The gut microbiota and plasma metabolites on functional dyspepsia: a study integrating Mendelian randomization and experimental validation

Objective This two-sample Mendelian randomization (MR) investigation aimed to explore how gut microbiota influences functional dyspepsia (FD) via plasma metabolites. The results were then confirmed in vivo . Methods A GWAS of 7,738 people was used to generate genetic instruments for 412 gut microbiota characteristics. The NHGRI-EBI GWAS Catalog listed 1,400 plasma metabolites, and the FinnGen biobank provided FD summary statistics. Using the inverse-variance weighted (IVW) approach, potential causal links between gut microbiota and plasma metabolites in FD were assessed. To make sure it was resilient, pleiotropy and heterogeneity evaluations were performed. For experimental validation, the combination of 0.2% iodoacetamide gavage combined with tail-clamp stress was used to create an FD rat model. Fecal and plasma samples from the rats were analyzed to verify the MR findings. Results Three gut microbiota taxa and two microbial metabolic pathways were identified to be associated with FD. The superpathway of pyridoxal 5′-phosphate biosynthesis and salvage (OR: 0.89; 95% CI: 0.81–0.97; p = 0.01), p_Actinobacteria (0.85, 0.77–0.94, p = 0.002), and s_Bifidobacterium adolescentis (0.86, 0.75–0.97, p = 0.017) were protective factors against FD. In contrast, the superpathway of menaquinol-8 biosynthesis II (1.13, 1.03–1.25, p = 0.01) and s_Lachnospiraceae bacterium_5_1_63FAA (1.09, 1.02–1.16, p = 0.008) were identified as risk factors. MR analysis of 1,400 plasma metabolites using IVW, weighted median, and other methods ( p < 0.05), along with pleiotropy and heterogeneity tests, suggested that these three microbiota features and two pathways may influence FD pathogenesis through the regulation of 81 plasma metabolites or metabolite ratios. Animal studies further identified the p_ Actinobacteria and two differential metabolites: alpha-hydroxyisocaproate and kynurenate. Conclusion Three gut microbiota taxa and two pathways reflecting microbial composition and activity were associated with FD and linked to alterations in 81 metabolites or metabolite ratios. This study identifies a correlation between altered p_ Actinobacteria abundance and changes in alpha-hydroxyisocaproate and kynurenate levels in FD, offering a perspective centered on the gut microbiota and metabolites for the early detection, diagnosis, and treatment of this condition.