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

ABSTRACT 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.