Introduction: Modern dietary habits often involve consumption of high-fat, high-fructose diets (HFFD). Given the pivotal role of the Farnesoid X receptor (FXR) and its regulation of fibroblast growth factors (FGF)-15/21 in maintaining glucose and lipid homeostasis, this study investigated the effects of lubiprostone alone and in combination with bile acid on the gut-pancreas axis and metabolic outcomes in animals subjected to HFFD.

Methods: Thirty-six male Wistar rats were randomly assigned to six groups: control diet (Ctrl), HFFD, HFFD plus vehicle (HFFD-V), HFFD plus bile acid (HFFD-B), HFFD plus lubiprostone (HFFD-L), and HFFD plus both bile acid and lubiprostone (HFFD-BL). Following 8 weeks on their respective diets, the rats received treatments for 10 days. Assessments included anthropometric measures, dietary intake, biomarkers of glucose and lipid metabolism, plasma levels of FGF-5, FGF-15, and FGF-21, and intestinal FXR expression.

Results: Rats consuming the HFFD demonstrated increased Lee index, adiposity, and deteriorated lipid profiles. Additionally, FXR protein expression and plasma FGF-15 decreased, while FGF-21 increased significantly. The elevated FGF-21 was associated with pancreatic β-cell dysfunction, evidenced by reduced HOMA-β, elevated blood glucose, and decreased insulin levels. Co-administration of lubiprostone with bile acid effectively reversed these metabolic disturbances.

Conclusion: Combined lubiprostone and bile acid therapy represents a promising approach to ameliorate metabolic impairments related to HFFD, with potential therapeutic benefits in the context of increasing consumption of saturated fats and fructose-rich beverages