Astragalus polysaccharide reduces the severity of acute pancreatitis under a high-fat diet through enriching L. reuteri and propionate.

Acute pancreatitis (AP) is a severe digestive disorder, worsened by a high-fat diet (HFD) through inflammation and gut microbiota disruption. Astragalus polysaccharides (APS), known for their anti-inflammatory properties, may alleviate HFD-induced exacerbation of AP by modulating gut microbiota. This study investigates the effect of APS on AP severity under a HFD (HAP). Results show that HFD significantly worsens AP, with elevated serum enzymes, pro-inflammatory cytokines, and pancreatic damage. Single-cell RNA sequencing revealed increased ICAM1⁺ neutrophils and activation of the NF-κB/necroptosis pathway in HAP mice. Treatment with APS reduced neutrophil infiltration, downregulated NF-κB, and suppressed necroptosis. APS also restored gut microbiota balance, boosting Lactobacillus reuteri (L. reuteri) and propionate (PA) levels. Interventions with L. reuteri or PA reduced HAP severity, with combined treatment showing synergistic effects. These findings suggest that the protective effect of APS is mediated by microbiota-dependent mechanisms, highlighting the gut-pancreas axis as a potential therapeutic target for AP.