Gut microbiota-derived riboflavin mediates protective effects of MUC2 in acute pancreatitis via CD40-macrophage pathway.

BACKGROUND: Gut barrier dysfunction is critical in the pathogenesis of acute pancreatitis (AP), yet the underlying mechanisms remain unclear. Mucin 2 (MUC2), the primary component of the intestinal mucus layer, is essential for gut homeostasis and microbial eubiosis. This study aimed to elucidate the protective mechanism of intestinal MUC2 in AP. RESULTS: We reported that intestinal MUC2 expression was decreased in AP patients and correlated with disease severity. Intestinal epithelial-specific Muc2 knockout (Muc2ΔIEC) mice demonstrated exacerbated AP in a gut microbiota-dependent manner. Decreased abundance of Lactobacillus and correlated reduced levels of riboflavin were found in Muc2ΔIEC mice after AP induction. Supplementation with riboflavin effectively ameliorated AP in Muc2ΔIEC mice, whereas administration of an engineered strain deficient in riboflavin synthesis failed to provide a 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. CONCLUSION: Our study demonstrates that intestinal MUC2 deficiency is associated with reduced levels of microbiota-derived riboflavin, which could partially suppress pro-inflammatory macrophage activation via the CD40 pathway. Targeting the microbiota-derived riboflavin in AP may help to ameliorate the disease course. Video Abstract.