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However, the underlying mechanisms remain unclear. Therefore, we investigated the efficacy of electroacupuncture in mice with IBD and depression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>An IBD mouse model of depression was established using 2.0% dextran sodium sulfate (DSS). After electroacupuncture, general condition and behavior were evaluated. Colon morphology was observed using hematoxylin and eosin staining. Serum inflammatory factors were detected using enzyme\u2010linked immunosorbent assay. Microglial activation was measured using immunofluorescence. Hippocampal protein expression was assessed using Western blotting and real\u2010time fluorescence quantitative polymerase chain reaction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>DSS\u2010induced model mice exhibited significant depression\u2010like behaviors and colon pathology. Serum and colon IL\u20101\u03b2 expression was elevated (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01), while IL\u20104, IL\u201010, and TGF\u2010\u03b21 expression was decreased (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01 or <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). Hippocampal microglial activation was evident, with increased IL\u20101\u03b2 expression (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01) and reduced IL\u20104, IL\u201010, TGF\u2010\u03b21, JAK1, STAT6, and p\u2010STAT6 expression (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01 or <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). Electroacupuncture resolved these changes; though its effects were significantly weakened after IL\u20104 and p\u2010STAT6 inhibitor administration (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01 or <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). Transcriptomic sequencing of hippocampal tissue indicates that pro\u2010inflammatory pathways such as TNF\/NF\u2010\u03baB\/mTOR are activated in the model group. Electroacupuncture can activate the IL\u20104\u2013mediated JAK\u2013STAT signaling pathway, inhibit the activation of pro\u2010inflammatory signaling pathways, upregulate neuroprotective genes such as Slc2a3, Mef2d, and Jak1, and exert anti\u2010inflammatory effects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>IL\u20104\u2010JAK1\u2010STAT6 signaling may be an important pathway in mediating the efficacy of electroacupuncture in IBD with comorbid depression, particularly promoting microglial M2 polarization and improving neuroinflammation.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.70572","type":"journal-article","created":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T09:24:15Z","timestamp":1755509055000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["<scp>IL<\/scp>\u20104\u2010<scp>JAK1<\/scp>\u2010<scp>STAT6<\/scp> Pathway Mediates Electroacupuncture's Effect on Microglial <scp>M2<\/scp> Polarization to Treat Inflammatory Bowel Disease With Comorbid Depression"],"prefix":"10.1111","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-3277-1333","authenticated-orcid":false,"given":"Sihui","family":"Cao","sequence":"first","affiliation":[{"name":"School of Acupuncture\u2010Moxibustion, Tuina and Rehabilitation Hunan University of Chinese Medicine  Changsha Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Acupuncture\u2010Moxibustion, Tuina and Rehabilitation Hunan University of Chinese Medicine  Changsha Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6666-2483","authenticated-orcid":false,"given":"Lin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, National Clinical Research Center for Mental Disorders, and National Center for Mental Disorders The Second Xiangya Hospital of Central South University  Changsha Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuqiang","family":"Li","sequence":"additional","affiliation":[{"name":"School of Acupuncture\u2010Moxibustion, Tuina and Rehabilitation Hunan University of Chinese Medicine  Changsha Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lv","family":"Jia","sequence":"additional","affiliation":[{"name":"School of Acupuncture\u2010Moxibustion, Tuina and Rehabilitation Hunan University of Chinese Medicine  Changsha Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxiang","family":"Huang","sequence":"additional","affiliation":[{"name":"School of Acupuncture\u2010Moxibustion, Tuina and Rehabilitation Hunan University of Chinese Medicine  Changsha Hunan 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