Tgr5 is a membrane-bound bile acid receptor that negatively regulates immune cells, although the molecular mechanisms behind this observation remain elusive. Here we report that Tgr5 is upregulated in macrophages during stimulation with Listeria monocytogenes and that Tgr5-deficient macrophages are hyperinflammatory and mice with myeloid Tgr5 deficiency are more susceptible to Listeria monocytogenes sepsis. Unexpectedly, Tgr5-deficient macrophages show reduced glycolysis and ATP citrate lyase expression, which cumulates in acetyl-CoA deficiency and impaired metabolic-epigenetic gene silencing, driving macrophages toward a hyperinflammatory phenotype during bacterial sepsis.