Do an Altered Gut Microbiota and an Associated Leaky Gut Affect COVID-19 Severity?

Abstract

Coronavirus disease 2019 (COVID-19), which has been declared a pandemic, has exhibited a wide range of severity worldwide. Although this global variation is largely affected by socio-medical situations in each country, there is also high individual-level variation attributable to elderliness and certain underlying medical conditions, including high blood pressure, diabetes, and obesity. As both elderliness and the aforementioned chronic conditions are often associated with an altered gut microbiota, resulting in disrupted gut barrier integrity, and gut symptoms have consistently been associated with more severe illness in COVID-19 patients, it is possible that dysfunction of the gut as a whole influences COVID-19 severity. This article summarizes the accumulating evidence that supports the hypothesis that an altered gut microbiota and its associated leaky gut may contribute to the onset of gastrointestinal symptoms and occasionally to additional multiorgan complications that may lead to severe illness by allowing leakage of the causative coronavirus into the circulatory system.

Full text

Do an Altered Gut Microbiota and an Associated Leaky Gut
Affect COVID-19 Severity?
Heenam Stanley Kim
a
a
Division of Biosystems & Biomedical Sciences, College of Health Sciences, Korea University, Seoul, Republic of Korea
ABSTRACT Coronavirus disease 2019 (COVID-19), which has been declared a pan-
demic, has exhibited a wide range of severity worldwide. Although this global varia-
tion is largely affected by socio-medical situations in each country, there is also high
individual-level variation attributable to elderliness and certain underlying medical
conditions, including high blood pressure, diabetes, and obesity. As both elderliness
and the aforementioned chronic conditions are often associated with an altered gut
microbiota, resulting in disrupted gut barrier integrity, and gut symptoms have con-
sistently been associated with more severe illness in COVID-19 patients, it is possible
that dysfunction of the gut as a whole influences COVID-19 severity. This article sum-
marizes the accumulating evidence that supports the hypothesis that an altered gut
microbiota and its associated leaky gut may contribute to the onset of gastrointesti-
nal symptoms and occasionally to additional multiorgan complications that may lead
to severe illness by allowing leakage of the causative coronavirus into the circulatory
system.
KEYWORDS COVID-19, SARS-CoV-2, coronavirus, gut microbiota, gut barrier integrity,
leaky gut
KEY MESSAGES
While the following remains to be empirically demonstrated, accumulating
evidence supports the hypothesis that an altered gut microbiota and an
associated leaky gut may contribute to the onset of coronavirus disease 2019
(COVID-19)-related gastrointestinal symptoms, such as diarrhea and, in severe
cases, multiorgan complications.
Testing for a leaky gut and fecal and plasma viral loads may be useful for
diagnosing the seriously ill or for preventing transmission by fecal shedding of the
virus.
Fecal microbiota transplantation (FMT), next-generation probiotics focusing on
butyrate-producing gut microbes, or simply increasing the daily intake of dietary
fiber may be considered in improving the gut health of COVID-19 patients.
CORONAVIRUS AND THE CORONAVIRUS DISEASE (COVID-19) PANDEMIC
Coronaviruses are enveloped, positive-sense, single-stranded RNA viruses with a ge-
nome size of ;30 kb (1, 2). They are classified into four genera,
a
,
b
,
g
, and
d
, based on
their genomes, and
a
- and
b
-coronaviruses infect mammals (1). In humans, mild upper
respiratory tract infections, such as the common cold, have been reported to be caused
by
a
-coronaviruses (3). However, in the last 2 decades, the world has witnessed three
serious outbreaks of more fatal coronavirus diseases in humans, including COVID-19,
which has become a pandemic of an unprecedented scale that is pushing health care
to its limits worldwide. As of December 2020, over 70 million cases have been reported
globally (https://coronavirus.jhu.edu/map.html). The first cases of COVID-19 were reported
Citation Kim HS. 2021. Do an altered gut
microbiota and an associated leaky gut affect
COVID-19 severity? mBio 12:e03022-20. https://
doi.org/10.1128/mBio.03022-20.
Editor Maria Gloria Dominguez Bello, Rutgers,
The State University of New Jersey
Copyright © 2021 Kim. This is an open-access
article distributed under the terms of the
Creative Commons Attribution 4.0
International license.
Address correspondence to
hstanleykim@korea.ac.kr.
Published 12 January 2021
January/February 2021 Volume 12 Issue 1 e03022-20 ®mbio.asm.org 1
PERSPECTIVE
Clinical Science and Epidemiology

in 2019 (2).Thisdiseaseiscausedbysevereacuterespiratorysyndromecoronavirus2
(SARS-CoV-2), which is related to the bat origin
b
-coronavirus strain SARS-CoV-1, the
causative agent of the SARS outbreak of 2002. The SARS outbreak lasted for 2 years
and affected 29 countries, resulting in 8,096 cases and 774 deaths (4; https://www.who
.int/publications/m/item/summary-of-probable-sars-cases-with-onset-of-illness-from-1
-november-2002-to-31-july-2003). Another zoonotic coronavirus strain, SARS-CoV, was
the causative agent of the Middle East respiratory syndrome (MERS) outbreak in 2012,
which had spread to 27 countries, with 858 known deaths since then (https://www.who
.int/health-topics/middle-east-respiratory-syndrome-coronavirus-mers#tab=tab_1). Because
SARS-CoV-2 is closely related to these strains, it is also likely to have originated from
bats (5). COVID-19 has affected the world more negatively than either SARS or MERS
because of its high contagiousness, which is estimated to be 2- to 3-fold higher than
that of influenza (6). The case-fatality rates of COVID-19 vary widely in different coun-
tries, ranging from 1% to 15%; however, the rate typically lies between 2% and 4%
(https://ourworldindata.org/coronavirus).
COVID-19 PATHOGENESIS
SARS-CoV-2 infects primarily the respiratory system and may cause various symp-
toms, ranging from mild illness to significant hypoxia due to acute respiratory distress
syndrome (7). Common COVID-19 symptoms include fever, cough, myalgia, fatigue,
and pneumonia (2, 7). Diarrhea, nausea, and vomiting have also been reported, indicat-
ing that the gastrointestinal (GI) tract is also a site of infection (8–12). A substantial pro-
portion of patients appear to have detectable GI symptoms, though this proportion
varies depending on the different patient groups studied (9, 13). A recent modeling
study using large data sets of reported cases suggested that SARS-CoV-2-infected
patients first develop a fever and then respiratory symptoms, followed by GI tract
symptoms, if they ever occur (14).
The virus uses its spike (S) protein to interact with angiotensin-converting enzyme 2
(ACE2), which is present on the surface of the epithelial cells lining the organs, includ-
ing the lungs and GI tract (10, 15–17). Once the virus binds to ACE2, the type 2 trans-
membrane serine protease present in the host cell promotes viral uptake by cleaving
ACE2 and activating the viral S protein, which mediates the entry of the virus into host
cells (16). Next, the viral RNA genome enters the nucleus for replication. Viral reproduc-
tion kills the host cell, ultimately damaging the surrounding tissues as the cell destruc-
tion spreads.
Epithelial cells, alveolar macrophages, and dendritic cells are the main components
of innate immunity in the airway (18). Dendritic cells residing underneath the epithelial
cells and alveolar macrophages are the first to respond to viruses. Additionally, cellular
damage in the lungs can lead to the release of the cytokines interleukin 8 (IL-8) and IL-
6 by epithelial cells (19). As IL-8 acts as a chemoattractant to recruit neutrophils and T
cells to the infection site, T cell responses are promptly initiated via antigen presenta-
tion by dendritic cells and macrophages. CD4
1
T cells activate B cells to produce virus-
specific antibodies, whereas CD8
1
T cells kill the cells infected by the virus (20). In
most cases, these local immune responses resolve viral infections. However, in some
cases, the immune system is overwhelmed by viral damage. Conversely, the immune
system may trigger a strong inflammatory cascade. Thus, in severe COVID-19 patients,
the infiltration of numerous immune cells has been observed in the lungs (21), apart
from the increased plasma concentrations of proinflammatory cytokines, including IL-
6, IL-1
b
, and tumor necrosis factor alpha (7, 22). This phenomenon of abnormal cyto-
kine overproduction is known as a “cytokine storm,”and it has been suggested as a
cause of massive inflammation and tissue damage in patients, often leading to a seri-
ous outcome (23). However, the existence of this phenomenon in COVID-19 is currently
controversial (24).
Apart from these direct effects, SARS-CoV-2 can indirectly damage the host by in-
hibiting the regular enzymatic function of ACE2 by binding to it. For example, altered
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ACE2 functionality in the lungs may contribute to the pathophysiological process of vi-
rus-induced acute lung injury (25). The expression of ACE2 in gut enterocytes is also an
important regulator of dietary amino acid homeostasis, innate immunity, gut microbial
ecology, and susceptibility to colitis; therefore, its inhibition can cause intestinal inflam-
mation (26).
While postmortem examination is invaluable in dissecting details of COVID-19 pathol-
ogy, little has been reported to date. However, it is now clear that diffuse alveolar damage
with capillary congestion and necrosis of pneumocytes, along with various additional fea-
tures, is the major manifestation in the lung (27). Intriguingly, data also showed that
COVID-19 causes extrapulmonary manifestations in various organs, including the GI tract,
liver, kidney, heart, spleen, brain, and bone marrow, with occasional traces of viral infection
(Fig. 1) (28–30). Moreover, in an autopsy series of 22 patients focusing on the bodily distri-
bution of SARS-CoV-2, the researchers were able to detect and quantify viral loads in multi-
ple organs, including the lungs, pharynx, heart, liver, brain, and kidneys in most dead
patients (31). The kidneys had the highest viral load among non-respiratory tract organs
examined, even in patients without a history of kidney disease (31). Although more exten-
sivestudiesareneeded,thesefindings suggest that extrapulmonary multiorgan dysfunc-
tion may be associated with severe illness in patients with COVID-19, and it is likely caused
by direct exposure to SARS-CoV-2. Consistently, a recent study showed that a high plasma
load of SARS-CoV-2 is associated with increased disease severity and risk of mortality (32).
ALTERED GUT MICROBIOTA MAY LEAD TO SEVERE COVID-19 SYMPTOMS
A substantial proportion of hospitalized patients with respiratory symptoms also
have GI symptoms, such as diarrhea, nausea, and vomiting (8–12, 33). Furthermore,
seriously affected patients tend to present SARS-CoV-2 in the GI tissues or have GI
symptoms, suggesting that the involvement of this virus in the GI tract increases dis-
ease severity (Fig. 1) (9, 13, 33). Nevertheless, the presence of SARS-CoV-2 in the GI
tract may not always lead to GI symptoms (Fig. 1). For instance, in a study conducted
in Singapore, 50% of the examined COVID-19 patients had a detectable level of virus in
their feces, but only half of them showed GI symptoms, such as diarrhea (34). In a study
of 12 young COVID-19 patients under 18 years of age (3 asymptomatic and 9 with mild
FIG 1 Lines of evidence supporting the hypothesis that a leaky gut affects COVID-19 severity and
further studies that are needed. Current evidence supporting the emerging idea (in the green box)
and evidence directly supporting the hypothesis (in the yellow box) are shown in the blue boxes
with reference numbers. The ideas that are needed to be established through further research to
support the emerging idea and the hypothesis are highlighted in matching green and yellow boxes,
respectively.
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symptoms), the virus was detected in patient feces at higher and longer-lasting levels
than in nasopharyngeal samples (35). In fact, although SARS-CoV-2 is capable of infect-
ing human gut enterocytes when tested on human small intestinal organoids (Fig. 1)
(36), it may differ in an actual healthy gut. This stems from the multiple defense sys-
tems that protect it, including a thick mucus layer (;700
m
m) (37), colonization resist-
ance conferred by the gut microbiome (38), an epithelial layer with tight junctions, and
numerous host factors, such as immunoglobulin A, proteases, and peptides with pro-
tective and antimicrobial functions (37, 39).
Because SARS-CoV-2 can be prevalent in the GI tract regardless of the presence of
symptoms, gut health at the time of infection may be critical for symptom develop-
ment. Elderly patients or those with certain underlying medical conditions, such as
high blood pressure, diabetes, and obesity, are highly vulnerable to the disease (Fig. 1
and 2) (40, 41; https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/
people-at-increased-risk.html). Both elderliness and chronic conditions may be associ-
ated with an altered gut microbiota that affects gut barrier integrity, such that patho-
gens and pathobionts gain more access to the surface of the enterocytes (Fig. 1 and 2)
(38, 39, 42–49). Even among younger individuals, who are typically less likely to de-
velop symptomatic COVID-19, patients with obesity or diabetes tend to manifest more
severe symptoms, suggesting that the presence of chronic conditions has a stronger
effect than younger age (Fig. 1) (50). As elderly people are generally patients with
chronic diseases, they can be highly vulnerable to COVID-19 (51).
In a recent study, Gu et al. showed a significant reduction in bacterial diversity in
gut microbiota samples collected from COVID-19 patients compared with those
obtained from healthy controls (Fig. 1) (52). Additionally, they observed an enrichment
of opportunistic pathogens and depletion in the abundance of beneficial bacteria,
including those belonging to the Ruminococcaceae and Lachnospiraceae families. Such
changes in the gut microbiota are generally considered typical signs of dysbiosis and
FIG 2 Model for COVID-19 pathogenesis leading to extrapulmonary complications. Localized infections by SARS-CoV-2
mostly begin in the respiratory system and then progress to the GI tract; they may later develop into a systemic disease,
resulting in multiorgan complications. Disrupted gut barrier integrity associated with elderliness or underlying chronic
conditions, such as hypertension, diabetes, and obesity, may be a crucial effector that allows the virus to gain access to ACE2
on the enterocytes and leak out of the GI tract to spread throughout the body. If SARS-CoV-2 penetrates the gut barrier, it
may cause inflammation due to overly reactive immune responses that thereby further increase its leakage from the gut.
Contrastingly, in a healthy GI tract with a higher number of T
reg
cells due to their activation by butyrate, such as in young
healthy children, the virus may be contained in the GI tract and excreted in feces without posing a considerable threat to
the other organs of the body.
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an unhealthy gut (44–46). Moreover, the researchers found that influenza A (H1N1)
infection reduced gut microbiome diversity in patients but resulted in an overall micro-
bial composition different from that in COVID-19 patients (52). In another study, Zuo et
al. reported significant gut microbiome alterations in COVID-19 patients (53), and they
found an inverse correlation between the abundance of the beneficial gut species
Faecalibacterium prausnitzii and disease severity (Fig. 1). Notably, they found the abun-
dance of a few Bacteroides spp., which downregulate the expression of ACE2 in the
murine gut, to be inversely correlated with SARS-CoV-2 load in patient fecal samples
(53). This finding emphasizes the importance of the interrelationship between the gut
microbiome, ACE2 expression, and viral infection. In another study that reported a
strong correlation between COVID-19 risk and an altered gut microbiota (54), Gou et
al. argued that unhealthy gut microbiomes may be the underlying reason for the pre-
disposition of normal individuals to severe COVID-19 (54).
Notably, these studies demonstrating a close link between gut microbiota dysbiosis
and COVID-19 severity have reported a common finding (52–54). Beneficial bacteria,
whose abundance was reduced in COVID-19 patients, were reported to belong to the
families Ruminococcaceae or Lachnospiraceae (52), a single species F. prausnitzii (53),
and the class Clostridia (54). The class Clostridia includes the family Ruminococcaceae,
which includes the species F. prausnitzii, which is one of the major butyric acid-produc-
ing bacteria in the gut (55). While the beneficial impact of F. prausnitzii on human
health is well established (56), a subspecies that causes a predisposition to atopic der-
matitis in infants and young children by competing with the beneficial members of the
species has been identified (57). The intricate microbial interactions and the physiology
involving this important butyrate-producing species warrant future investigations to
understand its influence on human health and disease (57, 58).
Butyric acid, produced by many beneficial gut bacteria belonging to Clostridia,isa
short-chain fatty acid (SCFA), which, along with propionic and acetic acids, is a fermen-
tation product of dietary fiber that plays a pivotal role in gut health (Fig. 2). It helps
maintain gut barrier integrity by serving as an important energy source for colono-
cytes, inhibiting the activation of NF-κB, activating the G protein-coupled receptor pair
of GPR41 and GPR43, inhibiting histone deacetylase activity, which causes anti-inflam-
matory activities, and promoting regulatory T cells (T
reg
) cells (59–64). T
reg
cells have a
central role in the suppression of inflammatory and allergic responses (Fig. 2) (59).
Depletion of certain butyric acid producers in the gut microbiota has been identified in
a few chronic diseases, including allergies, inflammatory diseases, colorectal cancer,
and Crohn’s disease (56, 57, 65).
DISRUPTED GUT BARRIER INTEGRITY MAY BE ATTRIBUTABLE TO EXTRAPULMONARY
COMPLICATIONS, INCLUDING HEART, LIVER, KIDNEY, AND BRAIN DYSFUNCTION
Along with having respiratory and GI symptoms, COVID-19 patients often manifest
other symptoms, such as headache and hepatic, pancreatic, and cardiac dysfunction
(66). This coincides with the fact that ACE2, the receptor for SARS-CoV-2, is expressed
not only in the lungs and the GI tract but also in various other organs, including the
liver, heart, kidneys, bladder, and brain (19, 25, 29). Since ACE2 regulates vital proc-
esses, such as normal cardiac function (e.g., blood pressure control), optimal beta-cell
function, and insulin sensitivity (25), if these organs are damaged or their essential
ACE2 functions are blocked by the virus, various complications may occur (67).
Histopathological evidence for viral infection and/or actual viral components has been
observed in various internal organs in biopsy samples from severely ill patients or from
autopsy specimens (28–31).
Thus, it is important to determine how SARS-CoV-2 reaches internal organs other
than the lungs or GI tract. Altered gut microbiotas, which may be associated with eld-
erliness and certain underlying medical conditions that predispose COVID-19 patients
to severe symptoms, often lead to disrupted gut barrier integrity (Fig. 1 and 2) (42–49).
While a link between patients with severe illness, gut symptoms (e.g., diarrhea), and a
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leaky gut still needs to be established (Fig. 1), it is highly likely to be the case because
patients with diarrhea present increased levels of systemic IL-6 and fecal calprotectin,
which are indicators of gut inflammation and disrupted gut integrity, such as a thinned
mucus layer and reduced tight junctions between enterocytes (Fig. 2) (68). Drastically
elevated plasma IL-6 concentrations have been associated with the presence of SARS-
CoV-2 RNA in the plasma of critically ill patients (32, 69). It is therefore plausible that
critically ill COVID-19 patients may have a disrupted gut barrier, also known as a “leaky
gut”(47–49, 70), which may allow SARS-CoV-2 to not only bind to ACE2 on the entero-
cytes but also exit the GI tract and enter the bloodstream, allowing it to access various
organs expressing ACE2 throughout the body (Fig. 2). If SARS-CoV-2 penetrates the gut
barrier, it may cause inflammation due to overly reactive immune responses, thereby
further increasing gut leakage (Fig. 2) (59). Contrastingly, in a healthy GI tract with a
high number of T
reg
cells that are activated by butyrate, such a proinflammatory
response may be blocked (59). However, a link between a leaky gut, plasma viral load,
and extrapulmonary multiorgan dysfunction remains to be established (Fig. 1).
CONCLUSIONS AND PERSPECTIVES
A strong pattern has emerged from patients with severe COVID-19, as many of
them are either elderly or have certain underlying medical conditions which may be
associated with an altered gut microbiota (38, 39, 42–49). Such dysbiosis of the gut
microbiota may be associated with disrupted gut barrier integrity, which may allow
SARS-CoV-2 to gain access to the otherwise well-protected enterocytes and to circulate
and infect internal organs expressing ACE2 (Fig. 2). If this is what is happening in the
serious cases of this illness that present extrapulmonary multiorgan dysfunction, test-
ing for a leaky gut and fecal and plasma viral loads will be of high value for a more
accurate prognosis, particularly for those likely to have altered gut microbiotas (Fig. 3).
FIG 3 Exploiting the gut microbiota for better COVID-19 disease prevention and management. Testing for leaky gut and
fecal and plasma viral loads may be used to improve diagnoses for seriously ill patients and for establishing a basis for
transmission precautions from some patients who may have prolonged fecal shedding of the virus even after viral
clearance in the respiratory tract. This presents the intriguing, but presently unsubstantiated, possibility that an inflamed
leaky gut, which may be associated with a higher risk of severe illness, may be improved or treated via a few
interventions. FMT, production of next-generation probiotics focusing on butyrate-producing gut microbes, or simply
increasing the daily intake of dietary fiber may be considered in improving the gut health of COVID-19 patients.
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Furthermore, fecal viral load data can also be useful for informing transmission precau-
tions, because some patients may have prolonged fecal shedding of the virus even af-
ter viral clearance in the respiratory tract (Fig. 3) (33, 35).
While developing treatments and vaccines for COVID-19 is of prime significance,
exploiting the gut microbiota to improve disease prevention and management may
also be important (Fig. 3). The first treatment to be considered for the seriously ill may
be fecal microbiota transplantation (FMT). This practice enables stool infusion from a
healthy individual to a patient with presumed gut microbial dysbiosis (71). FMT has
been remarkably successful in the treatment of Clostridioides difficile infection (CDI)
(72). Although FMT has shown only marginal success in treating other conditions, such
as inflammatory bowel disease and metabolic disorders, COVID-19 may not be the
same because, unlike these inflammatory disorders, it is an infectious disease as CDI,
which has a clear and simpler therapeutic target. However, in any case, safety issues
associated with carrying over undetected additional potential pathogens need to be
seriously considered before FMT can be explored in the context of COVID-19 (72). The
development of next-generation probiotics focusing on butyrate-producing gut
microbes can also be pursued (73). However, these novel microbial therapeutics still
need to overcome the hurdles of the regulatory framework (73). Lastly, simply increas-
ing the daily intake of dietary fiber may markedly help improve gut health (74), as fiber
is directly utilized by beneficial gut microbes to produce SCFAs, with butyrate being a
key substance (74). This dietary adaptation may be the most easy and effective method
that can be considered to be implemented immediately to prevent severe COVID-19 or
just for general health improvement.
ACKNOWLEDGMENTS
This work was supported by grants NRF-2018R1A2B2006456, 2018M3A9F3055923,
and 2015M3C9A4053393 from the National Research Foundation (NRF) of the Republic
of Korea.
I declare no competing interests.
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