Longitudinal alterations of gut microbiota associated with intrahepatic cholestasis of pregnancy: results from a large cohort study in China.

BACKGROUND

Intrahepatic cholestasis of pregnancy (ICP) is a significant pregnancy-specific hepatic disorder, yet the mechanisms linking the gut microbiota to ICP remain unclear.

METHODS

Based on the Tongji-Huaxi-Shuangliu Birth Cohort, we included 4956 participants with repeated 16S rRNA sequencing data and clinical records in early, middle, and late pregnancy. We evaluated early pregnancy gut microbiota in relation to ICP risk, characterised longitudinal changes in women with and without ICP, and assessed hepatic markers as potential mediators.

FINDINGS: Women with ICP exhibited different temporal changes in microbial diversity compared to non-ICP participants. Thirty-nine genera demonstrated significant associations with ICP in early pregnancy, and 9 genera showed consistent associations across pregnancy, with Family_XIII_AD3011_group, UCG_005 and Christensenellaceae_R-7_group exhibiting strong associations (PFDR < 0.05). Co-abundance network analyses uncovered different microbial interactions between women with and without ICP throughout pregnancy, characterised by increased modularity and decreased correlation strength in ICP (P < 0.05). NetMoss-based network comparison identified key driver genera of ICP progression, including UCG-005, Dialister, Holdemania, and Christensenellaceae_R-7_group. Mediation analyses revealed early pregnancy hepatic markers as crucial mediators in the microbiota-ICP association, with alanine aminotransferase mediating 27.08% and 20.06% of the effects of UCG_005 and Christensenellaceae_R-7_group on ICP, respectively (PFDR < 0.05).

INTERPRETATION: This study revealed distinct gut microbial signatures of ICP manifesting in early gestation, with progressive dysbiotic alterations characterising its pathophysiological trajectory throughout pregnancy.

FUNDING: NKRDPC-2024YFC2707602, NSFC-82473646, SPNSF-2024NSFSC0578 for XF P. NSFDYS-82325043 for A P. NSFC-82301924 for D S, SSTP-2023ZYD0120 for J W, SPHCCRSP-23LCYJ013 for Y H.