{
  "cutoff": "2026-10-09",
  "note": "Selected publication milestones, not an exhaustive history or discovery priority claim.",
  "milestones": [
    {
      "pmid": "11297958",
      "year": "2001",
      "title": "Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial.",
      "doi": "10.1016/S0140-6736(00)04259-8",
      "url": "https://pubmed.ncbi.nlm.nih.gov/11297958/",
      "interpretation": "A defined perinatal probiotic regimen tests eczema prevention."
    },
    {
      "pmid": "18806780",
      "year": "2008",
      "title": "Innate immunity and intestinal microbiota in the development of Type 1 diabetes.",
      "doi": "10.1038/nature07336",
      "url": "https://pubmed.ncbi.nlm.nih.gov/18806780/",
      "interpretation": "Microbiota and host genotype interact in experimental autoimmune diabetes."
    },
    {
      "pmid": "22442383",
      "year": "2012",
      "title": "Microbial exposure during early life has persistent effects on natural killer T cell function.",
      "doi": "10.1126/science.1219328",
      "url": "https://pubmed.ncbi.nlm.nih.gov/22442383/",
      "interpretation": "Neonatal versus adult colonization distinguishes an immune-development window in mice."
    },
    {
      "pmid": "26424567",
      "year": "2015",
      "title": "Early infancy microbial and metabolic alterations affect risk of childhood asthma.",
      "doi": "10.1126/scitranslmed.aab2271",
      "url": "https://pubmed.ncbi.nlm.nih.gov/26424567/",
      "interpretation": "Early microbial taxa link human risk observations with recipient-mouse airway experiments."
    },
    {
      "pmid": "27518660",
      "year": "2016",
      "title": "Innate Immunity and Asthma Risk in Amish and Hutterite Farm Children.",
      "doi": "10.1056/NEJMoa1508749",
      "url": "https://pubmed.ncbi.nlm.nih.gov/27518660/",
      "interpretation": "Amish–Hutterite observations combine with contrasting dust perturbations in mice."
    },
    {
      "pmid": "27133167",
      "year": "2016",
      "title": "Variation in Microbiome LPS Immunogenicity Contributes to Autoimmunity in Humans.",
      "doi": "10.1016/j.cell.2016.04.007",
      "url": "https://pubmed.ncbi.nlm.nih.gov/27133167/",
      "interpretation": "Different bacterial LPS signals link human cohorts with NOD-mouse experiments."
    },
    {
      "pmid": "35930838",
      "year": "2022",
      "title": "A Placebo-controlled double-blinded test of the biodiversity hypothesis of immune-mediated diseases: Environmental microbial diversity elicits changes in cytokines and increase in T regulatory cells in young children.",
      "doi": "10.1016/j.ecoenv.2022.113900",
      "url": "https://pubmed.ncbi.nlm.nih.gov/35930838/",
      "interpretation": "Daycare biodiversity intervention tests immune and microbiome markers."
    },
    {
      "pmid": "42705251",
      "year": "2026",
      "title": "Use of the bacterial lysate OM-85 for the primary prevention of wheezing lower respiratory illness in preschool children: a randomised, placebo-controlled trial.",
      "doi": "10.1016/S0140-6736(26)01443-1",
      "url": "https://pubmed.ncbi.nlm.nih.gov/42705251/",
      "interpretation": "ORBEX reports a null clinical primary outcome after bacterial-lysate treatment."
    }
  ],
  "gaps": [
    "Microbial quality, amount, route and timing are distinct exposures, not one hygiene variable.",
    "Human autoimmune clinical prevention remains a separate missing causal branch.",
    "Positive eczema effects do not consistently extend to sensitization, food allergy or asthma.",
    "Clinical effects may occur without durable microbial engraftment or diversity change; the mediator needs identification.",
    "Environmental soil interventions need disease-incidence follow-up beyond immune biomarkers.",
    "Shared cohort/trial reports and post-hoc genotype/delivery subgroups require prospective independent validation."
  ],
  "decisive_experiment": "Register microbial-factor/consortium restoration in an objectively baseline-defined infant population, with credible placebo, measured exposure/engagement and immune mediation. Prespecify clinical eczema, asthma and separately powered autoimmune endpoints, retain all randomized participants, and independently replicate dose/window and host-genotype predictions. Include antigen/diet/barrier and infection-indication controls."
}