Sex-specific modulation of gut-derived metabolites in calcific aortic stenosis
C Chong-Nguyen, S Atighetchi, C Ferro, B Yilmaz, H Sokol, M Siepe, D Reineke, D Tomii, M Nakase, C Wingert, C Dupuy, L Nadal-Desbarats, Y Banz, Y Doering, T PilgrimAbstract
Background
Sex-related differences in calcific aortic stenosis (CAS) are increasingly recognized, with divergent clinical presentation, valve morphology, and calcification burden. Whether gut microbiota–derived metabolites contribute to these sex-specific differences remains largely unexplored.
Objective
To investigate sex-specific differences in gut-derived metabolite profiles in patients with CAS and to assess CAS × sex interactions.
Methods
Among 55 patients with CAS (41 men, 14 women), targeted serum metabolomics quantified TRP-derived metabolites, bile acids, SCFAs, and TMA/TMAO-related metabolites and 16s RNA sequencing was performed. Sex-stratified analyses and CAS × sex interaction models were performed.
Results
Baseline characteristics revealed sex-specific differences in hemoglobin, lipid profile (total and HDL cholesterol), and aortic valve area, while age, BMI, renal function, and aortic valve calcium score were comparable between sexes (p>0,05). Distinct sex-specific metabolic signatures were observed. In males with CAS, inflammatory TRP metabolites—including kynurenine (p=0.040), 3-hydroxyanthranilic acid (p=0.045), and xanthurenic acid (p=0.015)—were significantly higher compared with non-CAS males. In contrast, females with CAS demonstrated higher TMAO levels compared with non-CAS females (p=0.087). Direct comparison between CAS females and males revealed lower picolinic acid and kynurenic acid, but higher indole-3-acetamide and indole-3-lactic acid in females (all p<0.05). Significant CAS × sex interactions were observed for cholic acid (p=0.016) and trimethylamine (p=0.019), indicating sex-dependent modulation of gut-derived metabolic pathways. At the taxonomic level, sex-specific differences in gut microbiota composition were modest but consistent. Females with CAS showed higher relative abundance or prevalence of Bifidobacterium and Lactobacillus/Leuconostoc, whereas males exhibited higher representation of Coriobacteriaceae and Actinobacteria, taxa previously associated with cardiometabolic risk. Notably, some taxa demonstrated differences in prevalence without corresponding differences in relative abundance, or vice versa, highlighting subtle sex-related microbial patterning rather than overt dysbiosis.
Conclusion
CAS is associated with sex-specific gut-derived metabolic signatures, with preferential activation of inflammatory TRP pathways in males and enhanced TMAO-related signaling in females. These findings suggest that sex modulates gut–host metabolic interactions in CAS and support the integration of sex-specific analyses in future mechanistic and therapeutic studies.Summary Figure