Gut Microbiota-Derived Riboflavin Mediates Protective Effects of MUC2 in Acute Pancreatitis via CD40-Macrophage Pathway

Gut barrier dysfunction is critical in the pathogenesis of acute pancreatitis (AP). We report that intestinal Mucin 2 (MUC2) expression is decreased in AP patients and correlates with disease severity. Intestinal epithelial-specific Muc2 knockout (Muc2 IEC) mice demonstrated exacerbated AP in a gut microbiota-dependent manner. Decreased abundance of Lactobacillus and correlated reduced level of riboflavin was found in Muc2 IEC mice after AP induction. Supplementation with riboflavin effectively ameliorated AP in Muc2 IEC mice, whereas administration of an engineered strain deficient in riboflavin synthesis failed to provide protective effect. MUC2 deficiency aggravated a macrophage-dominant immune imbalance in the pancreas, which was reversed by riboflavin. In vitro experiments revealed that riboflavin suppresses pro-inflammatory macrophage activation by inhibiting the CD40 signaling pathway. This inhibition preserved mitochondrial function and reversed the histone H3 acetylation at pro-inflammatory gene promoters. Targeting the microbiota-derived riboflavin in AP may help to ameliorate the disease course.