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

Abstract 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.