Alterations in the gut microbiota have been associated with many autoimmune and inflammatory diseases including type 1 diabetes (T1D). It is postulated that microbial dysbiosis can perturb normal immune development and increase autoimmune responses. It is not known whether T1D associated microbial alterations are caused by altered environmental exposures or whether genetically driven host factors may also contribute. We have investigated changes in the intestinal environment linked to alterations in the microbiota in both the NOD mouse model of T1D and using stool samples from T1D patients and first-degree relatives at risk of developing disease. We have found that NOD mice have a significantly different microbiota and signs of inflammation and perturbations in both the ileum and colon compared with disease protected mice. Specific T1D associated genetic loci were found to contribute to these changes, supporting a role for host genetics in establishing a T1D associated microbiota. Using a novel proteomic approach, we now demonstrate alterations in both human gut derived and bacterial derived proteins in stool samples from T1D patients and in individuals at high-risk of developing disease. These findings are a first step in understanding the interrelationship between gut microbiota, host intestinal responses and T1D risk.