Farnesoid X Receptor Regulated Sepsis-Induced Abnormal Bile Acid Metabolism via the Fibroblast Growth Factor 15/Fibroblast Growth Factor Receptor 4 Pathway

Objective: The study aims to investigate the mechanism of Farnesoid X receptor (FXR) activation in sepsis-induced abnormal bile acid metabolism and the metabolism status of each bile acid type.

Methods: The sepsis mouse model was developed via lipopolysaccharide intraperitoneal injection and confirmed via hematoxylin and eosin (H&E) staining. FXR Agonist activated the FXR/Fibroblast Growth Factor (FGF)15/FGFR pathway via quantitative real-time polymerase chain reaction and Western blot. Consequently, metabolomics and bioinformatics analysis were conducted to identify the alterations in each kind of bile acid content following FXR Agonist/inhibitor intervention.

Results: The H&E staining indicated that FXR activation alleviates the liver injury of the sepsis mouse model. The increased FGF15 and FXFR expression levels and decreased CYP7A1 demonstrated FXR/FGF15/FGFR pathway activation following FXR Agonist treatment. Furthermore, total bile acid, interleukin (IL)-6, and tumor necrosis factor-α concentrations were downregulated after FXR activation, whereas IL-10 concentration was upregulated, indicating the alleviated effect of FXR Agonist in sepsis. Consequently, metabolomics and bioinformatics analysis determined that T-a-MCA were downregulated in both FXR Agonist and inhibitor groups, whereas six bile acid types were altered in the control group.

Conclusion: FXR activation was crucial in alleviating sepsis-induced hepatic injury and cholestasis through the FGF15/FGFR signaling pathway, and FXR may act as a potential preventive and intervention target of sepsis.

FGF15/FXFR pathway; bile acid; farnesoid X receptor; metabolomics; sepsis.