{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T18:34:25Z","timestamp":1786732465213,"version":"build-2736575974"},"reference-count":85,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["RS-2025-00521406"],"award-info":[{"award-number":["RS-2025-00521406"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    Major depressive disorder is a prevalent mood disorder characterized by affective and cognitive impairment. Alterations in gut microbiota have been implicated in its pathophysiology, as stress-related microbial changes can disrupt intestinal barrier integrity and promote inflammatory activation along the microbiota\u2013gut\u2013brain axis. Although environmental enrichment (EE) has been shown to exert beneficial effects on stress-related behaviors, its influence on gut microbiota under chronic stress conditions remains unclear. Here, we examined the effects of EE on depressive-like behavior, stress-related molecular markers in the brain, gut microbiota composition, and intestinal barrier function in a chronic unpredictable mild stress (CUMS) mouse model. Following CUMS exposure for 5 weeks, mice were housed in either a standard environment or EE for 4 weeks. EE significantly reduced immobility time in the tail suspension test and restored tryptophan hydroxylase\u2011positive cell numbers in the dorsal raphe nucleus while reversing glucocorticoid receptor\u2011positive cell expression in the hippocampus. Microbiota analysis revealed that CUMS elevated alpha diversity and altered beta diversity, accompanied by increases in stress\u2011associated taxa\u2014including\n                    <jats:italic>Firmicutes<\/jats:italic>\n                    ,\n                    <jats:italic>Desulfobacterota<\/jats:italic>\n                    ,\n                    <jats:italic>Patescibacteria<\/jats:italic>\n                    , and\n                    <jats:italic>Ruminococcus<\/jats:italic>\n                    \u2014and reductions in beneficial taxa such as\n                    <jats:italic>Akkermansia<\/jats:italic>\n                    . EE prevented the CUMS-induced alterations, reestablishing microbial diversity and community structure toward control levels and partially reversing the taxonomic changes. In the colon, CUMS reduced claudin\u20111 expression and increased IL\u20116 and NF\u2011\u03baB protein levels, reflecting impaired barrier integrity and enhanced inflammatory responses. EE attenuated the CUMS-induced intestinal disruptions, restoring tight junction protein expression and reducing inflammatory markers. In conclusion, EE may serve as a non\u2011pharmacological intervention capable of stabilizing the microbiota\u2013gut\u2013brain axis in depressive\u2011like states.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0355857","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T17:56:53Z","timestamp":1786730213000},"page":"e0355857","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Environmental enrichment attenuates chronic stress\u2013induced disruptions in the gut microbiota, intestinal barrier, and brain"],"prefix":"10.1371","volume":"21","author":[{"given":"Seung Ju","family":"Kang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyeong Ju","family":"Nam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1779-5992","authenticated-orcid":true,"given":"Min Kyung","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,8,14]]},"reference":[{"key":"pone.0355857.ref001","doi-asserted-by":"crossref","first-page":"16065","DOI":"10.1038\/nrdp.2016.65","article-title":"Major depressive disorder","volume":"2","author":"C Otte","year":"2016","journal-title":"Nat Rev Dis Primers"},{"issue":"10161","key":"pone.0355857.ref002","doi-asserted-by":"crossref","first-page":"2299","DOI":"10.1016\/S0140-6736(18)31948-2","article-title":"Depression","volume":"392","author":"GS 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Zhang","year":"2011","journal-title":"Cytotechnology"},{"issue":"16","key":"pone.0355857.ref076","doi-asserted-by":"crossref","first-page":"12822","DOI":"10.3390\/ijms241612822","article-title":"Chronic stress that changed intestinal permeability and induced inflammation was restored by estrogen","volume":"24","author":"Y Li","year":"2023","journal-title":"Int J Mol Sci"},{"issue":"3","key":"pone.0355857.ref077","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1093\/ecco-jcc\/jjac148","article-title":"Autophagy Reduces the Degradation and Promotes Membrane Localization of Occludin to Enhance the Intestinal Epithelial Tight Junction Barrier against Paracellular Macromolecule Flux","volume":"17","author":"K Saha","year":"2023","journal-title":"J Crohns Colitis"},{"key":"pone.0355857.ref078","doi-asserted-by":"crossref","first-page":"1556744","DOI":"10.3389\/fnins.2025.1556744","article-title":"Chronic unpredictable mild stress induces anxiety-like behavior in female C57BL\/6N 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