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

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.

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.

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.

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.

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.