Bile acid derivatives from gut microbiota promote GBPs-mediated activation of caspase-4/11 by LPS through .

Lipopolysaccharide (LPS) mediated caspases-4 (humans) and caspase-11 (rodent) (caspase-4/11) signaling can cause maturation of inflammatory cytokine IL-1β and cellular pyroptosis in the macrophages through guanylate-binding proteins (GBPs). However, how caspase-4/11s bind with GBPs together to activate caspase-4/11 by LPS remains elusive. We here found that BA derivatives from gut microbiota can regulate sensitivity of macrophages to LPS and Gram-negative bacteria through . BA derivatives such as deoxycholic acid (DCA) could induce expression through sphingosine-1-phosphate receptor 2 (S1PR2) in the macrophages of mice and humans. Both murine and human knockout (KO) macrophages did not produce immune response(s) to LPS or gram negative bacteria. KO mice had also reduced inflammatory responses to LPS or typhimurium ( T) infection. Mechanistically, could bind intracellular proteases caspase-4/11 with GBP1 together in the macrophages of human and mice to cause LPS-mediated activation of caspase-4/11. Thus, BA derivatives from gut microbiota promote GBPs-mediated activation of caspase-4/11 by LPS through .