The gut microbial metabolite phenylacetylglutamine exacerbates severe acute pancreatitis by promoting ferroptosis and TLR4/NF-κB signaling pathways.

Severe acute pancreatitis (SAP) is a life-threatening abdominal disease. In recent years, multiple studies have suggested that gut microbiota metabolites play a key role in regulating SAP disease outcomes. The gut microbial metabolite phenylacetylglutamine (PAGln) exerts important effects in inflammation and oxidative stress-induced injury; however, its role in SAP remains unexplored. In this study, caerulein and LPS were used to induce experimental SAP models in mice and AR42J cells, followed by histopathological, biochemical, and molecular biological analyses. SAP induced hemorrhagic necrosis of the pancreas, SAP-associated lung injury, intestinal barrier dysfunction, and significantly elevated circulating PAGln levels. Compared to the SAP group, PAGln administration significantly exacerbated inflammation, SAP-associated pulmonary injury, and intestinal barrier dysfunction. Mechanistically, PAGln may influence SAP-induced pancreatic injury and extrapancreatic organ injury by regulating ferroptosis and the TLR4/NF-κB signaling pathway. This study preliminarily demonstrates that PAGln, a gut microbial metabolite, exacerbates pancreatic injury, lung injury, and intestinal barrier dysfunction in SAP, potentially through activation of ferroptosis and the TLR4/NF-κB signaling pathway.