Roles of Human Gut Microbiota in Liver Cirrhosis Risk: A Two-Sample Mendelian Randomization Study.

ABSTRACT

BACKGROUND: Accumulating evidence suggests that alterations in gut microbiota composition and diversity are associated with liver cirrhosis. But whether gut microbiota promotes or hampers the genesis and development of liver cirrhosis remains vague. OBJECTIVES: This study aimed to establish a causal relationship between gut microbiota and the development of liver fibrosis and cirrhosis. To achieve this, we employed a 2-sample Mendelian randomization (MR) analysis utilizing genome-wide association study (GWAS) summary statistics. This approach enabled us to assess the potential impact of gut microbiota on liver cirrhosis. METHODS: The independent genetic instruments of gut microbiota were obtained from the MiBioGen (up to 18,340 participants), which is a large-scale genome-wide genotype and 16S fecal microbiome dataset. Cirrhosis data were derived from the FinnGen biobank analysis, which included 214,403 individuals of European ancestry (811 patients and 213,592 controls). To assess the causal relationship between gut microbiota and cirrhosis, we applied 4 different methods of MR analysis: the inverse-variance weighted method (IVW), the MR-Egger regression, the weighted median analysis (WME), and the weighted mode. Furthermore, sensitivity analyses were conducted to evaluate heterogeneity and horizontal pleiotropy. RESULTS: Results of MR analyses provided evidence of a causal association between 4 microbiota features and cirrhosis, including 2 family [Lachnosiraceae odds ratio (OR) 1.82626178; 95% confidence interval (CI) 1.05208209, 3.17012532; P = 0.0323194; Lactobacillaceae OR 0.62897502; 95% CI 0.42513162, 0.93055788; P = 0.02033345] and 2 genus [Butyricicoccus OR 0.41432215; 95% CI 0.22716865, 0.75566257; P = 0.0040564; Lactobacillus OR 0.6663767; 95% CI 0.45679511, 0.97211616; P = 0.03513627]. CONCLUSIONS: Our findings offered compelling evidence of a causal association between gut microbiota and cirrhosis in European population and identified specific bacteria taxa that may regulate the genesis and progression of liver fibrosis and cirrhosis, may offer a new direction for the treatment of cirrhosis.