{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T00:55:16Z","timestamp":1791593716023,"version":"4.3.4"},"reference-count":92,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Inflammatory Bowel Disease (IBD), comprising Crohn\u2019s Disease and Ulcerative Colitis, is a chronic inflammatory condition of the gastrointestinal tract with a remarkably high prevalence of psychiatric comorbidities, particularly Major Depressive Disorder (MDD). The traditional monoaminergic hypothesis of depression is insufficient to explain the complex etiology of MDD, paving the way for new paradigms, such as the inflammatory hypothesis of depression. This narrative review critically explores IBD as a human clinical model to investigate the connection between chronic inflammation and depression. It is argued that gut dysbiosis, a central feature of IBD, is a fundamental trigger that, through a compromised gut barrier, drives systemic inflammation and, subsequently, neuroinflammation. We detail the molecular and cellular mechanisms that link intestinal inflammation to central nervous system (CNS) dysfunction, including microglial activation, hypothalamic-pituitary-adrenal (HPA) axis dysregulation, and kynurenine pathway activation, which diverts tryptophan metabolism from serotonin synthesis to the production of neurotoxic metabolites. Robust epidemiological evidence demonstrating a bidirectional association between IBD and depression is discussed, suggesting a shared pathophysiology rather than a simple cause-and-effect relationship. Furthermore, we review the implications and emerging therapeutics, highlighting the antidepressant effects of immunobiologicals, such as anti-TNF therapies, and the potential of emerging interventions that target the microbiome, such as probiotics, psychobiotics, fecal microbiota transplantation, and anti-inflammatory diets. Furthermore, we address the limitations of the current literature, such as the lack of a quantitative definition for dysbiosis and the scarcity of clinical trials with integrated neuropsychiatric outcomes, and propose directions for future translational research. We conclude that IBD should be considered a systemic disease with significant psychiatric repercussions, advocating for an integrated therapeutic approach that combines immunomodulatory, neuromodulatory, and microbiological interventions to treat both gut and brain pathology effectively.<\/jats:p>","DOI":"10.3389\/fphar.2026.1793292","type":"journal-article","created":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T04:27:29Z","timestamp":1775017649000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Targeting the gut-immune-brain axis: pharmacological insights from depression in inflammatory bowel disease"],"prefix":"10.3389","volume":"17","author":[{"given":"J\u00falia Le\u00e3o Batista","family":"Sim\u00f5es","sequence":"first","affiliation":[{"name":"Graduate Program in Biochemistry, Federal University of Santa Catarina (UFSC)","place":["Florian\u00f3polis, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ge\u00f3rgia de Carvalho","family":"Braga","sequence":"additional","affiliation":[{"name":"Medical School, Federal University of Fronteira Sul","place":["Chapec\u00f3, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles Elias","family":"Assmann","sequence":"additional","affiliation":[{"name":"Graduate Program in Biological Sciences, Toxicological Biochemistry, Federal University of Santa Maria","place":["Santa Maria, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margarete Dulce","family":"Bagatini","sequence":"additional","affiliation":[{"name":"Graduate Program in Medical Sciences, Federal University of Fronteira Sul","place":["Chapec\u00f3, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2916","DOI":"10.3390\/BIOMEDICINES13122916","article-title":"Understanding how mental health influences IBD outcomes: a review of potential culprit biological mechanisms","volume":"13","author":"Abdelbadiee","year":"2025","journal-title":"Biomedicines"},{"key":"B2","doi-asserted-by":"publisher","first-page":"2013","DOI":"10.1053\/j.gastro.2020.07.064","article-title":"Defining endpoints and biomarkers in inflammatory bowel disease: moving the needle through clinical trial design","volume":"159","author":"Abreu","year":"2020","journal-title":"Gastroenterology"},{"key":"B3","doi-asserted-by":"publisher","first-page":"9715","DOI":"10.3390\/IJMS25179715","article-title":"Insights into gut dysbiosis: inflammatory diseases, obesity, and restoration approaches","volume":"25","author":"Acevedo-Rom\u00e1n","year":"2024","journal-title":"Int. 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