**1. Introduction**

Zinc is among the trace inorganics that are found in body fluids and tissues in small amounts but are essential for body growth and function. About 85% of zinc in the body is found in muscle and bone, 11% in skin and liver, and the rest in all other tissues. Interestingly, no single test reflects the zinc status in the whole body; however, tests for plasma or serum zinc are the most widely used [1]. Zinc in plasma is bound nearly 60% to albumin, 40% to macroglobulins, and 3% to amino acids and the renal ultrafiltration fraction [2]. Human metabolic pathways show that zinc is involved in the function of many

**Citation:** Zupo, R.; Sila, A.; Castellana, F.; Bringiotti, R.; Curlo, M.; De Pergola, G.; De Nucci, S.; Giannelli, G.; Mastronardi, M.; Sardone, R. Prevalence of Zinc Deficiency in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis. *Nutrients* **2022**, *14*, 4052. https://doi.org/10.3390/ nu14194052

Academic Editors: Omorogieva Ojo and Amanda R Amorim Adegboye

Received: 13 August 2022 Accepted: 23 September 2022 Published: 29 September 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/).

enzymes, being an integral component of nearly 10 percent of the human proteome (e.g., of several key enzymes and transcription factors). According to recent dietary guidelines, an adult daily intake of 11 mg (males) and 8 mg (females) is recommended [2]. Dietary zinc sources include a wide range of edible sources [3]. Oysters have the greatest zinc concentration per serving, although red meat and poultry supply most of the zinc in the diet. Beans, nuts, different types of shellfish (such as crabs and lobsters), whole grains, fortified breakfast cereals, and dairy products are other good sources [4]. Phytates, found in whole-grain bread, cereals, legumes, and other foods, bind to zinc and prevent its absorption [5,6]. Consequently, zinc bioavailability from cereal and plant diets is lower than from animal foods, despite the significant zinc content in many cereal and plant foods. Citric acid may improve absorption, whereas iron, copper, calcium, fiber, and phytates may inhibit it. Zinc is an essential element for the integrity of bodily structures and activities. Zinc acts as a cofactor for various enzymes involved in growth, cell signaling pathways, cellular activities, immune function, and tissue repair.

Once ingested, zinc is absorbed in the small intestine, both the distal duodenum and proximal jejunum. However, research has yet to shed light on zinc homeostasis in enterocytes and the molecular processes intrinsic to intestinal absorption. In particular, the transfer of zinc through enterocytes upon absorption, its subsequent basolateral release into the bloodstream, and the involvement of zinc-binding or zinc-transport proteins in this process need to be elucidated, apart from the already known metallothionein. In addition, the involvement of zinc-transporters in the cytoplasmic organelles of enterocytes (such as ZnT-2, ZnT-4, ZnT-6, and ZnT-7) in cellular zinc trafficking and homeostasis needs to be investigated in intestinal cell models in vitro to understand the regulation of zinc transit at the enterocyte level. Zinc levels are often low in patients with chronic diarrhea and malabsorptive disorders [7].

This is why trace elements deficiency is common in patients with inflammatory bowel disease (IBD) during both active disease and remission [8,9]. Increased zinc losses occur mostly in conjunction with diarrhea, ostomies, and high-exit fistulas, often experienced in IBD. In conjunction with the chronic malabsorption state in cases of intestinal inflammation, micronutrient leaks are likely responsible for zinc deficiency from the disease onset. Reports indicate that subclinical zinc deficiency may lead to mucosal inflammation in these patients, as well as exacerbate colitis, and increase the production of pro-inflammatory cytokines [10].

Of note, biologically speaking, zinc homeostasis is strongly affected by a balance between the zinc-binding protein metallothionein and the expression of two zinc transporters. Because albumin is the zinc transporter, a low albumin level, mainly common to IBD patients experiencing malnutrition, malabsorption, an increased fractional catabolic rate of albumin, and increased albumin transfer out of the vascular system, may affect zinc levels.

Extensive reports so far substantiate the burden of micronutrient deficiencies in malabsorptive settings. However, studies investigating zinc deficiency in IBD patients are few, heterogeneous, and were performed in small patient subsets. The findings are often fragmented, whereas the deficiencies spectrum is broad. Here, we conducted a systematic review and meta-analysis of available data to estimate the prevalence of zinc deficiency in IBD, looking at the pattern of prevalence profiles across the two well-known forms of IBD, presumed to reflect the intrinsic difference in the inflammatory site.
