The gut microbial metabolite phenylacetylglutamine (PAGln) exacerbates pancreatic injury, lung injury, and intestinal barrier dysfunction in severe acute pancreatitis, potentially through activation of ferroptosis and the TLR4/NF-κB signaling pathway.
SAP induction significantly elevated circulating PAGln levels compared to control conditions.
PAGln administration significantly exacerbated inflammation compared to the SAP group alone.
PAGln promoted ferroptosis as a mechanism contributing to SAP-induced pancreatic and extrapancreatic organ injury.
PAGln activated the TLR4/NF-κB signaling pathway as a mechanism underlying its exacerbation of SAP.
SAP induced SAP-associated lung injury and intestinal barrier dysfunction in the experimental model.
PAGln is a gut microbial metabolite that exerts important effects in inflammation and oxidative stress-induced injury.
This research suggests that a molecule called phenylacetylglutamine (PAGln), produced by gut bacteria, plays a harmful role in severe acute pancreatitis (SAP), a life-threatening condition involving dangerous inflammation of the pancreas. The researchers found that when mice were given an experimental form of SAP, their blood levels of PAGln rose significantly. When additional PAGln was administered to these mice, the damage to the pancreas, lungs, and intestinal lining became considerably worse compared to mice with SAP alone. The study investigated how PAGln causes this worsening and identified two key biological mechanisms. First, PAGln appears to promote a form of cell death called ferroptosis, which is driven by iron and lipid oxidation and can damage organ tissue. Second, PAGln activates a well-known inflammatory signaling chain called the TLR4/NF-κB pathway, which amplifies the body's inflammatory response and contributes to multi-organ damage. These findings were demonstrated in both live mouse models and in pancreatic cell cultures. This research matters because SAP is associated with high rates of serious complications and death, partly due to injury spreading beyond the pancreas to organs like the lungs and gut. This study suggests that gut bacteria and their metabolites — particularly PAGln — may be important contributors to how severe the disease becomes. Understanding this connection could eventually help identify new targets for treatment or new ways to predict disease severity in SAP patients.
Lu S, Zhao Y, Gong Y, Chen F, Yuan J, Dong W. (2026). The gut microbial metabolite phenylacetylglutamine exacerbates severe acute pancreatitis by promoting ferroptosis and TLR4/NF-κB signaling pathways.. International immunopharmacology. https://doi.org/10.1016/j.intimp.2026.116919