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High-altitude hypoxia is closely associated with an increased incidence of depressive symptoms; however, the underlying mechanisms remain unclear. Methods: In this study, mice were subjected to 7 days of hypoxic exposure simulating high-altitude environments at 3000 m (14.4% O2) and 4000 m (12.7% O2). Depressive-like behaviors were assessed using the open field test, tail suspension test, and forced swim test. Enzyme-linked immunosorbent assays were employed to measure markers related to inflammatory responses, oxidative stress, and hypothalamic\u2013pituitary\u2013adrenal (HPA) axis activity. Additionally, 16S ribosomal RNA sequencing was performed to analyze alterations in the gut microbiota. Untargeted metabolomics was used to examine metabolite changes in the colon and hippocampus. Validation analyses included measurements of hippocampal immunofluorescence density and cortical neurotransmitter levels. Results: Hypoxic exposure induced depressive-like behaviors, as well as colonic and hippocampal tissue damage. It also exacerbated inflammation and oxidative stress, reduced gut microbiota diversity, disrupted tryptophan metabolism, decreased cortical neurotransmitter levels and brain-derived neurotrophic factor (BDNF), and increased the immunofluorescence density of hippocampal neuron\u2013glial antigen 2 and oligodendrocyte transcription factor 2. These effects exhibited an intensity\u2013toxicity relationship. Conclusions: Acute hypoxia is associated with gut microbiota imbalance, disrupted tryptophan metabolism, inflammatory responses, and dysfunction of the HPA axis, alongside negative emotional states. These multidimensional alterations are strongly correlated, suggesting a potential regulatory network involving the gut microbiota\u2013tryptophan metabolism axis in hypoxia-induced emotional changes.<\/jats:p>","DOI":"10.31083\/ap47626","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T10:41:17Z","timestamp":1777459277000},"source":"Crossref","is-referenced-by-count":2,"title":["Acute Hypoxic Exposure May Contribute to Depressive-Like Behaviors in Mice Through Disruption of Gut Microbiota Homeostasis"],"prefix":"10.31083","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-5194-7145","authenticated-orcid":true,"given":"Ruiying","family":"Cheng","sequence":"first","affiliation":[{"name":"Qinghai Provincial Key Laboratory of Tibetan Medicine Pharmacology and Safety Evaluation, Northwest Institute of Plateau Biology, Chinese Academy of Science, 810008 Xining, Qinghai, China"},{"name":"School of Psychology, Chengdu Medical College, 610500 Chengdu, Sichuan, China"},{"name":"University of Chinese Academy of Sciences, 10049 Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5210-7382","authenticated-orcid":true,"given":"Yajun","family":"Qiao","sequence":"additional","affiliation":[{"name":"Qinghai Provincial Key Laboratory of Tibetan Medicine Pharmacology and Safety Evaluation, Northwest Institute of Plateau Biology, Chinese Academy of Science, 810008 Xining, Qinghai, China"},{"name":"School of Psychology, Chengdu Medical College, 610500 Chengdu, Sichuan, China"},{"name":"University of Chinese Academy of Sciences, 10049 Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5294-3038","authenticated-orcid":true,"given":"Huimin","family":"Zheng","sequence":"additional","affiliation":[{"name":"Qinghai Provincial Key Laboratory of Tibetan Medicine Pharmacology and Safety Evaluation, Northwest Institute of Plateau Biology, Chinese Academy of Science, 810008 Xining, Qinghai, China"},{"name":"Department of Psychiatry, The People's Hospital of Jiangmen, Southern Medical University, 529000 Jiangmen, Guangdong, China"},{"name":"Medical College, Qinghai Minzu University, 810001 Xining, Qinghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5622-1474","authenticated-orcid":true,"given":"Xiaohui","family":"Li","sequence":"additional","affiliation":[{"name":"Qinghai Provincial Key Laboratory of Tibetan Medicine Pharmacology and Safety Evaluation, Northwest Institute of Plateau Biology, Chinese Academy of Science, 810008 Xining, Qinghai, China"},{"name":"Department of Psychiatry, The People's Hospital of Jiangmen, Southern Medical University, 529000 Jiangmen, Guangdong, China"},{"name":"Medical College, Qinghai University, 810001 Xining, Qinghai, 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