Gut microbiota-related mechanisms that impact colorectal cancer risk after bariatric surgery

Bariatric surgery, currently the most effective treatment for morbid obesity, has become increasingly common in the US. Besides substantial and sustained weight loss, bariatric surgery leads to dramatic changes in many aspects of human physiology, including glycemic control, bile acid metabolism, immunosurveillance, and gut microbiota. These changes, if sustained after surgery, may affect the risk of colorectal cancer (CRC). On one hand, reduced obesity, insulin resistance, and systemic inflammation may lower CRC risk; meanwhile, increased exposures to some bile acids (e.g., ursodeoxycholic acid) and beneficial bacteria (e.g., Akkermansia muciniphila & Faecalibacterium prausnitzii) may also lower CRC risk. On the other hand, increased exposures to other bile acids (e.g., deoxycholic acid) and bacteria (e.g., aerotolerant species) may increase CRC risk after bariatric surgery. While the interplays of gut microbiota with host metabolism & immunity have been implicated in CRC etiology, it is unclear what sustained changes in gut microbiota are induced by bariatric surgery and how post-surgery “gut microbiota-host interactions” may impact CRC risk. Longitudinal studies with repeated collections of biospecimens (e.g., blood & stool) and patient data (e.g., diet & medication) are needed to tackle these questions but currently lacking. ●Building on a longitudinal cohort of bariatric surgery patients, we propose to investigate, in Aim 1 (targeted evaluation): pre- to 1-year and 3-years post-surgery changes in potential CRC-related bacteria (e.g., Fusobacterium nucleatum, enterotoxigenic B. fragilis, & pks+ E. coli), major microbial metabolites (e.g., bile acids & short-chain fatty acids), and established markers of systemic and microbial inflammation (e.g., C-reactive protein & LPS-binding protein); in Aim 2 (omics-wide discovery): the most significantly and consistently altered bacteria, microbial metabolites, and inflammatory & immune response proteins at 1- and 3-years post- vs. pre-surgery, using shotgun metagenomics, global metabolomics, and proteomics; in Aim 3 (in vivo experiments): the causality and molecular mechanisms of post- vs. presurgery gut microbiota in CRC carcinogenesis. We will perform fecal microbiota transplant (FMT) on antibiotictreated, genetic mouse models of CRC using preserved pre- and 3-years post-surgery stools and compare adenoma/tumor burden, colonocyte biology, and systemic & intestinal inflammation between those groups and with mice receiving a group of bacteria with the largest and consistent post-surgery increases as identified in Aim 2 and with control. ●Leveraging a longitudinal cohort of bariatric surgery patients and applying state-ofthe-art multi-omics and FMT in pre-clinical models, our study will fill research gaps regarding sustained postbariatric surgery changes in gut microbiota and microbial molecules and how they contribute to patients' metabolic, inflammatory, and immunological profiles, and eventually CRC risk. Our results may translate into better patient advice on post-surgery gut health and CRC risk and novel therapies targeting gut microbiota, microbial molecules, and/or immunosurveillance to reduce CRC risk among individuals with morbid obesity.