Molecular mechanisms of polyphenols for the treatment of insomnia through the modulation of gut-brain axis and mitochondrial metabolism

Insomnia is one of the neurodegenerative disorders in which the duration or quality of sleep is insufficient and is accompanied by severe distress and daytime dysfunction. However, current pharmacological interventions were accomponied with  unavoidable side effects. In recent years, natural polypheonls were in the spotlight of treating insomnia with high efficacy and less side effects. This review systematically examines the therapeutic effects of polyphenols on insomnia, focusing on the underlying molecular mechanisms involving the neurotransmitters, gut-brain axis and mitochondrial function. Evidence suggests that polyphenols enhance sleep quality by modulating γ-aminobutyric acid receptors, serotonin 5-hydroxytryptamine, and dopamine levels within the central nervous system. Meanwhile, polyphenols could improve the intestinal environment by improving insomnia-induced intestinal barrier disorders, gut flora disorders, and down-regulation of metabolite and neurotransmitter expression. Polyphenols also inhibits the production of inflammatory factors in the gut, hypothalamic-pituitary-adrenal axis, vagus nerve, and brain to alleviate insomnia-induced neuroinflammation from the gut-brain axis pathway. In addition, polyphenols have the ability to restore mitochondrial function via inhibiting the expression of inflammatory factors and pathways, and  reactivating mitochondrial autophagy, thereby improving insomnia. This review provides deep insights for the development of therapeutic strategies against insomnia, as well as other neurodegenerative disorders.