Zinc inhibits lethal inflammatory shock by preventing microbe‐induced interferon signature in intestinal epithelium (original) (raw)
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The Journal of Nutritional Biochemistry, 2013
The essential micronutrient zinc has long been known to be a functional component of diverse structural proteins and enzymes. More recently, important roles for free or loosely bound intracellular zinc as a signaling factor have been reported. Insufficient zinc intake was shown to exacerbate symptoms in mouse models of inflammation such as experimental colitis, while zinc supplementation was found to improve intestinal barrier function. Herein, we provide evidence that intracellular zinc is essential for maintaining intestinal epithelial integrity when cells are exposed to the inflammatory cytokine Tumor Necrosis Factor (TNF)α. Using the human intestinal Caco-2/TC7 cell line as an in vitro model, we demonstrate that depletion of intracellular zinc affects TNFα-triggered signaling by shifting intestinal cell fate from survival to death. The mechanism underlying this effect was investigated. We show that TNFα promotes a zinc-dependent survival pathway that includes modulation of gene expression of transcription factors and signaling proteins. We have identified multiple regulatory steps regulated by zinc availability which include the induction of cellular Inhibitor of APoptosis (cIAP2) mRNA, possibly through activation of Nuclear Factor-Kappa B (NF-κB), as both nuclear translocation of the p65 subunit of NF-κB and up-regulation of cIAP2 mRNA were impaired following zinc depletion. Moreover, X-linked inhibitor of apoptosis protein level was profoundly reduced by zinc depletion. Our results provide a possible molecular explanation for the clinical observation that zinc supplements ameliorate Crohn's disease symptoms and decrease intestinal permeability in experimental colitis.
The many functions of zinc in inflammatory conditions of the gastrointestinal tract
The Journal of Trace Elements in Experimental Medicine
A variety of inflammatory gastrointestinal diseases are associated with altered zinc metabolism or deficiency. Acute and chronic diarrheal disorders may cause deficiency because of increased losses, altered immunity or decreased absorption. When the small intestinal barrier is altered by inflammation, zinc supplementation may be beneficial not only in correcting the deficiency but also because it improves the small bowel mucosal capacity of absorbing water and electrolytes. Zinc is known to have antioxidant properties being a membrane stabilizer, scavenging reactive oxygen metabolites and regulating cytokine synthesis through the activation of transcription factors and this has relevant potential in inflammatory bowel diseases. Moreover, the element stimulates tissue healing and repair in experimental ulcers directly through promoting cell proliferation, protein synthesis and growth factors production and scavenging free radicals. Interest is growing in supplementary therapies with ...
Iranian Journal of Microbiology, 2019
Background and Objectives: Inflammation in the intestine causes diarrhea due to an increased release of pro-inflammatory cytokines such as TNF-α, IL-1, and IL-6. These are triggered by the exposure of E. coli-LPS to epithelial cells of the intestinal mucosa as well as low concentration of zinc in plasma such as in infants or children who are experiencing diarrhea. This paper aims to determine the effects of zinc supplementation on pro-inflammatory cytokines (TNF-α, IL-1 and IL-6) in mice with E. coli-LPS-induced diarrhea. Materials and Methods: This study used a controlled trial experimental design in the laboratory. A sample size of 20 mice were randomly divided into 4 groups: 1) Control group was given standard foods, 2) Trial group was given E. coli-LPS 2.5 mg/kg/oral once on day1, 3) Prevention group was given E. coli-LPS + 30 mg/kg/oral of zinc once daily for 12 days, 4) Therapeutic group was given E. coli-LPS, and were then given 30 mg/kg/oral of zinc once daily for 12 days if...
Life Sciences, 1997
In a previous study we have shown that zinc deficiency caused several alterations in intestine of rats. Here we reporl that interleukin-l~(IL-1~) is involved in the zinc deficiency-induced mucosal damage and that cyclosporine A (CSA) protects the intestine against both structural and functional alterations by different mechanisms. The zinc deficient (ZD) rats were maintained on a zinc deficient diet for 40 days. They received a daily injection of CSA (12 mg/kg) for the last 10 days. The histological analysis of small intestine revealed that the dramatic alterations induced by zinc deficiency (ulcerations, inflammation, edema, vasodilatation), were not present after CSA treatment, The IL-1~gene expression, analyzed by PCR, was increased in the three intestinal regions of ZD rats, as compared to C rats. There was a relation between increasing IL-1~expression and increased severity of damage, and the highest cytokine elevation was in the most damaged region, i.e. the jejunum. After CSA administration the IL-1~mRNA was similar to control rats. The intestinal cell proliferation, measured as crypt cell production rate and Iabelling index, as well the cell renewal, measured as cell migration rate and turnover time, were affected by zinc deficiency. After CSA treatment, all these variables were similar to control rats, suggesting that CSA induces a stimulation of intestinal cell proliferation in zinc deficiency. Finally, the decrease in the disaccharidase activities induced by zinc deficiency was abrogated by CSA treatment. KqYWord: interleukin-lp, eyclosporirteA, cell proliferation, intestine, zinc deficiency Zinc is an essential metal involved in many biochemical processes (1) and its deficiency is associated with a wide range of physiological defects which includes disorders of the skin, neurological, immune and reproductive systems (2). Different Correspondence to: Elena Mengheri, Istituto Nazionale Nutrizione,
The Journal of nutritional biochemistry, 2008
Zinc (Zn) is an essential nutrient that affects immune function, especially within the digestive system, although the underlying mechanisms are not well understood. This study examined the effects of short-term moderate Zn restriction on intestinal health and immune function in lipopolysaccharide (LPS)-challenged mice through plasma cytokine profiling and histological evaluation of intestinal tissue sections. Adult male mice were fed with a Zn-adequate (40 ppm) or a Zn-marginal (4 ppm) diet for 4 weeks, and then a bacterial challenge was simulated by intraperitoneal injection of LPS (10 microg/g body weight [BW]) or saline (control). BW was recorded weekly, and feed intake was recorded daily over the last week. Voluntary locomotor activity was assessed 6 and 24 h after the challenge. Plasma and tissues were collected 0, 6 or 24 h after the challenge for analysis. Histological analysis of intestinal samples included evaluation of villi length and width, lamina propria (LP) width, cry...
Zinc treatment ameliorates diarrhea and intestinal inflammation in undernourished rats
BMC Gastroenterology, 2014
Background: WHO guidelines recommend zinc supplementation as a key adjunct therapy for childhood diarrhea in developing countries, however zinc's anti-diarrheal effects remain only partially understood. Recently, it has been recognized that low-grade inflammation may influence stunting. In this study, we examined whether oral zinc supplementation could improve weight, intestinal inflammation, and diarrhea in undernourished weanling rats. Methods: Rats were undernourished using a northeastern Brazil regional diet (RBD) for two weeks, followed by oral gavage with a saturated lactose solution (30 g/kg) in the last 7 days to induce osmotic diarrhea. Animals were checked for diarrhea daily after lactose intake. Blood was drawn in order to measure serum zinc levels by atomic absorption spectroscopy. Rats were euthanized to harvest jejunal tissue for histology and cytokine profiles by ELISA. In a subset of animals, spleen samples were harvested under aseptic conditions to quantify bacterial translocation. Results: Oral zinc supplementation increased serum zinc levels following lactose-induced osmotic diarrhea. In undernourished rats, zinc improved weight gain following osmotic diarrhea and significantly reduced diarrheal scores by the third day of lactose intake (p < 0.05), with improved jejunum histology (p < 0.0001). Zinc supplementation diminished bacterial translocation only in lactose-challenged undernourished rats (p = 0.03) compared with the untreated challenged controls and reduced intestinal IL-1β and TNF-α cytokines to control levels. Conclusion: Altogether our findings provide novel mechanisms of zinc action in the setting of diarrhea and undernutrition and support the use of zinc to prevent the vicious cycle of malnutrition and diarrhea.
Synthesis of inducible nitric oxide synthase (iNOS) in the intestine may result in local tissue damage. We investigated whether a challenge with interleukin-1a could give rise to intestinal iNOS expression and diarrhea in rats of differing zinc status. Weaning male rats were fed a zinc-deficient (ZD) diet (2 mg zinc/kg) for 4 wk to induce zinc deficiency or a zinc-supplemented diet (50.8 mg zinc/kg; controls, including pair-fed (PF) and ad libitum (AL) consumption groups), and then subcutaneously injected with interleukin-1a (2 1 107 units/kg body wt). Without the interleukin-1a challenge, ZD rats had significantly lower plasma zinc concentration than the other groups. Intestinal metallothionein-1 mRNA abundance was lower in ZD rats than in AL rats. iNOS was expressed in the intestine of ZD rats but not in the others. None of the rats experienced diarrhea during the feeding period. Interleukin-1a led to a reduction in plasma zinc concentration, enhancement in intestinal metallothion...
Zinc in Infection and Inflammation
Micronutrient homeostasis is a key factor in maintaining a healthy immune system. Zinc is an essential micronutrient that is involved in the regulation of the innate and adaptive immune responses. The main cause of zinc deficiency is malnutrition. Zinc deficiency leads to cell-mediated immune dysfunctions among other manifestations. Consequently, such dysfunctions lead to a worse outcome in the response towards bacterial infection and sepsis. For instance, zinc is an essential component of the pathogen-eliminating signal transduction pathways leading to neutrophil extracellular traps formation, as well as inducing cell-mediated immunity over humoral immunity by regulating specific factors or differentiation. Additionally, zinc deficiency plays a role in inflammation, mainly elevating inflammatory response as well as damage to host tissue. Zinc is involved in the modulation of the proinflammatory response by targeting Nuclear Factor Kappa B, a transcription factor that is the master ...
International Journal of Molecular Sciences, 2021
The objective of the present study was to review the existing data on the association between Zn status and characteristics of gut microbiota in various organisms and the potential role of Zn-induced microbiota in modulating systemic effects. The existing data demonstrate a tight relationship between Zn metabolism and gut microbiota as demonstrated in Zn deficiency, supplementation, and toxicity studies. Generally, Zn was found to be a significant factor for gut bacteria biodiversity. The effects of physiological and nutritional Zn doses also result in improved gut wall integrity, thus contributing to reduced translocation of bacteria and gut microbiome metabolites into the systemic circulation. In contrast, Zn overexposure induced substantial alterations in gut microbiota. In parallel with intestinal effects, systemic effects of Zn-induced gut microbiota modulation may include systemic inflammation and acute pancreatitis, autism spectrum disorder and attention deficit hyperactivity...
Zinc as a Gatekeeper of Immune Function
Nutrients
After the discovery of zinc deficiency in the 1960s, it soon became clear that zinc is essential for the function of the immune system. Zinc ions are involved in regulating intracellular signaling pathways in innate and adaptive immune cells. Zinc homeostasis is largely controlled via the expression and action of zinc “importers” (ZIP 1–14), zinc “exporters” (ZnT 1–10), and zinc-binding proteins. Anti-inflammatory and anti-oxidant properties of zinc have long been documented, however, underlying mechanisms are still not entirely clear. Here, we report molecular mechanisms underlying the development of a pro-inflammatory phenotype during zinc deficiency. Furthermore, we describe links between altered zinc homeostasis and disease development. Consequently, the benefits of zinc supplementation for a malfunctioning immune system become clear. This article will focus on underlying mechanisms responsible for the regulation of cellular signaling by alterations in zinc homeostasis. Effects ...