IAR Journal of Medicine and Surgery Research Emerging Role of Nutraceuticals in Covid 19

Abstract

The global pandemic of SARS-CoV-2, claiming thousands of lives
each day has brought the world to a standstill. Such devastating and great impact
of Coronavirus disease (COVID-19) is due to unexpectedly rapid spread, which
did not allow for much preparedness. The scientists are working hard to come up
with a vaccine, but nothing fruitful has been produced so far due to the rapid
spread of the virus. Multiple drugs have been tried to target the virus, but no
specific drug is there to prevent the spread of virus. Hence, we analysed the role
of non-pharmacological substances such as nutraceuticals, probiotics and dietary
supplements in reducing the susceptibility and mitigating the symptoms of
COVID 19. In current scenario, when there is dearth of specific antiviral agents,
theses substances could prove to be great importance due to their easy availability
and no known side effects if administered in large doses. Scientific evidence has
also suggested the beneficial role of bacterial and molecular products on immune
response against the viruses. They could also regulate the inflammatory response
and prevent endothelial damage. However, due to lack of specific data, rigorous
clinical trials should be conducted to confirm the beneficial role of these
supplements, probiotics and nutraceuticals in this period of crises.

Full text

IAR Journal of Medicine and Surgery Research
ISSN Print : 2709-1899 | ISSN Online : 2709-1902
Frequency : Bi-Monthly
Language : English
Origin : KENYA
Website : https://www.iarconsortium.org/journal-info/IARJMSR
74
Emerging Role of Nutraceuticals in Covid 19
Abstract: The global pandemic of SARS-CoV-2, claiming thousands of lives
each day has brought the world to a standstill. Such devastating and great impact
of Coronavirus disease (COVID-19) is due to unexpectedly rapid spread, which
did not allow for much preparedness. The scientists are working hard to come up
with a vaccine, but nothing fruitful has been produced so far due to the rapid
spread of the virus. Multiple drugs have been tried to target the virus, but no
specific drug is there to prevent the spread of virus. Hence, we analysed the role
of non-pharmacological substances such as nutraceuticals, probiotics and dietary
supplements in reducing the susceptibility and mitigating the symptoms of
COVID 19. In current scenario, when there is dearth of specific antiviral agents,
theses substances could prove to be great importance due to their easy availability
and no known side effects if administered in large doses. Scientific evidence has
also suggested the beneficial role of bacterial and molecular products on immune
response against the viruses. They could also regulate the inflammatory response
and prevent endothelial damage. However, due to lack of specific data, rigorous
clinical trials should be conducted to confirm the beneficial role of these
supplements, probiotics and nutraceuticals in this period of crises.
Keywords: SARS-CoV-2, virus, supplements, probiotics and nutraceuticals.
INTRODUCTION
Since December 2019, Coronavirus Disease (COVID 19) has
created a global health crisis. It is known to be caused by SARS-Cov-2, a
single stranded RNA virus 2 which has approx 79% genomic similarity
with bat derived SARS like CoV suggesting that it has passed from Bats
to humans via some unknown intermediate and the first case was detected
in Wuhan province of China [1]. The World health organization (WHO)
declared it a pandemic on 11 March 2020 [2]. The suggested mode of
transmission is mainly via Human to Human contact, through droplet
released from an infected person. The clinical course of the disease may
range from asymptomatic cases to severe pneumonia. However, the
common clinical features are fever, dry cough, myalgia, anosmia,
dyspnea and anorexia which may rapidly progress to respiratory distress.
In severe cases, Acute respiratory distress (ARDS), Shock, Metabolic
acidosis, disseminated intravascular coagulation (DIC) and multiple organ
dysfunction syndrome (MODS) may develop [3]. As of September 2020,
there are total of 30 million positive cases globally with 5 million cases in India itself and has claimed 9 million lives
worldwide so far [4]. It has led to an extreme emergency situation with an overwhelmingly large number of cases in a
short span of time. To curb the pandemic, worldwide large number of researches are going to discover a vaccine against
COVID 19, however nothing fruitful has been produced yet. There is also no specific treatment available for it.
Currently, the patients are mainly managed symptomatically by preventing the inflammation and supportive care with
Oxygen supplementation and ventilatory support in severe cases [1]. Multiple drugs ranging from antibiotics and
antimalarials to antivirals and corticosteroids have been tried so far, but only remdesivir out of all antivirals, has been
found to be effective in shortening the recovery period of hospitalized patients [5]. Chloroquine (CQ) and hydroxy
chloroquine (HCQ), which gained so much attention has shown mixed benefits. It was found that the HCQ could reduce
the viral load in 6 days of administration especially when given with azithromycin [6]. However, other studies have
reported about the potential safety hazards associated with the administration of these drugs especially with the higher
dosages that could lead to increased mortality [7]. Corticosteroids were found to reduce inflammation and inhibited the
cytokine storm associated with COVID 19 thereby preventing the progression to severity [8]. Another drug, tocilizumab,
which is an antibody targeting Interleukin-6 (IL-6) receptors is still under investigation [9].
Review Article
Article History
Received: 15.10.2020
Accepted: 29.10.2020
Revision: 08.11.2020
Published: 10.11.2020
Author Details
Naaz Huda1, Dawar Rajni*2, Rani Anita3
and Kaur Charanjeet4
Authors Affiliations
1Junior Resident MD 2nd Year,
Biochemistry, VMMC & SJH.Delhi, India
2Associate Professor, Department of
Biochemistry, VMMC& SJH, India
3Dir, Professor, Department of
Biochemistry, VMMC& SJH, India
4Dir Prof and HOD, Department of
Biochemistry,VMMC & SJH, India
Corresponding Author*
Dawar Rajni
How to Cite the Article:
Naaz Huda, Dawar Rajni, Rani Anita and Kaur
Charanjeet (2020); Emerging Role of
Nutraceuticals in Covid 19. IAR J. Med &
Surg Res. 1(3) 74-82.
Copyright @ 2020: This is an open-access article
distributed under the terms of the Creative
Commons Attribution license which permits
unrestricted use, distribution, and reproduction
in any medium for non commercial use
(NonCommercial, or CC-BY-NC) provided the
original author and source are credited.

Naaz Huda et al., IAR J. Med & Surg Res; Vol-1, Iss- 3 (Nov-Dec, 2020): 74-82
75
Since many drugs are still under the trial, there is a
paucity of specific pharmacological therapy against
COVID 19, non-pharmacological substances such as
nutraceuticals, which are isolated nutrients, herbal
products, diets and dietary supplements. These are
known to strengthen the defense mechanisms by their
anti-inflammatory and anti-oxidant properties and could
be utilized to build up the immunity. These are the
bioactive substances present inside the food, which
includes nutrients such as Zinc, vitamin D and C,
Curcumin and also some biologically active non
nutrient molecules such as Polyphenols and probiotics.
The major advantage of using these foods derived
molecules is that they are readily available, accessible,
natural and usually with low or no toxicity and could
get approved easily [10]. Some of these substances are
already being used for many chronic illnesses and
cancers, but there still no specific studies and sufficient
data regarding their usefulness in COVID 19. However,
we will try to review their possible beneficial role in
SARS-CoV-2 infection.
MATERIAL AND METHODS
This review was designed keeping in mind the
best review practices. The PubMed was searched for
articles on nutraceuticals, probiotics and diet
supplementation for the prevention and treatment of
COVID 19. Studies reporting on in vitro, in vivo, or
human studies were selected and study subjects,
interventions and outcomes were systematically
analyzed.
Pathogenesis
The Coronavirus disease is caused by SARS-
CoV-2 virus, which is a ss RNA virus [1]. The virus
enters the human body through the ACE 2 receptors
which are distributed in different tissues and organs,
forming the basis of multiple organ failure in patients of
COVID 19 [11].
Initially, the virus enters the mucous
membrane in upper respiratory tract via nasal or
pharyngeal epithelium or enters directly to lower
respiratory tract and infect bronchial and alveolar
epithelial cells through the ACE 2 receptors expressed
in lungs. At this stage, the virus may enter the
bloodstream from lungs resulting in viremia [12]. The
virus then affects other organs expressing ACE2 such as
blood vessels, heart, GI tract and kidneys. GI tract may
be involved directly by oral route as well through
ingestion of virus. In severe cases, pulmonary
involvement along with systemic inflammation may
develop. The inflammatory process may culminate into
a cytokine storm affecting other organs of the body
[13].
Immune responses, innate and adaptive plays a
crucial role in fighting off the invading virus or may
induce the cytokine storm while invading the virus,
responsible for immune-pathological damage in patients
with coronavirus disease [14]. The patients at the risk
for the unfavourable outcomes include old age, high
body mass index (BMI), male sex, and those with
underlying co morbidities such as hypertension, obesity,
diabetes, chronic respiratory disease, cardiovascular
disease, chronic kidney disease and obesity [15]. It was
suggested that the SARS-Cov-2 virus binds to the
ACE2 under the conditions of low cytosolic pH [16].
Low cytosolic pH is found under certain conditions
such as diabetes, hypertension and old age, thus
increasing the chances of acquiring the infection [17].
NUTRACEUTICALS
Endothelial dysfunction has been found as a
result of chronic respiratory infection, majorly due to
systemic inflammatory response and also due to oxygen
stress. Endothelial dysfunction predisposes to increased
platelet aggregation and increased coagulation [18]. In
severe cases of COVID 19, due to the widespread
pulmonary inflammation, there is development of
haemorrhage and microthrombi. This predisposes the
patients to intravascular coagulopathy [19]. Also, as a
result of widespread systemic inflammation, there is
release of inflammatory mediators such as interleukins,
cytokines, tumor necrosis factors. These inflammatory
mediators further lead to the endothelial injury by
contributing to the clotting and thrombosis [20]. In
addition to the inflammation, the oxidative stress also
exposes to the hypercoagulation and thrombosis,
particularly NOX2 derived ROS [21].
Thus, inflammation and oxidative stress act in
synergistic manner and propagate a vicious cycle
leading to the atherogenic plaque formation.
Nutraceuticals, such as vit C, A, E, along with some
minerals such as Zn, Cu and polyphenols, by
maintaining proper redox homeostasis could be helpful
in preventing the plaque formation.
ZINC:
Zinc is an essential micronutrient, involved in
cell growth. It also plays a role in metabolic processes
and immune system. It is also known to be a co factor
for various enzymatic processes [22]. It is important for
the differentiation, proliferation, maturation and proper
functioning of lymphocytes and regulates the immune
response [23]. Zinc deficiency has been found to
increase the susceptibility of infectious and
inflammatory disorders. It also plays a role in proper
functioning of natural killer cells, thereby mounting an
immune response against tumors and viruses [24].
It was found that the supplementation with
zinc sulphate at 20mg/day for 5 months was associated
with reduced mortality in case of acute lower
respiratory tract infection [25]. Decreased levels of zinc
have been found to result in impaired macrophage

Naaz Huda et al., IAR J. Med & Surg Res; Vol-1, Iss- 3 (Nov-Dec, 2020): 74-82
76
phagocytosis, thus further impairing the immune
response [26]. Zinc is also involved in viral recognition
with the help of zinc-finger protein ZCCHC3, which
binds the viral RNA and detects the intracellular viruses
by activating the retinoic acid inducible gene-1 (RIG-1)
like receptors. This further activates the antiviral genes
leading to an antiviral response [27]. In normal
physiological state, zinc is found bound to intracellular
metallothionein proteins, which has some antiviral
properties. Metallothionein sequesters the zinc from
viral metalloproteins and facilitates the antiviral
signalling. Zinc supplementation augments the
metallothionein expression, thus further augmenting the
antiviral signalling pathway [28]. Some studies have
also suggested that increased intracellular zinc levels
could disturb the viral replication of RNA viruses such
as influenza, polio virus, SARS-CoV-2 [29]. Velthuis et
al. conducted an enzymatic study using a recombinant
RNA dependent RNA polymerase (RdRp) purified from
E.coli and found that the zinc directly inhibited the
SARS-CoV-2 RdRp elongation and reduced the
template binding[29].
Approximately, 20% of the world population
has low levels of zinc. The zinc deficiency has been
found to be associated with diminished antibody
production, altering the immune system. There is also
reduced production of cytokines by mononuclear cells,
reduced chemotaxis and disturbed respiratory burst of
the neutrophils [30]. Taking in consideration the
antiviral, immunomodulatory and antioxidant
properties, zinc supplementation could reduce the
severity of COVID 19 infection, there by preventing the
development of complications. Chloroquine, which was
used initially for the treatment of COVID 19, acted as a
zinc ionophore by allowing the zinc entry inside the
infected cell. However, its use was soon discontinued
due to its toxicity profile [31].
POLYPHENOLS:
These are the compounds present in the plant
foods. They are known to have antiplatelet and
anticoagulant effect. They reduce platelet aggregation
and suppress the thrombin activity [32]. They also exert
beneficial effect by downregulating the NADPH
oxidase and thus reducing the oxidative stress [33].
Some polyphenols also have anti-inflammatory
properties, by modulating the cytokine production and
increases the pro inflammatory gene expression [34].
It includes:
Resveratrol: It is a polyphenolic compound
synthesised by plants in response to UV rays, viruses,
fungi and toxins. It is present in Red vine, berries, nuts,
etc [35]. It has shown some beneficial effects against
certain diseases such as certain malignancies,
cardiovascular and respiratory diseases [36]. It is known
to have anti-inflammatory, antioxidant and antiviral
effect. Resveratrol is an agonist to sirtuin deacetylase
SIRTI, which is a regulator of multiple metabolisms.
SIRTI inhibits the apoptosis and activates the cell cycle
by deacetylating the Trp53 [35]. It was found in one of
the studies that the inhaled resveratrol protected the
mice from accelerated aging. It also maintained the lung
structure, prevented DNA damage in parenchymal cells
and prevented the loss of lung function [36]. Taking
into the consideration all these effects, it could be used
as prophylactic agent to curb the deterioration of lung
structure and function. However, since no enough data
is available yet, it is still under the trials.
Curcumin: It is a bioactive phenolic compound,
extracted from the rhizomes of Curcuma longa. It is
most commonly used spice in Asian countries,
commonly known as Turmeric. Since ancient times, it
has been exploited for its anti-inflammatory properties
and has shown beneficial effects in arthritis,
inflammatory bowel disease. Antimutagenic and
antimicrobial properties have also been described for
curcumin [37]. It also posses‘ antiviral properties
against several viruses such as influenza virus, HIV,
hep A and Zika virus. It basically inhibits the viral entry
into the cell, prevents viral replication and viral protein
expression and stimulates the production of interferons
and cytokines. It binds to the receptor binding domain
of the viral spike protein and blocks the host cell
receptors, i.e. ACE2 in case of COVID 19 [38]. It also
supresses the production of certain cytokines such as
IL6, IL8 , TNF α and thus could prevent the cytokine
storm associated with the severe COVID 19 infection
[39]. Also, owing to its anticoagulant properties due to
inhibition of platelet aggregation, it could also prevent
the DIC in SARS-CoV-2 and could serve as a potential
treatment option [40].
Hydroxytyrosol: It is also a phenolic compound, found
in the olive tree leaves and olive oil. This compound is
known for its antioxidant, anti-inflammatory and
antiviral properties [41]. Its most important property is
removal of reactive oxygen species, thereby preventing
the oxidative stress. At the intracellular level, it has
shown scavenging properties against superoxide anion,
hydrogen peroxide and has shown to reduce the
production of these anions in experimental models
[42,43]. It can also modulate the pro inflammatory
transcription factor NF-κB, which is known to control
the expression of many genes involved in the
production of cell adhesion molecules, chemokines,
cytokines, interleukins etc [44]. Thus, by reducing the
oxidative and inflammatory response, it can serve as a
good adjuvant therapy along with antiviral drugs in
COVID 19.
VITAMIN C
Vitamin C is water soluble vitamin, which
helps in collagen synthesis, protects against oxidative
damage and maintains proper functioning of many
enzymes by acting as a cofactor. Human beings lack an
enzyme L-gluconolactone, essential for the synthesis of

Naaz Huda et al., IAR J. Med & Surg Res; Vol-1, Iss- 3 (Nov-Dec, 2020): 74-82
77
vitamin C. Hence, it must be provided externally
through the diet [45]. Vitamin C is essential for innate
and adaptive immune system. It also plays an essential
role in maintaining the epithelial and endothelial barrier
function, maintains vasodilation and reduces the
production of pro inflammatory mediators [46]. A
deficiency of Vit C leads of poor wound healing and
scurvy [47].
The redox properties of Vitamin c have been
utilized in treatment of known cancer patients. Many
studies have shown Tumour regression, longer survival
periods and better quality of life in patients receiving
Vitamin C supplementation than in patients receiving
only chemotherapeutic drugs and conventional anti-
cancer regimes. [48,49]. The antioxidant property of
Vitamin C has also been used in clinical trials against
Viral diseases. In certain in-vitro experiments Vitamin
C has been found to be active against Virus in presence
of copper or iron [50]. Ascorbic acid is found to achieve
high concentrations inside macrophages and
lymphocytes [51]. With addition of Vitamin C
lymphocyte proliferation, oxidative death and
phagocytic activities were found to increase [52].
Following a Viral infection, phagocytes are
activated in the body with formation of free radicals and
reactive oxygen species (ROS). ROS damages the host
cells and tissues. In RSV infection in children it has
found that production of ROS causes inflammatory
damage to the lung tissues [53]. Antioxidants have been
found to reduces these injuries and tissue toxicities
through mechanism of free radical scavenging [54].
Vitamin C is a scavenger of free radicals and generates
other antioxidants like tocopherol and
tetrahydrobiopterin [46]. Utilizing this property, trials
have been run in patients of common cold and Herpes
Zoster Virus. Though considerable reduction in post
herpetic neuralgia and pain was observed in the group
receiving IV vit C, no significant effect was found in
prognosis of common cold [55,56].
In certain experiments, using Glunolactone
knockout mice, it was found that the knockout mice
have higher chance of infectivity and morbidity after
exposure to H1N1 influenza viruses [57]. In another
experiment, H3N2 influenza virus was inoculated into
the noses of Gulo knock out mice and higher mortality
was recorded than in normal mice [58].
The mechanism behind mortality in COVID 19
is thought to be generation of excess cytokine and
induction of oxidative stress leading to ARDS and
Multi organ failure. The virus after entering the body,
induces a cytokine storm which causes membrane
damage of the endothelial cells and infiltration of
neutrophils [59]. This is also substantiated by the fact
that COVID 19 patients show an increase in levels of
hsCRP and IL6, which are the inflammatory markers
[60]. The antioxidant properties of Vitamin C can be
utilized in reduction of this cytokine storm and
oxidative stress and thereby preventing the
complications associated with the COVID 19 infection
[61]. Administration of Vit C has shown to decrease
levels of IL6 through a mechanism that blocks release
of IL6 induced by Endothelin 1 in humans in earlier
studies [62]. These properties may be used in treatment
of Covid19. Vit C has already been used for the
treatment of SARS-CoV-1 outbreak, which occurred in
2003 [63,64].
Large doses of IV Vitamin C has been proven
to be efficient in ARDS caused by influenza virus.
There are case reports showing remarkable
improvement in lung conditions following a high dose
of IV Vitamin C in patients of ARDS caused by
influenza virus [65].
Keeping the above in mind, Vitamin C can be
used in prophylaxis and trial of reduction of cytokine
storm in late stage of severe COVID 19 disease.
VITAMIN D
Vitamin D is a fat soluble vitamin, well known
for its role in bone metabolism and absorption of Ca,
Mg and Phosphate. It can be taken through the diet in
the form for of vitamin D2 (ergocalciferol) or it is
produced by the action of sun on the skin in the form of
vitamin d3 (cholecalciferol). However, the active form
of vitamin D is 1,25-dihyroxicholecalciferol (calcitriol)
[66]. The deficiency of Vitamin D has been found to be
associated with various pathologies such as cancer,
inflammation, depression, immunological disorders,
osteoporosis ,etc. [67]. It acts via a nuclear receptor and
influences the immune and inflammatory responses by
regulating the gene expression.
It has been established that Vitamin D prevents
from the respiratory infections via many mechanisms
[68]. The receptors for it are expressed in respiratory
epithelial cells and in respiratory system macrophages.
Under the influence of Vitamin D, there increased
production of catelicidin from the macrophages.
Catelicidin, by destructing the structure of various
viruses such as influenza A, prevents the infection [69].
Vitamin D also modulates the inflammatory
responses by affecting the immune mechanism. It
upregulates the NF-κB inhibitory protein, thus
inhibiting the NF-κB production. NF-κB is responsible
for the production and mobilization of inflammatory
mediators ( GM-CSF, IL-5, IL-6, VCAM-1, ICAM-1)
and results in an amplified inflammatory response and
tissue damage [70,71]. Vitamin D, by maintaining the
integrity of cellular barrier strengthens the immune
function [72]. Due to its role in mitigation of
inflammation and maintaining the immunity, the role of
vitamin D has been studied in various respiratory
infections. A meta-analysis which took into
consideration 25 Randomized controlled trials, found

Naaz Huda et al., IAR J. Med & Surg Res; Vol-1, Iss- 3 (Nov-Dec, 2020): 74-82
78
that administration of vitamin D could reduce the risk
of acute respiratory tract infections [73]. In one of the
retrospective study, it was found that the elder men with
comorbid condition and with lower levels of Vitamin D
were at more risk of acquiring COVID 19 infection
[74]. Certain epidemiological studies have also studied
the role of vitamin D deficiency in onset and severity of
respiratory infections and the risk of development of
severe lung damage [75].
Based on the above-mentioned evidences, it is
necessary to evaluate the role of usefulness of Vitamin
D supplementation in COVID 19 patients. It should be
evaluated on a large scale since no data regarding the
dosage, mode of administration and safety profile is
available with respect to COVID 19.
PROBIOTICS
COVID 19, like other structurally similar
Coronaviruses, bind to host ACE2 receptor with a spike
glycoprotein. Following binding to host receptors, it
brings about inflammation and injury to lung tissue
[76]. ACE2 is expressed on alveolar epithelial cells, and
on epithelial cells of trachea, bronchi, alveolar
macrophages and monocytes. ACE2 receptors are also
found in colon and ileum on the luminal surface of
differentiated epithelial cells or enterocytes. In the
intestine, ACE2 receptors regulate gut microbiota and
homeostasis of dietary amino acids. ACE2 receptors
have also been found to be involved with susceptibility
of colitis. Few studies have shown altered gut
microbiota in ACE2 mutants [77].
During the SARS-CoV outbreak in Hong
Kong,2003, evidence of viral replication in intestine
was also found, along with in lung tissues [78]. COVID
19 is found to be genetically similar to the other SARS
like viruses, particularly in the binding domains
[79,80].Hence, we could explore the role of intestine in
COVID19 infection and pathogenesis. It is a known fact
that a percentage of COVID19 patients present with
intestinal symptoms along with the usual respiratory
symptoms and fever.
During the beginning of the pandemic, studies
conducted in Zhejiang province, China showed 11.4%
of patients have diarrhoea, vomiting or other GI
symptoms [81].There are existing Case studies in
Wuhan Children‘s hospital where children presented
only with acute gastroenteritis, with absence of any
respiratory symptoms and on testing, were found to be
COVID19 positive [82].
A large number of diverse bacteria, fungi and
few viruses colonize our intestinal mucosa, vagina,
eyes, skin and respiratory system. In intestine, colon
harbours the maximum number of commensal bacteria
or ‗intestinal flora‘, now called ‗intestinal microbiota‘.
A portion of our diet is composed of fibres or complex
carbohydrates, which after reaching the intestine are
acted upon by these bacteria, producing many different
metabolites having 1 to 6 C atoms. Most common
metabolite produced are Short chain fatty acids like
butyrate, acetate, propionate. These play an important
part in keeping the intestinal epithelial barrier intact,
cell proliferation and host immune regulation [83]. The
most common species producing SCFA in the gut are
Bacteroides, Bifidobacterium, Streptococcus and
Provotella. These molecules also stimulate anti-
inflammatory processes in the host [85,86]. The
exposure of gut mucosa to microbes since birth up to
first few years of life train naïve cells of the immune
system, helping to develop immune tolerance [86].
There are also studies showing the existence of
a gut-lung axis, with exchange and interaction of
microbes and immune regulatory molecules between
the two organs. Metabolites, mostly SCFA produced in
the gut, enter the bloodstream and control immune
mechanisms in brain and lungs also [87].Few mice
experiments have been conducted to explain the
underlying mechanism in this phenomenon. It has been
found in one experiment that Limosilactobacillus
reuteri, Clostridium orbiscindes, Lactobacillus crispatus
and Enterococcus faecalis help resisting respiratory
infections in C57BL/6 mice, possibly through
extracellular signalling by Nod2 and GM-CSF in
alveolar macrophages [88].
In view of the above, we can explore the uses
of probiotics in modifying disease progression in
COVID 19. A probiotic is live microorganisms, which
is provided to the body through food and exert a
beneficial effect on the host. The most common portal
for probiotic have been yoghurt which is often loaded
with Lactobacillus, Saccharomyces and Bacillus [89].
There are some RCTs showing benefits
conferred by Probiotics on Ventilator associated
Pneumonia patients. Patients of VAP were provided
with Bifidobacterium, L.casei and
galactooligosccharides supplementation. They showed
better prognosis than in the group supplied with placebo
[90]. In double blinded RCTs conducted among infants,
low incidence of AURTIs was found in groups
receiving probiotics in diet. Incidence of upper
respiratory tract was found to be low though no
significant difference in severity was found [91].
A study in China showed presence of
Clostridia spp. was negatively corelated with presence
of inflammation and disease severity in COVID19,
while presence of Ruminococcus was positively
corelated [92].
COVID 19 infection is associated with
cytokine storm, an increase in levels of CRP and IL6,
IL12, TNF alpha. The anti-inflammatory roles of
bacterial products of diet fibre can be utilized in
reducing levels of these, thereby reducing tissue toxicity

Naaz Huda et al., IAR J. Med & Surg Res; Vol-1, Iss- 3 (Nov-Dec, 2020): 74-82
79
and damage in COVID 19 [93,94]. Probiotics can bind
to the virus and disrupt virus-host attachment [95].
Currently, probiotics are not a part of any
treatment protocol against COVID 19, but they may
improve the over all response of the patient by their
ability to modulate the systemic inflammatory and
immune response.
Conflicts of Interest: The authors declare no conflict
of interest.
Funding: This research received no external funding.
REFERENCES
1. Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al.
Genomic characterisation and epidemiology of
2019 novel coronavirus: implications for virus
origins and receptor binding. Lancet 2020;395:565-
74.
2. Zhu, N., Zhang, D., Wang, W., Li, X., Yang, B.,
Song, J., Zhao, X., Huang, B., Shi, W., Lu, R., Niu,
P., Zhan, F., Ma, X., Wang, D., Xu, W., Wu, G.,
Gao, G.F., Tan, W., China Novel Coronavirus
Investigating and Research Team, 2020. A novel
coronavirus from patients with pneumonia in
China, 2019. N. Engl. J. Med. 382, 727–733.
https://doi.org/10.1056/NEJMoa2001017.
3. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y,
et al. Epidemiological and clinical characteristics
of 99 cases of 2019 NCP in Wuhan, China: a
descriptive study. Lancet 2020;395:507-13
4. COVID-19 Map Johns Hopkins Coronavirus
Resource Center. Available online:
https://coronavirus.jhu.edu/ map.html
5. Beigel, J.H.; Tomashek, K.M.; Dodd, L.E.; Mehta,
A.K.; Zingman, B.S.; Kalil, A.C.; Hohmann, E.;
Chu, H.Y.; Luetkemeyer, A.; Kline, S.; et al.
Remdesivir for the Treatment of Covid-19—
Preliminary Report. New. Engl. J. Med. 2020.
6. Yazdany J, Kim AHJ. Use of hydroxychloroquine
and chloroquine during the COVID-19 pandemic:
what every clinician should know. Ann Intern Med
2020; 172: 754–755
7. 3. Lane JCE, Weaver J, Kostka K, et al. Safety of
hydroxychloroquine, alone and in combination
with azithromycin, in light of rapid widespread use
for COVID-19: a multinational, network cohort and
self-controlled case series study. medRxiv 2020
https://doi.org/10. 1101/2020.04.08.20054551 Not
peer reviewed.
8. Russell, B.; Moss, C.; Rigg, A.; Van Hemelrijck,
M. COVID-19 and treatment with NSAIDs and
corticosteroids: Should we be limiting their use in
the clinical setting? Ecancermedicalscience 2020,
14
9. Tocilizumab in COVID-19 Pneumonia (TOCIVID-
19)—Full Text View—ClinicalTrials.gov.
Available online:
https://clinicaltrials.gov/ct2/show/NCT04317092
10. Santini, A., Cammarata, S.M., Capone, G., Ianaro,
A., Tenore, G.C., Pani, L., Novellino, E., 2018.
Nutraceuticals: opening the debate for a regulatory
framework. Br. J. Clin. Pharmacol. 84, 659–672.
https://doi.org/10.1111/bcp.13496.
11. Hashimoto, T., Perlot, T., Rehman, A., Trichereau,
J., Ishiguro, H., Paolino, M., Sigl, V., Hanada, T.,
Hanada, R., Lipinski, S., Wild, B., Camargo,
S.M.R., Singer, D., Richter, A., Kuba, K.,
Fukamizu, A., Schreiber, S., Clevers, H., Verrey,
F., Rosenstiel, P., Penninger, J.M., 2012. ACE2
links amino acid malnutrition to microbial ecology
and intestinal inflammation. Nature 487, 477–481.
https://doi. org/10.1038/nature11228.
12. Wang LS, Wang YR, Ye DW, et al. Review of the
2019 novel coronavirus (COVID-19) based on
current evidence. Int J Antimicrob Agents 2020;
55: 10594
13. . Zhou F, Yu T, Du R, et al. Clinical course and
risk factors for mortality of adult inpatients with
COVID-19 in Wuhan, China: a retrospective cohort
study. Lancet 2020; 395: 1054–1062.
14. Li G, Fan Y, Lai Y, Han T, Li Z, Zhou P, et al.
Coronavirus infections and immune responses. J
Med Virol. 2020
15. Zhou F, Yu T, Du R, et al. Clinical course and risk
factors for mortality of adult in patients with
COVID-19 in Wuhan, China: a retrospective cohort
study. Lancet 2020; 395: 1054–1062
16. Cure, E., Cumhur Cure, M., 2020b. Comment on
―Organ-protective effect of angiotensinconverting
enzyme 2 and its effect on the prognosis of
COVID-19. J. Med. Virol.
17. Resnick, L.M., Gupta, R.K., Sosa, R.E., Corbett,
M.L., Laragh, J.H., 1987. Intracellular pH in
human and experimental hypertension. Proc. Natl.
Acad. Sci. U.S.A. 84, 7663–7667.
18. Loffredo, L.; Perri, L.; Catasca, E.; Pignatelli, P.;
Brancorsini, M.; Nocella, C.; De Falco, E.;
Bartimoccia, S.; Frati, G.; Carnevale, R.; et al.
Dark chocolate acutely improves walking
autonomy in patients with peripheral artery disease.
J. Am. Heart Assoc. 2014, 3
19. Loffredo, L.; Cangemi, R.; Perri, L.; Catasca, E.;
Calvieri, C.; Carnevale, R.; Nocella, C.; Equitani,
F.; Ferro, D.; Violi, F.; et al. Impaired flow-
mediated dilation in hospitalized patients with
community-acquired pneumonia. Eur. J. Intern.
Med. 2
20. Huang, C.; Wang, Y.; Li, X.; Ren, L.; Zhao, J.; Hu,
Y.; Zhang, L.; Fan, G.; Xu, J.; Gu, X.; et al.
Clinical features of patients infected with 2019
novel coronavirus in Wuhan, China. Lancet 2020,
395, 497–506.
21. Guzik, T.J.; Mohiddin, S.A.; Dimarco, A.; Patel,
V.; Savvatis, K.; Marelli-Berg, F.M.; Madhur,
M.S.; Tomaszewski, M.; Maffia, P.; Nicklin, S.A.;
et al. COVID-19 and the cardiovascular system:
Implications for risk assessment, diagnosis, and
treatment options

Naaz Huda et al., IAR J. Med & Surg Res; Vol-1, Iss- 3 (Nov-Dec, 2020): 74-82
80
22. Hoang, B.X., Hoang, H.Q., Han, B., 2020. Zinc
Iodide in combination with Dimethyl Sulfoxide for
treatment of SARS-CoV-2 and other viral
infections. Med. Hypotheses 143, 109866
23. . Wessels I, Maywald M, Rink L. Zinc as a
gatekeeper of immune function. Nutrients. (2017)
9:1286. doi: 10.3390/nu912128
24. Allen JI, Perri RT, McClain CJ, Kay NE.
Alterations in human natural killer cell activity and
monocyte cytotoxicity induced by zinc deficiency.
J Lab Clin Med. (1983) 102:577–89.
25. Malik A, Taneja DK, Devasenapathy N,
Rajeshwari K. Zinc supplementation for prevention
of acute respiratory infections in infants: a
randomized controlled trial. Indian Pediatr. (2014)
51:780–4. doi: 10.1007/s13312-014-0503-z
26. Gao H, Dai W, Zhao L, Min J, Wang F. The role of
zinc and zinc homeostasis in macrophage function.
J Immunol Res. (2018) 2018:6872621. doi:
10.1155/2018/687262
27. Haase H, Rink L. Functional significance of zinc-
related signaling pathways in immune cells. Annu
Rev Nutr. (2009) 29:133–52. doi:
10.1146/annurev-nutr-080508-141119
28. Read, S. A., Obeid, S., Ahlenstiel, C., & Ahlenstiel,
G. (2019). The role of zinc in antiviral immunity.
Advances in Nutrition, 10, 696–710. https://
doi.org/10.1093/advances/nmz013
29. te Velthuis, A.J.W., van den Worm, S.H.E., Sims,
A.C., Baric, R.S., Snijder, E.J., van Hemert, M.J.,
2010. Zn(2+) inhibits coronavirus and arterivirus
RNA polymerase activity in vitro and zinc
ionophores block the replication of these viruses in
cell culture. PLoS Pathog. 6, e1001176
30. Ibs, K.-H., Rink, L., 2003. Zinc-altered immune
function. J. Nutr. 133 https://doi.org/
10.1093/jn/133.5.1452S,
31. Xue, J., Moyer, A., Peng, B., Wu, J., Hannafon,
B.N., Ding, W.-Q., 2014. Chloroquine is a zinc
ionophore. PloS One 9, e109180.
https://doi.org/10.1371/journal. pone.0109180.
32. Bayard, V.; Chamorro, F.; Motta, J.; Hollenberg,
N.K. Does flavanol intake influence mortality from
nitric oxide-dependent processes? Ischemic heart
disease, stroke, diabetes mellitus, and cancer in
Panama. Int. J. Med. Sci. 2007, 4, 53–58.
33. Yahfoufi, N.; Alsadi, N.; Jambi, M.; Matar, C. The
Immunomodulatory and Anti-Inflammatory Role
of Polyphenols. N
34. Vázquez-Calvo, Á.; Jiménez de Oya, N.; Martín-
Acebes, M.A.; Garcia-Moruno, E.; Saiz, J.-C.
Antiviral Properties of the Natural Polyphenols
Delphinidin and Epigallocatechin Gallate against
the Flaviviruses West Nile Virus, Zika Virus, and
Dengue Virus
35. Wahedi, H.M., Ahmad, S., Abbasi, S.W., 2020.
Stilbene-based natural compounds as promising
drug candidates against COVID-19. J. Biomol.
Struct. Dyn. 1–10. https://
doi.org/10.1080/07391102.2020.1762743
36. Navarro, S., Reddy, R., Lee, J., Warburton, D.,
Driscoll, B., 2017. Inhaled resveratrol treatments
slow ageing-related degenerative changes in mouse
lung
37. Pagano, E., Romano, B., Izzo, A. A., & Borrelli, F.
(2018). The clinical efficacy of curcumin-
containing nutraceuticals: An overview of
systematic reviews. Pharmacological Research,
38. Yuan, M., Wu, N. C., Zhu, X., Lee, C.-C. D., So,
R. T. Y., … Wilson, I. A. (2020). A highly
conserved cryptic epitope in the receptor-binding
domains of SARS-CoV-2 and SARS-CoV
39. Sordillo, P. P., & Helson, L. (2015). Curcumin
suppression of cytokine release and cytokine storm.
A potential therapy for patients with Ebola and
other severe viral infections. In Vivo, 29(1), 1–4.
40. Utomo, R.Y.; Ikawati, M.; Meiyanto, E. Revealing
the Potency of Citrus and Galangal Constituents to
Halt SARS-CoV-2 Infection
41. Zoric, N., Horvat, I., Kopjar, N., Vucemilovic, A.,
Kremer, D., Tomic, S., Kosalec, I., 2013.
Hydroxytyrosol expresses antifungal activity in
vitro. Curr. Drug Targets 14, 992–998
42. Bisignano, G., Tomaino, A., Lo Cascio, R., Crisafi,
G., Uccella, N., Saija, A., 1999. On the in-vitro
antimicrobial activity of oleuropein and
hydroxytyrosol. J. Pharm. Pharmacol. 51, 971–97
43. Zwane, R.E., Parker, A., Kudanga, T., Davids,
L.M., Burton, S.G., 2012. Novel, biocatalytically
produced hydroxytyrosol dimer protects against
ultraviolet-induced J.L. Quiles et al. Environmental
Research 191 (2020) 110053 10 cell death in
human immortalized keratinocytes. J.
44. Killeen, M.J., Linder, M., Pontoniere, P., Crea, R.,
2014. NF-κβ signaling and chronic inflammatory
diseases: exploring the potential of natural products
to drive new therapeutic opportunities. Drug
Discov. Today 19, 373–378.
45. ] K.A. Naidu, Vitamin C in human health and
disease is still a mystery? An overview, Nutr. J. 2
(2003) 7
46. May, J.M.; Harrison, F.E. Role of vitamin C in the
function of the vascular endothelium. Antioxid.
Redox Signal. 2013, 19, 2068–2083.
47. ] W.J. McCormick, Cancer: a collagen disease,
secondary to a nutritional deficiency, Arch. Pediatr.
76 (4) (1959) 166–171
48. ] E. Cameron, A. Campbell, The orthomolecular
treatment of cancer. II. Clinical trial of high-dose
ascorbic acid supplements in advanced human
cancer, Chem. Biol. Interact. 9 (4) (
49. ] E.T. Creagan, C.G. Moertel, J.R. O‘Fallon, et al.,
Failure of high-dose vitamin C (ascorbic acid)
therapy to benefit patients with advanced cancer. A
controlled trial, N. Engl. J. Med. 301 (13) (1979)
687–690.
50. ] L.A. While, C.Y. Freeman, B.D. Forrester, et al.,
In vitro effect of ascorbic acid on infectivity of
herpesviruses and paramyxoviruses, J. Clin.
Microbiol. 24 (1986) 527–531

Naaz Huda et al., IAR J. Med & Surg Res; Vol-1, Iss- 3 (Nov-Dec, 2020): 74-82
81
51. ] A.C. Carr, Vitamin C and immune function,
Nutrients 9 (2017) 1211
52. ] B. Leibovitz, B.V. Siegel, Ascorbic acid and the
immune response, Adv. Exp. Med. Biol. 135
(1981) 1–25.
53. ] Y.M. Hosakote, P.D. Jantzi, D.L. Esham, et al.,
Viral-mediated in hibition of antioxidant enzymes
contributes to the pathogenesis of severe
respiratory syncytial virus bronchiolitis, Am. J.
Respir. Crit. Care Med. 183 (2011) 1550–1560
54. ] S.M. Castro, A. Guerrero-Plata, G. Suarez-Real,
et al., Antioxidant treatment ameliorates respiratory
syncytial virus-induced disease and lung
inflammation, Am. J. Respir. Crit. Care Med. 174
(2006) 1361–1369.
55. ] J.Y. Chen, C.Y. Chang, P.H. Feng, et al., Plasma
vitamin C is lower in postherpetic neuralgia
patients and administration of vitamin C reduces
spontaneous pain but not brush-evoked pain, Clin.
J. Pain 25 (2009) 562–569.
56. ] H. Hemila, E. Chalker, Vitamin C for preventing
and treating the common cold, Cochrane Database
Syst. Rev. 1 (2013) CD000980.
57. ] S. Dey, B. Bishayi, Killing of S. aureus in murine
peritoneal macrophages by ascorbic acid along
with antibiotics chloramphenicol or ofloxacin:
correlation with inflammation, Microb. Pathog. 115
(2018) 239–250
58. ] W. Li, N. Maeda, M.A. Beck, Vitamin C
deficiency increases the lung pathology of
influenza virus-infected gulo-/- mice, J. Nutr. 136
(2006) 2611–2616
59. ] A.A. Fowler III, C. Kim, L. Lepler, R. Malhotra,
O. Debesa, R. Natarajan, B.J. Fisher, A. Syed, C.
DeWilde, A. Priday, V. Kasirajan, Intravenous
vitamin C as adjunctive therapy for
enterovirus/rhinovirus induced acute respiratory
distress syndrome, World J. Crit. Care Med. 6 (1)
(2017) 85–90
60. L. Chen, H.G. Liu, W. Liu, J. Liu, K. Liu, J. Shang,
Y. Deng, S. Wei, [Analysis of clinical features of
29 patients with 2019 novel coronavirus
pneumonia]. Zhonghua Jie He He Hu Xi Za Zhi
Zhonghua Jiehe He Huxi Zazhi, Chin. J. Tuberc.
Respir. Dis. 43 (0) (2020) E005, h
61. ] ] Marik PE. Vitamin C: An essential ―stress
hormone‖ during sepsis. J Thorac Disease
2020;12:S84–
62. Hemil€ a H, Chalker E. Vitamin C can shorten the
length of stay in the ICU: A meta-analysis.
Nutrients 2019;11:708
63. ] Arabi YM, Fowler R, Hayden FG. Critical care
management of adults with community-acquired
severe respiratory viral infection. Intensive Care
Med 2020;46:315–28
64. ] Hemila H. Vitamin C and SARS coronavirus. J
Antimicrob Chemother 2003;52:1049–50.
65. ] M.J. Gonzalez, et al., High dose vitamin C and
influenza: a case report, J. Orthomol. Med. 33 (3)
(2018), isom.ca/article/high-dose-vitamin-c-
influenzacase-report/
66. Aranow, C., 2011. Vitamin D and the immune
system. J. Invest. Med. 59, 881–886.
https://doi.org/10.2310/JIM.0b013e31821b8755.
67. Holick, M.F., 2017. The vitamin D deficiency
pandemic: approaches for diagnosis, treatment and
prevention. Rev. Endocr. Metab. Disord. 18, 153–
165. H
68. . Grant, W.B.; Lahore, H.; McDonnell, S.L.;
Baggerly, C.A.; French, C.B.; Aliano, J.L.;
Bhattoa, H.P. Evidence that Vitamin D
Supplementation Could Reduce Risk of Influenza
and COVID-19 Infections and Deaths. Nutrients
2020, 12, 988.
69. 4. Tripathi, S.; Tecle, T.; Verma, A.; Crouch, E.;
White, M.; Hartshorn, K.L. The human cathelicidin
LL-37 inhibits influenza a viruses through a
mechanism distinct from that of surfactant protein
d or defensins. J. Gen. Virol. 2013, 94, 40–49
70. 5. Chen, Y.; Zhang, J.; Ge, X.; Du, J.; Deb, D.K.;
Li, Y.C. Vitamin D receptor inhibits nuclear factor
κb activation by interacting with IκB kinase β
protein. J. Biol. Chem. 2013, 288, 19450–19458.
[CrossRef]
71. Bonizzi, G.; Karin, M. The two NF-κB activation
pathways and their role in innate and adaptive
immunity. Trends Immunol. 2004, 25, 280–288
72. Adams, K.K., Baker, W.L., Sobieraj, D.M., 2020.
Myth Busters: Dietary Supplements and COVID-
19. Ann Pharmacother 1060028020928052.
73. Martineau, A.R.; Jolliffe, D.A.; Hooper, R.L.;
Greenberg, L.; Aloia, J.F.; Bergman, P.; Dubnov-
Raz, G.; Esposito, S.; Ganmaa, D.; Ginde, A.A.; et
al. Vitamin D supplementation to prevent acute
respiratory tract infections: Systematic review and
meta-analysis of individual participant data.
74. Raharusun, P., Priambada, S., Budiarti, C., Agung,
E., Budi, C., 2020. Patterns of COVID19 Mortality
and Vitamin D: an Indonesian Study. SSRN.
75. Hansdottir, S., Monick, M.M., 2011. Vitamin D
effects on lung immunity and respiratory diseases.
Vitam. Horm. 86, 217–237.
76. Rivellese, F., & Prediletto, E. (2020). ACE2 at the
centre of COVID-19 from paucisymptomatic
infections to severe pneumonia. Autoimmunity
Reviews, 19(6),
77. Hashimoto, T., Perlot, T., Rehman, A., Trichereau,
J., Ishiguro, H., Paolino, M., Sigl, V., Hanada, T.,
Hanada, R., Lipinski, S., Wild, B., Camargo, S. M.
R., Singer, D., Richter, A., Kuba, K., Fukamizu,
A., Schreiber, S., Clevers, H., Verrey, F., ...
Penninger, J. M. (2012). ACE2 links amino acid
malnutrition to microbial ecology and intestinal
inflammation. Nature, 487, 477–481
78. Leung, W. K., To, K. F., Chan, P. K., Chan, H. L.,
Wu, A. K., Lee, N., Yuen, K. Y., & Sung, J. J.
(2003). Enteric involvement of severe acute
respiratory syndrome-associated coronavirus
infection. Gastroenterology, 125(4), 1011–1017

Naaz Huda et al., IAR J. Med & Surg Res; Vol-1, Iss- 3 (Nov-Dec, 2020): 74-82
82
79. . Wu F, Zhao S, Yu B, et al. A new coronavirus
associated with human respiratory disease in China.
Nature 2020; 579: 265–269.
80. Lu R, Zhao X, Li J, et al. Genomic
characterisation and epidemiology of 2019 novel
coronavirus: implications for virus origins and
receptor binding. Lancet 2020;
81. Jin, X., Lian, J. S., Hu, J. H., Gao, J., Zheng, L.,
Zhang, Y. M., Hao, S. R., Jia, H. Y., Cai, H.,
Zhang, X. L., Yu, G. D., Xu, K. J., Wang, X. Y.,
Gu, J. Q., Zhang, S. Y., Ye, C. Y., Jin, C. L., Lu, Y.
F., Yu, X., ... Yang, Y. (2020). Epidemiological,
clinical and virological characteristics of 74 cases
of coronavirus-infected disease 2019 (COVID-19)
with gastrointestinal symptoms. Gut, 69, 1002–
1009
82. Cai, X., Ma, Y., Li, S., Chen, Y., Rong, Z., & Li,
W. (2020). Clinical characteristics of 5 COVID-19
cases with non-respiratory symptoms as the first
manifestation in children. Frontiers in Pediatrics, 8,
258.
83. Flint HJ, Bayer EA, Rincon MT, et al.
Polysaccharide utilization by gut bacteria: potential
for new insights from genomic analysis. Nat Rev
Microbiol 2008; 6: 1
84. Ratajczak W, Rył A, Mizerski A, et al.
Immunomodulatory potential of gut
microbiomederived short-chain fatty acids
(SCFAs). Acta Biochim Pol 2019; 66: 1–2.
85. Koh A, De Vadder F, Kovatcheva-Datchary P, et
al. From dietary fiber to host physiology:
shortchain fatty acids as key bacterial metabolites.
Cell 2016; 165: 1332–1345.
86. Milani, C., Duranti, S., Bottacini, F., Casey, E.,
Turroni, F., Mahony, J., Belzer, C., Delgado
Palacio, S., Arboleya Montes, S., Mancabelli, L.,
Lugli, G. A., Rodriguez, J. M., Bode, L., De Vos,
W., Gueimonde, M., Margolles, A., Van Sinderen,
D., & Ventura, M. (2017). The first microbial
colonizers of the human gut: Composition,
activities, and health implications of the infant gut
microbiota. Microbiology and Molecular Biology
Reviews, 81(4), e00036–e117
87. Anand, S., & Mande, S. S. (2018). Diet, microbiota
and gut-lung connection. Frontiers in
Microbiology, 9, 2147.
88. Brown, R. L., Sequeira, R. P., & Clarke, T. B.
(2017). The microbiota protects against respiratory
infection via GM-CSF signaling. Nature
Communications, 8(1), 1512
89. Syngai, G. G., Gopi, R., Bharali, R., Dey, S.,
Lakshmanan, G. M., & Ahmed, G. (2016).
Probiotics - the versatile functional food
ingredients. Journal of Food Science and
Technology, 53(2), 921–933
90. nde, M., & Margolles, A. (2017). Probiotics, gut
microbiota, and their influence on host health and
disease. Molecular Nutrition & Food Research,
61(1), https://doi.org/10.1002/mnfr. 201600240.
Schuijt, T. J., Lankelma, J. M., Scicluna, B. P., De
souse e Melo, F., Roelofs, J. J., de Boer, J. D.,
Hoogendijk, A. J., de Beer, R., de Vos, A., Belzer,
C., de Vos, W. M., van der Poll, T., & Wiersinga,
W. J. (2016). The gut microbiota plays a protective
role in the host defence against pneumococcal
pneumonia. Gut, 65(4), 575–583.
https://doi.org/10. 1136/gutjnl-2015-309728. S
91. Luoto, R., Ruuskanen, O., Waris, M., Kalliomäki,
M., Salminen, S., & Isolauri, E. (2014). Prebiotic
and probiotic supplementation prevents rhinovirus
infections in preterm infants: A randomized,
placebo-controlled trial. Journal of Allergy and
Clinical Immunology, 133(2), 405–413. H
92. Gou, W., Fu, Y., Yue, L., Chen, G., Cai, X., Shuai,
M., Xu, F., Yi, X., Chen, H., Zhu, Y. J., Xiao, M.,
Jiang, Z., Miao, Z., Xiao, C., Shen, B., Wu, X.,
Zhao, H., Ling, W., Wang, J., ... Zheng, J. (2020).
Gut microbiota may underlie the predisposition of
healthy individuals to COVID-19. MedRxiv
93. Esposito K and Giugliano D. Whole-grain intake
cools down inflammation. Am J Clin Nutr 2
94. . Goletzke J, Buyken AE, Joslowski G, et al.
Increased intake of carbohydrates from sources
with a higher glycemic index and lower
consumption of whole grains during puberty are
prospectively associated with higher IL-6
concentrations in younger adulthood among
healthy individuals. J Nutr 2014; 144: 1586–1593.
95. Infusino, F., Marazzato, M., Mancone, M., Fedele,
F., Mastroianni, C. M., Severino, P., Ceccarelli, G.,
Santinelli, L., Cavarretta, E., Marullo, A., Miraldi,
F., Carnevale, R., Nocella, C., Biondi-Zoccai, G.,
Pagnini, C., Schiavon, S., Pugliese, F., Frati, G., &
d'Ettorre, G. (2020). Diet supplementation,
probiotics, and nutraceuticals in SARSCoV-2
infection: A scoping review. Nutrients, 1