PROJECT SUMMARY/ABSTRACT Microscopic colitis (MC) is a chronic inflammatory disorder of the large intestine with a rising global incidence. MC primarily affects older adults, in whom it accounts for a significant proportion of cases of chronic diarrhea and fecal incontinence. The growing burden of the disease is primarily thought to be related to its increased recognition, an aging population and polypharmacy. Yet, the exact etiology remains largely unknown. This proposal will expand upon emerging evidence from our group and others that medications such as proton pump inhibitors (PPIs), non-steroidal anti-inflammatory drugs (NSAIDs) and exogenous hormone use are associated with increased risk of MC and that among patients with chronic diarrhea, the gut microbiota in active MC is characterized by dysbiosis and unique compositional and functional changes. Our central hypothesis is that the pathogenesis of MC is, at least in part, related to pharmacologic-induced perturbations in the aging gut microbiota. To test this hypothesis, we have assembled the first nationwide gastrointestinal histopathology cohort, with a validated definition for MC (n = 14,000) and over 20 years of follow up as well as a highly- phenotyped colonoscopy-based cohort (n = 1600) with detailed questionnaires and biobanking of blood and stool samples. Our specific aims include: 1) identification of key pharmacologic determinants of MC (Aim 1); 2) identifying novel microbial signatures of MC in older adults with chronic diarrhea (Aim 2); 3) characterizing the structure and function of the gut microbiota according to MC disease activity (Aim 2); 4) identifying microbial communities and metabolites that mediate the relationship between medication-related risk factors and MC (Aim 3). The proposed work will have significant clinical and mechanistic implications. First, current guidelines recommend discontinuing “potential” pharmacologic triggers as an adjunct therapy, particularly in recurrent or refractory disease. However, as this approach may lead to unnecessary discontinuation of important medications such as antihypertensive and lipid-lowering drugs, that have been linked to MC in some studies, findings from our high quality pharmacoepidemiologic studies could directly inform clinical guidelines. Second, the results of our microbiome studies could provide valuable data on use of gut microbiota signatures as a non-invasive biomarker for diagnosing MC in older adults with chronic diarrhea. Lastly, the proposed work is significant as it enhances our fundamental understanding of the relationship between commonly prescribed medications, the aging gut microbiota, and gut inflammation in older adults. The proposal is innovative in its assembly of high- level multidisciplinary team with complementary set of expertise and use of start-of-the-art computational methods to characterize the relationship between medications and the gut microbiota in MC. Given the aging U.S. population, the gr...