Vitamin D3 Improves Hypothalamic–Pituitary–Adrenal Axis Function, Immunological Responses, and Gut Dysbiosis in Sleep Desynchrony

PURPOSE: Chronic sleep desynchrony proliferates in modern society, characterized by extended wakefulness and disrupted circadian rhythms over a long period, and is associated with various physiological and immune dysfunctions. This study investigated the health effects of long-term sleep desynchrony and subsequent vitamin D3 treatment, alongside sleep recovery, on biological factors in C57BL/6J mice by assessing their body weight, metabolic activity, stress response, immune function, and gut microbiota composition. METHODS: Mice underwent 28 days of sleep desynchrony using a Lafayette chamber to model chronic disruption of the HPA axis, immune function, and gut microbiota. FINDING: Sleep desynchrony did not significantly alter body weight, food intake, or water consumption, suggesting that metabolic homeostasis was preserved. However, stress hormone analysis revealed impaired HPA axis regulation in the sleep-desynchronized mice, as indicated by suppressed corticosterone levels after dexamethasone injection. Notably, vitamin D3 treatment restored the HPA axis function by enhancing corticosterone suppression. Behavioral tests of the mice indicated that sleep desynchrony reduced nest-building ability, locomotor activity, and anxiety-like behaviors, whereas vitamin D3 treatment improved their motor function. Furthermore, vitamin D3 treatment alleviated immune dysregulation by reducing neutrophil levels and increasing lymphocyte counts, suggesting a role in restoring immune balance after sleep desynchrony. Regarding gut microbiota composition, sleep desynchrony disrupted microbial diversity, reducing Bacteroidota and increasing Firmicutes, leading to dysbiosis. Vitamin D3 treatment shifted the microbiota composition toward eubiosis, aligning it closer to control-group levels. Additionally, sleep desynchrony impaired the expression of tight junction proteins in the proximal colon, compromising intestinal barrier integrity. Vitamin D3 treatment restored the levels of key tight junction proteins, such as ZO-1 and claudin, thereby maintaining gut barrier function. CONCLUSION: Vitamin D3 treatment serves as a promising intervention for mitigating the adverse health effects of chronic sleep desynchrony on the HPA axis, immune function, and gut microbiota, providing potential therapeutic benefits for preserving physiological homeostasis in the middle of a long-term sleep deficiency or chronic sleep deprivation.