Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific disorder, which is characterized by raised serum bile acid level and liver transaminases, and adverse fetal outcome. The etiology and mechanism of ICP are complicated and poorly understood, thus therapies have been largely empiric. The gut microbiome differs from the first to the third trimester in healthy pregnant women, and there is a close link between microbial dysbiosis and several pregnancy-related diseases. However, the critical impact of the gut microbiota and its signaling on the regulation of ICP remains elusive. Here, we report that the gut microbiome differed significantly between ICP individuals and healthy controls, and colonization with ICP microbiota was sufficient to induce intrahepatic cholestasis in pregnant mice.. 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 characterized by raised serum bile acid level and liver transaminases, and adverse fetal outcome. The etiology and mechanism of ICP are complicated and poorly understood, thus therapies have been largely empiric. The gut microbiome differs from the first to the third trimester in healthy pregnant women, and there is a close link between microbial dysbiosis and several pregnancy-related diseases. However, the critical impact of the gut microbiota and its signaling on the regulation of ICP remains elusive. Here, we report that the gut microbiome differed significantly between ICP individuals and healthy controls, and colonization with ICP microbiota was sufficient to induce intrahepatic cholestasis in pregnant mice. Metagenomic analysis revealed that Bacteroides fragilis was increased in individuals with ICP and B. fragilis-colonized recipient mice resulted in increased bile acid levels, cholestatic liver injury, and adverse fetal outcome. B. fragilis altered the bile acid metabolism and deconjugated glycodeoxycholic acid (GDCA) through its BSH activity, which was accompanied by farnesoid X receptor (FXR) signaling suppression and excessive bile acids synthesis and destructive bile excretion. We further revealed that GDCA was identified as a novel FXR agonist to improve B. fragilis-induced intrahepatic cholestasis in the pregnant murine model. Indeed, treatment of an ICP mouse model with GDCA exerted preventive and therapeutic effects that improved the ICP phenotype. We propose that modulation of the gut microbiota-bile acid-FXR axis may be of potential value for ICP treatment.