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Zinc (Zn) is known to be the primary physiological inducer of the expression of the metallothionein (MT) superfamily of small stress\u2010responsive proteins. The expression of MTs in various tissues is induced or enhanced (including the gastrointestinal tract (GIT)) by a variety of stimuli, including infection and inflammation. However, the MTs\u2019 exact role in inflammation is still subject to debate. In order to establish whether or not MTs are the sole vectors in the Zn\u2010based modulation of intestinal inflammation, we used transcriptomic and metagenomic approaches to assess the potential effect of dietary Zn, the mechanisms underlying the MTs\u2019 beneficial effects, and the induction of previously unidentified mediators. We found that the expression of endogenous MTs in the mouse GIT was stimulated by an optimized dietary supplementation with Zn. The protective effects of dietary supplementation with Zn were then evaluated in mouse models of chemically induced colitis. The potential contribution of MTs and other pathways was explored via transcriptomic analyses of the ileum and colon in Zn\u2010treated mice. The microbiota\u2019s role was also assessed via fecal 16S rRNA sequencing. We found that high\u2010dose dietary supplementation with Zn induced the expression of MT\u2010encoding genes in the colon of healthy mice. We next demonstrated that the Zn diet significantly protected mice in the two models of induced colitis. When comparing Zn\u2010treated and control mice, various genes were found to be differentially expressed in the colon and the ileum. Finally, we found that Zn supplementation did not modify the overall structure of the fecal microbiota, with the exception of (i) a significant increase in endogenous\n                    <jats:italic>Clostridiaceae<\/jats:italic>\n                    , and (ii) some subtle but specific changes at the family and genus levels. Our results emphasize the beneficial effects of excess dietary Zn on the prevention of colitis and inflammatory events in mouse models. The main underlying mechanisms were driven by the multifaceted roles of MTs and the other potential molecular mediators highlighted by our transcriptomic analyses although we cannot rule out contributions by other factors from the host and\/or the microbiota.\n                  <\/jats:p>","DOI":"10.1096\/fj.202000562rr","type":"journal-article","created":{"date-parts":[[2020,7,30]],"date-time":"2020-07-30T23:38:37Z","timestamp":1596152317000},"page":"12615-12633","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["High\u2010dose dietary supplementation with zinc prevents gut inflammation: Investigation of the role of metallothioneins and beyond by transcriptomic and metagenomic studies"],"prefix":"10.1096","volume":"34","author":[{"given":"Beno\u00eet","family":"Folign\u00e9","sequence":"first","affiliation":[{"name":"Univ. 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