Several lines of evidence have implicated stress in the endoplasmic reticulum (ER stress) of intestinal cells to the pathogenesis of IBD. ER stress is a common feature in tissues from individuals with IBD, and mutations in genes in ER homeostasis are risk factors for both ulcerative colitis and Crohn’s disease. In animal models, genetic deletion of factors required for resolution of ER stress sensitizes to intestinal inflammation or results in spontaneous inflammation, whereas chemical mitigation of ER stress protects from inflammation. Overall, it is clear that unresolved ER stress can both cause and exacerbate intestinal inflammation. It remains largely unknown, however, what factors trigger ER stress, especially in the context of IBD pathogenesis in humans. Our project will evaluate roles of the human microbiome in regulation of ER stress in human cells and the contribution of such roles to the pathogenesis of IBD. Our goal is to define causal roles of the human microbiome in IBD and to lay the groundwork for the development of novel diagnostics and therapeutics.