{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T13:34:38Z","timestamp":1761744878273,"version":"build-2065373602"},"reference-count":45,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T00:00:00Z","timestamp":1761696000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"physician scientist training and future medical technology implementation for solving clinical challenges in nervous system","award":["RS-2023-00223501"],"award-info":[{"award-number":["RS-2023-00223501"]}]},{"name":"Hallym University Research Fund"},{"name":"Yuhan Corporation Fund"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The gut\u2013brain axis regulates brain functions and maintains central nervous system homeostasis and intestinal balance. Migraine patients often present with gastrointestinal (GI) comorbidities, with stronger associations observed in chronic migraine (CM) than in episodic migraine (EM). To investigate migraine-related GI alterations, nitroglycerin (NTG)-induced mouse models of EM (N = 15) and CM (N = 15) were established using single or repeated NTG injections (10 mg\/kg). EM mice were euthanized 4 h after a single injection, whereas CM mice received NTG every other day for 9 days and were euthanized after the fifth injection. On the day of sacrifice, GI tissues were analyzed for morphological changes, cytokine expression, calcitonin gene-related peptide (CGRP) levels, and immune cell profiles. NTG-treated groups exhibited significant reductions in both food intake and body weight compared with controls. In addition, colon length was markedly shortened in the chronic migraine (CM) model (p &lt; 0.01). Molecular analyses revealed distinct cytokine expression profiles between models: the episodic migraine (EM) model showed increased levels of proinflammatory cytokines (IL-1\u03b2, IL-6, and IL-8; p &lt; 0.01), whereas the CM model displayed elevated anti-inflammatory cytokines (IL-4, IL-10, and TGF-\u03b2; p &lt; 0.01), particularly in the colon. CGRP expression was also markedly upregulated throughout the gastrointestinal tract, with the highest expression observed in the colon of CM mice (p &lt; 0.01). Flow cytometric immune profiling further demonstrated divergent immune cell patterns, with increased Th17 (p = 0.0085) and B cell (p = 0.0199) populations in EM, while CM was characterized by enrichment of T cells (p = 0.0221), regulatory T cells (Tregs) (p = 0.0114), and macrophages (p = 0.0062), indicating more pronounced immune alterations in the distal colon. These findings indicate that CM involves more severe gut\u2013brain axis dysregulation than EM, supporting the potential of gut-targeted therapies as adjunct strategies in chronic migraine.<\/jats:p>","DOI":"10.3390\/ijms262110493","type":"journal-article","created":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T09:16:24Z","timestamp":1761729384000},"page":"10493","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Distinct Gut\u2013Brain Axis Dysregulation in Episodic Versus Chronic Migraine: Insights from NTG-Induced Mouse Models"],"prefix":"10.3390","volume":"26","author":[{"given":"Dae-Chul","family":"Shin","sequence":"first","affiliation":[{"name":"Department of Biomedical Science, Hallym University, Chuncheon 24252, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harry","family":"Jung","sequence":"additional","affiliation":[{"name":"Institute of New Frontier Research Team, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Songyi","family":"Park","sequence":"additional","affiliation":[{"name":"Institute of New Frontier Research Team, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dan-Gyeong","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science, Hallym University, Chuncheon 24252, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0609-1551","authenticated-orcid":false,"given":"Sang-Hwa","family":"Lee","sequence":"additional","affiliation":[{"name":"Institute of New Frontier Research Team, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea"},{"name":"Department of Neurology, Chuncheon Sacred Heart Hospital, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2656-9222","authenticated-orcid":false,"given":"Jong-Hee","family":"Sohn","sequence":"additional","affiliation":[{"name":"Institute of New Frontier Research Team, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea"},{"name":"Department of Neurology, Chuncheon Sacred Heart Hospital, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/s10194-023-01563-8","article-title":"FGF-21 and GDF-15 are increased in migraine and associated with the severity of migraine-related disability","volume":"24","author":"He","year":"2023","journal-title":"J. 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