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Gut microbiota, which produces a wide array of neuroactive compounds, is a critical modulator in this bidirectional dialog. Perturbations in the gut microbiota have been implicated in neurological disorders such as depression and stress. Distinct from humans and other monogastric animals, ruminants possess a unique, microbially dense gastrointestinal compartment, the rumen, that facilitates the digestion of fibrous plant materials. These ruminal microbes are likely key contributors to rumen-brain crosstalk. Unlike certain microbe-derived neuroactive compounds produced in the hindgut that are minimally absorbed and primarily excreted in feces, those generated in rumen can reach the small intestine, where they are largely absorbed and affect central nervous system through systemic regulation in addition to the vagal pathway. Notably, emerging evidence suggests that rumen microbiota dysbiosis under stress is associated with abnormal behavior, altered hormonal and neurotransmitter levels. In this review, we introduce the concept of the rumen-microbiome-brain axis by comparing the anatomical structures and microbial characteristics of the intestine and the rumen, emphasizing the neuroactive potential of rumen microbiome and underlying mechanisms. Advances in this frontier hold tremendous promise to reveal a novel dimension of the gut-microbiome-brain axis, providing transformative opportunities to improve ruminant welfare, productivity, and agricultural sustainability.<\/jats:p>","DOI":"10.1186\/s40104-025-01289-4","type":"journal-article","created":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T06:24:18Z","timestamp":1764224658000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Unveiling the rumen-microbiome-brain circuit: a unique dimension of gut-brain axis in ruminants"],"prefix":"10.1186","volume":"16","author":[{"given":"Himani","family":"Joshi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon","family":"Bernard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caleb","family":"Lemley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9993-6745","authenticated-orcid":false,"given":"Peixin","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,27]]},"reference":[{"key":"1289_CR1","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1038\/nrgastro.2009.35","volume":"6","author":"SH Rhee","year":"2009","unstructured":"Rhee SH, Pothoulakis C, Mayer EA. 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