{
  "abstract": "Background Intrahepatic cholestasis of pregnancy (ICP) is a liver disease of pregnancy characterized by elevated maternal serum bile acids, leading to adverse perinatal outcomes and potential long-term immune dysfunction in offspring. Metformin has shown hepatoprotective effects, but its role in ICP remains unclear. This study aimed to identify factors affecting ICP prognosis and investigate whether metformin ameliorates ICP by modulating bile acid metabolism.Methods A retrospective cohort study involving 24 ICP patients and 17 healthy pregnant women was conducted to analyze risk factors for adverse neonatal outcomes. An ICP mouse model was established to investigate the therapeutic effects of metformin. Biochemical analysis, H&E staining, high-performance liquid chromatography, and RT-qPCR were used to evaluate serum total bile acid (TBA) levels, liver and placental histopathology, fecal bile acid composition, and the expression of bile acid metabolism-related genes in maternal livers and T-cell transcription factors in offspring livers.Results Clinical data identified maternal TBA as an independent risk factor for preterm birth and low birth weight in ICP. In the ICP mouse model, elevated serum TBA, hepatocyte swelling with inflammatory infiltration, and increased placental IL-6 levels were observed. ICP offspring exhibited reduced birth weight and survival rate, accompanied by a disrupted hepatic RORγt/Foxp3 balance. Metformin treatment significantly reversed these pathological changes, reducing maternal serum TBA and placental IL-6, improving neonatal outcomes, and restoring hepatic immune homeostasis in offspring. Fecal bile acid profiling revealed that metformin altered the bile acid composition, decreasing T-β-MCA levels and increasing CDCA levels. Mechanistically, metformin activated FXR-FGF15 signaling, suppressing CYP7A1 and CYP8B1, thereby inhibiting de novo bile acid synthesis in the liver.Conclusions Maternal TBA level is a critical determinant of adverse perinatal outcomes in ICP and is associated with altered hepatic T-cell immunity in offspring. Metformin improves pregnancy outcomes and restores hepatic immune homeostasis in an ICP mouse model by activating the FXR signaling pathway to regulate bile acid metabolism.",
  "authors": [
    {
      "affiliations": [
        "Experimental Teaching Center of Preventive Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, China"
      ],
      "name": "Wanwen Huang"
    },
    {
      "affiliations": [
        "Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, China"
      ],
      "name": "Hongying Fan"
    },
    {
      "affiliations": [
        "Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, China"
      ],
      "name": "Qiongxi Lin"
    }
  ],
  "title": "IDDF2026-ABS-0250 Metformin ameliorates intrahepatic cholestasis of pregnancy and restores offspring immune homeostasis by activating the FXR signaling pathway",
  "uid": "48dd53b7-e19e-5be6-a5b8-24a3318f3757"
}