Study on molecular mechanisms related to hepatic fibrosis by Mendelian randomization combined with transcriptome analysis

Abstract

Abstract Background Recent studies have proved the association between the gut microbiota (GM) through gut-brain axis and liver diseases, including hepatic fibrosis (HF) and hepatic encephalopathy (HE). Nevertheless, the specific gut microbial taxa identified in these studies have shown variability. Furthermore, it's important to note that observational studies cannot definitively demonstrate causation.Our study aims to explain the potential causal relationship between gut flora and HF and HE through transcriptome and Mendelian randomization analysis.Methods: A Mendelian randomization study was conducted using pooled statistics from the MiBioGen database of genome-wide Association Studies (GWAS) of GM and HF. The main analytical method for evaluating causality was the inverse variance weighting (IVW) method. In addition, sensitivity analyses were performed using Cochrane's Q test, MR-Egger intercept test, MR-PRESSO global test and leave-one analysis. Subsequently, transcriptomic analysis was conducted to assess variations in gene expression in patients with HF, investigating their potential correlations with immune cell infiltration and immune factor levels. The relationship between these genes and HE was also investigated.Results: At the site significance level, it was found that the presence of Lachnospiraceae(OR = 1.981, 95%CI: 1.183 − 3.315, P = 0.009) may be associated with a high risk of HF, while Butyricicoccus(OR = 0.414, 95%CI: 0.227 − 0.756, P = 0.004) is associated with a low risk of HF. In addition, SNP-related genes were extracted in the expression profile of GSE57193, which were successively COPG2, KLF14 and TSGA13. Our study also revealed the differences in the expression of related genes in patients with HF, as well as correlations with levels of immune cell infiltration and immune factors. The results revealed that these genes are significantly associated with immune cells and immune factors and play an important role in the immune microenvironment. At the same time, this study also explored the relationship between these genes and hepatic encephalopathy and discovered that they are significantly correlated with the regulatory genes of HE and are regulated by multiple transcription factors and signaling pathways.Conclusion: Our study is the first to apply transcriptome and Mendelian randomization analysis to explain the potential causal relationship between gut flora and HF and HE. These findings shed new light on the molecular mechanisms between gut flora and HF and hepatic encephalopathy and may provide valuable insights into their underlying mechanisms for further investigation.