{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:00:34Z","timestamp":1787029234271,"version":"build-2736575974"},"reference-count":108,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T00:00:00Z","timestamp":1761868800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"crossref"}]},{"name":"European Union NextGenerationEU"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Major depressive disorder (MDD) is a complex, multifactorial condition involving dysregulation across immune, neural, and metabolic systems. Omega-3 polyunsaturated fatty acids (n-3 PUFAs), particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have emerged as promising adjunctive interventions, with evidence supporting their efficacy in alleviating depressive symptoms. Here, we synthesize current knowledge on the interconnected biological pathways through which n-3 PUFAs may exert antidepressant effects. A growing body of evidence implicates the gut\u2013brain axis as a central pathway through which n-3 PUFAs may exert antidepressant effects. By shaping microbiota composition and metabolite production, n-3 PUFAs influence intestinal permeability, immune activation, and vagal signaling, thereby contributing to both immunomodulatory and neurochemical effects. In combination, n-3 PUFAs modulate peripheral and central inflammation by promoting specialized pro-resolving mediators, downregulating pro-inflammatory cytokines, and influencing microglial activation. Parallel actions on neuronal membrane composition and lipid raft integrity affect neurotransmitter signaling, synaptic plasticity, and neurogenesis, with downstream effects on neural function. Additional pathways, including hypothalamic\u2013pituitary\u2013adrenal axis regulation and oxidative stress reduction, further integrate n-3 PUFA actions across multiple systems. Collectively, these mechanisms suggest that n-3 PUFAs act as network modulators, supporting recovery in depression. Translational research highlights the importance of EPA-predominant formulations, optimal dosing, and patient stratification. By framing n-3 PUFAs activity within a multi-level systems biology perspective, this review provides a comprehensive mechanistic understanding and underscores their potential as targeted adjunctive strategies for MDD.<\/jats:p>","DOI":"10.3390\/nu17213426","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T14:00:33Z","timestamp":1762178433000},"page":"3426","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Restoring Balance: The Role of Omega-3 Polyunsaturated Fatty Acids on the Gut\u2013Brain Axis and Other Interconnected Biological Pathways to Improve Depression"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6869-5337","authenticated-orcid":false,"given":"Floriana","family":"De Cillis","sequence":"first","affiliation":[{"name":"Department of Pharmacological and Biomolecular Sciences, University of Milan, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2244-1782","authenticated-orcid":false,"given":"Veronica","family":"Begni","sequence":"additional","affiliation":[{"name":"Biological Psychiatry Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1238-5440","authenticated-orcid":false,"given":"Patrizia","family":"Genini","sequence":"additional","affiliation":[{"name":"Department of Pharmacological and Biomolecular Sciences, University of Milan, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Leo","sequence":"additional","affiliation":[{"name":"Biological Psychiatry Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1699-5060","authenticated-orcid":false,"given":"Marco Andrea","family":"Riva","sequence":"additional","affiliation":[{"name":"Department of Pharmacological and Biomolecular Sciences, University of Milan, 20133 Milan, Italy"},{"name":"Biological Psychiatry Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9963-848X","authenticated-orcid":false,"given":"Annamaria","family":"Cattaneo","sequence":"additional","affiliation":[{"name":"Department of Pharmacological and Biomolecular Sciences, University of Milan, 20133 Milan, Italy"},{"name":"Biological Psychiatry Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Berk, M., Williams, L.J., Jacka, F.N., O\u2019Neil, A., Pasco, J.A., Moylan, S., Allen, N.B., Stuart, A.L., Hayley, A.C., and Byrne, M.L. 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