Background. Hypertension affects over 1.28 billion adults worldwide, including a significant number of women. Although the gut microbiome is implicated in the onset and progression of hypertension, few studies have examined the relationship in middle-aged women. Methods. Within an established cohort, we investigated the relationship between gut microbiota and its metabolites in normotensive vs. hypertensive middle-aged women (n=108) matched for age (56.6+/-0.91 years) and body mass index (24.3+/-0.24 kg/m2). Fecal microbiota analysis was performed using 16S rRNA sequencing and serum metabolites were analyzed using LC-MS/QTOF. Associations between the microbiota, metabolomic alterations and systemic inflammatory cytokines were statistically examined to uncover their interrelationships and potential role in disease progression. Results. Women with hypertension had gut dysbiosis with an increased Firmicutes/Bacteroidetes ratio and higher abundances of inflammatory taxa including Anaerostipes and Collinsella. Untargeted serum metabolomics demonstrated that hypertensive participants had elevated levels of tryptophan, the pro-inflammatory metabolite kynurenine and lower levels of health-promoting indoles produced by the action of gut microbiota on tryptophan (p<0.05). These findings were confirmed in microbiota analysis showing a reduced abundance of indole-producing species (Alistipes shahii, Bacteroides faecichinchillae, Bacteroides stercoris)(p<0.05) suggesting a lower microbial activity of tryptophan-indole metabolism. Furthermore, hypertension increased inflammatory markers including an elevated IL12/IL10 ratio, interferon-? and tumor necrosis factor-?. The IL-12/IL-10 ratio demonstrated a positive correlation with kynurenine levels, emphasizing the involvement of cytokines and gut microbiota in driving systemic inflammation in hypertension. Conclusion. Imbalances in microbiota-regulated tryptophan metabolism contribute to systemic inflammation in hypertensive, middle-aged women, presenting a potentially modifiable target for intervention.

The authors have declared no competing interest.

Not a clinical trial

This work was supported by a grant of the Bundesministerium für Bildung und Forschung (BMBF, Germany, FKZ: 0315540) and by a grant of the ERA-HDHL Initiative: Gut metabotypes as Biomarkers for Nutrition and Health (BLE, Germany, FKZ: 2816ERA14E & 2816ERA13E and the National Science and Engineering and Research Council (NSERC, Canada) SS and CM received funding from Eye?s High Fellowships at the University of Calgary.

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The Conjoint Health Research Ethics Board at the University of Calgary (REB17-1973) granted approval for the study.

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The 16S rRNA gene-sequences data supporting the conclusions of this article are deposited at the National Center for Biotechnology Information (BioProject SRA PRJNA922681).