Akkermansia Muciniphila Alleviates Severe Acute Pancreatitis via Amuc1409-Ube2k-Foxp3 Axis in Regulatory T Cells

Severe acute pancreatitis (SAP) is a critical condition characterized by an imbalance between systemic inflammatory response syndrome (SIRS) and compensatory anti-inflammatory response syndrome (CARS). Disruptions in intestinal microbiota exacerbate this imbalance; however, the mechanisms by which commensal bacteria regulate SAP-induced SIRS and/or CARS remain unclear. This study reports that the abundance of the gut commensal Akkermansia is significantly reduced in fecal samples from patients with acute pancreatitis (AP) and is inversely associated with the severity of systemic inflammatory responses. Using Foxp3-DTR and IL-10-KO mice, it is found that Akkermansia muciniphila and its derived protein Amuc_1409 can suppress SAP-induced pancreatic and systemic inflammation by increasing peripheral regulatory T cells (Tregs) and enhancing the IL-10 expression. Mechanistically, Amuc_1409 interacts with Ube2k to reduce the ubiquitination degradation of Foxp3, and it promotes the differentiation of Tregs and the production of IL-10, effectively alleviating inflammation induced by SAP. These findings highlight A. muciniphila and its derivative Amuc_1409 as promising probiotic and biomolecule for managing acute pancreatitis and potentially other inflammatory conditions.