Gut microbiota affects the role of mPXR agonist PCN in alleviating sepsis-induced liver injury by regulating YAP activation.

Abstract

BACKGROUND: Sepsis severity is primarily driven by exaggerated inflammatory responses that contribute to hepatic injury. The pregnane X receptor (PXR), a nuclear receptor that regulates xenobiotic and endobiotic metabolism, plays a crucial protective role against sepsis-induced liver injury and modulates hepatic regeneration. Concurrently, the gut microbiota contributes to sepsis pathogenesis via intestinal signaling and the gut-liver axis. This study aimed to evaluate how the gut microbiota mediates the protective effects exerted by the mouse PXR (mPXR) agonist pregnenolone-16α‑carbonitrile (PCN) against sepsis-induced liver injury and to elucidate the underlying mechanisms. METHODS: Sepsis was induced by cecal ligation and puncture (CLP) or lipopolysaccharide (LPS) treatment. Mice were pretreated with PCN for three consecutive days prior to model construction. Gut microbiota depletion was achieved using a cocktail of broad-spectrum antibiotics (ABX), and fecal microbiota transplantation (FMT) was performed to restore microbial communities. RESULTS: We found that depletion of gut microbiota abrogated PCN-mediated hepatoprotection in septic mice. Conversely, FMT from PCN-treated donors attenuated sepsis-induced liver injury. Furthermore, PCN-activated PXR significantly altered the gut microbiota composition in septic mice. Mechanistically, PCN treatment enhanced activation of the Yes-associated protein (YAP) signaling pathway, an effect that was diminished upon depletion of gut microbiota. Correspondingly, FMT from PCN-treated donors enhanced YAP activation and upregulated its downstream target proteins in septic mice. CONCLUSIONS: In summary, this study demonstrated that the gut microbiota mediated the protective effects of PCN against sepsis-induced liver injury by activating the YAP pathway. These findings provide novel insights into the role of gut microbiota in PXR-mediated protection during sepsis.