Metformin ameliorates injury in obesity-related severe acute pancreatitis and modulates a gut microbiota-associated metabolite that promotes M2 polarization of adipose tissue macrophages

Gut microbiota (GM) and their associated metabolites in the white adipose tissue (WAT) may exacerbate obesity-related severe acute pancreatitis (SAP). We compared the microbiota of obese versus non-obese acute pancreatitis (AP) in humans and mice, and used a diet-induced obesity SAP mouse model to determine whether obesity alters WAT metabolites and whether metformin (Met) reduces inflammation by modulating microbiota-related metabolites that promote M2 polarization of adipose tissue macrophages (ATMs). Public microbiota datasets from obese and non-obese patients with AP were analyzed. In mice, obese and no-obese SAP models were treated with or without Met. Fecal microbiota and epididymal white adipose tissue (eWAT) metabolites were profiled, followed by integrative microbiome–metabolome correlation analyses. ATM polarization in WAT was assessed by flow cytometry, and IL-10 expression in pancreatic and WAT was evaluated by immunohistochemistry (IHC). In vitro, RAW264.7 cells were treated with lipopolysaccharide (LPS) and palmitic acid (PA) to model ATMs in pancreatitis. The effects of L-hexanoylcarnitine (L-HC), a microbiota-related metabolite, on M2 polarization were then assessed. Oral microbiota enrichment in patients with AP differed according to obesity status. Functional prediction indicated enrichment of ubiquinol biosynthesis and lipid-related pathways in the oral microbiota of obese patients with AP. In SAP mice, obesity worsened pancreatic and lung injury, induced shifts in the GM with reduced alpha diversity, and altered WAT metabolite profiles. Integrative analyses revealed links between the GM and WAT metabolites. Met reduced pancreatic and lung injury, promoted M2 polarization of ATMs, and upregulated IL-10 levels in the pancreas and WAT. Met significantly altered community composition but not alpha diversity and modified WAT metabolites associated with the GM, with hexanoylcarnitine (HC) and isomaltose upregulated. In vitro, L-HC induced M2 polarization of ATMs in pancreatitis, as reflected by increased Pparg mRNA expression and elevated CD206 protein levels. Obesity alters oral microbiota and GM and WAT metabolites, thereby worsening AP. Met attenuates inflammatory injury in obesity-associated SAP and is associated alterations in the GM and increased microbiota-related HC, which promotes ATM M2 polarization. These findings suggest a potential mechanism by which Met attenuates inflammatory injury in obesity-related SAP.