Therapeutic supplementation with zinc in the management of COVID-19-related diarrhea and ageusia/dysgeusia: mechanisms and clues for a personalized dosage regimen

Abstract

Zinc supplementation is indicated for diarrhea and taste disorders, which are both features of COVID-19 . Nevertheless, this strategy has not been tested for the treatment of these secondary complications in the current pandemic. Through an updated review, a practical appraisal was considered as a means of providing a medical nexus of therapeutic zinc regimens as an adjunct in the management of COVID-19-related diarrhea and ageusia/dysgeusia. While diarrhea and taste disorders are consequences of COVID-19, zinc supplementation is useful for non-COVID-19 patients with these clinical problems. The overwhelming evidence for supplementing with zinc in diarrhea and pneumonia is associated with the treatment of children, while for taste disorders the use of supplementing with zinc is more examined in adults. Whereas COVID-19 is more prevalent in adults, precautions should be exercised not to translate the zinc dosage used for children with diarrhea and taste disorders into the current pandemic. Therapeutic doses of zinc used for adults (∼50-150 mg/day of elemental zinc) could be included in the treatment strategies for COVID-19, but this proposal should be examined through randomized studies.

Keywords: COVID-19; clinical nutrition; hypozincemia; intensive care; zinc.

Figure 1

Biological rationale for supplementing with zinc to mitigate COVID-19–related diarrhea. The gut is affected by both SARS-COV-2 and zinc deficiency, each of which affects the intestinal epithelium and related cells. SARS-CoV-2 binds to the ACE2 receptor and hence blocks the binding of Ang II to this receptor. As a consequence, the conversion of Ang II to Ang-(1–7) is decreased, reducing the anti-inflammatory effects mediated by the Mas receptor.^, In addition, the binding of Ang II to AT1R is increased relative to its binding to AT2R, thereby leading to a higher production of pro-inflammatory cytokines. After endocytosis, SARS-CoV-2 per se triggers the production of pro-inflammatory cytokines via PAK-1 and AP-1.^, Zinc deficiency, in turn, affects the tight junction, while reducing the maintenance of Paneth cells via an impaired action of zinc transporters (eg, ZIP4 and ZIP7).^, Moreover, low zinc content in the granule alongside reduced action of ZnT2 leads to less formation of antimicrobial peptides, which are crucial elements for a healthy gut microbiota composition,^, whereas there is more stimulus for the production of pro-inflammatory cytokines upon dysbiosis. SARS-CoV-2 itself also reduces the formation of antimicrobial peptides due to the inhibition of B0AT1, which decreases the influx of tryptophan, a fundamental amino acid that activates the mTOR complex so that antimicrobial peptides can be generated. Zinc deficiency also affects the Goblet cell by reducing the production of mucus, and this is another way in which the gut barrier integrity can be damaged. In summary, the pathophysiological processes aforementioned may imply diarrhea, while zinc supplementation can be hypothesized as a tool to mitigate this clinical problem. Abbreviations: ACE2, angiotensin-converting enzyme 2; Ang (1–7), angiotensin (1-7); Ang I, angiotensin I; Ang II, angiotensin II; AT1R, angiotensin II receptor type 1; AT2R, angiotensin II receptor type 2; B0AT1, broad neutral amino acid transporter; COVID-19, coronavirus disease 2019; mTOR, mechanistic target of rapamycin; NF-κB, nuclear factor-kappa B; PAK-1, p21-activated kinase 1; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TNF-α, tumor necrosis factor alpha; ZIP4, zinc transporter 4 precursor; ZIP7, zinc transporter 7 precursor; ZnT2, zinc transporter-2.

Figure 2

Potential mechanisms of COVID-19–related ageusia/dysgeusia and zinc supplementation. SARS-CoV-2 affects the lingual epithelium by binding to the ACE2, thereby triggering pro-inflammatory cytokines, which may decrease the regeneration and proliferation of tongue cells. Renin–angiotensin-related proteins are expressed in taste buds, modulating the perception of salty and sweet flavors; given that SARS-CoV-2 penetrates the taste cells via renin–angiotensin-related proteins, the virus can inhibit salty and sweet tastes, decreasing the central stimulus for energy intake and hence affecting nutritional adequacy and the recovery from COVID-19. During zinc deficiency, the zinc content in the lingual epithelium would be expected to be low, affecting its regeneration and proliferation as the main consequences.^, In addition, low zinc content in such a tissue can decrease carbonic anhydrase activity. Insofar as zinc content in the salivary glands may decline during zinc deficiency,^, low salivary zinc content is particularly linked to decreased activity of carbonic anhydrase 6, also called gustin, whose enzyme is a trophic factor that promotes the growth and development of taste buds.^, Thus, zinc supplementation could be a reasonable approach for reversing the harmful effects of zinc deficiency in this scenario or a booster for the perception of salty taste,^, which can be considered the pivotal taste for stimulating energy intake from salt meals and ultimately ameliorating nutritional adequacy and recovery from COVID-19. Abbreviations: ACE2, angiotensin-converting enzyme 2; COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2