GPX3 IS REQUIRED TO MEDIATE PROTECTIVE EFFECTS OF GPX1 LOSS IN COLITIS

Abstract Reactive oxygen species (ROS) have long been known to contribute the development and severity of Inflammatory Bowel Disease. However, more recent data indicates ROS may not always be pathogenic, in fact necessary for intestinal homeostasis. Thus, role intestine, antioxidant proteins which regulate ROS, contextual dose-dependent. Members glutathione peroxidase (GPx) family are antioxidants that reduce hydrogen peroxide water. Previously, we determined loss GPx1, most widely expressed GPx, protected against dextran sodium sulfate (DSS)-induced colitis augmented proliferation. To better understand how a stepwise increase affect phenotypes, Gpx1-/- mice were next crossed with Gpx3 null yield double-knockout (DKO) mice. First, assessed baseline proliferation, apoptosis, DNA damage colon. Interestingly, while displayed increased proliferation compared WT mice, this was observed DKO Furthermore, had no change apoptosis or damage, yet both Together, these suggest lose survival benefits GPx1 upon greater reduction capabilities. Next, effects combined GPx3 context inflammation colitis. At baseline, multiplex cytokine profiling identified higher levels colitis-associated cytokines, including IL-12, CCL4, CCL5, as either cohorts. Pro-inflammatory changes pronounced aging, one-year-old showed TNF-α IL-17, well histologic evidence chronic absent similarly aged tested experimental DSS Here, less severe injury model, weight trend towards shortened colons Finally, altered ROS-mediated signaling is impact interactions microbiota, microbial diversity associated protection from establish whether impacted gut microbiome, stool harvested WT, Gpx1-/-, bacterial by 16S RNA sequencing. line colitis, evenness whereas there between Taken together, indicate required mediate anti-inflammatory loss. combinatorial GPx induces colonic at during DSS-induced highlighting dose-dependent capacity intestine.