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Our study explores whether MeHg and high\u2010fat diet (HFD) can impair the intestinal barrier with microbiota dysbiosis in mice. Weanling mice were fed to HFD or standard diet for 40\u2009days. In the last 20\u2009days of diets, mice received either MeHg (20\u2009mg\/L) or drinking water. Proximal small intestine, cecum, and hair samples were collected. Villus length, crypt depth, villus\/crypt length, mucin2 and lysozyme\u2010positive cell counts, ZO\u20101 and occludin gene expression, and intestinal functional permeability were analyzed to assess the intestinal barrier. Blood samples were drawn to assess lipid parameters. Gut microbiome profiling was conducted with DNA from fecal\/cecal samples. In addition, we analyzed ZO\u20101 immunofluorescence in the colon and small intestine. HFD increased MDA, Mucin2, and reduced villus height, crypt depth, villus\/crypt length, lysozyme(+)\u2010cell count, and increased intestinal permeability, regardless of MeHg intoxication. MeHg\u2010HFD combination affected the intestinal barrier, decreasing ZO\u20101, occludin, and Nrf2 transcription, and increased permeability. HFD increased total plasma cholesterol and triglycerides. Only MeHg\u2010HFD reduced microbiome alpha\u2010diversity along with colonic ZO\u20101 immunolabeling loss compared to non\u2010intoxicated mice fed a control diet. Regardless of diet, the genera <jats:italic>Streptococcus<\/jats:italic>, <jats:italic>Psychrobacter<\/jats:italic>, <jats:italic>Facklamia<\/jats:italic>, and <jats:italic>Corynebacterium<\/jats:italic> were severely depleted following MeHg intoxication. Other groups, such as <jats:italic>Atopostipes<\/jats:italic> and <jats:italic>Jeotgalicoccus<\/jats:italic>, were not altered by MeHg or HFD alone, but were significantly reduced by the combined HFD\u2010MeHg. Synergistic effects of MeHg\u2010HFD on the mucosa\u2010associated microbiota are more pronounced than their individual effects. Our findings suggest that MeHg intoxication does not cause extensive dysbiosis but led to intestinal barrier disruption.<\/jats:p>","DOI":"10.1002\/tox.24469","type":"journal-article","created":{"date-parts":[[2025,2,9]],"date-time":"2025-02-09T22:39:44Z","timestamp":1739140784000},"page":"975-989","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Methylmercury Chronic Exposure and a High\u2010Fat Diet Induce Gut Microbiome Alterations and Intestinal Barrier Disruption in Mice"],"prefix":"10.1002","volume":"40","author":[{"given":"Gabriella A.","family":"Matos","sequence":"first","affiliation":[{"name":"Laboratory of Tissue Healing, Ontogeny and Nutrition, Department of Morphology, Institute of Biomedicine Federal University of Ceara  Fortaleza Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Nunes\u2010Costa","sequence":"additional","affiliation":[{"name":"CNC \u2013 Center 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