Abstract
Background & Aims: Bacterial translocation and intestinal dysbiosis due to gut barrier dysfunction are widely recognized as major causes of the initiation and development of intra-abdominal sepsis. Systemic bacterial translocation and hepatic activation of the myeloid differentiation primary response gene 88 (MyD88) can disturb bile acid (BAs) metabolism, further exacerbating intestinal dysbiosis. The Farnesoid X receptor (FXR) and fibroblast growth factor (FGF) 15/19 are well known to be involved in the control of BAs synthesis and enterohepatic circulation. However, the influence of intestinal microbiota on intestinal MyD88 signaling, the FXR/FGF15 axis, as well as gut-liver crosstalk during sepsis remains unclear. The present study aims to decipher the role of intestinal MyD88 in abdominal sepsis, its impact on intestinal FXR signaling and FGF15-mediated gut-liver crosstalk.
Methods: Expression levels of FXR and FGF15 in the liver and intestines, alongside assessments of gut barrier function, were evaluated in septic wild-type (WT) mice 24 hours post-caecal ligation and puncture (CLP) surgery. Subsequently, the FXR agonist INT-747 was administered to explore the relationship between FXR activation and gut barrier function. Further investigations involved MyD88-deficient mice with specific deletion of MyD88 in intestinal epithelial cells (MyD88△IEC), subjected to CLP to examine the interplay among intestinal MyD88, FXR, gut barrier function, microbiota, and BA composition. Additionally, fecal microbiota transplantation (FMT) from septic mice to MyD88△IEC mice was conducted to study the impact of dysbiosis on intestinal MyD88 expression during sepsis, using floxed (MyD88fl/fl) mice as controls. Finally, the effects of the probiotic intervention on gut barrier function and sepsis outcomes in CLP mice were investigated.
Results: Induction of sepsis via CLP led to hepatic cholestasis, suppressed FXR-FGF15 signaling, altered gut microbiota composition, and compromised gut barrier function. Administration of INT-747 increased intestinal FXR and FGF15 expression, strengthened gut barrier function, and enhanced barrier integrity. Interestingly, MyD88△IEC mice exhibited partial reversal of sepsis-induced changes in FXR signaling, BA metabolism, and intestinal function, suggesting enhanced FXR expression upon MyD88 knockdown. Moreover, FMT from septic mice activated intestinal MyD88, subsequently suppressing FXR-FGF15 signaling, exacerbating cholestasis, and ultimately compromising gut barrier function. Probiotic treatment during abdominal sepsis mitigated flora disturbances, reduced MyD88 activation in the intestinal epithelium, increased FXR expression, alleviated cholestasis, and consequently reduced barrier damage.
Conclusions: This study highlights the critical role of MyD88/FXR signaling in intestinal epithelial cells as a pivotal mediator of the detrimental effects induced by sepsis-related intestinal dysbiosis on barrier function and bile acid metabolism. Probiotics show promise in restoring intestinal homeostasis by leveraging intestinal MyD88 and FXR signaling to preserve barrier function and improve survival.