Probiotics, Prebiotics and Dietary Approaches During COVID-19 Pandemic

4/25/2021 Review article: Probiotics, prebiotics and dietary approaches during COVID-19 pandemic
Trends Food Sci Technol. 2021 Feb; 108: 187–196. PMCID: PMC7833886
Published online 2020 Dec 14. doi: 10.1016/j.tifs.2020.12.009 PMID: 33519087
Review article: Probiotics, prebiotics and dietary approaches

during COVID-19 pandemic
Jielun Hu,a,b,c,1 Lin Zhang,a,b,1 Winnie Lin,a,b,d Whitney Tang,a,b Francis K.L. Chan,a,b,d and Siew C. Nga,b,d,∗
aCenter for Gut Microbiota Research, Department of Medicine and Therapeutics, The Chinese University of
Hong Kong, Hong Kong, China

bInstitute of Digestive Disease, State Key Laboratory of Digestive Disease, LKS Institute of Health Science,
The Chinese University of Hong Kong, Hong Kong, China

cState Key Laboratory of Food Science and Technology, China-Canada Joint Lab of Food Science and
Technology (Nanchang), Nanchang University, Nanchang, China

dMicrobiota I-Center (MagIC) Limited, The Chinese University of Hong Kong, Hong Kong, China
∗Corresponding author. Department of Medicine and Therapeutics, The Chinese University of Hong Kong,
Shatin, Hong Kong, China.

1Joint first authors.
Received 2020 Jul 16; Revised 2020 Nov 11; Accepted 2020 Dec 10.
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Abstract
Background
Patients with COVID-19 caused by SARS-CoV-2 exhibit diverse clinical manifestations and severity
including enteric involvement. Commensal gut bacteria can contribute to defense against potential
pathogens by promoting beneficial immune interactions. Interventions targeting the gut microbiome
may have systemic anti-viral effects in SARS-CoV-2 infection.
Scope and approach

To summarise alterations of gut microbiota in patients with COVID-19 including impact of specific
bacteria on disease severity, discuss current knowledge on the role of probiotics, prebiotics and dietary
approaches including vitamin D in preventing and reducing disease susceptibility and review clinical
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833886/ 1/22
studies using probiotics to target coronavirus. A literature review on SARS-CoV-2, COVID-19, gut
microbiome and immunity was undertaken and relevant literature was summarised and critically
examined.
Key findings and conclusions

Integrity of gut microbiome was perturbed in SARS-CoV-2 infections and associated with disease
severity. Poor prognosis in SARS-CoV-2 infection was observed in subjects with underlying co-
morbidities who had increased gut permeability and reduced gut microbiome diversity. Dietary
microbes, including probiotics or selected prebiotics of Chinese origin, had anti-viral effects against
other forms of coronavirus, and could positively impact host immune functions during SARS-CoV-2
infection. Numerous studies are investigating the role of probiotics in preventing and reducing
susceptibility to SARS-CoV-2 infection in healthcare workers, household contacts and affected
patients. An approach to strengthen intestinal barrier and lower pro-inflammatory states by adopting a
more diversified diet during COVID-19 pandemic.
SARS-CoV-2 infection is associated with immune dysfunction and gut microbiota alterations.
Delineating mechanisms of probiotics, prebiotics and diet with anti-SARS-CoV-2 immunity present
opportunities for discovery of microbial therapeutics to prevent and treat COVID-19.
Keywords: SARS-CoV-2, Probiotics, Prebiotics, Diet, Nutrition
1. Introduction
In December 2019, the Coronavirus disease 2019 (COVID-19), caused by a novel coronavirus SARS-
CoV-2, emerged in Wuhan, Hubei province, China (Li, Fan, et al., 2020) and soon spread rapidly across
the world (Li, Guan, et al., 2020). To date, more than 9.2 million people have contracted COVID-19
infection with over 470,000 deaths worldwide. Therapeutic options are limited and clinically proven
vaccine are lacking. In particular, there is a need for safe and effective interventions to prevent, reduce
susceptibility and lessen the severity of COVID-19 (Amanat & Krammer, 2020). A striking observation
during the pandemic is the heterogenous presentation and clinical outcomes of infected subjects across
different geographic locations. Elderly individuals, along with those with pre-existing conditions, such
as diabetes mellitus, hypertension, cardiovascular diseases and cancer have a demonstrated higher risk
for developing more severe disease as well as suffering a higher risk of mortality, suggesting that the
immune system may play a crucial role (Wang, Hu, et al., 2020). Patients with severe disease commonly
presented with lymphopenia and a cytokine storm leading to acute respiratory distress syndrome and
multi-organ failure. Lymphopenia can result in defects in anti-viral immunity and compromise innate
and adaptive immune response contributing to poor prognosis (Azkur et al., 2020).
The gastrointestinal (GI) tract is the largest immunological organ in the body and home to trillions of
microbes; the link between the GI tract and COVID-19 has been supported by reports of GI symptoms
such as diarrhea in COVID-19 patients (Ng & Tilg, 2020). Microbes that reside in the human gut are key
contributors to host metabolism and immunity and represent potential targets for novel therapeutics
(Grifoni et al., 2020). In January 2020, the China National Health Commission and National
Administration of Traditional Chinese Medicine Guidelines recommended the use of probiotics along
with conventional treatment in patients with COVID-19 infection to improve the balance of intestinal
flora and prevent secondary bacterial infections. The use of probiotics has also been suggested to
flatten the curve of COVID-19 but currently evidence remain scarce (Baud et al., 2020). Since the
outbreak of COVID-19, over 21,000 Google searches on “probiotics and immunity” have been
performed in March 2020 by several channels and vehicles on probiotic products that can boost
immunity. This simple finding suggests that the field of microbiome research is not only blossoming
but also strongly highlights the need for advancement. One of the major caveats remains the lack of
perspective from the society, scientists and healthcare professionals, who may misinterpret data or are
anticipating a direct translation of such complex research from the bench to the bedside. To date, the
rationale for using probiotics in COVID-19 has been mostly derived from indirect evidence (Mak et al.,
2020
). The current understanding is that the gut microbiome (referred to as the collective genomes of
the diverse microbiota that reside in the gastrointestinal tracts of humans) can both regulate and be
regulated by invading viruses, facilitating either stimulatory or suppressive effects. Some commensal
gut bacteria can contribute to defense against potential pathogens by communicating with human cells
and promoting beneficial immune interactions (Cabinian et al., 2018). This depicts a mechanism whereby
exposure to dietary microbes, including probiotics or prebiotics, could positively impact immune
function during infections (Jespersen et al., 2015).
In this perspective review, we described recent evidence showing altered gut microbiota in patients
with COVID-19 including impact of specific bacteria and their involvement in immunity and disease
severity. Secondly, we debated current knowledge on the role of probiotics, prebiotics, nutritional
modulation in preventing and reducing susceptibility to COVID-19. Finally, we reviewed clinical
studies using probiotics to target coronavirus and implications for future study design and introduction
of precision nutrition in COVID-19.
2. Gut microbiome responses to SARS-CoV-2 infection

As with other infectious diseases, it is conceivable that the integrity of the gut microbiome could be
perturbed by SARS-CoV-2 leading to gut dysbiosis in the host (Fig. 1 ). Fig. 1 shows the possible
mechanisms of dysbiosis by SAR-CoV-2 virus infection and susceptible populations. Emerging signs
show a link between gut functionality and microbiome responses to SARS-CoV-2. For instance, some
patients with SARS-CoV-2 present with gastrointestinal (GI) symptoms including diarrhea and
vomiting. The viral entry receptor, angiotensin converting enzyme 2 (ACE2) and virus nucleocapsid
protein are present in gastrointestinal epithelial cells, and SARS-CoV-2 virus are repeatedly detected in
fecal samples across different cohorts (Ng & Tilg, 2020). The highest mortality and morbidity in SARS-
CoV-2 infection is in the elderly, and those with co-morbidities including obesity and diabetes; these
underlying conditions have been associated with increased gut permeability, intestinal inflammation
and reduced gut microbiome diversity (Liu et al., 2017). The gut-lung crosstalk has also been proposed to
contribute to the pathogenesis of SARS-CoV-2 infection. Considering that pulmonary inflammation is
common in patients in SARS-CoV-2 infection, direct suppression or promotion of viral infection by the
gut microbiome may play a role (Dang & Marsland, 2019). Theoretically, these data point to an
opportunity for interventions targeting the gut microbiome that may have systemic anti-viral effects in
SARS-CoV-2 infection.
Open in a separate window

Fig. 1
Possible mechanisms of dysbiosis by SAR-CoV-2 virus infection and susceptible populations.
A recent study from Hong Kong showed that patients with SARS-CoV-2 infection had significant
alterations in fecal microbiomes compared with controls, characterized by enrichment of opportunistic
pathogens (Clostridium hathewayi, Actinomyces viscous, and Bacteroides nordii) and depletion of
beneficial commensals (Faecalibacterium prausnitzii, Lachnospiraceae bacterium, Eubacterium
rectale, Ruminococcus obeum, and Dorea formicigenerans) (Zuo, Zhan, et al., 2020). Depleted symbionts
and gut dysbiosis persisted even after clearance of SARS-CoV-2 in respiratory samples and resolution
of respiratory symptoms. Gut bacteria that correlated with efficient viral clearance such as
Bacteroidetes species may have a protective role in combating SARS-CoV-2 infection by hampering
host entry through ACE2 (Zuo, Zhang, et al., 2020). Of interest was the observation that three bacterial
members of the phylum Firmicutes (specifically, the genus Coprobacillus, and the two species
Clostridium ramosum and Clostridium hathewayi) were associated with increased clinical severity of
SARS-CoV-2 infection. This association is of particular interest, since Coprobacillus has been shown
to upregulate colonic ACE-2 in mice (Naama et al., 2017). Faecalibacterium prausnitzii, which was found
to have a strong negative correlation with the severity of COVID-19, had anti-inflammatory activity in
the gut (Sokol et al., 2008). Another finding of interest was a negative correlation between fecal SARS-
CoV-2 load and the abundance of specific gut bacteria such as certain Bacteroides species (Bacteroides
dorei, Bacteroides thetaiotaomicron, Bacteroides massiliensis and Bacteroides ovatus). These species
were associated with a reduction in ACE2 expression in the mouse gut (Naama et al., 2017), suggesting
that they may limit the ability of SARS-CoV-2 to enter into enterocytes. These findings corroborated
with that of a separate study showing lowered gut microbiota diversity and levels of butyrate-
producers, and higher levels of opportunistic pathogens in patients with SARS-CoV-2 infection
compared with H1N1 patients and healthy controls. In addition, seven bacterial strains (Streptococcus,
Fusicatenibacter, Collinsella, Dorea, Agathobacter, Eubacterium hallii group, Ruminococcus torques
group) could be regarded as a COVID-19 diagnostic biomarker (Gu et al., 2020). To date, it remains
unclear whether the dysbiotic microbial communities are a cause or a consequence of COVID-19.
However, metabolic alterations associated with inflammation might act as microbial stressors and
promote the outgrowth of dysbiotic species. These data indicate that strategies to alter the intestinal
microbiota might reduce the disease severity of COVID-19 (Zuo, Zhang, et al., 2020).
3. Interactions of gut microbiome and lung immunity in SARS-CoV-2

infection
Manipulation of gut microbiota by antibiotics, probiotics, prebiotics, and natural products or diets
represents a promising therapeutic strategy for lung diseases in clinical and experimental studies (Zhang,
Li, Wang, Tan, Zhang and Feng, 2020). The pathogenesis of SARS-CoV-2 infection relates to dysfunctional
immune response including excessive infiltration of monocytes, macrophages and T cells, systemic
cytokine storm, pneumonia and multi-organ damage (Zhang, Tan, et al., 2020). Defining these key immune
cell subsets and their states in SARS-CoV-2 infection is a crucial step in obtaining insights into the
immune clearance mechanism and developing new therapeutic strategies for patients with COVID-19.
Xu et al. described pathological findings in severe SARS-CoV-2 and demonstrated aberrant immune
cell infiltrates in the lung (Xu et al., 2020). In this regard, reduction and functional exhaustion of CD8+ T
cells was shown in parallel with a rise in inflammatory cytokine levels in patients with severe COVID-
19 (Diao et al., 2020). Importantly, gut microbiota influences the balance between pro-inflammatory and
regulatory responses and shape host immune system (Zheng et al., 2020). Fig. 2 shows interactions
between the human gut and lung and potential positive immune responses triggered by probiotics or
prebiotics. Prebiotics provide the energy for probiotics growth. Several probiotics including Bacillus,
Lactobacilli, Bifidobacteria have been reported to have positive immune activity against common
upper respiratory tract infections, via increasing Natural killer cell activity, increasing T suppressor or
T helper cells, decreasing B lymphocytes, increasing saliva IgA concentrations, increasing IL-10
production and enhancing levels of interferon-alpha.

Fig. 2
Interactions between the human gut and lung and potential positive immune response triggered by
probiotics and prebiotics.
4. Role of probiotics and SARS-CoV-2 infection

While the beneficial effect of probiotics (defined as live microorganisms that when administered in
adequate amounts confer a health benefit on the host) was originally thought to stem from
improvement in the intestinal microbial balance, there is now substantial evidence that probiotics can
also provide benefits by modulating host immune functions (Klaenhammer et al., 2012). Probiotics has
been shown to shape T cell subsets (Lee & Kim, 2017), stimulates antimicrobial peptide production by
Paneth cells (Bevins & Salzman, 2011) and direct Th17 cells differentiation in the small intestinal tract
(Ivanov et al., 2008). Understanding the fundamental immunological process underlying clinical
manifestations of SARS-CoV-2 infection is vital for the identification and rational design of effective
therapies. Laboratory studies have reported that certain probiotics have anti-viral effects including
against other forms of coronavirus (Chai et al., 2013). Others have reported the potential of probiotics to
interact with ACE2, the host entry receptor of SARS-CoV-2 virus; for instance, some lactobacilli have
been reported to release peptides with high affinity for ACE during milk fermentation (Li et al., 2019).
Recently, Paenibacillus bacteria were shown to naturally produce carboxypeptidases homologous to
ACE2 in structure and function (Minato et al., 2020). A recent study showed that Toll-like Receptor
(TLR4) signaling was essential for the effects of preventive intranasal treatment with probiotic
Lacticaseibacillus rhamnosus GG in a neonatal mouse model of influenza infection (Kumova et al., 2019).
Interestingly, human cathelicidin, LL-37, is one of the best-studied human antimicrobial peptides that
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have a wide-spectrum activity against bacteria and viruses (Mookherjee et al., 2020) and could be
effectively delivered by food-grade probiotics including Lactococcus lactis expression system (Mierau &
Kleerebezem, 2005
). The protective immunomodulatory effect of cathelicidin-expressing Lactococcus
lactis (Wong et al., 2012), may help open new avenues of combating SARS-CoV-2 infection using
antimicrobial peptides-expressing probiotics delivery system. Whether these or other
immunomodulatory effects, following local or oral administration, could be effective in SARS-CoV-2
infected individuals remains unknown. Some clinical trials have demonstrated that specific probiotics
can reduce the incidence and duration of common upper respiratory tract infections, especially in
children but also with some data in adults (King et al., 2014) and long-term nursing home residents (Van
Puyenbroeck et al., 2012
).
Recently, new guidelines from the WHO recommends against antibiotic therapy or prophylaxis for
patients with mild and moderate COVID-19 unless there is concurrent suspected bacterial infection
(https://www.who.int/publications/i/item/clinical-management-of-covid-19). Another setting whereby
probiotics may play a role relates to perturbed microbiota caused by antibiotics (Palleja et al., 2018). As
empirical antibiotics are widely used in the early phase of COVID-19 outbreak and may lead to more
severe and unfavorable dysbiosis, reinforcement of colonic microbiota using probiotics has been
proposed to reduce susceptibility to subsequent secondary co-infections. More clinical trials are
necessary to confirm the role of probiotics and to determine the optimal strain(s), dosing regimens,
time and duration of intervention for SARS-CoV-2 infection.
5. Role of prebiotics and SARS-CoV-2 infection

Prebiotics play a widely recognized role in the regulation of intestinal microbiota. Prebiotics are special
fibers with selective fermenting ingredients that are needed by gut microbes. It selectively stimulates
favourable growth and/or enhance activities of indigenous probiotic bacteria. Prebiotic therapies have
been shown to be associated with improvement in gut-related diseases such as constipation, diarrhea, as
well as non-gut disorders including reduction of the risks of osteoporosis, atherosclerotic
cardiovascular disease associated with dyslipidemia, insulin resistance, obesity, and possibly type 2
diabetes (Wang, Xiao, Tian, Zhao and Chen, 2020). Large amounts of prebiotic fiber provide an abundance of
food for a range of gut bacteria and when utilized this can result in an excess of gas in the intestine.
The most common side effects of prebiotics are abdominal bloating and discomfort, occurring when
large doses are consumed (Marteau & Seksik, 2004). Compared to probiotics, there has been less
information on the use of prebiotics for addressing respiratory infections. Some studies support the use
of galactans and fructans in infant formulae in reducing upper respiratory infections (Shahramian et al.,
2018) and a meta-analysis of synbiotics demonstrated efficacy in lowering respiratory tract infections
(Chan et al., 2020). Research in mice showed that the dietary fiber, inulin, conferred protection against
influenza A by shaping Ly6c (−) patrolling monocyte hematopoiesis and CD8+ T Cell (Trompette et al.,
2018). Traditional Chinese medicine has been playing an important role in the prevention, treatment and
rehabilitation of COVID-19 (Ren et al., 2020). Recent data from the National Administration of
Traditional Chinese Medicine showed that a Traditional Chinese Medicine (TCM) named “Lung
Cleansing and Detoxifying Decoction (Qing Fei Pai Du Tang)”, which consists of carbohydrate
polymers may have therapeutic effects in SARS-CoV-2 infection. The “Lung Cleansing and
Detoxifying Decoction” was given to 214 COVID-19 patients, and the symptoms of 90 percent of the
patients were notably relieved after 3-day-treatment of this Traditional Chinese Medicine (Zhao et al.,
2020). These carbohydrate polymers are polysaccharides within the family of prebiotics comprising of
oligosaccharides and polysaccharides. Considering that cellular immunity plays a critical role in
eliminating viral infections, the most significant properties of polysaccharides rest in their
immunomodulatory activities (Li, Fan, et al., 2020). For example, Chinese yam polysaccharides carry
immunomodulatory and immune enhancement functions and have served as adjuvants in developing
vaccines (Wu et al., 2020). Glycyrrhiza polysaccharide could activate the immune system by promoting
the maturation, differentiation and reproduction of immune cells such as lymphocytes and
macrophages, as well as activating the reticuloendothelial system (Luo et al., 2017). Guan et al. analyzed
1099 cases of COVID-19 in China and found lymphocytopenia to be one of the most common features
and subjects with lymphopenia were less likely to survive (Li, Peri, et al., 2020). IL-6 and IL-8 negatively
correlated with lymphocyte count and IL-6 kinetics was associated with disease severity (Zhang, Tan, et
al., 2020
). For example, dietary sugar beet fiber has been shown to increase the proportion of CD8+ IEL,
especially in cecal mucosa (Ishizuka & Tanaka, 2002).
Importantly, prebiotics is closely related to the growth and function of probiotics. Gut microbes,
especially probiotics, degrade various prebiotics such as fructan, glucan, arabinoxylan. The end
products, short chain fatty acids (SCFAs) have been demonstrated to have regulatory effects on host
immunity. SCFAs are involved in host immune response by different pathways through specific
receptors, and vary in intensity of G protein-coupled receptors (GPCRS) receptor activation (Trompette
et al., 2014
). In addition, butyric acid and propionic acid from prebiotics fermentation by gut microbiota
can affect differentiation or functions of T cells, macrophages and dendritic cells. These SCFAs
directly impact B cell intrinsic functions to moderately enhance class-switch DNA recombination
(CSR). In human and mouse B cells, butyrate and propionate decrease B cell Aicda and Prdm1 by
upregulating select miRNAs that target Aicda and Prdm1 mRNA-3′ UTRs through inhibition of histone
deacetylation (HDAC) of miRNA host genes. By acting as HDAC inhibitors, SCFAs can impair
intestinal and systemic T-dependent and T-independent antibody responses (Sanchez et al., 2020).
Glycans, or polysaccharides, are included in prebiotics. They are carbohydrate-based polymers that
regulate a variety of processes including immunity (Lauc et al., 2016). Glycan diversity represents one of
the main defenses of all higher organisms against infection, and the repertoire of glycans changes with
age, especially in the age ranges that are most susceptible to SARS-CoV2 infection. Furthermore, both
SARS-Cov-2 virus and its principal cellular target ACE2 are known to be highly glycosylated (Walls et
al., 2020
). A recent study analyzed site-specific N-linked glycosylation of MERS and SARS S
glycoproteins, indicating that each of these glycosylation sites can be occupied by up to ten different
glycans (called glycoforms), which greatly extends epitope diversity (Watanabe et al., 2020). Furthermore,
glycans are one of the principal regulators of antibody effector functions and many other aspects of the
immune system (Lauc & Sinclair, 2020).
6. Nutritional and dietary approaches to restore a healthy microbiota

Diet has a key impact on the gut microbiota and can influence gut microbial richness and diversity.
High intake of animal proteins, saturated fat, sugar, and salt has been reported to stimulate the growth
of pathogenic bacteria leading to alterations of the intestinal barrier, whereas consumption of complex
polysaccharides and plant protein was associated with an increase of beneficial bacteria which
stimulate SCFA production. Omega-3, polyphenols, and micronutrients can confer health benefits via
modulation of the gut microbiota (Rinninella et al., 2019). In addition, branched-chain amino acids can
increase intestinal immunoglobulin levels hence improving gut barrier (Elmadfa & Meyer, 2019). High-
quality proteins are a crucial component of an anti-inflammatory diet. Nutritional dietary components
known to exert anti-inflammatory and antioxidant properties include omega-3 fatty acids, vitamin C,
vitamin E, and phytochemicals such as carotenoids and polyphenols that are commonly found in plant-
based foods. Plant-based fiber also has prebiotic effects such as promoting the growth of bacteria that
are associated with health benefits, such as Bifidobacterium and Lactobacillus spp. Moreover, reduce
potential pathogens such as Clostridium spp (Iddir et al., 2020). Most microbial species in the GI tract
belong to Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria and these microbial
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populations aim to provide nutrients and maintain homeostasis in the host (Gombart et al., 2020). Modern
diets in developed nations have shifted away from diets high in phytochemical rich fruits, vegetables,
polysaccharides and fibres, lean meats to one that is low in fibres and high in processed foods with
exposure to food additives, refined sugar and hydrogenated fats (Jew et al., 2009). One approach key
during COVID-19 pandemic is to strengthen intestinal barrier against pathogens, increase intestinal
motility and lower a pro-inflammatory state (Trottein & Sokol, 2020) by adopting a more diversified diet
with moderate increase in high-fiber and plant-based foods.
Food diversity is the corner stone for every being against COVID-19 pandemic. In light of the
complexity of the gut microbiota ecosystem, a single food item may not dramatically shift its overall
landscape (McCann, 2000). A diversified diet such like the Mediterranean diet has positive effect on
immunity with abundant supply of dietary fibers. It was found in vitro that galactooligosaccharides
(GOS) and arabinoxylan increased the production of T helper cell 1 IFN-γ, whereas the T helper cell 1
cytokine TNF-α was decreased (Bermudez-Brito, 2015). Following the Mediterranean dietary pattern,
characterized by high consumption of whole grains, vegetables, legume, nuts, extra-virgin olive oil
(rich in polyphenols), consumption of fats where unsaturated fatty acids dominate, and low
consumption of processed meats and refined sugars, can have favourable modulation of relative gut
microbial abundance and diversity to maintain its homeostasis (De Filippis, 2016). Moreover,
micronutrients obtained from such diet, namely vitamins A, B6, B12, C, D, E, folate, iron, selenium,
magnesium, zinc and copper optimize the innate and adaptive immunity since many micronutrients cast
functional roles in our immune system (Maggini et al., 2018). Lastly, a diversified diet includes fermented
dairy products, fermented soybeans and vegetables that contain naturally occurred probiotics,
Lactobacillus bulgaricus and Streptococcus thermophiles (Ghosh et al., 2019). Considering the synergetic
effect of microbial-diet-host interaction, food diversity is important to maintain immunity by creating a
nurturing environment for microbiota cultivation (De Filippo et al., 2010).
Of particular relevance is the enhancement of intestinal butyrate production through promotion of

microbial interactions using dietary approaches, which can strengthen gut epithelial cell health.
Universally, Bifidobacteria and Lactobacilli have been considered beneficial species with butyrate
production. Faecalibacterium (F) prausnitzii has been shown to be reduced in patients with COVID
-19 (Zuo, Zhang, et al., 2020). The role of F. prausnitzii in stimulating butyrate (Lopez-Siles et al., 2017) and
their anti-inflammatory properties (Sokol et al., 2008) in the intestine have been consistently reported and
attracted increasing interest in restoring this beneficial gut bacterium to facilitate treatment for
inflammatory bowel disease (Lopez-Siles et al., 2017). F. prausnitzii could be stimulated by different
substrates derived from diet or prebiotics, including inulin (Ramirez-Farias et al., 2009), dietary fibre (Benus
et al., 2010
), polydextrose and soluble corn fiber (Hooda et al., 2012). Table 1 shows natural foods
containing high content of prebiotics (such as fibers, oligosaccharides) or probiotics (such as
bifidobacteria and lactobacillus) beneficial to build a resilient and diversified gut microbiota.
Table 1
Natural foods containing high content of prebiotics (such as fibers, oligosaccharides) or
probiotics (such as bifidobacterial and lactobacillus).
Food Group (and their associated nutrients) Specific Food to Consume

Whole grains (fibers, oligosaccharides, whole wheat, barley, brown rice
minerals, and vitamins)
Vegetables and fruits (fibers, oligosaccharides, most leafy vegetables, legumes, mushrooms, and fruits
and vitamins A, B, C, D, E, K)
Plant-based protein (soluble fibers and amino beans, tofu, chickpeas, lentils, nuts
acids)
Fiber-fortified food (oligosaccharides) cereals, breads, drinks, supplements
Fermented dairy (bifidobacterial and yogurt, kefir, sweet acidophilus milk, buttermilk; cheese:
lactobacillus) cheddar, Gouda, mozzarella, and cottage
Fermented beans or vegetables (lactobacillus) miso, sauerkraut, sour pickles soybeans (tempeh)
7. Dietary approaches during COVID-19 pandemic

The WHO published a set of recommendations to promote a shift from a Westernized modern diet to a
more diversified diet to protect against malnutrition and non-communicable diseases (Organization
WHO). Dietitians in Canada recommend a healthy diet rich in fruit and vegetables, protein foods and
whole grains to support a strong immune system. Academy of Dietetics and Nutrition suggests a
variety of foods to obtain key nutrients in supporting the immune system. Due to the limited data on the
beneficial or harmful strains of bacteria in SARS-CoV-2 infection, researches in this area and diets
adhering to modest qualities of naturally fermented food needs to be urgently investigated. A
diversified diet for a healthy individual daily includes five servings or more of fruits, vegetables
(excluding starchy vegetables) including legumes, nuts, and whole grains; minimize free sugars (all
sugar added to foods in the manufacturing or cooking processes); up to 30% of total energy intake
comes from fats while unsaturated fats are preferred over saturated fats; avoid industrially produced
trans-fat; and less than 5 g of salt (Mozaffarian et al., 2014). As subjects with type 2 diabetes mellitus,
obesity, cardiovascular disease, and other chronic diseases had a worst prognosis and higher mortality
when infected with SARS-CoV-2, hydration and adequate nutrients are key components to prevent
malnutrition and maintain homeostasis of the metabolism and physiology in these individuals (Volkert et
al., 2019
). In a recent study among 7300 individuals with COVID-19 (among which nearly 1000 had
type 2 diabetes mellitus) in Hubei Province, China, subjects with well-controlled blood glucose (upper
limit ≤ 10 mmol/L) had a reduced risk for complications and mortality (Zhu et al., 2020). The overall
nutrition management for suspected or infected cases is to control blood sugar in those with diabetes or
metabolic diseases and to maintain nutrition and hydration. In subjects with gastrointestinal symptoms
with sensory loss – anosmia, hyposmia, and dysgeusia, food high in calories and proteins in small
bouts every two to 3 h and fluid intake of 60–120 mL every 15 min to compensate water loss through
fever are recommended (Reithner, 1981). In infected patients who require intensive care, a timely manner
to initiate enteral nutrition (EN) within 24–36 h of admission to ICU or within 12 h of
intubation/placement of mechanical ventilator is recommended (Barazzoni et al., 2020). A fiber free
formula is more tolerable to patients with significant gastrointestinal dysfunction. In addition, evidence
linking vitamin D deficiency with COVID-19 severity is growing with data suggesting a correlation
between insufficient vitamin D level and COVID-19 mortality (Rhodes et al., 2020). Therefore, vitamin D
supplementation at moderate dose is recommended for individuals at risk of deficiency, including those
living in institutions or individuals with darker skin. Fig. 3 illustrates dietary and nutritional
recommendations during COVID-19.

Fig. 3
Dietary and nutritional recommendations during COVID-19.
8. Clinical trials of probiotics for prevention or treatment of SARS-CoV-2

infection
At a time when drugs are being tested with no clear success as yet, probiotics have been considered in
clinical trials to reduce the burden and severity of COVID-19. It is highly likely that inter-individual
variation in gut microbiome will impact on the efficacy of proposed microbiota interventions for
SARS-COV-2 infection. No published studies so far have reported the use of probiotics as add-on
therapy for the management of COVID-19. However, the International Scientific Association of
Probiotics and Prebiotics (IASPP) has highlighted that scientists and clinicians globally are
investigating the relationship between the gut microbiome and susceptibility to COVID-19 and
assessing the role of various probiotics strains to lower viral load via different mechanisms. Scientists
in University of Antwerp, Belgium are exploring whether specific strains of lactobacilli in the
nasopharynx and oropharynx could potentially reduce viral activity via a multifactorial mode of action,
including barrier-enhancing and anti-inflammatory effects, and reduce the risk of secondary bacterial
infections in COVID-19. They are also investigating the potential of specific strains of lactobacilli with
immunostimulatory effects as adjuvants for intranasal SARS-CoV-2 vaccination, or the potential of a
genetically engineered antigen-producing organism for vaccine delivery. Other researchers at the North
Carolina State University, USA, are actively engineering Lactobacillus acidophilus probiotics
expressing COVID-19 proteins to be tested as potential vaccines. In the United Kingdom, a Phase II
randomized, double-blind, placebo-controlled trial is being conducted to determine the efficacy and
safety of oral Live Biotherapeutic MRx-4DP0004 in addition to standard supportive care for
hospitalized patients with COVID-19. Researchers from Duke University are developing protocols to
study prevention and treatment of COVID-19 in a range of at-risk populations including healthcare
providers, hospitalized patients, and nursing home and nursing home workers. An initial multicenter,
randomized, double blind, placebo-controlled phase 2 trial will assess if the probiotic Lactobacillus
rhamnosus GG has a role in prevention and treatment of COVID-19 infection. Researchers from the
Chinese University of Hong Kong has identified a probiotic formula derived from analysis of depleted
bacteria in fecal samples of COVID-19 patients that persisted even after recovery and discharge form
hospitals, and this formula will be investigated in a randomized controlled trial for patients who have
recovered from COVID-19 to rebalance their gut microbiota. Table 2 summarises ongoing clinical
studies of probiotic intervention in COVID-19.
Table 2
Ongoing clinical studies of probiotic intervention in COVID-19.
Placebo
Country ClinicalTrials.gov Study type Study subjects Age Sample Intervention
ID group size
Italy NCT04368351 Retrospective COVID-19 patients ≥18 70 Standard of care
Case-Control requiring years (Azithromycin an
hospitalization hydroxychloroqui
vs
Bacteriotherapy
(SivoMixx:
Streptococcus
thermophiles, 2
Bifidobacterium
strains, 5
Lactobacillus stra
Azithromycin and
Hydroxychloroqu
Mexico NCT04517422 RCT COVID-19 patients 18–60 300 Combination of
requiring year Lactobacillus
hospitalization old plantarum
CECT7481,
Lactobacillus
plantarum CECT
7484, Lactobacill
plantarum CECT
7485, and
Pediococcus
acidilactici CECT
7483 vs Placebo
a
Hong Approved by Pilot study COVID-19 Patients ≥18 50 Synbiotic (CUHK
Kong CUHK-NTEC requiring years Synbiotic vs
CREC: CRE- hospitalization Standard care)
2020.407

a
The Joint Chinese University of Hong Kong – New Territories East Cluster Clinical Research Ethics Committee:
CUHK-NTEC CREC.
9. Conclusion and future directions
SARS-CoV-2 associated-immune dysfunction and alterations in the gut microbiota present an exciting
opportunity for studies and discovery of microbial therapeutics to prevent and treat SARS-CoV-2
infection. There is a pressing need to characterize specific microbial species, prebiotics, or a
combination that can boost immunity, and better understand mechanisms of precision symbiotic with
anti-viral immunity for SARS-CoV-2 infection. In addition to bacteria, other key microorganisms, such
as viruses, phages, yeast and fungi, are also present in the gut. These microorganisms, which likely
regulate the activity of the host and of the other gut microbes may be as important as bacteria. It was
recently shown that patients with COVID-19 had significantly altered gut mycobiome with a 3-fold
increase in fungal diversity and pathogens from the genus Aspergillus and patients who had more than
two Aspergillus pathogens in high abundance had more severe disease. These fungi were also present
in the feces despite nasopharyngeal clearance of SARS-CoV-2, hinting to persistent colonization of
fungal pathogen and a potential threat to the host in the longer term (Zuo, Zhan, et al., 2020). The gut
mycobiome offer an additional dimension to the investigation of host–microorganism interactions in
SARS-CoV-2 infection.
Importantly, different methodologies should be adopted to study associations between dietary and
microbiome effects and susceptibility to SARS-CoV-2 infection and disease severity. An international
approach will allow inclusion of populations from different locations and various background, dietary
patterns, and environmental exposures. Adequately powered studies that recruit COVID-19 patients
and healthy individuals to collect clinical data, host genetic parameters, dietary datasets, immune
phenotyping, and multi-omics microbiome markers are needed. A collaborative international approach
is essential for unravelling the determinants of clinical outcomes of SARS-CoV-2 infection and for
designing targeted therapeutic and preventative microbial measures. The moderating effects of high
fiber especially the choice of the high-fiber food type, freshly fermented, and diverse foods should also
be investigated as preventative and mitigating measures. Novel technologies and delivery systems such
as nanotechnology can efficiently help in designing intelligent functional foods with the possibility of
localized delivery in the gut (Kalantar-Zadeh et al., 2020).
Another consideration is whether the composition of one's microbial profile can influence the
immunomodulatory treatment and response to drugs or vaccine. Several anti-viral drugs have been
investigated to combat SARS-COV2 virus and on May 1, 2020, the anti-viral Remdesivir became the
first drug to receive emergency FDA approval for the treatment of COVID-19 (Grein et al., 2020).
Although there is no direct evidence of gut microbiome interaction with Remdesivir, there is precedent
for gut microbiome modulation of other anti-viral drugs (Dominguez-Diaz et al., 2019). It has been reported
that enzymes belonging to the common gut microbiota constituents Bacteroides thetaiotaomicron and
Bacteroides ovatus functionally impact activity and toxicity of the oral antiviral Brivudine. The ability
of 76 human gut bacteria to metabolise 176 drugs including several with antiviral activity has also
recently been characterized (Zimmermann et al., 2019). In addition, a clinical phase I study demonstrated
that the gut microbiota plays a major role in generating an optimal antibody response against influenza
shot, which indicated vaccines response could be affected by gut microbiota (Hagan et al., 2019). For
instance, probiotics and/or prebiotics could positively boost the immune system to increase influenza
vaccine efficacy in humans (Van Puyenbroeck et al., 2012). These questions that remain are challenging and
will require innovative approaches. Ultimately, these efforts should lead to deeper insight into host-
microbial relationships and provide exciting new opportunities to improve host immunity to conquer
COVID-19, either through microbiota modulation, for prevention, or enhancing vaccine response.
Nutritional and dietary strategies directed at restoring established beneficial microbiota, which can
possibly suppress viral infection in the elderly and those with underlying health problems, may be an
effective strategy to mitigate the unwanted effects of this virus. Ultimately, a comprehensive
mechanistic-based approach, coupled with carefully conducted multicenter randomized, controlled

trials will advance our knowledge to address the potential of microbiota and dietary manipulation as an
alternative management option for SARS-CoV-2 infection.
Authors’ contributions
Jielun Hu, Lin Zhang, Winnie Lin were responsible for conception, literature review, writing and
revising the manuscript. Whitney assisted in the graphical figures’ preparation. Siew C Ng and Francis
KL Chan provided critical revisions of the final manuscript. All authors agreed to the final version of
manuscript.
Declaration of competing interest

The authors declare that they have no conflict of interest.
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4/25/2021 Review article: Probiotics, prebiotics and dietary approaches during COVID-19 pandemic

Review article: Probiotics, prebiotics and dietary approaches

Hong Kong, Hong Kong, China

The Chinese University of Hong Kong, Hong Kong, China

Technology (Nanchang), Nanchang University, Nanchang, China

Shatin, Hong Kong, China.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Scope and approach

Key findings and conclusions

Keywords: SARS-CoV-2, Probiotics, Prebiotics, Diet, Nutrition

2. Gut microbiome responses to SARS-CoV-2 infection

Open in a separate window

Possible mechanisms of dysbiosis by SAR-CoV-2 virus infection and susceptible populations.

3. Interactions of gut microbiome and lung immunity in SARS-CoV-2

Open in a separate window

4. Role of probiotics and SARS-CoV-2 infection

5. Role of prebiotics and SARS-CoV-2 infection

6. Nutritional and dietary approaches to restore a healthy microbiota

Of particular relevance is the enhancement of intestinal butyrate production through promotion of

Food Group (and their associated nutrients) Specific Food to Consume

7. Dietary approaches during COVID-19 pandemic

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Dietary and nutritional recommendations during COVID-19.

8. Clinical trials of probiotics for prevention or treatment of SARS-CoV-2

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9. Conclusion and future directions

mechanistic-based approach, coupled with carefully conducted multicenter randomized, controlled

Declaration of competing interest

1. Amanat F., Krammer F. SARS-CoV-2 vaccines: Status report. Immunity. 2020;52(4):583–589.

41. Lopez-Siles M., Duncan S.H., Garcia-Gil L.J., Martinez-Medina M. Faecalibacterium

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