SARS-CoV-2 Infection and Gastrointestinal Involvement: The Tip of the Iceberg
The outbreak of the coronavirus disease of 2019 (COVID-19),
which evolved into a pandemic, is a life-threatening condition
that has now officially recorded one million confirmed deaths in
the United States as of May 2022 . In the last two years, a lot
of attention has been placed worldwide on the finding of effective
treatments. COVID-19 is the cause of an enveloped, non-segmented,
single-strand RNA virus known as severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) that attacks the body cells
to cause infection in the respiratory system . The SARS-CoV-2
spike protein binds to the cell’s angiotensin converting enzyme
2 (ACE2) receptors. ACE2 receptors are widespread in human
tissues, explaining the multiorgan dysfunction reported in patients
. ACE2 receptors are highly abundant in the gastrointestinal (GI)
tract and evidence of SARS-CoV-2 replication and inflammatory
response to the GI infection have been reported in COVID-19
patients . Additionally, COVID-19 vaccinated people develop
multisystemic symptoms that could be associated with the diversity
of the immune response to the viral protein . The pathogenesis
of SARS-CoV-2 infection is not totally understood. It is not clear
the role of the viral replication in the GI tract and the effects of
the immune response against the cells infected with SARS-CoV-2.
This article explores the current knowledge about the GI system
involvement in the COVID-19, the post-acute COVID-19 syndrome
(PACS) and the COVID 19 vaccine side effects that lead to diverse
gastrointestinal manifestation and disease severity outcomes.
The acute period or COVID-19, that lasts approximately four
weeks , is driven initially by replication of SARS-CoV-2 in the
cells, that seems to last longer in GI tract cells , and then by an
exaggerated immune/inflammatory response to the virus that
damages tissues [2,6], COVID-19 is a primary respiratory transmitted
illness that presents with fever, fatigue, cough, shortness of breath,
muscle or body aches, headache, sore throat, congestion or runny
nose, loss of taste or smell, nausea, vomiting and diarrhea . GI
manifestations are reported in 11.4-61.1% of individuals with
COVID-19(6), and are different across the literature reviewed in
frequency, presentation [8,9], onset time  and clinical outcome
. The majority of COVID-19-associated GI symptoms are mild and
self-limiting. Also, acute pancreatitis, acute appendicitis, intestinal
obstruction, bowel ischemia, abdominal compartment syndrome
are described with less frequency . The presence of viral
nucleocapsid protein has been verified in almost the entirety of the
GI lumen, such as gastric, duodenal and rectal glandular epithelial
cells, apart from the esophagus [2,5,6] and the high prevalence of
viral shedding in stool, particularly after viral RNA negativity in
respiratory specimens, have led to the idea of a possible viral fecaloral
transmission . Only interaction between SARS-CoV-2 and ACE2 receptors might be enough to disrupt the normal function
of ACE2 pathway and result in diarrhea and inflammation 
but the pathophysiology of the infection in the GI tract seems to
be more complex. One study reported that fecal calprotectin (FC)
and serum calprotectin (SC) might have the potency to assess
the prognosis in COVID-19 patients, but increased FC and SC did
not feature GI symptoms or even diarrhea in COVID-19(9). Also,
elevated FC suggested an inflammatory response in the gut, which
was significantly correlated with IL-6 . Furthermore, in the GI
tract the microbiota that colonizes it plays a variety of important
physiological roles in the body, through multiple recognized axes
(brain, lung, estrogen) [4,13], and is altered during SARS-CoV-2
infection. COVID-19 patients had significantly reduced bacterial
diversity, a significantly higher relative abundance of opportunistic
pathogens (Streptococcus, Rothia, Veillonella and Actinomyces),
and a lower relative abundance of anti-inflammatory symbionts
compared to non-infected [10,14]. The persistent dysbiosis
produces barrier dysfunction, translocation of bacterial products,
hyperinflammation and immune dysregulation . Ultimately,
prolonged and disorganized inflammation is also an important
cause of autoimmune response and has been described in other viral
infections and autoimmune disorders [13,15,16]. After the acute
period and during at least one year post infection, some individuals
develop long-term sequelae or post-acute COVID-19 syndrome
(PACS) . PACS also known as long-COVID is part of the postacute
infection syndromes group, characterized by an unexplained
failure to recover from an infectious disease . The majority
of manifestations in PACS are systemic, neurological, cardiorespiratory,
and gastrointestinal . The gastrointestinal-related
symptoms in these patients include loss of appetite, nausea, weight
loss, abdominal pain, heartburn, dysphagia, altered bowel motility
and irritable bowel syndrome . The syndrome may develop not
only in COVID-19 hospitalized patients and evidence indicates that
it can develop regardless of the severity of the original symptoms.
Common features are viral persistence, a continuous dysbiosis, and
aberrant immunological response with a persistent inflammation
that can lead to autoimmunity [4,15,16].
Despite the benefits of the SARS-CoV-2 vaccination in the
control of the pandemic, the immune response to the virus antigen
and autoimmunity have been linked to some rare serious adverse
events . Sides effects are usually less serious than developing
COVID-19 or complications associated with coronavirus infections,
mostly being mild to moderate and have lasted no longer than a
few days . Typically, pain at the injection site, fever, fatigue,
headache, muscle pain, chills, nauseous and diarrhea are the
most frequently reported [18,19]. It is not clear if the side effects
observed after vaccination are due to the produced antibodies
against the viral spike protein (more studied antibodies) or antiidiotype
antibodies that resemble the spike protein structure
. This same mechanism that could be involved in the off-target
vaccine effects could also explain the autoimmune response during
the acute period of the infection .
Currently the main therapeutic effort for COVID 19, such as
antiviral and vaccines, have their main effect early in the viral
infection, while immunosuppressive and anti-inflammatory
therapies focus on targeting later stages of COVID-19 have been
centered in the pulmonary manifestations . The GI tract plays a
significant role throughout the course of the disease; therefore, this
has recently prompted the exploration of several therapies directed
to the control in the GI tract of SARS CoV-2 infection, the immune
response and the microbial dysbiosis. . A recent trial explored
the possibility of oral-fecal transmission and oropharyngeal tissues
as reservoirs for SARS-CoV-2, by testing the effects of Niclosamide
treatment on fecal shedding of the virus, but the results were not
significant between the study groups . The effect of berberine,
that acts inhibiting key factors in cell signal transduction on
intestinal function in patients with severe SARS-CoV-2 infection,
was also explored in a clinical trial to target the inflammatory
response by balancing the intestinal microenvironment during
severe Covid-19 . Lastly, other studies, exploring the correlation
between intestinal microbiota and COVID-19, recommend including
probiotics and prebiotics in the patient’s therapy regimen, which
could reduce inflammation and improve disease conditions by
modulating the immune system, infected patients .
COVID-19 is the first disease event since the beginning of the
XX century to demand an urgent global healthcare response, that
disrupted everyday life on earth in 2019. Since this moment, a lot
of effort has been put into getting the knowledge to develop the
required tools to control the coronavirus pandemic worldwide, but
our knowledge of the disease is still limited because it is an evolving
situation that continues to challenge healthcare professionals and
societies. There is still controversy in most of the aspects related
to this viral infection in the GI tract that therefore requires further
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