{
  "slug": "gut-microbiome-systemic-causality",
  "title": "Gut microbial community composition as a primary systemic cause",
  "claim": "In humans, prespecified changes in gut microbial community composition are primary upstream causes of disease across distant-organ disease classes.",
  "update_date": "2026-10-05",
  "search_cutoff": "2026-10-05",
  "framework_for_addendum": "HSEF v5.3 causal distinctions",
  "historical_scorecard_schema": "5.4",
  "regraded": false,
  "status": "curated_local_addendum",
  "full_academic_review_complete": false,
  "summary": "Microbiota can causally influence systemic phenotypes in defined models and selected human settings. Engraftment, clinical benefit and disease initiation remain different claims; positive and null FMT studies prevent a universal intervention narrative.",
  "timeline": [
    {
      "year": "2010",
      "source_id": "P20620945",
      "design": "Gnotobiotic arthritis model",
      "finding": "A defined commensal species restored Th17-related autoimmunity and arthritis in susceptible mice.",
      "limit": "Host genotype and immune context are part of the demonstrated causal system.",
      "historical_anchor_only": false
    },
    {
      "year": "2012",
      "source_id": "P22728514",
      "design": "Randomized lean-donor transfer in metabolic syndrome",
      "finding": "Insulin sensitivity improved at six weeks after allogenic transfer.",
      "limit": "Short-term metabolic response is not proof that dysbiosis initiated common metabolic disease.",
      "historical_anchor_only": false
    },
    {
      "year": "2013",
      "source_id": "P24009397",
      "design": "Obesity-discordant twin microbiota in mice",
      "finding": "Donor-related adiposity phenotypes and diet-dependent rescue were transmissible.",
      "limit": "Recipient environment and diet condition the transfer phenotype.",
      "historical_anchor_only": false
    },
    {
      "year": "2015",
      "source_id": "P26633628",
      "design": "Human metagenomic medication analysis",
      "finding": "Metformin-associated signals were separated from diabetes-associated microbial signatures.",
      "limit": "Observed disease signatures can partly reflect treatment; correction notice retained.",
      "historical_anchor_only": false
    },
    {
      "year": "2017",
      "source_id": "P28978426",
      "design": "Metabolic-syndrome FMT trial",
      "finding": "Short-term insulin-sensitivity response depended on baseline microbiota and was not sustained at 18 weeks.",
      "limit": "Responder prediction and durability require independent prospective testing.",
      "historical_anchor_only": false
    },
    {
      "year": "2020",
      "source_id": "P32150549",
      "design": "FMT-TRIM randomized placebo-controlled trial",
      "finding": "Engraftment occurred without clinically significant metabolic effects during follow-up.",
      "limit": "Microbial target engagement is insufficient to assume systemic efficacy.",
      "historical_anchor_only": false
    },
    {
      "year": "2024",
      "source_id": "P38686220",
      "design": "GUT-PARFECT Parkinson trial",
      "finding": "A mild long-term motor benefit was reported after donor FMT.",
      "limit": "Small phase-2 study and specific comparator do not establish universal efficacy.",
      "historical_anchor_only": false
    },
    {
      "year": "2024",
      "source_id": "P39073834",
      "design": "Independent Parkinson FMT randomized trial",
      "finding": "FMT did not produce clinically meaningful improvement.",
      "limit": "Donor, bowel preparation and outcome differences need direct comparison, not selective citation.",
      "historical_anchor_only": false
    },
    {
      "year": "2025",
      "source_id": "P39800192",
      "design": "THEMATIC cirrhosis randomized trial",
      "finding": "FMT was tolerated; recurrence patterns suggested benefit on a secondary outcome.",
      "limit": "Secondary and post hoc contrasts must retain their analysis status.",
      "historical_anchor_only": false
    },
    {
      "year": "2025",
      "source_id": "P40316655",
      "design": "Human obesity-donor transfer to chow-fed mice",
      "finding": "Microbial/metabolite differences appeared without reproducing metabolic or behavioural obesity phenotypes.",
      "limit": "A bounded transfer null does not erase effects under other diets or host conditions.",
      "historical_anchor_only": false
    }
  ],
  "gaps": [
    {
      "id": "G1",
      "question": "Which host, donor and dietary context determines efficacy?",
      "source_ids": [
        "P24009397",
        "P28978426",
        "P32150549",
        "P40316655"
      ],
      "alternative": "Microbial functions may require permissive host ecology or dietary substrate.",
      "discriminating_test": "Factorial donor/function-by-diet testing with colonization measures; prespecified host phenotypes and independent recipient replication.",
      "gap_type": "bounded_causal_uncertainty",
      "interpretation": "An unresolved inference or scope limit in the checked evidence, not a claim that no relevant study exists anywhere."
    },
    {
      "id": "G2",
      "question": "Does engraftment deliver a durable systemic effect?",
      "source_ids": [
        "P22728514",
        "P28978426",
        "P32150549"
      ],
      "alternative": "Stool compositional change may lack functional relevance or fade before clinical benefit.",
      "discriminating_test": "Longer randomized studies with function/metabolites, metabolic outcomes and post-treatment follow-up; define target engagement before outcome analysis.",
      "gap_type": "bounded_causal_uncertainty",
      "interpretation": "An unresolved inference or scope limit in the checked evidence, not a claim that no relevant study exists anywhere."
    },
    {
      "id": "G3",
      "question": "What explains opposing Parkinson trial results?",
      "source_ids": [
        "P38686220",
        "P39073834"
      ],
      "alternative": "Comparator activity, bowel cleansing, donor properties or measurement choices may create apparent disagreement.",
      "discriminating_test": "Harmonized multisite trial with matched preparation, sham expectations, donor characterization and common motor/nonmotor endpoints.",
      "gap_type": "bounded_causal_uncertainty",
      "interpretation": "An unresolved inference or scope limit in the checked evidence, not a claim that no relevant study exists anywhere."
    },
    {
      "id": "G4",
      "question": "Does a microbial change initiate disease or modify an established disease?",
      "source_ids": [
        "P20620945",
        "P26633628",
        "P39800192",
        "P32150549"
      ],
      "alternative": "Medication, transit, inflammation or disease can generate the microbial signature.",
      "discriminating_test": "Prospective pre-onset cohorts plus randomized disease-stage interventions and time-ordered mediator analysis; control treatment, diet and transit.",
      "gap_type": "bounded_causal_uncertainty",
      "interpretation": "An unresolved inference or scope limit in the checked evidence, not a claim that no relevant study exists anywhere."
    }
  ],
  "source_cards": [
    {
      "id": "P20620945",
      "pmid": "20620945",
      "doi": "10.1016/j.immuni.2010.06.001",
      "title": "Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/20620945/",
      "issue_year": "2010",
      "electronic_date": "",
      "access_depth": "abstract_excerpt_checked",
      "checked_details": "Primary record and selected abstract passages checked; no complete-paper appraisal credited.",
      "publication_types": [
        "Journal Article",
        "Research Support, N.I.H., Extramural"
      ],
      "correction_notices": [],
      "cohort_note": "No independence claim made; cohort identity beyond the cited report was not exhaustively audited.",
      "baseline_access_depth": "abstract_metadata",
      "complete_paper_examined_in_this_update": false
    },
    {
      "id": "P22728514",
      "pmid": "22728514",
      "doi": "10.1053/j.gastro.2012.06.031",
      "title": "Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/22728514/",
      "issue_year": "2012",
      "electronic_date": "2012-06-20",
      "access_depth": "abstract_excerpt_checked",
      "checked_details": "Primary record and selected abstract passages checked; no complete-paper appraisal credited.",
      "publication_types": [
        "Journal Article",
        "Randomized Controlled Trial",
        "Research Support, Non-U.S. Gov't"
      ],
      "correction_notices": [
        {
          "type": "ErratumIn",
          "pmid": "",
          "note": ""
        }
      ],
      "cohort_note": "No independence claim made; cohort identity beyond the cited report was not exhaustively audited.",
      "baseline_access_depth": "abstract_metadata",
      "complete_paper_examined_in_this_update": false,
      "notice_check_scope": "Linked notice presence was checked in the primary record; its scientific impact was not verified in this update."
    },
    {
      "id": "P24009397",
      "pmid": "24009397",
      "doi": "10.1126/science.1241214",
      "title": "Gut microbiota from twins discordant for obesity modulate metabolism in mice.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/24009397/",
      "issue_year": "2013",
      "electronic_date": "",
      "access_depth": "abstract_excerpt_checked",
      "checked_details": "Primary record and selected abstract passages checked; no complete-paper appraisal credited.",
      "publication_types": [
        "Journal Article",
        "Research Support, N.I.H., Extramural",
        "Research Support, Non-U.S. Gov't",
        "Twin Study"
      ],
      "correction_notices": [],
      "cohort_note": "No independence claim made; cohort identity beyond the cited report was not exhaustively audited.",
      "baseline_access_depth": "abstract_metadata",
      "complete_paper_examined_in_this_update": false
    },
    {
      "id": "P26633628",
      "pmid": "26633628",
      "doi": "10.1038/nature15766",
      "title": "Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/26633628/",
      "issue_year": "2015",
      "electronic_date": "2015-12-02",
      "access_depth": "abstract_excerpt_checked",
      "checked_details": "Primary record and selected abstract passages checked; no complete-paper appraisal credited.",
      "publication_types": [
        "Journal Article",
        "Research Support, Non-U.S. Gov't"
      ],
      "correction_notices": [
        {
          "type": "ErratumIn",
          "pmid": "28470190",
          "note": ""
        }
      ],
      "cohort_note": "No independence claim made; cohort identity beyond the cited report was not exhaustively audited.",
      "baseline_access_depth": "abstract_metadata",
      "complete_paper_examined_in_this_update": false,
      "notice_check_scope": "Linked notice presence was checked in the primary record; its scientific impact was not verified in this update."
    },
    {
      "id": "P28978426",
      "pmid": "28978426",
      "doi": "10.1016/j.cmet.2017.09.008",
      "title": "Improvement of Insulin Sensitivity after Lean Donor Feces in Metabolic Syndrome Is Driven by Baseline Intestinal Microbiota Composition.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/28978426/",
      "issue_year": "2017",
      "electronic_date": "",
      "access_depth": "abstract_excerpt_checked",
      "checked_details": "Primary record and selected abstract passages checked; no complete-paper appraisal credited.",
      "publication_types": [
        "Journal Article"
      ],
      "correction_notices": [],
      "cohort_note": "No independence claim made; cohort identity beyond the cited report was not exhaustively audited.",
      "baseline_access_depth": "abstract_metadata",
      "complete_paper_examined_in_this_update": false
    },
    {
      "id": "P32150549",
      "pmid": "32150549",
      "doi": "10.1371/journal.pmed.1003051",
      "title": "Fecal microbiota transplantation for the improvement of metabolism in obesity: The FMT-TRIM double-blind placebo-controlled pilot trial.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/32150549/",
      "issue_year": "2020",
      "electronic_date": "2020-03-09",
      "access_depth": "full_text_partial",
      "checked_details": "Methods and engraftment Results: clamp M-value was the primary metabolic measure at six weeks; engraftment varied and persisted. Primary abstract reports no clinically significant metabolic effect.",
      "publication_types": [
        "Journal Article",
        "Randomized Controlled Trial",
        "Research Support, N.I.H., Extramural",
        "Research Support, Non-U.S. Gov't"
      ],
      "correction_notices": [],
      "cohort_note": "No independence claim made; cohort identity beyond the cited report was not exhaustively audited.",
      "baseline_access_depth": "abstract_metadata",
      "complete_paper_examined_in_this_update": false
    },
    {
      "id": "P38686220",
      "pmid": "38686220",
      "doi": "10.1016/j.eclinm.2024.102563",
      "title": "Safety and efficacy of faecal microbiota transplantation in patients with mild to moderate Parkinson's disease (GUT-PARFECT): a double-blind, placebo-controlled, randomised, phase 2 trial.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/38686220/",
      "issue_year": "2024",
      "electronic_date": "2024-03-27",
      "access_depth": "abstract_excerpt_checked",
      "checked_details": "Primary record and selected abstract passages checked; no complete-paper appraisal credited.",
      "publication_types": [
        "Journal Article"
      ],
      "correction_notices": [],
      "cohort_note": "No independence claim made; cohort identity beyond the cited report was not exhaustively audited.",
      "baseline_access_depth": "full_text_complete",
      "complete_paper_examined_in_this_update": false
    },
    {
      "id": "P39073834",
      "pmid": "39073834",
      "doi": "10.1001/jamaneurol.2024.2305",
      "title": "Fecal Microbiota Transplantation for Treatment of Parkinson Disease: A Randomized Clinical Trial.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/39073834/",
      "issue_year": "2024",
      "electronic_date": "",
      "access_depth": "abstract_excerpt_checked",
      "checked_details": "Primary record and selected abstract passages checked; no complete-paper appraisal credited.",
      "publication_types": [
        "Journal Article",
        "Multicenter Study",
        "Randomized Controlled Trial"
      ],
      "correction_notices": [],
      "cohort_note": "No independence claim made; cohort identity beyond the cited report was not exhaustively audited.",
      "baseline_access_depth": "abstract_metadata",
      "complete_paper_examined_in_this_update": false
    },
    {
      "id": "P39800192",
      "pmid": "39800192",
      "doi": "10.1016/j.jhep.2024.12.047",
      "title": "Microbiota transplant for hepatic encephalopathy in cirrhosis: The THEMATIC trial.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/39800192/",
      "issue_year": "2025",
      "electronic_date": "2025-01-10",
      "access_depth": "abstract_excerpt_checked",
      "checked_details": "Primary record and selected abstract passages checked; no complete-paper appraisal credited.",
      "publication_types": [
        "Journal Article",
        "Randomized Controlled Trial",
        "Clinical Trial, Phase II"
      ],
      "correction_notices": [],
      "cohort_note": "No independence claim made; cohort identity beyond the cited report was not exhaustively audited.",
      "baseline_access_depth": "abstract_metadata",
      "complete_paper_examined_in_this_update": false
    },
    {
      "id": "P40316655",
      "pmid": "40316655",
      "doi": "10.1038/s41598-025-99047-z",
      "title": "Fecal transplantation from humans with obesity to mice drives a selective microbial signature without impacting behavioral and metabolic health.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/40316655/",
      "issue_year": "2025",
      "electronic_date": "2025-05-02",
      "access_depth": "abstract_excerpt_checked",
      "checked_details": "Primary record and selected abstract passages checked; no complete-paper appraisal credited.",
      "publication_types": [
        "Journal Article"
      ],
      "correction_notices": [],
      "cohort_note": "No independence claim made; cohort identity beyond the cited report was not exhaustively audited.",
      "baseline_access_depth": "abstract_metadata",
      "complete_paper_examined_in_this_update": false
    }
  ],
  "access_counts": {
    "full_text_partial": 1,
    "abstract_excerpt_checked": 9,
    "metadata_only": 0
  },
  "browser_messages": 2,
  "targeted_check": {
    "pmid": "32150549",
    "provider_access": "selected primary full-text passages reported by Consensus",
    "independent_primary_body_crosscheck": true,
    "verification_scope": "Methods and engraftment Results: clamp M-value was the primary metabolic measure at six weeks; engraftment varied and persisted. Primary abstract reports no clinically significant metabolic effect."
  },
  "editorial_warning": "",
  "reading_limit": "This focused addendum does not establish 50–70 complete primary Methods/Results examinations per review. Baseline reading receipts and scores retain their original scope.",
  "method": "Case-specific Consensus records assisted gap discovery, chronology and targeted paper questions. Shared template wording about an amyloid-specific Deep follow-up is not evidence of a Deep run for this topic; the dated source records establish the actual use and access limits. Primary identifiers, selected abstract passages, correction notices and available primary-body passages were cross-checked. Generated absence cells, duplicate milestones and unsupported access claims were rejected."
}