Changes in the gut microbiota has been implicated in the pathogenesis of many autoimmune conditions including type 1 diabetes (T1D). We performed an analysis of associations between the gut microbiota and T1D genetic risk using a mouse model of T1D. We studied T1D susceptible NOD mice from five colonies and identified a core NOD microbiome independent of animal house and distinct from disease protected B6 mice. We demonstrate that disease protective alleles at the Idd3/5 (IL2, Ctla4, Slc11a1 and Acadl) but not MHC loci, which mediate profound protection from T1D, are associated with disruption of the NOD core microbiome. Comparison of the intestine of type 1 diabetes susceptible NOD mice with protected strains revealed subclinical pathology in the NOD intestine including increased immune cell infiltrates and reduced goblet cell mucous production, which were partly corrected by protective alleles of the Idd3/5 loci. Immunotherapeutic administration of interleukin-2, mimicking the effects of the protective Idd3 allele, was able to reduce gut inflammation and increase goblet cell mucous production in NOD mice and shift the microbiota. Analysis of a human cohort of 1392 healthy individuals with matched gut microbiota and genetic profiling revealed that increased genetic risk of T1D was also associated with suggestive alterations in the microbiota. These findings demonstrate for the first time that T1D associated genetic variants that restore immune tolerance to islet antigens also result in functional changes in the gut immune system and resultant changes in the microbiota.