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HPA-Gut Microbiome Axis Dysregulation in Sleep Deprivation: Pharmacological and Microbial Rescue of Lacrimal Gland Homeostasis

ABSTRACT: Sleep deprivation (SD) disrupts systemic homeostasis, yet its impact on lacrimal gland integrity through neuroendocrine–microbial pathways remains unclear. Using a male mice SD model, we show that chronic SD activates the hypothalamic-pituitary-adrenal (HPA) axis, elevates corticosterone, alters gut microbiota, and depletes short-chain fatty acids (SCFAs). These alterations coincide with lacrimal gland atrophy, reduced tear secretion, and increased CD4⁺/CD8⁺ T cell infiltration, accompanied by activation of IL-17-associated inflammatory pathways. Pharmacological inhibition of glucocorticoid synthesis with metyrapone preserves lacrimal gland structure and function while attenuating immune activation. Microbiome-directed interventions, including SCFA supplementation and fecal microbiota transplantation, rebalance gut communities, suppress proinflammatory T cell responses, and maintain lacrimal gland homeostasis. Transcriptomic and immunohistochemical analyses further reveal that all three interventions converge on downregulation of IL-17 signaling. Collectively, these findings establish an HPA-gut microbiome-lacrimal gland axis links neuroendocrine stress to microbial dysbiosis and ocular inflammation, and they suggest therapeutic strategies for SD-associated lacrimal gland dysfunction.

ORGANISM(S): Mus musculus

PROVIDER: GSE302528 | GEO | 2025/12/21

REPOSITORIES: GEO

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HPA-Gut Microbiome Axis Dysregulation in Sleep Deprivation: Pharmacological and Microbial Rescue of Lacrimal Gland Homeostasis

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