Effects of Dendrobium officinale on chronic fatigue in rats: Modulation of tryptophan metabolism.

ETHNOPHARMACOLOGICAL RELEVANCE: Chronic fatigue is a prolonged and persistent state of mental and physical exhaustion that is not readily relieved by rest. Dendrobium officinale Kimura & Migo (D. officinale), a traditional tonic medicinal and edible herb, which have been reported to possess diverse pharmacological activities, including anti-fatigue, immunomodulatory, and gut microbiota-modulating effects. Nevertheless, the effects and underlying mechanisms on chronic fatigue remain largely unexplored.

AIM OF THE STUDY: This study aimed to evaluate the effects of D. officinale in a rat model of chronic fatigue induced by complex poor lifestyles, and to elucidate the underlying mechanisms via tryptophan (TRP) metabolic modulation.

MATERIALS AND METHODS: A rat model of chronic fatigue was established through complex poor lifestyles, including over stress, inadequate sleep, irregular diet, and over work. The animals were then randomly allocated into five groups: a normal control group (NC), a model control group (MC), and three groups treated with D. officinale water extract (DOW) at doses of 0.1, 0.2, and 0.4 g/kg via oral gavage. After a 4-week intervention, the effects of DOW were subjected by general sign observation, swimming test, elevated plus maze (EPM) and open field tests (OFT). Furthermore, 16S rRNA gene sequencing, LC-MS analysis, Western blotting (WB), and quantitative real-time PCR (qRT-PCR) were performed to assess gut microbiota composition, TRP metabolites, and key metabolic enzymes, thereby elucidating the potential mechanisms by which DOW ameliorates chronic fatigue.

RESULTS: DOW markedly improved exercise endurance, alleviated depression-like behaviour as well as attenuated dysregulation of the neuroendocrine-immune (NEI) system. In addition, DOW modulated gut microbiota disturbances and substantially increased the levels of TRP-derived indole metabolites, including indole (IDN), indole-3-acetic acid (IAA), indole-3-propionic acid (IPA), and indole-3-aldehyde (IAld). Meanwhile, it restored the inhibited kynurenine (KYN) metabolic pathway and promoted hepatic expression of key KYN-pathway enzymes, including tryptophan 2,3-dioxygenase 2 (TDO2), kynurenine 3-monooxygenase (KMO), and kynurenine aminotransferase 1 (KAT1), thereby enhancing the production of downstream KYN metabolite, including 3-Hydroxyanthranilic acid (3-HAA), Quinolinic acid (QA), Picolinic acid (PA), and Xanthurenic acid (XA). Correlation analysis further demonstrated that the alleviation of chronic-fatigue-related symptoms and behavioral abnormalities by DOW was strongly associated with its regulation of TRP metabolism.

CONCLUSION: DOW effectively alleviated chronic fatigue induced by complex poor lifestyles in rats, and its underlying mechanism may involve modulating the gut microbiota to enhance the synthesis of indole-derived metabolites, and upregulating the expression of key enzymes in the KYN pathway to promote the generation of KYN-derived metabolites, thereby restoring TRP metabolic homeostasis.