Gastrointestinal Infections Modulate the Risk for Insulin Autoantibodies as the First-Appearing Autoantibody in the TEDDY Study

OBJECTIVE To investigate gastrointestinal infection episodes (GIEs) in relation to the appear-ance of islet autoantibodies in The Environmental Determinants of Diabetes in the Young (TEDDY) cohort. RESEARCH DESIGN AND METHODS GIEs on risk of autoantibodies against either insulin (IAA) or GAD (GADA) as the first-appearing autoantibody were assessed in a 10-year follow-up of 7,867 children. Stool virome was characterized in a nested case-control study. RESULTS GIE reports (odds ratio [OR] 2.17 [95% CI 1.39–3.39]) as well as Norwalk viruses found in stool (OR 5.69 [1.36–23.7]) at <1 year of age were associated with an increased IAA risk at 2–4 years of age. GIEs reported at age 1 to <2 years correlated with a lower risk of IAA up to 10 years of age (OR 0.48 [0.35–0.68]). GIE reports at any other age were associated with an increase in IAA risk (OR 2.04 for IAA when GIE was observed 12–23 months prior [1.41–2.96]). Impacts on GADA risk were limited to GIEs <6 months prior to autoantibody development in children <4 years of age (OR 2.16 [1.54–3.02]). CONCLUSIONS Bidirectional associations were observed. GIEs were associated with increased IAA risk when reported before 1 year of age or 12–23 months prior to IAA. Nor-walk virus was identified as one possible candidate factor. GIEs reported during the 2nd year of life were associated with a decreased IAA risk.