Akkermansia muciniphila alleviates colonic epithelial endoplasmic reticulum stress through activation of farnesoid X receptors in murine experimental colitis

Abstract

Abstract Background Endoplasmic reticulum (ER) stress-related mucin depletion could be involved in the pathogenesis of inflammatory bowel disease (IBD). Akkermansia muciniphila (A. muciniphila), a symbiotic bacterium of the mucus layer, 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. Methods Colitis was induced by adding 2.5% 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. UHPLC high-resolution orbitrap mass spectrometry-based metabolomic analyses were performed on faeces. 16S rRNA sequencing were used to quantify and characterize the gut microbiota of mice and human. Colons were collected from mice and analyzed by histopathology, quantitative PCR and immunofluorescence. Colon biopsies from the patients with ulcerative colitis (UC) and controls were collected and analyzed by immunohistochemistry. Results Metabolite pathway enrichment analysis demonstrated that colitis-affected metabolites after A. muciniphila supplementation were mainly enriched in mineral absorption, bile secretion and protein digestion and absorption. P-hydroxyphenyl acetic acid, which showed the highest VIP scores, was significantly increased by A. muciniphila, and could cause ER stress. A. muciniphila supplementation changed the relative abundance and composition of intestinal microbiotaespecially a decrease inParasutterella, which showed the potential role in bile acid maintenance. A. muciniphila supplementation protected colon shortening, histological injury, intestinal inflammation and barrier damage in wild-type (WT) mice but not in farnesoid X receptor-null (FXR−/−) mice. Mechanistically, A. muciniphila supplementation activated FXR/SHP signaling, which directly increased X-box binding protein-1 splicing (XBP1s) and phosphorylated inositol requiring enzyme 1α (p-IRE1α) expression, and in turn formed XBP1s-SHP regulatory loop in response to ER stress. We further showed that the abundance of A. muciniphila in faeces from UC patients positively correlates with p-IRE1α expression. Conclusions Our results suggest that A. muciniphila supplementation alleviates DSS-induced colitis involvement of the IRE1α/XBP1 ER stress pathway via FXR/SHP axis activation.