Gut microbiota-derived phenylalanine metabolites exacerbate elderly-onset acute pancreatitis by promoting mitophagy and enhancing cell death

Elderly-onset acute pancreatitis (EOAP) shows increased severity and mortality, yet the age-related mechanisms underlying its pathogenesis remain incompletely understood. Here, we define the role of gut microbiota dysbiosis in enhancing the severity of EOAP through altered phenylalanine (PA) metabolism. Aged mice and elderly patients displayed elevated phenaceturic acid (PAC) and phenylacetylglutamine (PG), along with increased Escherichia-Shigella abundance. Fecal microbiota transplantation (FMT) from aged donors reproduced the aggravated inflammatory phenotype in young recipient mice. Mechanistically, PAC compromises mitochondrial integrity and induces apoptosis, thereby enhancing inflammatory responses. Our findings highlight dysregulated apoptosis and mitochondrial homeostasis as underlying mechanisms contributing to EOAP severity, and suggest that targeting microbial PA metabolism may offer a novel therapeutic avenue for EOAP. Video Abstract