Zinc absorption in the small intestine is one of the main mechanisms regulating the systemic homeostasis of this essential trace element. This review summarizes the key aspects of human zinc homeostasis and distribution. In particular, current knowledge on human intestinal zinc absorption and the influence of diet-derived factors on bioaccessibility and bioavailability as well as intrinsic luminal and basolateral factors with an impact on zinc uptake are discussed. Their investigation is increasingly performed using in vitro cellular intestinal models, which are continually being refined and keep gaining importance for studying zinc uptake and transport via the human intestinal epithelium. The vast majority of these models is based on the human intestinal cell line Caco-2 in combination with other relevant components of the intestinal epithelium, such as mucin-secreting goblet cells and in vitro digestion models, and applying improved compositions of apical and basolateral media to mimic the in vivo situation as closely as possible. Particular emphasis is placed on summarizing previous applications as well as key results of these models, comparing their results to data obtained in humans, and discussing their advantages and limitations.

Approximately 1 billion people worldwide suffer from zinc deficiency, with severe consequences for their well-being, such as critically impaired intestinal health. In addition to an extreme degeneration of the intestinal epithelium, the intestinal mucus is seriously disturbed in zinc-deficient (ZD) animals. The underlying cellular processes as well as the relevance of zinc for the mucin-producing goblet cells, however, remain unknown. To this end, this study examines the impact of zinc deficiency on the synthesis, production, and secretion of intestinal mucins as well as on the zinc homeostasis of goblet cells using the in vitro goblet cell model HT-29-MTX. Zinc deprivation reduced their cellular zinc content, changed expression of the intestinal zinc transporters ZIP-4, ZIP-5, and ZnT1 and increased their zinc absorption ability, outlining the regulatory mechanisms of zinc homeostasis in goblet cells. Synthesis and secretion of mucins were severely disturbed during zinc deficiency, affecting both MUC2 and MUC5AC mRNA expression with ongoing cell differentiation. A lack of zinc perturbed mucin synthesis predominantly on the post-translational level, as ZD cells produced shorter O-glycans and the main O-glycan pattern was shifted in favor of core-3-based mucins. The expression of glycosyltransferases that determine the formation of core 1-4 O-glycans was altered in zinc deficiency. In particular, B3GNT6 mRNA catalyzing core 3 formation was elevated and C2GNT1 and C2GNT3 elongating core 1 were downregulated in ZD cells. These novel insights into the molecular mechanisms impairing intestinal mucus stability during zinc deficiency demonstrate the essentiality of zinc for the formation and maintenance of this physical barrier.

Selenium homeostasis depends on hepatic biosynthesis of selenoprotein P (SELENOP) and SELENOP-mediated transport from the liver to e.g. the brain. In addition, the liver maintains copper homeostasis. Selenium and copper metabolism are inversely regulated, as increasing copper and decreasing selenium levels are observed in blood during aging and inflammation. Here we show that copper treatment increased intracellular selenium and SELENOP in hepatocytes and decreased extracellular SELENOP levels. Hepatic accumulation of copper is a characteristic of Wilson’s disease. Accordingly, SELENOP levels were low in serum of Wilson’s disease patients and Wilson’s rats. Mechanistically, drugs targeting protein transport in the Golgi complex mimicked some of the effects observed, indicating a disrupting effect of excessive copper on intracellular SELENOP transport resulting in its accumulation in the late Golgi. Our data suggest that hepatic copper levels determine SELENOP release from the liver and may affect selenium transport to peripheral organs such as the brain.

Trace elements such as zinc, manganese, copper, or iron are essential for a wide range of physiological functions. It is therefore crucial to ensure an adequate supply of these elements to the body. Many previous investigations have dealt with the role of transport proteins, in particular their selectivity for, and competition between, different ions. Another so far less well investigated major factor influencing the absorption of trace elements seems to be the intestinal mucus layer. This gel-like substance covers the entire gastrointestinal tract and its physiochemical properties can be mainly assigned to the glycoproteins it contains, so-called mucins. Interaction with mucins has already been demonstrated for some metals. However, knowledge about the impact on the respective bioavailability and competition between those metals is still sketchy. This review therefore aims to summarize the findings and knowledge gaps about potential effects regarding the interaction between gastrointestinal mucins and the trace elements iron, zinc, manganese, and copper. Mucins play an indispensable role in the absorption of these trace elements in the neutral to slightly alkaline environment of the intestine, by keeping them in a soluble form that can be absorbed by enterocytes. Furthermore, the studies so far indicate that the competition between these trace elements for uptake already starts at the intestinal mucus layer, yet further research is required to completely understand this interaction.

Plant-based diets usually contain more nutrient-dense foods such as vegetables, legumes, whole grains, and fruits than a standard Western diet. Yet, the amount and especially the bioavailability of several nutrients, such as trace elements, is supposed to be lower in comparison to diets with consumption of animal-derived foods. Based on this, the Nutritional Evaluation (NuEva) study (172 participants) was initiated to compare the trace element status of omnivores, flexitarians, vegetarians, and vegans. Serum selenium, zinc, and copper concentrations and biomarkers were evaluated at baseline and during a 12-month intervention with energy- and nutrient-optimized menu plans. The implementation of optimized menu plans did not substantially influence the status of trace elements. At baseline, serum selenium biomarkers were lower in vegetarians and vegans compared to omnivores and flexitarians. The zinc intake of vegetarians and vegans was significantly lower compared to omnivores, whereas the Phytate Diet Score was increased. Accordingly, total serum zinc concentrations were reduced in vegans which was, however, only significant in women and was further supported by the analysis of free zinc. Regarding copper status, no differences were observed for total serum copper. Overall, we identified selenium and zinc as critical nutrients especially when maintaining a vegan diet.