Aberrant gut microbiota alters host bile acid metabolism and contributes to intrahepatic cholestasis of pregnancy
Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific disorder, which is associated with an increased risk of adverse perinatal outcomes. The etiology and mechanism of ICP are complicated and poorly understood, thus therapies have been largely empiric. Currently, the mainstay of treatment for ICP has been ursodeoxycholic acid (UDCA). However, the largest randomized controlled clinical trial (PITCHES trial) and several Cochrane database meta-analyses found that there was no evidence in reducing adverse perinatal outcomes using UDCA versus placebo, raising controversy in the treatment of ICP. As such, there is an urgent unmet clinical need for this serious disease. In this study, we demonstrated that the abundance of Bacteroides fragilis (B. fragilis) was substantially increased in individuals with ICP. B. fragilis colonization could suppress FXR signaling through mediating bile acid metabolism and result in excessive bile acid synthesis and disrupted bile acid excretion, highlighting the role of bile acids and FXR in gut microbiota-mediated ICP development. Most importantly, our finding revealed that GDCA was identified as a novel FXR agonist and might be of potential value in the prevention and treatment of ICP.