{
  "$schema_version": "5.3",
  "review_mode": "fresh",
  "claim_restatement": {
    "index_wording": "Gut–Brain Axis Drives Psychiatric Disease",
    "entry_form": "phenomenon",
    "gradeable_restatement": "Gut microbial dysbiosis is an upstream cause of human psychiatric disease, acting through microbial metabolites, immune and vagal pathways, and correction of dysbiosis is disease-modifying.",
    "restatement_required": true,
    "split_into": [],
    "parent_claim": null,
    "scope_qualifiers": [
      {
        "qualifier": "Species, genotype, baseline disease, diet, dose and timing",
        "determinable_before_outcome": true,
        "determined_from": "Enrollment and experimental design, before results; no responder-defined scope.",
        "action": "retained"
      }
    ]
  },
  "hypothesis": {
    "name": "Gut–Brain Axis Drives Psychiatric Disease",
    "central_claim": "Gut microbial dysbiosis is an upstream cause of human psychiatric disease, acting through microbial metabolites, immune and vagal pathways, and correction of dysbiosis is disease-modifying.",
    "proposed_mechanism": "Gut microbial dysbiosis is an upstream cause of human psychiatric disease, acting through microbial metabolites, immune and vagal pathways, and correction of dysbiosis is disease-modifying.",
    "claimed_scope": "Human depression, anxiety and psychosis. Rodent behaviours, ASD-related mechanistic examples and physiological endpoints retain their own scope.",
    "claimed_level": [
      "initiation",
      "progression",
      "generalization"
    ],
    "is_conjunctive": true,
    "conjunctive_note": "The index prescribes weakest-link aggregation. Its descriptive SC1 can impose an associational floor; this limitation and primary-subclaim/scope sensitivities will be exposed rather than changing the rule after evidence appraisal."
  },
  "rubric_routing": {
    "primary_rubric": "04-microbiome-systemic.md",
    "secondary_rubrics": [
      "07-psychiatry-neuromodulation.md",
      "05-immunology-inflammation.md"
    ],
    "index_notes_applied": [
      "The index prescribes weakest-link aggregation. Its descriptive SC1 can impose an associational floor; this limitation and primary-subclaim/scope sensitivities will be exposed rather than changing the rule after evidence appraisal."
    ],
    "rubric_fit_note": "Exact archived v5.3 framework. Any stale index empirical framing is rechecked against primary results."
  },
  "subclaim_matrix": {
    "subclaims": [
      {
        "id": "SC1",
        "statement": "Gut microbial composition correlates reproducibly with specific human psychiatric states.",
        "subclaim_type": "existence",
        "scope": "human depression, anxiety and psychotic disorders",
        "claimed_scope": "human depression, anxiety and psychotic disorders",
        "governing_rubric": "04-microbiome-systemic.md",
        "key_evidence_anchor": "Medication-, diet- and transit-aware cohorts",
        "hsef_level": "Β",
        "confidence": "Moderate",
        "governing_cap_or_threshold": "Quoted boundary and upward audit below.",
        "rationale": "Human associations recur in independent cohorts, including medication-adjusted analyses, but diversity direction and taxonomic signatures vary. This existence subclaim contains association rather than causation [28,31–32,52–54,61–62]."
      },
      {
        "id": "SC2",
        "statement": "Defined microbial manipulation changes behavioral phenotypes through identified mediators.",
        "subclaim_type": "mechanism",
        "scope": "named experimental systems; human attribution separate",
        "claimed_scope": "named experimental systems; human attribution separate",
        "governing_rubric": "04-microbiome-systemic.md",
        "key_evidence_anchor": "Defined strains, metabolite or vagal subtraction and rescue",
        "hsef_level": "Ε",
        "confidence": "Moderate",
        "governing_cap_or_threshold": "Quoted boundary and upward audit below.",
        "rationale": "Defined strains, vagal subtraction, central CB1 blockade and metabolite exposure/rescue establish context-bounded mouse mechanisms. Negative species, developmental and receptor contrasts map boundaries [7,10,39–41,44,58–59]."
      },
      {
        "id": "SC3",
        "statement": "These microbiota-to-brain mechanisms make a clinically meaningful causal contribution to human psychiatric disease.",
        "subclaim_type": "generalization",
        "scope": "human depressive, anxiety and psychotic disorders; diagnoses fixed at baseline",
        "claimed_scope": "human depressive, anxiety and psychotic disorders; diagnoses fixed at baseline",
        "governing_rubric": "04-microbiome-systemic.md",
        "key_evidence_anchor": "Randomized microbial interventions, clinical outcomes and time-ordered human mediator tests",
        "hsef_level": "Γ",
        "confidence": "Moderate",
        "governing_cap_or_threshold": "Quoted boundary and upward audit below.",
        "rationale": "Human RCTs include positive, null and analysis-dependent results. Clinical efficacy has scoped causal support, but attribution to the nominated dysbiosis-to-brain pathways and durable disease modification across these diagnoses is unresolved [13–27,47–51]."
      }
    ],
    "aggregation_rule": "weakest-link",
    "aggregation_preregistered": true,
    "aggregation_rationale": "The index prescribes weakest-link aggregation. Its descriptive SC1 can impose an associational floor; this limitation and primary-subclaim/scope sensitivities will be exposed rather than changing the rule after evidence appraisal.",
    "primary_subclaim_id": "SC3",
    "aggregation_derivation": "The preregistered weakest-link aggregation returns Β because SC1 is descriptive association. This is a consequence of that conjunction and does not downgrade the demonstrated animal mechanisms to association. Primary-subclaim and scope-matched sensitivities return Γ for SC3. Positive human treatment comparisons warrant causal credit for the tested treatment; they do not alone establish that the specified microbial mechanisms are an upstream general cause. No necessity requirement is imposed on a merely contributory mechanism.",
    "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": "Bounded microbial amplification",
        "core_claim": "Microbial functions influence specific behaviours under defined antecedent stress, diet or developmental conditions.",
        "explains_what_nominal_does_not": "Microbial functions influence specific behaviours under defined antecedent stress, diet or developmental conditions.",
        "strongest_supporting_evidence": [
          "Vagal and central CB1 contrasts plus species and receptor negatives narrow distinct mechanisms [7,10,40–44]."
        ],
        "strongest_contradictory_evidence": [
          "These compatible pathways do not establish a single universal microbial signature or human disease initiator."
        ],
        "hsef_level_for_this_model": "Ε",
        "rationale": "Vagal and central CB1 contrasts plus species and receptor negatives narrow distinct mechanisms [7,10,40–44]. These compatible pathways do not establish a single universal microbial signature or human disease initiator."
      },
      {
        "rank_in_tournament": 2,
        "model_id": "M5",
        "is_nominal": false,
        "name": "Stress-to-brain and stress-to-gut feedback",
        "core_claim": "An upstream host state changes microbial ecology, which can feed back on brain function.",
        "explains_what_nominal_does_not": "An upstream host state changes microbial ecology, which can feed back on brain function.",
        "strongest_supporting_evidence": [
          "Neural circuit/gland perturbations establish host-to-gut causation; donor-transfer rescue establishes a feedback leg [4,10,42]."
        ],
        "strongest_contradictory_evidence": [
          "One direction does not exclude the other; human relative contributions remain unresolved."
        ],
        "hsef_level_for_this_model": "Ε",
        "rationale": "Neural circuit/gland perturbations establish host-to-gut causation; donor-transfer rescue establishes a feedback leg [4,10,42]. One direction does not exclude the other; human relative contributions remain unresolved."
      },
      {
        "rank_in_tournament": 3,
        "model_id": "M4",
        "is_nominal": false,
        "name": "Medication-related dysbiosis",
        "core_claim": "Psychotropics directly alter microbial growth and community composition.",
        "explains_what_nominal_does_not": "Psychotropics directly alter microbial growth and community composition.",
        "strongest_supporting_evidence": [
          "Drug screens and cohort exposure contrasts support medication effects [36,54,57,61]; that support is in vitro plus observational, so universal caps 1 and 2 hold this model at Γ."
        ],
        "strongest_contradictory_evidence": [
          "Drug-free cohorts and adjusted associations persist; medication cannot explain every signal [28,53,55,62]."
        ],
        "hsef_level_for_this_model": "Γ",
        "rationale": "Drug screens and cohort exposure contrasts support medication effects [36,54,57,61]; that support is in vitro plus observational, so universal caps 1 and 2 hold this model at Γ. Drug-free cohorts and adjusted associations persist; medication cannot explain every signal [28,53,55,62]."
      },
      {
        "rank_in_tournament": 4,
        "model_id": "M3",
        "is_nominal": false,
        "name": "Diet, transit and illness-state confounding",
        "core_claim": "Host behaviour and GI physiology create microbial associations with diagnosis.",
        "explains_what_nominal_does_not": "Host behaviour and GI physiology create microbial associations with diagnosis.",
        "strongest_supporting_evidence": [
          "IBS overlap, diet analyses and treatment-conditioned follow-up provide material alternatives [35–36,59–60]."
        ],
        "strongest_contradictory_evidence": [
          "The ASD diet example is an external comparator, not direct proof for every registered psychiatric disease."
        ],
        "hsef_level_for_this_model": "Γ",
        "rationale": "IBS overlap, diet analyses and treatment-conditioned follow-up provide material alternatives [35–36,59–60]. The ASD diet example is an external comparator, not direct proof for every registered psychiatric disease."
      },
      {
        "rank_in_tournament": 5,
        "model_id": "M1",
        "is_nominal": true,
        "name": "General upstream microbial psychiatric cause",
        "core_claim": "Dysbiosis initiates psychiatric disease and its correction durably modifies disease.",
        "explains_what_nominal_does_not": "Dysbiosis initiates psychiatric disease and its correction durably modifies disease.",
        "strongest_supporting_evidence": [
          "Human-donor transfer and several clinical treatment signals are its strongest supports [1–2,16–19,23,37]."
        ],
        "strongest_contradictory_evidence": [
          "Animal proxies, heterogeneity, null trials and unverified human mediation block this full-scope interpretation."
        ],
        "hsef_level_for_this_model": "Γ",
        "rationale": "Human-donor transfer and several clinical treatment signals are its strongest supports [1–2,16–19,23,37]. Animal proxies, heterogeneity, null trials and unverified human mediation block this full-scope interpretation."
      }
    ],
    "tournament_summary": "Descriptive comparison; does not modify the nominal score. The neural-gland manipulation [42] distinguishes a host-to-gut arrow from a purely upstream microbial account. The trial labelled ITT versus compliant mITT comparison [13] and the PROVIT clinical/metabolic dissociation [15,56] distinguish robust clinical mechanism from parallel biomarker change.",
    "study_separating_rank1_from_rank2": "The neural-gland manipulation [42] distinguishes a host-to-gut arrow from a purely upstream microbial account. The trial labelled ITT versus compliant mITT comparison [13] and the PROVIT clinical/metabolic dissociation [15,56] distinguish robust clinical mechanism from parallel biomarker change.",
    "nominal_wins_only_by_funding_artifact": false,
    "level_unchanged_by_tournament": true
  },
  "evidence_inventory": [
    {
      "n": 1,
      "pmid": "27491067",
      "title": "Transferring the blues: Depression-associated gut microbiota induces neurobehavioural changes in the rat.",
      "citation": "Kelly JR, Borre Y, O' Brien C et al. Transferring the blues: Depression-associated gut microbiota induces neurobehavioural changes in the rat. Journal of psychiatric research. 2016.",
      "doi": "10.1016/j.jpsychires.2016.07.019",
      "pmcid": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/27491067/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27491067/",
      "tier": "A",
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      "opened": true,
      "opened_on": "2026-10-05",
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      "study_id": "PMID27491067",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1",
        "SC2"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human donors / recipient rats",
      "decisive_perturbation": true,
      "endogenous": false,
      "direction": "positive",
      "what_it_shows": "Depression-donor transfer induced anhedonia and anxiety-like behaviour in microbiota-depleted rats, with tryptophan changes.",
      "what_it_does_not_show": "Crude transfer and recipient depletion do not identify a microbial mediator or show initiation in the human donors.",
      "confounders_present": [
        "Crude transfer and recipient depletion do not identify a microbial mediator or show initiation in the human donors."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
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        "supporting_count": 0,
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    },
    {
      "n": 2,
      "pmid": "27067014",
      "title": "Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host's metabolism.",
      "citation": "Zheng P, Zeng B, Zhou C et al. Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host's metabolism. Molecular psychiatry. 2016.",
      "doi": "10.1038/mp.2016.44",
      "pmcid": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/27067014/",
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      "relates_to_subclaims": [
        "SC1",
        "SC2"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human donors / germ-free mice",
      "decisive_perturbation": true,
      "endogenous": false,
      "direction": "positive",
      "what_it_shows": "MDD microbiota transferred behavioural and metabolic differences to germ-free recipients.",
      "what_it_does_not_show": "Forced-swim immobility is a proxy, and metabolic covariation does not establish the required human mediator.",
      "confounders_present": [
        "Forced-swim immobility is a proxy, and metabolic covariation does not establish the required human mediator."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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    },
    {
      "n": 3,
      "pmid": "27315483",
      "title": "Microbial Reconstitution Reverses Maternal Diet-Induced Social and Synaptic Deficits in Offspring.",
      "citation": "Buffington SA, Di Prisco GV, Auchtung TA et al. Microbial Reconstitution Reverses Maternal Diet-Induced Social and Synaptic Deficits in Offspring. Cell. 2016.",
      "doi": "10.1016/j.cell.2016.06.001",
      "pmcid": "PMC5102250",
      "url": "https://pubmed.ncbi.nlm.nih.gov/27315483/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27315483/",
      "tier": "A",
      "source_tier": "A",
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      "status_flags": [
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      "relates_to_subclaims": [
        "SC2"
      ],
      "favors_models": [],
      "evidence_class": "Strong",
      "system": "maternal-diet mouse model",
      "decisive_perturbation": true,
      "endogenous": false,
      "direction": "positive",
      "what_it_shows": "Cohousing, transfer and defined commensal reconstitution altered social behaviour and synaptic plasticity after maternal high-fat diet.",
      "what_it_does_not_show": "This is a neurodevelopmental model outside the registered human depression, anxiety and psychosis scope.",
      "confounders_present": [
        "This is a neurodevelopmental model outside the registered human depression, anxiety and psychosis scope."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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    },
    {
      "n": 4,
      "pmid": "33535879",
      "title": "Involvement of the microbiota-gut-brain axis in chronic restraint stress: disturbances of the kynurenine metabolic pathway in both the gut and brain.",
      "citation": "Deng Y, Zhou M, Wang J et al. Involvement of the microbiota-gut-brain axis in chronic restraint stress: disturbances of the kynurenine metabolic pathway in both the gut and brain. Gut microbes. 2021.",
      "doi": "10.1080/19490976.2020.1869501",
      "pmcid": "PMC7872056",
      "url": "https://pubmed.ncbi.nlm.nih.gov/33535879/",
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      "tier": "A",
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      "opened_on": "2026-10-05",
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      "relates_to_subclaims": [
        "SC2"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "restraint-stress mice",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "positive",
      "what_it_shows": "IDO inhibition and microbiota interventions partially rescued stress-associated behaviour and kynurenine abnormalities.",
      "what_it_does_not_show": "Stress is the initiating exposure and the interventions do not isolate one exclusively microbial pathway.",
      "confounders_present": [
        "Stress is the initiating exposure and the interventions do not isolate one exclusively microbial pathway."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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    },
    {
      "n": 5,
      "pmid": "38378622",
      "title": "Gut dysbiosis induces the development of depression-like behavior through abnormal synapse pruning in microglia-mediated by complement C3.",
      "citation": "Hao W, Ma Q, Wang L et al. Gut dysbiosis induces the development of depression-like behavior through abnormal synapse pruning in microglia-mediated by complement C3. Microbiome. 2024.",
      "doi": "10.1186/s40168-024-01756-6",
      "pmcid": "PMC10877840",
      "url": "https://pubmed.ncbi.nlm.nih.gov/38378622/",
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      "tier": "A",
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      "opened_on": "2026-10-05",
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      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "stress-donor mouse transfer",
      "decisive_perturbation": true,
      "endogenous": false,
      "direction": "positive",
      "what_it_shows": "Stress-donor microbiota transferred behaviour and complement-associated synaptic abnormalities to recipients.",
      "what_it_does_not_show": "C3/CR3 changes accompany the phenotype; the abstract does not independently resolve every mediator necessity contrast.",
      "confounders_present": [
        "C3/CR3 changes accompany the phenotype; the abstract does not independently resolve every mediator necessity contrast."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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    },
    {
      "n": 6,
      "pmid": "32187541",
      "title": "Changes in Gut Microbiota by Chronic Stress Impair the Efficacy of Fluoxetine.",
      "citation": "Siopi E, Chevalier G, Katsimpardi L et al. Changes in Gut Microbiota by Chronic Stress Impair the Efficacy of Fluoxetine. Cell reports. 2020.",
      "doi": "10.1016/j.celrep.2020.02.099",
      "pmcid": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/32187541/",
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      "relates_to_subclaims": [
        "SC2"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "stress-donor mice",
      "decisive_perturbation": true,
      "endogenous": false,
      "direction": "positive",
      "what_it_shows": "Transferred microbiota impaired fluoxetine response and neurogenesis; 5-hydroxytryptophan alleviated the deficits.",
      "what_it_does_not_show": "A downstream precursor rescue is not proof that the same pathway initiates human MDD.",
      "confounders_present": [
        "A downstream precursor rescue is not proof that the same pathway initiates human MDD."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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    {
      "n": 7,
      "pmid": "37131071",
      "title": "Gut microbiota changes require vagus nerve integrity to promote depressive-like behaviors in mice.",
      "citation": "Siopi E, Galerne M, Rivagorda M et al. Gut microbiota changes require vagus nerve integrity to promote depressive-like behaviors in mice. Molecular psychiatry. 2023.",
      "doi": "10.1038/s41380-023-02071-6",
      "pmcid": "PMC10615761",
      "url": "https://pubmed.ncbi.nlm.nih.gov/37131071/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37131071/",
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      "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Materials and methods:paragraph3, 1:Materials and methods:paragraph4, 1:Materials and methods:paragraph13, 1:Materials and methods:paragraph18, 2:Results:paragraph9. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2"
      ],
      "favors_models": [],
      "evidence_class": "Strong",
      "system": "mouse transfer / vagotomy",
      "decisive_perturbation": true,
      "endogenous": false,
      "direction": "positive",
      "what_it_shows": "Vagotomy before stress-donor inoculation abrogated behavioural, neurogenic and inflammatory effects; Methods describe blinded analysis.",
      "what_it_does_not_show": "Subdiaphragmatic vagotomy is physiologically broad; effects and surgical boundaries are within the recipient model.",
      "confounders_present": [
        "Subdiaphragmatic vagotomy is physiologically broad; effects and surgical boundaries are within the recipient model."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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    },
    {
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      "pmid": "27045844",
      "title": "Regulation of prefrontal cortex myelination by the microbiota.",
      "citation": "Hoban AE, Stilling RM, Ryan FJ et al. Regulation of prefrontal cortex myelination by the microbiota. Translational psychiatry. 2016.",
      "doi": "10.1038/tp.2016.42",
      "pmcid": "PMC4872400",
      "url": "https://pubmed.ncbi.nlm.nih.gov/27045844/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27045844/",
      "tier": "A",
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      "opened_on": "2026-10-05",
      "status_checked_on": "2026-10-05",
      "study_id": "PMID27045844",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "germ-free / colonized mice",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "positive",
      "what_it_shows": "Post-weaning colonization reversed myelin-related gene changes in germ-free prefrontal cortex.",
      "what_it_does_not_show": "Molecular and ultrastructural regulation is not a psychiatric clinical endpoint.",
      "confounders_present": [
        "Molecular and ultrastructural regulation is not a psychiatric clinical endpoint."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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    },
    {
      "n": 9,
      "pmid": "31645720",
      "title": "The microbiota regulate neuronal function and fear extinction learning.",
      "citation": "Chu C, Murdock MH, Jing D et al. The microbiota regulate neuronal function and fear extinction learning. Nature. 2019.",
      "doi": "10.1038/s41586-019-1644-y",
      "pmcid": "PMC6818753",
      "url": "https://pubmed.ncbi.nlm.nih.gov/31645720/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31645720/",
      "tier": "A",
      "source_tier": "A",
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      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-05",
      "status_checked_on": "2026-10-05",
      "study_id": "PMID31645720",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2"
      ],
      "favors_models": [],
      "evidence_class": "Strong",
      "system": "germ-free and antibiotic-treated mice",
      "decisive_perturbation": true,
      "endogenous": false,
      "direction": "positive",
      "what_it_shows": "Microbial depletion impaired fear extinction, with developmental-window dependence of restoration and altered neuronal activity.",
      "what_it_does_not_show": "Fear learning is a defined behavioural function; identified metabolite differences alone do not establish human anxiety disease causation.",
      "confounders_present": [
        "Fear learning is a defined behavioural function; identified metabolite differences alone do not establish human anxiety disease causation."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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      }
    },
    {
      "n": 10,
      "pmid": "33311466",
      "title": "Effect of gut microbiota on depressive-like behaviors in mice is mediated by the endocannabinoid system.",
      "citation": "Chevalier G, Siopi E, Guenin-Macé L et al. Effect of gut microbiota on depressive-like behaviors in mice is mediated by the endocannabinoid system. Nature communications. 2020.",
      "doi": "10.1038/s41467-020-19931-2",
      "pmcid": "PMC7732982",
      "url": "https://pubmed.ncbi.nlm.nih.gov/33311466/",
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      "tier": "A",
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        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-05",
      "status_checked_on": "2026-10-05",
      "study_id": "PMID33311466",
      "access_depth": "full_text_partial",
      "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph9, 1:Results:paragraph16, 2:Discussion:paragraph4. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2"
      ],
      "favors_models": [],
      "evidence_class": "Strong",
      "system": "stress-donor mice / eCB rescue",
      "decisive_perturbation": true,
      "endogenous": false,
      "direction": "positive",
      "what_it_shows": "Central eCB enhancement rescued transferred behaviours, central CB1 antagonism blocked rescue, and Lactobacillus complementation restored behavioural and lipid signals.",
      "what_it_does_not_show": "Some individual contrasts were nonsignificant; downstream rescue narrows this model rather than establishing all human depression causes.",
      "confounders_present": [
        "Some individual contrasts were nonsignificant; downstream rescue narrows this model rather than establishing all human depression causes."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
        "retrieved": false,
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      }
    },
    {
      "n": 11,
      "pmid": "31231198",
      "title": "Role of Tryptophan in Microbiota-Induced Depressive-Like Behavior: Evidence From Tryptophan Depletion Study.",
      "citation": "Lukić I, Getselter D, Koren O et al. Role of Tryptophan in Microbiota-Induced Depressive-Like Behavior: Evidence From Tryptophan Depletion Study. Frontiers in behavioral neuroscience. 2019.",
      "doi": "10.3389/fnbeh.2019.00123",
      "pmcid": "PMC6558209",
      "url": "https://pubmed.ncbi.nlm.nih.gov/31231198/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31231198/",
      "tier": "A",
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        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-05",
      "status_checked_on": "2026-10-05",
      "study_id": "PMID31231198",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "germ-free mice / tryptophan depletion",
      "decisive_perturbation": true,
      "endogenous": false,
      "direction": "positive",
      "what_it_shows": "Acute tryptophan depletion changed the behavioural phenotype and brain serotonin of germ-free mice more strongly than SPF mice.",
      "what_it_does_not_show": "Depletion is a broad nutritional challenge and germ-free development differs from adult human dysbiosis.",
      "confounders_present": [
        "Depletion is a broad nutritional challenge and germ-free development differs from adult human dysbiosis."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
        "retrieved": false,
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      }
    },
    {
      "n": 12,
      "pmid": "35819092",
      "title": "Roseburia hominis Alleviates Neuroinflammation via Short-Chain Fatty Acids through Histone Deacetylase Inhibition.",
      "citation": "Song L, Sun Q, Zheng H et al. Roseburia hominis Alleviates Neuroinflammation via Short-Chain Fatty Acids through Histone Deacetylase Inhibition. Molecular nutrition & food research. 2022.",
      "doi": "10.1002/mnfr.202200164",
      "pmcid": "PMC9787297",
      "url": "https://pubmed.ncbi.nlm.nih.gov/35819092/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35819092/",
      "tier": "A",
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      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-05",
      "status_checked_on": "2026-10-05",
      "study_id": "PMID35819092",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "germ-free rats / defined strain",
      "decisive_perturbation": true,
      "endogenous": false,
      "direction": "positive",
      "what_it_shows": "Roseburia hominis reduced microglial activation and depressive behaviours; SCFA treatments reproduced molecular anti-inflammatory effects.",
      "what_it_does_not_show": "SCFA molecular rescue is not a demonstrated exclusive mediator of the behavioural effect in humans.",
      "confounders_present": [
        "SCFA molecular rescue is not a demonstrated exclusive mediator of the behavioural effect in humans."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
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      }
    },
    {
      "n": 13,
      "pmid": "35654766",
      "title": "Clinical, gut microbial and neural effects of a probiotic add-on therapy in depressed patients: a randomized controlled trial.",
      "citation": "Schaub AC, Schneider E, Vazquez-Castellanos JF et al. Clinical, gut microbial and neural effects of a probiotic add-on therapy in depressed patients: a randomized controlled trial. Translational psychiatry. 2022.",
      "doi": "10.1038/s41398-022-01977-z",
      "pmcid": "PMC9163095",
      "url": "https://pubmed.ncbi.nlm.nih.gov/35654766/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35654766/",
      "tier": "A",
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      "kind": "rct",
      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-05",
      "status_checked_on": "2026-10-05",
      "study_id": "NCT02957591",
      "access_depth": "full_text_partial",
      "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Patients and methods:paragraph3, 2:Results:paragraph12, 2:Results:paragraph14, 3:Discussion:paragraph1, 1:Patients and methods:paragraph0, 1:Patients and methods:paragraph6, 2:Results:paragraph0, 2:Results:paragraph2, 2:Results:paragraph3, 2:Results:paragraph4, 2:Results:paragraph5, 2:Results:paragraph6. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human interventional",
      "decisive_perturbation": false,
      "endogenous": true,
      "direction": "mixed",
      "what_it_shows": "HAM-D time-by-group benefit occurred in the compliant mITT sample, while the paper-labelled ITT interaction was nonsignificant; Lactobacillus enrichment correlated with symptoms.",
      "what_it_does_not_show": "The ITT table has 47 completers out of 60 included; adherence exclusions, baseline imbalance and attrition limit inference. Correlation is not randomized mediation.",
      "confounders_present": [
        "The ITT table has 47 completers out of 60 included; adherence exclusions, baseline imbalance and attrition limit inference. Correlation is not randomized mediation."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
        "retrieved": false,
        "supporting_count": 0,
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    },
    {
      "n": 14,
      "pmid": "37314797",
      "title": "Acceptability, Tolerability, and Estimates of Putative Treatment Effects of Probiotics as Adjunctive Treatment in Patients With Depression: A Randomized Clinical Trial.",
      "citation": "Nikolova VL, Cleare AJ, Young AH et al. Acceptability, Tolerability, and Estimates of Putative Treatment Effects of Probiotics as Adjunctive Treatment in Patients With Depression: A Randomized Clinical Trial. JAMA psychiatry. 2023.",
      "doi": "10.1001/jamapsychiatry.2023.1817",
      "pmcid": "PMC10267847",
      "url": "https://pubmed.ncbi.nlm.nih.gov/37314797/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37314797/",
      "tier": "A",
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      ],
      "opened": true,
      "opened_on": "2026-10-05",
      "status_checked_on": "2026-10-05",
      "study_id": "NCT03893162",
      "access_depth": "full_text_partial",
      "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Methods:paragraph0, 1:Methods:paragraph1, 1:Methods:paragraph2, 1:Methods:paragraph3, 1:Methods:paragraph4. 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": "positive",
      "what_it_shows": "A masked pilot add-on probiotic trial estimated favourable effects on selected depression and anxiety measures with low attrition.",
      "what_it_does_not_show": "Feasibility and effect-size estimation preceded a definitive efficacy trial; this report does not establish microbial mediator necessity or disease modification.",
      "confounders_present": [
        "Feasibility and effect-size estimation preceded a definitive efficacy trial; this report does not establish microbial mediator necessity or disease modification."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
        "retrieved": false,
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      }
    },
    {
      "n": 15,
      "pmid": "33171595",
      "title": "PROVIT: Supplementary Probiotic Treatment and Vitamin B7 in Depression-A Randomized Controlled Trial.",
      "citation": "Reininghaus EZ, Platzer M, Kohlhammer-Dohr A et al. PROVIT: Supplementary Probiotic Treatment and Vitamin B7 in Depression-A Randomized Controlled Trial. Nutrients. 2020.",
      "doi": "10.3390/nu12113422",
      "pmcid": "PMC7695208",
      "url": "https://pubmed.ncbi.nlm.nih.gov/33171595/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33171595/",
      "tier": "A",
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      "kind": "rct",
      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-05",
      "status_checked_on": "2026-10-05",
      "study_id": "NCT03300440",
      "access_depth": "full_text_partial",
      "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:3. Results:paragraph5, 2:3. Results:paragraph6, 2:3. Results:paragraph7, 2:3. Results:paragraph10, 2:3. Results:paragraph11, 2:3. Results:paragraph12. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human interventional",
      "decisive_perturbation": false,
      "endogenous": true,
      "direction": "mixed",
      "what_it_shows": "PROVIT changed microbial profiles but clinical outcome measures did not differ from placebo plus biotin.",
      "what_it_does_not_show": "Inpatient treatment improved both arms; microbiome change cannot be substituted for a positive psychiatric endpoint.",
      "confounders_present": [
        "Inpatient treatment improved both arms; microbiome change cannot be substituted for a positive psychiatric endpoint."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
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    },
    {
      "n": 16,
      "pmid": "34875345",
      "title": "Bifidobacterium breve CCFM1025 attenuates major depression disorder via regulating gut microbiome and tryptophan metabolism: A randomized clinical trial.",
      "citation": "Tian P, Chen Y, Zhu H et al. Bifidobacterium breve CCFM1025 attenuates major depression disorder via regulating gut microbiome and tryptophan metabolism: A randomized clinical trial. Brain, behavior, and immunity. 2022.",
      "doi": "10.1016/j.bbi.2021.11.023",
      "pmcid": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/34875345/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34875345/",
      "tier": "A",
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      "status_flags": [
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      "opened": true,
      "opened_on": "2026-10-05",
      "status_checked_on": "2026-10-05",
      "study_id": "PMID34875345",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human interventional",
      "decisive_perturbation": true,
      "endogenous": true,
      "direction": "positive",
      "what_it_shows": "Randomized CCFM1025 supplementation improved HDRS and MADRS change relative to placebo and altered serotonin-turnover measures.",
      "what_it_does_not_show": "Small short-term trial; peripheral turnover and parallel microbial changes do not isolate the cause of benefit or prove durability.",
      "confounders_present": [
        "Small short-term trial; peripheral turnover and parallel microbial changes do not isolate the cause of benefit or prove durability."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
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      }
    },
    {
      "n": 17,
      "pmid": "29731182",
      "title": "Effect of probiotic and prebiotic vs placebo on psychological outcomes in patients with major depressive disorder: A randomized clinical trial.",
      "citation": "Kazemi A, Noorbala AA, Azam K et al. Effect of probiotic and prebiotic vs placebo on psychological outcomes in patients with major depressive disorder: A randomized clinical trial. Clinical nutrition (Edinburgh, Scotland). 2019.",
      "doi": "10.1016/j.clnu.2018.04.010",
      "pmcid": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/29731182/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29731182/",
      "tier": "A",
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      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-05",
      "status_checked_on": "2026-10-05",
      "study_id": "PMID29731182",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human interventional",
      "decisive_perturbation": true,
      "endogenous": true,
      "direction": "mixed",
      "what_it_shows": "Probiotic supplementation improved BDI relative to placebo and prebiotic in MDD; prebiotic benefit and unadjusted mediator ratios were null.",
      "what_it_does_not_show": "Attrition was material and adjusted metabolite associations do not establish a necessary microbial mediator.",
      "confounders_present": [
        "Attrition was material and adjusted metabolite associations do not establish a necessary microbial mediator."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
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      }
    },
    {
      "n": 18,
      "pmid": "28483500",
      "title": "Probiotic Bifidobacterium longum NCC3001 Reduces Depression Scores and Alters Brain Activity: A Pilot Study in Patients With Irritable Bowel Syndrome.",
      "citation": "Pinto-Sanchez MI, Hall GB, Ghajar K et al. Probiotic Bifidobacterium longum NCC3001 Reduces Depression Scores and Alters Brain Activity: A Pilot Study in Patients With Irritable Bowel Syndrome. Gastroenterology. 2017.",
      "doi": "10.1053/j.gastro.2017.05.003",
      "pmcid": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/28483500/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28483500/",
      "tier": "A",
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      "opened": true,
      "opened_on": "2026-10-05",
      "status_checked_on": "2026-10-05",
      "study_id": "PMID28483500",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human IBS interventional",
      "decisive_perturbation": true,
      "endogenous": false,
      "direction": "mixed",
      "what_it_shows": "NCC3001 reduced depression scores and altered emotional brain responses in IBS, with no significant anxiety or IBS-symptom benefit.",
      "what_it_does_not_show": "IBS with mood scores is distinct from primary MDD; fecal community profiles were similar and mediator attribution remains unresolved.",
      "confounders_present": [
        "IBS with mood scores is distinct from primary MDD; fecal community profiles were similar and mediator attribution remains unresolved."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
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      }
    },
    {
      "n": 19,
      "pmid": "42309058",
      "title": "Adjunctive fecal microbiota transplantation for major depressive disorder: A randomized, double-blind, placebo-controlled trial.",
      "citation": "Li J, Wang Y, Li R et al. Adjunctive fecal microbiota transplantation for major depressive disorder: A randomized, double-blind, placebo-controlled trial. Cell host & microbe. 2026.",
      "doi": "10.1016/j.chom.2026.05.017",
      "pmcid": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/42309058/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42309058/",
      "tier": "A",
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      "status_flags": [
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      "opened": true,
      "opened_on": "2026-10-05",
      "status_checked_on": "2026-10-05",
      "study_id": "PMID42309058",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human interventional",
      "decisive_perturbation": false,
      "endogenous": true,
      "direction": "mixed",
      "what_it_shows": "Adjunctive randomized FMT improved HAMD-17 reductions at weeks two and eight, without a significant week-eight remission difference; the abstract reports bile-acid mediation analysis.",
      "what_it_does_not_show": "Only abstract accessible; primary endpoint hierarchy, registration timing, missing-data treatment and mediation assumptions cannot be confirmed. Statistical mediation is not mediator manipulation.",
      "confounders_present": [
        "Only abstract accessible; primary endpoint hierarchy, registration timing, missing-data treatment and mediation assumptions cannot be confirmed. Statistical mediation is not mediator manipulation."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
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      }
    },
    {
      "n": 20,
      "pmid": "36637229",
      "title": "Feasibility, Acceptability, and Safety of Faecal Microbiota Transplantation in the Treatment of Major Depressive Disorder: A Pilot Randomized Controlled Trial.",
      "citation": "Green JE, Berk M, Mohebbi M et al. Feasibility, Acceptability, and Safety of Faecal Microbiota Transplantation in the Treatment of Major Depressive Disorder: A Pilot Randomized Controlled Trial. Canadian journal of psychiatry. Revue canadienne de psychiatrie. 2023.",
      "doi": "10.1177/07067437221150508",
      "pmcid": "PMC10192831",
      "url": "https://pubmed.ncbi.nlm.nih.gov/36637229/",
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      "what_it_does_not_show": "The trial was not designed to establish clinical efficacy; exploratory quality-of-life and gastrointestinal outcomes do not establish MDD causation.",
      "confounders_present": [
        "The trial was not designed to establish clinical efficacy; exploratory quality-of-life and gastrointestinal outcomes do not establish MDD causation."
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      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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      "pmid": "36653035",
      "title": "Effect of short-term, high-dose probiotic supplementation on cognition, related brain functions and BDNF in patients with depression: a secondary analysis of a randomized controlled trial.",
      "citation": "Schneider E, Doll JPK, Schweinfurth N et al. Effect of short-term, high-dose probiotic supplementation on cognition, related brain functions and BDNF in patients with depression: a secondary analysis of a randomized controlled trial. Journal of psychiatry & neuroscience : JPN. 2023.",
      "doi": "10.1503/jpn.220117",
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        "SC3"
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      "direction": "mixed",
      "what_it_shows": "A secondary analysis found immediate verbal recall and hippocampal activation differences; other cognitive measures were null.",
      "what_it_does_not_show": "Same NCT02957591 cohort as the HAM-D report; low-adherence exclusions and multiple outcomes limit independent causal weight.",
      "confounders_present": [
        "Same NCT02957591 cohort as the HAM-D report; low-adherence exclusions and multiple outcomes limit independent causal weight."
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      "pmid": "28943228",
      "title": "Effect of Lactobacillus rhamnosus HN001 in Pregnancy on Postpartum Symptoms of Depression and Anxiety: A Randomised Double-blind Placebo-controlled Trial.",
      "citation": "Slykerman RF, Hood F, Wickens K et al. Effect of Lactobacillus rhamnosus HN001 in Pregnancy on Postpartum Symptoms of Depression and Anxiety: A Randomised Double-blind Placebo-controlled Trial. EBioMedicine. 2017.",
      "doi": "10.1016/j.ebiom.2017.09.013",
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      "relates_to_subclaims": [
        "SC3"
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      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human pregnancy interventional",
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      "endogenous": false,
      "direction": "positive",
      "what_it_shows": "HN001 allocation lowered postpartum depression and anxiety screening scores.",
      "what_it_does_not_show": "Mood was a secondary outcome of an offspring-eczema trial; screening scores and postpartum prevention do not establish the full psychiatric mechanism.",
      "confounders_present": [
        "Mood was a secondary outcome of an offspring-eczema trial; screening scores and postpartum prevention do not establish the full psychiatric mechanism."
      ],
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      "n": 23,
      "pmid": "26706022",
      "title": "Clinical and metabolic response to probiotic administration in patients with major depressive disorder: A randomized, double-blind, placebo-controlled trial.",
      "citation": "Akkasheh G, Kashani-Poor Z, Tajabadi-Ebrahimi M et al. Clinical and metabolic response to probiotic administration in patients with major depressive disorder: A randomized, double-blind, placebo-controlled trial. Nutrition (Burbank, Los Angeles County, Calif.). 2016.",
      "doi": "10.1016/j.nut.2015.09.003",
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      "url": "https://pubmed.ncbi.nlm.nih.gov/26706022/",
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      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human interventional",
      "decisive_perturbation": true,
      "endogenous": true,
      "direction": "positive",
      "what_it_shows": "An MDD randomized probiotic trial reported greater BDI improvement with changes in insulin, hs-CRP and glutathione.",
      "what_it_does_not_show": "Multiple biomarkers and short follow-up do not identify a microbial mediator or sustained disease modification.",
      "confounders_present": [
        "Multiple biomarkers and short follow-up do not identify a microbial mediator or sustained disease modification."
      ],
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      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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      "n": 24,
      "pmid": "39232392",
      "title": "The effects of Lactobacillus plantarum PS128 in patients with major depressive disorder: an eight-week double-blind, placebo-controlled study.",
      "citation": "Lin SK, Kuo PH, Hsu CY et al. The effects of Lactobacillus plantarum PS128 in patients with major depressive disorder: an eight-week double-blind, placebo-controlled study. Asian journal of psychiatry. 2024.",
      "doi": "10.1016/j.ajp.2024.104210",
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      "url": "https://pubmed.ncbi.nlm.nih.gov/39232392/",
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      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human interventional",
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      "direction": "negative",
      "what_it_shows": "An eight-week PS128 MDD trial found no between-group depression advantage or significant inflammatory, permeability or community changes.",
      "what_it_does_not_show": "Small trial and one formulation do not refute every microbiota pathway; within-arm improvement is not treatment efficacy.",
      "confounders_present": [
        "Small trial and one formulation do not refute every microbiota pathway; within-arm improvement is not treatment efficacy."
      ],
      "verification": "verified",
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      "n": 25,
      "pmid": "30388595",
      "title": "Probiotic Lactobacillus Plantarum 299v decreases kynurenine concentration and improves cognitive functions in patients with major depression: A double-blind, randomized, placebo controlled study.",
      "citation": "Rudzki L, Ostrowska L, Pawlak D et al. Probiotic Lactobacillus Plantarum 299v decreases kynurenine concentration and improves cognitive functions in patients with major depression: A double-blind, randomized, placebo controlled study. Psychoneuroendocrinology. 2019.",
      "doi": "10.1016/j.psyneuen.2018.10.010",
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      "url": "https://pubmed.ncbi.nlm.nih.gov/30388595/",
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      "study_id": "LP299V-MDD-2019",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human interventional",
      "decisive_perturbation": false,
      "endogenous": true,
      "direction": "mixed",
      "what_it_shows": "LP299v augmentation improved selected cognitive tests and reduced kynurenine among analysed completers.",
      "what_it_does_not_show": "The abstract does not demonstrate depression-score superiority; cognition, kynurenine and mood must remain separate endpoints.",
      "confounders_present": [
        "The abstract does not demonstrate depression-score superiority; cognition, kynurenine and mood must remain separate endpoints."
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      "pmid": "39924003",
      "title": "Exploring the mechanisms of action of probiotics in depression: Results from a randomized controlled pilot trial.",
      "citation": "Nikolova VL, Cleare AJ, Young AH et al. Exploring the mechanisms of action of probiotics in depression: Results from a randomized controlled pilot trial. Journal of affective disorders. 2025.",
      "doi": "10.1016/j.jad.2025.01.153",
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      "url": "https://pubmed.ncbi.nlm.nih.gov/39924003/",
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      "system": "human secondary RCT analysis",
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      "direction": "mixed",
      "what_it_shows": "The Nikolova cohort follow-up found transient between-group microbial differences and anxiety-associated taxa, with null inflammatory differences.",
      "what_it_does_not_show": "Same NCT03893162 trial as the clinical pilot; within-group richness changes were not superior to placebo and do not prove mediation.",
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        "Same NCT03893162 trial as the clinical pilot; within-group richness changes were not superior to placebo and do not prove mediation."
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      "pmid": "39271063",
      "title": "Probiotic Lactobacillus plantarum 299v supplementation in patients with major depression in a double-blind, randomized, placebo-controlled trial: A metabolomics study.",
      "citation": "Godzien J, Kalaska B, Rudzki L et al. Probiotic Lactobacillus plantarum 299v supplementation in patients with major depression in a double-blind, randomized, placebo-controlled trial: A metabolomics study. Journal of affective disorders. 2025.",
      "doi": "10.1016/j.jad.2024.09.058",
      "pmcid": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/39271063/",
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      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
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      "evidence_class": "Weak",
      "system": "human secondary RCT analysis",
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      "direction": "positive",
      "what_it_shows": "Exploratory metabolomics after LP299v showed changes in acylcarnitines and other metabolites.",
      "what_it_does_not_show": "Same underlying trial as the earlier cognition report; altered metabolite panels are neither independent efficacy replication nor proven causal mediators.",
      "confounders_present": [
        "Same underlying trial as the earlier cognition report; altered metabolite panels are neither independent efficacy replication nor proven causal mediators."
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      "n": 28,
      "pmid": "30718848",
      "title": "The neuroactive potential of the human gut microbiota in quality of life and depression.",
      "citation": "Valles-Colomer M, Falony G, Darzi Y et al. The neuroactive potential of the human gut microbiota in quality of life and depression. Nature microbiology. 2019.",
      "doi": "10.1038/s41564-018-0337-x",
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      "url": "https://pubmed.ncbi.nlm.nih.gov/30718848/",
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      "relates_to_subclaims": [
        "SC1"
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      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human population cohorts",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "positive",
      "what_it_shows": "Population and validation datasets linked butyrate-producing taxa to quality of life and depression after antidepressant adjustment.",
      "what_it_does_not_show": "Replicated association does not establish direction; predicted neuroactive capacity is not measured brain delivery.",
      "confounders_present": [
        "Replicated association does not establish direction; predicted neuroactive capacity is not measured brain delivery."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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      "pmid": "37386523",
      "title": "Microbiome and tryptophan metabolomics analysis in adolescent depression: roles of the gut microbiota in the regulation of tryptophan-derived neurotransmitters and behaviors in human and mice.",
      "citation": "Zhou M, Fan Y, Xu L et al. Microbiome and tryptophan metabolomics analysis in adolescent depression: roles of the gut microbiota in the regulation of tryptophan-derived neurotransmitters and behaviors in human and mice. Microbiome. 2023.",
      "doi": "10.1186/s40168-023-01589-9",
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      "url": "https://pubmed.ncbi.nlm.nih.gov/37386523/",
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      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1",
        "SC2"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "adolescent cohorts / stressed mice",
      "decisive_perturbation": true,
      "endogenous": false,
      "direction": "positive",
      "what_it_shows": "Roseburia intestinalis rescued stress-related mouse behaviour and tryptophan metabolism alongside adolescent microbial associations.",
      "what_it_does_not_show": "Human first diagnosis and post-sertraline profiles are observational; mouse rescue is not a randomized adolescent treatment result.",
      "confounders_present": [
        "Human first diagnosis and post-sertraline profiles are observational; mouse rescue is not a randomized adolescent treatment result."
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      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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    {
      "n": 30,
      "pmid": "30531975",
      "title": "GABA-modulating bacteria of the human gut microbiota.",
      "citation": "Strandwitz P, Kim KH, Terekhova D et al. GABA-modulating bacteria of the human gut microbiota. Nature microbiology. 2019.",
      "doi": "10.1038/s41564-018-0307-3",
      "pmcid": "PMC6384127",
      "url": "https://pubmed.ncbi.nlm.nih.gov/30531975/",
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      "study_id": "PMID30531975",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1",
        "SC2"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "bacterial culture / human association",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "positive",
      "what_it_shows": "Cultured bacteria produced or used GABA, and human Bacteroides abundance correlated with depression-related brain signatures.",
      "what_it_does_not_show": "Bacterial GABA capacity does not show adequate brain exposure, human mediator necessity or clinical benefit.",
      "confounders_present": [
        "Bacterial GABA capacity does not show adequate brain exposure, human mediator necessity or clinical benefit."
      ],
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    {
      "n": 31,
      "pmid": "33268363",
      "title": "Landscapes of bacterial and metabolic signatures and their interaction in major depressive disorders.",
      "citation": "Yang J, Zheng P, Li Y et al. Landscapes of bacterial and metabolic signatures and their interaction in major depressive disorders. Science advances. 2020.",
      "doi": "10.1126/sciadv.aba8555",
      "pmcid": "PMC7710361",
      "url": "https://pubmed.ncbi.nlm.nih.gov/33268363/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33268363/",
      "tier": "A",
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      "opened_on": "2026-10-05",
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      "study_id": "PMID33268363",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
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      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human case-control multiomics",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "positive",
      "what_it_shows": "MDD samples differed in bacteria, virome and fecal metabolites and yielded a discriminatory marker panel.",
      "what_it_does_not_show": "Classifier performance and coexpression cannot determine initiation or temporal direction.",
      "confounders_present": [
        "Classifier performance and coexpression cannot determine initiation or temporal direction."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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    {
      "n": 32,
      "pmid": "25882912",
      "title": "Altered fecal microbiota composition in patients with major depressive disorder.",
      "citation": "Jiang H, Ling Z, Zhang Y et al. Altered fecal microbiota composition in patients with major depressive disorder. Brain, behavior, and immunity. 2015.",
      "doi": "10.1016/j.bbi.2015.03.016",
      "pmcid": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/25882912/",
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      "study_id": "PMID25882912",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human case-control",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "positive",
      "what_it_shows": "Active MDD had higher alpha diversity and altered taxa, including lower Faecalibacterium linked to severity.",
      "what_it_does_not_show": "Direction of diversity differs from reduced-diversity reports; treatment-response groups and diagnosis do not isolate microbial causation.",
      "confounders_present": [
        "Direction of diversity differs from reduced-diversity reports; treatment-response groups and diagnosis do not isolate microbial causation."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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      "pmid": "37074710",
      "title": "Interplay of Metabolome and Gut Microbiome in Individuals With Major Depressive Disorder vs Control Individuals.",
      "citation": "Amin N, Liu J, Bonnechere B et al. Interplay of Metabolome and Gut Microbiome in Individuals With Major Depressive Disorder vs Control Individuals. JAMA psychiatry. 2023.",
      "doi": "10.1001/jamapsychiatry.2023.0685",
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      "url": "https://pubmed.ncbi.nlm.nih.gov/37074710/",
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      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human cohorts / MR",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "mixed",
      "what_it_shows": "MDD had energy and lipid metabolic signatures; MR suggested some lipid changes associated with the disease process.",
      "what_it_does_not_show": "The instruments address metabolites rather than a defined microbial mediator; coarse cross-study microbiome links cannot validate dysbiosis-wide causation.",
      "confounders_present": [
        "The instruments address metabolites rather than a defined microbial mediator; coarse cross-study microbiome links cannot validate dysbiosis-wide causation."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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    },
    {
      "n": 34,
      "pmid": "33594816",
      "title": "Unraveling the Microbial Mechanisms Underlying the Psychobiotic Potential of a Bifidobacterium breve Strain.",
      "citation": "Tian P, Bastiaanssen TFS, Song L et al. Unraveling the Microbial Mechanisms Underlying the Psychobiotic Potential of a Bifidobacterium breve Strain. Molecular nutrition & food research. 2021.",
      "doi": "10.1002/mnfr.202000704",
      "pmcid": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/33594816/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33594816/",
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      "opened_on": "2026-10-05",
      "status_checked_on": "2026-10-05",
      "study_id": "PMID33594816",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "defined-strain stress mice",
      "decisive_perturbation": true,
      "endogenous": false,
      "direction": "positive",
      "what_it_shows": "CCFM1025 but not a comparator B. breve strain improved stress behaviour and produced distinct microbial/metabolic profiles.",
      "what_it_does_not_show": "Strain comparisons narrow function but genomic predictions and parallel metabolites do not identify every mediator.",
      "confounders_present": [
        "Strain comparisons narrow function but genomic predictions and parallel metabolites do not identify every mediator."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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    {
      "n": 35,
      "pmid": "34750528",
      "title": "Altered metabolome and microbiome features provide clues in understanding irritable bowel syndrome and depression comorbidity.",
      "citation": "Han L, Zhao L, Zhou Y et al. Altered metabolome and microbiome features provide clues in understanding irritable bowel syndrome and depression comorbidity. The ISME journal. 2022.",
      "doi": "10.1038/s41396-021-01123-5",
      "pmcid": "PMC8940891",
      "url": "https://pubmed.ncbi.nlm.nih.gov/34750528/",
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      ],
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      "opened_on": "2026-10-05",
      "status_checked_on": "2026-10-05",
      "study_id": "PMID34750528",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human IBS cohorts",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "positive",
      "what_it_shows": "IBS discovery/validation cohorts linked tryptophan and serotonin metabolites to depression comorbidity.",
      "what_it_does_not_show": "IBS, diet and transit can influence both mood and stool; this is not primary psychiatric disease randomization.",
      "confounders_present": [
        "IBS, diet and transit can influence both mood and stool; this is not primary psychiatric disease randomization."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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    },
    {
      "n": 36,
      "pmid": "34290352",
      "title": "The change of gut microbiota in MDD patients under SSRIs treatment.",
      "citation": "Shen Y, Yang X, Li G et al. The change of gut microbiota in MDD patients under SSRIs treatment. Scientific reports. 2021.",
      "doi": "10.1038/s41598-021-94481-1",
      "pmcid": "PMC8295378",
      "url": "https://pubmed.ncbi.nlm.nih.gov/34290352/",
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        "none_found"
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      "opened_on": "2026-10-05",
      "status_checked_on": "2026-10-05",
      "study_id": "PMID34290352",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1"
      ],
      "favors_models": [],
      "evidence_class": "Weak",
      "system": "human treated MDD cohort",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "positive",
      "what_it_shows": "Microbial composition and diversity shifted after symptom improvement under escitalopram.",
      "what_it_does_not_show": "Follow-up was conditioned on improvement; drug exposure, recovery and time are inseparable without an appropriate comparator.",
      "confounders_present": [
        "Follow-up was conditioned on improvement; drug exposure, recovery and time are inseparable without an appropriate comparator."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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    },
    {
      "n": 37,
      "pmid": "35618633",
      "title": "Multi-Probiotics ameliorate Major depressive disorder and accompanying gastrointestinal syndromes via serotonergic system regulation.",
      "citation": "Tian P, Zou R, Wang L et al. Multi-Probiotics ameliorate Major depressive disorder and accompanying gastrointestinal syndromes via serotonergic system regulation. Journal of advanced research. 2023.",
      "doi": "10.1016/j.jare.2022.05.003",
      "pmcid": "PMC10006521",
      "url": "https://pubmed.ncbi.nlm.nih.gov/35618633/",
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      "status_checked_on": "2026-10-05",
      "study_id": "PMID35618633",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human treatment / stressed mice",
      "decisive_perturbation": true,
      "endogenous": false,
      "direction": "positive",
      "what_it_shows": "A three-strain formula improved depression and GI scores relative to placebo; a separate stress model investigated serotonergic effects.",
      "what_it_does_not_show": "The abstract does not supply complete human design or mediator-subtraction details; mouse mechanisms cannot be substituted for human mediation.",
      "confounders_present": [
        "The abstract does not supply complete human design or mediator-subtraction details; mouse mechanisms cannot be substituted for human mediation."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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      }
    },
    {
      "n": 38,
      "pmid": "24315484",
      "title": "Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders.",
      "citation": "Hsiao EY, McBride SW, Hsien S et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell. 2013.",
      "doi": "10.1016/j.cell.2013.11.024",
      "pmcid": "PMC3897394",
      "url": "https://pubmed.ncbi.nlm.nih.gov/24315484/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24315484/",
      "tier": "A",
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      "status_checked_on": "2026-10-05",
      "study_id": "PMID24315484",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "maternal immune activation mice",
      "decisive_perturbation": true,
      "endogenous": false,
      "direction": "positive",
      "what_it_shows": "B. fragilis ameliorated selected behaviours and barrier abnormalities; administration of an elevated metabolite induced behavioural abnormalities.",
      "what_it_does_not_show": "Antecedent maternal immune activation and neurodevelopmental outcomes are outside the registered human SC3 scope.",
      "confounders_present": [
        "Antecedent maternal immune activation and neurodevelopmental outcomes are outside the registered human SC3 scope."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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    },
    {
      "n": 39,
      "pmid": "21876150",
      "title": "Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve.",
      "citation": "Bravo JA, Forsythe P, Chew MV et al. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proceedings of the National Academy of Sciences of the United States of America. 2011.",
      "doi": "10.1073/pnas.1102999108",
      "pmcid": "PMC3179073",
      "url": "https://pubmed.ncbi.nlm.nih.gov/21876150/",
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      "tier": "A",
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      "opened": true,
      "opened_on": "2026-10-05",
      "status_checked_on": "2026-10-05",
      "study_id": "PMID21876150",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2"
      ],
      "favors_models": [],
      "evidence_class": "Strong",
      "system": "defined-strain mouse / vagotomy",
      "decisive_perturbation": true,
      "endogenous": false,
      "direction": "positive",
      "what_it_shows": "JB-1 changed stress behaviour and regional GABA receptor expression; effects were absent after vagotomy.",
      "what_it_does_not_show": "Healthy-mouse stress responses and a broad nerve lesion do not prove human psychiatric onset or generalize to all strains.",
      "confounders_present": [
        "Healthy-mouse stress responses and a broad nerve lesion do not prove human psychiatric onset or generalize to all strains."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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    },
    {
      "n": 40,
      "pmid": "35143877",
      "title": "Bacteroides species differentially modulate depression-like behavior via gut-brain metabolic signaling.",
      "citation": "Zhang Y, Fan Q, Hou Y et al. Bacteroides species differentially modulate depression-like behavior via gut-brain metabolic signaling. Brain, behavior, and immunity. 2022.",
      "doi": "10.1016/j.bbi.2022.02.007",
      "pmcid": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/35143877/",
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      "status_checked_on": "2026-10-05",
      "study_id": "PMID35143877",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2"
      ],
      "favors_models": [],
      "evidence_class": "Strong",
      "system": "MDD donors / defined bacteria in mice",
      "decisive_perturbation": true,
      "endogenous": false,
      "direction": "mixed",
      "what_it_shows": "Specific Bacteroides species recapitulated behaviour and neurogenesis effects of MDD-donor transfer, while B. ovatus did not.",
      "what_it_does_not_show": "Species boundaries are informative; depletion protocols and recipient proxies limit endogenous human inference.",
      "confounders_present": [
        "Species boundaries are informative; depletion protocols and recipient proxies limit endogenous human inference."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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      }
    },
    {
      "n": 41,
      "pmid": "35165440",
      "title": "A gut-derived metabolite alters brain activity and anxiety behaviour in mice.",
      "citation": "Needham BD, Funabashi M, Adame MD et al. A gut-derived metabolite alters brain activity and anxiety behaviour in mice. Nature. 2022.",
      "doi": "10.1038/s41586-022-04396-8",
      "pmcid": "PMC9170029",
      "url": "https://pubmed.ncbi.nlm.nih.gov/35165440/",
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      "study_id": "PMID35165440",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2"
      ],
      "favors_models": [],
      "evidence_class": "Strong",
      "system": "engineered bacteria / mice",
      "decisive_perturbation": true,
      "endogenous": false,
      "direction": "positive",
      "what_it_shows": "Defined 4EP biosynthesis increased 4EPS exposure, altered myelination and anxiety-like behaviour; oligodendrocyte-directed treatment prevented behaviour.",
      "what_it_does_not_show": "Engineered exposure establishes a molecule pathway in mice, not its sufficient concentration or necessity in human anxiety disorders.",
      "confounders_present": [
        "Engineered exposure establishes a molecule pathway in mice, not its sufficient concentration or necessity in human anxiety disorders."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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      }
    },
    {
      "n": 42,
      "pmid": "39121857",
      "title": "Stress-sensitive neural circuits change the gut microbiome via duodenal glands.",
      "citation": "Chang H, Perkins MH, Novaes LS et al. Stress-sensitive neural circuits change the gut microbiome via duodenal glands. Cell. 2024.",
      "doi": "10.1016/j.cell.2024.07.019",
      "pmcid": "PMC11425084",
      "url": "https://pubmed.ncbi.nlm.nih.gov/39121857/",
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      "study_id": "PMID39121857",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2"
      ],
      "favors_models": [],
      "evidence_class": "Strong",
      "system": "mouse neural circuits / gut glands",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "positive",
      "what_it_shows": "Neural activation and gland ablation causally linked psychological-state circuits to Lactobacillus and host defence.",
      "what_it_does_not_show": "This directly supports brain-to-gut direction in a mouse pathway; it does not prove that every human microbial association is reactive.",
      "confounders_present": [
        "This directly supports brain-to-gut direction in a mouse pathway; it does not prove that every human microbial association is reactive."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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      }
    },
    {
      "n": 43,
      "pmid": "31582799",
      "title": "Oral selective serotonin reuptake inhibitors activate vagus nerve dependent gut-brain signalling.",
      "citation": "McVey Neufeld KA, Bienenstock J, Bharwani A et al. Oral selective serotonin reuptake inhibitors activate vagus nerve dependent gut-brain signalling. Scientific reports. 2019.",
      "doi": "10.1038/s41598-019-50807-8",
      "pmcid": "PMC6776512",
      "url": "https://pubmed.ncbi.nlm.nih.gov/31582799/",
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      "opened_on": "2026-10-05",
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      "study_id": "PMID31582799",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "oral SSRI / mouse vagotomy",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "positive",
      "what_it_shows": "Oral SSRI activated gut neural signalling and its tail-suspension effect required intact vagal signalling.",
      "what_it_does_not_show": "Vagal dependence is not specific to microbial mechanisms and does not prove microbes mediate the SSRI benefit.",
      "confounders_present": [
        "Vagal dependence is not specific to microbial mechanisms and does not prove microbes mediate the SSRI benefit."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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    },
    {
      "n": 44,
      "pmid": "30522820",
      "title": "Mechanisms Underlying Microbial-Mediated Changes in Social Behavior in Mouse Models of Autism Spectrum Disorder.",
      "citation": "Sgritta M, Dooling SW, Buffington SA et al. Mechanisms Underlying Microbial-Mediated Changes in Social Behavior in Mouse Models of Autism Spectrum Disorder. Neuron. 2019.",
      "doi": "10.1016/j.neuron.2018.11.018",
      "pmcid": "PMC6645363",
      "url": "https://pubmed.ncbi.nlm.nih.gov/30522820/",
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      "opened": true,
      "opened_on": "2026-10-05",
      "status_checked_on": "2026-10-05",
      "study_id": "PMID30522820",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2"
      ],
      "favors_models": [],
      "evidence_class": "Strong",
      "system": "multiple ASD mouse models",
      "decisive_perturbation": true,
      "endogenous": false,
      "direction": "positive",
      "what_it_shows": "L. reuteri rescued social deficits across models through vagus and oxytocin-receptor dependence, without restoring overall community composition.",
      "what_it_does_not_show": "Strong bounded mechanism outside human SC3; therapeutic action without composition restoration challenges a generic normalization narrative.",
      "confounders_present": [
        "Strong bounded mechanism outside human SC3; therapeutic action without composition restoration challenges a generic normalization narrative."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
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      }
    },
    {
      "n": 45,
      "pmid": "30066368",
      "title": "Short-chain fatty acids: microbial metabolites that alleviate stress-induced brain-gut axis alterations.",
      "citation": "van de Wouw M, Boehme M, Lyte JM et al. Short-chain fatty acids: microbial metabolites that alleviate stress-induced brain-gut axis alterations. The Journal of physiology. 2018.",
      "doi": "10.1113/JP276431",
      "pmcid": "PMC6187046",
      "url": "https://pubmed.ncbi.nlm.nih.gov/30066368/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30066368/",
      "tier": "A",
      "source_tier": "A",
      "kind": "primary",
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        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-05",
      "status_checked_on": "2026-10-05",
      "study_id": "PMID30066368",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "stressed mice / SCFA supplementation",
      "decisive_perturbation": true,
      "endogenous": false,
      "direction": "mixed",
      "what_it_shows": "SCFA supplementation alleviated selected anhedonia, stress response and permeability changes while weight and some receptor outcomes remained unaffected.",
      "what_it_does_not_show": "Supplementation does not establish endogenous deficiency as the initiating cause; effects were behavioural-test and stress-context specific.",
      "confounders_present": [
        "Supplementation does not establish endogenous deficiency as the initiating cause; effects were behavioural-test and stress-context specific."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
        "retrieved": false,
        "supporting_count": 0,
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        "notable_contrasting_statements": []
      }
    },
    {
      "n": 46,
      "pmid": "25263219",
      "title": "Discovery and characterization of gut microbiota decarboxylases that can produce the neurotransmitter tryptamine.",
      "citation": "Williams BB, Van Benschoten AH, Cimermancic P et al. Discovery and characterization of gut microbiota decarboxylases that can produce the neurotransmitter tryptamine. Cell host & microbe. 2014.",
      "doi": "10.1016/j.chom.2014.09.001",
      "pmcid": "PMC4260654",
      "url": "https://pubmed.ncbi.nlm.nih.gov/25263219/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25263219/",
      "tier": "A",
      "source_tier": "A",
      "kind": "primary",
      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-05",
      "status_checked_on": "2026-10-05",
      "study_id": "PMID25263219",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2"
      ],
      "favors_models": [],
      "evidence_class": "Strong",
      "system": "bacterial genetics / biochemistry",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "positive",
      "what_it_shows": "Two microbial decarboxylases produced tryptamine, establishing a concrete biochemical capacity.",
      "what_it_does_not_show": "No psychiatric phenotype, in vivo brain exposure or clinical mediation was demonstrated.",
      "confounders_present": [
        "No psychiatric phenotype, in vivo brain exposure or clinical mediation was demonstrated."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
        "retrieved": false,
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        "contrasting_count": 0,
        "notable_contrasting_statements": []
      }
    },
    {
      "n": 47,
      "pmid": "31078831",
      "title": "Gut feelings: A randomised, triple-blind, placebo-controlled trial of probiotics for depressive symptoms.",
      "citation": "Chahwan B, Kwan S, Isik A et al. Gut feelings: A randomised, triple-blind, placebo-controlled trial of probiotics for depressive symptoms. Journal of affective disorders. 2019.",
      "doi": "10.1016/j.jad.2019.04.097",
      "pmcid": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/31078831/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31078831/",
      "tier": "A",
      "source_tier": "A",
      "kind": "rct",
      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-05",
      "status_checked_on": "2026-10-05",
      "study_id": "PMID31078831",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human interventional",
      "decisive_perturbation": false,
      "endogenous": true,
      "direction": "mixed",
      "what_it_shows": "A triple-blind trial found nonspecific depressive-symptom improvement, a cognitive-reactivity signal and no significant microbiota change.",
      "what_it_does_not_show": "High attrition and subgroup findings constrain inference; vulnerability measures are not a positive primary depression treatment result.",
      "confounders_present": [
        "High attrition and subgroup findings constrain inference; vulnerability measures are not a positive primary depression treatment 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": []
      }
    },
    {
      "n": 48,
      "pmid": "26052224",
      "title": "Immunomodulatory Effects of Probiotic Supplementation in Schizophrenia Patients: A Randomized, Placebo-Controlled Trial.",
      "citation": "Tomasik J, Yolken RH, Bahn S et al. Immunomodulatory Effects of Probiotic Supplementation in Schizophrenia Patients: A Randomized, Placebo-Controlled Trial. Biomarker insights. 2015.",
      "doi": "10.4137/BMI.S22007",
      "pmcid": "PMC4454091",
      "url": "https://pubmed.ncbi.nlm.nih.gov/26052224/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26052224/",
      "tier": "A",
      "source_tier": "A",
      "kind": "primary",
      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-05",
      "status_checked_on": "2026-10-05",
      "study_id": "NCT01242371",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human secondary RCT biomarkers",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "mixed",
      "what_it_shows": "Schizophrenia probiotic supplementation altered vWF and selected immune proteins, with several only borderline signals.",
      "what_it_does_not_show": "Same NCT01242371 program as the symptom trial; immune markers do not establish a positive PANSS endpoint or mediator necessity.",
      "confounders_present": [
        "Same NCT01242371 program as the symptom trial; immune markers do not establish a positive PANSS endpoint or mediator necessity."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
        "retrieved": false,
        "supporting_count": 0,
        "mentioning_count": 0,
        "contrasting_count": 0,
        "notable_contrasting_statements": []
      }
    },
    {
      "n": 49,
      "pmid": "27871802",
      "title": "Probiotic normalization of Candida albicans in schizophrenia: A randomized, placebo-controlled, longitudinal pilot study.",
      "citation": "Severance EG, Gressitt KL, Stallings CR et al. Probiotic normalization of Candida albicans in schizophrenia: A randomized, placebo-controlled, longitudinal pilot study. Brain, behavior, and immunity. 2017.",
      "doi": "10.1016/j.bbi.2016.11.019",
      "pmcid": "PMC5373951",
      "url": "https://pubmed.ncbi.nlm.nih.gov/27871802/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27871802/",
      "tier": "A",
      "source_tier": "A",
      "kind": "rct",
      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-05",
      "status_checked_on": "2026-10-05",
      "study_id": "NCT01242371",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Weak",
      "system": "human secondary RCT analysis",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "mixed",
      "what_it_shows": "Probiotic allocation reduced Candida antibodies in males, with sex and serostatus dependent bowel and psychiatric trends.",
      "what_it_does_not_show": "Same schizophrenia trial program; trends and subgroup antibody changes cannot replace the null total PANSS result.",
      "confounders_present": [
        "Same schizophrenia trial program; trends and subgroup antibody changes cannot replace the null total PANSS 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": []
      }
    },
    {
      "n": 50,
      "pmid": "24940526",
      "title": "Effect of probiotic supplementation on schizophrenia symptoms and association with gastrointestinal functioning: a randomized, placebo-controlled trial.",
      "citation": "Dickerson FB, Stallings C, Origoni A et al. Effect of probiotic supplementation on schizophrenia symptoms and association with gastrointestinal functioning: a randomized, placebo-controlled trial. The primary care companion for CNS disorders. 2014.",
      "doi": "10.4088/PCC.13m01579",
      "pmcid": "PMC4048142",
      "url": "https://pubmed.ncbi.nlm.nih.gov/24940526/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24940526/",
      "tier": "A",
      "source_tier": "A",
      "kind": "primary",
      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-05",
      "status_checked_on": "2026-10-05",
      "study_id": "NCT01242371",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human interventional",
      "decisive_perturbation": false,
      "endogenous": true,
      "direction": "mixed",
      "what_it_shows": "A schizophrenia trial found no significant PANSS total benefit but less severe bowel difficulty.",
      "what_it_does_not_show": "Somatic benefit does not establish psychosis disease modification; one trial does not exhaust strain-specific possibilities.",
      "confounders_present": [
        "Somatic benefit does not establish psychosis disease modification; one trial does not exhaust strain-specific possibilities."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
        "retrieved": false,
        "supporting_count": 0,
        "mentioning_count": 0,
        "contrasting_count": 0,
        "notable_contrasting_statements": []
      }
    },
    {
      "n": 51,
      "pmid": "28068788",
      "title": "A double-blind, randomized, placebo-controlled trial of Lactobacillus helveticus and Bifidobacterium longum for the symptoms of depression.",
      "citation": "Romijn AR, Rucklidge JJ, Kuijer RG et al. A double-blind, randomized, placebo-controlled trial of Lactobacillus helveticus and Bifidobacterium longum for the symptoms of depression. The Australian and New Zealand journal of psychiatry. 2017.",
      "doi": "10.1177/0004867416686694",
      "pmcid": "PMC5518919",
      "url": "https://pubmed.ncbi.nlm.nih.gov/28068788/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28068788/",
      "tier": "A",
      "source_tier": "A",
      "kind": "rct",
      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-05",
      "status_checked_on": "2026-10-05",
      "study_id": "PMID28068788",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human interventional",
      "decisive_perturbation": false,
      "endogenous": true,
      "direction": "negative",
      "what_it_shows": "An ITT low-mood trial found no probiotic advantage on psychological measures or blood biomarkers.",
      "what_it_does_not_show": "Moderate low mood rather than confirmed MDD constrains scope; suggested responder populations remain untested.",
      "confounders_present": [
        "Moderate low mood rather than confirmed MDD constrains scope; suggested responder populations remain untested."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
        "retrieved": false,
        "supporting_count": 0,
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        "contrasting_count": 0,
        "notable_contrasting_statements": []
      }
    },
    {
      "n": 52,
      "pmid": "35309369",
      "title": "Multi-Omics Analysis Reveals Aberrant Gut-Metabolome-Immune Network in Schizophrenia.",
      "citation": "Fan Y, Gao Y, Ma Q et al. Multi-Omics Analysis Reveals Aberrant Gut-Metabolome-Immune Network in Schizophrenia. Frontiers in immunology. 2022.",
      "doi": "10.3389/fimmu.2022.812293",
      "pmcid": "PMC8927969",
      "url": "https://pubmed.ncbi.nlm.nih.gov/35309369/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35309369/",
      "tier": "A",
      "source_tier": "A",
      "kind": "primary",
      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-05",
      "status_checked_on": "2026-10-05",
      "study_id": "PMID35309369",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human schizophrenia case-control",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "positive",
      "what_it_shows": "Multiomics linked bacteria, metabolites and cytokines and distinguished schizophrenia cases from controls.",
      "what_it_does_not_show": "High AUC does not establish causal direction and can reflect shared confounding or overfitting.",
      "confounders_present": [
        "High AUC does not establish causal direction and can reflect shared confounding or overfitting."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
        "retrieved": false,
        "supporting_count": 0,
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        "notable_contrasting_statements": []
      }
    },
    {
      "n": 53,
      "pmid": "37119525",
      "title": "Multiomics Analyses Reveal Microbiome-Gut-Brain Crosstalk Centered on Aberrant Gamma-Aminobutyric Acid and Tryptophan Metabolism in Drug-Naïve Patients with First-Episode Schizophrenia.",
      "citation": "Wang Z, Yuan X, Zhu Z et al. Multiomics Analyses Reveal Microbiome-Gut-Brain Crosstalk Centered on Aberrant Gamma-Aminobutyric Acid and Tryptophan Metabolism in Drug-Naïve Patients with First-Episode Schizophrenia. Schizophrenia bulletin. 2024.",
      "doi": "10.1093/schbul/sbad026",
      "pmcid": "PMC10754168",
      "url": "https://pubmed.ncbi.nlm.nih.gov/37119525/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37119525/",
      "tier": "A",
      "source_tier": "A",
      "kind": "primary",
      "status_flags": [
        "ErratumIn: PMID37232499"
      ],
      "opened": true,
      "opened_on": "2026-10-05",
      "status_checked_on": "2026-10-05",
      "study_id": "PMID37119525",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "drug-naive first-episode schizophrenia",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "positive",
      "what_it_shows": "Integrated microbiome, metabolome and imaging data associated neurotransmitter pathways with symptoms and genetic risk.",
      "what_it_does_not_show": "Observational mediation is not randomized microbial causation. Linked erratum PMID37232499 is retained; affected numerical claims were not used.",
      "confounders_present": [
        "Observational mediation is not randomized microbial causation. Linked erratum PMID37232499 is retained; affected numerical claims were not used."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
        "retrieved": false,
        "supporting_count": 0,
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        "contrasting_count": 0,
        "notable_contrasting_statements": []
      }
    },
    {
      "n": 54,
      "pmid": "32065949",
      "title": "Alteration of the gut microbiome in first-episode drug-naïve and chronic medicated schizophrenia correlate with regional brain volumes.",
      "citation": "Ma X, Asif H, Dai L et al. Alteration of the gut microbiome in first-episode drug-naïve and chronic medicated schizophrenia correlate with regional brain volumes. Journal of psychiatric research. 2020.",
      "doi": "10.1016/j.jpsychires.2020.02.005",
      "pmcid": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/32065949/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32065949/",
      "tier": "A",
      "source_tier": "A",
      "kind": "primary",
      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-05",
      "status_checked_on": "2026-10-05",
      "study_id": "PMID32065949",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human first-episode / medicated schizophrenia",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "mixed",
      "what_it_shows": "Alpha diversity was lower in chronically medicated but not first-episode drug-naive schizophrenia; both groups showed taxonomic differences.",
      "what_it_does_not_show": "Medication, illness duration and severity are not independently randomized; brain correlations do not establish a microbial initiator.",
      "confounders_present": [
        "Medication, illness duration and severity are not independently randomized; brain correlations do not establish a microbial initiator."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
        "retrieved": false,
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        "notable_contrasting_statements": []
      }
    },
    {
      "n": 55,
      "pmid": "32235826",
      "title": "Metagenome-wide association of gut microbiome features for schizophrenia.",
      "citation": "Zhu F, Ju Y, Wang W et al. Metagenome-wide association of gut microbiome features for schizophrenia. Nature communications. 2020.",
      "doi": "10.1038/s41467-020-15457-9",
      "pmcid": "PMC7109134",
      "url": "https://pubmed.ncbi.nlm.nih.gov/32235826/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32235826/",
      "tier": "A",
      "source_tier": "A",
      "kind": "primary",
      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-05",
      "status_checked_on": "2026-10-05",
      "study_id": "PMID32235826",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1",
        "SC2"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "medication-free schizophrenia / mouse transfer",
      "decisive_perturbation": true,
      "endogenous": false,
      "direction": "positive",
      "what_it_shows": "A metagenomic classifier replicated, and schizophrenia-enriched S. vestibularis induced mouse social and neurotransmitter changes.",
      "what_it_does_not_show": "Human direction remains observational and mouse social deficits are not the full schizophrenia syndrome.",
      "confounders_present": [
        "Human direction remains observational and mouse social deficits are not the full schizophrenia syndrome."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
        "retrieved": false,
        "supporting_count": 0,
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        "contrasting_count": 0,
        "notable_contrasting_statements": []
      }
    },
    {
      "n": 56,
      "pmid": "36005642",
      "title": "The PROVIT Study-Effects of Multispecies Probiotic Add-on Treatment on Metabolomics in Major Depressive Disorder-A Randomized, Placebo-Controlled Trial.",
      "citation": "Kreuzer K, Reiter A, Birkl-Töglhofer AM et al. The PROVIT Study-Effects of Multispecies Probiotic Add-on Treatment on Metabolomics in Major Depressive Disorder-A Randomized, Placebo-Controlled Trial. Metabolites. 2022.",
      "doi": "10.3390/metabo12080770",
      "pmcid": "PMC9414726",
      "url": "https://pubmed.ncbi.nlm.nih.gov/36005642/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36005642/",
      "tier": "A",
      "source_tier": "A",
      "kind": "primary",
      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-05",
      "status_checked_on": "2026-10-05",
      "study_id": "NCT03300440",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1",
        "SC3"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human secondary RCT metabolites",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "mixed",
      "what_it_shows": "PROVIT shifted several stool metabolites, including butyrate, with no significant serum metabolomic changes.",
      "what_it_does_not_show": "Same NCT03300440 trial as the null clinical report; stool target engagement does not establish antidepressant efficacy.",
      "confounders_present": [
        "Same NCT03300440 trial as the null clinical report; stool target engagement does not establish antidepressant efficacy."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
        "retrieved": false,
        "supporting_count": 0,
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        "contrasting_count": 0,
        "notable_contrasting_statements": []
      }
    },
    {
      "n": 57,
      "pmid": "29555994",
      "title": "Extensive impact of non-antibiotic drugs on human gut bacteria.",
      "citation": "Maier L, Pruteanu M, Kuhn M et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature. 2018.",
      "doi": "10.1038/nature25979",
      "pmcid": "PMC6108420",
      "url": "https://pubmed.ncbi.nlm.nih.gov/29555994/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29555994/",
      "tier": "A",
      "source_tier": "A",
      "kind": "primary",
      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-05",
      "status_checked_on": "2026-10-05",
      "study_id": "PMID29555994",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1"
      ],
      "favors_models": [],
      "evidence_class": "Strong",
      "system": "in vitro drug screen",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "positive",
      "what_it_shows": "Many human-targeted drugs inhibited commensal strains, with antipsychotics overrepresented.",
      "what_it_does_not_show": "In vitro susceptibility validates a plausible medication confound, not the size or direction of every in vivo psychiatric association.",
      "confounders_present": [
        "In vitro susceptibility validates a plausible medication confound, not the size or direction of every in vivo psychiatric association."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
        "retrieved": false,
        "supporting_count": 0,
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        "notable_contrasting_statements": []
      }
    },
    {
      "n": 58,
      "pmid": "15133062",
      "title": "Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice.",
      "citation": "Sudo N, Chida Y, Aiba Y et al. Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. The Journal of physiology. 2004.",
      "doi": "10.1113/jphysiol.2004.063388",
      "pmcid": "PMC1664925",
      "url": "https://pubmed.ncbi.nlm.nih.gov/15133062/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/15133062/",
      "tier": "A",
      "source_tier": "A",
      "kind": "primary",
      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-05",
      "status_checked_on": "2026-10-05",
      "study_id": "PMID15133062",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC2"
      ],
      "favors_models": [],
      "evidence_class": "Strong",
      "system": "germ-free / gnotobiotic mice",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "mixed",
      "what_it_shows": "Early colonization and defined organisms altered restraint-induced HPA responses, with timing and bacterial-mutant boundaries.",
      "what_it_does_not_show": "HPA responses are physiological endpoints, not diagnosis; late failure maps development rather than adult treatment inevitability.",
      "confounders_present": [
        "HPA responses are physiological endpoints, not diagnosis; late failure maps development rather than adult treatment inevitability."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
        "retrieved": false,
        "supporting_count": 0,
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        "contrasting_count": 0,
        "notable_contrasting_statements": []
      }
    },
    {
      "n": 59,
      "pmid": "35508109",
      "title": "Microbiota alterations in proline metabolism impact depression.",
      "citation": "Mayneris-Perxachs J, Castells-Nobau A, Arnoriaga-Rodríguez M et al. Microbiota alterations in proline metabolism impact depression. Cell metabolism. 2022.",
      "doi": "10.1016/j.cmet.2022.04.001",
      "pmcid": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/35508109/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35508109/",
      "tier": "A",
      "source_tier": "A",
      "kind": "primary",
      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-05",
      "status_checked_on": "2026-10-05",
      "study_id": "PMID35508109",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1",
        "SC2"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human cohorts / mouse and fly perturbations",
      "decisive_perturbation": true,
      "endogenous": false,
      "direction": "positive",
      "what_it_shows": "Proline-linked human signals were complemented by dietary, transfer, transporter and microbial perturbations in mice and flies.",
      "what_it_does_not_show": "Cross-system convergence supports a bounded pathway; no randomized human proline/microbial prevention or treatment mechanism was tested.",
      "confounders_present": [
        "Cross-system convergence supports a bounded pathway; no randomized human proline/microbial prevention or treatment mechanism was tested."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
        "retrieved": false,
        "supporting_count": 0,
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        "contrasting_count": 0,
        "notable_contrasting_statements": []
      }
    },
    {
      "n": 60,
      "pmid": "34767757",
      "title": "Autism-related dietary preferences mediate autism-gut microbiome associations.",
      "citation": "Yap CX, Henders AK, Alvares GA et al. Autism-related dietary preferences mediate autism-gut microbiome associations. Cell. 2021.",
      "doi": "10.1016/j.cell.2021.10.015",
      "pmcid": "",
      "url": "https://pubmed.ncbi.nlm.nih.gov/34767757/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34767757/",
      "tier": "A",
      "source_tier": "A",
      "kind": "primary",
      "status_flags": [
        "ErratumIn: PMID38242089"
      ],
      "opened": true,
      "opened_on": "2026-10-05",
      "status_checked_on": "2026-10-05",
      "study_id": "PMID34767757",
      "access_depth": "abstract_metadata",
      "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human autism dietary-confounding comparator",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "negative",
      "what_it_shows": "A large metagenomic study supported restricted diet and stool consistency as mediators of ASD microbiome associations, with negligible direct diagnostic associations.",
      "what_it_does_not_show": "Outside registered depression/anxiety/psychosis; informative confounding analogue, not direct refutation of those diseases. Erratum PMID38242089 retained.",
      "confounders_present": [
        "Outside registered depression/anxiety/psychosis; informative confounding analogue, not direct refutation of those diseases. Erratum PMID38242089 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": []
      }
    },
    {
      "n": 61,
      "pmid": "39794490",
      "title": "Medication use is associated with distinct microbial features in anxiety and depression.",
      "citation": "Dilmore AH, Kuplicki R, McDonald D et al. Medication use is associated with distinct microbial features in anxiety and depression. Molecular psychiatry. 2025.",
      "doi": "10.1038/s41380-024-02857-2",
      "pmcid": "PMC12092254",
      "url": "https://pubmed.ncbi.nlm.nih.gov/39794490/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39794490/",
      "tier": "A",
      "source_tier": "A",
      "kind": "primary",
      "status_flags": [
        "UpdateOf: PMID38562901"
      ],
      "opened": true,
      "opened_on": "2026-10-05",
      "status_checked_on": "2026-10-05",
      "study_id": "PMID39794490",
      "access_depth": "full_text_partial",
      "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 3:Discussion:paragraph7, 3:Discussion:paragraph10. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human depression/anxiety cohorts",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "mixed",
      "what_it_shows": "Antidepressant exposure explained more microbial beta-diversity variation than diagnostic status in the studied cohorts.",
      "what_it_does_not_show": "Cross-sectional medication assignment and indication remain confounded; this does not erase diagnosis-associated taxa in other datasets.",
      "confounders_present": [
        "Cross-sectional medication assignment and indication remain confounded; this does not erase diagnosis-associated taxa in other datasets."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
        "retrieved": false,
        "supporting_count": 0,
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        "contrasting_count": 0,
        "notable_contrasting_statements": []
      }
    },
    {
      "n": 62,
      "pmid": "38017662",
      "title": "Gut feelings: the relations between depression, anxiety, psychotropic drugs and the gut microbiome.",
      "citation": "Brushett S, Gacesa R, Vich Vila A et al. Gut feelings: the relations between depression, anxiety, psychotropic drugs and the gut microbiome. Gut microbes. 2023.",
      "doi": "10.1080/19490976.2023.2281360",
      "pmcid": "PMC10730195",
      "url": "https://pubmed.ncbi.nlm.nih.gov/38017662/",
      "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38017662/",
      "tier": "A",
      "source_tier": "A",
      "kind": "primary",
      "status_flags": [
        "none_found"
      ],
      "opened": true,
      "opened_on": "2026-10-05",
      "status_checked_on": "2026-10-05",
      "study_id": "PMID38017662",
      "access_depth": "full_text_partial",
      "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph1, 1:Results:paragraph2, 1:Results:paragraph3. No complete-paper or supplement audit claimed.",
      "relates_to_subclaims": [
        "SC1"
      ],
      "favors_models": [],
      "evidence_class": "Moderate",
      "system": "human Lifelines cohort",
      "decisive_perturbation": false,
      "endogenous": false,
      "direction": "positive",
      "what_it_shows": "Most internalizing-disorder microbial associations survived psychotropic and further GI/diet adjustments, while alpha diversity was not significantly associated.",
      "what_it_does_not_show": "Adjustment does not establish temporality or eliminate residual confounding; the result counters a medication-only explanation without proving a microbial initiator.",
      "confounders_present": [
        "Adjustment does not establish temporality or eliminate residual confounding; the result counters a medication-only explanation without proving a microbial initiator."
      ],
      "verification": "verified",
      "verification_note": "Bounded source attribution; not proof of the nominal mechanism.",
      "citation_context": {
        "retrieved": false,
        "supporting_count": 0,
        "mentioning_count": 0,
        "contrasting_count": 0,
        "notable_contrasting_statements": []
      }
    }
  ],
  "verification_summary": {
    "load_bearing_claims_checked": 66,
    "verified": 66,
    "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": "Human associations recur in independent cohorts, including medication-adjusted analyses, but diversity direction and taxonomic signatures vary. This existence subclaim contains association rather than causation [28,31–32,52–54,61–62].",
      "resulting_ceiling": "Β"
    }
  ],
  "cap_precedence_resolutions": [
    {
      "collision": "Perturbation in a defined setting versus broader inference",
      "subclaim_scope_cap_binds_on": "Gut microbial dysbiosis is an upstream cause of human psychiatric disease, acting through microbial metabolites, immune and vagal pathways, and correction of dysbiosis is disease-modifying.",
      "subclaim_scope_threshold_binds_on": "The precise experimentally tested subclaim scope",
      "resolution": "“A perturbation crosses a threshold within the system it was actually run in. A universal cap governs the inference from that system to the hypothesis’s claimed scope.” Microbiome rubric04 governs transfer and strain function; psychiatry rubric07 governs diagnosis, endpoints and clinical masking. Inert placebo probiotic trials do not inherit an automatic psychedelic unblinding penalty. Rodent immobility alone is a weak human disease proxy, but convergent subtraction and rescue retain their actual model credit. SC3 is below Δ for the registered mechanism and generalization, not because a contributory mechanism must be universally necessary.",
      "note": "Convergent lines are assessed as a set; one weak leg is not re-capped over the assembled case."
    }
  ],
  "boundary_check_BGD": [
    {
      "subclaim_id": "SC1",
      "field_valid_perturbation_quote": "\n- Gnotobiotic or transfer experiment showing phenotype movement, at minimum\n- Even without defined-consortium precision or robust rescue, a transfer paradigm in vivo is the minimum that crosses this threshold\n\nPer **Cap precedence** above, a gnotobiotic or forced-transfer experiment crosses Δ for the recipient-animal subclaim it was actually run in, while universal cap 5 (seeding or forced-transfer paradigms cap at Γ) still blocks the inference from that result to endogenous human biology — score the two scopes separately rather than choosing between the rules.",
      "qualifying_evidence_present": "no",
      "qualifying_evidence_citation": "PMID27491067, PMID27067014, PMID37386523, PMID32235826, PMID35508109",
      "gamma_hard_rules_triggered": [],
      "disease_phenotype_relevance": "yes",
      "perturbation_result_positive": "no",
      "perturbation_result_note": "Human associations recur in independent cohorts, including medication-adjusted analyses, but diversity direction and taxonomic signatures vary. This existence subclaim contains association rather than causation [28,31–32,52–54,61–62].",
      "ceiling_from_boundary_check": "Γ"
    },
    {
      "subclaim_id": "SC2",
      "field_valid_perturbation_quote": "\n- Gnotobiotic or transfer experiment showing phenotype movement, at minimum\n- Even without defined-consortium precision or robust rescue, a transfer paradigm in vivo is the minimum that crosses this threshold\n\nPer **Cap precedence** above, a gnotobiotic or forced-transfer experiment crosses Δ for the recipient-animal subclaim it was actually run in, while universal cap 5 (seeding or forced-transfer paradigms cap at Γ) still blocks the inference from that result to endogenous human biology — score the two scopes separately rather than choosing between the rules.",
      "qualifying_evidence_present": "yes",
      "qualifying_evidence_citation": "PMID27491067, PMID27067014, PMID27315483, PMID38378622, PMID32187541, PMID37131071, PMID31645720, PMID33311466, PMID31231198, PMID35819092, PMID37386523, PMID33594816, PMID35618633, PMID24315484, PMID21876150, PMID35143877, PMID35165440, PMID30522820, PMID30066368, PMID32235826, PMID35508109",
      "gamma_hard_rules_triggered": [],
      "disease_phenotype_relevance": "yes",
      "perturbation_result_positive": "yes",
      "perturbation_result_note": "Defined strains, vagal subtraction, central CB1 blockade and metabolite exposure/rescue establish context-bounded mouse mechanisms. Negative species, developmental and receptor contrasts map boundaries [7,10,39–41,44,58–59].",
      "ceiling_from_boundary_check": "Δ or higher"
    },
    {
      "subclaim_id": "SC3",
      "field_valid_perturbation_quote": "\n- Gnotobiotic or transfer experiment showing phenotype movement, at minimum\n- Even without defined-consortium precision or robust rescue, a transfer paradigm in vivo is the minimum that crosses this threshold\n\nPer **Cap precedence** above, a gnotobiotic or forced-transfer experiment crosses Δ for the recipient-animal subclaim it was actually run in, while universal cap 5 (seeding or forced-transfer paradigms cap at Γ) still blocks the inference from that result to endogenous human biology — score the two scopes separately rather than choosing between the rules.",
      "qualifying_evidence_present": "no",
      "qualifying_evidence_citation": "PMID34875345, PMID29731182, PMID28483500, PMID26706022, PMID35618633",
      "gamma_hard_rules_triggered": [
        "Human mechanistic attribution and the registered generalization remain unresolved despite several positive treatment trials."
      ],
      "disease_phenotype_relevance": "yes",
      "perturbation_result_positive": "no",
      "perturbation_result_note": "Human RCTs include positive, null and analysis-dependent results. Clinical efficacy has scoped causal support, but attribution to the nominated dysbiosis-to-brain pathways and durable disease modification across these diagnoses is unresolved [13–27,47–51].",
      "ceiling_from_boundary_check": "Γ"
    }
  ],
  "thresholds_tested": [
    {
      "subclaim_id": "SC1",
      "threshold": "Δ",
      "requirement_quoted": "Requires a transfer paradigm or causal perturbation in vivo.",
      "satisfied": "no",
      "supporting_evidence": [
        "[1] Depression-donor transfer induced anhedonia and anxiety-like behaviour in microbiota-depleted rats, with tryptophan changes.",
        "[2] MDD microbiota transferred behavioural and metabolic differences to germ-free recipients.",
        "[29] Roseburia intestinalis rescued stress-related mouse behaviour and tryptophan metabolism alongside adolescent microbial associations.",
        "[55] A metagenomic classifier replicated, and schizophrenia-enriched S. vestibularis induced mouse social and neurotransmitter changes.",
        "[59] Proline-linked human signals were complemented by dietary, transfer, transporter and microbial perturbations in mice and flies."
      ],
      "what_would_cross_it": "A causal interpretation would require an amended causal subclaim rather than upgrading descriptive association by sample size."
    },
    {
      "subclaim_id": "SC2",
      "threshold": "Δ",
      "requirement_quoted": "Requires a transfer paradigm or causal perturbation in vivo.",
      "satisfied": "yes",
      "supporting_evidence": [
        "[1] Depression-donor transfer induced anhedonia and anxiety-like behaviour in microbiota-depleted rats, with tryptophan changes.",
        "[2] MDD microbiota transferred behavioural and metabolic differences to germ-free recipients.",
        "[3] Cohousing, transfer and defined commensal reconstitution altered social behaviour and synaptic plasticity after maternal high-fat diet.",
        "[5] Stress-donor microbiota transferred behaviour and complement-associated synaptic abnormalities to recipients.",
        "[6] Transferred microbiota impaired fluoxetine response and neurogenesis; 5-hydroxytryptophan alleviated the deficits.",
        "[7] Vagotomy before stress-donor inoculation abrogated behavioural, neurogenic and inflammatory effects; Methods describe blinded analysis.",
        "[9] Microbial depletion impaired fear extinction, with developmental-window dependence of restoration and altered neuronal activity.",
        "[10] Central eCB enhancement rescued transferred behaviours, central CB1 antagonism blocked rescue, and Lactobacillus complementation restored behavioural and lipid signals.",
        "[11] Acute tryptophan depletion changed the behavioural phenotype and brain serotonin of germ-free mice more strongly than SPF mice.",
        "[12] Roseburia hominis reduced microglial activation and depressive behaviours; SCFA treatments reproduced molecular anti-inflammatory effects.",
        "[29] Roseburia intestinalis rescued stress-related mouse behaviour and tryptophan metabolism alongside adolescent microbial associations.",
        "[34] CCFM1025 but not a comparator B. breve strain improved stress behaviour and produced distinct microbial/metabolic profiles.",
        "[37] A three-strain formula improved depression and GI scores relative to placebo; a separate stress model investigated serotonergic effects.",
        "[38] B. fragilis ameliorated selected behaviours and barrier abnormalities; administration of an elevated metabolite induced behavioural abnormalities.",
        "[39] JB-1 changed stress behaviour and regional GABA receptor expression; effects were absent after vagotomy.",
        "[40] Specific Bacteroides species recapitulated behaviour and neurogenesis effects of MDD-donor transfer, while B. ovatus did not.",
        "[41] Defined 4EP biosynthesis increased 4EPS exposure, altered myelination and anxiety-like behaviour; oligodendrocyte-directed treatment prevented behaviour.",
        "[44] L. reuteri rescued social deficits across models through vagus and oxytocin-receptor dependence, without restoring overall community composition.",
        "[45] SCFA supplementation alleviated selected anhedonia, stress response and permeability changes while weight and some receptor outcomes remained unaffected.",
        "[55] A metagenomic classifier replicated, and schizophrenia-enriched S. vestibularis induced mouse social and neurotransmitter changes.",
        "[59] Proline-linked human signals were complemented by dietary, transfer, transporter and microbial perturbations in mice and flies."
      ],
      "what_would_cross_it": ""
    },
    {
      "subclaim_id": "SC2",
      "threshold": "Ε",
      "requirement_quoted": "Requires context-specific causal effect with defined limits. A transferable phenotype exists, but microbial identity or generalizability remains incomplete.",
      "satisfied": "yes",
      "supporting_evidence": [
        "[1] Depression-donor transfer induced anhedonia and anxiety-like behaviour in microbiota-depleted rats, with tryptophan changes.",
        "[2] MDD microbiota transferred behavioural and metabolic differences to germ-free recipients.",
        "[3] Cohousing, transfer and defined commensal reconstitution altered social behaviour and synaptic plasticity after maternal high-fat diet.",
        "[5] Stress-donor microbiota transferred behaviour and complement-associated synaptic abnormalities to recipients.",
        "[6] Transferred microbiota impaired fluoxetine response and neurogenesis; 5-hydroxytryptophan alleviated the deficits.",
        "[7] Vagotomy before stress-donor inoculation abrogated behavioural, neurogenic and inflammatory effects; Methods describe blinded analysis.",
        "[9] Microbial depletion impaired fear extinction, with developmental-window dependence of restoration and altered neuronal activity.",
        "[10] Central eCB enhancement rescued transferred behaviours, central CB1 antagonism blocked rescue, and Lactobacillus complementation restored behavioural and lipid signals.",
        "[11] Acute tryptophan depletion changed the behavioural phenotype and brain serotonin of germ-free mice more strongly than SPF mice.",
        "[12] Roseburia hominis reduced microglial activation and depressive behaviours; SCFA treatments reproduced molecular anti-inflammatory effects.",
        "[29] Roseburia intestinalis rescued stress-related mouse behaviour and tryptophan metabolism alongside adolescent microbial associations.",
        "[34] CCFM1025 but not a comparator B. breve strain improved stress behaviour and produced distinct microbial/metabolic profiles.",
        "[37] A three-strain formula improved depression and GI scores relative to placebo; a separate stress model investigated serotonergic effects.",
        "[38] B. fragilis ameliorated selected behaviours and barrier abnormalities; administration of an elevated metabolite induced behavioural abnormalities.",
        "[39] JB-1 changed stress behaviour and regional GABA receptor expression; effects were absent after vagotomy.",
        "[40] Specific Bacteroides species recapitulated behaviour and neurogenesis effects of MDD-donor transfer, while B. ovatus did not.",
        "[41] Defined 4EP biosynthesis increased 4EPS exposure, altered myelination and anxiety-like behaviour; oligodendrocyte-directed treatment prevented behaviour.",
        "[44] L. reuteri rescued social deficits across models through vagus and oxytocin-receptor dependence, without restoring overall community composition.",
        "[45] SCFA supplementation alleviated selected anhedonia, stress response and permeability changes while weight and some receptor outcomes remained unaffected.",
        "[55] A metagenomic classifier replicated, and schizophrenia-enriched S. vestibularis induced mouse social and neurotransmitter changes.",
        "[59] Proline-linked human signals were complemented by dietary, transfer, transporter and microbial perturbations in mice and flies."
      ],
      "what_would_cross_it": ""
    },
    {
      "subclaim_id": "SC2",
      "threshold": "Ζ",
      "requirement_quoted": "Requires:\n- Defined consortium or strain-level causal evidence\n- Rescue logic\n- Replication across at least two relevant models or cohorts",
      "satisfied": "no",
      "supporting_evidence": [
        "[1] Depression-donor transfer induced anhedonia and anxiety-like behaviour in microbiota-depleted rats, with tryptophan changes.",
        "[2] MDD microbiota transferred behavioural and metabolic differences to germ-free recipients.",
        "[3] Cohousing, transfer and defined commensal reconstitution altered social behaviour and synaptic plasticity after maternal high-fat diet.",
        "[5] Stress-donor microbiota transferred behaviour and complement-associated synaptic abnormalities to recipients.",
        "[6] Transferred microbiota impaired fluoxetine response and neurogenesis; 5-hydroxytryptophan alleviated the deficits.",
        "[7] Vagotomy before stress-donor inoculation abrogated behavioural, neurogenic and inflammatory effects; Methods describe blinded analysis.",
        "[9] Microbial depletion impaired fear extinction, with developmental-window dependence of restoration and altered neuronal activity.",
        "[10] Central eCB enhancement rescued transferred behaviours, central CB1 antagonism blocked rescue, and Lactobacillus complementation restored behavioural and lipid signals.",
        "[11] Acute tryptophan depletion changed the behavioural phenotype and brain serotonin of germ-free mice more strongly than SPF mice.",
        "[12] Roseburia hominis reduced microglial activation and depressive behaviours; SCFA treatments reproduced molecular anti-inflammatory effects.",
        "[29] Roseburia intestinalis rescued stress-related mouse behaviour and tryptophan metabolism alongside adolescent microbial associations.",
        "[34] CCFM1025 but not a comparator B. breve strain improved stress behaviour and produced distinct microbial/metabolic profiles.",
        "[37] A three-strain formula improved depression and GI scores relative to placebo; a separate stress model investigated serotonergic effects.",
        "[38] B. fragilis ameliorated selected behaviours and barrier abnormalities; administration of an elevated metabolite induced behavioural abnormalities.",
        "[39] JB-1 changed stress behaviour and regional GABA receptor expression; effects were absent after vagotomy.",
        "[40] Specific Bacteroides species recapitulated behaviour and neurogenesis effects of MDD-donor transfer, while B. ovatus did not.",
        "[41] Defined 4EP biosynthesis increased 4EPS exposure, altered myelination and anxiety-like behaviour; oligodendrocyte-directed treatment prevented behaviour.",
        "[44] L. reuteri rescued social deficits across models through vagus and oxytocin-receptor dependence, without restoring overall community composition.",
        "[45] SCFA supplementation alleviated selected anhedonia, stress response and permeability changes while weight and some receptor outcomes remained unaffected.",
        "[55] A metagenomic classifier replicated, and schizophrenia-enriched S. vestibularis induced mouse social and neurotransmitter changes.",
        "[59] Proline-linked human signals were complemented by dietary, transfer, transporter and microbial perturbations in mice and flies."
      ],
      "what_would_cross_it": "Orthogonal microbial gene subtraction and add-back at measured endogenous exposure, with matched behaviour and off-target controls across independent systems."
    },
    {
      "subclaim_id": "SC3",
      "threshold": "Δ",
      "requirement_quoted": "Requires a transfer paradigm or causal perturbation in vivo.",
      "satisfied": "no",
      "supporting_evidence": [
        "[16] Randomized CCFM1025 supplementation improved HDRS and MADRS change relative to placebo and altered serotonin-turnover measures.",
        "[17] Probiotic supplementation improved BDI relative to placebo and prebiotic in MDD; prebiotic benefit and unadjusted mediator ratios were null.",
        "[18] NCC3001 reduced depression scores and altered emotional brain responses in IBS, with no significant anxiety or IBS-symptom benefit.",
        "[23] An MDD randomized probiotic trial reported greater BDI improvement with changes in insulin, hs-CRP and glutathione.",
        "[37] A three-strain formula improved depression and GI scores relative to placebo; a separate stress model investigated serotonergic effects."
      ],
      "what_would_cross_it": "Prospectively registered human psychiatric benefit linked to a specified microbial function by mediator-selective subtraction/add-back or a valid instrument, with durability, replication and diagnosis-specific negative controls."
    }
  ],
  "generalization_check": {
    "generalization_tested": "yes",
    "context_boundary_mapped": "yes",
    "internal_negative_controls": [
      "B. ovatus did not recapitulate the selected Bacteroides effects [40]",
      "Oxytocin-receptor deficiency prevented L. reuteri rescue [44]",
      "Late colonization failed to normalize early HPA programming [58]",
      "PS128, PROVIT and schizophrenia PANSS comparisons were null [15,24,50]"
    ],
    "note": "Animal pathway and timing boundaries are mapped, but human cross-diagnosis mechanism, durability and prevention remain incompletely tested. ASD examples cannot carry the registered human SC3."
  },
  "falsification_patterns_met": [
    {
      "pattern": "Target engagement without clinical advantage",
      "evidence": "PROVIT changed microbiota/stool metabolites without clinical superiority [15,56].",
      "downgrade_applied": false
    },
    {
      "pattern": "Somatic and psychiatric endpoints dissociate",
      "evidence": "Schizophrenia bowel difficulty improved while PANSS did not [50].",
      "downgrade_applied": false
    },
    {
      "pattern": "Community normalization is not required for every microbial treatment effect",
      "evidence": "L. reuteri rescue occurred without community restoration [44].",
      "downgrade_applied": false
    }
  ],
  "pitfalls_flagged": [
    {
      "pitfall": "Therapeutic effect misread as mechanistic proof",
      "where": "Parallel symptom, taxon or metabolite changes in clinical trials [13,16,19,26]."
    },
    {
      "pitfall": "Transferability misread as endogenous human primacy",
      "where": "Recipient depletion and behavioural proxies in donor-transfer experiments [1–2]."
    },
    {
      "pitfall": "Counting overlapping reports as independent trials",
      "where": "Schaub, Nikolova, Rudzki, PROVIT and Dickerson secondary analyses share trial families."
    },
    {
      "pitfall": "Scope fitted to the result",
      "where": "No microbial responder subgroup is adopted after seeing benefit; baseline diagnoses and diet are fixed before outcome."
    }
  ],
  "causal_tally_audit": {
    "tally_claimed_by_document": 25,
    "tally_after_audit": 25,
    "items_rejected": [
      "Null and negative contrasts are discriminators, not positive threshold crossings. Reports and replications are not independent causal lines.",
      "Positive clinical treatment comparisons have treatment-level credit; they are not counted as selective human mediator tests. The decisive flags for broad physiological host-to-gut and HPA endpoints are excluded from psychiatric-mechanism crossings."
    ]
  },
  "steelman": {
    "case_one_rung_higher": "The case for Γ overall is that experimental biology is extensive and SC3 contains randomized human signals, including FMT with engraftment and statistical mediation [19]. This is compelling for the primary-subclaim sensitivity. A literal weakest-link rule, however, cannot promote the associational SC1 by importing SC2 evidence.",
    "case_one_rung_lower": "The case for Α is that human signatures are heterogeneous and several treatments are null [15,24,50–51]. It fails because reproducible adjusted associations exist and negative treatment formulations do not erase them [28,62].",
    "which_rejected": "Retain Β under the registered rule; display Γ as the primary and scope-matched sensitivities. Reject Α because the phenomenon is observed, and reject an undisclosed switch to Γ aggregation. The conjunction design, rather than a generic claim that all microbiome evidence is weak, explains this result.",
    "blocking_cap_threshold_or_missing_experiment": "Missing experiment: Randomize prospectively defined MDD or first-episode psychosis participants to a functionally characterized consortium versus an otherwise matched consortium lacking the nominated microbial enzyme, with an add-back arm, stable medication and diet, and independent multisite replication. Register diagnosis-specific primary endpoints, engraftment, mediator exposure, masking, missing-data policy and follow-up before enrollment."
  },
  "final_score": {
    "hsef_level": "Β",
    "hsef_descriptor": "Associational",
    "confidence": "Moderate",
    "confidence_rationale": "62 primary reports with 7 selected partial-body examinations; density, heterogeneous controls and incomplete access set the confidence, not correctness.",
    "rests_on_non_peer_reviewed_work": false,
    "rationale": "The preregistered weakest-link aggregation returns Β because SC1 is descriptive association. This is a consequence of that conjunction and does not downgrade the demonstrated animal mechanisms to association. Primary-subclaim and scope-matched sensitivities return Γ for SC3. Positive human treatment comparisons warrant causal credit for the tested treatment; they do not alone establish that the specified microbial mechanisms are an upstream general cause. No necessity requirement is imposed on a merely contributory mechanism."
  },
  "role_of_mechanism": {
    "classification": "reinforcing / stabilizing factor",
    "derivation_step_matched": 5,
    "derivation": "Within animal stress-transfer models, microbial manipulation sustains or amplifies phenotypes after an antecedent stress or diet exposure. Human upstream initiation and rate limitation are not established. Brain-to-gut neural perturbations and drug effects demonstrate that direction can also run from host state to microbial ecology [42–43,57].",
    "tournament_used_as_tiebreaker": false,
    "note": "Derived from causal direction, not tournament rank."
  },
  "extended_scoring_MSD": {
    "momentum": {
      "value": "Mechanistic only",
      "artifact": "The 2026 randomized FMT adjunctive MDD study directly perturbs microbial communities and measures symptoms and engraftment [19]. Its null remission contrast and abstract-only access qualify, rather than erase, its causal-test momentum.",
      "justification": "The 2026 randomized FMT adjunctive MDD study directly perturbs microbial communities and measures symptoms and engraftment [19]. Its null remission contrast and abstract-only access qualify, rather than erase, its causal-test momentum."
    },
    "stability": {
      "value": "Stable",
      "trigger": "No specific verified pending result is used to claim Fragile status. A prospectively registered mediator-specific multisite trial could materially change SC3; this is a proposed test, not a known forthcoming readout.",
      "justification": "No specific verified pending result is used to claim Fragile status. A prospectively registered mediator-specific multisite trial could materially change SC3; this is a proposed test, not a known forthcoming readout."
    },
    "divergence": {
      "implied_level": null,
      "implied_level_basis": "No single field-implied level is defensible from conflicting framings.",
      "assessed_level": "Β",
      "gap_in_rungs": null,
      "value": "Contested",
      "justification": "No manufactured field consensus or arithmetic gap."
    },
    "calibration_note": "M/S/D never modify HSEF level or confidence."
  },
  "change_record": {
    "applies": false,
    "prior_level": "Ranking categorical verdict visible; no prior letter used as a target",
    "prior_confidence": null,
    "prior_source": null,
    "derived_before_consulting_prior": false,
    "new_level": "Β",
    "direction": "newly assigned",
    "what_moved_it": "Fresh primary evidence appraisal; not blinded.",
    "divergence_from_other_reviewers": null
  },
  "proposed_decisive_experiments": [
    {
      "name": "Registered boundary experiment",
      "experiment": "Randomize prospectively defined MDD or first-episode psychosis participants to a functionally characterized consortium versus an otherwise matched consortium lacking the nominated microbial enzyme, with an add-back arm, stable medication and diet, and independent multisite replication. Register diagnosis-specific primary endpoints, engraftment, mediator exposure, masking, missing-data policy and follow-up before enrollment.",
      "readout": "Sustained psychiatric symptoms and functioning plus time-resolved microbial function, serum mediator and CNS-relevant target engagement",
      "critical_control": "Matched consortia, off-target and GI symptom controls, credible masking, stable psychotropics, measured diet/transit, randomized mediator function and baseline strata fixed before outcomes",
      "supporting_result": "Benefit follows the nominated microbial function, disappears with selective subtraction and returns with add-back, without being explained by GI comfort or altered drug exposure",
      "falsifying_result": "Adequate target engagement leaves the registered psychiatric endpoint unchanged, or equivalent benefit occurs with the function-deleted comparator"
    }
  ],
  "knowledge_gaps": [
    {
      "name": "Gap 1",
      "statement": "Prospectively registered, mediator-specific human perturbation; statistical mediation should report sequential exchangeability and alternative mediator assumptions.",
      "relevance": "Limits mechanism identification or scope."
    },
    {
      "name": "Gap 2",
      "statement": "Separate symptom benefit from remission, functioning and persistence after treatment withdrawal.",
      "relevance": "Limits mechanism identification or scope."
    },
    {
      "name": "Gap 3",
      "statement": "Recruit diagnosis-specific medication-naive or stable-medication cohorts with measured diet, transit and GI symptoms, rather than adjusting poorly measured confounders.",
      "relevance": "Limits mechanism identification or scope."
    },
    {
      "name": "Gap 4",
      "statement": "Map strain, microbial gene, metabolite exposure and host receptor boundaries; no single alpha-diversity target is justified.",
      "relevance": "Limits mechanism identification or scope."
    },
    {
      "name": "Gap 5",
      "statement": "Obtain complete trial protocols, supplements and correction notices before treating the newest FMT or corrected multiomics reports as decisive publication evidence.",
      "relevance": "Limits mechanism identification or scope."
    }
  ],
  "review_metadata": {
    "review_date": "2026-10-05",
    "reviewer": "Codex",
    "evidence_base_note": "62 primary reports; cutoff 2026-10-05; bounded critical review, not exhaustive systematic review.",
    "literature_tools_available": true,
    "literature_tools_note": "Life Sciences Literature PubMed/Europe PMC; signed-in Consensus browser discovery and indexed full-text extraction; independent checks against original sections. Zero Consensus API calls.",
    "skill_version": "5.3",
    "validator_run": "exact archived v5.3 validator 2.3; see validator.txt",
    "validator_warnings_addressed": "Phenomenon entry was restated as the preregistered causal claim. No real phenomenon is labelled refuted; warning is explicitly justified.",
    "consensus_consistency_audit": "2026-10-09; supplementary provenance/source reconciliation; original grading retained; prior grades visible."
  },
  "is_calibration_entry": {
    "value": false,
    "entry_role": "not_calibration",
    "blind_graded": null,
    "completed_blinded_calibration": false,
    "expected_band_sealed_at": "",
    "target_sha256": "",
    "target_authorship": "not applicable",
    "target_author_saw_review": null,
    "future_run_status": "not prepared",
    "unblinded_reason": "Ranking categorical verdict and index guidance were visible. No completed blinded calibration claimed."
  },
  "upper_ladder_check": {
    "final_level_below_zeta": true,
    "equivalents_considered": [
      {
        "kind": "mendelian_randomization",
        "available": false,
        "why_not_sufficient": "Valid human therapeutic perturbations and natural experiments remain available; unethical disease induction is unnecessary. Clinical symptom RCTs supply treatment-level causal evidence, and animal strain/metabolite/vagal tests support distinct mechanisms. Their convergence is assessed as a set, but no examined set establishes the general upstream human attribution, sustained function and cross-diagnosis prediction needed for the higher thresholds."
      },
      {
        "kind": "natural_experiment",
        "available": true,
        "why_not_sufficient": "Valid human therapeutic perturbations and natural experiments remain available; unethical disease induction is unnecessary. Clinical symptom RCTs supply treatment-level causal evidence, and animal strain/metabolite/vagal tests support distinct mechanisms. Their convergence is assessed as a set, but no examined set establishes the general upstream human attribution, sustained function and cross-diagnosis prediction needed for the higher thresholds."
      },
      {
        "kind": "dose_response_across_populations",
        "available": false,
        "why_not_sufficient": "Valid human therapeutic perturbations and natural experiments remain available; unethical disease induction is unnecessary. Clinical symptom RCTs supply treatment-level causal evidence, and animal strain/metabolite/vagal tests support distinct mechanisms. Their convergence is assessed as a set, but no examined set establishes the general upstream human attribution, sustained function and cross-diagnosis prediction needed for the higher thresholds."
      },
      {
        "kind": "withdrawal_rechallenge",
        "available": false,
        "why_not_sufficient": "Valid human therapeutic perturbations and natural experiments remain available; unethical disease induction is unnecessary. Clinical symptom RCTs supply treatment-level causal evidence, and animal strain/metabolite/vagal tests support distinct mechanisms. Their convergence is assessed as a set, but no examined set establishes the general upstream human attribution, sustained function and cross-diagnosis prediction needed for the higher thresholds."
      },
      {
        "kind": "therapeutic_perturbation_hard_endpoint",
        "available": true,
        "why_not_sufficient": "Valid human therapeutic perturbations and natural experiments remain available; unethical disease induction is unnecessary. Clinical symptom RCTs supply treatment-level causal evidence, and animal strain/metabolite/vagal tests support distinct mechanisms. Their convergence is assessed as a set, but no examined set establishes the general upstream human attribution, sustained function and cross-diagnosis prediction needed for the higher thresholds."
      }
    ],
    "convergence_present": true,
    "cap_reapplied_to_convergent_set": false
  },
  "provenance_header": {
    "sources_total": 62,
    "claims_total": 66,
    "claims_verified": 66,
    "claims_unverified": 0,
    "claims_contradicted": 0,
    "tier_a_sources": 62,
    "generated_by": "Codex; HSEF v5.3",
    "gate_passed": true
  },
  "claims": [
    {
      "id": "C1",
      "text": "Depression-donor transfer induced anhedonia and anxiety-like behaviour in microbiota-depleted rats, with tryptophan changes. Crude transfer and recipient depletion do not identify a microbial mediator or show initiation in the human donors.",
      "carries_number": false,
      "load_bearing_for": [
        "SC1",
        "SC2"
      ],
      "source_ns": [
        1
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C2",
      "text": "MDD microbiota transferred behavioural and metabolic differences to germ-free recipients. Forced-swim immobility is a proxy, and metabolic covariation does not establish the required human mediator.",
      "carries_number": false,
      "load_bearing_for": [
        "SC1",
        "SC2"
      ],
      "source_ns": [
        2
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C3",
      "text": "Cohousing, transfer and defined commensal reconstitution altered social behaviour and synaptic plasticity after maternal high-fat diet. This is a neurodevelopmental model outside the registered human depression, anxiety and psychosis scope.",
      "carries_number": false,
      "load_bearing_for": [
        "SC2"
      ],
      "source_ns": [
        3
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C4",
      "text": "IDO inhibition and microbiota interventions partially rescued stress-associated behaviour and kynurenine abnormalities. Stress is the initiating exposure and the interventions do not isolate one exclusively microbial pathway.",
      "carries_number": false,
      "load_bearing_for": [
        "SC2"
      ],
      "source_ns": [
        4
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C5",
      "text": "Stress-donor microbiota transferred behaviour and complement-associated synaptic abnormalities to recipients. C3/CR3 changes accompany the phenotype; the abstract does not independently resolve every mediator necessity contrast.",
      "carries_number": false,
      "load_bearing_for": [
        "SC2"
      ],
      "source_ns": [
        5
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C6",
      "text": "Transferred microbiota impaired fluoxetine response and neurogenesis; 5-hydroxytryptophan alleviated the deficits. A downstream precursor rescue is not proof that the same pathway initiates human MDD.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2"
      ],
      "source_ns": [
        6
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C7",
      "text": "Vagotomy before stress-donor inoculation abrogated behavioural, neurogenic and inflammatory effects; Methods describe blinded analysis. Subdiaphragmatic vagotomy is physiologically broad; effects and surgical boundaries are within the recipient model.",
      "carries_number": false,
      "load_bearing_for": [
        "SC2"
      ],
      "source_ns": [
        7
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Materials and methods:paragraph3, 1:Materials and methods:paragraph4, 1:Materials and methods:paragraph13, 1:Materials and methods:paragraph18, 2:Results:paragraph9. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C8",
      "text": "Post-weaning colonization reversed myelin-related gene changes in germ-free prefrontal cortex. Molecular and ultrastructural regulation is not a psychiatric clinical endpoint.",
      "carries_number": false,
      "load_bearing_for": [
        "SC2"
      ],
      "source_ns": [
        8
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C9",
      "text": "Microbial depletion impaired fear extinction, with developmental-window dependence of restoration and altered neuronal activity. Fear learning is a defined behavioural function; identified metabolite differences alone do not establish human anxiety disease causation.",
      "carries_number": false,
      "load_bearing_for": [
        "SC2"
      ],
      "source_ns": [
        9
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C10",
      "text": "Central eCB enhancement rescued transferred behaviours, central CB1 antagonism blocked rescue, and Lactobacillus complementation restored behavioural and lipid signals. Some individual contrasts were nonsignificant; downstream rescue narrows this model rather than establishing all human depression causes.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2"
      ],
      "source_ns": [
        10
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph9, 1:Results:paragraph16, 2:Discussion:paragraph4. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C11",
      "text": "Acute tryptophan depletion changed the behavioural phenotype and brain serotonin of germ-free mice more strongly than SPF mice. Depletion is a broad nutritional challenge and germ-free development differs from adult human dysbiosis.",
      "carries_number": false,
      "load_bearing_for": [
        "SC2"
      ],
      "source_ns": [
        11
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C12",
      "text": "Roseburia hominis reduced microglial activation and depressive behaviours; SCFA treatments reproduced molecular anti-inflammatory effects. SCFA molecular rescue is not a demonstrated exclusive mediator of the behavioural effect in humans.",
      "carries_number": false,
      "load_bearing_for": [
        "SC2"
      ],
      "source_ns": [
        12
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C13",
      "text": "HAM-D time-by-group benefit occurred in the compliant mITT sample, while the paper-labelled ITT interaction was nonsignificant; Lactobacillus enrichment correlated with symptoms. The ITT table has 47 completers out of 60 included; adherence exclusions, baseline imbalance and attrition limit inference. Correlation is not randomized mediation.",
      "carries_number": false,
      "load_bearing_for": [
        "SC1",
        "SC3"
      ],
      "source_ns": [
        13
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Patients and methods:paragraph3, 2:Results:paragraph12, 2:Results:paragraph14, 3:Discussion:paragraph1, 1:Patients and methods:paragraph0, 1:Patients and methods:paragraph6, 2:Results:paragraph0, 2:Results:paragraph2, 2:Results:paragraph3, 2:Results:paragraph4, 2:Results:paragraph5, 2:Results:paragraph6. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C14",
      "text": "A masked pilot add-on probiotic trial estimated favourable effects on selected depression and anxiety measures with low attrition. Feasibility and effect-size estimation preceded a definitive efficacy trial; this report does not establish microbial mediator necessity or disease modification.",
      "carries_number": false,
      "load_bearing_for": [
        "SC3"
      ],
      "source_ns": [
        14
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Methods:paragraph0, 1:Methods:paragraph1, 1:Methods:paragraph2, 1:Methods:paragraph3, 1:Methods:paragraph4. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C15",
      "text": "PROVIT changed microbial profiles but clinical outcome measures did not differ from placebo plus biotin. Inpatient treatment improved both arms; microbiome change cannot be substituted for a positive psychiatric endpoint.",
      "carries_number": false,
      "load_bearing_for": [
        "SC1",
        "SC3"
      ],
      "source_ns": [
        15
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 2:3. Results:paragraph5, 2:3. Results:paragraph6, 2:3. Results:paragraph7, 2:3. Results:paragraph10, 2:3. Results:paragraph11, 2:3. Results:paragraph12. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C16",
      "text": "Randomized CCFM1025 supplementation improved HDRS and MADRS change relative to placebo and altered serotonin-turnover measures. Small short-term trial; peripheral turnover and parallel microbial changes do not isolate the cause of benefit or prove durability.",
      "carries_number": true,
      "load_bearing_for": [
        "SC3"
      ],
      "source_ns": [
        16
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C17",
      "text": "Probiotic supplementation improved BDI relative to placebo and prebiotic in MDD; prebiotic benefit and unadjusted mediator ratios were null. Attrition was material and adjusted metabolite associations do not establish a necessary microbial mediator.",
      "carries_number": false,
      "load_bearing_for": [
        "SC3"
      ],
      "source_ns": [
        17
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C18",
      "text": "NCC3001 reduced depression scores and altered emotional brain responses in IBS, with no significant anxiety or IBS-symptom benefit. IBS with mood scores is distinct from primary MDD; fecal community profiles were similar and mediator attribution remains unresolved.",
      "carries_number": true,
      "load_bearing_for": [
        "SC3"
      ],
      "source_ns": [
        18
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C19",
      "text": "Adjunctive randomized FMT improved HAMD-17 reductions at weeks two and eight, without a significant week-eight remission difference; the abstract reports bile-acid mediation analysis. Only abstract accessible; primary endpoint hierarchy, registration timing, missing-data treatment and mediation assumptions cannot be confirmed. Statistical mediation is not mediator manipulation.",
      "carries_number": true,
      "load_bearing_for": [
        "SC3"
      ],
      "source_ns": [
        19
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C20",
      "text": "A pilot MDD FMT trial met feasibility and acceptability targets and reported successful masking checks. The trial was not designed to establish clinical efficacy; exploratory quality-of-life and gastrointestinal outcomes do not establish MDD causation.",
      "carries_number": false,
      "load_bearing_for": [
        "SC3"
      ],
      "source_ns": [
        20
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C21",
      "text": "A secondary analysis found immediate verbal recall and hippocampal activation differences; other cognitive measures were null. Same NCT02957591 cohort as the HAM-D report; low-adherence exclusions and multiple outcomes limit independent causal weight.",
      "carries_number": false,
      "load_bearing_for": [
        "SC3"
      ],
      "source_ns": [
        21
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C22",
      "text": "HN001 allocation lowered postpartum depression and anxiety screening scores. Mood was a secondary outcome of an offspring-eczema trial; screening scores and postpartum prevention do not establish the full psychiatric mechanism.",
      "carries_number": true,
      "load_bearing_for": [
        "SC3"
      ],
      "source_ns": [
        22
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C23",
      "text": "An MDD randomized probiotic trial reported greater BDI improvement with changes in insulin, hs-CRP and glutathione. Multiple biomarkers and short follow-up do not identify a microbial mediator or sustained disease modification.",
      "carries_number": false,
      "load_bearing_for": [
        "SC3"
      ],
      "source_ns": [
        23
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C24",
      "text": "An eight-week PS128 MDD trial found no between-group depression advantage or significant inflammatory, permeability or community changes. Small trial and one formulation do not refute every microbiota pathway; within-arm improvement is not treatment efficacy.",
      "carries_number": true,
      "load_bearing_for": [
        "SC3"
      ],
      "source_ns": [
        24
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C25",
      "text": "LP299v augmentation improved selected cognitive tests and reduced kynurenine among analysed completers. The abstract does not demonstrate depression-score superiority; cognition, kynurenine and mood must remain separate endpoints.",
      "carries_number": true,
      "load_bearing_for": [
        "SC3"
      ],
      "source_ns": [
        25
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C26",
      "text": "The Nikolova cohort follow-up found transient between-group microbial differences and anxiety-associated taxa, with null inflammatory differences. Same NCT03893162 trial as the clinical pilot; within-group richness changes were not superior to placebo and do not prove mediation.",
      "carries_number": false,
      "load_bearing_for": [
        "SC1",
        "SC3"
      ],
      "source_ns": [
        26
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C27",
      "text": "Exploratory metabolomics after LP299v showed changes in acylcarnitines and other metabolites. Same underlying trial as the earlier cognition report; altered metabolite panels are neither independent efficacy replication nor proven causal mediators.",
      "carries_number": true,
      "load_bearing_for": [
        "SC3"
      ],
      "source_ns": [
        27
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C28",
      "text": "Population and validation datasets linked butyrate-producing taxa to quality of life and depression after antidepressant adjustment. Replicated association does not establish direction; predicted neuroactive capacity is not measured brain delivery.",
      "carries_number": false,
      "load_bearing_for": [
        "SC1"
      ],
      "source_ns": [
        28
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C29",
      "text": "Roseburia intestinalis rescued stress-related mouse behaviour and tryptophan metabolism alongside adolescent microbial associations. Human first diagnosis and post-sertraline profiles are observational; mouse rescue is not a randomized adolescent treatment result.",
      "carries_number": false,
      "load_bearing_for": [
        "SC1",
        "SC2"
      ],
      "source_ns": [
        29
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C30",
      "text": "Cultured bacteria produced or used GABA, and human Bacteroides abundance correlated with depression-related brain signatures. Bacterial GABA capacity does not show adequate brain exposure, human mediator necessity or clinical benefit.",
      "carries_number": false,
      "load_bearing_for": [
        "SC1",
        "SC2"
      ],
      "source_ns": [
        30
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C31",
      "text": "MDD samples differed in bacteria, virome and fecal metabolites and yielded a discriminatory marker panel. Classifier performance and coexpression cannot determine initiation or temporal direction.",
      "carries_number": false,
      "load_bearing_for": [
        "SC1"
      ],
      "source_ns": [
        31
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C32",
      "text": "Active MDD had higher alpha diversity and altered taxa, including lower Faecalibacterium linked to severity. Direction of diversity differs from reduced-diversity reports; treatment-response groups and diagnosis do not isolate microbial causation.",
      "carries_number": false,
      "load_bearing_for": [
        "SC1"
      ],
      "source_ns": [
        32
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C33",
      "text": "MDD had energy and lipid metabolic signatures; MR suggested some lipid changes associated with the disease process. The instruments address metabolites rather than a defined microbial mediator; coarse cross-study microbiome links cannot validate dysbiosis-wide causation.",
      "carries_number": false,
      "load_bearing_for": [
        "SC1",
        "SC3"
      ],
      "source_ns": [
        33
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C34",
      "text": "CCFM1025 but not a comparator B. breve strain improved stress behaviour and produced distinct microbial/metabolic profiles. Strain comparisons narrow function but genomic predictions and parallel metabolites do not identify every mediator.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2"
      ],
      "source_ns": [
        34
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C35",
      "text": "IBS discovery/validation cohorts linked tryptophan and serotonin metabolites to depression comorbidity. IBS, diet and transit can influence both mood and stool; this is not primary psychiatric disease randomization.",
      "carries_number": false,
      "load_bearing_for": [
        "SC1"
      ],
      "source_ns": [
        35
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C36",
      "text": "Microbial composition and diversity shifted after symptom improvement under escitalopram. Follow-up was conditioned on improvement; drug exposure, recovery and time are inseparable without an appropriate comparator.",
      "carries_number": false,
      "load_bearing_for": [
        "SC1"
      ],
      "source_ns": [
        36
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C37",
      "text": "A three-strain formula improved depression and GI scores relative to placebo; a separate stress model investigated serotonergic effects. The abstract does not supply complete human design or mediator-subtraction details; mouse mechanisms cannot be substituted for human mediation.",
      "carries_number": false,
      "load_bearing_for": [
        "SC2",
        "SC3"
      ],
      "source_ns": [
        37
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C38",
      "text": "B. fragilis ameliorated selected behaviours and barrier abnormalities; administration of an elevated metabolite induced behavioural abnormalities. Antecedent maternal immune activation and neurodevelopmental outcomes are outside the registered human SC3 scope.",
      "carries_number": false,
      "load_bearing_for": [
        "SC2"
      ],
      "source_ns": [
        38
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C39",
      "text": "JB-1 changed stress behaviour and regional GABA receptor expression; effects were absent after vagotomy. Healthy-mouse stress responses and a broad nerve lesion do not prove human psychiatric onset or generalize to all strains.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2"
      ],
      "source_ns": [
        39
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C40",
      "text": "Specific Bacteroides species recapitulated behaviour and neurogenesis effects of MDD-donor transfer, while B. ovatus did not. Species boundaries are informative; depletion protocols and recipient proxies limit endogenous human inference.",
      "carries_number": false,
      "load_bearing_for": [
        "SC2"
      ],
      "source_ns": [
        40
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C41",
      "text": "Defined 4EP biosynthesis increased 4EPS exposure, altered myelination and anxiety-like behaviour; oligodendrocyte-directed treatment prevented behaviour. Engineered exposure establishes a molecule pathway in mice, not its sufficient concentration or necessity in human anxiety disorders.",
      "carries_number": true,
      "load_bearing_for": [
        "SC2"
      ],
      "source_ns": [
        41
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C42",
      "text": "Neural activation and gland ablation causally linked psychological-state circuits to Lactobacillus and host defence. This directly supports brain-to-gut direction in a mouse pathway; it does not prove that every human microbial association is reactive.",
      "carries_number": false,
      "load_bearing_for": [
        "SC2"
      ],
      "source_ns": [
        42
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C43",
      "text": "Oral SSRI activated gut neural signalling and its tail-suspension effect required intact vagal signalling. Vagal dependence is not specific to microbial mechanisms and does not prove microbes mediate the SSRI benefit.",
      "carries_number": false,
      "load_bearing_for": [
        "SC2"
      ],
      "source_ns": [
        43
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C44",
      "text": "L. reuteri rescued social deficits across models through vagus and oxytocin-receptor dependence, without restoring overall community composition. Strong bounded mechanism outside human SC3; therapeutic action without composition restoration challenges a generic normalization narrative.",
      "carries_number": false,
      "load_bearing_for": [
        "SC2"
      ],
      "source_ns": [
        44
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C45",
      "text": "SCFA supplementation alleviated selected anhedonia, stress response and permeability changes while weight and some receptor outcomes remained unaffected. Supplementation does not establish endogenous deficiency as the initiating cause; effects were behavioural-test and stress-context specific.",
      "carries_number": false,
      "load_bearing_for": [
        "SC2"
      ],
      "source_ns": [
        45
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C46",
      "text": "Two microbial decarboxylases produced tryptamine, establishing a concrete biochemical capacity. No psychiatric phenotype, in vivo brain exposure or clinical mediation was demonstrated.",
      "carries_number": false,
      "load_bearing_for": [
        "SC2"
      ],
      "source_ns": [
        46
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C47",
      "text": "A triple-blind trial found nonspecific depressive-symptom improvement, a cognitive-reactivity signal and no significant microbiota change. High attrition and subgroup findings constrain inference; vulnerability measures are not a positive primary depression treatment result.",
      "carries_number": false,
      "load_bearing_for": [
        "SC1",
        "SC3"
      ],
      "source_ns": [
        47
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C48",
      "text": "Schizophrenia probiotic supplementation altered vWF and selected immune proteins, with several only borderline signals. Same NCT01242371 program as the symptom trial; immune markers do not establish a positive PANSS endpoint or mediator necessity.",
      "carries_number": false,
      "load_bearing_for": [
        "SC3"
      ],
      "source_ns": [
        48
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C49",
      "text": "Probiotic allocation reduced Candida antibodies in males, with sex and serostatus dependent bowel and psychiatric trends. Same schizophrenia trial program; trends and subgroup antibody changes cannot replace the null total PANSS result.",
      "carries_number": false,
      "load_bearing_for": [
        "SC3"
      ],
      "source_ns": [
        49
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C50",
      "text": "A schizophrenia trial found no significant PANSS total benefit but less severe bowel difficulty. Somatic benefit does not establish psychosis disease modification; one trial does not exhaust strain-specific possibilities.",
      "carries_number": false,
      "load_bearing_for": [
        "SC3"
      ],
      "source_ns": [
        50
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C51",
      "text": "An ITT low-mood trial found no probiotic advantage on psychological measures or blood biomarkers. Moderate low mood rather than confirmed MDD constrains scope; suggested responder populations remain untested.",
      "carries_number": false,
      "load_bearing_for": [
        "SC3"
      ],
      "source_ns": [
        51
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C52",
      "text": "Multiomics linked bacteria, metabolites and cytokines and distinguished schizophrenia cases from controls. High AUC does not establish causal direction and can reflect shared confounding or overfitting.",
      "carries_number": false,
      "load_bearing_for": [
        "SC1"
      ],
      "source_ns": [
        52
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C53",
      "text": "Integrated microbiome, metabolome and imaging data associated neurotransmitter pathways with symptoms and genetic risk. Observational mediation is not randomized microbial causation. Linked erratum PMID37232499 is retained; affected numerical claims were not used.",
      "carries_number": false,
      "load_bearing_for": [
        "SC1"
      ],
      "source_ns": [
        53
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C54",
      "text": "Alpha diversity was lower in chronically medicated but not first-episode drug-naive schizophrenia; both groups showed taxonomic differences. Medication, illness duration and severity are not independently randomized; brain correlations do not establish a microbial initiator.",
      "carries_number": false,
      "load_bearing_for": [
        "SC1"
      ],
      "source_ns": [
        54
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C55",
      "text": "A metagenomic classifier replicated, and schizophrenia-enriched S. vestibularis induced mouse social and neurotransmitter changes. Human direction remains observational and mouse social deficits are not the full schizophrenia syndrome.",
      "carries_number": false,
      "load_bearing_for": [
        "SC1",
        "SC2"
      ],
      "source_ns": [
        55
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C56",
      "text": "PROVIT shifted several stool metabolites, including butyrate, with no significant serum metabolomic changes. Same NCT03300440 trial as the null clinical report; stool target engagement does not establish antidepressant efficacy.",
      "carries_number": false,
      "load_bearing_for": [
        "SC1",
        "SC3"
      ],
      "source_ns": [
        56
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C57",
      "text": "Many human-targeted drugs inhibited commensal strains, with antipsychotics overrepresented. In vitro susceptibility validates a plausible medication confound, not the size or direction of every in vivo psychiatric association.",
      "carries_number": false,
      "load_bearing_for": [
        "SC1"
      ],
      "source_ns": [
        57
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C58",
      "text": "Early colonization and defined organisms altered restraint-induced HPA responses, with timing and bacterial-mutant boundaries. HPA responses are physiological endpoints, not diagnosis; late failure maps development rather than adult treatment inevitability.",
      "carries_number": false,
      "load_bearing_for": [
        "SC2"
      ],
      "source_ns": [
        58
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C59",
      "text": "Proline-linked human signals were complemented by dietary, transfer, transporter and microbial perturbations in mice and flies. Cross-system convergence supports a bounded pathway; no randomized human proline/microbial prevention or treatment mechanism was tested.",
      "carries_number": false,
      "load_bearing_for": [
        "SC1",
        "SC2"
      ],
      "source_ns": [
        59
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C60",
      "text": "A large metagenomic study supported restricted diet and stool consistency as mediators of ASD microbiome associations, with negligible direct diagnostic associations. Outside registered depression/anxiety/psychosis; informative confounding analogue, not direct refutation of those diseases. Erratum PMID38242089 retained.",
      "carries_number": false,
      "load_bearing_for": [
        "SC1"
      ],
      "source_ns": [
        60
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C61",
      "text": "Antidepressant exposure explained more microbial beta-diversity variation than diagnostic status in the studied cohorts. Cross-sectional medication assignment and indication remain confounded; this does not erase diagnosis-associated taxa in other datasets.",
      "carries_number": false,
      "load_bearing_for": [
        "SC1"
      ],
      "source_ns": [
        61
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 3:Discussion:paragraph7, 3:Discussion:paragraph10. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "C62",
      "text": "Most internalizing-disorder microbial associations survived psychotropic and further GI/diet adjustments, while alpha diversity was not significantly associated. Adjustment does not establish temporality or eliminate residual confounding; the result counters a medication-only explanation without proving a microbial initiator.",
      "carries_number": false,
      "load_bearing_for": [
        "SC1"
      ],
      "source_ns": [
        62
      ],
      "verification": "verified",
      "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph1, 1:Results:paragraph2, 1:Results:paragraph3. No complete-paper or supplement audit claimed.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "CSC1",
      "text": "Human associations recur in independent cohorts, including medication-adjusted analyses, but diversity direction and taxonomic signatures vary. This existence subclaim contains association rather than causation [28,31–32,52–54,61–62].",
      "carries_number": false,
      "load_bearing_for": [
        "SC1"
      ],
      "source_ns": [
        1,
        2,
        13,
        15,
        26,
        28,
        29,
        30,
        31,
        32,
        33,
        35,
        36,
        47,
        52,
        53,
        54,
        55,
        56,
        57,
        59,
        60,
        61,
        62
      ],
      "verification": "verified",
      "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "CSC2",
      "text": "Defined strains, vagal subtraction, central CB1 blockade and metabolite exposure/rescue establish context-bounded mouse mechanisms. Negative species, developmental and receptor contrasts map boundaries [7,10,39–41,44,58–59].",
      "carries_number": false,
      "load_bearing_for": [
        "SC2"
      ],
      "source_ns": [
        1,
        2,
        3,
        4,
        5,
        6,
        7,
        8,
        9,
        10,
        11,
        12,
        29,
        30,
        34,
        37,
        38,
        39,
        40,
        41,
        42,
        43,
        44,
        45,
        46,
        55,
        58,
        59
      ],
      "verification": "verified",
      "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "CSC3",
      "text": "Human RCTs include positive, null and analysis-dependent results. Clinical efficacy has scoped causal support, but attribution to the nominated dysbiosis-to-brain pathways and durable disease modification across these diagnoses is unresolved [13–27,47–51].",
      "carries_number": false,
      "load_bearing_for": [
        "SC3"
      ],
      "source_ns": [
        13,
        14,
        15,
        16,
        17,
        18,
        19,
        20,
        21,
        22,
        23,
        24,
        25,
        26,
        27,
        33,
        37,
        47,
        48,
        49,
        50,
        51,
        56
      ],
      "verification": "verified",
      "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.",
      "verified_on": "2026-10-05",
      "note": ""
    },
    {
      "id": "CH",
      "text": "Microbes causally influence defined animal behaviours, and some human adjunctive trials report benefit. A general upstream, disease-modifying microbial cause of depression, anxiety and psychosis remains unestablished.",
      "carries_number": false,
      "load_bearing_for": [
        "SC3"
      ],
      "source_ns": [
        7,
        10,
        13,
        19,
        50,
        62
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