International Journal of

Molecular Sciences

Review
Gut Microbiota Dysbiosis in COVID-19: Modulation and
Approaches for Prevention and Therapy
Virna Margarita Martín Giménez 1 , Javier Modrego 2,3 , Dulcenombre Gómez-Garre 2,3,4, * ,
Walter Manucha 5,6 and Natalia de las Heras 4, *

1 Instituto de Investigaciones en Ciencias Químicas, Facultad de Ciencias Químicas y Tecnológicas,

Universidad Católica de Cuyo, San Juan 5400, Argentina; vmartin@uccuyo.edu.ar
2 Laboratorio de Riesgo Cardiovascular y Microbiota, Hospital Clínico San Carlos-Instituto de Investigación
Sanitaria San Carlos (IdISSC), 28040 Madrid, Spain; javier.modrego@salud.madrid.org
3 Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud
Carlos III, 28029 Madrid, Spain
4 Departamento de Fisiología, Facultad de Medicina, Plaza Ramón y Cajal, s/n. Universidad Complutense,
28040 Madrid, Spain
5 Área de Farmacología, Departamento de Patología, Facultad de Ciencias Médicas,
Universidad Nacional de Cuyo, Mendoza 5500, Argentina; wmanucha@fcm.uncu.edu.ar
6 Instituto de Medicina y Biología Experimental de Cuyo (IMBECU), Consejo Nacional de Investigaciones
Científicas y Tecnológicas (CONICET), Mendoza 5500, Argentina
* Correspondence: mgomezgarre@salud.madrid.org (D.G.-G.); nlashera@ucm.es (N.d.l.H.)

Abstract: Inflammation and oxidative stress are critical underlying mechanisms associated with
COVID-19 that contribute to the complications and clinical deterioration of patients. Additionally,
COVID-19 has the potential to alter the composition of patients’ gut microbiota, characterized by a
decreased abundance of bacteria with probiotic effects. Interestingly, certain strains of these bacteria
produce metabolites that can target the S protein of other coronaviruses, thereby preventing their
transmission and harmful effects. At the same time, the presence of gut dysbiosis can exacerbate
inflammation and oxidative stress, creating a vicious cycle that perpetuates the disease. Furthermore,
it is widely recognized that the gut microbiota can metabolize various foods and drugs, producing
by-products that may have either beneficial or detrimental effects. In this regard, a decrease in
Citation: Martín Giménez, V.M.;
Modrego, J.; Gómez-Garre, D.;
short-chain fatty acid (SCFA), such as acetate, propionate, and butyrate, can influence the overall
Manucha, W.; de las Heras, N. Gut inflammatory and oxidative state, affecting the prevention, treatment, or worsening of COVID-19.
Microbiota Dysbiosis in COVID-19: This review aims to explore the current evidence regarding gut dysbiosis in patients with COVID-19,
Modulation and Approaches for its association with inflammation and oxidative stress, the molecular mechanisms involved, and the
Prevention and Therapy. Int. J. Mol. potential of gut microbiota modulation in preventing and treating SARS-CoV-2 infection. Given that
Sci. 2023, 24, 12249. https:// gut microbiota has demonstrated high adaptability, exploring ways and strategies to maintain good
doi.org/10.3390/ijms241512249 intestinal health, as well as an appropriate diversity and composition of the gut microbiome, becomes
Academic Editor: Rustam I. Aminov crucial in the battle against COVID-19.

Received: 11 July 2023

Keywords: gut microbiota; inflammation; immune system; COVID-19; SARS-CoV-2; probiotics
Revised: 28 July 2023
Accepted: 29 July 2023
Published: 31 July 2023

1. Introduction
COVID-19 (by the acronym of Coronavirus Disease of 2019) is a respiratory disease
Copyright: © 2023 by the authors. caused by a novel coronavirus (SARS-CoV-2, by the abbreviation of Severe Acute Respi-
Licensee MDPI, Basel, Switzerland. ratory Syndrome Coronavirus 2) that continues to affect millions of people worldwide.
This article is an open access article While most COVID-19 patients experience respiratory symptoms, up to 20% exhibit gas-
distributed under the terms and trointestinal symptoms, such as diarrhea [1], suggesting that the gastrointestinal tract is an
conditions of the Creative Commons additional site of SARS-CoV-2 infection apart from the lungs.
Attribution (CC BY) license (https:// SARS-CoV-2 enters host cells by using the angiotensin-converting enzyme 2 (ACE2)
creativecommons.org/licenses/by/ receptor, which is highly expressed in both the respiratory and gastrointestinal tracts.
4.0/).

Int. J. Mol. Sci. 2023, 24, 12249. https://doi.org/10.3390/ijms241512249 https://www.mdpi.com/journal/ijms

Int. J. Mol. Sci. 2023, 24, 12249 2 of 16

Consequently, ACE2 plays a significant role in regulating intestinal inflammation and the
microbial ecology of the gut.
Since the gastrointestinal tract serves as the largest immune organ in humans and
plays a critical role in defending against infections by pathogens, it is crucial to comprehend
the impact of SARS-CoV-2 infection on the host’s gut microbiota and its potential long-term
effects on human health.

2. General Concept of Gut Microbiota in a Healthy State and in Dysbiosis

The microbiota is a community of live microorganisms (bacteria, viruses, fungi, archaea
and protozoa) that inhabit humans and help us maintain homeostasis [2]. This mutually
beneficial relationship is so close that we are considered as a “holobiont”, a superorganism
made up of the host and the microorganisms that live in symbiosis with it [3]. The concept
of microbiome refers to the set of microorganisms, their genes, and derived metabolites in
an ecosystem. The human being has about 23,000 genes, while the microbiota contributes
a number 150 times greater. Human microbiota consists of the 10–100 trillion symbiotic
microbial cells harbored by each person, mainly bacteria [4,5]. Most of these are in the
gut, and more than 90% of the bacteria of our entire organism are found in the colon
only [6]. These data are important considering that most of the studies are carried out on
fecal samples, which mainly represent the distal intestinal (colonic) microbiota. Thus, fecal
specimens are naturally collected, may be sampled repeatedly, and constitute a less invasive
procedure than others, such as intestinal biopsy sample collection, luminal brushing, and
intestinal fluid aspirate, which are not suitable methods for healthy people [7,8]. However,
it is important to clarify that stool samples do not represent the totality of the microbiota
adhered to the intestinal epithelium and that the bacteria of the upper intestinal tracts are
not correctly detected [9].
The conformation of the microbiota in each subject is unique and is determined by
a multitude of factors, such as the way we are born, whether it is by vaginal delivery or
caesarean section [10], the type of diet [11], drug intake (mainly antibiotics) [12], and even
if one lives in an urban or rural environment [13].
The bacteria that predominate in the intestinal microbiota belong to the Bacteroidetes
and Firmicutes phyla [14], and in most individuals, the microbiota could be classified
into one of three enterotypes according to the dominant genera Bacteroides, Prevotella
or Ruminococcus [15], mainly by the effects of diet [16]. Gut microbiota has a profound
influence on human physiology and nutrition, and it has been demonstrated to be essential
for human life [17]. The more different types of bacteria in the gut and the more evenly
distributed they are, the greater the diversity. A diverse microbiome can perform many
more functions, making the whole system more stable. In fact, a diverse and balanced
intestinal microbiota ensures the correct functioning of the digestive tract, strengthens the
immune system, and improves metabolism [18,19].
Gut microbiota performs a wide variety of biochemical and physiological functions
that influence the host’s metabolism [20]. The microorganisms that compose it have various
enzymes that make it possible to transform mainly carbohydrates and other nutrients
and components of food that cannot be digested or absorbed in the intestine [21]. These
are fermented in the colon and the main carbohydrate-derived metabolites are the short-
chain fatty acids (SCFA) acetate, propionate, and butyrate [22]. These metabolites play
a very important role for human health, highlighting the reinforcement of the intestinal
barrier, the nutrition of the protective mucosa of the intestine, improving transit in the
large intestine, as well as the balance of blood glucose levels, among others [23]. However,
the westernized lifestyle, characterized by a diet with high content in proteins and fats,
less physical activity, greater consumption of drugs and greater stress, produces changes
in our microbiota that alter its functions [24]. These alterations are known as intestinal
dysbiosis and produce a general deterioration in health that manifests itself with symptoms
such as diarrhea/constipation, inflammation, fatigue, allergies and even behavior changes.
Intestinal dysbiosis has been shown to be behind diseases such as allergies, asthma, in-
 crease in plasmatic levels of lipopolysaccharides, favoring inflammatory p
sense, the intestinal microbiota could be related to metabolic and trophic f
tion of intestinal hormones and regulators of the immune system, in ad
Int. J. Mol. Sci. 2023, 24, 12249
involved in the regulation of fat deposits in adipose tissue [31]. 3 of 16
As we have previously mentioned, gut microbiota plays a key role in
strengthening the host’s immune system to fight against multiple infect
flammatory bowel diseases, cardiovascular and neurodegenerative diseases, or cancer,
those of others
among viral[25–29].
originObese[32]. Gutare
patients microbiota
an example of composition and its
gut microbiota dysbiosis, products
showing
impact on the
a decrease immune
in the system
Bacteroidetes andand
population inflammatory processes.
a proportional increase Thewhen
in Firmicutes gut micro
compared to gut microbiota of non-obese individuals [30]. Also, they present a lower
ablemicrobial
to induce anti-inflammatory responses, but also maintains the balan
biodiversity compared to normal weight individuals, and with an increase in
pro-inflammatory and anti-inflammatory
plasmatic levels of lipopolysaccharides, responses
favoring inflammatory to modulate
processes. In this sense,the im
the intestinal
against microbiota
pathogens. could be related
Therefore, thereto metabolic and trophic functions,
is a synergism between secretion of
the immune
intestinal hormones and regulators of the immune system, in addition to being involved in
gut the
microbiota,
regulation of fatwhich
deposits helps to prevent
in adipose tissue [31]. and adequately manage differen
may affectAs wethehavehost’s health.
previously Likewise,
mentioned, gut microbiota-derived
gut microbiota plays a key role in educating metabolites
and
strengthening the host’s immune system to fight against multiple infections, especially
collaborate with
those of viral originthe
[32].immunomodulatory
Gut microbiota compositionand anti-viral
and its products have actions of intest
a positive
through thetheinhibition
impact on immune system ofandviral replication
inflammatory andThe
processes. thegutimprovement
microbiota is not only of immu
able to induce anti-inflammatory responses, but also maintains the balance between the
the pro-inflammatory
increase in epithelial endurance and regulatory T cell production [33
and anti-inflammatory responses to modulate the immune response
thors have
against suggested
pathogens. the there
Therefore, existence of direct
is a synergism communication
between the immune systembetween and the gut
gut microbiota, which helps to prevent and adequately manage
lungs, known as the gut–lung axis, which allows the bidirectional transp different infections that
may affect the host’s health. Likewise, gut microbiota-derived metabolites are also able
toxins and metabolites
to collaborate synthesized and
with the immunomodulatory by gut andactions
anti-viral lungofmicrobiota through th
intestinal microbiota
circulatory
through thesystem
inhibition[35–37]. Therefore,
of viral replication and the gut microbiota
improvement disorders
of immune response would
by be
the increase in epithelial endurance and regulatory T cell production [33,34]. Several
worsening
authors haverespiratory
suggested the outcomes such
existence of direct as in a SARS-CoV-2
communication infection
between gut microbiota and [35–40
crobiota composition
lungs, known mayaxis,
as the gut–lung explain, at least
which allows in part, the
the bidirectional susceptibility,
transport of microbial inte
toxins and metabolites synthesized by gut and lung microbiota through the lymphatic
nosis of the infection by SARS-CoV-2 in human patients, which would ma
and circulatory system [35–37]. Therefore, gut microbiota disorders would be responsible
ota for
intervention an important
worsening respiratory outcomes strategy
such as in ato resolve or
SARS-CoV-2 mitigate
infection [35–40].this patholog
Thus,
gut microbiota composition may explain, at least in part, the susceptibility, intensity, and
prognosis of the infection by SARS-CoV-2 in human patients, which would make gut
3. Effects ofintervention
microbiota Gut Microbiota on
an important the Development
strategy and
to resolve or mitigate this Prognosis
pathology. of COV
3. Some clinical
Effects of studies
Gut Microbiota have
on the shown and
Development thatPrognosis
the gut microbiota
of COVID-19 in COVI
significantly different
Some clinical studies from thatthat
have shown of the
healthy controls
gut microbiota [41]. The
in COVID-19 level
patients is of gu
significantly different from that of healthy controls [41]. The level
been reported to be directly proportional to the severity of COVID-19 and of gut dysbiosis has been
reported to be directly proportional to the severity of COVID-19 and the concentrations of
tions of pro-inflammatory
pro-inflammatory andmarkers
and pro-oxidative pro-oxidative
in the plasmamarkers in the
[38–40] (Figure 1). plasma [38–4

Figure 1. SARS-CoV-2 severity is associated with increased gut dysbiosis, a pro-inflammatory and
Figure 1. SARS-CoV-2 severity is associated with increased gut dysbiosis, a pro-i
pro-oxidant state, and an activated immune response. Created with BioRender.com.
pro-oxidant state, and an activated immune response. Created with BioRender.co

COVID-19 patients exhibit a decreased abundance of certain benefici

as Bifidobacterium and Lactobacillus, and an increase in potential pathogen
as Streptococcus and Clostridium [42,43]. On the other hand, Faecalibacterium
Int. J. Mol. Sci. 2023, 24, 12249 4 of 16

COVID-19 patients exhibit a decreased abundance of certain beneficial bacteria, such

as Bifidobacterium and Lactobacillus, and an increase in potential pathogenic bacteria, such
as Streptococcus and Clostridium [42,43]. On the other hand, Faecalibacterium prausnitzii,
the main butyrate-producing bacteria, has been found to have a negative correlation with
symptoms such as chest tightness after physical activity and cough [44]. Another study
revealed a higher abundance of Ruminococcus gnavus, a bacterium associated with intestinal
inflammation, as well as lower levels of Faecalibacterium prausnitzii in the gut microbiota
of COVID-19 patients [42]. A recent systematic review identified the main alterations in
the gut microbiota of COVID-19 patients, including a higher abundance of Bacteroides,
Clostridium, Rothia, and Streptococcus, and a lower presence of Bifidobacterium, Ruminococcus,
Alistipes, Blautia, Eubacterium, Faecalibacterium, and Roseburia compared to non-infected
subjects [41]. Some of these alterations have been associated with COVID-19 severity and
poor prognosis [41].
It is important to note that, following the resolution of the acute phase, some patients
may gradually restore their gut microbiota composition to its pre-infection state. However,
for others, their gut microbiota may undergo long-term changes, transitioning to a less
healthy profile [45]. It has been reported that microbiota dysbiosis was not restored to
normal levels even 6 months after SARS-CoV-2 infection [46]. Moreover, several studies
have indicated that gut dysbiosis observed after the resolution of the infection could be
involved in the persistence of some symptoms in fully recovered patients, a phenomenon
known as “long COVID-19” [47–49]. In this sense, Zhou et al. [44] discovered that patients
with persistent COVID-19 have reduced bacterial diversity three months after discharge,
and the bacterium Intestinibacter bartlettii showed a positive correlation with persistent
symptoms like fatigue, myalgia, and anorexia. Additionally, the authors observed that
persistent respiratory and neuropsychiatric symptoms were correlated with opportunistic
intestinal pathogens, while patients without persistent COVID-19 had a richer presence
of butyrate-producing bacteria, including Bifidobacterium pseudocatenulatum and Faecalibac-
terium prausnitzii. Therefore, it is advisable not to leave the restoration of the gut microbiota
to chance.
Although the global population has been severely affected by COVID-19, it has been
identified that elderly patients or those with diabetes, hypertension, asthma, or cancer
have worse clinical outcomes than the general population (Figure 2). In this sense, it
is well-known that elderly patients or those with diabetes, hypertension, asthma, and
cancer are associated with less gut microbiota diversity, which would be directly related
to the higher morbidity and mortality observed in these risk groups compared to non-
risk groups [32,50,51]. Smokers are also considered a risk population for bad prognosis
of COVID-19 since cigarette smoking may alter gut microbiota abundance and composi-
tion [52]. Similarly, it has also been proposed that some geographic regions with high levels
of air pollution (because of multiple polluting human activities), showed one of the highest
morbidity and mortality rates of COVID-19 during the pandemic, at least in part, since
air pollution constitutes an environmental factor which also may significantly contribute
to gut dysbiosis [53]. That is, individuals with high susceptibility to acquire the infection
by SARS-CoV-2 and to have a bad prognosis tend to have gut dysbiosis, which leads to a
pro-inflammatory and pro-oxidative general state that debilitates the immune function of
infected individuals [54] (Figure 2).
Oral antibiotics can have acute or long-term effects as they eliminate antiproteolytic
bacteria and increase proteolytic activities in the colon, impairing the gut barrier and
causing intestinal inflammation [55,56]. In some cases, the use of antibiotics to prevent
complications during COVID-19 has been detected, which may lead to the exacerbation of
gut dysbiosis and have a negative impact on the course of the viral infection [57,58].
x FOR PEER REVIEW 5 of 17

Int. J. Mol. Sci. 2023, 24, 12249 5 of 16

Figure 2. Characteristics of gut dysbiosis in high-risk COVID-19 patients and main symptoms
associated with SARS-CoV-2 infection. Created with BioRender.com.
Figure 2. Characteristics of gut dysbiosis in high-risk COVID-19 patients and main symptoms asso-
4. Effects
ciated with SARS-CoV-2 of COVID-19
infection. Createdonwith
Microbiota Alterations
BioRender.com.
The way SARS-CoV-2 can affect the gut microbiome independently of hospitalization
and treatment has been investigated with K18-hACE2 mice (K18-ACE2tg mice) that overex-
Oral antibiotics can have acute or long-term effects as they eliminate antiproteolytic
press ACE2 [59]. These mice are characterized by the development of severe respiratory
bacteria and increase proteolytic
disease in a virusactivities
dose-dependentin themanner,
colon,resembling
impairing the
that gutoccurs
which barrier and caus-
in COVID-19
patients. The
ing intestinal inflammation investigators
[55,56]. In some have cases,
demonstrated
the use thatofSARS-CoV-2
antibiotics infection inducescom-
to prevent gut
microbiota dysbiosis in mice, which correlated with abnormalities on Paneth cells and
plications during COVID-19 has been detected, which may lead to the exacerbation of gut
Goblet cells, and with the increment of epithelial barrier permeability. The investigators
dysbiosis and haveobserved
a negative impact
a decrease onmicrobiota
in gut the course of the
diversity viral infection
of infected mice [59]. [57,58].
Several mechanisms could explain how COVID-19 can impact the gut microbiota.
Firstly, direct infection of colonocytes by the SARS-CoV-2 virus could lead to alterations
4. Effects of COVID-19 on Microbiota Alterations
in the intestinal barrier and bacterial composition through the stimulation of pathogen-
The way SARS-CoV-2
associatedcan affectpatterns
molecular the gut(PAMPs)
microbiome
receptors.independently of hospitalization
Invasion of SARS-CoV-2 can activate
various pattern recognition receptors, including Toll-like receptors (TLRs), RIG-I-like re-
and treatment has been investigated with K18-hACE2 mice (K18-ACE2tg mice) that over-
ceptors (RLRs), and NOD-like receptors (NLRs) which are recognized by innate immune
express ACE2 [59]. cells
These suchmice are characterized
as dendritic by the triggering
cells and macrophages, development of severe
the release respiratory
of pro-inflammatory
disease in a virus dose-dependent manner, resembling that which occurs in COVID-19
cytokines via the nuclear factor kB (NF-kB) and JAK/STAT signaling pathways [60]. This
underlying inflammatory state induced by the infection can have a negative impact on
patients. The investigators have demonstrated that SARS-CoV-2 infection induces gut mi-
the gut microbiota. As a result, an imbalanced gut microbiota may occur, characterized
crobiota dysbiosis inbymice, which
an increase in thecorrelated
abundance withof the abnormalities
Proteobacteria phylum on Paneth cells
(including andsuch
families Goblet
as
cells, and with the increment of epithelial
Enterobacteriaceae) and a decreasebarrier permeability.
in commensal Theasinvestigators
bacteria such Eubacterium andobserved
Roseburia
genera (Figure
a decrease in gut microbiota 3).
diversity of infected mice [59].
Furthermore, oxidative stress has been considered as another important factor affecting
Several mechanisms
COVID-19 could
[61]. In explain
COVID-19 how COVID-19
patients, can impact
8-isoprostaglandin the levels,
F2 alpha gut microbiota.
considered
Firstly, direct infection of colonocytes
as a marker of oxidative by thedamage,
tissue SARS-CoV-2 virus[62],
were elevated could
and inlead to alterations
a recent study [38],
COVID-19 patients showed significantly higher values
in the intestinal barrier and bacterial composition through the stimulation of pathogen- of hydrogen peroxide (H 2 O2 ) and
NADPH oxidase 2 (NOX2) activity in serum, as well as TNF-α and IL-6. These results
associated molecular werepatterns
accompanied (PAMPs) receptors.
by an increase Invasion
in the serum levels ofofzonulin,
SARS-CoV-2
an indirect can
marker activate
of the
various pattern recognition
permeability receptors, including
of the intestinal mucosa Toll-like
[63]. On thereceptors
contrary, the(TLRs), RIG-I-like
flow-mediated re-
dilation
measured in the brachial artery and the availability
ceptors (RLRs), and NOD-like receptors (NLRs) which are recognized by innate immuneof nitric oxide decreased significantly in
these patients, generating endothelial dysfunction [38]. As already described, SARS-CoV-2
cells such as dendritic cellsonand
depends macrophages,
the ACE2 triggering
receptor protein theintestinal
to enter the releasecellsof pro-inflammatory
of the host [64], and
cytokines via the nuclear factor kB (NF-kB) and JAK/STAT signaling pathways [60]. This
underlying inflammatory state induced by the infection can have a negative impact on the
gut microbiota. As a result, an imbalanced gut microbiota may occur, characterized by an
increase in the abundance of the Proteobacteria phylum (including families such as Enter-
 Int. J. Mol. Sci. 2023, 24, 12249 6 of 16

ACE2 has, among others, the function of degrading angiotensin II (AngII). Consequently,
Ang II levels increase significantly, and therefore the levels of superoxide anions and other
OR PEER REVIEW 6 of 17
reactive oxygen species also increase [65]. This will result in a high oxidative stress state in
patients, which will also affect intestinal cells exacerbating the progression of COVID-19 [66]
(Figure 3).

Figure 3. Possible mechanisms by which

Figure 3. Possible mechanismsSARS-CoV-2 infection
by which SARS-CoV-2 induces
infection inducesdysbiosis
dysbiosis ofof thethe
gut gut micro-
micro-
biota are as follows: (1) activation of Toll-like receptors (TLRs) triggers
biota are as follows: (1) activation of Toll-like receptors (TLRs) triggers the release of pro-inflamma-the release of pro-inflammatory

tory cytokines throughcytokines

the nuclearthrough the nuclear factor κB (NF-κB) signaling pathways; (2) the virus destroys tight
factor κB (NF-κB) signaling pathways; (2) the virus destroys tight
junction proteins, leading to the disruption of the intestinal physical barrier and increased perme-
junction proteins, leading to(3)the
ability; disruptionofofangiotensin-converting
down-regulation the intestinal physical enzyme 2barrier
(ACE2) and and increased
B0AT1 expressionpermea-
in
bility; (3) down-regulation ofepithelial
intestinal angiotensin-converting
cells decreases the production enzyme 2 (ACE2)peptides
of antimicrobial and B0AT1 expression in
(AMPs), facilitating
thedecreases
intestinal epithelial cells growth of pathogens; (4) mitochondrial
the production dysfunction and peptides
of antimicrobial high oxidative stress induced
(AMPs), by the
facilitating the
virus infection occurs. This infection-induced underlying inflammatory and oxidative state induces
growth of pathogens; (4) mitochondrial dysfunction and high oxidative stress induced by the virus
microbiota dysbiosis characterized by a decrease in the abundance of commensal bacteria such as the
infection occurs. This infection-induced underlyingand
genera Eubacterium and Faecalibacterium, inflammatory
an increase in the and oxidative
abundance state
of the genus induces mi-
Enterococcus
crobiota dysbiosis characterized
and proteolyticby a decrease
bacteria. in theor abundance
These bacteria of commensal
the lipopolysaccharides bacteria
(LPS) that they contain,such
mightas the
translocate into the circulatory system and be recognized by innate
genera Eubacterium and Faecalibacterium, and an increase in the abundance of the genus Enterococcus cells, resulting in increased pro-
inflammatory responses and endothelial dysfunction. This creates a vicious circle that exacerbates
and proteolytic bacteria. These bacteria or the lipopolysaccharides (LPS) that they contain, might
the progression of COVID-19. Ang-II: angiotensin II; BoAT1: sodium-dependent neutral amino acid
translocate into the circulatory
transporter; system and be
Glu: Glutamine; IL-6:recognized by lipopolysaccharides;
interleukin 6; LPS: innate cells, resulting in increased
mTOR: mechanistic target pro-
inflammatory responses and endothelial
of rapamycin; dysfunction.
NO: nitric oxide; SCFAs: short-chainThisfatty
creates a vicious
acids; TNF-α: tumoral circle
necrosisthat exacerbates
factor alpha;
Try: tryptophan. Created with BioRender.com.
the progression of COVID-19. Ang-II: angiotensin II; BoAT1: sodium-dependent neutral amino acid
transporter; Glu: Glutamine; IL-6: interleukin 6; LPS: lipopolysaccharides; mTOR: mechanistic tar-
get of rapamycin; NO: nitric oxide; SCFAs: short-chain fatty acids; TNF-α: tumoral necrosis factor
alpha; Try: tryptophan. Created with BioRender.com.
Int. J. Mol. Sci. 2023, 24, 12249 7 of 16

In addition, the way SARS-CoV-2 can impact the gut microbiota involves the disrup-
tion of the intestinal physical barrier by the virus, leading to impaired intestinal perme-
ability and the destruction of tight junction proteins like occludin, junctional adhesion
molecule-A (JAMA), and claudin-A. This disruption can facilitate the leakage of opportunis-
tic microorganisms into the bloodstream, resulting in systemic inflammation [67]. Another
potential mechanism involves the role of the neutral amino acid transporter B0AT1 in regu-
lating the intestinal amino acid metabolism. ACE2 also acts as a chaperone for B0AT1 in the
small intestine [68]. Glutamine and tryptophan are substrates for B0AT1 and promote the
formation of tight junctions via the mTOR signaling pathway. Therefore, during COVID-19
infection, the interaction between ACE2 and B0AT1 could lead to the down-regulation of
B0AT1 expression on the membranes of intestinal cells. This downregulation could reduce
the formation of antimicrobial peptides by Paneth cells and create a favorable environment
for the growth of opportunistic bacteria in the intestine, thus establishing a dynamic vicious
cycle [69] (Figure 3).
As we previously mentioned, the state of dysbiosis favored by SARS-CoV2 infection
decreases the abundance of butyrate-producing bacteria. Butyrate can inhibit histone
deacetylase activity, which therefore increases histone acetylation, chromatin opening
and influences on gene regulation. In this sense, the NF-κB signaling pathway has less
influence on the transcription of genes that encode for pro-inflammatory cytokines [45].
Thus, butyrate can differentiate naive T cells to Treg cells, which play a central role in
suppressing inflammatory responses through the inhibition of histone deacetylase. In fact,
this T-cell subset have the capacity to release a great variety of anti-inflammatory cytokines
and prevent tissue damage [70]. Consequently, a lower butyrate concentration is reflected
in lesser anti-inflammatory and immunoregulatory capacities at systemic level [71].

5. Underlying Mechanisms of the Gut Microbiota Effects on COVID-19 Onset

and Evolution
Many mechanisms may relate the gut microbiota dysbiosis to the development and
clinical outcomes of COVID-19. COVID-19 patients show a diminution of Lactobacillus
species that may produce lactic acid because of carbohydrate fermentation, and the in-
activation of viruses such as SARS-CoV-2 by pH changes. Interestingly, some strains of
L. casei, L. plantatum and L. fermentum produce bacterial metabolites that attack the spike
glycoprotein of other coronaviruses, preventing their transmission. In addition, bacteria
belonging to the phylum Firmicutes can synthesize high amounts of butyrate, which is the
main energy source of colonic epithelial cells responsible to produce antiviral compounds
that would prevent SARS-CoV-2 invasion and multiplication [54,72]. Moreover, gut micro-
biota improves antiviral immunity by increasing the amount and stimulating the function
of immune cells and interferon synthesis, among many other mechanisms [73]. During
viral infections, gut microbiota modulates the macrophage and neutrophil activity against
respiratory viruses, such as SARS-CoV-2, and can improve respiratory defenses through
the induction of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling,
thus promoting pathogen destruction and elimination by alveolar macrophages [74]. It has
also been determined that host cellular microRNAs modulated by human gut microbiota
may regulate viral replication and host gene expression implicated in the development and
progression of COVID-19 [34].
Likewise, another study showed that low levels of Collinsella would predict elevated
COVID-19 mortality rates [75]. One possible explanation of this phenomenon may be
the fact that Collinsella produces ursodeoxycholate. This bile acid is able to inhibit the
binding between SARS-CoV-2 and its receptor ACE2, as well as to reduce the levels of
pro-inflammatory cytokines (TNF-α, IL-2, IL-1β, IL-6 and IL-4), causing anti-inflammatory,
antioxidant and anti-apoptotic effects and reducing the alveolar fluid accumulation ob-
served during the acute respiratory distress syndrome associated with COVID-19 [75].
Regarding ACE2, the receptor for SARS-CoV-2 may have a dual function in COVID-19 dis-
ease: worsening infection by increasing SARS-CoV-2 cell entry or attenuating inflammation
Int. J. Mol. Sci. 2023, 24, x FOR PEER REVIEW

Int. J. Mol. Sci. 2023, 24, 12249 the small intestine. Thus, high or low COVID-19 infectivity could be influenced
8 of 16 a
pendent on gut microbiota composition [80–83].
and organ failure by balancing the ACE/ACE2 axis [76–79]. It has been reported that gut
6. Modulation of Gut Microbiota: Approaches in Prevention and Intervention in
microbiota can up- or down-regulate the ACE2 expression in colonic cells and enterocytes
COVID-19
of the small intestine. Thus, high or low COVID-19 infectivity could be influenced and
dependent on gut microbiota
Accumulating composition
evidence suggests[80–83].
that diet plays a crucial role in modulating
crobiota composition.
6. Modulation Nutritional
of Gut Microbiota: disorders,
Approaches characterized
in Prevention by excessive intake
and Intervention
quality foods, can lead to gut dysbiosis by promoting the growth of unhealthy micr
in COVID-19
This,Accumulating
in turn, induces chronic
evidence inflammation
suggests that diet playsthat contributes
a crucial to the immune
role in modulating gut impa
microbiota composition. Nutritional disorders, characterized by
and hyperinflammation observed during COVID-19 infection. Dietary fats havexcessive intake of low-
quality foods, can lead to gut dysbiosis by promoting the growth of unhealthy microbiota.
found to alter the gut microbiota by increasing the abundance of Gram-negative b
This, in turn, induces chronic inflammation that contributes to the immune impairment and
in the gut and intestinal
hyperinflammation observedpermeability.
during COVID-19 This can worsen
infection. the have
Dietary fats exaggerated
been foundinflamma
to
sponse
alter the seen in COVID-19
gut microbiota by facilitating
by increasing the abundancebacterial translocation
of Gram-negative andinthe
bacteria release of
the gut
and intestinal permeability.
flammatory endotoxins This can worsen the exaggerated
(lipopolysaccharides) inflammatory
into the systemic response seen [84–87]
circulation
in COVID-19 by facilitating bacterial translocation and the release of pro-inflammatory
In COVID-19 patients, high concentrations of the SARS-CoV-2 virus are of
endotoxins (lipopolysaccharides) into the systemic circulation [84–87].
served in the gut.
In COVID-19 The increased
patients, intestinal
high concentrations permeability
of the mentioned
SARS-CoV-2 virus are often earlier
observedmay con
to
in the leakage
the gut. of the virus
The increased intopermeability
intestinal the circulation, leading
mentioned to may
earlier systemic distribution
contribute to the and
tially
leakagecausing multiorgan
of the virus complications
into the circulation, leading to[88]. Therefore,
systemic controlling
distribution the amou
and potentially
causing multiorgan complications [88]. Therefore, controlling the amount,
quency, and quality of ingested foods in COVID-19 patients becomes crucial to p frequency, and
quality of ingested foods in COVID-19 patients becomes crucial to prevent nutritional
nutritional disorders and reduce the severity of the disease [89,90] (Figure 4).
disorders and reduce the severity of the disease [89,90] (Figure 4).

Figure 4. Possible nutritional and therapeutic interventions on gut microbiota and their beneficial
effects in4.COVID-19
Figure Possiblepatients. Created
nutritional andwith BioRender.com.
therapeutic interventions on gut microbiota and their b
effects in COVID-19 patients. Created with BioRender.com.

A study has even suggested that the consumption of a healthy homemade diet
the pandemic confinement may have enriched the beneficial gut microbiota in man
Int. J. Mol. Sci. 2023, 24, 12249 9 of 16

A study has even suggested that the consumption of a healthy homemade diet during
the pandemic confinement may have enriched the beneficial gut microbiota in many
individuals, resulting in a better prognosis for COVID-19 [91]. One study conducted on
95 healthy adults showed that individuals who followed a balanced diet with a high daily
consumption of vegetables, fruits, and nuts had a significantly lower risk (approximately
86% lower) of developing COVID-19 compared to those with an imbalanced diet and
lower intake of these products. This difference in risk could be attributed to variations
in gut microbiota diversity and composition between the two groups [92]. Thus, the
prognosis of COVID-19 not only depends on gut microbiota composition but also on the
available substrates that influence the gut microbiota metabolism. In this context, a study
determined that high-glucose diets based on starch, galactose, and sucrose were strongly
associated with a poor disease prognosis, while low-glucose diets primarily composed of
whole grains were strongly correlated with a favorable COVID-19 prognosis [93]. Similarly,
traditional Chinese medicines, mainly based on plant extracts, may also be useful in the
treatment of COVID-19 due to their ability to positively modify the gut microbiota [94].
For example, Zhengganxifeng decoction is known to help prevent gut dysbiosis while
preserving intestinal barrier integrity and increasing the abundance of SCFA-producing
bacteria, which can be beneficial in the prevention and treatment of COVID-19 [95].
A direct correlation has been found between a high consumption of fermented foods
(e.g., cabbage) and a low COVID-19 death rate. One possible explanation is that these
foods contain significant amounts of sulforaphane precursors, which are important natural
activators of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), one of the most powerful
antioxidants in humans. Nrf2 can help counteract the pro-oxidative mechanisms induced
by the imbalance in the ACE/ACE2 axis during COVID-19. Furthermore, fermented
vegetables contain abundant Lactobacillus, which are also known to activate Nrf2 [96].
SCFAs produced through the fermentation of dietary fiber by gut microbiota have
been shown to have anti-inflammatory effects and promote tolerance and resistance to
viral pathogens [97]. In fact, butyrate administration has been proposed as supportive
therapy in COVID-19 treatment [98]. One study revealed that SCFAs derived from the gut
microbiota metabolism can reduce respiratory and intestinal viral loads by down-regulating
ACE2 and enhancing adaptive immunity through free fatty acid (FFA) receptors 3 (GPR41)
and 2 (GPR43) in male animals. SCFAs directly interact with these G protein-coupled
receptors (GPR41 and GPR43) [99]. Additionally, the same study proposed a novel role for
the gut microbiota in reducing hypercoagulation associated with COVID-19 by limiting
the proliferation of megakaryocytes and platelet turnover through the Sh2b3-Mpl axis.
Sh2b3 is an adaptor protein that regulates various signal transduction pathways, including
the thrombopoietin (TPO) pathway, and plays a crucial role in regulating the coagulation
response [99].
Another study demonstrated that treatment of human endothelial progenitor cells with
docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), two N-3 polyunsaturated
fatty acids derived from the diet, effectively inhibited the expression of IL-6 and impeded
the entry of SARS-CoV-2 into these cells. This mechanism was mediated by the gut
microbiota-derived metabolite trimethylamine-N-oxide (TMAO). The stimulation of TMAO
induced by DHA and EPA leads to the inactivation of the NF-κB signaling pathway, reduced
expression of ACE2 and transmembrane serine protease 2, as well as inactivation of the
MAPK/p38/JNK signaling pathways and down-regulation of microRNA (miR)-221. These
findings provide further evidence that gut microbiota and its metabolites may act as
regulatory mediators of cytokine production and cellular infection mechanisms by SARS-
CoV-2 [100].
It has been suggested that nutritional manipulation of the gut microbiota through
interventions such as the consumption of probiotics, prebiotics, or symbiotics, may reduce
inflammation and reinforce the immune response during COVID-19 infection, helping
prevent or attenuate the severity of this viral infection [54,72,101]. This has been supported
by clinical studies in which COVID-19 patients who consumed probiotics continuously
Int. J. Mol. Sci. 2023, 24, 12249 10 of 16

since their disease diagnosis had a shorter clinical course, milder symptoms, and fewer
digestive symptoms compared to those who did not consume probiotics [102,103]. Another
clinical study found that the administration to COVID-19 patients of a novel symbiotic
formula, composed of Bifidobacterium strains, xylooligosaccharide, resistant dextrin, and
galactooligosaccharides, during 4–5 weeks of treatment accelerated SARS-CoV-2 antibody
(IgG) formation, decreased nasopharyngeal viral load and pro-inflammatory markers (IL-6,
MCP-1, M-CSF, TNF-α, and IL-1RA), and restored the gut microbiota dysbiosis [104]. In
addition, some dietary microbes that can beneficially modulate the host’s gut microbiota
have shown potent antiviral actions against other types of coronaviruses, making them
potentially useful for the treatment of COVID-19 [105,106]. Probiotics have a strong impact
on the immune system by improving the production of type I interferons, natural killer
cells, T cells, antigen-presenting cells, and specific antibodies, which can act at the respi-
ratory level [107]. The effects of probiotics on gut microbiota composition may also have
therapeutic actions in COVID-19 by regulating different mechanisms involved in its patho-
genesis, including SARS-CoV-2 entry through ACE2 receptors, immune response activation
and immunomodulation mediated by NLR family pyrin domain-containing 3 (NLRP3),
immune cell recruitment responsible for associated pulmonary and cardiovascular damage,
and impairment of metabolic pathways related to COVID-19 prognosis [108].
On the other hand, fecal microbiota transplantation (FMT) from healthy to infected
patients has been proposed as a promissory therapy in the treatment of COVID-19, since
this procedure has shown the ability to induce a significant change in the gut microbiota
composition towards species of bacteria that are known to induce anti-inflammatory effects
(e.g., IL-10 production) in other viral infections [35–37]. Likewise, studies in COVID-19
patients have shown that FMT improved part of the gastrointestinal symptoms, blood
immunity markers (increasing memory B and double positive T cells), as well as gut micro-
biota composition with a significant increase in Bifidobacterium and Faecalibacterium [109].
However, more preclinical, and clinical studies would be necessary to establish a causal
relationship between FMT and the regulation of the intestinal microbiota in these patients
and understand the impact of altered gut microbiota on post-infection recovery.
Some studies have also suggested that the gut microbiota can improve the efficacy
of COVID-19 vaccines and reduce associated adverse effects. This is because the success
and safety of vaccination largely depend on the appropriate immune state of vaccinated
individuals, enabling them to develop proper immunity against SARS-CoV-2 and be pre-
pared for future reinfections [110–113]. In fact, it has been reported that the T cell response
induced by COVID-19 mRNA vaccines is inversely correlated with the expression of acti-
vation protein 1 (AP-1). Moreover, AP-1 is positively correlated with the gut microbiota’s
fucose/rhamnose degradation pathway [114]. Furthermore, it is known that the immune
response to COVID-19 vaccines tends to decrease with age due to gut dysbiosis, usually
associated with aging [115].
Interestingly, not only gut microbiota, through bacteria, may modulate host immunity
and affect the severity of SARS-CoV-2 infection, but also gut virome (viruses) and fungi
(mycobiome) could do it [116–119]. The human gut virome consists of numerous resident
viruses that may be crucial in immunoregulation and other related aspects, including the
pathophysiology of various diseases, including COVID-19 [119]. In this context, Lu et al.
discovered that the DNA of the crAss-like phages family was increased in COVID-19
patients compared to healthy controls. Furthermore, the viral family Tectiviridae and the
bacterial family Bacteroidaceae exhibited significant co-increases during the course of SARS-
CoV-2 infection, suggesting a linked evolution between the virome and bacteriome [117].
Similarly, it has also been observed that there are differences in the virome due to SARS-
CoV-2 infection, and this dissimilarity may contribute to the severity of the disease and
the recovery process [116]. Scientific evidence regarding mycobiome is more limited, but
some studies are emerging. In this regard, Reinold et al. have observed a reduced diversity,
richness, and uniformity and an increase in the relative abundance of the Ascomycota
phylum in severe/critical COVID-19 patients compared to non-severe cases. This study
Int. J. Mol. Sci. 2023, 24, 12249 11 of 16

shows that the dominant fungal species were variable between patients, even within patient
groups. However, in contrast to what has been described in the microbiota, where no major
phylum has been found, Ascomycota phylum was present with a relative abundance > 75%
in most severe/critical COVID-19 patients [118]. It has also been reported that hospitalized
COVID-19 patients exhibit an increased presence of fungal pathogens from the Candida and
Aspergillus genera (both Ascomycota phylum) compared to non-infected individuals. Since
some fungal genera found increased in SARS-CoV-2 patients can produce antimicrobial
metabolites that affect bacterial proliferation, the mycobiome could further induce gut
microbiota dysbiosis [118]. Unstable gut mycobiomes persisted in a subset of COVID-19
patients for up to 12 days after the clearance of SARS-CoV-2 from the nasopharynx [45].
Therefore, therapeutic strategies aimed at targeting the gut virome and mycobiome could
be beneficial in combating this viral disease. Further studies are necessary to determine
whether the proliferation of both viral and fungal microorganisms is a cause or a con-
sequence of SARS-CoV-2 infection itself and whether they are related to gut microbiota
dysbiosis.

7. Conclusions and Prospects

The COVID-19 pandemic has taught us numerous lessons, and perhaps one of the most
significant is the recognition of the crucial role the gut microbiota plays in its pathophysiol-
ogy and prognosis, which had been previously underestimated. It has also highlighted the
importance of maintaining good intestinal health to prevent the devastating consequences
of a disease that will be remembered by all of mankind. Advancing our understanding
of the close and bidirectional relationship between COVID-19 and the gut microbiota, as
well as its implications for nutritional and therapeutic management (with both natural and
synthetic drugs), holds great importance. Another essential aspect to be addressed should
be the further study of the intestinal virome and mycobiome and the recognition of their
key participation in the COVID-19 pandemic (beyond the assessment of harmful/beneficial
bacteria populations which are better studied), two novel and very interesting concepts that
have recently emerged within the complex system of the gut microbiota. This knowledge
will enable us to be better prepared for future pandemics, thereby avoiding the repetition
of past mistakes.

Author Contributions: V.M.M.G.: Introduce the effects of gut microbiota on development and prog-
nosis of COVID-19 and underlying mechanisms. Designed, conceptualized the work and literature
survey. J.M.: Introduce underlying mechanisms of the gut microbiota effects on COVID-19 onset and
evolution and modulation of gut microbiota composition. Data compilation, figure design and review
writing. D.G.-G.: Introduce underlying mechanisms of the gut microbiota effects on COVID-19
onset and evolution and modulation of gut microbiota composition. Designed, conceptualized the
work, figure design and editing. W.M.: Introduce the effects of gut microbiota on development and
prognosis of COVID-19 and underlying mechanisms. Designed, conceptualized the work, literature
survey and review writing. N.d.l.H.: Introduce the general concept of gut microbiota in a healthy
state and in dysbiosis and modulation of gut microbiota composition. Conceptualized the work,
literature survey, figure design and writing and proof. All authors contributed to the manuscript
writing and proof reading and reviewing. All authors have read and agreed to the published version
of the manuscript.
Funding: This work has been partially supported by grants from Instituto de Salud Carlos III (FIS
PI22/01608) and the European Regional Development’s funds (FEDER) awarded to N. de las Heras
and J. Modrego. J. Modrego is staff of Biomedical Research Networking Centre in Cardiovascular
Diseases (CIBERCV). W. Manucha has received grant funding PICTO Secuelas COVID-19 and PICT
2020 Seria A 4000 from Agencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico
y la Innovación (FONCyT).
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Int. J. Mol. Sci. 2023, 24, 12249 12 of 16

Acknowledgments: We thank Silvia Sánchez-González from Cardiovascular Risk and Microbiota Lab-
oratory (Hospital Clínico San Carlos-Instituto de Investigación Sanitaria San Carlos (IdISSC), 28040
Madrid, Spain) for her participation in the design and elaboration of the figures of the manuscript.
Conflicts of Interest: The authors declare no conflict of interest.

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