Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the virus responsible for coronavirus disease 2019 (COVID-19), has infected more than 625 million to date and caused more than 6.5 million deaths . Although COVID-19 is primarily a respiratory disease, it can also cause neurological and digestive symptoms.
A new Nutrients study explores the impact of COVID-19 on the gut, where researchers summarize current knowledge about the underlying mechanisms and potential therapeutic approaches.
Study: COVID-19 and intestinal injury. Image credit: crystal light / Shutterstock.com
Introduction
About one in 15 patients with COVID-19 report gastrointestinal (GI) symptoms such as diarrhea, nausea, and vomiting, while about 50% of these individuals experience abdominal pain. However, the actual distribution of these symptoms varies between countries, regions and even between individuals, suggesting an important role for both genetic and environmental factors.
COVID-19 tends to affect men more severely, with a higher risk of death compared to women. People aged 65 and over are also at higher risk of adverse outcomes and as a result have been prioritized for vaccination against COVID-19.
Children under the age of five are also more likely to get severe COVID-19. In addition, children can develop a rare complication called multisystem inflammatory syndrome in children (MIS-C), with a small percentage having a fatal outcome.
Gastrointestinal symptoms of COVID-19 occur regardless of age, as several previous studies have shown. The gastrointestinal wall consists of an epithelial layer of the mucosa, with a submucosal lamina propria. In this wall are patches of gut-associated lymphoid tissue (MALT/GALT).
Cytokines in COVID-19
SARS-CoV-2 induces inflammation and an antiviral response in the intestinal wall. The single-stranded ribonucleic acid (RNA) genome of SARS-CoV-2 is sensed by toll-like receptors (TLRs) on intestinal epithelial cells. These receptors activate the innate immune system and produce inflammatory cytokines, some of which include interferons (IFN) and tumor necrosis factor (TNF)-α.
IFNs act through their receptors to activate the JAK/STAT pathway, thereby causing IFN-stimulated gene (ISG) expression that prevents replication and infection of adjacent cells by SARS-CoV-2. Multiple mechanisms of antiviral activity of IFN have been reported, including cleavage of viral nucleotides by RNases, inhibition of viral translation by RNA-activated protein kinase (PKR), and inhibition of virion release.
In addition to these antireplicative actions, IFNs induce apoptosis of infected cells and activate innate and adaptive immune responses, including the recruitment of cytotoxic T cells to kill infected cells.
Multiple mechanisms of viral escape have been previously described, including inhibition of IFN production, blocking of IFN binding, or competition with IFN/IFN cofactors for receptor binding. This indicates the importance of IFNs in the fight against SARS-CoV-2 infection. Conversely, IFN hyperactivity can cause deleterious effects on the host.
TNF-α is another key antiviral cytokine for inducing cell apoptosis. Its dominance marks advanced COVID-19 in contrast to earlier stages with IFN.
In addition, TNF-α is released by CD4 cells and is associated with stronger antibody responses. Its capacity for apoptotic regulation is protective, but could be potentially harmful in its activation of inflammatory responses.
These inflammatory mediators promote the recruitment of immune cells that initiate an inflammatory response, leading to tissue damage and gastrointestinal symptoms.”
Cellular immunity in COVID-19
Both resident and newly recruited circulating phagocytes remove cellular debris, while infected cells undergo apoptosis, thereby intensifying the process. This is indicated by increases in fecal calprotectin due to its release from neutrophils.
Neutrophil extracellular traps (NETs) are also increased in severe COVID-19, along with double-stranded DNA, neutrophil elastase, and myeloperoxidase, all of which are signs of increased neutrophil activity.
Dendritic cells (DCs) also phagocytose viral particles and proteins. SARS-CoV-2 appears to reduce the number and function of DCs, as well as impair the production of antiviral type I IFN.
In addition, T and B cells are impaired, leading to reduced induction of an effective innate immune response. This occurs through depletion of CD4 T cells, which are promoters of B cell antibody production and antiviral cytokine release, as well as cytotoxic CD8 T cells.
Lymphopenia associated with COVID-19 is thought to be due to lysis of infected cells, disruption of their normal life cycle, or lymphoid atrophy. This condition could also be due to sequestration of white blood cells in large numbers in the intestine; however, there is still a lack of evidence to support this theory other than the association of intestinal symptoms such as diarrhea with severe COVID-19.
Intestinal dysbiosis
Another consistently observed change following SARS-CoV-2 infection of the gut is gut dysbiosis, which is characterized by alterations in the gut microbiome leading to corresponding disruptions in host homeostasis and inflammation .
Mechanisms of intestinal injury related to COVID-19
Innate immune activation following direct infection of intestinal epithelial cells, together with epithelial barrier damage and dysbiosis, results in the recruitment of neutrophils, macrophages and dendritic cells (DCs) to the intestinal wall in answer Short-chain fatty acids (SCFAs) such as acetate, propionate and butyrate have powerful anti-inflammatory and immunomodulatory effects. Its loss increases the risk of severe inflammation.
Apart from changes in the metabolite profile and inflammation induced by SARS-CoV-2 binding to intestinal angiotensin-converting enzyme 2 (ACE2) receptors, secondary effects on the gut microbiome cause dysbiosis.
Bacterial molecules such as lipopolysaccharides can trigger severe inflammatory changes and, together with increased cytokine levels, could disrupt the intestinal barrier. This could result in prolonged dysregulation of host physiology and immune responses.
Malnutrition is another result of COVID-19, perhaps due to long periods of intensive care unit (ICU) admission. This could be related to poor metabolism and absorption of nutrients in the gut, perhaps due to down-regulation of ACE2, which may potentiate other adverse outcomes such as dysbiosis and increased intestinal permeability .
The result is “a positive feedback loop for further translocation of gut microbes and potentiation of inflammation, culminating in systemic inflammation and cytokine storm.” This is known to be associated with severe COVID-19 and acute respiratory distress syndrome (ARDS).
Microbes translocated into the systemic circulation could perhaps trigger an overwhelming systemic inflammatory immune response. This may account for lymphopenia, inflammatory markers, and gut dysbiosis.
Severity of COVID-19 is associated with reduced richness of the gut microbiome. Several studies have shown that dysbiosis is linked to respiratory failure, even three months after recovering from severe COVID-19; however, a “good” microbial profile is associated with favorable outcomes. Interestingly, gut dysbiosis is also associated with gut symptoms in post-acute COVID-19 syndrome (PACS).
ACE2 in COVID-19
Many of the effects mentioned above can be explained by the presence of ACE2 receptors on intestinal cells throughout the gastrointestinal tract, especially the intestinal epithelium. After infection, SARS-CoV-2 down-regulates ACE2 expression as the receptor is removed after binding. This causes inflammation and damage to the intestinal epithelial barrier. The resulting disruption of the fluid barrier, with electrolyte dysregulation, could explain the diarrhea.
In addition, ACE2 is related to multiple intestinal functions, including blood circulation, motility, and inflammation. Some research suggests a potential tryptophan imbalance, which represents a potentially correctable cause and therapeutic approach.
COVID-19 could also affect gut function by hypoxemia of gut cells, as has been shown in other conditions such as type 2 diabetes and obstructive sleep apnea that are associated with intermittent gut hypoxia . Pneumonia can also cause intestinal symptoms through increased sympathetic activity.
Interestingly, patients with inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are at low risk for COVID-19. This may be because many of them are on anti-TNF-α treatment, thus reducing the risk of massive dysregulated inflammation.
Treatment against covid-19
Drugs such as remdesivir, molnupiravir, nirmatrelvir (Paxlovid), baricitinib, and dexamethasone are approved or candidate drugs to mitigate the severity and improve survival of COVID-19. In addition, monoclonal antibodies have been used to block the binding of SARS-CoV-2 and prevent viral entry into host cells. The casirivimab-imdevimab or bamlanivimab-etesevimab cocktail is sometimes used in mild or moderate COVID-19 to prevent disease progression.
Probiotics containing Lactobacillus and Bifidobacterium could help protect the gut microbiome against T-cell infiltration, inflammation, and the resulting immune dysregulation. Intravenous administration of human ACE2 could help restore the physiological activity of this key receptor in the human host and is currently being evaluated in clinical trials.
A protective diet is also important to restore digestion and maintain mucosal integrity and immunity, including elements such as omega-3 fatty acids and docosahexaenoic acid (DHA) which have antiviral action, vitamin C, folate and iron, that strengthen the immune system.