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Using a male mouse 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\u207a\/CD8\u207a 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 pro-inflammatory T cell responses, and maintain lacrimal gland homeostasis. Transcriptomic and immunohistochemical analyses further reveal that all three interventions converge on the\u00a0downregulation of IL-17 signaling. Collectively, these findings establish an HPA-gut microbiome-lacrimal gland axis that links neuroendocrine stress to microbial dysbiosis and ocular inflammation, and they suggest therapeutic strategies for SD-associated lacrimal gland dysfunction.<\/jats:p>","DOI":"10.1038\/s42003-026-09657-0","type":"journal-article","created":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T11:36:49Z","timestamp":1770377809000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Sleep deprivation disrupts lacrimal gland homeostasis via hypothalamic-pituitary-adrenal axis and gut dysbiosis in mice"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2711-146X","authenticated-orcid":false,"given":"Shenzhen","family":"Huang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shufan","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxiao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoting","family":"Pei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dingli","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengru","family":"Ba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuting","family":"Xuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duliurui","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingwen","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3186-144X","authenticated-orcid":false,"given":"Zhijie","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,6]]},"reference":[{"key":"9657_CR1","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1146\/annurev-psych-010213-115205","volume":"66","author":"MR Irwin","year":"2015","unstructured":"Irwin, M. 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