Akkermansia muciniphila alleviates endoplasmic reticulum stress via activation of farnesoid X receptors in colitis

Endoplasmic reticulum (ER) stress-related mucin depletion could be involved in the pathogenesis of inflammatory bowel disease (IBD). 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% 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. 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 with the highest VIP (Variable Importance in Projection) scores, significantly increased by A. muciniphila, was synthesized from acetic acid which could cause ER stress. A. muciniphila supplementation decrease the abundance of Parasutterella, which showed the potential role in bile acid maintenance. A. muciniphila supplementation protected colon shortening, histological injury in wild-type (WT) mice but not in farnesoid X receptor-null (FXR-/-) mice. Our results suggest that A. muciniphila supplementation alleviates DSS-induced colitis involvement of the IRE1α/XBP1 ER stress pathway via FXR axis activation. A. muciniphila supplementation in appropriate dose might extend the therapeutic benefit for the treatment of UC.