Methylmercury Chronic Exposure and a High‐Fat Diet Induce Gut Microbiome Alterations and Intestinal Barrier Disruption in Mice

ABSTRACT Methylmercury (MeHg) is markedly toxic to humans. Our study explores whether MeHg and high‐fat diet (HFD) can impair the intestinal barrier with microbiota dysbiosis in mice. Weanling mice were fed to HFD or standard diet for 40 days. In the last 20 days of diets, mice received either MeHg (20 mg/L) or drinking water. Proximal small intestine, cecum, and hair samples were collected. Villus length, crypt depth, villus/crypt length, mucin2 and lysozyme‐positive cell counts, ZO‐1 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‐1 immunofluorescence in the colon and small intestine. HFD increased MDA, Mucin2, and reduced villus height, crypt depth, villus/crypt length, lysozyme(+)‐cell count, and increased intestinal permeability, regardless of MeHg intoxication. MeHg‐HFD combination affected the intestinal barrier, decreasing ZO‐1, occludin, and Nrf2 transcription, and increased permeability. HFD increased total plasma cholesterol and triglycerides. Only MeHg‐HFD reduced microbiome alpha‐diversity along with colonic ZO‐1 immunolabeling loss compared to non‐intoxicated mice fed a control diet. Regardless of diet, the genera Streptococcus , Psychrobacter , Facklamia , and Corynebacterium were severely depleted following MeHg intoxication. Other groups, such as Atopostipes and Jeotgalicoccus , were not altered by MeHg or HFD alone, but were significantly reduced by the combined HFD‐MeHg. Synergistic effects of MeHg‐HFD on the mucosa‐associated 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.