Impact of dietary manganese on experimental colitis in mice

Abstract

Diet plays a significant role in the pathogenesis of inflammatory bowel disease (IBD). A recent epidemiological study has shown an inverse relationship between nutritional manganese (Mn) status and IBD patients. Mn is an essential micronutrient required for normal cell function and physiological processes. To date, the roles of Mn in intestinal homeostasis remain unknown and the contribution of Mn to IBD has yet to be explored. Here, we provide evidence that Mn is critical for the maintenance of the intestinal barrier and that Mn deficiency exacerbates dextran sulfate sodium (DSS)-induced colitis in mice. Specifically, when treated with DSS, Mn-deficient mice showed increased morbidity, weight loss, and colon injury, with a concomitant increase in inflammatory cytokine levels and oxidative and DNA damage. Even without DSS treatment, dietary Mn deficiency alone increased intestinal permeability by impairing intestinal tight junctions. In contrast, mice fed a Mn-supplemented diet showed slightly increased tolerance to DSS-induced experimental colitis, as judged by the colon length. Despite the well-appreciated roles of intestinal microbiota in driving inflammation in IBD, the gut microbiome composition was not altered by changes in dietary Mn. We conclude that Mn is necessary for proper maintenance of the intestinal barrier and provides protection against DSS-induced colon injury. K E Y W O R D Scolitis, gut microbiota, inflammatory bowel disease, manganese, tight junction 2930 | CHOI et al. | RNA isolation and RT-PCR

A missense variant in SLC39A8 confers risk for Crohn’s disease by disrupting manganese homeostasis and intestinal barrier integrity

“…Consistent with our finding that Mn deficiency is sufficient to disrupt intestinal barrier function (Fig. 3), an Mn-deficient diet renders mice susceptible to epithelial injury in the DSS model, which is characterized by increased inflammatory cytokines and exacerbated histopathology in the colon (45).…”

Impact of Dietary Manganese on Intestinal Barrier and Inflammatory Response in Broilers Challenged with Salmonella Typhimurium

“…A similar result has also been reported where Mn markedly increased the production of inflammatory cytokines and chemokines in human monocyte-derived macrophages [18]. However, Choi and colleagues reported that a diet with adequate Mn notably depressed the expression of inflammatory cytokines TNF-α, IL-6, IL-1β, and IL-10 when compared to the Mn-deficient diet in colon mucosa of DSS-treated mice [42]. Excess Mn exposure was also reported to inhibit or induce the expression of genes of proinflammatory cytokines in chickens [19,41], indicating that dietary Mn modifies inflammatory cytokines in a dose-dependent manner and/or is dependent on the experimental model.…”

“…These results are congruent with previous outcomes in mice and indicate that Mn is necessary for proper maintenance of the intestinal barrier. For example, Mn provided protection against dextran sulfate sodium (DSS)-induced colon injury [42]. It was postulated that the positive effect of Mn on the intestinal barrier was mediated by MnSOD [23], which is in agreement with the efficacious protection of the small intestine from ionizing radiation damage through overexpression of MnSOD in mice [43].…”

Pleiotropic ZIP8 A391T implicates abnormal manganese homeostasis in complex human disease

“…Both the heterozygous and homozygous Zip8 393T-KI male mice exhibited a more severe phenotype than WT mice. We note a recent report of enhanced susceptibility to DSS-induced injury in mice fed Mn-deficient chow ( 45 ). We acknowledge that our experiments do not directly test that abnormal Mn homeostasis specifically drives the colitis phenotype, and future experiments will test variable Mn dietary content.…”