Tryptophan-Kynurenine shunt and depletion of indole-producing Firmicutes: A new Gut-Heart axis in Calcific Aortic Stenosis (GUT-CAS)

Introduction: Calcific aortic stenosis (CAS) is a progressive valvular disease characterized by lipid accumulation, inflammation, and osteogenic remodeling. Emerging evidence implicates gut microbiota-derived metabolites in cardiovascular pathology, yet their contribution to valvular disease remains poorly defined. The aim of this study was to investigate gut microbiota and metabolite signatures in patients with CAS and explore causal relationships using Mendelian randomization (MR). Methods: In a prospective cohort of 54 patients with CAS and 41 age, sex, BMI-balanced non-CAS controls, we performed integrated microbiome and metabolomic profiling. Gut microbial composition was assessed by 16S rRNA sequencing, and circulating levels of tryptophan derivatives, short-chain fatty acids, bile acids, and TMA/TMAO-related metabolites were quantified. MR analyses were performed to assess causal contributions of key metabolic and inflammatory markers to CAS. Results: Baseline characteristics were comparable between groups. CAS patients exhibited a distinct tryptophan metabolic profile, characterized by higher concentrations of inflammatory kynurenine-pathway metabolites and lower indole-3-sulfate. With consistent effect sizes despite modest statistical significance after multiple testing correction. Pathway-level analyses supported preferential routing of tryptophan toward inflammatory host metabolism. In contrast, global microbiota diversity and overall community structure were preserved. However, CAS was associated with depletion of specific Firmicutes taxa, including Eubacterium coprostanoligenes, a key cholesterol-converting bacterium mediating intestinal cholesterol-to-coprostanol transformation. MR analyses suggested LDL cholesterol and lipoprotein(a) as upstream triggers of CAS, whereas ALPL and tryptophan/kynurenine metabolites appear downstream and might reflect systemic inflammation and local metabolic consumption. Sex-stratified analyses revealed enhanced kynurenine pathway activation in males, whereas females exhibited relatively higher TMAO and indole-related metabolites. Conclusion: CAS is characterized by a focused gut-host metabolic reprogramming defined by inflammatory tryptophan catabolism and loss of cholesterol-transforming microbial functions, rather than global dysbiosis. These findings identify a potential gut, valve metabolic axis contributing to valvular calcification, with potential sex-specific effects.