Citrus peel polysaccharide attenuates high-sugar/high-fat diet-induced hyperlipidemic pancreatitis via the gut-pancreas axis.

Citrus peel polysaccharide (CPP), an acidic heteropolysaccharide with a molecular weight of 73,243 Da, was investigated for its potential to attenuate high-sugar/high-fat (HSHF) diet-induced hyperlipidemic pancreatitis (HLP) through modulation of the gut pancreas axis. In a murine model, dietary CPP intervention significantly lowered serum levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-c), free fatty acids (FFA) while elevating high-density lipoprotein cholesterol (HDL-c), and concurrently reduced fasting blood glucose (FBG) and fasting insulin (FINS) levels, thereby ameliorating both dyslipidemia and hyperglycemia (P < 0.01). Histopathological and biochemical assessments demonstrated that CPP alleviated pancreatic acinar cell injury and fibrosis. Furthermore, CPP restored intestinal barrier function by upregulating tight junction proteins (ZO-1, Claudin-1, Occludin), which correlated with reduced systemic and pancreatic inflammation. Gut microbiota analysis revealed that CPP-induced enrichment of beneficial genera (Faecalibaculum and Candidatus_Saccharimonas) contributed to decreased lipopolysaccharide (LPS) translocation (P < 0.01). Mechanistically, CPP-mediated downregulation of LPS suppressed the activation of the pancreatic Vascular Endothelial Growth Factor B / Vascular Endothelial Growth Factor Receptor 1 / Signal Transducer and Activator of Transcription 3 (VEGFB/VEGFR1/STAT3) signaling pathway, thereby mitigating inflammatory responses and fibrotic progression. These findings illustrate the multi-target protective effects of CPP as a dietary macromolecule, highlighting its potential in ameliorating HLP through gut microbiota remodeling, barrier reinforcement and inhibition of LPS-mediated signaling.