Genetically Predicted Gut Microbiota Mediate the Association Between Fatty Acids and Intrahepatic Cholestasis of Pregnancy: A Mendelian Randomization Analysis

Fatty acids (FAs) and gut bacteria likely play vital roles in intrahepatic cholestasis of pregnancy (ICP). However, the causal connection between FAs, gut microbiota, and ICP has not yet been confirmed. To investigate the associations of FAs, gut bacteria, and ICP, a Mendelian randomization (MR) analysis with two samples was performed to identify the potential causal relationships between FAs and ICP. The potential mediating role of gut bacteria in FAs and ICP was analyzed by a two-step MR analysis. False discovery rate (FDR) correction was conducted to correct the bias of multiple tests. MR analysis revealed that higher omega-6 FAs/total FAs (odds ratio [OR] = 2.563, 95% confidence interval [CI] = 1.362-4.824, FDR <i>p</i> = 0.016), linoleic acids/total FAs (OR = 3.812, 95%CI = 1.966-7.388, FDR <i>p</i> = 0.001), and average number of methylene groups (OR = 1.968, 95%CI = 1.390-2.785, FDR <i>p</i> = 0.001) are potential risk factors for ICP. However, omega-3 FAs (OR = 0.587, 95%CI = 0.394-0.874, FDR <i>p</i> = 0.031) and the average number of double bonds in an FA chain (OR = 0.575, 95%CI = 0.435-0.759, FDR <i>p</i> = 0.001) could reduce the risk of ICP. The abundance of 25 gut bacteria showed significant causal effects on ICP, among which <i>Dokdonella</i> may play a crucial role in modulating the effects of FAs on ICP. Our research results suggest that the effects of FA on ICP likely vary according to their different types. <i>Dokdonella</i> abundance plays a significant role in mediating the causal interactions between FAs and ICP.