Mendelian randomization supports causality between gut microbiota and chronic hepatitis B.

Abstract

Observational studies have provided evidence of a close association between gut microbiota and the progression of chronic hepatitis B (CHB). However, establishing a causal relationship between gut microbiota and CHB remains a subject of investigation. Genome-wide association study (GWAS) summary data of gut microbiota came from the MiBioGen consortium, while the GWAS summary data of CHB came from the Medical Research Council Integrative Epidemiology Unit (IEU) Open GWAS project. Based on the maximum likelihood (ML), Mendelian randomization (MR)-Egger regression, inverse variance weighted (IVW), MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO), and weighted-mode and weighted-median methods, we conducted a bidirectional, two-sample, MR analysis to explore the causal relationship between the gut microbiota and CHB. Additionally, we evaluated the genetic associations between individual gut microbes and CHB using the Linkage disequilibrium score regression (LDSC) program. According to the IVW method estimates, genetically predicted class Alphaproteobacteria (odds ratio [OR] = 0.57; 95% confidence interval [CI], 0.34-0.96; false discovery rate [FDR] = 0.046), genus Family XIII AD3011 group (OR = 0.60; 95% CI, 0.39-0.91; FDR = 0.026), genus Prevotella 7 (OR = 0.73; 95% CI, 0.56-0.94; FDR = 0.022) exhibited a protective effect against CHB. On the other hand, family Family XIII (OR = 1.79; 95% CI, 1.03-3.12; FDR = 0.061), genus Eggerthella group (OR = 1.34; 95% CI, 1.04-1.74; FDR = 0.043), genus Eubacterium ventriosum group (OR = 1.59; 95% CI, 1.01-2.51; FDR = 0.056), genus Holdemania (OR = 1.35; 95% CI, 1.00-1.82; FDR = 0.049), and genus Ruminococcus gauvreauii group (OR = 1.69; 95% CI, 1.10-2.61; FDR = 0.076) were associated with an increased risk of CHB. The results from LDSC also indicated a significant genetic correlation between most of the aforementioned gut microbiota and CHB. Our reverse MR analysis demonstrated no causal relationship between genetically predicted CHB and gut microbiota, and we observed no significant horizontal pleiotropy or heterogeneity of instrumental variables (IVs). In this study, we identified three types of gut microbiota with a protective effect on CHB and five types with an adverse impact on CHB. We postulate that this information will facilitate the clinical prevention and treatment of CHB through fecal microbiota transplantation.