Causal relationship between gut microbiome, plasma metabolites, inflammation, and aortic stenosis: A multi-omics Mendelian randomization analysis

As life expectancy increases and the population ages, aortic stenosis (AS) is the most common heart valve disease. Despite rapid improvements in interventional treatment options in recent years, morbidity and mortality from asymptomatic AS remain high. To date, there is no pharmacological therapy to prevent AS. In this study, we used multi-omics to systematically investigate potential causal association between the gut microbiome, human blood metabolites, inflammation and risk of AS, and search for potential biomarker for AS. Single-nucleotide polymorphisms associated with 207 gut microbiota, 1091 blood metabolites and the ratios of 309 metabolites, 731 immune cell phenotypes, 91 circulating inflammatory proteins, as exposures all were selected from recent large genome-wide association study and explored their causal association with AS using Mendelian randomization methods. We used the inverse variance weighted estimation method as the main method and other methods as supplementary methods. Mendelian randomization analysis has shown that 7 gut microbiota, 80 metabolites, 29 immune cells phenotypes, and 6 circulating inflammatory proteins are causally associated with AS. Co-localization analysis showed a significant correlation between 1-stearoyl-2-acryloyl-GPE levels and AS, with a P -value of .981 for posterior probability for hypothesis 4. In addition, metabolic pathway analysis revealed that the valine, leucine, and isoleucine biosynthesis ( P = .0312) pathways were associated with AS. Four omics, including 207 gut microbiota, 1091 blood metabolites and the ratios of 309 metabolites, 731 immune cells, and 91 inflammatory proteins were used in this study to explain the causal relationship between multi-omics and AS.