Abigail Podany1, Jessica Rauchut1, Tong Wu2, Yuka Imamura Kawasawa3,4, Justin Wright5, Regina Lamendella5, David I Soybel1, Shannon L Kelleher1,2,6. 1. Department of Surgery, Penn State Hershey College of Medicine, Hershey, PA. 2. Department of Biomedical and Nutritional Sciences, University of Massachusetts Lowell, Lowell, MA. 3. Department of Pharmacology, Penn State Hershey College of Medicine, Hershey, PA. 4. Department of Biochemistry and Molecular Biology, Institute for Personalized Medicine, Penn State Hershey College of Medicine, Hershey, PA. 5. Department of Biology, Juniata College, Huntingdon, PA. 6. Department of Cellular and Molecular Physiology, Penn State Hershey College of Medicine, Hershey, PA.
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.
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.
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