Unraveling the causal relationship between gut microbiota and chronic hepatitis B: A large-scale mediation Mendelian randomization analysis.

Observational evidence links gut microbiota dysbiosis to chronic hepatitis B (CHB) progression, but causal mechanisms remain unclear. Genome-wide association study (GWAS) data for gut microbiota were sourced from the MiBioGen Consortium and Dutch Microbiome Project, with CHB outcome data from the GWAS Catalog. Initial analyses used two-sample and reverse Mendelian randomization (MR) to explore causality between gut microbiota and CHB. Further two-step and multivariable MR analyses revealed mediation by cytokines, metabolites, and immune cells. The study identified 16 microbial taxa causally related to CHB. Bifidobacterium longum (β = -0.298, p = 0.037), Bacteroides coprocola (β = -0.256, p = 0.014), and Bacteroides salyersiae (β = -0.119, p = 0.022) were linked to reduced CHB risk. Ten taxa, including Butyrivibrio (β = 0.164, p = 0.009), Butyrivibrio crossotus (β = 0.227, p = 0.009), Eggerthella sp. id.819 (β = 0.251, p = 0.039), Bacteroides xylanisolvens (β = 0.282, p = 0.026), Dorea longicatena (β = 0.284, p = 0.035), and Prevotella copri (β = 0.349, p = 0.045), were associated with increased CHB risk. Multi-omics analyses identified 1 cytokine, 10 metabolites, and 24 immune cells as key mediators linking gut microbiota to CHB outcome. These findings confirm causal relationships, uncover underlying mechanisms, and enhance understanding of the gut-liver axis in CHB etiology and pathology.