Potential Dietary Interventions for COVID‑19 Infection Based on the Gut‑Immune Axis: An Update Review on Bioactive Component of Macronutrients

Marzieh Nejati, Parvin Dehghan, Fataneh Hashempour-Baltork, Adel Mirza Alizadeh, Parastou Farshi, Kianoush Khosravi-Darani


Recently emerged coronavirus, known as SARS‑CoV‑2 or Covid‑19 is considered as a serious threat for human health. Due to unavailable specific drugs for this virus, there is an urgent need for supportive cares. Epigenetic immune boosting approaches and developing anti‑inflammatory agents by gut‑associated bioactive macronutrients can be plausible protective cares for COVID‑19. Suitable intake of bioactive macronutrients including prebiotics, fatty acids, proteins and branched‑chain amino acids may result in anti‑viral responses through modulating macrophages and dendritic cells via Toll‑like receptors, decreasing viral load, inactivating the enveloped viruses, increasing the anti‑inflammatory metabolites and inhibiting the proliferation of microbial organisms. Bioactive macronutrients may help in promotion of immunological responses and recovery acceleration against Covid‑19. This review focuses on the mechanisms of bioactive macronutrients and related clinical trials on enveloped viruses with emphasis on gut‑microbiome‑immune axis. Macronutrients and this axis may be conducive strategies to protect host against the viral infection.


Coronavirus; functional food; immune system; nutrients; prebiotic

Full Text:



WHO. WHO-convened Global Study of Origins of SARSCoV-2: China Part. 2021. Available from: https://www.who.int/

docs/default-source/coronaviruse/who-convened-global-study-oforigins-of-sars-cov-2-china-part-joint-report.pdf. [Last accessed

on 2021 Feb 10].

WHO, 2021. World Health Organization (WHO). COVID-19

Weekly Epidemiological Update Data as received by WHO

from national authorities, as of 21 March 2021, 10 am CET.

Available from: https://www.who.int/publications/m/item/weeklyepidemiological-update-on-covid-19--[Last accessed on 2021

Mar 23].

Banerjee A, Kulcsar K, Misra V, Frieman M, Mossman K. Bats

and coronaviruses. Viruses 2019;11:41.

Chen Y, Liu Q, Guo D. Emerging coronaviruses: Genome

structure, replication, and pathogenesis. J Med Virol


Guarner J. Three emerging coronaviruses in two decades: The

story of SARS, MERS, and now COVID‑19. Am J Clin Pathol


Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, et al.

A pneumonia outbreak associated with a new coronavirus of

probable bat origin. Nature 2020;579:270‑3.

Chan JF, Kok KH, Zhu Z, Chu H, To KK, Yuan S, et al.

Genomic characterization of the 2019 novel human‑pathogenic

coronavirus isolated from a patient with atypical pneumonia after

visiting Wuhan. Emerg Microbes Infect 2020;9:221‑36.

Zhang N, Wang L, Deng X, Liang R, Su M, He C, et al. Recent

advances in the detection of respiratory virus infection in

humans. J Med Virol 2020;92:408‑17.

Perlman S. Another decade, another coronavirus. N Engl J Med


Lai CC, Shih TP, Ko WC, Tang HJ, Hsueh PR. Severe acute

respiratory syndrome coronavirus 2 (SARS‑CoV‑2) and

corona virus disease‑2019 (COVID‑19): The epidemic and the

challenges. Int J Antimicrob Agents 2020;55:105924.

CDC. 2021. Available from: https://www.cdc.gov/

coronavirus/2019-ncov/faq.html#Spread. [Last accessed on 2021

Feb 10].

The Lancet Respiratory Medicine. COVID-19 transmission-up in

the air. Lancet Respir Med. 2020;8:1159.

Coico R, Sunshine G. Immunology, A short course. 14.

Hypersensitivity: Type I. Hoboken NJ, USA: John Wiley & sons,

Inc.; 2009. p. 221‑35.

van der Hoek L, Pyrc K, Jebbink MF, Vermeulen‑Oost W,

Berkhout RJ, Wolthers KC, et al. Identification of a new human

coronavirus. Nat Med 2004;10:368‑73.

Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical

features of patients infected with 2019 novel coronavirus in

Wuhan, China. Lancet 2020;395:497‑506.

Chafekar A, Fielding BC. MERS‑CoV: Understanding the latest

human coronavirus threat. Viruses 2018;10:93.

Woo PC, Lau SK, Chu Cm, Chan Kh, Tsoi Hw, Huang Y, et al.

Characterization and complete genome sequence of a novel

coronavirus, coronavirus HKU1, from patients with pneumonia.

J Virol 2005;79:884‑95.

Deng SQ, Peng HJ. Characteristics of and public health

responses to the coronavirus disease 2019 outbreak in China.

J Clin Med 2020;9:575.

Guan Wj, Ni Zy, Hu Y, Liang Wh, Ou Cq, He Jx, et al. Clinical

characteristics of coronavirus disease 2019 in China. N Engl J

Med 2020;382:1708‑20.

Spiegel M, Schneider K, Weber F, Weidmann M, Hufert FT.

Interaction of severe acute respiratory syndrome‑associated

coronavirus with dendritic cells. J Gen Virol 2006;87:1953‑60.

Cheng PK, Wong DA, Tong LK, Ip SM, Lo AC, Lau CS, et al.

Viral shedding patterns of coronavirus in patients with probable

severe acute respiratory syndrome. Lancet 2004;363:1699‑700.

Belouzard S, Chu VC, Whittaker GR. Activation of the SARS

coronavirus spike protein via sequential proteolytic cleavage at

two distinct sites. Proc Natl Acad Sci USA 2009;106:5871‑6.

Bosch BJ, van der Zee R, de Haan CA, Rottier PJ. The

coronavirus spike protein is a class I virus fusion protein:

Structural and functional characterization of the fusion core

complex. J Virol 2003;77:8801‑11.

Baranov PV, Henderson CM, Anderson CB, Gesteland RF,

Atkins JF, Howard MT. Programmed ribosomal frameshifting in

decoding the SARS‑CoV genome. Virology 2005;332:498‑510.

Snijder EJ, Bredenbeek PJ, Dobbe JC, Thiel V, Ziebuhr J,

Poon LL, et al. Unique and conserved features of genome and

proteome of SARS‑coronavirus, an early split‑off from the

coronavirus group 2 lineage. J Mol Biol 2003;331:991‑1004.

Boehm M, Nabel EG. Angiotensin‑converting enzyme 2‑‑A new

cardiac regulator. N Engl 2002;347:1795‑7.

Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M,

Stagliano N, et al. A novel angiotensin‑converting enzyme–

related carboxypeptidase (ACE2) converts angiotensin I to

angiotensin 1‑9. Circ Res 2000;87:e1‑9.

Keidar S, Kaplan M, Gamliel‑Lazarovich A. ACE2 of the

heart: From angiotensin I to angiotensin (1–7). Cardiovasc Res


Towler P, Staker B, Prasad SG, Menon S, Tang J, Parsons T,

et al. ACE2 X‑ray structures reveal a large hinge‑bending

motion important for inhibitor binding and catalysis. J Biol


Wu K, Peng G, Wilken M, Geraghty RJ, Li F. Mechanisms of

host receptor adaptation by severe acute respiratory syndrome

coronavirus. J. Biol 2012;287:8904‑11.

Wu K, Li W, Peng G, Li F. Crystal structure of NL63 respiratory

coronavirus receptor‑binding domain complexed with its human

receptor. Proc Natl Acad Sci USA 2009;106, 19970‑4.

Baig AM, Khaleeq A, Ali U, Syeda H. Evidence of the

COVID‑19 virus targeting the CNS: Tissue distribution, host–

virus interaction, and proposed neurotropic mechanisms. ACS

Chem Neurosci 2020;11:995‑8.

Glowacka I, Bertram S, Herzog P, Pfefferle S, Steffen I,

Muench MO, et al. Differential downregulation of ACE2 by the

spike proteins of severe acute respiratory syndrome coronavirus

and human coronavirus NL63. J Virol 2010;84:1198‑205.

Wang S, Guo F, Liu K, Wang H, Rao S, Yang P, et al.

Endocytosis of the receptor‑binding domain of SARS‑CoV

spike protein together with virus receptor ACE2. Virus Res


Imai Y, Kuba K, Rao S, Huan Y, Guo F, Guan B, et al.

Angiotensin‑converting enzyme 2 protects from severe acute

lung failure. Nature 2005;436:112‑6.

Hamming I, Timens W, Bulthuis M, Lely A, Navis G,

van Goor H. Tissue distribution of ACE2 protein, the functional

receptor for SARS coronavirus. A first step in understanding

SARS pathogenesis. J Pathol 2004;203:631‑7.

Cheung CY, Poon LL, Ng IH, Luk W, Sia SF, Wu MH, et al.

Cytokine responses in severe acute respiratory syndrome

coronavirus‑infected macrophages in vitro: Possible relevance to pathogenesis. J Virol 2005;79:7819‑26.

Law HK, Cheung CY, Ng HY, Sia SF, Chan YO, Luk W,

et al. Chemokine up‑regulation in sars‑coronavirus–

infected, monocyte‑derived human dendritic cells. Blood


Yen YT, Liao F, Hsiao CH, Kao CL, Chen YC, Wu‑Hsieh BA.

Modeling the early events of severe acute respiratory syndrome

coronavirus infection in vitro. J Virol 2006;80:2684‑93.

He L, Ding Y, Zhang Q, Che X, He Y, Shen H, et al. Expression

of elevated levels of pro‐inflammatory cytokines in SARS‐CoV‐

infected ACE2+cells in SARS patients: Relation to the acute lung

injury and pathogenesis of SARS. J Pathol 2006;210:288‑97.

Gao QY, Chen YX, Fang JY. 2019 novel coronavirus infection

and gastrointestinal tract. J Dig Dis 2020;21:125‑6.

Nguyen TM, Zhang Y, Pandolfi PP. Virus against virus:

A potential treatment for 2019‑nCov (SARS‑CoV‑2) and other

RNA viruses. Cell Res 2020;30:189‑90.

Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al.

Remdesivir and chloroquine effectively inhibit the recently

emerged novel coronavirus (2019‑nCoV) in vitro. Cell Res


Islam MT, Sarkar C, El‐Kersh DM, Jamaddar S, Uddin SJ,

Shilpi JA, et al. Natural products and their derivatives against

coronavirus: A review of the non‐clinical and pre‐clinical data.

Phytother Res 2020;34:2471‑92.

Lupton JR, Brooks GA, Butte NF, Caballero B,

Flatt JP, Fried SK, et al. Dietary reference intakes for energy,

carbohydrate, fiber, fat, fatty acids, cholesterol, protein, and

amino acids. NAP: Washington, DC, USA 2002;5:589-768.

Kierstein S, Krytska K, Kierstein G, Hortobágyi L, Zhu X,

Haczku A. Sugar consumption increases susceptibility to allergic

airway inflammation and activates the innate immune system in

the lung. J Allergy Clin Immunol 2008;121:S196.

Lin CS, Chang CJ, Lu CC, Martel J, Ojcius DM, Ko YF, et al.

Impact of the gut microbiota, prebiotics, and probiotics on

human health and disease. Biomed J 2014;37:259‑68.

Hutkins RW, Krumbeck JA, Bindels LB, Cani PD, Fahey G Jr,

Goh YJ, et al. Prebiotics: Why definitions matter. Curr Opin

Biotechnol 2016;37:1‑7.

Manning T, Gibson G. Microbial‑gut interactions in health

and disease. Prebiotics. Best Pract Res Clin Gastroenterol


Shamasbi SG, Dehgan P, Charandabi SMA, Aliasgarzadeh A,

Mirghafourvand M. The effect of resistant dextrin as a prebiotic

on metabolic parameters and androgen level in women with

polycystic ovarian syndrome: A randomized, triple‑blind,

controlled, clinical trial. Eur J Nutr 2019;58:629‑40.

Dehghan P, Farhangi MA, Nikniaz L, Nikniaz Z,

Asghari‐Jafarabadi M. Gut microbiota‐derived metabolite

trimethylamine N‐oxide (TMAO) potentially increases the risk

of obesity in adults: An exploratory systematic review and dose‐

response meta‐analysis. Obes Rev 2020;19:76.

Enaud R, Prevel R, Ciarlo E, Beaufils F, Wieërs G, Guery B,

et al. The gut‑lung axis in health and respiratory diseases:

A place for inter‑organ and inter‑kingdom crosstalks. Front Cell

Infect Microbiol 2020;10:9.

Farhangi MA, Dehghan P, Namazi N. Prebiotic supplementation

modulates advanced glycation end‑products (AGEs),

soluble receptor for AGEs (sRAGE), and cardiometabolic

risk factors through improving metabolic endotoxemia:

A randomized‑controlled clinical trial. Eur J Nutr


Farhangi MA, Javid AZ, Sarmadi B, Karimi P, Dehghan P.

A randomized controlled trial on the efficacy of resistant dextrin,

as functional food, in women with type 2 diabetes: Targeting the

hypothalamic–pituitary–adrenal axis and immune system. Clin

Nutr 2018;37:1216‑23.

Hakimi S, Farhan F, Farshbaf‑Khalili A, Dehghan P,

Javadzadeh Y, Abbasalizadeh S, et al. The effect of prebiotic

vaginal gel with adjuvant oral metronidazole tablets on treatment

and recurrence of bacterial vaginosis: A triple‑blind randomized

controlled study. Arch Gynecol Obstet 2018;297:109‑16.

Tabrizi A, Khalili L, Homayouni-Rad A, Pourjafar H, Dehghan P,

Ansari F. Prebiotics, as promising functional food to patients with

psychological disorders: A review on mood disorders, sleep, and

cognition. NeuroQuantology 2019;17:1-9.

Hashempour‑Baltork F, Hosseini H, Shojaee‑Aliabadi S,

Torbati M, Alizadeh AM, Alizadeh M. Drug resistance and the

prevention strategies in food borne bacteria: An update review.

Adv Pharm Bull 2019;9:335‑47.

Blaut M. Relationship of prebiotics and food to intestinal

microflora. Eur J Nutr 2002;41(Suppl 1):I11‑6.

Gibson GR, Wang X. Enrichment of bifidobacteria from human

gut contents by oligofructose using continuous culture. FEMS

Microbiol Lett 1994;118:121‑7.

Barcelo A, Claustre J, Moro F, Chayvialle JA, Cuber JC,

Plaisancié P. Mucin secretion is modulated by luminal factors in

the isolated vascularly perfused rat colon. Frontline Gastroenterol


Vulevic J, Drakoularakou A, Yaqoob P, Tzortzis G, Gibson GR.

Modulation of the fecal microflora profile and immune function

by a novel trans‑galactooligosaccharide mixture (B‑GOS) in

healthy elderly volunteers. Am J Clin Nutr 2008;88:1438‑46.

Lehtoranta L, Pitkäranta A, Korpela R. Probiotics in

respiratory virus infections. Eur J Clin Microbiol Infect Dis


Luoto R, Ruuskanen O, Waris M, Kalliomäki M, Salminen S,

Isolauri E. Prebiotic and probiotic supplementation prevents

rhinovirus infections in preterm infants: A randomized,

placebo‑controlled trial. J Allergy Clin Immunol


Arslanoglu S, Moro GE, Boehm G. Early Supplementation

of prebiotic oligosaccharides protects formula‑fed infants

against infections during the first 6 months of life. J Nutr


Firmansyah A, Pramita G, Carrie Fassler A, Haschke F,

Link‑Amster H. Improved humoral immune response to

measles vaccine in infants receiving infant cereal with

fructooligosaccharides. J Pediatr Gastroenterol Nutr


Bakker‑Zierikzee AM, Tol EA, Kroes H, Alles MS, Kok FJ,

Bindels JG. Faecal SIgA secretion in infants fed on

pre‑ or probiotic infant formula. Pediatr Allergy Immunol


Duggan C, Penny ME, Hibberd P, Gil A, Huapaya A, Cooper A,

et al. Oligofructose‑supplemented infant cereal: 2 randomized,

blinded, community‑based trials in Peruvian infants. Am J Clin

Nutr 2003;77:937‑42.

Waligora‑Dupriet AJ, Campeotto F, Nicolis I, Bonet A,

Soulaines P, Dupont C, et al. Effect of oligofructose

supplementation on gut microflora and well‑being in young

children attending a day care centre. Int J Food Microbiol


Lomax AR, Cheung LV, Noakes PS, Miles EA, Calder PC.

Inulin‑type β2‑1 fructans have some effect on the antibody response to seasonal influenza vaccination in healthy middle‑aged humans. Front Immunol 2015;6:490.

Seidel C, Boehm V, Vogelsang H, Wagner A, Persin C, Glei M,

et al. Influence of prebiotics and antioxidants in bread on the

immune system, antioxidative status and antioxidative capacity

in male smokers and non‑smokers. Br J Nutr 2007;97:349‑56.

Langkamp-Henken B, Bender BS, Gardner EM,

Herrlinger-Garcia KA, Kelley MJ, Murasko DM, et al.

Nutritional formula enhanced immune function and reduced days

of symptoms of upper respiratory tract infection in seniors. J Am

Geriatr Soc 2004;52:3‑12.

Langkamp‑Henken B, Wood SM, Herlinger‑Garcia KA,

Thomas DJ, Stechmiller JK, Bender BS, et al. Nutritional

formula improved immune profiles of seniors living in nursing

homes. J Am Geriatr Soc 2006;54:1861‑70.

Guigoz Y, Rochat F, Perruisseau‑Carrier G, Rochat I, Schiffrin E.

Effects of oligosaccharide on the faecal flora and non‑specific

immune system in elderly people. Nutr Res 2002;22:13–25.

Bunout D, Hirsch S, Pía de la Maza M, Muñoz C, Haschke F,

Steenhout P, et al. Effects of prebiotics on the immune response

to vaccination in the elderly. JPEN J 2002;26:372‑6.

Daliri EBM, Lee BH, Oh DH. Safety of probiotics in health

and disease. In The Role of Functional Food Security in Global

Health. Elsevier; 2019. p. 603‑22.

Hashempour‑Baltork F, Torbati M, Azadmard‑Damirchi S,

Savage GP. Quality properties of sesame and olive oils

incorporated with flaxseed oil. Adv Pharm Bull 2017;7:97‑101.

Hashempour‑Baltork F, Torbati M, Azadmard‑Damirchi S,

P Savage G. Chemical, rheological and nutritional characteristics

of sesame and olive oils blended with linseed oil. Adv Pharm

Bull 2018;8:107‑13.

Hashempour‐Baltork F, Torbati M, Azadmard‐Damirchi S,

Savage GP. Quality properties of puffed corn snacks incorporated

with sesame seed powder. Food Sci Nutr 2018;6:85‑93.

de Jong AJ, Kloppenburg M, Toes REM, Ioan‑Facsinay A.

Fatty acids, lipid mediators, and T‑cell function. Front Immunol


Conti P, Ronconi G, Caraffa A, Gallenga C, Ross R, Frydas I,

et al. Induction of pro‑inflammatory cytokines (IL‑1 and

IL‑6) and lung inflammation by Coronavirus‑19 (COVID‑19

or SARS‑CoV‑2): Anti‑inflammatory strategies. J Biol Regul

Homeost Agents 2020;34:327‑31.

Rocha D, Caldas A, Oliveira L, Bressan J, Hermsdorff H.

Saturated fatty acids trigger TLR4‑mediated inflammatory

response. Atherosclerosis 2016;244:211‑5.

Gomaa AM, El‑Aziz EAA. Omega‑3 fatty acids decreases

oxidative stress, tumor necrosis factor‑alpha, and interleukin‑1

beta in hyperthyroidism‑induced hepatic dysfunction rat model.

Pathophysiology 2016;23:295‑301.

Das UN. Can essential fatty acids reduce the burden of

disease(s)? Lipids Health Dis 2008;7:9.

Das UN. Can Bioactive Lipids Inactivate

Coronavirus (COVID‑19)? Arch Med Res 2020;51:282‑6.

Chandrabose KA, Cuatrecasas P, Pottathil R. Interferon‑mediated

changes in lipid metabolism. Tex Rep Biol Med 1981;41:499‑508.

Pottathil R, Chandrabose KA, Cuatrecasas P, Lang DJ.

Establishment of the interferon‑mediated antiviral state:

Role of fatty acid cyclooxygenase. Proc Natl Acad Sci USA


Purasiri P, McKechnie A, Heys S, Eremin O. Modulation in vitro

of human natural cytotoxicity, lymphocyte proliferative response

to mitogens and cytokine production by essential fatty acids.

Immunology 1997;92:166‑72.

Horrobin DF. Essential fatty acids, immunity and viral infections.

J Nutr Med 1990;1:145‑51.

Roessler C, Kuhlmann K, Hellwing C, Leimert A, Schumann J.

Impact of polyunsaturated fatty acids on miRNA profiles of

monocytes/macrophages and endothelial cells‑A pilot study. Int J

Mol Sci 2017;18:284.

Gutiérrez S, Svahn SL, Johansson ME. Effects of omega‑3 fatty

acids on immune cells. Int J Mol Sci 2019;20:5028.

Kumar N, Gupta G, Anilkumar K, Fatima N, Karnati R,

Reddy GV, et al. 15‑Lipoxygenase metabolites of α‑linolenic

acid, [13‑(S)‑HPOTrE and 13‑(S)‑HOTrE], mediate

anti‑inflammatory effects by inactivating NLRP3 inflammasome.

Sci Rep 2016;6:31649.

Hellwing C, Tigistu‑Sahle F, Fuhrmann H, Käkelä R,

Schumann J. Lipid composition of membrane microdomains

isolated detergent‑free from PUFA supplemented RAW264.7

macrophages. J Cell Physiol 2018;233:2602‑12.

Schoeniger A, Fuhrmann H, Schumann J. LPS‑ or Pseudomonas

aeruginosa‑mediated activation of the macrophage TLR4

signaling cascade depends on membrane lipid composition


Superti F, Marziano ML, Donelli G, Marchetti M, Seganti L.

Enhancement of rotavirus infectivity by saturated fatty acids.

Comp Immunol Microbiol Infect Dis 1995;18:129‑35.

Rubin RH, Wilkinson RA, Xu L, Robinson DR. Dietary marine

lipid does not alter susceptibility of (NZBxNZW) F1 mice to

pathogenic microorganisms. Prostaglandins 1989;38:251‑62.

Fritsche KL, Johnston PV. Modulation of eicosanoid production

and cell‐mediated cytotoxicity by dietary α‐linolenic acid in

BALB/c mice. Lipids 1989;24:305‑11.

Fernandes G, Tomar V, Venkatraman MN, Venkatraman JT.

Potential of diet therapy on murine AIDS. J Nutr


Xi S, Cohen D, Chen LH. Effects of fish oil on cytokines and

immune functions of mice with murine AIDS. J Lipid Res


Giron DJ. Inhibition of viral replication in cell cultures treated

with prostaglandin E1. Proc Soc Exp Biol Med 1982;170:25‑8.

Kohn A, Gitelman J, Inbar M. Unsaturated free fatty acids

inactivate animal enveloped viruses. Arch Virol 1980;66:301‑7.

Bégin ME, Manku MS, Horrobin DF. Plasma fatty acid

levels in patients with acquired immune deficiency syndrome

and in controls. Prostaglandins Leukot Essent Fatty Acids


Byleveld M, Pang GT, Clancy RL, Roberts DC. Fish oil feeding

enhances lymphocyte proliferation but impairs virus‑specific

T lymphocyte cytotoxicity in mice following challenge with

influenza virus. Clin Exp Immunol 2000;119:287‑92.

Byleveld PM, Pang GT, Clancy RL, Roberts DC. Fish oil

feeding delays influenza virus clearance and impairs production

of interferon‑gamma and virus‑specific immunoglobulin A in the

lungs of mice. J Nutr 1999;129:328‑35.

Morita M, Kuba K, Ichikawa A, Nakayama M, Katahira J,

Iwamoto R, et al. The lipid mediator protectin D1 inhibits

influenza virus replication and improves severe influenza. Cell


Huang H, Chen Y, Ye J. Inhibition of hepatitis C virus replication

by peroxidation of arachidonate and restoration by vitamin E.

Proc Natl Acad Sci USA 2007;104:18666‑70.

Leu GZ, Lin TY, Hsu JT. Anti‑HCV activities of selective

polyunsaturated fatty acids. Biochem Biophys Res Commun


Jones GJB, Roper RL. The effects of diets enriched in omega‑3

polyunsaturated fatty acids on systemic vaccinia virus infection. Sci Rep 2017;7:15999.

Blanco A, Blanco G. Medical Biochemistry. Academic Press;

Li P, Yin YL, Li D, Kim SW, Wu, G. Amino acids and immune

function. Br J Nutr 2007;98:237‑52.

Siqueiros‑Cendón T, Arévalo‑Gallegos S, Iglesias‑Figueroa BF,

García‑Montoya IA, Salazar‑Martínez J, Rascón‑Cruz Q.

Immunomodulatory effects of lactoferrin. Acta Pharmacol


Sun H, Jenssen H. Milk Derived Peptides with Immune

Stimulating Antiviral Properties. Milk Protein. Rijeka, Croatia:

Intech; 2012. p. 45‑82.

Ng TB, Lam TL, Au TK, Ye XY, Wan CC. Inhibition of human

immunodeficiency virus type 1 reverse transcriptase, protease

and integrase by bovine milk proteins. Life Sci 2001;69:2217‑23.

Karacabey K. The effect of nutritional elements on the immune

system. J Obes Weight Loss Ther 2012;9:1‑6.

Chandra RK. Nutrition and the immune system: An introduction.

Am J Clin Nutr 1997;66:460‑3.

Rytter MJ, Kolte L, Briend A, Friis H, Christensen VB. The

immune system in children with malnutrition‑‑A systematic

review. PLoS One 2014;9:e105017.

Gruppen EG, Garcia E, Connelly MA, Jeyarajah EJ, Otvos JD,

Bakker SJL, et al. TMAO is associated with mortality: Impact of

modestly impaired renal function. Sci Rep 2017;7:13781.

Mafune A, Iwamoto T, Tsutsumi Y, Nakashima A,

Yamamoto I, Yokoyama K, et al. Associations among serum

trimethylamine‑N‑oxide (TMAO) levels, kidney function

and infarcted coronary artery number in patients undergoing

cardiovascular surgery: A cross‑sectional study. Clin Exp

Nephrol 2016;20:731‑9.

Mente A, Chalcraft K, Ak H, Davis AD, Lonn E, Miller R, et al.

The relationship between trimethylamine‑n‑oxide and prevalent

cardiovascular disease in a multiethnic population living in

Canada. Can J Cardiol 2015;31:1189‑94.

Martinon F, Burns K, Tschopp J. The inflammasome: A molecular

platform triggering activation of inflammatory caspases and

processing of proIL‑β. Mol. Cell 2002;10:417‑26.

Martinon F, Tschopp J. Inflammatory caspases and

inflammasomes: Master switches of inflammation. Cell Death

Differ 2007;14:10‑22.

Takahashi M. NLRP3 inflammasome as a novel player in

myocardial infarction. Int Heart J 2014;55:101‑5.

Chen Ml, Zhu Xh, Ran L, Lang Hd, Yi L, Mi Mt.

Trimethylamine‐N‐oxide induces vascular inflammation by

activating the NLRP3 inflammasome through the SIRT3‐SOD2‐

mtROS signaling pathway. Am Heart J 2017;6:e006347.

Wang W, Yang Q, Sun Z, Chen X, Yang C, Ma X. Editorial:

Advance of interactions between exogenous natural bioactive

peptides and intestinal barrier and immune responses. Curr

Protein Pept Sci 2015;16:574‑5.

Zhao J, Zhang X, Liu H, Brown MA, Qiao S. Dietary protein

and gut microbiota composition and function. Curr Protein Pept

Sci 2019;20:145‑54.

Barker HA. Amino acid degradation by anaerobic bacteria. Annu

Rev Biochem 1981;50:23‑40.

Macfarlane S, Macfarlane GT. Regulation of short‑chain fatty

acid production. Proc Nutr Soc 2003;62:67‑72.

Ma N, Tian Y, Wu Y, Ma X. Contributions of the interaction

between dietary protein and gut microbiota to intestinal health.

Curr Protein Pept Sci 2017;18:795‑808.

Veiga P, Gallini CA, Beal C, Michaud M, Delaney ML,

DuBois A, et al. Bifidobacterium animalis subsp. lactis

fermented milk product reduces inflammation by altering a

niche for colitogenic microbes. Proc Natl Acad Sci USA 2010;


Fan P, Li L, Rezaei A, Eslamfam S, Che D, Ma X. Metabolites

of dietary protein and peptides by intestinal microbes and their

impacts on gut. Curr Protein Pept Sci 2015;16:646‑54.

Keller L, Surette MG. Communication in bacteria: An ecological

and evolutionary perspective. Nat Rev Microbiol 2006;4:249‑58.

Marsland BJ. Regulating inflammation with microbial

metabolites. Nat Med 2016;22:581‑3.

Ma N, Ma X. Dietary amino acids and the gut‐microbiome‐

immune axis: Physiological metabolism and therapeutic

prospects. Compr Rev Food Sci Food Saf 2018;18:221‑42.

Makino S, Ikegami S, Kume A, Horiuchi H, Sasaki H, Orii N.

Reducing the risk of infection in the elderly by dietary intake of

yoghurt fermented with Lactobacillus delbrueckii ssp. bulgaricus

OLL1073R‑1. Br J Nutr 2010;104:998‑1006.

Halpern GM, Vruwink KG, Van De Water J, Keen CL,

Gershwin ME. Influence of long‑term yoghurt consumption in

young adults. Int J Immunother 1991;7:205‑10.

Micke P, Beeh KM, Schlaak JF, Buhl R. Oral supplementation

with whey proteins increases plasma glutathione levels of

HIV‑infected patients. Eur J Clin Invest 2001;31:171‑8.

Sattler FR, Rajicic N, Mulligan K, Yarasheski KE, Koletar SL,

Zolopa A, et al. Evaluation of high‑protein supplementation in

weight‑stable HIV‑positive subjects with a history of weight loss:

A randomized, double‑blind, multicenter trial. Am J Clin Nutr


Butorov EV. Impact of high protein intake on viral load and

hematological parameters in HIV‑infected patients. Curr HIV

Res 2017;15:345‑54.

Ahmed M, Henson DA, Sanderson MC, Nieman DC, Gillitt ND,

Lila MA. The protective effects of a polyphenol‑enriched protein

powder on exercise‑induced susceptibility to virus infection.

Phytother Res 2014;28:1829‑36.

Pinnock CB, Graham NM, Mylvaganam A, Douglas RM.

Relationship between milk intake and mucus production in adult

volunteers challenged with rhinovirus‑2. Am Rev Respir Dis


Vitetta L, Coulson S, Beck SL, Gramotnev H, Du S, Lewis S.

The clinical efficacy of a bovine lactoferrin/whey protein

Ig‑rich fraction (Lf/IgF) for the common cold: A double blind

randomized study. Complement Ther Med 2013;21:164‑71.

Ochoa TJ, Chea‑Woo E, Baiocchi N, Pecho I, Campos M,

Prada A, et al. Randomized double‑blind controlled trial of

bovine lactoferrin for prevention of diarrhea in children. J Pediatr


Wolber FM, Broomfield AM, Fray L, Cross ML, Dey D. Supplemental

dietary whey protein concentrate reduces rotavirus‑induced disease

symptoms in suckling mice. J Nutr 2005;135:1470‑4.

Low PP, Rutherfurd KJ, Gill HS, Cross ML. Effect of dietary whey

protein concentrate on primary and secondary antibody responses in

immunized BALB/c mice. Int Immunopharmacol 2003;3:393‑401.

Wahl A, Swanson MD, Nochi T, Olesen R, Denton PW,

Chateau M, et al. Human breast milk and antiretrovirals

dramatically reduce oral HIV‑1 transmission in BLT humanized

mice. PLoS Pathog 2012;8:e1002732.

Wakabayashi H, Kurokawa M, Shin K, Teraguchi S,

Tamura Y, Shiraki K. Oral lactoferrin prevents body weight

loss and increases cytokine responses during herpes simplex

virus type 1 infection of mice. Biosci Biotechnol Biochem