LAUSR

Bacterial infections are a major cause of chronic infections and mortality. Innate immune control is crucial for protection against bacterial pathogens. Bile acids facilitate intestinal absorption of lipid-soluble nutrients and modulate various metabolic pathways through the farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5 (TGR5). Here, we identified a new role of FXR and TGR5 in promoting inflammasome activation during bacterial infection. Caspase-1/11 activation and release of cleaved interleukin (IL)-1β in FXR- and TGR5-deficient mouse bone marrow-derived macrophages upon Listeria monocytogenes or Escherichia coli infection was significantly reduced. In contrast, FXR- or TGR5-deficiency did not affect the transcription of caspase-1/11 and IL-1β. Inflammasome activation is critical for host immune defense against bacterial infections. Consistent with this, the deletion of FXR or TGR5 impaired effective clearance of L. monocytogenes or E. coli in vitro and in vivo, which was associated with greater mortality and bacterial burden than that of wild-type mice. Pretreatment with an FXR agonist decreased bacterial burden in vitro and increased survival in vivo. Thus, FXR and TGR5 promote inflammasome-mediated antimicrobial responses and may represent novel antibacterial therapeutic targets.