Metallothionein: A Novel Therapeutic Target for Treatment of Inflammatory Bowel Disease

Dostie, Kristen; Thees, Amy; Lynes, Michael A.

doi:10.2174/1381612824666180717110236

Cited by 14 publications

(16 citation statements)

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“…One gene that is highly overexpressed upon Smarcad1-KO in steady state and colitis is Mt1, coding for metallothionein. Metallothionein has been reported to protect against colitis in mouse models, but its role in this process requires further investigation [27,[69][70][71][72][73]. Another gene that is upregulated upon Smarcad1 deletion codes for Bambi.…”

Section: Discussionmentioning

confidence: 99%

Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium

et al. 2020

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Background: How intestinal epithelial cells interact with the microbiota and how this is regulated at the gene expression level are critical questions. Smarcad1 is a conserved chromatin remodeling factor with a poorly understood tissue function. As this factor is highly expressed in the stem and proliferative zones of the intestinal epithelium, we explore its role in this tissue. Results: Specific deletion of Smarcad1 in the mouse intestinal epithelium leads to colitis resistance and substantial changes in gene expression, including a striking increase of expression of several genes linked to innate immunity. Absence of Smarcad1 leads to changes in chromatin accessibility and significant changes in histone H3K9me3 over many sites, including genes that are differentially regulated upon Smarcad1 deletion. We identify candidate members of the gut microbiome that elicit a Smarcad1-dependent colitis response, including members of the poorly understood TM7 phylum. Conclusions: Our study sheds light onto the role of the chromatin remodeling machinery in intestinal epithelial cells in the colitis response and shows how a highly conserved chromatin remodeling factor has a distinct role in anti-microbial defense. This work highlights the importance of the intestinal epithelium in the colitis response and the potential of microbial species as pharmacological and probiotic targets in the context of inflammatory diseases. Background The intestinal epithelium is a highly dynamic tissue that is constantly renewed within a few days, driven by intestinal stem cells that reside at the base of intestinal crypts [1, 2]. Intestinal stem cells and their derivatives express many factors involved in DNA replication, DNA repair, chromatin packaging, and chromatin remodeling, including ATP-dependent remodeling factors [3]. The roles of these factors in genomic and epigenomic stability of this tissue are likely of great importance. Understanding epithelial biology is complicated by the fact that this tissue is in close proximity to the gut microbiota, which normally is either innocuous or even beneficial to the host, but can become pathogenic. How intestinal epithelial cells interact with the host immune system and the microbiota and how this is regulated at the gene expression level are critical questions.

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Section: Discussionmentioning

confidence: 99%

Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium

et al. 2020

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“…MT-positive cells can be observed infiltrating the lamina propria in patients with inflammatory and infectious colitis, with the number of MT-positive cells correlated with the severity of colitis (33). Anti-MT antibodies have been developed for use in mouse models of IBD and represent a potential novel therapeutic target for patients (34). It cannot be concluded from our analysis that an increase in MT gene expression is solely linked to stress because glucocorticoid exposure can also induce MT gene expression, thus possibly indicating a treatment effect in these biopsies (35).…”

Section: Top Go Biological Processes Differentiating Onset Agvhd Vementioning

confidence: 99%

Stress responses, M2 macrophages, and a distinct microbial signature in fatal intestinal acute graft-versus-host disease

Holtan¹,

Shabaneh²,

Betts³

et al. 2019

JCI Insight

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“…An MT-specific monoclonal antibody has been used as a novel therapeutic in murine models of IBD. 34 The disparities regarding the protective or non-protective effects of MTs 19,32,35,36 may be attributed to a variety of factors, including (i) differences in dose levels and dose timing in chemically induced colitis, (ii) differences in the time points at which clinical measurements were made and tissue samples were collected following induction of colitis, and (iii) microbiome heterogeneity in mice strains housed in different animal facilities. 31 Thus, we need to better understanding the nuances of the MTs' complex functions and how these proteins influence the pathogenesis of IBD.…”

Section: Introductionmentioning

confidence: 99%

“…41 However, there is little mechanistic evidence of the MTs' involvement in the reported therapeutic benefits of Zn supplementation. 34 In the present study, we performed a transcriptomic analysis of the ileum and colon, in order to assess the potential role of MTs (and possibly other factors) in the prevention of GIT inflammation by oral Zn supplementation. The protective effects of this diet were evaluated in two gold-standard mouse models in which colitis is induced by trinitrobenzenesulfonic acid (TNBS) or DSS.…”

Section: Introductionmentioning

confidence: 99%

“…In line with the latter results, the release of MTs leads to activation of inflammatory responses, progressive inflammation, and the subsequent expansion of MT synthesis. An MT‐specific monoclonal antibody has been used as a novel therapeutic in murine models of IBD 34 . The disparities regarding the protective or non‐protective effects of MTs 19,32,35,36 may be attributed to a variety of factors, including (i) differences in dose levels and dose timing in chemically induced colitis, (ii) differences in the time points at which clinical measurements were made and tissue samples were collected following induction of colitis, and (iii) microbiome heterogeneity in mice strains housed in different animal facilities 31 .…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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Metallothionein: A Novel Therapeutic Target for Treatment of Inflammatory Bowel Disease

Cited by 14 publications

References 0 publications

Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium

Smarcad1 mediates microbiota-induced inflammation in mouse and coordinates gene expression in the intestinal epithelium

Stress responses, M2 macrophages, and a distinct microbial signature in fatal intestinal acute graft-versus-host disease

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

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