<i>Akkermansia muciniphila</i> outer membrane protein Amuc_0904 modulates intestinal homeostasis by promoting goblet cell differentiation

<i>Akkermansia muciniphila</i> is recognized as a promising probiotic that improves the symptoms of a variety of diseases. However, the role and mechanism of <i>A. muciniphila</i> in regulating intestinal homeostasis remain to be explored. Here, we discovered that <i>A. muciniphila</i> 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 <i>A. muciniphila</i> 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 <i>Escherichia coli</i> 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 <i>A. muciniphila</i>-mediated intestinal homeostasis recovery and provides a bioactive molecule with the potential to treat intestinal disorders.