Effects of nutrients on immunomodulation in patients with severe COVID-19: Current knowledge

Table 1 Role of micro- and macro-nutrients in the immune system

Micro-/macro-nutrient	Clinical outcomes	Affected cells and cytokines	Immunological outcomes	Ref.
Proteins	Whey protein has antiviral properties; supplementation facilitates the patients' recovery in viral infections	DNA or RNA polymerases, reverse transcriptase, integrase, etc.	Antiviral activities against enveloped and non-enveloped viruses; inhibit the entrance of the virus into the cell; inhibit the virus enzymes activity; prevent virus replication	Siqueiros et al[19], 2014; Nejati et al[20], 2021; Ng et al[21], 2001; Ng et al[43], 2015; Olsen et al[44], 2014
Lipids/omega-3	Improvement of oxygenation and reduced length of stay after omega-3 administration; normalization of blood pH, reducing base excess; improves renal function	IL-6, IL-8, IL-1beta, free radicals	Altering the composition of cell membranes and modulating cell signaling; decrease the pro-inflammatory response by reducing the levels of proinflammatory cytokines IL-6, IL-8, IL-1beta, and free radicals	Hawryłkowicz et al[62], 2021; Romano et al[73], 2020; McClave et al[74], 2016; Vivar-Sierra et al[79], 2021; Asher et al[81], 2021; Doaei et al[83], 2021
Vitamin B12	Combined supplementation resulted in lower necessity of oxygen and ICU admission; increased levels of B12 are correlated to higher risk of ICU admission, intubation, and death	T and B lymphocytes, NK cells; antibodies	Cell differentiation and proliferation; maintenance of the ratio between T helper and cytotoxic cells; influence on NK cell activity; in association with folate and production of antibodies	Gombart et al[2], 2020; Chaari et al[86], 2021; Ersöz et al[92], 2021; Tan et al[99], 2020
Vitamin D	Increased mortality in patients with low vitamin D levels; high dose supplementation is related to successful treatment of high risk elderly patients	Antimicrobial peptides; T cells, macrophages	Production of antimicrobial peptides in the respiratory epithelium; helps maintain cell junctions and gaps; decreasing the cytokine storm; inhibiting type 1 T helper cell response and T cell induction; its deficiency causes deprivation in the production and performance of macrophages	Dankers et al[105], 2016; Gombart et al[106], 2005; Greiller and Martineau[107], 2015; Grant et al[108], 2020; Cantorna et al[109], 2015; Ilie et al[110], 2020; Rhodes et al[111], 2021; Annweiler et al[113], 2020
Calcium	Calcium associated with albumin is capable of decreasing metabolic dysfunctions and organ damage during the COVID-19 infection	Cytotoxic T lymphocytes; IL-1, IL-6	Hypocalcemia as a result of hypoalbuminemia; increased pro-inflammatory cytokines IL-1 and IL-6 interfere with calcium metabolism; lower levels of lymphocyte counts related to higher levels of D-dimer in critically ill patients	Alemzadeh et al[116], 2021; Alsagaff et al[126], 2021; Mendez et al[127], 2021
Iron	Maintaining adequate levels of iron is related to lower levels of respiratory failure	T cells, B cells, macrophages	Chelation/deficiency: Enhances IFN-γ signaling and STAT1 activation which may stabilize the TH1 phenotype in early TH polarization; activates the transcription factors hypoxia-inducible factor (HIF)-1α and nuclear factor (NF)-IL6 in macrophages. Supplementation/overload: in TH1 cells, stimulates the production of GM-CS, and reduces expression of the T-box transcription factor T-BET; inhibits ICAM1 and MHC-II expression in macrophages, impairing TH1 immunity; in B cells, counteracts the Ig class switch towards IgG; may promote TH2 polarization	Tojo et al[131], 2021; Sonnweber et al[133], 2020; Akhtar et al[138], 2021; Nairz and Weiss[164], 2020
Copper	There is still no evidence to support the supplementation of copper in COVID-19 patients	Macrophages, neutrophils, NK cells; IL-2	Participates in the functioning of innate immune cells (e.g., it accumulates in macrophage phagolysosomes to combat pathogens); has intrinsic antimicrobial properties; acts in defense against reactive oxygen species; has a role in IL-2 production and response; maintains intracellular antioxidant balance; has a role in differentiation and proliferation of T cells	Zhou et al[130], 2020; Zeng et al[140], 2021; Rani et al[143], 2021
Zinc	Currently there is no evidence of interferences of this element regarding severe cases	Th1 cells; IL-2, IL-1β, IL-6, IL-8	Acute zinc deficiency promotes the adhesion of monocytes to endothelial cells in vitro and reduces the production of TH1 profile cytokines including IFN-γ, IL-2, and TNF-α; it has the potential to inhibit the inflammatory process by stimulating the release of IL-1-β depending on the transcription factor NF-κB; low levels of zinc are associated with an increase in IL-6, IL-8, and TNF-α which contributes to inflammation	Gammoh et al[144], 2017; Elalfy et al[153], 2021; Thomas et al[154], 2021; Abdelmaksoud et al[155], 2021; Mariani et al [165], 2006
Magnesium	This nutrient is capable of reducing the necessity of oxygen and intensive care unit admission	Natural killer cells, CD8 killer T cells, monocytes, macrophages, leukocytes	Reduction of immune cell toxicity; cytokine storm favoring; decreased anti-oxidant and anti-inflammatory action, energy depletion, muscle catabolism, and prothrombotic conditions	Tang et al[159], 2020; DiNicolantonio and O’keefe[160], 2021; van Niekerk et al[161], 2018; Zhu et al[162], 2021; Iotti et al[163], 2020; Nairz and Weiss[164], 2020