Excess Dietary Zinc Intake in Neonatal Mice Causes Oxidative Stress and Alters Intestinal Host–Microbe Interactions

Abstract

Scope Greater than 68% of young infants are exposed to dietary zinc (Zn) levels that are higher than the Tolerable Upper Intake Limit. However, the consequences of excess dietary Zn during early life on intestinal function and host–microbe interactions are unknown. Methods and Results Neonatal mice are gavaged with 100 Zn µg d–1 from postnatal day (PN) 2 through PN10 and indices of intestinal function and host–microbe interactions are compared to unsupplemented mice. Excess dietary Zn causes oxidative stress, increases goblet cell number and mucus production, and are associated with increased intestinal permeability and systemic inflammation. Over 900 genes are differentially expressed; 413 genes display a fold‐change >1.60. The Gene Ontology Biological processes most significantly affected include biological adhesion, the immune system, metabolic processes, and response to stimulus. Key genes most highly and significantly upregulated include ALDH2, MT1, TMEM6, CDK20, and COX62b, while CALU, ST3GAL4, CRTC2, SLC28A2, and COMMA1 are downregulated. These changes are associated with a microbiome enriched in pathogenic taxa including Pseudomonadales and Campylobacter, and greater expression of bacterial stress response genes. Conclusion Excess dietary Zn may have unforeseen influences on epithelial signaling pathways, barrier function, and luminal ecology in the intestine that may have long‐term consequences on intestinal health.

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

“…It was recently reported that excess dietary Zn causes oxidative stress, enhances gut permeability, and modifies the microbiota in mouse pups 108 . However, metal absorption, gene regulation, gut permeability, lack of strong innate and adaptive immunity, and the concept of dysbiosis in neonates may differ considerably from the integrated physiologic processes in adults.…”

The gut microbiota and its interactions with cardiovascular disease

“…Dietary zinc–curcumin supplementation improved the gut dysbiosis associated with zinc dysregulation and the cardiotoxicity induced by doxorubicin in rats (Wu, et al , ), providing a basis for future clinical studies to support the development of novel approaches for cardiotoxicity prevention. However, zinc supplementation affected the gut microbial composition in a dosage‐dependent manner (Watson, et al , ), and excess dietary zinc increased intestinal permeability and enriched pathogenic gut microbial species (Podany, et al , ), suggesting that zinc levels have critical effects on the susceptibility of individuals to pathogenic effects and disease severity.…”

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“…Zinc is necessary for the function of Paneth cells, which prevent pathogenic microbial invasion in the intestine, a risk for subsequent hepatic inflammation via α-defensin production [105]. However, the presence of excess dietary zinc increases oxidative stress with an increased intestinal permeability that should be avoided [106]. An appropriate and effective supplementation strategy is therefore necessary, even for trace elements.…”