Akkermansia muciniphila‐Derived N‐Acetylspermidine Modulates the Localization of Intestinal α1,2‐Fucosylated Proteins to Maintain Gut Homeostasis

The growing incidence of inflammatory bowel diseases, including colitis and Crohn's disease, poses a critical challenge for global healthcare. Current development of α1,2-fucosylation-enhancing strategies shows significant potential as a colitis treatment modality by promoting gut homeostasis. Although certain probiotics alleviate colitis by enhancing intestinal α1,2-fucosylation, the molecular mechanisms by which probiotics-derived metabolites modulate this process remain unclear. This study found that the probiotic Akkermansia muciniphila (A. muciniphila) enhanced intestinal α1,2-fucosylation, a crucial factor contributing to its colitis-alleviating effects. Specifically, A. muciniphila-derived N-acetylspermidine upregulated α1,2-fucosylation, thereby enhancing barrier integrity and suppressing inflammation, which are reversed upon α1,2-fucosylation inhibition. Mechanistically, N-acetylspermidine upregulated HDAC2 via PIM1 inhibition, leading to decreased chromatin accessibility at the TP73 locus, subsequently increasing the expression of α1,2-fucosylation-associated gene C1GALT1C1. Furthermore, N-acetylspermidine-induced α1,2-fucosylation enhancement facilitated the membrane localization of ZO-1 and ZO-2, while suppressing C3 secretion, both of which contributed to colitis alleviation. Together, our findings elucidate how A. muciniphila and its metabolite N-acetylspermidine regulate intestinal α1,2-fucosylation to maintain gut homeostasis and highlight their therapeutic potential in developing biological therapies for colitis.