Tissue Specific Function of Intestinal Epithelial Axin 1 in Gut and Microbial Homeostasis

Gut homeostasis is maintained by the constituents of the intestinal ecosystem, including epithelial and immune cell populations and the resident microbiota. Wnt/β-catenin is a crucial signaling pathway required to maintain intestinal homeostasis, and its dysregulation is implicated in colorectal cancers and intestinal inflammation. However, much is still unknown regarding its role in regulating the gut microbiome. Axin1 is a scaffold protein that negatively regulates activated Wnt/β-catenin signaling and is upregulated in the serum of ulcerative colitis and endometriosis patients. Our previous data has shown that Axin1 plays a distinct role in Salmonella infection in vitro. However, the role of intestinal Axin1 signaling in maintaining mucosal health and the microbiome has not been elucidated. Here, we identified the upregulation of intestinal Axin1 in human inflammatory bowel diseases. To explore the effects and mechanism of intestinal Axin1 in regulating intestinal homeostasis and inflammation, we generated two novel mouse models with conditional knockout of Axin1 in intestinal epithelial (Axin1∆IEC) and Paneth (Axin1∆PC) cells to compare with control (Axin1LoxP) mice. Axin1∆IEC mice have increased Wnt/β-catenin signaling, altered goblet and Paneth cell morphology, and increased Akkermansia muciniphila. Axin1 deficiency in intestinal epithelial and Paneth cells decreased susceptibility to DSS-induced colitis. Furthermore, we demonstrate a novel role of Paneth cell specific Axin1 in inflammation and the microbiome and a therapeutic function of Axin1-associated Akkermansia muciniphila in an IBD model. We also explore the tissue-specific deletion of Axin1 in regulating the gut microbiota in our Axin1∆IEC, Axin1∆PC, and myeloid specific Axin1(Axin1∆Lyz) knockout models. We found that all Axin1 conditional knockout mice have alterations in Ruminococcaceae, Lachnospiraceae NK4A136, and Muribaculaceae and changes in bacterial genes associated with DNA repair, xenobiotic metabolism, and environmental processing. Lastly, we show evidence that loss of intestinal epithelial Axin1 enriched Odoribacter and Clostidales in Axin1∆IEC female mice, leading to susceptibility to diet-induced obesity and metabolic dysfunction. This thesis presents new roles of Axin1 in regulating microbial and intestinal homeostasis. Elucidating the mechanisms behind Axin1 regulation of the intestinal mucosa will help develop novel therapeutics for treating IBD and other intestinal disorders.