 55, "pmid": "30833732", "title": "Antibody neutralization of microbiota-derived circulating peptidoglycan dampens inflammation and ameliorates autoimmunity.", "citation": "Huang Z, Wang J, Xu X et al. Antibody neutralization of microbiota-derived circulating peptidoglycan dampens inflammation and ameliorates autoimmunity. Nature microbiology. 2019.", "doi": "10.1038/s41564-019-0381-1", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/30833732/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30833732/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID30833732", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "animal in vivo", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "Neutralizing circulating microbial peptidoglycan reduces autoimmune arthritis/EAE with NOD2 dependence.", "what_it_does_not_show": "Adult systemic microbial-factor effects are not early-life deprivation, but show harmful commensal signaling can be causal.", "confounders_present": [ "Adult systemic microbial-factor effects are not early-life deprivation, but show harmful commensal signaling can be causal." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 56, "pmid": "26287682", "title": "Microbiota-Dependent Activation of an Autoreactive T Cell Receptor Provokes Autoimmunity in an Immunologically Privileged Site.", "citation": "Horai R, Zárate-Bladés CR, Dillenburg-Pilla P et al. Microbiota-Dependent Activation of an Autoreactive T Cell Receptor Provokes Autoimmunity in an Immunologically Privileged Site. Immunity. 2015.", "doi": "10.1016/j.immuni.2015.07.014", "pmcid": "PMC4544742", "url": "https://pubmed.ncbi.nlm.nih.gov/26287682/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26287682/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID26287682", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal in vivo", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Commensal-dependent autoreactive TCR activation triggers spontaneous uveitis in a model.", "what_it_does_not_show": "Genetically restricted model; does not establish the human attributable fraction.", "confounders_present": [ "Genetically restricted model; does not establish the human attributable fraction." ], "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": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 57, "pmid": "33077601", "title": "Interactions between host genetics and gut microbiota determine susceptibility to CNS autoimmunity.", "citation": "Montgomery TL, Künstner A, Kennedy JJ et al. Interactions between host genetics and gut microbiota determine susceptibility to CNS autoimmunity. Proceedings of the National Academy of Sciences of the United States of America. 2020.", "doi": "10.1073/pnas.2002817117", "pmcid": "PMC7959502", "url": "https://pubmed.ncbi.nlm.nih.gov/33077601/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33077601/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID33077601", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal in vivo", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "Microbiome transfer and defined L. reuteri can worsen EAE in selected genotypes.", "what_it_does_not_show": "Host genetics reverses the effect of a nominal probiotic; not a universal species label or human intervention result.", "confounders_present": [ "Host genetics reverses the effect of a nominal probiotic; not a universal species label or human intervention result." ], "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": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 58, "pmid": "25705822", "title": "Randomized trial of peanut consumption in infants at risk for peanut allergy.", "citation": "Du Toit G, Roberts G, Sayre PH et al. Randomized trial of peanut consumption in infants at risk for peanut allergy. The New England journal of medicine. 2015.", "doi": "10.1056/NEJMoa1414850", "pmcid": "PMC4416404", "url": "https://pubmed.ncbi.nlm.nih.gov/25705822/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25705822/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "ErratumIn: PMID27464222" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "LEAP_PARENT", "access_depth": "full_text_partial", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 0:Methods:paragraph1, 0:Methods:paragraph4, 1:Results:paragraph1, 1:Results:paragraph2. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "Early peanut feeding prevents oral-challenge-confirmed peanut allergy in predefined at-risk cohorts.", "what_it_does_not_show": "Dietary antigen exposure, not microbial restoration; linked correction details unexamined; cannot be credited as hygiene-mechanism proof.", "confounders_present": [ "Dietary antigen exposure, not microbial restoration; linked correction details unexamined; cannot be credited as hygiene-mechanism proof." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 59, "pmid": "26943128", "title": "Randomized Trial of Introduction of Allergenic Foods in Breast-Fed Infants.", "citation": "Perkin MR, Logan K, Tseng A et al. Randomized Trial of Introduction of Allergenic Foods in Breast-Fed Infants. The New England journal of medicine. 2016.", "doi": "10.1056/NEJMoa1514210", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/26943128/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26943128/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID26943128", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "EAT has a null intention-to-treat food-allergy primary outcome and favorable adherent/subtype analyses.", "what_it_does_not_show": "Dietary antigen intervention and per-protocol selection do not prove microbial-deprivation causality.", "confounders_present": [ "Dietary antigen intervention and per-protocol selection do not prove microbial-deprivation 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": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 60, "pmid": "26942922", "title": "Effect of Avoidance on Peanut Allergy after Early Peanut Consumption.", "citation": "Du Toit G, Sayre PH, Roberts G et al. Effect of Avoidance on Peanut Allergy after Early Peanut Consumption. The New England journal of medicine. 2016.", "doi": "10.1056/NEJMoa1514209", "pmcid": "PMC12333932", "url": "https://pubmed.ncbi.nlm.nih.gov/26942922/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26942922/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "LEAP_PARENT", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "LEAP-On retains food-allergen tolerance after avoidance in the earlier consumption group.", "what_it_does_not_show": "Same parent cohort; not independent microbial prevention evidence.", "confounders_present": [ "Same parent cohort; not independent microbial prevention evidence." ], "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": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 61, "pmid": "33055153", "title": "Biodiversity intervention enhances immune regulation and health-associated commensal microbiota among daycare children.", "citation": "Roslund MI, Puhakka R, Grönroos M et al. Biodiversity intervention enhances immune regulation and health-associated commensal microbiota among daycare children. Science advances. 2020.", "doi": "10.1126/sciadv.aba2578", "pmcid": "PMC7556828", "url": "https://pubmed.ncbi.nlm.nih.gov/33055153/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33055153/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID33055153", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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": "supports", "what_it_shows": "Short daycare biodiversity intervention changes skin/gut communities and immune markers.", "what_it_does_not_show": "Short-term marker endpoints do not demonstrate reduced allergic or autoimmune disease incidence.", "confounders_present": [ "Short-term marker endpoints do not demonstrate reduced allergic or autoimmune disease incidence." ], "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": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 62, "pmid": "35930838", "title": "A Placebo-controlled double-blinded test of the biodiversity hypothesis of immune-mediated diseases: Environmental microbial diversity elicits changes in cytokines and increase in T regulatory cells in young children.", "citation": "Roslund MI, Parajuli A, Hui N et al. A Placebo-controlled double-blinded test of the biodiversity hypothesis of immune-mediated diseases: Environmental microbial diversity elicits changes in cytokines and increase in T regulatory cells in young children. Ecotoxicology and environmental safety. 2022.", "doi": "10.1016/j.ecoenv.2022.113900", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/35930838/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35930838/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID35930838", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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": "supports", "what_it_shows": "Blinded sandbox comparison with 13 children per group changes cytokine/community measures.", "what_it_does_not_show": "Age 3-5, very small groups and biomarker outcomes; no verified clinical prevention endpoint.", "confounders_present": [ "Age 3-5, very small groups and biomarker outcomes; no verified clinical prevention endpoint." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 63, "pmid": "38688234", "title": "Urban indoor gardening enhances immune regulation and diversifies skin microbiota - A placebo-controlled double-blinded intervention study.", "citation": "Saarenpää M, Roslund MI, Nurminen N et al. Urban indoor gardening enhances immune regulation and diversifies skin microbiota - A placebo-controlled double-blinded intervention study. Environment international. 2024.", "doi": "10.1016/j.envint.2024.108705", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/38688234/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38688234/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID38688234", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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": "supports", "what_it_shows": "Blinded indoor gardening changes skin microbial diversity and IL-10.", "what_it_does_not_show": "Adult volunteer intervention and short immune-marker outcomes are not early-life disease-incidence evidence.", "confounders_present": [ "Adult volunteer intervention and short immune-marker outcomes are not early-life disease-incidence evidence." ], "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": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] } ], "verification_summary": { "load_bearing_claims_checked": 67, "verified": 67, "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": "Farm, sibling, infant microbiome and antibiotic data repeatedly predict selected immune outcomes, but signs vary by disease, age and exposure. Familial, dietary, infection and indication effects are not uniformly eliminated. The registered predictive association component is Β, not a negation of specific causal interventions reported separately.", "resulting_ceiling": "Β" } ], "cap_precedence_resolutions": [ { "collision": "Perturbation in a defined setting versus broader inference", "subclaim_scope_cap_binds_on": "Reduced early-life microbial exposure causally increases the incidence of allergic and autoimmune disease.", "subclaim_scope_threshold_binds_on": "The precise experimentally tested subclaim scope", "resolution": "Recipient colonization and immune-pathway perturbations cross within SC2's specified model context. The 04 transfer threshold and universal cap 5 bind different inferences: recipient causality is not endogenous human population causality. Clinical eczema trials are phenotypic interventions, so their restricted effect is not re-capped as a biomarker. Soil and immune-profile studies remain cap-4 limited for disease prevention. Clinical and model directions vary without deleting unsuccessful subjects or strains from scope.", "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- Cell-type-specific conditional knockout or depletion\n- Pathway-specific blockade (not broad immunosuppression) changing disease course\n- Human targeted therapy with mechanistic alignment showing disease-modifying effect", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "", "gamma_hard_rules_triggered": [ "Positive restricted experiments retain their experimental scope; associations and proxy movement do not establish the complete clinical claim." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "Farm, sibling, infant microbiome and antibiotic data repeatedly predict selected immune outcomes, but signs vary by disease, age and exposure. Familial, dietary, infection and indication effects are not uniformly eliminated. The registered predictive association component is Β, not a negation of specific causal interventions reported separately.", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC2", "field_valid_perturbation_quote": "\n- Cell-type-specific conditional knockout or depletion\n- Pathway-specific blockade (not broad immunosuppression) changing disease course\n- Human targeted therapy with mechanistic alignment showing disease-modifying effect", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "PMID11297958, PMID18762327, PMID23083673, PMID22442383, PMID25157157, PMID26339029, PMID31235962", "gamma_hard_rules_triggered": [ "Positive restricted experiments retain their experimental scope; associations and proxy movement do not establish the complete clinical claim." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "Defined colonization, epithelial A20 and Treg MyD88/RORgamma-t controls establish context-specific immune/disease effects in recipient models. Selected randomized human microbial regimens also modify eczema risk, while others are null or adverse. This supports Ε for specified exposure/host/phenotype contexts, not an interchangeable class of protective microbes.", "ceiling_from_boundary_check": "Δ or higher" }, { "subclaim_id": "SC3", "field_valid_perturbation_quote": "\n- Cell-type-specific conditional knockout or depletion\n- Pathway-specific blockade (not broad immunosuppression) changing disease course\n- Human targeted therapy with mechanistic alignment showing disease-modifying effect", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "", "gamma_hard_rules_triggered": [ "Positive restricted experiments retain their experimental scope; associations and proxy movement do not establish the complete clinical claim." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "The complete human allergic-and-autoimmune incidence claim has partial mechanistic support, but no source set isolates a generalized early microbial deficit as the cause across the registered disease classes. Specific eczema prevention is real and retained; overall-null respiratory trials, bidirectional infection associations and harmful commensal mechanisms constrain transfer. Food-antigen tolerance and short-term soil immune markers cannot fill the missing autoimmune clinical branch.", "ceiling_from_boundary_check": "Γ" } ], "thresholds_tested": [ { "subclaim_id": "SC1", "threshold": "Δ", "requirement_quoted": "Requires pathway- or cell-type-resolved causal perturbation affecting disease or phenotype.", "satisfied": "no", "supporting_evidence": [], "what_would_cross_it": "A causal claim above association needs prospective microbial identity/quantity measurement with stronger genetic/familial and indication controls or a selective exposure instrument against the prespecified disease endpoint." }, { "subclaim_id": "SC2", "threshold": "Δ", "requirement_quoted": "Requires pathway- or cell-type-resolved causal perturbation affecting disease or phenotype.", "satisfied": "yes", "supporting_evidence": [ "[3] Perinatal LGG reduces primary eczema incidence in a high-risk randomized trial.", "[5] HN001 reduces eczema, while HN019 and sensitization comparisons are null.", "[7] Maternal probiotic mixtures reduce eczema in infants of allergic mothers.", "[43] Neonatal but not adult colonization prevents excess iNKT and induced lung/colitis pathology.", "[46] Defined Clostridia colonization protects allergen sensitization through barrier/innate-cell effects.", "[47] Low-dose dust/endotoxin protects experimental asthma, requiring epithelial A20.", "[48] Defined live consortia suppress model food allergy through Treg MyD88/RORgamma-t necessity." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Ε", "requirement_quoted": "Requires context-specific causality with explicit scope restriction.", "satisfied": "yes", "supporting_evidence": [ "[3] Perinatal LGG reduces primary eczema incidence in a high-risk randomized trial.", "[5] HN001 reduces eczema, while HN019 and sensitization comparisons are null.", "[7] Maternal probiotic mixtures reduce eczema in infants of allergic mothers.", "[43] Neonatal but not adult colonization prevents excess iNKT and induced lung/colitis pathology.", "[46] Defined Clostridia colonization protects allergen sensitization through barrier/innate-cell effects.", "[47] Low-dose dust/endotoxin protects experimental asthma, requiring epithelial A20.", "[48] Defined live consortia suppress model food allergy through Treg MyD88/RORgamma-t necessity." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Ζ", "requirement_quoted": "Requires multiple convergent causal manipulations and reduced plausibility of downstream-only interpretations.", "satisfied": "no", "supporting_evidence": [ "[3] Perinatal LGG reduces primary eczema incidence in a high-risk randomized trial.", "[5] HN001 reduces eczema, while HN019 and sensitization comparisons are null.", "[7] Maternal probiotic mixtures reduce eczema in infants of allergic mothers.", "[43] Neonatal but not adult colonization prevents excess iNKT and induced lung/colitis pathology.", "[46] Defined Clostridia colonization protects allergen sensitization through barrier/innate-cell effects.", "[47] Low-dose dust/endotoxin protects experimental asthma, requiring epithelial A20.", "[48] Defined live consortia suppress model food allergy through Treg MyD88/RORgamma-t necessity." ], "what_would_cross_it": "Independent exposure/strain and host-pathway manipulations with rescue must replicate clinical or functional effects across relevant contexts and constrain developmental, cage, diet and delivery confounds." }, { "subclaim_id": "SC3", "threshold": "Δ", "requirement_quoted": "Requires pathway- or cell-type-resolved causal perturbation affecting disease or phenotype.", "satisfied": "no", "supporting_evidence": [], "what_would_cross_it": "Prospectively register defined microbial restoration versus credible control in baseline-defined human settings, verify engagement, and measure clinical allergic and autoimmune incidence over sufficient follow-up. Replicate beyond one strain/regimen and do not select protected subgroups after results." } ], "generalization_check": { "generalization_tested": "yes", "context_boundary_mapped": "yes", "internal_negative_controls": [ "HN019 does not reproduce HN001 eczema benefit (PMID18762327).", "Several LGG/mixture prevention trials are overall null; L. acidophilus increases sensitization (PMID17208600, PMID28784701).", "ORBEX primary off-drug wheezing endpoint is null (PMID42705251).", "SCFA mixture and heat-inactivated consortia do not reproduce live consortium protection (PMID31235962).", "Adult colonization does not reproduce neonatal iNKT protection (PMID22442383).", "Microbial ligand signaling can worsen autoimmunity or airway inflammation (PMID30833732, PMID26261989)." ], "note": "Strain, dose, early versus later timing, maternal versus infant administration, delivery mode, genotype and disease endpoint map genuine boundaries. Post-hoc cesarean findings and genotype interactions are not prospectively validated rescue scopes. A human atopy/eczema outcome is not a clinical autoimmune incidence endpoint." }, "falsification_patterns_met": [ { "pattern": "Generalization fails across interventions, endpoints and host contexts", "evidence": "Clinical nulls, increased sensitization and harmful microbial signaling oppose blanket protection; narrow causal effects remain.", "downgrade_applied": false } ], "pitfalls_flagged": [ { "pitfall": "Quantity replaces exposure identity", "where": "Commensals, pathogens, microbial metabolites, diversity and dose can produce different directions." }, { "pitfall": "Secondary/subgroup outcomes promoted", "where": "Overall trial nulls and post-hoc cesarean benefit remain distinct." }, { "pitfall": "Antigen tolerance credited to microbes", "where": "LEAP/EAT manipulate food introduction, not microbial exposure." }, { "pitfall": "Recipient-to-human transfer", "where": "Germ-free and induced-allergy models retain their own causal scope." } ], "causal_tally_audit": { "tally_claimed_by_document": 6, "tally_after_audit": 6, "tally_unit": "Positive qualifying study units across scoped subclaims, not independent causal lines or full-claim necessity/sufficiency.", "screened_discriminating_contrasts": 36, "items_rejected": [ "Null and negative contrasts are discriminators, not positive threshold crossings. Reports and replications are not independent causal lines.", "Reports sharing participants, models or instruments are not independent causal lines.", "Pivotal nulls do not earn positive threshold crossings." ] }, "steelman": { "case_one_rung_higher": "One rung above, Δ: randomized microbial regimens prevent some clinical eczema and model rescues identify immune mechanisms. Yet the registered SC3 includes generalized human allergic and autoimmune incidence from reduced exposure, not only a supplied product's eczema effect. Human autoimmune clinical mediation and transferable prospective context prediction remain unverified.", "case_one_rung_lower": "One rung below, Β: population farm/diversity data are associational and recent clinical respiratory-prevention data are null. However, selective consortia/pathway experiments and genuine clinical eczema randomizations supply mechanistic and restricted causal content beyond association.", "which_rejected": "Retain Γ for the broad SC3 with narrow SC2 Ε. Reject both generalized clinical protection and a claim that microbes have no causal immune effects.", "blocking_cap_threshold_or_missing_experiment": "Missing experiment: Register microbial-factor/consortium restoration in an objectively baseline-defined infant population, with credible placebo, measured exposure/engagement and immune mediation. Prespecify clinical eczema, asthma and separately powered autoimmune endpoints, retain all randomized participants, and independently replicate dose/window and host-genotype predictions. Include antigen/diet/barrier and infection-indication controls." }, "final_score": { "hsef_level": "Γ", "hsef_descriptor": "Mechanistically plausible, partial system support", "confidence": "Moderate", "confidence_rationale": "63 primary reports with 6 selected partial-body examinations; density, heterogeneous controls and methodological heterogeneity set the confidence, not correctness and not the reviewer's access depth. Re-tested against the High band text, which requires extensive independent replication across labs, models and assay modalities: the band holds at Moderate.", "rests_on_non_peer_reviewed_work": false, "rationale": "Overall Γ follows the registered complete human incidence SC3, with SC1 at Β and exposure-specific immune/clinical SC2 at Ε. Positive eczema trials and mechanistic recipient experiments are retained without claiming generalized protection from asthma or autoimmunity. Neither a universal biomarker cap nor a negative-trial veto is imposed on the narrow clinical successes; the broad conjunction has not crossed its own causal boundary." }, "role_of_mechanism": { "classification": "reinforcing / stabilizing factor", "derivation_step_matched": 5, "derivation": "Selective model perturbations and clinical eczema effects show that microbial exposure is not merely an outcome marker in all settings. Both harmful and protective immune effects occur. Universal prevention, initiation and rate limitation for the registered disease classes are not demonstrated, nor universal requirement. Step 5 supports a context-dependent immune susceptibility modifier; its direction must be specified by factor and host.", "tournament_used_as_tiebreaker": false, "note": "Derived from causal direction, not tournament rank." }, "extended_scoring_MSD": { "momentum": { "value": "Mechanistic only", "artifact": "Defined Treg MyD88/RORgamma-t manipulations (PMID31235962), recent farm-factor mapping (PMID42517701) and blinded environmental biodiversity interventions (PMID35930838, PMID38688234) test immune mechanisms. ORBEX supplies completed clinical boundary evidence; no new outcome is assumed for protocol-only programs.", "justification": "Defined Treg MyD88/RORgamma-t manipulations (PMID31235962), recent farm-factor mapping (PMID42517701) and blinded environmental biodiversity interventions (PMID35930838, PMID38688234) test immune mechanisms. ORBEX supplies completed clinical boundary evidence; no new outcome is assumed for protocol-only programs." }, "stability": { "value": "Stable", "trigger": "No verified named pending result was identified that demonstrably determines the full-scope letter; this is a bounded search finding, not proof that none exists.", "justification": "No verified named pending result was identified that demonstrably determines the full-scope letter; this is a bounded search finding, not proof that none exists." }, "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": "The two framings carry different implied levels, so no single implied level and no arithmetic gap can be stated. Popular and much review-level framing treats loss of early microbial exposure as an established cause of the rise in allergy and autoimmunity, which would imply a level well above the assessed \u0393 for the registered conjunction, while the trial literature cited here is a mixture of a few positive eczema results and overall-null respiratory and autoimmune branches. No manufactured field consensus is asserted." }, "calibration_note": "M/S/D never modify HSEF level or confidence." }, "change_record": { "applies": false, "prior_level": "none assigned", "prior_confidence": null, "prior_source": null, "derived_before_consulting_prior": true, "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": "Register microbial-factor/consortium restoration in an objectively baseline-defined infant population, with credible placebo, measured exposure/engagement and immune mediation. Prespecify clinical eczema, asthma and separately powered autoimmune endpoints, retain all randomized participants, and independently replicate dose/window and host-genotype predictions. Include antigen/diet/barrier and infection-indication controls.", "readout": "Prespecified clinical disease incidence and mediator engagement over sufficient pediatric follow-up", "critical_control": "Product identity/viability, dose, colonization versus transient exposure, maternal/infant timing, diet and allergens, barrier status, antibiotic indication, pathogen infection and familial risk", "supporting_result": "Defined restoration changes clinical incidence with the predicted immune mediator and independently replicated baseline context", "falsifying_result": "Adequate engagement changes only immune markers, fails clinical endpoints, or harms predefined groups; apparent benefit is confined to unregistered subgroup analyses" } ], "knowledge_gaps": [ { "name": "Gap 1", "statement": "Microbial quality, amount, route and timing are distinct exposures, not one hygiene variable.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 2", "statement": "Human autoimmune clinical prevention remains a separate missing causal branch.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 3", "statement": "Positive eczema effects do not consistently extend to sensitization, food allergy or asthma.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 4", "statement": "Clinical effects may occur without durable microbial engraftment or diversity change; the mediator needs identification.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 5", "statement": "Environmental soil interventions need disease-incidence follow-up beyond immune biomarkers.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 6", "statement": "Shared cohort/trial reports and post-hoc genotype/delivery subgroups require prospective independent validation.", "relevance": "Limits mechanism identification or scope." } ], "review_metadata": { "review_date": "2026-10-11", "reviewer": "Codex", "evidence_base_note": "63 primary reports; literature cutoff 2026-10-09; source examination UTC date 2026-10-12; bounded critical review, not exhaustive systematic review.", "literature_tools_available": true, "literature_tools_note": "Life Sciences Literature PubMed/Entrez, separately logged public original-body retrieval, and Consensus Pro browser searches. Provider output retained as observed browser text with citation-link mappings, or as previously exported connector documents where present. AI synthesis is not primary full-text verification. Consensus retrieved/included counts are not examined-primary counts. Scite is queried per case where connected; received tallies/outgoing reference contexts are not audited incoming contrasting statements. Tool receipts record actual use. Supplementary discovery outputs do not earn primary-count credit. No independent blinded review.", "skill_version": "5.3", "validator_run": "PASS: exact archived HSEF v5.3 validator rerun after final sealing.", "validator_warnings_addressed": "No warnings.", "limits": "Bounded source-based critical review; no complete-paper/supplement audit, independent scientific peer review or blinded calibration. Revision cases retain original prose outside the three framework output blocks and have explicit correction logs." }, "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": "Defined consortium rescue, selective host-cell mediator loss, human prevention randomization and farm/genetic/sibling comparisons were considered. They constrain distinct errors in narrow contexts. No broad same-scope causal set is re-capped from one weak observational leg, but the examined human autoimmune and generalized deprivation branches remain incomplete. The upper ladder remains reachable with an appropriate clinical intervention or natural experiment." }, { "kind": "natural_experiment", "available": true, "why_not_sufficient": "Defined consortium rescue, selective host-cell mediator loss, human prevention randomization and farm/genetic/sibling comparisons were considered. They constrain distinct errors in narrow contexts. No broad same-scope causal set is re-capped from one weak observational leg, but the examined human autoimmune and generalized deprivation branches remain incomplete. The upper ladder remains reachable with an appropriate clinical intervention or natural experiment." }, { "kind": "dose_response_across_populations", "available": true, "why_not_sufficient": "Defined consortium rescue, selective host-cell mediator loss, human prevention randomization and farm/genetic/sibling comparisons were considered. They constrain distinct errors in narrow contexts. No broad same-scope causal set is re-capped from one weak observational leg, but the examined human autoimmune and generalized deprivation branches remain incomplete. The upper ladder remains reachable with an appropriate clinical intervention or natural experiment." }, { "kind": "withdrawal_rechallenge", "available": false, "why_not_sufficient": "Defined consortium rescue, selective host-cell mediator loss, human prevention randomization and farm/genetic/sibling comparisons were considered. They constrain distinct errors in narrow contexts. No broad same-scope causal set is re-capped from one weak observational leg, but the examined human autoimmune and generalized deprivation branches remain incomplete. The upper ladder remains reachable with an appropriate clinical intervention or natural experiment." }, { "kind": "therapeutic_perturbation_hard_endpoint", "available": true, "why_not_sufficient": "Defined consortium rescue, selective host-cell mediator loss, human prevention randomization and farm/genetic/sibling comparisons were considered. They constrain distinct errors in narrow contexts. No broad same-scope causal set is re-capped from one weak observational leg, but the examined human autoimmune and generalized deprivation branches remain incomplete. The upper ladder remains reachable with an appropriate clinical intervention or natural experiment." } ], "convergence_present": false, "cap_reapplied_to_convergent_set": false }, "provenance_header": { "sources_total": 63, "claims_total": 67, "claims_verified": 67, "claims_unverified": 0, "claims_contradicted": 0, "tier_a_sources": 63, "generated_by": "Codex; HSEF v5.3", "gate_passed": true }, "claims": [ { "id": "C1", "text": "Amish/Hutterite asthma and innate-immune differences accompany different dust exposure; Amish dust protects adult mice via MyD88/TRIF. Human comparison is nonrandomized; adult dust instillation is not a neonatal deprivation experiment.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 1 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 0:METHODS:paragraph1, 0:METHODS:paragraph6, 1:RESULTS:paragraph6. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C2", "text": "Farm microbial diversity associates inversely with asthma in two population studies. Farm setting has multiple correlated exposures; measured diversity mediation is not selective causal manipulation.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 2 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C3", "text": "Perinatal LGG reduces primary eczema incidence in a high-risk randomized trial. Specific strain/regimen/phenotype; no proof of general asthma or autoimmune prevention.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 3 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C4", "text": "Finnish LGG follow-up retains eczema benefit but not skin-test reactivity difference. Same parent trial with attrition; not independent replication or broad atopy prevention.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 4 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C5", "text": "HN001 reduces eczema, while HN019 and sensitization comparisons are null. Strain and endpoint boundaries; probiotic exposure is not interchangeable with environmental diversity.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 5 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C6", "text": "HN001 follow-up retains eczema/rhinoconjunctivitis benefit; HN019 and other endpoints remain null or nonsignificant. Same randomization as the two-strain study; selected secondary outcomes do not show uniform protection.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 6 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C7", "text": "Maternal probiotic mixtures reduce eczema in infants of allergic mothers. No sensitization benefit; incomplete follow-up and selected maternal eligibility limit generalization.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 7 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C8", "text": "L. reuteri trial is null for cumulative eczema but reduces IgE-associated eczema in a subset/time window. Primary and secondary findings differ; wheeze is not improved.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 8 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C9", "text": "Early L. acidophilus increases colonization without eczema prevention and with increased sensitization. Specific regimen; does not prove all microbial exposure harmful, but contradicts blanket benefit.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 9 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C10", "text": "Prenatal-only LGG does not prevent eczema or change cord immune markers. Timing/regimen boundary; postnatal benefit cannot be assumed from this null.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 10 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C11", "text": "Registered multispecies trial is null for primary diagnosed eczema, with selected positive secondary sensitization/atopic-eczema findings. Original Methods preserve broad recruited risk mix and endpoint hierarchy; secondary benefit is not primary success.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 11 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Methods:paragraph2, 1:Methods:paragraph9. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C12", "text": "Five-year electronic follow-up of the same trial finds no asthma/eczema protection. Shared parent trial, retention and routine-record ascertainment; not independent randomization.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 12 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C13", "text": "Infant LGG/inulin trial shows no significant eczema or asthma prevention. CI permits some effects; null cannot be discarded because another LGG regimen worked.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 13 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C14", "text": "PROMPT follow-up finds no allergy/asthma/eczema benefit at five years. Same parent intervention and selected at-risk Asian cohort, with follow-up attrition.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 14 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C15", "text": "SPRING respondent follow-up finds no allergic-disease advantage after maternal probiotics. Small responding subset and questionnaire outcomes limit precision and independence.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 15 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C16", "text": "Whole-cohort long-term allergy comparison is null with higher inhalant sensitization; favorable cesarean finding is post hoc. Baseline delivery mode is measurable, but subgroup choice after results does not prospectively confirm it; substantial attrition.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 16 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C17", "text": "Subset analysis does not find diversity/composition mediation of a prior eczema-prevention benefit. Same maternal-mixture trial and selected full-term vaginal/breastfed subset; microbiome modulation is not established as mediator.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 17 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C18", "text": "Small PRL2010 trial has no significant dermatitis-incidence difference, with favorable severity-course signals. Preliminary and subgroup/secondary results; no established prevention benefit.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 18 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C19", "text": "ORBEX randomizes 822 children; OM-85 does not improve primary time to first wheezing lower-respiratory illness in the off-drug observation period. Wheezing endpoint and age/lysate regimen are defined; clinical null does not rule out every exposure, and target engagement was not verified here.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 19 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C20", "text": "Maternal LGG study relates changed milk TGF-beta2 to lower infant eczema. Related Finnish LGG program/subset; immune-marker association is not proved mediation.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 20 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C21", "text": "Probiotic exposure alters infant immune markers, with higher CRP associated with lower later eczema risk. Secondary immune analyses in a parent trial; biomarkers and association do not prove the clinical mediator.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 21 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C22", "text": "NPSR1 analysis in a probiotic trial finds suggestive eczema associations but no general asthma/sensitization association. Exploratory genotype analyses and shared trial recruitment do not validate prospective protective subtypes.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 22 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C23", "text": "TLR variants interact differently with HN001 and HN019 in a selected trial subset. Many variant/outcome comparisons, European-ancestry selection and parent-trial overlap limit causal independence.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 23 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C24", "text": "Probiotic mixture reduces eczema in a small completed high-risk infant cohort. Marked attrition and no sensitization/total-IgE difference; no systemic autoimmune endpoint.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 24 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C25", "text": "Late-infant probiotic mixture reduces eczema but not asthma, sensitization or other allergy endpoints. Short follow-up and a specific daycare-entry regimen do not establish a universal neonatal window.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 25 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C26", "text": "CHILD early taxa/metabolite deficits precede asthma risk; defined bacteria improve airway inflammation in recipient progeny. Human risk association and germ-free transfer differ in scope; early wheeze/atopy is not every later clinical asthma phenotype.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 26 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C27", "text": "PASTURE microbiome maturation and butyrate measures relate to farm protection and later asthma. Statistical mediation shares exposure/confounding and microbiome model assumptions.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 27 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C28", "text": "Replicated farm-dust genera/metabolite and receptor-interaction analyses explain much of an inverse asthma association. Mediation, inferred microbial functions and gene-environment interaction do not replace selective human exposure randomization.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 28 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C29", "text": "Farm milk exposure associates with Treg measures and lower asthma/sensitization. Diet, milk components and farming covary; immune cells are not a verified causal mediator.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 29 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C30", "text": "Maternal farm exposure and neonatal BAFF/B-cell maturation associate with later allergy measures. Observational FARMFLORA cohort, small immune-marker comparisons and sex differences limit causality.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 30 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C31", "text": "PASTURE farm exposure and dendritic-cell properties associate with childhood asthma. Selected subset, in-vitro stimulation and shared cohort do not give independent disease perturbation.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 31 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C32", "text": "Maternal farming alters some TH17/Treg relationships but not baseline TH17 marker expression. Prenatal genetics/exposure correlations and marker endpoints do not prove prevention.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 32 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C33", "text": "Siblings associate with infant nasal/fecal community profiles. Cross-sectional microbial composition has no direct later disease intervention endpoint.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 33 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C34", "text": "Maternal farm groups differ in milk microbial and immune-protein profiles. Milk profiles are not a trial of later clinical allergy or autoimmune incidence.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 34 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C35", "text": "More older siblings relates to lower hay fever but not asthma in a twin-family survey. Family size is an exposure proxy with disease-specific nulls and shared familial causes.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 35 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C36", "text": "Sibling/daycare contact associates with more early wheeze and less later wheeze/asthma. Age reversal and nonrandomized social exposure prevent a simple protective-microbe interpretation.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 36 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C37", "text": "Early farm residence is protective in some sex-specific adult outcomes; current-only exposure can relate to higher asthma risk. Recall, occupation and sex-dependent confounding; not prospective selective exposure manipulation.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 37 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C38", "text": "Farm-related dust diversity has a stronger inverse asthma association than nasal diversity. Association and several nonsignificant richness/nasal comparisons; no causal environmental metabolite test.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 38 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C39", "text": "LPS structural activity differs by microbial source; E. coli but not B. dorei LPS protects NOD mice. Human infant data are observational; mouse LPS is intraperitoneal, not natural mucosal colonization; correction retained.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 39 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Results:paragraph15. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C40", "text": "Infant T1D progressors show diversity loss between seroconversion and diagnosis. Temporal changes after autoimmunity begins cannot prove microbial deficiency initiated it.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 40 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C41", "text": "Male-to-female microbiota transfer alters hormones and protects NOD recipients through androgen signaling. Genotype/sex and forced-transfer context restrict endogenous human inference.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 41 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C42", "text": "Commensals and defined colonization modify diabetes in MyD88-deficient NOD mice. Germ-free/genotype context and broad innate signaling are not a human population necessity proof.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 42 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C43", "text": "Neonatal but not adult colonization prevents excess iNKT and induced lung/colitis pathology. Germ-free developmental deprivation and induced models require separate human adjudication.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 43 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Main text:paragraph5, 1:Main text:paragraph8. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C44", "text": "Defined Clostridia increase colonic Treg function and resistance to induced disease. Specific community/model effects do not imply every microbe or all disease classes are protective.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 44 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C45", "text": "A selected 17-strain human-derived consortium improves Treg function and induced mouse pathology. Human origin of strains is not a human clinical trial; selected consortium and recipient physiology set scope.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 45 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C46", "text": "Defined Clostridia colonization protects allergen sensitization through barrier/innate-cell effects. Antibiotic and gnotobiotic preparations restrict ordinary human incidence inference.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 46 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C47", "text": "Low-dose dust/endotoxin protects experimental asthma, requiring epithelial A20. Exposure identity, dose and barrier pathway are specific; human A20 association is not intervention evidence.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 47 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C48", "text": "Defined live consortia suppress model food allergy through Treg MyD88/RORgamma-t necessity. SCFA mixture fails and durable Clostridial engraftment is not established; genetic allergy model and correction limit broad human transfer.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 48 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 0:Results:paragraph16, 0:Results:paragraph17, 0:Results:paragraph20, 0:Results:paragraph21. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C49", "text": "More and earlier infections precede islet autoimmunity/progression in genetically susceptible children. Few clinical progressors and immune susceptibility/reverse-causality alternatives; infection is not equivalent to benign commensal exposure.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 49 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C50", "text": "Infant antibiotic prescription associates with later T1D, with generally compatible but often nonsignificant sibling results. Indication, infection and direct drug effects remain; no selective commensal-deprivation causal test.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 50 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C51", "text": "TEDDY gastrointestinal infection associations with autoantibodies change direction by age and timing. Autoantibody endpoints and exposure-specific effects do not show universal clinical autoimmune protection.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 51 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C52", "text": "Enterovirus exposure and gluten interaction associate with increased celiac autoimmunity. Genetic-risk nested cohort; combines viral and dietary factors rather than a generalized microbial-deficit mechanism.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 52 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C53", "text": "Neonatal vancomycin but not streptomycin increases experimental asthma; adult treatment is null. Antibiotic and developmental pleiotropy remain, with explicit drug and age boundaries.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 53 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C54", "text": "Combined LPS/beta-glucan promotes steroid-refractory inflammatory asthma through Dectin-1/TLR4. Different dose/route/context; genuine contrary direction to blanket microbial protection, with linked correction retained.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 54 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C55", "text": "Neutralizing circulating microbial peptidoglycan reduces autoimmune arthritis/EAE with NOD2 dependence. Adult systemic microbial-factor effects are not early-life deprivation, but show harmful commensal signaling can be causal.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 55 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C56", "text": "Commensal-dependent autoreactive TCR activation triggers spontaneous uveitis in a model. Genetically restricted model; does not establish the human attributable fraction.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 56 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C57", "text": "Microbiome transfer and defined L. reuteri can worsen EAE in selected genotypes. Host genetics reverses the effect of a nominal probiotic; not a universal species label or human intervention result.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 57 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C58", "text": "Early peanut feeding prevents oral-challenge-confirmed peanut allergy in predefined at-risk cohorts. Dietary antigen exposure, not microbial restoration; linked correction details unexamined; cannot be credited as hygiene-mechanism proof.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 58 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 0:Methods:paragraph1, 0:Methods:paragraph4, 1:Results:paragraph1, 1:Results:paragraph2. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C59", "text": "EAT has a null intention-to-treat food-allergy primary outcome and favorable adherent/subtype analyses. Dietary antigen intervention and per-protocol selection do not prove microbial-deprivation causality.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 59 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C60", "text": "LEAP-On retains food-allergen tolerance after avoidance in the earlier consumption group. Same parent cohort; not independent microbial prevention evidence.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 60 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C61", "text": "Short daycare biodiversity intervention changes skin/gut communities and immune markers. Short-term marker endpoints do not demonstrate reduced allergic or autoimmune disease incidence.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 61 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C62", "text": "Blinded sandbox comparison with 13 children per group changes cytokine/community measures. Age 3-5, very small groups and biomarker outcomes; no verified clinical prevention endpoint.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 62 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "C63", "text": "Blinded indoor gardening changes skin microbial diversity and IL-10. Adult volunteer intervention and short immune-marker outcomes are not early-life disease-incidence evidence.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 63 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-12", "note": "" }, { "id": "CSC1", "text": "Farm, sibling, infant microbiome and antibiotic data repeatedly predict selected immune outcomes, but signs vary by disease, age and exposure. Familial, dietary, infection and indication effects are not uniformly eliminated. The registered predictive association component is Β, not a negation of specific causal interventions reported separately.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 1, 2, 22, 23, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 49, 50, 51, 52 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-12", "note": "" }, { "id": "CSC2", "text": "Defined colonization, epithelial A20 and Treg MyD88/RORgamma-t controls establish context-specific immune/disease effects in recipient models. Selected randomized human microbial regimens also modify eczema risk, while others are null or adverse. This supports Ε for specified exposure/host/phenotype contexts, not an interchangeable class of protective microbes.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 24, 25, 26, 29, 30, 31, 32, 34, 39, 41, 42, 43, 44, 45, 46, 47, 48, 53, 54, 55, 56, 57, 61, 62, 63 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-12", "note": "" }, { "id": "CSC3", "text": "The complete human allergic-and-autoimmune incidence claim has partial mechanistic support, but no source set isolates a generalized early microbial deficit as the cause across the registered disease classes. Specific eczema prevention is real and retained; overall-null respiratory trials, bidirectional infection associations and harmful commensal mechanisms constrain transfer. Food-antigen tolerance and short-term soil immune markers cannot fill the missing autoimmune clinical branch.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 35, 36, 37, 38, 39, 40, 49, 50, 51, 52, 58, 59, 60, 61, 62, 63 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-12", "note": "" }, { "id": "CH", "text": "Specific microbial exposures can shape immune regulation and prevent some eczema; a generalized hygiene-to-allergy-and-autoimmunity causal chain is not established.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 3, 5, 19, 48, 51, 62 ], "verification": "verified", "verified_against": "Bounded synthesis of examined sources; score is adjudication.", "verified_on": "2026-10-12", "note": "" } ], "citation_ledger": [ { "n": 1, "citation": "Stein MM, Hrusch CL, Gozdz J et al. 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Lancet (London, England). 2001.", "tier": "A", "kind": "rct", "pmid": "11297958", "doi": "10.1016/S0140-6736(00)04259-8", "url": "https://pubmed.ncbi.nlm.nih.gov/11297958/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "FINN_LGG", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C3", "CSC2", "CSC3", "CH" ] }, { "n": 4, "citation": "Kalliomäki M, Salminen S, Poussa T et al. Probiotics and prevention of atopic disease: 4-year follow-up of a randomised placebo-controlled trial. Lancet (London, England). 2003.", "tier": "A", "kind": "rct", "pmid": "12788576", "doi": "10.1016/S0140-6736(03)13490-3", "url": "https://pubmed.ncbi.nlm.nih.gov/12788576/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "FINN_LGG", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C4", "CSC2", "CSC3" ] }, { "n": 5, "citation": "Wickens K, Black PN, Stanley TV et al. A differential effect of 2 probiotics in the prevention of eczema and atopy: a double-blind, randomized, placebo-controlled trial. The Journal of allergy and clinical immunology. 2008.", "tier": "A", "kind": "rct", "pmid": "18762327", "doi": "10.1016/j.jaci.2008.07.011", "url": "https://pubmed.ncbi.nlm.nih.gov/18762327/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "NZ_HN001_HN019", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C5", "CSC2", "CSC3", "CH" ] }, { "n": 6, "citation": "Wickens K, Black P, Stanley TV et al. A protective effect of Lactobacillus rhamnosus HN001 against eczema in the first 2 years of life persists to age 4 years. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 2012.", "tier": "A", "kind": "rct", "pmid": "22702506", "doi": "10.1111/j.1365-2222.2012.03975.x", "url": "https://pubmed.ncbi.nlm.nih.gov/22702506/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "NZ_HN001_HN019", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C6", "CSC2", "CSC3" ] }, { "n": 7, "citation": "Rautava S, Kainonen E, Salminen S et al. Maternal probiotic supplementation during pregnancy and breast-feeding reduces the risk of eczema in the infant. The Journal of allergy and clinical immunology. 2012.", "tier": "A", "kind": "rct", "pmid": "23083673", "doi": "10.1016/j.jaci.2012.09.003", "url": "https://pubmed.ncbi.nlm.nih.gov/23083673/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "FINN_MATERNAL_MIX", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C7", "CSC2", "CSC3" ] }, { "n": 8, "citation": "Abrahamsson TR, Jakobsson T, Böttcher MF et al. Probiotics in prevention of IgE-associated eczema: a double-blind, randomized, placebo-controlled trial. The Journal of allergy and clinical immunology. 2007.", "tier": "A", "kind": "rct", "pmid": "17349686", "doi": "10.1016/j.jaci.2007.01.007", "url": "https://pubmed.ncbi.nlm.nih.gov/17349686/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID17349686", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C8", "CSC2", "CSC3" ] }, { "n": 9, "citation": "Taylor AL, Dunstan JA, Prescott SL. Probiotic supplementation for the first 6 months of life fails to reduce the risk of atopic dermatitis and increases the risk of allergen sensitization in high-risk children: a randomized controlled trial. The Journal of allergy and clinical immunology. 2007.", "tier": "A", "kind": "rct", "pmid": "17208600", "doi": "10.1016/j.jaci.2006.08.036", "url": "https://pubmed.ncbi.nlm.nih.gov/17208600/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID17208600", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C9", "CSC2", "CSC3" ] }, { "n": 10, "citation": "Boyle RJ, Ismail IH, Kivivuori S et al. Lactobacillus GG treatment during pregnancy for the prevention of eczema: a randomized controlled trial. Allergy. 2011.", "tier": "A", "kind": "rct", "pmid": "21121927", "doi": "10.1111/j.1398-9995.2010.02507.x", "url": "https://pubmed.ncbi.nlm.nih.gov/21121927/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID21121927", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C10", "CSC2", "CSC3" ] }, { "n": 11, "citation": "Allen SJ, Jordan S, Storey M et al. Probiotics in the prevention of eczema: a randomised controlled trial. Archives of disease in childhood. 2014.", "tier": "A", "kind": "rct", "pmid": "24947281", "doi": "10.1136/archdischild-2013-305799", "url": "https://pubmed.ncbi.nlm.nih.gov/24947281/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "WALES_ISRCTN26287422", "access_depth": "full_text_partial", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Methods:paragraph2, 1:Methods:paragraph9. No complete-paper or supplement audit claimed.", "carries_claims": [ "C11", "CSC2", "CSC3" ] }, { "n": 12, "citation": "Davies G, Jordan S, Brooks CJ et al. Long term extension of a randomised controlled trial of probiotics using electronic health records. Scientific reports. 2018.", "tier": "A", "kind": "rct", "pmid": "29769554", "doi": "10.1038/s41598-018-25954-z", "url": "https://pubmed.ncbi.nlm.nih.gov/29769554/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "WALES_ISRCTN26287422", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C12", "CSC2", "CSC3" ] }, { "n": 13, "citation": "Cabana MD, McKean M, Caughey AB et al. Early Probiotic Supplementation for Eczema and Asthma Prevention: A Randomized Controlled Trial. Pediatrics. 2017.", "tier": "A", "kind": "rct", "pmid": "28784701", "doi": "10.1542/peds.2016-3000", "url": "https://pubmed.ncbi.nlm.nih.gov/28784701/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID28784701", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C13", "CSC2", "CSC3" ] }, { "n": 14, "citation": "Loo EX, Llanora GV, Lu Q et al. Supplementation with probiotics in the first 6 months of life did not protect against eczema and allergy in at-risk Asian infants: a 5-year follow-up. International archives of allergy and immunology. 2014.", "tier": "A", "kind": "rct", "pmid": "24247661", "doi": "10.1159/000356338", "url": "https://pubmed.ncbi.nlm.nih.gov/24247661/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID24247661", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C14", "CSC2", "CSC3" ] }, { "n": 15, "citation": "Shipton EV, Foxcroft K, Dekker Nitert M et al. OFFSPRING: A SPRING Follow-Up Study Assessing the Efficacy of Maternal Probiotics and Allergic Disease in the Child. International archives of allergy and immunology. 2024.", "tier": "A", "kind": "rct", "pmid": "38104554", "doi": "10.1159/000535179", "url": "https://pubmed.ncbi.nlm.nih.gov/38104554/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID38104554", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C15", "CSC2", "CSC3" ] }, { "n": 16, "citation": "Kallio S, Kukkonen AK, Savilahti E et al. Perinatal probiotic intervention prevented allergic disease in a Caesarean-delivered subgroup at 13-year follow-up. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 2019.", "tier": "A", "kind": "primary", "pmid": "30472801", "doi": "10.1111/cea.13321", "url": "https://pubmed.ncbi.nlm.nih.gov/30472801/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "FINN_MIX_NCT00298337", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C16", "CSC2", "CSC3" ] }, { "n": 17, "citation": "Puisto R, Gómez-Gallego C, Collado MC et al. The Role of Infant Gut Microbiota Modulation by Perinatal Maternal Probiotic Intervention in Atopic Eczema Risk Reduction. Neonatology. 2025.", "tier": "A", "kind": "rct", "pmid": "39074448", "doi": "10.1159/000540075", "url": "https://pubmed.ncbi.nlm.nih.gov/39074448/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "FINN_MATERNAL_MIX", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C17", "CSC2", "CSC3" ] }, { "n": 18, "citation": "Anania C, Matys V, Marra S et al. Effect of Supplementation with a Specific Probiotic (Bifidobacterium bifidum PRL2010) in Pregnancy for the Prevention of Atopic Dermatitis in Children: Preliminary Results of a Randomized Trial. Nutrients. 2025.", "tier": "A", "kind": "rct", "pmid": "40005000", "doi": "10.3390/nu17040673", "url": "https://pubmed.ncbi.nlm.nih.gov/40005000/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID40005000", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C18", "CSC2", "CSC3" ] }, { "n": 19, "citation": "Morgan WJ, Mauger DT, Bacharier LB et al. Use of the bacterial lysate OM-85 for the primary prevention of wheezing lower respiratory illness in preschool children: a randomised, placebo-controlled trial. Lancet (London, England). 2026.", "tier": "A", "kind": "rct", "pmid": "42705251", "doi": "10.1016/S0140-6736(26)01443-1", "url": "https://pubmed.ncbi.nlm.nih.gov/42705251/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "ORBEX_NCT02148796", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C19", "CSC2", "CSC3", "CH" ] }, { "n": 20, "citation": "Rautava S, Kalliomäki M, Isolauri E. Probiotics during pregnancy and breast-feeding might confer immunomodulatory protection against atopic disease in the infant. The Journal of allergy and clinical immunology. 2002.", "tier": "A", "kind": "rct", "pmid": "11799376", "doi": "10.1067/mai.2002.120273", "url": "https://pubmed.ncbi.nlm.nih.gov/11799376/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "FINN_LGG", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C20", "CSC2", "CSC3" ] }, { "n": 21, "citation": "Marschan E, Kuitunen M, Kukkonen K et al. Probiotics in infancy induce protective immune profiles that are characteristic for chronic low-grade inflammation. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 2008.", "tier": "A", "kind": "rct", "pmid": "18266878", "doi": "10.1111/j.1365-2222.2008.02942.x", "url": "https://pubmed.ncbi.nlm.nih.gov/18266878/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "FINN_MIX_NCT00298337", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C21", "CSC2", "CSC3" ] }, { "n": 22, "citation": "P K, M K, K K et al. Interaction of NPSR1 genotypes and probiotics in the manifestation of atopic eczema in early childhood. Allergologia et immunopathologia. 2014.", "tier": "A", "kind": "rct", "pmid": "24439655", "doi": "10.1016/j.aller.2013.10.001", "url": "https://pubmed.ncbi.nlm.nih.gov/24439655/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "FINN_MIX_NCT00298337", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C22", "CSC1", "CSC3" ] }, { "n": 23, "citation": "Marlow G, Han DY, Wickens K et al. Differential effects of two probiotics on the risks of eczema and atopy associated with single nucleotide polymorphisms to Toll-like receptors. Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. 2015.", "tier": "A", "kind": "rct", "pmid": "25779902", "doi": "10.1111/pai.12371", "url": "https://pubmed.ncbi.nlm.nih.gov/25779902/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "NZ_HN001_HN019", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C23", "CSC1", "CSC3" ] }, { "n": 24, "citation": "Kim JY, Kwon JH, Ahn SH et al. Effect of probiotic mix (Bifidobacterium bifidum, Bifidobacterium lactis, Lactobacillus acidophilus) in the primary prevention of eczema: a double-blind, randomized, placebo-controlled trial. 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Gut. 2020.", "tier": "A", "kind": "primary", "pmid": "31744911", "doi": "10.1136/gutjnl-2019-319809", "url": "https://pubmed.ncbi.nlm.nih.gov/31744911/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "TEDDY", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C52", "CSC1", "CSC3" ] }, { "n": 53, "citation": "Russell SL, Gold MJ, Hartmann M et al. Early life antibiotic-driven changes in microbiota enhance susceptibility to allergic asthma. 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Ecotoxicology and environmental safety. 2022.", "tier": "A", "kind": "rct", "pmid": "35930838", "doi": "10.1016/j.ecoenv.2022.113900", "url": "https://pubmed.ncbi.nlm.nih.gov/35930838/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID35930838", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C62", "CSC2", "CSC3", "CH" ] }, { "n": 63, "citation": "Saarenpää M, Roslund MI, Nurminen N et al. Urban indoor gardening enhances immune regulation and diversifies skin microbiota - A placebo-controlled double-blinded intervention study. 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No complete-paper or supplement audit claimed.", "carries_claims": [ "C63", "CSC2", "CSC3" ] } ], "independence_basis": { "required": false, "lines": [ { "label": "Specific human prevention randomizations", "sources": [ 3, 5, 11, 19 ], "excludes_error": "Constrain baseline confounding, with product, outcome and timing differences rather than one shared protective effect." }, { "label": "Defined microbial and cellular mechanism", "sources": [ 47, 48, 43 ], "excludes_error": "Constrain a purely associational explanation in models; induction, recipient physiology and developmental conditions remain." }, { "label": "Farm and prospective population patterns", "sources": [ 1, 2, 27, 28 ], "excludes_error": "Constrain trial-product-only interpretation, but correlated environments and reused cohort resources remain." }, { "label": "Contrary autoimmune directions", "sources": [ 55, 57, 51, 52 ], "excludes_error": "Constrain blanket microbial benefit, with host genotype, infection identity and biomarker-to-clinical endpoint limits." } ], "shared_failure_mode_checked": true, "note": "Finnish LGG follow-ups/subsets, Finnish probiotic-mixture reports, HN001/HN019 follow-ups and genotype analyses each share parent randomization. PASTURE and related farm cohorts share recruitment and environmental measurements. TEDDY and DIABIMMUNE reports can overlap participants. One trial reported several times counts as one causal line; different clinical products are not interchangeable mechanism replications." }, "consensus_validation": { "completed": true, "status": "completed_original_source_reconciliation", "provider_mode": "Consensus Pro signed-in browser; observed output and citation link mappings", "queries": [ "https://consensus.app/search/early-microbial-exposure-allergies/NMVL2m6dRq-NikiKrXPoqg/" ], "query_record_note": "Exact visible question/response retained privately in raw browser receipt.", "primary_comparison_count": 6, "primary_comparisons": [ { "pmid": "11297958", "doi": "10.1016/S0140-6736(00)04259-8", "source_type": "primary study report", "study_group": "FINN_LGG", "access_depth": "abstract_metadata", "consensus_aspect": "Defined probiotic regimen and eczema", "result_comparison": "The original Finnish trial supports reduced eczema in a specified high-risk perinatal LGG regimen. This restricted positive result does not establish a universal probiotic effect, prevent every allergy, or identify protection from autoimmune disease.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/11297958/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\hygiene-hypothesis\\examinations\\original-0-20-1400.json" ], "body_receipts": [] }, { "pmid": "18762327", "doi": "10.1016/j.jaci.2008.07.011", "source_type": "primary study report", "study_group": "NZ_HN001_HN019", "access_depth": "abstract_metadata", "consensus_aspect": "Strain specificity challenges consistent efficacy", "result_comparison": "In the original randomized comparison HN001 reduced eczema while HN019 did not, and atopy comparisons were nonsignificant. Consensus's broad wording about consistently positive eczema trials must retain this strain-specific contrast.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/18762327/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\hygiene-hypothesis\\examinations\\original-0-20-1400.json" ], "body_receipts": [] }, { "pmid": "24947281", "doi": "10.1136/archdischild-2013-305799", "source_type": "primary study report", "study_group": "WALES_ISRCTN26287422", "access_depth": "full_text_partial", "consensus_aspect": "Primary versus secondary endpoints", "result_comparison": "The original Wales trial had a null primary diagnosed-eczema comparison, with favorable secondary sensitization and atopic-eczema results. The body also shows enrollment of both familial-risk levels. The later five-year follow-up is the same parent trial, not independent replication.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/24947281/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\hygiene-hypothesis\\examinations\\original-0-20-1400.json" ], "body_receipts": [ "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\hygiene-hypothesis\\body-presentation-receipts\\24947281-s1-p2-9.json" ] }, { "pmid": "42705251", "doi": "10.1016/S0140-6736(26)01443-1", "source_type": "primary study report", "study_group": "ORBEX_NCT02148796", "access_depth": "abstract_metadata", "consensus_aspect": "Missing completed clinical bacterial-lysate trial", "result_comparison": "Consensus omitted ORBEX and portrayed bacterial-lysate evidence as largely biomarker-based. The original 822-participant report tested a clinical primary endpoint during subsequent off-treatment observation and found no significant benefit: hazard ratio1.16, confidence interval0.82–1.64. It is a completed clinical null, not an unreported biomarker-only study.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/42705251/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\hygiene-hypothesis\\examinations\\original-0-20-1400.json", "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\hygiene-hypothesis\\examinations\\original-18-19-6500.json" ], "body_receipts": [] }, { "pmid": "35930838", "doi": "10.1016/j.ecoenv.2022.113900", "source_type": "primary study report", "study_group": "PMID35930838", "access_depth": "abstract_metadata", "consensus_aspect": "Daycare biodiversity is an intermediate-outcome intervention", "result_comparison": "The original small randomized soil-enrichment study reports microbiome and immune-marker changes over14days. It does not demonstrate prevention of diagnosed allergy or autoimmunity. Consensus helped locate this original source, but the marker-to-disease boundary remains.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/35930838/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\hygiene-hypothesis\\examinations\\original-60-63-4000.json" ], "body_receipts": [] }, { "pmid": "27133167", "doi": "10.1016/j.cell.2016.04.007", "source_type": "primary study report", "study_group": "PMID27133167", "access_depth": "full_text_partial", "consensus_aspect": "Microbial quality and experimental system", "result_comparison": "The original report pairs observational infant cohorts with injected LPS experiments in NOD mice. E. coli and B. dorei signals differ. It supports exposure-specific biology rather than a general rule that more microbes protect humans; the linked correction is retained, with its detailed changes unexamined.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/27133167/", "source_examination_receipts": [ "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\hygiene-hypothesis\\examinations\\original-20-40-1300.json" ], "body_receipts": [ "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\hygiene-hypothesis\\body-presentation-receipts\\27133167-s1-p15.json" ] } ], "grade_changed": false, "grade_change_note": "Source-based adjudication; no independent blinded regrade claimed.", "raw_receipts": [ { "path": "deliverables\\hsef_v53_remaining_priority_11_15_2026-10-11\\hygiene-hypothesis\\consensus-browser-2026-10-11.json", "sha256": "29b8b82df5e554ac216c28c0979968e1d2776e76f07a8408b18ac06398c8798c" } ], "independent_blinded_audit": false, "cutoff": "2026-10-09", "completed_utc": "2026-10-12T19:49:41.535787+00:00", "conclusion": "Endpoint hierarchy, experimental scope and original-source limits determine the evidence cards; provider wording does not override them." } }