Dose-dependent dissociation between intestinal protection and pancreatic outcome following licochalcone A treatment in severe acute pancreatitis.

Introduction: Severe acute pancreatitis (SAP) is frequently accompanied by intestinal barrier dysfunction, systemic inflammation, and gut microbiota dysbiosis. Licochalcone A (LicA) exhibits anti-inflammatory and barrier-protective properties, but its dose-dependent effects on the gut-pancreas axis in SAP remain unclear. Methods: SAP was induced in mice by caerulein plus lipopolysaccharide. Mice were pretreated with low- or high-dose LicA prior to SAP induction. Pancreatic injury, inflammatory cell infiltration, tissue edema, and systemic and local cytokine levels were assessed by histology, immunohistochemistry, and ELISA. Ileal injury and barrier integrity were evaluated by histology and immunofluorescence. The composition of the gut microbiota was explored using 16S rRNA gene sequencing. Results: Low-dose LicA attenuated SAP severity, evidenced by lowered serum amylase and lipase levels, reduced systemic and pancreatic IL-1β and TNF-α levels, decreased inflammatory cell infiltration, and improved pancreatic histopathology. In contrast, high-dose LicA did not alleviate pancreatic injury and was associated with exacerbated acinar damage and persistent systemic inflammation. Notably, both LicA doses preserved ileal morphology, maintained tight junction protein expression, and reduced local intestinal inflammation. In an exploratory gut microbiota analysis (n = 3 per group), low-dose LicA was associated with partial normalization of SAP-associated microbial changes, whereas high-dose LicA was associated with a different pattern; these findings should be interpreted cautiously and require validation in larger cohorts. Conclusion: These findings indicate a dose-dependent dissociation between intestinal protection and pancreatic outcome following LicA treatment in SAP. While LicA preserves intestinal barrier integrity across doses, only low-dose treatment couples these local benefits to systemic and pancreatic protection, underscoring the importance of dose optimization when targeting the gut-pancreas axis. Microbiota findings are preliminary and require validation in larger cohorts.