Gut Microbiota Regulates Systemic Inflammatory Response and Compensatory Anti-Inflammatory Response Syndromes by Targeting PF4+ Macrophages in Acute Pancreatitis

Acute pancreatitis (AP) begins with pancreatic local inflammation, leading to the onset of systemic inflammatory response syndrome (SIRS), followed by compensatory anti-inflammatory response syndrome (CARS), which causes immune paralysis and higher mortality rate. We have demonstrated that AP disrupts the balance of the gut microbiota that aggravates disease progression; however, the role of gut microbiota in the development of SIRS/CARS remains poorly understood. Here, we observed a lower abundance of Bacteroides thetaiotaomicron (B. thetaiotaomicron) that increased the infiltration of PF4⁺ macrophages in AP patient and mouse models, which, in turn, promoted the recruitment of Th2 cells and neutrophils and exacerbated SIRS/CARS. Supplementation with B. thetaiotaomicron increased the expression of the enzyme N-methyltransferase (NMMT) and enhanced the production of 1-methylnicotinamide (1MNA) in the gut epithelial cells, which inhibited PF4⁺ macrophages dependent SIRS/CARS by targeting ELF4, a transcript factor of PF4. Our findings provide novel interventions for AP patients with SIRS/CARS through modulating gut microbiota.