Altered kynurenine and indole tryptophan pathways in calcific aortic stenosis: cross-sectional evidence for a gut-host metabolic imbalance (GUT-CAS)

Background: Calcific aortic stenosis (CAS) is a progressive valvular disease characterized by lipid accumulation and osteogenic remodeling. The contribution of gut microbiota-derived metabolites to CAS remains unclear. Objective: To investigate gut microbiome-associated metabolomic signatures in calcific aortic stenosis and to assess genetic evidence for causal contributions of selected metabolic and inflammatory markers using Mendelian randomization. Methods: In a prospective cohort of 54 CAS patients and 41 BMI-matched controls, we performed integrated 16S rRNA gene sequencing and targeted metabolomic profiling. MR analyses were conducted to assess genetically predicted effects of selected metabolic and inflammatory markers on CAS. Results: The principal finding was a selective activation of tryptophan metabolism toward the kynurenine pathway. The kynurenine-to-indole-3-sulfate (KI) ratio was the only tryptophan metabolite finding to survive BH-FDR correction (p = 0.0031, q = 0.013). Its inverse association with indexed aortic valve area (Spearman rho 0.310, p = 0.036, n = 46) was attenuated after adjustment for age and BMI (p = 0.111), suggesting a relationship that may be partly confounded by these variables. In contrast, global microbiome diversity and overall community structure were preserved. MR analyses identified lipoprotein(a) as a genetically supported causal risk factor for CAS (Wald ratio OR = 1.116, p < 0.001), independent of the gut-related metabolic findings. Exploratory sex-stratified analyses suggested stronger kynurenine-pathway alterations in male patients, but require replication. Conclusion: In this exploratory study, calcific aortic stenosis was associated with a selective shift in tryptophan metabolism toward the kynurenine pathway, observable in the absence of global gut microbial differences. These findings are exploratory and hypothesis-generating, suggesting that altered tryptophan partitioning at the gut-host interface may be a feature of CAS biology warranting prospective validation.