Akkermansia muciniphila outer membrane protein Amuc_0904 modulates intestinal homeostasis by promoting goblet cell differentiation

Akkermansia muciniphila is recognized as a promising probiotic that improves the symptoms of a variety of diseases. However, the role and mechanism of A. muciniphila in regulating intestinal homeostasis remain to be explored. Here, we discovered that A. muciniphila was dramatically increased during colitis recovery, and its colonization greatly increased goblet cells to protect the intestinal barrier in mice. Amuc_0904, a previously uncharacterized A. muciniphila outer membrane protein, was identified to induce goblet cell differentiation. Mechanistically, Amuc_0904 directly interacted with MET and decreased its phosphorylation in epithelia, leading to decreased Wnt/β-catenin signaling and enhanced oxidative phosphorylation and mitochondrial function. Furthermore, Amuc_0904 and engineered probiotic Escherichia coli Nissle 1917 expressing Amuc_0904 were demonstrated to protect mice from colitis and colitis-associated colorectal cancer. The study reveals a previously unknown mechanism of A. muciniphila-mediated intestinal homeostasis recovery and provides a bioactive molecule with the potential to treat intestinal disorders.