Assessing causal relationships between gut microbiotas, metabolites, and pulmonary arterial hypertension through univariate Mendelian randomization study and bioinformatics analysis

BACKGROUND: Recent research has linked gut microbiotas and metabolites to the development and progression of pulmonary arterial hypertension (PAH) through the gut-lung axis. However, current studies on the causal relationship between gut microbiotas, gut microbiota derived metabolites, and PAH lack conclusive evidence. This study employed Mendelian randomization and bioinformatics analysis to reveal the possible causal links among them. METHODS: Summary statistics of gut microbiotas, metabolites, and PAH were from GWAS. Univariate Mendelian randomization (inverse variance weighted and weighted median), reverse Mendelian randomization, and verification through other PAH GWAS cohorts were used to analyze the possible causal relationships between these gut microbiotas or gut microbiota derived metabolites and PAH. In addition, Cochran's Q statistic, MR-Egger regression intercept, MR-PRESSO global test, and the leave-one-out method were used for the sensitivity analysis. Based on this, we carried out an initial bioinformatics analysis to investigate its potential biological mechanisms. RESULTS: Preliminary screening of the present research revealed four gut microbiotas ( Genus Eubacteriumfissicatenagroup , Genus RuminococcaceaeUCG002, Genus Tyzzerella3, and Genus Sutterella) and one metabolite (taurolithocholate 3-sulfate) correlated with PAH. However, after validation in other PAH GWAS cohorts, only genetically increased Genus Tyzzerella3 (odds ratio: 0.54, 95% confidence interval: 0.37-0.80, P = 0.0018) correlated with a reduced risk for PAH, a relationship may be related to the keratan sulfate and glycosphingolipid synthesis. No significant heterogeneity, pleiotropy, or reversal causation effect was observed ( P > 0.05). CONCLUSION: Our Mendelian randomization analysis establishes a significant correlation between Genus Tyzzerella3 and PAH, positioning it as a prominent protective factor for PAH.