Bariatric surgery, such as vertical sleeve gastrectomy (VSG), is currently the most effective long-term treatment for obesity and results in a ~70% remission rate of type 2 diabetes (T2DM), often occurring within days to weeks after surgery before significant weight loss. In addition, bariatric surgery decreases the lifetime risk of developing cancer, including colorectal cancer (CRC). The mechanism(s) by which this occurs remain elusive. Our understanding of the mechanisms by which bariatric surgery decreases CRC risk has been severely limited by the lack of an appropriate preclinical rodent model. Bariatric procedures, such as VSG, result in elevated circulating bile acid concentrations and metabolically beneficial hydrophilic shifts in circulating bile acid profiles which contribute to the metabolic benefits of bariatric surgery. TGR5 is a bile acid receptor central to mediating the metabolic benefits of bile acids. TGR5 maintains glucose homeostasis, decreases inflammatory cytokine secretion and protects against inflammatory bowel disease. Downstream signaling components of TGR5 are increased after bariatric surgery in humans. Our preliminary data show that TGR5 signaling contributes to the body weight-independent glucoregulatory benefits of VSG by promoting hydrophilic shifts in the circulating bile acid pool. Importantly, increased bile acid hydrophobicity is associated with CRC development in humans and promotes colonic inflammation, colonic ER stress and systemic insulin resistance, all of which are risk factors for CRC development. Our preliminary data show body weight-independent reductions in colonic inflammation, ER stress and decreased Wnt/β-catenin/APC signaling in VSG-operated mice. Therefore, we hypothesize that VSG surgery reduces the incidence of CRC through hydrophilic bile acid-mediated reductions in colonic insulin resistance, inflammation and ER stress. In Aim 1 we will determine the efficacy of VSG to interfere with an inflammatory protumorigenic environment for CRC and the contribution of TGR5-mediated hydrophilic shifts in the circulating bile acid pool to this effect using an azoxymethane/dextran sodium sulphate (AOM/DSS) induced Tgr5+/+ and Tgr5-/- mouse model of CRC. To this end histology, insulin sensitivity, ER stress signaling and inflammatory signaling will be assessed. Since the gut microbiome plays a key role in modulating bile acid pool composition, colonic bile acid profiles and microbial populations will be assessed. RNAseq will be performed on colon mucosa samples to identify novel therapeutic targets. In Aim 2 we will determine the efficacy of VSG to interfere with tumorigenesis and metastasis and the contribution of TGR5-mediated hydrophilic shifts in the circulating bile acid pool to this effect in human CRC cells using an orthotopic Tgr5+/+ and Tgr5-/- mouse model. Our proposed work has the potential to identify the mechanisms by which bariatric surgery decreases the risk of CRC, so that non-surgical therapies that pharmacologically mimic the effect of bariatric surgery to decrease the risk of CRC can be developed.