Intestinal epithelial Axin1 deficiency protects against colitis via altered gut microbiota

Abstract

Background and AimsIntestinal homeostasis is maintained by specialized host cells and the gut microbiota. Wnt/{beta}-catenin signaling is essential for gastrointestinal development and homeostasis, and its dysregulation has been implicated in inflammation and colorectal cancer. Axin1 negatively regulates activated Wnt/{beta}-catenin signaling, but little is known regarding its role in regulating host-microbial interactions in health and disease. Here, we aim to demonstrate that intestinal Axin1 determines gut homeostasis and host response to inflammation. MethodsThe expression of Axin1 was analyzed in human IBD datasets. To explore the effects and mechanism of intestinal Axin1 in regulating intestinal homeostasis and colitis, we generated mouse models with Axin1 conditional knockout in intestinal epithelial (Axin1{Delta}IEC) and Paneth cells (Axin1{Delta}PC) to compare with control (Axin1LoxP) mice. ResultsWe found increased Axin1 expression in the colonic epithelium of human IBD. Axin1{Delta}IEC mice exhibited altered goblet cell spatial distribution, Paneth cell morphology, reduced lysozyme expression, and enriched Akkermansia muciniphila. Absence of intestinal epithelial and Paneth cell Axin1 decreased susceptibility to DSS-induced colitis in vivo. Axin1{Delta}IEC and Axin1{Delta}PC became more susceptible to DSS-colitis after cohousing with control mice, suggesting the non-colitogenic effect is driven by the gut microbiota. ConclusionWe found loss of intestinal Axin1 protects against colitis, which is likely driven through Paneth cell Axin1 and the microbiota. Our study demonstrates a novel role of Axin1 in mediating intestinal homeostasis and the microbiota. Further mechanistic studies using specific Axin1 mutations elucidating how Axin1 modulates microbiome and host inflammatory response, will provide new therapeutic strategies for human IBD. What you Need to Know1. Background and ContextWnt/beta-catenin is a fundamental molecular pathway that affects intestinal proliferation and differentiation. Axin1 negatively regulates activated Wnt/{beta}-catenin signaling, but little is known regarding its role in the microbiome. Dysfunction of Wnt/beta-catenin was reported in human inflammatory bowel disease (IBD) and Axin1 serum level was elevated in patients with UC. 2. New FindingsWe found increased Axin1 expression at both the mRNA and protein level in human IBD. Specifically, we identified increased Axin1 expression positive correlated with pro-inflammatory cytokines IL-6 and TNF- in CD. Our study, for the first time, identifies links between the gut microbiota and intestinal Axin1 in intestinal inflammation through utilization of innovative deletion mouse models in intestinal epithelium and Paneth cells. Loss of intestinal Axin1 plays a novel role in intestinal inflammation by altering the Paneth cells and microbiome (e.g., enriched Akkermansia mucinlphila). Our study has provided insights into the molecular mechanism that might contribute to IBD, especially the novel role of Paneth cell Axin1 in colitis. 3. LimitationsThere are no human or mice studies assessing the role of intestinal epithelial and Paneth cell Axin1 in inflammation and the microbiome. 4. ImpactFurther explorations of the gut microbiota and Axin1 interaction as we report will provide novel mechanistic strategies for therapeutic approaches for human IBD by targeting intestinal Axin1 and Axin1-associated microbiome.