TBA

This study explores the role of bile acids in exacerbating sepsis through the activation of the NLRP3 inflammasome. Bile acids, identified as danger-associated molecular patterns (DAMPs), can trigger both signal 1 and signal 2 of the NLRP3 inflammasome in inflammatory macrophages, leading to a prolonged calcium influx and enhanced inflammasome activation when combined with ATP. Experimental cholestasis was found to sensitize mice to LPS-induced sepsis, while treatment with cholestyramine, a bile acid sequestrant, protected the mice. Additionally, the study highlights the regulatory role of the farnesoid X receptor (FXR), which negatively regulates the NLRP3 inflammasome by physically interacting with NLRP3 and caspase 1. Fxr-null mice were more susceptible to endoxemia shock, whereas FXR-overexpressing mice showed increased resistance to sepsis. These findings suggest that bile acids and FXR are key modulators of sepsis pathogenesis, offering potential therapeutic implications for cholestasis-associated sepsis by targeting FXR