Gut microbiota tryptophan and cholesterol pathways alterations in calcific aortic stenosis
C Chong-Nguyen, S Atighetchi, C Ferro, B Yilmaz, H Sokol, M Siepe, D Reineke, D Tomii, M Nakase, C Dupuy, Y Banz, L Nadal-Desbarats, C Wingert, Y Doering, T PilgrimAbstract
Background
Calcific aortic stenosis (CAS) is a progressive valvular disease characterized by lipid accumulation, inflammation, and osteogenic remodeling. However, the contribution of gut microbiota dysbiosis and microbial-derived metabolites—particularly tryptophan (TRP) metabolic pathways—remains incompletely understood and the cholesterol-related mechanisms remain unclear.
Objective
To characterize gut microbiota composition and circulating microbial-derived metabolites associated with CAS, with a specific focus on TRP metabolism, independently of body mass index (BMI).
Methods
In a prospective cohort including 55 CAS patients and 55 non-CAS controls, gut microbiota composition was assessed using 16S rRNA sequencing, and targeted serum metabolomics quantified TRP-derived metabolites, short-chain fatty acids (SCFAs), bile acids, and TMA/TMAO-related metabolites. Comparisons between CAS and non-CAS patients were performed in the full cohort and after BMI matching. Effect sizes were estimated using Cliff’s delta for metabolites and Cohen’s f² for microbial taxa, with multiple testing correction using the Benjamini–Hochberg method.
Results
Baseline characteristics including age, sex distribution, cardiovascular risk factors, medication use, and coronary artery disease were comparable between groups (p > 0,05). CAS patients exhibited a distinct TRP metabolic signature characterized by consistent upregulation of inflammatory kynurenine pathway metabolites compared to non CAS patients. After BMI matching, CAS patients showed higher concentrations of xanthurenic acid (p=0.039), indole-3-acetamide (p=0.045), and 3-hydroxyanthranilic acid (p=0.028), with concordant effect sizes (Cliff’s δ ≈0.23–0.28). Kynurenine levels demonstrated a consistent upward trend (p≈0.06). At the microbial level, CAS was associated with depletion of Firmicutes-related taxa, including Eubacterium coprostanoligenes, a cholesterol-reducing bacterium involved in the conversion of cholesterol to coprostanol, suggesting impaired gut-mediated cholesterol metabolism. In multivariable logistic regression, BMI category remained independently associated with CAS status (β=1.21, p=0.024), supporting a contributory role of metabolic status beyond microbiota-derived signatures.
Conclusion
CAS is associated with a coherent gut microbiota–metabolite signature reflecting a state of chronic low-grade inflammation, characterized by activation of the kynurenine arm of tryptophan catabolism and depletion of cholesterol-modulating bacterial taxa. These alterations persist after BMI matching, indicating disease-specific inflammatory and metabolic remodeling beyond shared cardiometabolic risk factors. Together, these findings support a gut–cholesterol–TRP–inflammation axis contributing to the initiation and progression of valvular calcification.Summary Figure