GV-971 prevents severe acute pancreatitis by remodeling the microbiota-metabolic-immune axis

Despite recent advances, severe acute pancreatitis (SAP) remains an extremely lethal inflammation with limited treatment options. Here, we provide compelling evidence of GV-971 (sodium oligomannate), an anti-Alzheimer's medication, as being a protective agent in various mouse SAP models. Microbiome sequencing, along with fecal microbiota transplantation and mass cytometry technology, unveiled that GV-971 reshapes the gut microbiota, increasing Faecalibacterium populations and modulating both peripheral and intestinal immune systems. A metabolomics analysis of cecal contents from GV-971–treated SAP mice further identified short-chain fatty acids, including propionate and butyrate, as key metabolites in inhibiting macrophage M1 polarization and subsequent lethal inflammation by blocking the MAPK pathway. These findings suggest GV-971 as a promising therapeutic for SAP by targeting the microbiota metabolic immune axis. For metabolite treatment, prior to experimentation, sodium propionate, and sodium butyrate were pre-incubated with RAW264.7 cells for 24 hours. Subsequently, the corresponding metabolites were administered in combination with 1 μg/mL LPS for 6 hours. Following this treatment, RAW 264.7 cells were collected for RNA-Sequencing to study the impact of propionate and butyrate on transcriptome.