Bile acid metabolism and sleep: Mechanistic interplay and clinical implications of the gut–liver–brain axis

Abstract The bidirectional interplay between sleep and metabolic homeostasis is fundamental to physiological health. While the roles of glucose and lipid metabolism in sleep regulation have been extensively characterized, bile acids (BAs), which are traditionally viewed as digestive surfactants, are emerging as critical metabolic messengers with distinct circadian rhythmicity and pleiotropic signaling functions. This review systematically elucidates the signaling network of the gut–liver–brain axis mediated by BAs through the nuclear Farnesoid X receptor and the membrane Takeda G protein‐coupled receptor 5. Accumulating evidence suggests that BAs are not only precisely regulated by the hepatic circadian clock but also modulate the central nervous system function by crossing the blood–brain barrier or via vagal afferent pathways. Specifically, recent findings highlight that aberrantly elevated BAs can infiltrate the central nervous system to disrupt the master circadian clock and modulate neurocircuitry governing arousal, thereby contributing to sleep fragmentation and circadian misalignment. Furthermore, this review discusses the potential of BA profiles as systemic biomarkers in obstructive sleep apnea, chronic insomnia, and related metabolic comorbidities. Finally, we propose that targeting BA metabolic receptors and the gut microbiota represents a promising translational strategy for the management of sleep disorders and their metabolic consequences.