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As the pathogenesis remains poorly understood, the currently available treatment regimens are mostly symptomatic therapies with little satisfactory curative effect. The emerging paradigm of gut\u2013brain axis has highlighted gut dysbiosis as a key etiological factor to elicit neuro\u2010inflammation and jeopardize the central nervous system homeostasis. In this study, we evaluated the ameliorating effects of flaxseed lignans on the gut microbiome to regain the gut micro\u2010environmental functionality and alleviate MDD. The lignans significantly mitigated the severity of disease and markedly altered the gut microbiota structure in the participants. In the MDD mouse model, the lignans reversed the experimental depression\u2010like behaviors, repaired neural and gut damage and restored barrier integrity. Of great significance, the lignans elevated the levels of 5\u2010hydroxytryptamine (5\u2010HT), brain\u2010derived neurotrophic factor (BDNF) and \u03b3\u2010aminobutyric acid (GABA), and markedly attenuated microglial and systemic inflammation. Mechanistically, the lignans inhibited the IL\u201017\/AP\u20101\/NF\u2010\u03baB axis through direct interaction with the Fos protein. In the BV\u20102 cells, the lignan enterolactone reduced levels of nitric oxide and pro\u2010inflammatory cytokines, further validating the anti\u2010inflammatory mechanism of the lignans. Together, these findings demonstrate that lignans exert potent antidepressant effects by modulating the gut\u2013brain axis and resolving neuro\u2010inflammation, providing useful information for the development of novel therapeutic strategies for MDD prevention and treatment.<\/jats:p>","DOI":"10.1002\/biof.70122","type":"journal-article","created":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T02:13:18Z","timestamp":1780107198000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Lignans Alleviate Depression by Modulating the Gut\u2013Brain Axis: Effect and Mechanism Based on Multi\u2010Omics Analyses"],"prefix":"10.1002","volume":"52","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-9739-3282","authenticated-orcid":false,"given":"Liang","family":"Liu","sequence":"first","affiliation":[{"name":"Genomics Research Center (Key Laboratory of Gut Microbiota and Pharmacogenomics of Heilongjiang Province, 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