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 (= 108) from Alberta's Tomorrow Project (AB, Canada) were matched for age (56.6 ± 0.9 yr) and body mass index (24.3 ± 0.2 kg/m). Fecal microbiota was analyzed using 16S rRNA sequencing, whereas serum was assessed using untargeted metabolomics and lipidomics. Hypertensive women exhibited selective taxonomic shifts, evidenced by an elevated Firmicutes/Bacteroidetes ratio and enrichment of proinflammatory taxa, includingand. Circulating levels of tryptophan and its proinflammatory metabolite kynurenine were significantly elevated, whereas microbiota-derived indoles, known for their anti-inflammatory effects, were reduced. This metabolic shift was paralleled by a depletion of indole-producing species (,,), suggesting impaired microbial tryptophan-to-indole conversion. Serum inflammatory cytokines, including interferon-γ, tumor necrosis factor-α, and 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 proinflammatory 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.The mechanisms linking gut microbiota to hypertension remain unclear. This study shows that hypertension is linked to shifts in the abundance of functionally relevant gut microbial taxa in middle-aged women. Changes were characterized by expansion of proinflammatory bacteria, systemic inflammation, and altered metabolite production. Specifically, we show hypertension to modify microbial-driven tryptophan metabolism, enhance proinflammatory kynurenine while reducing anti-inflammatory indole. This metabolic imbalance amplifies inflammation, revealing a previously unrecognized microbiota-dependent pathway contributing to hypertension. n Anaerostipes Collinsella Alistipes shahii Bacteroides faecichinchillae Bacteroides stercoris2NEW & NOTEWORTHY
