Causal Relationship Among Intestinal Microbiota, Lipid Metabolites, and Cholangiocarcinoma: A Mendelian Randomization Study

Abstract

Background: Cholangiocarcinoma (CCA) is an aggressive tumor with a poor prognosis. Numerous animal experiments and clinical studies have indicated an association between the gut microbiota (GM) and the incidence of CCA. Additionally, patients with CCA often exhibit metabolic disorders, but there is a lack of evidence regarding causality. Therefore, elucidating the causal relationships among GM, plasma metabolites, and CCA is crucial and can provide insights for the prevention and treatment of CCA. Objective: We utilized summary statistics from the largest available genome-wide association studies, including gut microbiota (GM) data from the MiBioGen consortium (n = 18,340), plasma metabolites from four distinct human metabolomics studies, and cholangiocarcinoma (CCA) patient data from the UK Biobank (cases n = 832 and controls n = 475,259). We conducted bidirectional Mendelian randomization analyses to explore the causal relationship between GM and CCA. Additionally, we performed two mediation analyses and a two-step Mendelian randomization (MR) to identify potential mediating metabolites, offering guidance for the clinical early detection and intervention of CCA. Results: In our analysis, we identified that two types of gut microbes (Enterobacteriaceae and Enterobacteriales) increase the risk of cholangiocarcinoma (CCA), while eight types of gut microbes, including Lachnospiraceae and Eggerthella, have protective effects. Additionally, we identified 31 plasma metabolites significantly associated with CCA, with lipid metabolism disorders being a key factor. Notably, four plasma metabolites, such as Intermediate-Density Lipoprotein Triglycerides (IDL_TG), mediate the relationship between gut microbiota and CCA, highlighting the role of plasma metabolites as intermediaries. These findings underscore the potential of targeting gut microbiota and plasma metabolites for the prevention and treatment of CCA. Conclusion: Our research demonstrates that plasma metabolites play a pivotal role in the pathogenesis of CCA induced by gut microbiota. This finding deepens our understanding of how gut microbiota dysbiosis contributes to the development of CCA by influencing plasma metabolites.