Sepsis induced by cecal ligation and puncture led to hepatic cholestasis and compromised gut barrier function in mice.
Sepsis resulted in suppressed -FGF15 signaling and altered gut microbiota composition.
Activation of FXR through INT-747 improved gut barrier function and increased expression of FXR and FGF15.
Mice lacking showed partial recovery from sepsis-induced changes in FXR signaling and bile acid metabolism.
Fecal microbiota transplantation from septic mice activated intestinal Myd88, which suppressed FXR-FGF15 signaling and worsened cholestasis.
Probiotic treatment reduced Myd88 activation, increased FXR expression, alleviated cholestasis, and improved gut barrier integrity during sepsis.
Simplified
BACKGROUND AND AIMS: Bacterial translocation and intestinal 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 () can disturb bile acids (BAs) metabolism, further exacerbating intestinal dysbiosis. The farnesoid X receptor () 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 h post-cecal 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), 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 Myd88mice was conducted to study the impact of dysbiosis on intestinal Myd88 expression during sepsis, using floxed (Myd88) mice as controls. Finally, the effects of the probiotic intervention on gut barrier function and sepsis outcomes in CLP mice were investigated. △IEC △IEC fl/fl
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, Myd88mice 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. △IEC
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. In summary, disordered intestinal flora in septic mice specifically triggers intestinal epithelial Myd88 activation, inhibit the FXR-FGF15 axis, and then worsen intestinal barrier function impairment.
Key numbers
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7-day Survival Rate
Survival rate of mice treated with agonist INT-747 after CLP surgery.
725 OTUs
Gut Microbiota Richness
Number of operational taxonomic units identified in the INT-747 treatment group.
lower in -CLP mice
Bile Acid Levels
Comparison of total bile acid levels in -deficient mice vs. -sufficient mice post-CLP.
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Declarations. Ethics approval and consent to participate: The animal study was reviewed and approved by the Animal Protection and Utilization Committee of East Hospital affiliated with Tongji University. Competing interests: The authors declare no competing interests.
