Jing-Wen Yue, Yun-Feng Fang, Li Jiang, Tong-Shuai Wang, Zhen-Xian Zhang
Dysregulation of the tryptophan metabolic network-characterized by kynurenine pathway activation, 5-HT pathway inhibition, and microbial-indole pathway imbalance-is a key pathological mechanism in hypertension. These key molecules regulate targets such as SLC6A4, KYNU, and SLC6A2, potentially offering mechanistic insights for future precision intervention studies.
OBJECTIVE: This study aimed to characterize serum metabolic profiles in hypertensive patients and investigate the regulatory role of tryptophan metabolism.
METHODS: We employed an integrated metabolomics strategy that combined non-targeted screening with targeted validation. From November 2022 to November 2023, we enrolled 25 newly diagnosed, treatment-naïve hypertensive patients and 25 age- and sex-matched healthy controls (1:1 ratio) from a local Shanghai hospital, together with their clinical baseline data. Non-targeted metabolomics, combined with Principal Component Analysis (PCA) and Orthogonal Partial Least Squares Discriminant Analysis (OPLS-DA) were used to identify differential metabolic pathways. Subsequent targeted metabolomics analysis was conducted to quantify key molecules involved in the tryptophan metabolic pathway.
RESULTS: Non-targeted metabolomics revealed 2,931 metabolites, with 759 showing differential expression (296 up-regulated and 463 down-regulated), emphasizing tryptophan metabolism as the central dysfunctional pathway. Targeted validation confirmed abnormalities in three branches of tryptophan metabolism: 5-hydroxytryptamine (5-HT) was down-regulated by 30% (Fold change = 0.69, P = 0.002), while five metabolites, such as 5-HT acid (Fold change = 1.33, P = 0.002) and kynurenine (Fold change = 1.35, P = 0.004), exhibited significant up-regulation (all P < 0.05). Network pharmacology analysis indicated strong binding affinities between tryptamine metabolites (Serotonin and L-5-Hydroxytryptophan), kynurenine metabolites (3-Hydroxykynurenine and Kynurenine), and indole metabolites (Hydroxyindoleacetic acid and Indolelactic acid) with their respective targets SLC6A4, KYNU, and SLC6A2.
CONCLUSION: Dysregulation of the tryptophan metabolic network-characterized by kynurenine pathway activation, 5-HT pathway inhibition, and microbial-indole pathway imbalance-is a key pathological mechanism in hypertension. These key molecules regulate targets such as SLC6A4, KYNU, and SLC6A2, potentially offering mechanistic insights for future precision intervention studies.