Altered Tryptophan Metabolism and Gut Immune Crosstalk in Hypertensive Middle-Aged Women

The gut microbiome is increasingly recognized as a contributing factor in the pathogenesis of hypertension; however, there remains a significant gap regarding its role in middle-aged women, a demographic that has unique physiological and hormonal characteristics influencing both microbiome composition and blood pressure. Normotensive and hypertensive middle-aged women (n=108) from Alberta’s Tomorrow Project (AB, Canada) were matched for age (56.6 ± 0.9 years) and body mass index (24.3 ± 0.2 kg/m²). Fecal microbiota was analyzed using 16S rRNA sequencing while serum was assessed using untargeted metabolomics and lipidomics. Hypertensive women exhibited selective taxonomic shifts, evidenced by an elevated Firmicutes/Bacteroidetes ratio and enrichment of pro-inflammatory taxa, including Anaerostipes and Collinsella. Circulating levels of tryptophan and its pro-inflammatory metabolite kynurenine were significantly elevated, while microbiota-derived indoles, known for their anti-inflammatory effects were reduced. This metabolic shift was paralleled by a depletion of indole-producing species ( Alistipes shahii, Bacteroides faecichinchillae, Bacteroides stercoris), suggesting impaired microbial tryptophan-to-indole conversion. Serum inflammatory cytokines, including interferon-γ, tumor necrosis factor-α, and an elevated IL-12/IL-10 ratio, were increased in hypertensive participants. Notably, kynurenine was positively correlated with the IL-12/IL-10 ratio. Hypertension in middle-aged women is associated with altered abundance of functionally relevant taxa characterized by shifts in tryptophan metabolism toward pro-inflammatory kynurenine pathways at the expense of protective indole derivatives. Collectively, these findings highlight gut-immune-metabolic cross-talk contributing to hypertension and suggest microbiota-regulated tryptophan metabolism as a potentially modifiable therapeutic target.