Gastrointestinal Manifestations of COVID-19

Angiotensin-Converting Enzyme-2 Receptor Mechanism

SARS-CoV-2 has characteristic transmembrane trimeric proteins that enable the binding and fusion of the viral particle to the cellular membrane of the host cell. The virus enters the host cell by attaching to the angiotensin-converting enzyme-2 (ACE2) receptors, which have a high affinity for the spike (S) protein of the virus. These ACE2 receptors are expressed in pulmonary, esophageal, small intestinal, and colonic epithelial cells. GI manifestations of COVID-19 can be explained by the high expression of ACE2 receptors in the gut and extensive infection of the enterocytes. After cell entry, virus-specific RNA and proteins are generated in the host cytoplasm to generate new virions, which are then released into the GI tract. This explains the persistence of viral RNA in stool samples of infected patients.

Another mechanism by which COVID-19 can cause significant damage to the host is the cytokine storm, a hyperactivation of the immune system to evoke a substantial inflammatory response. T-helper cytokines, both Th1- and Th2-type responses, cause changes in contractility of inflamed intestinal smooth muscle. Th1-type cytokines downregulate L-type Ca ²⁺ channels and upregulate G protein signaling, which contributes to hypocontractility of inflamed intestinal smooth muscle. Conversely, Th2-type cytokines cause hypercontractilty by signal transducer and activator of transcription (STAT) 6 or mitogen-activated protein (MAP) kinase signaling pathways. A cytokine profile characterized by increased interleukin-2 (IL-2), IL-7, granulocyte-colony stimulating factor, interferon-gamma (IFN-γ) inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-α, and tumor necrosis factor-alpha (TNF-α) has been associated with COVID-19 disease severity. One study from Wuhan, China reported a significant association between elevated inflammatory markers and poor COVID-19 outcomes suggesting hyperinflammation as the main cause of decompensation. For example, mean ferritin serum/plasma levels in nonsurvivors were 1297.6 ng/mL versus 614.0 ng/mL in survivors ( P < .001) and mean IL-6 serum/plasma levels were 11.4 ng/mL in patients who did not survive versus 6.8 ng/mL in those who did ( P < .0001). IL-6 activation and secretion by infected cells causes hyperactivation of the innate immune system and increased vascular permeability as a result of activation of vascular endothelial growth factor (VEGF), which in turn causes shock and ARDS. Tocilizumab, a humanized monoclonal antibody binding the IL-6 receptor (IL-6R), can effectively block IL-6 signal transduction in patients with severe COVID-19. A meta-analysis of 2112 patients enrolled in the tocilizumab group and 6160 patients in the standard of care group found that tocilizumab use was associated with decreased all-cause mortality in patients with signs of hyperinflammation with C-reactive protein (CRP) levels of 100 mg/L or greater, but also with a longer hospital stay when CRP levels were less than 100 mg/L.

Impact of SARS-CoV-2 on Gut Microbiota

Increasing evidence of viral RNA detection in stool samples of infected patients underscores the importance of fecal-oral transmission of SARS-CoV-2. Multiple investigators have reported the presence of ribonucleotides of SARS-CoV-2 in the feces of up to 50% of infected patients. Furthermore, SARS-CoV-2 RNA has been found in specimens from the esophagus, stomach, duodenum, and rectum.

The gut microbiota plays an important role in the GI tract and is responsible for a variety of physiological processes, including protection against infections, regulation of the immune system, and metabolism. A balance in the diversity of gut flora is critical to performing these functions. Interestingly, studies have shown a significantly decreased bacterial diversity in gut flora, increased proportions of opportunistic infections, and a relative low abundance of beneficial symbionts in patients infected with COVID-19 compared with healthy controls. Some have suggested administration of probiotics or consideration of fecal microbiota transplantation (FMT) to improve the microbial dysbiosis in patients with COVID-19, but efficacy is unclear and these treatments have not been rigorously studied. ^,

Gut microbiota might also modulate pulmonary immunity through effects on lung microbiota. Gut dysbiosis has been associated with functional disability of alveolar macrophages to perform necessary function, including reduction in reactive oxygen species–mediated killing of bacteria. This association has been termed “gut-lung axis” and is reportedly bidirectional, where not only the microbial components such as endotoxins from the gut can change pulmonary immunity but lung infections also have a clinically significant impact on gut microbiota. To further prove this connection, studies have shown a link between gut dysbiosis and respiratory infections. Gut dysbiosis has been linked to increased risk for respiratory infections, but has also been shown to play a key role in the pathogenesis of sepsis, ARDS, and multiorgan failure in a culture-independent manner. ^, This association can be explained by the phenomenon of the leaky gut.

An intact intestinal barrier prevents bacterial translocation of gut flora and its metabolic components into the bloodstream and other organs. This protective barrier is dysregulated by unfavorable changes in the gut microbiota. Furthermore, gut dysbiosis also causes decreased production of bacteria-derived short-chain fatty acids such as butyric acid and acetic acid, which are vital in regulating the immune and inflammatory responses. This dysregulation facilitates the translocation of immunogenic bacterial components, including toxins and lipopolysaccharides, leading to uncontrolled immune activation and inflammation. Toll-like receptor 4 (TLR4) activation has been shown to play a pivotal role in this immune system activation. Dysregulated TLR4 activation is involved in acute systemic sepsis, in chronic inflammatory diseases, and in viral infections, such as influenza infection. Fig. 9.2 shows the proposed mechanism of how SARS-CoV-2 affects the lung and GI tract.