<i>Akkermansia muciniphila</i> alleviates experimental colitis through FXR-mediated repression of unspliced XBP1

ABSTRACT Endoplasmic reticulum (ER) stress-related mucin depletion could be involved in the pathogenesis of ulcerative colitis (UC). Akkermansia muciniphila (A. muciniphila ) uses mucin as its sole energy source and shows potential in the treatment of colitis. However, the effects and underlying mechanisms of A. muciniphila on colonic epithelial ER stress in colitis are largely unknown. Colitis was induced by adding 2.5% dextran sulfate sodium (DSS) in drinking water. Mice were orally administered A. muciniphila (3*10 ^ 7, 3*10 ^ 8 cfu/day) once daily for 10 days during DSS intervention. Ultra high performance liquid chromatography q-exactive orbitrap high-resolution mass spectrometry (UHPLC-Q-Orbitrap-HRMS)-based metabolomic analyses were performed on feces. 16S rRNA sequencing was used to quantify and characterize the gut microbiota of mice. Metabolomic analysis showed that P-hydroxyphenyl acetic acid (p-HPAA), the metabolite with the highest variable importance in projection (VIP) score that was elevated by A. muciniphila , was negatively correlated with acetic acid levels and exhibited a potential inhibitory effect on ER stress. Additionally, A. muciniphila supplementation decreases the abundance of Parasutterella, a genus implicated in bile acid homeostasis. By restoring the levels of deoxycholic (DCA) and ursodeoxycholic acid (UDCA), A. muciniphila administration normalized the bile acid pool size and composition altered by colitis. A. muciniphila supplementation protected colon shortening and histological injury in wild-type (WT) mice, but not in farnesoid X receptor-null (FXR −/− ) mice. Mechanistically, our results demonstrate that A. muciniphila alleviates DSS-induced colitis by targeting inositol requiring enzyme 1α(IRE1α) and unspliced XBP1 (XBP1u) within the ER stress pathway, with the regulation of XBP1u being FXR-dependent. Supplementation with A. muciniphila at appropriate doses may, thus, offer a promising therapeutic strategy for Ulcerative colitis (UC). IMPORTANCE UC is a chronic inflammatory disease in which inflammation begins in the rectum and extends proximally throughout the colon. A.muciniphia is significantly reduced in UC patients and shows promise as a next-generation probiotic. However, the mechanisms behind its protective effects are not fully understood. Our study reveals that A. muciniphila alleviates experimental colitis by reshaping the gut microbiome and correcting imbalances in bile acid metabolism. Crucially, we identify a novel mechanism where A. muciniphila acts through the host bile acid receptor FXR to suppress a specific ER stress pathway (XBP1u) in colon cells, thereby helping to restore the intestinal barrier. These findings provide a scientific basis for using A. muciniphila as a targeted therapeutic strategy for UC.