Causal Relationship Between Gut Microbiota and Liver Cirrhosis: 16S rRNA Sequencing and Mendelian Randomization Analyses

Background and Aims: Accumulating evidence highlights the association between the gut microbiota and liver cirrhosis. However, the role of the gut microbiota in liver cirrhosis remains unclear.Methods: We first assessed the differences in the composition of the bacterial community between CCl4-induced liver cirrhosis and control mice using 16S rRNA sequencing. We then performed a two-sample Mendelian randomization (MR) analysis to reveal the underlying causal relationship between the gut microbiota and liver cirrhosis. Causal relationships were analyzed using primary inverse variance weighting (IVW) and other supplemental MR methods. Furthermore, fecal samples from liver cirrhosis patients and healthy controls were collected to validate the results of the MR analysis.Results: Analysis of 16S rRNA sequencing indicated significant differences in gut microbiota composition between the cirrhosis and control groups. IVW analyses suggested that Alphaproteobacteria, Bacillales, NB1n, Rhodospirillales, Dorea, Lachnospiraceae, and Rhodospirillaceae were positively correlated with the risk of liver cirrhosis, whereas Butyricicoccus, Hungatella, Marvinbryantia, and Lactobacillaceae displayed the opposite effects. However, the weighted median and MR-PRESSO estimates further showed that only Butyricicoccus and Marvinbryantia presented stable negative associations with liver cirrhosis. No significant heterogeneity or horizontal pleiotropy was observed in the sensitivity analysis. Furthermore, the result of 16S rRNA sequencing also showed that healthy controls had a higher relative abundance of Butyricicoccus and Marvinbryantia than liver cirrhosis patients.Conclusions: Our study provides new causal evidence for the link between gut microbiota and liver cirrhosis, which may contribute to the discovery of novel strategies to prevent liver cirrhosis.