Akkermansia muciniphila NND9 Mitigates Ulcerative Colitis by Ameliorating the Gut Barrier via Suppressing DR5...

Ulcerative colitis (UC) is a type of inflammatory bowel disease without curative therapeutics. Recent studies demonstrate that Akkermansia muciniphila exerts mitigating effects on UC, but the underlying mechanisms remain unclear. In this study, we isolated a strain of A. muciniphila, designated NND9, from the feces of DSS-induced ulcerative colitis model mice and investigated its effects on UC of the mouse model. NND9 significantly alleviated UC severity in the mice by restoring gut barrier integrity through improving colonic mucus layer thickness, mitigating goblet cell depletion, and halting epithelial cell death. Mechanistically, NND9 suppressed the expression of the Tnfrsf10b gene encoding death receptor 5 (DR5) on the surface of colonic epithelial cells. Additionally, NND9 inhibited the phosphorylation of kinase 3 (RIPK3) and the pseudokinase mixed-lineage kinase domain-like protein (MLKL) associated with the necrotic apoptosis pathway, thereby reducing gut epithelial cell death. NND9 also markedly ameliorated the gut microbiome of the colitis mice. Untargeted metabolomics analysis demonstrated that NND9 modulated both tryptophan and bile acid metabolism. In conclusion, NND9 exhibits curative effects on UC by resolving inflammatory reactions of the gut mucosa through the DR5-RIPK3/p-RIPK3-MLKL/p-MLKL pathway and redressing gut dysbiosis. This study provides valuable information for the development of innovative therapeutic strategies for the treatment of UC.