Decoding Links between Gut Microbiota and Metabolic-associated Fatty Liver Disease: Meta-analysis and Mediation Study Uncover Species-specific Taxa and a Novel Bile Acid Mediator.

OBJECTIVE: Previous Mendelian randomization (MR) studies have suggested an association between the gut microbiome and metabolic-associated fatty liver disease (MAFLD). However, the reliance on 16S rRNA sequencing data has led to inconsistent findings and limited species-level insights. To address this, we conducted a de novo MR analysis using species-level shotgun metagenomic data, combined it with a meta-analysis to consolidate the existing evidence, and explored metabolite-mediated pathways.

METHODS: Bidirectional MR analyses were performed between 883 gut microbiota taxa (derived from shotgun metagenomic genome-wide association study) and MAFLD. Published MR studies (up to December 1, 2024) were identified using PubMed, Embase, Web of Science, and the Cochrane Library for meta-analysis. Multivariable MR (MVMR) and mediation analyses were applied to assess the mediating effects of 1,400 blood metabolites.

RESULTS: The de novo MR identified 25 MAFLD-associated microbial taxa. Integration with 7 published studies revealed 34 causal taxa, including 10 at the species level. Among the 1,400 metabolites, 53 showed causal links with MAFLD. MVMR and mediation analyses identified deoxycholate as a mediator of the effect of Bifidobacterium on MAFLD risk (22.06% mediation proportion).

CONCLUSION: This study elucidated the connections between species-level gut microbiota and MAFLD, highlighting the interplay between microbiota, metabolites, and disease pathogenesis. These findings provide novel insights into the potential therapeutic targets for MAFLD.