Abstract: International Journal of Molecular Sciences Review Micronutrient Improvement of Epithelial Barrier Function in Various Disease States: A Case for Adjuvant Therapy Katherine M. DiGuilio 1 , Elizabeth Rybakovsky 1 , Reza Abdavies 2 , Romy Chamoun 3 , Colleen A. Flounders 4 , Ariel Shepley-McTaggart 5 , Ronald N. Harty 5 and James M. Mullin 1,6, * 1 2 3 4 5 6 *



 Citation: DiGuilio, K.M.; Rybakovsky, E.; Abdavies, R.; Chamoun, R.; Flounders, C.A.; Shepley-McTaggart, A.; Harty, R.N.; Mullin, J.M. Micronutrient Improvement of Epithelial Barrier Function in Various Disease States: A Case for Adjuvant Therapy. Int. J. Lankenau Institute for Medical Research, 100 Lancaster Avenue, Wynnewood, PA 19096, USA; diguiliok@mlhs.org (K.M.D.); scimecae@mlhs.org (E.R.) Department of Biology, Temple University, 1900 North 12th Street, Philadelphia, PA 19122, USA; reza.abdavies@temple.edu Department of Medicine, Lankenau Medical Center, 100 Lancaster Avenue, Wynnewood, PA 19096, USA; chamounr@mlhs.org Department of Food and Nutrition Services, Pennsylvania Hospital, 800 Spruce Street, Philadelphia, PA 19107, USA; colleen.flounders@pennmedicine.upenn.edu Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce St., Philadelphia, PA 19104, USA; arielsh@vet.upenn.edu (A.S.-M.); rharty@vet.upenn.edu (R.N.H.) Division of Gastroenterology, Department of Medicine, Lankenau Medical Center, 100 Lancaster Avenue, Wynnewood, PA 19096, USA Correspondence: mullinj@mlhs.org Abstract: The published literature makes a very strong case that a wide range of disease morbidity associates with and may in part be due to epithelial barrier leak. An equally large body of published literature substantiates that a diverse group of micronutrients can reduce barrier leak across a wide array of epithelial tissue types, stemming from both cell culture as well as animal and human tissue models. Conversely, micronutrient deficiencies can exacerbate both barrier leak and morbidity. Focusing on zinc, Vitamin A and Vitamin D, this review shows that at concentrations above RDA levels but well below toxicity limits, these micronutrients can induce cell- and tissue-specific molecular-level changes in tight junctional complexes (and by other mechanisms) that reduce barrier leak. An opportunity now exists in critical care—but also medical prophylactic and therapeutic care in general—to consider implementation of select micronutrients at elevated dosages as adjuvant therapeutics in a variety of disease management. This consideration is particularly pointed amidst the COVID-19 pandemic. Mol. Sci. 2022, 23, 2995. https:// doi.org/10.3390/ijms23062995 Academic Editor: Edwin Lephart Keywords: micronutrient; tight junction; claudin; zinc; Vitamin A; Vitamin D; barrier function; inflammation; sepsis; virus; COVID; critical care Received: 11 February 2022 Accepted: 1 March 2022 Published: 10 March 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).