Tryptophan-Kynurenine shunt and depletion of indole-producing Firmicutes: A new Gut-Heart axis in Calcific Aortic Stenosis (GUT-CAS)
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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.
Novelty and Significance
What Is Known?
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Calcific aortic stenosis is a progressive fibro-calcific valvular disease driven by lipid accumulation, chronic inflammation, and osteogenic remodeling of valvular interstitial cells, for which no pharmacological therapy has proven effective.
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Gut microbiota modulate host cardiovascular homeostasis through bioactive metabolites including TMAO, bile acids, short-chain fatty acids, and tryptophan derivatives, yet their specific contribution to valvular disease remains poorly defined.
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LDL cholesterol and lipoprotein(a) are established risk factors for CAS, but the downstream immunometabolic consequences of valvular disease — and whether gut-derived pathways contribute causally — remain unknown.
What New Information Does This Article Contribute?
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This study demonstrates that CAS is associated with a targeted gut–host immunometabolic reprogramming — defined by preferential tryptophan routing toward the inflammatory kynurenine pathway and depletion of indole-producing microbiota — rather than global dysbiosis, identifying a disease-specific rather than generic gut disturbance signature.
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Depletion of Eubacterium coprostanoligenes in statin-naïve CAS patients implicates impaired microbial cholesterol-to-coprostanol transformation as a previously unrecognized gut-mediated mechanism linking intestinal cholesterol retention to valvular lipid accumulation, independent of bile acids and TMAO.
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Bidirectional Mendelian randomization establishes a causal hierarchy in CAS — positioning LDL and Lp(a) as upstream drivers and kynurenine pathway metabolites as downstream disease sequelae — while sex-stratified analyses reveal divergent gut–host programs that may underlie the well-described sex dimorphism in CAS phenotype.
Despite growing evidence for gut–cardiovascular interactions, no study has examined the microbiota– metabolite axis in CAS using an integrated multi-omics approach with causal inference. By combining 16S rRNA sequencing, targeted metabolomics, and bidirectional Mendelian randomization in a prospective BMI-matched cohort, this study moves beyond associative profiling to establish mechanistic and causal relationships. We show that CAS involves two discrete gut-mediated pathways, inflammatory tryptophan catabolism and impaired microbial cholesterol clearance, operating in the absence of global dysbiosis. Sex-stratified findings further reveal that these pathways are differentially engaged in males and females, providing a biological framework for sex-informed therapeutic strategies targeting the gut–valve axis.
