Identifying Causal Relations between Gut Microbiome, Metabolic Dysfunction-Associated Fatty Liver Disease and the Novel Mediators of Blood Metabolites

Abstract Background Research has established connection between gut microbiome and the risk of metabolic dysfunction-associated fatty liver disease (MAFLD). However, the causal relationships and the roles of potential mediating factors, such as blood metabolites, remain unclear. Methods We conducted a bidirectional and mediation Mendelian randomization (MR) study using the genome-wide summary statistics of gut microbial taxa (Dutch Microbiome Project, n = 7,738), blood lipids (UK Biobank, n =8,299), and the largest MAFLD GWAS data (1,483 cases and 17,781 controls). We used the inverse-variance weighted estimation method as our primary approach. The multivariable Mendelian randomization (MVMR) and two-step MR approaches were used to prioritize the most likely causal metabolites as mediators. Additionally, we conducted linkage disequilibrium score regression (LDSC) analyses to assess genetic correlations, and downstream gene-based analyses to investigate the shared biological mechanism. Results By testing the causal effects of 205 bacterial pathways and 207 taxa on MAFLD, we identified 5 microbial taxa causally associated with MAFLD, notably the species Parabacteroides merdae (OR [95%CI] = 1.191[1.022-1.388], p = 0.025). Among 1,399 blood metabolites, 53 showed causal associations with MAFLD, with pregnenetriol sulfate identified as a mediator for genus Parabacteroides on MAFLD (proportion mediated = 16.30%). LDSC analysis also provided suggestive evidence for a potential genetic correlation between them (r g = 2.124, p =0.009). Conclusions The study suggested a novel causal relationship between gut microbial taxa and MAFLD, especially the genus Parabacteroides merdae and blood metabolite pregnenetriol sulfate might mediate this relationship. Importance Our study reveals novel insights into how the intersection of microorganisms living in the human gut, known as the gut microbiome, influences the development of Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD), a condition increasingly recognized as a major global health concern. By identifying specific gut microbiome taxa and metabolites that contribute to the onset and progression of MAFLD, our findings enhance comprehension of this prevalent condition and unveil promising prospects for its prevention and intervention. We discovered that certain gut bacteria can affect the levels of blood metabolites, which in turn impact the liver’s health. This work carries significant implications for novel strategies for MAFLD prevention and treatment, including interventions aimed at modifying the gut microbiome. Our research underscores the gut-liver connection and its implications for metabolic diseases, contributing to future therapeutic developments that could improve public health worldwide. Graphic abstract