High‐dose dietary supplementation with zinc prevents gut inflammation: Investigation of the role of metallothioneins and beyond by transcriptomic and metagenomic studies

Abstract

Although it is known that zinc has several beneficial roles in the context of gut inflammation, the underlying mechanisms have not been extensively characterized. Zinc (Zn) is known to be the primary physiological inducer of the expression of the metallothionein (MT) superfamily of small stress‐responsive 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’ exact role in inflammation is still subject to debate. In order to establish whether or not MTs are the sole vectors in the Zn‐based modulation of intestinal inflammation, we used transcriptomic and metagenomic approaches to assess the potential effect of dietary Zn, the mechanisms underlying the MTs’ 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‐treated mice. The microbiota’s role was also assessed via fecal 16S rRNA sequencing. We found that high‐dose dietary supplementation with Zn induced the expression of MT‐encoding 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‐treated 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 Clostridiaceae, 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.

Dual therapy with zinc acetate and rifaximin prevents from ethanol-induced liver fibrosis by maintaining intestinal barrier integrity

“…Zhang et al [ 55 ] showed that zinc modified the cecal microbial community in broilers by making abundant in the populations of total bacteria, including Lactobacillus, and reducing the populations of Salmonella. Foligné et al [ 56 ] suggested that zinc supplementation provided a significant increase in endogenous Clostridiaceae in mice. Meanwhile, in a mouse steatohepatitis model, Kitagawa et al [ 27 ] have recently demonstrated that rifaximin improved ethanol-induced liver injury with drastic modification of the small intestine microbiota; they elucidated that rifaximin decreased the relative abundance of Erysipelotrichales and increased Bacteroidales.…”

Effect of dietary zinc supplementation on the gastrointestinal microbiota and host gene expression in theShank3B−/−mouse model of autism spectrum disorder

“…Neural, immunological and hormonal pathways all offer potential mechanisms by which gut microbes may influence neurological development. Changes in gut microbial composition and resulting functional differences have been observed with differential dietary zinc intake in porcine and murine models as well as human studies [72–74]. We recently described dietary zinc-induced reversal of ASD behaviours in Shank3B −/− KO mice [8, 49].…”

Effect of Dietary Zinc Supplementation on the Gastrointestinal Microbiota and Host Gene Expression in the Shank3B-/- Mouse Model of Autism Spectrum Disorder

“…Neural, immunological and hormonal pathways all offer potential mechanisms by which gut microbes may in uence neurological development. Changes in gut microbial composition and resulting functional differences have been observed with differential dietary zinc intake in porcine and murine models as well as human studies [72][73][74]. We recently described dietary zinc-induced reversal of ASD behaviours in Shank3B -/-KO mice [8,49].…”