key: cord-0828478-hvld2lgw
authors: Marasco, Giovanni; Lenti, Marco Vincenzo; Cremon, Cesare; Barbaro, Maria Raffaella; Stanghellini, Vincenzo; Di Sabatino, Antonio; Barbara, Giovanni
title: Implications of SARS‐CoV‐2 infection for neurogastroenterology
date: 2021-02-16
journal: Neurogastroenterol Motil
DOI: 10.1111/nmo.14104
sha: b45c6d5d5ba8d0eb57b6cda60a80d387a66bbe99
doc_id: 828478
cord_uid: hvld2lgw

BACKGROUND: Coronavirus disease 2019 (COVID‐19) is associated with gastrointestinal and hepatic manifestation in up to one fifth of patients. Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), the etiologic agent of COVID‐19, infects gastrointestinal epithelial cells expressing angiotensin‐converting enzyme 2 (ACE2) receptors triggering a cascade of events leading to mucosal and systemic inflammation. Symptomatic patients display changes in gut microbiota composition and function which may contribute to intestinal barrier dysfunction and immune activation. Evidence suggests that SARS‐CoV‐2 infection and related mucosal inflammation impact on the function of the enteric nervous system and the activation of sensory fibers conveying information to the central nervous system, which, may at least in part, contribute symptom generation such as vomiting and diarrhea described in COVID‐19. Liver and pancreas dysfunctions have also been described as non‐respiratory complications of COVID‐19 and add further emphasis to the common view of SARS‐CoV‐2 infection as a systemic disease with multiorgan involvement. PURPOSE: The aim of this review was to highlight the current knowledge on the pathophysiology of gastrointestinal SARS‐CoV‐2 infection, including the crosstalk with the gut microbiota, the fecal‐oral route of virus transmission, and the potential interaction of the virus with the enteric nervous system. We also review the current available data on gastrointestinal and liver manifestations, management, and outcomes of patients with COVID‐19.

organ failure. 3 Like many other coronaviruses, SARS-CoV-2 infects the gastrointestinal tract. 4, 5 Accordingly, in COVID-19 patients, beside respiratory manifestations, some patients complain of symptoms originating from the gastrointestinal tract, including nausea, vomiting, abdominal pain, and diarrhea. 1 Although the preferential route of infection of SARS-CoV-2 is through exhaled droplets, increasing evidence suggests that SARS-CoV-2 may be also transmitted by a fecal-oral route. Taken together, this evidence provides a rational basis for interpreting the common occurrence of gastrointestinal symptoms reported by COVID-19 infected patients. 6, 7 We aimed at summarizing the current evidence on the pathophysiology of gastrointestinal SARS-CoV-2 infection, fecal-oral route of virus transmission, the involvement of the enteric nervous system, clinical manifestations, treatments, and outcomes of patients with COVID-19.

SARS-CoV-2 is a novel single-stranded β-coronavirus, the seventh coronavirus so far described infecting humans, with a genome similarity up to 80% to other highly infective coronaviruses like those of the acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). 8 SARS-CoV-2 interacts with the host through its envelope spike glycoprotein 9 which binds the ACE2 receptor of the host ( Figure 1A ). The spike glycoprotein is composed of two subunits, namely S1 and S2, which favor, respectively, the binding of the virus to the cells and the fusion between the two cellular membranes. 10 This process is independent from the activity of the ACE enzyme since SARS-CoV-2 shows a high binding affinity to ACE2 receptors, reported to be comparable to that of SARS-CoV. 11, 12 After viral binding to ACE2 receptors, the transmembrane protease serine (TMPRSS)2 mediates the cleavage of spike glycoprotein, regulating the virus internalization into the host cell. 7 After internalization, the virus starts its replication using the cellular replication processes, which ends with new viral assemblies, viral secretion, and release of cytokine which contribute to symptom generation. 13 ACE2 receptors have been reported to be highly expressed in several organs of the human body beyond the lungs, such as endothelial cells, renal tubular epithelium, testes, kidneys, brain, heart, and liver. 7 However, the highest expression of ACE2 in the human body occurs in the brush border of intestinal enterocytes. 14, 15 ACE2 receptors and TMPRSS2 are abundantly expressed in gastric and intestinal epithelial cells and on the cilia of glandular epithelial cells, but not in esophageal squamous epithelial cells. 16, 17 In addition, it appeared that SARS-CoV-2 was not able to infect goblet cells across culture conditions. 18 In other seminal experiments, human or bat intestinal tissues 19 exposed to nasopharyngeal secretions obtained from COVID-19 patients were associated with rapid virus replication and a cytopathic response. Viral nucleocapsid proteins have been detected in the cytoplasm of gastric, duodenal, and rectal cells, but not in esophageal cells from a COVID-19-infected patient with SARS-CoV-2 fecal shedding. 16 The affinity of SARS-CoV-2 for the gastrointestinal tract is highlighted by the fact that between 10% and 20% of COVID-19 patients experience diarrhea as their first symptom before the onset of respiratory symptoms. 20 is an infection with a predominant airborne route of transmission through salivary droplets. 3 Nonetheless, the possibility that SARS-CoV-2 could be transmitted via a fecal-oral route was hypothesized early on after the description of the first cases of COVID-19 reported in visitors of the Seafood Market in Wuhan. 1 Accordingly, it was hypothesized that SARS-CoV-2 gained access via the gastrointestinal tract and subsequently infected the organism following the consumption of meat of illegally traded bats and pangolins. In enterocyte organoids infected with SARS-CoV-2, the virus was primarily secreted apically. 18 If the same occurs in vivo, the virus cloud be excreted in the lumen of the intestine and eliminated with the feces. In support of the fecal-oral route of transmission of SARS-CoV-2 and in line with the abovementioned gastrointestinal involvement in COVID-19, viral RNA was found in the stool of up to 50% of patients with 23 at

• SARS-CoV-2 is able to infect gastrointestinal tract and liver leading to cell damage and inflammation.

• Several data support the hypothesis of a fecal-oral route of SARS-CoV-2 transmission, but this still remains unproven.

• Dysbiosis described in COVID-19 patients may enhance inflammatory response and cytokine storm.

• Data suggest that the enteric nervous system may be affected either directly or indirectly by SARS-CoV-2 leading to gut dysfunction.

• Diarrhea and dysgeusia are the most reported gastrointestinal manifestations of COVID-19.

• No specific therapies have been investigated for gastrointestinal and hepato-biliopancreatic manifestations, which are self-limiting.

concentrations ranging from 10 3 to 10 5 copies/mL, up to 12 days from the initial assessment and even after nasopharyngeal swab became negative. 16 Several other reports described the detection of SARS-CoV-2 RNA in stool samples. 22 Taken together, this evidence suggests that a fecal-oral route of viral transmission is plausible; however, there are still some concerns. First, the detection of SARS-CoV-2 in the feces is based on RT-PCR techniques that may not be able to distinguish between viral fragments and a viable replicating virus. Indeed, while SARS-CoV-2 virus with infective potential was isolated from lungs or throat of COVID-19 patients, in the feces they were either not found 28 or isolated only in a small proportion of patients (35%). 25 Second, even if SARS-CoV-2 RNA has been detected in gastrointestinal specimens from most patients with digestive symptoms, this association was not statistically significant. 25

Growing evidence indicates that SARS-CoV2 infection is associated with neurological symptoms in a subgroup of patients with COVID-19 and that neurological involvement can aggravate the course of the disease. 29, 30 In both animal studies and in patients with neurological symptoms, coronaviruses show the ability to penetrate the cerebrospinal fluid 31 and damage the structure and function of the nervous system. 32 The mechanisms through which SARS-CoV2 enters the central nervous system remain unknown. 33 The most plausible route of invasion is through the blood-brain barrier. 31 Alternatively, it has been suggested that coronaviruses can migrate to the brain through sensory or motor nerve endings, achieving retrograde or anterograde neuronal transport through dynein and kinesin motor proteins. 34 Recently, Esposito et al 35 suggested that the enteric nervous system (ENS) could act as an entry route of SARS-CoV-2 to the brain and the virus would gain access to the brain via vagal and/or splanchnic nerves. A comparable mechanism of neurogenic transmission to the CNS was previously shown for herpes 36 and influenza viruses. 37 Previous reports showed that gastrointestinal inoculation of MERS-CoV in mice, another β-coronavirus sharing similarity with SARS-CoV-2, was associated with brain infection. 38 A recent histochemical study on small and large intestinal specimens and choroid plexus, and adjacent brain parenchyma obtained postmortem in COVID-19 patients, supports the anatomical plausibility for SARS-CoV-2 neuro-invasion through the ENS. 39 Indeed, ACE2 and TMPRSS2 were abundantly expressed in the perikarya of enteric neurons and glial cells, both in the myenteric and submucous plexus. Enteric neurons showed different levels of ACE2 staining intensity, suggesting a differential expression between neuronal subtypes ( Figure 2 ).

Intestinal mucosal biopsies obtained during endoscopy from one COVID-19 symptomatic patient revealed normal macroscopic findings, except for mild lymphocyte and plasma cell infiltration and interstitial edema. 16 If confirmed in larger series, this evidence would suggest that SARS-COV-2 infection is not associated with gross pathology detectable with routine diagnostic techniques F I G U R E 2 Panel 1: ACE2 expression in the human ENS of the large intestine. (A) Overview of the entire gut wall of a colon segment with immunofluorescence stainings for ACE2 (red), the glial marker S100b (green), and with the nuclear marker DAPI (blue). The white rectangles indicate the location of the high-power magnification micrographs below showing a representative submucous and myenteric ganglion. (B, C) Show representative submucous and myenteric ganglia stained for ACE2 (red), DAPI (blue), and the neuronal markers PGP9.5 (B, red) or HuC/D (C, red). The ACE2 staining can be found in neurons and glial cells and is considerably stronger in the colon compared to the small intestine. The overview is a standard epifluorescence image; details are maximum intensity projections of optical sections by structured illumination. Scale bars: overview 250 mm; details 50 mm. Panel 2: TMPRSS2 expression in the human ENS. (A) Overview of the entire gut wall of a colon segment with immunofluorescence stainings for TMPRSS2 (red), the neuronal marker HuC/D (green), and the nuclear marker DAPI (blue). (B, C) Show representative large intestinal myenteric ganglia stained for TMPRSS2 (red), DAPI (blue), and the neuronal markers HuC/D (B, red) or PGP9.5 (C, red). (D) Representative myenteric ganglion in the small intestine stained for TMPRSS2 (red), the glial marker S100b (green), and the nuclear marker DAPI (blue). Note that TMPRSS2 stainings were markedly stronger in enteric ganglia in the colon (A-C) than in the small intestine (D). The overview is a standard epifluorescence image; details are maximum intensity but may require more sophisticated assessment of tissue damage and dysfunction. A direct consequence of SARS-CoV-2 infection may be the reduction in the epithelial cell functional mass.

In line with this, epithelial cell damage has been shown in both bat and human enteroids which developed progressive cytopathic effect after SARS-CoV-2 inoculation. 19 In addition, Uzzan et al, 40 assessed plasma concentrations of the amino acid citrulline, a surrogate marker of enterocyte mass and function. 41 Compared to COVID-19 patients without gastrointestinal symptoms, those with symptoms (ie, nausea, vomiting, and loss of appetite) had lower plasma citrulline levels and low plasma citrulline was inversely correlated with inflammatory markers, including C-reactive protein and ferritin. 41 

Evidence is accumulating to support the biological plausibility for a direct or indirect involvement of the ENS in SARS-CoV-2 infection. Indeed, coronaviruses have a strong neuro-invasive potential as shown in previous studies after the outbreak of SARS-CoV-1.

These studies showed that viral particles could be detected in the brain, where they were located almost exclusively in neurons. 48 It has been suggested that SARS-CoV-2 infection of the central nervous system could occur via neuronal, pericellular, hematogenous, lymphatic, and Trojan routes (infecting migrating leukocytes). Studies in human brain organoids showed that SARS-CoV-2 infects neuronal cells within 2 days of exposure. In addition, SARS-CoV-2 exposure altered the distribution of tau from axons to soma, hyperphosphorylation, and apparent neuronal death. 49 Given the ability of SARS-CoV-2 to infect the gastrointestinal tract, the abundant neural network supplying the alimentary canal, and the fact that both ACE2 and TMPRSS2 are abundantly expressed in the enteric nerves (Figure 2 ), 39 the possibility of a ENS neuro-invasion, dysfunction, and damage should be of great concern.

In addition to a putative direct effect of the virus on enteric tion. 52 The activation of ENS reflexes and secretomotor responses may be viewed as a defense mechanism to expel the pathogen.

However, like in many other gastrointestinal infections, the price to be paid for this is represented by symptom development and eventually long-lasting derangements of gut sensory-motor functions in susceptible individuals. 53,54

In addition to the well-known activity of ACE2 in the reninangiotensin system (RAS), 55 this enzyme is also involved in the regulation of intestinal amino acid homeostasis and the expression of antimicrobial peptides which may contribute to the regulation of gut microbiota. The dietary amino acid tryptophan is able to modulate ACE2 function. 55 In laboratory animals, anorexia and malnutrition and reduction in tryptophan intake correlated to ACE2 dysfunction leading to altered expression of gut antimicrobial peptides, followed by gut dysbiosis and intestinal inflammation. 55 Accordingly, ACE2 knockout mice display increased susceptibility to intestinal inflammation induced by epithelial cell damage. 55 As ACE2 receptor downregulation has been reported in previous SARS coronavirus-induced lung injury, 56 ACE2 dysfunction has been postulated to participate to the development of COVID-19-related gastrointestinal symptom generation.

SARS-CoV-2 has been shown to be associated with an altered microbial community, 57,58 which in turn could participate in the COVID-19 systemic inflammatory response and cytokine storm. 24 Moreover, ACE2 downregulation by SARS-CoV-2 59 may produce itself changes in gut microbiota since this receptor normally acts as regulator of immunity. Previous data in patients with influenza showed changes in gut microbiota, which in turn reduced host immune response leading to greater lung damage. 60 Changes in gut microbiota composition and the potential benefit of microbiota modulation in COVID-19 have been recently investigated. 61 Actinomyces, and Erysipelatoclostridium, and all these genera, except the latter, were correlated with C-reactive protein and D-dimer levels suggesting a possible correlation between changes in fecal microbiota and systemic inflammation. 66 Although all these studies suffer from small sample size and lack of appropriate control groups, taken together, these results suggest the presence of an altered gut microbial community in patients with SARS-CoV-2 infection susceptibility and its association with gastrointestinal and systemic inflammation in COVID-19. Histologically, macro-vesicular steatosis, mild acute hepatitis, and minimal-to-mild portal inflammation were the most common findings. Viral PCR was detected in 11/20 (50%) patients, even if at very low levels in most cases, and its presence was not associated with ALT levels. Taking all these data together, viral-mediated injury seems to be the most plausible mechanism of liver damage.

Beside the respiratory and systemic manifestation of COVID-19, such as fever, dyspnea, cough, pneumonia, fatigue, headache, rhinorrhea, anosmia, and dysgeusia, symptoms involving the gastrointestinal tract have been also widely described ( Figure 3) 

Several case reports described a wide range of less frequent gastrointestinal manifestations. Among these, gastrointestinal bleeding has been described in several papers. [79] [80] [81] Little is known on the potential mechanisms involved. These may include inflammation- 

Theoretically, patients with inflammatory bowel disease (IBD) may be more susceptible to SARS-CoV-2 infection due to the chronic intestinal inflammatory state and the use of immunosuppressant agents. 88 Previous reports showed that compared to controls, patients with IBD showed a sustained higher ACE2 expression in the mucosa of the ileum and colon and higher soluble circulating levels of ACE2, independently of the presence of inflammation, 55,89 possibly related to higher expression of IFNγ which promotes ACE2 expression.

Moreover, trypsin-like proteases, which are responsible of S protein cleavage and SARS-CoV-2 internalization, have been reported to be upregulated in IBD patients. 90 However, to date there is no evidence supporting an increased susceptibility to SARS-CoV-2 infection due to ACE2 and TMPRSS2 upregulation. 88 

Celiac disease, an autoimmune gluten-related intestinal disease, is associated with increased risk of infections, including influenza 94 and pneumonia. 95 

Liver impairment in patients with COVID-19, defined by the alteration of blood liver enzymes, is a common finding, and it has been reported since the description of the first case series from

China. 98 Liver test abnormalities (ie, altered transaminases and/or bilirubin) were found to be common in most reports, ranging from 16% to 53% of the series. 1, 20, 74, 98, 99 In most cases, transaminases were more commonly increased in patients with severe COVID-19, especially those requiring admission to the intensive care unit. 1 Also, severe liver alteration was uncommon, and transaminase alterations were not necessarily associated with a worse outcome. 99 Later, a systematic review and meta-analysis reported all published data from Asian populations until April 4, including a total of 1948 individuals. 100 The pooled prevalence of liver injury was 12% 98 Later, more data regarding liver injury emerged (Table 1) . [101] [102] [103] [104] [105] [106] [107] [108] According to another retrospective series of 2273 patients who tested positive for SARS-CoV-2, transaminase alterations were common, but mild in most of the cases. 104 In a multivariable analysis, severe acute liver injury was significantly associated with increased blood inflammatory markers (ferritin and interleukin 6). Also, patients with severe liver injury showed higher rates of intensive care unit admission, acute kidney injury, and mortality.

Data regarding the outcome of COVID-19 in patients with a preexisting liver disease are still scant. In the largest studies from the United States focusing on this issue, 250/2780 patients (9%) with COVID-19 were affected by a liver disease, and liver cirrhosis was reported in 50 patients. 103 The most commonly reported liver diseases were fatty liver disease and non-alcoholic steatohepatitis.

After propensity matching, the risk of death was increased (risk ratio 3.0) compared to patients with no known liver disease, as well as the risk of hospitalization. Given the observational nature of the study, the possible causes of this finding were not further investigated.

The magnitude of the impact of COVID-19 in patients with a transplanted liver is yet to be clearly defined. According to a series from an Italian liver transplant center, three out of 111 transplanted patients died from severe COVID-19. All of them were elderly male and were transplanted more than 10 years before. On the contrary, three out of 40 patients who had been recently transplanted and were on immunosuppressants seem to have developed a milder disease. Hence, Bhoori et al. 109 suggested not to withdraw immunosuppressants in these patients. According to a report from the United States, 110 out of 38 transplanted patients with COVID-19, seven (18%) died after a median symptom onset time of 19 days.

In these patients, acute kidney injury was also noticed in more than half of the cases, and it might have represented the most important contributor of the unfavorable outcome. Upon admission, liver function tests were within the limit of normal in most cases. Unlike the study by Bhoori et al, 109 Lee et al 110 

Several reports identified the presence of acute acalculous cholecystitis in COVID-19 patients. [111] [112] [113] No definitive data are available for explaining cholecystitis origin, which may be bloodstream-related or due to SARS-CoV-2 direct infection on bile ducts through ACE2 receptor binding, which levels are higher even in this district. 114 However, a case report on a resected gallbladder after cholecystitis highlighted the presence of SARS-CoV-2 within the tissue, thus confirming viral presence. 113 Pancreatic involvement, defined as an increase in serum amylase and/or lipase or overt acute pancreatitis, has also been described in few reports or case series. [115] [116] [117] [118] In the largest retrospective case series, elevated serum lipase was found in 14/83 cases (16.8%), and this was correlated with higher rates of admission to the intensive care unit and need for intubation. 117 However, the number of cases described is rather small and most patients were severely obese.

Indeed, the lack of proper diagnostic imaging is another strong limit.

Finally, given the importance of the spleen-liver axis in maintaining the immunological homeostasis, 119 even the role of the spleen in contributing to the clinical picture of COVID-19 has been explored in a few studies. In particular, spleen atrophy, mainly affecting the white pulp, was observed in post-mortem cases of COVID-19. 120 A study exploring spleen function in 66 COVID-19 patients admitted to an internal medicine ward found a high prevalence of IgM memory Bcell depletion, and this was associated with greater mortality and development of superimposed bacterial infections. 121 However, more data are still needed in order to ascertain the role of SARS-CoV-2 in causing direct liver damage, pancreatic, and splenic involvement. 

Acute infection gastroenteritis of bacterial, protozoan, and viral nature is currently the strongest known risk factor for the development of irritable bowel syndrome (IBS) and functional dyspepsia. 54 A systematic review and meta-analysis showed that >10% of patients with infectious enteritis develop IBS. 128 138 whereas other molecules act on virus internalization mechanisms. 7 On this line, it has been reported an amelioration of diarrhea after antiviral treatment. 139 It is worth noticing that several drugs currently used for COVID-19 treatment may also cause gastrointestinal symptoms. 122 Indeed, chloroquine, hydroxychloroquine, and lopinavir/ritonavir may induce nausea, vomiting, abdominal pain, and diarrhea in up to 30% of patients. [140] [141] [142] Moreover, antibiotics and antivirals used for COVID-19 treatment may cause dysbiosis and diarrhea. The China National Health Commission has been among the first to recommend probiotics in severe COVID-19 patients to ameliorate gut microbial homeostasis, to prevent bacterial infections, and to likely obtain antiviral effect. 143 Indeed, probiotics may favor the innate and adaptive immune response, interfere with virus lifecycle through the production of antiviral metabolites. 144 Thus, symptomatic treatments for each gastrointestinal symptom may be advised, 122 in addition to specific nutritional recommendations and micronutrients supplementation. 145 No specific treatment for treating liver injury exists. 

The authors have no competing interests. 

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Clinical characteristics of coronavirus disease (COVID-19) patients with gastrointestinal symptoms: A report of 164 cases

COVID-19 and coagulation: Bleeding and thrombotic manifestations of SARS-CoV-2 infection

Impact of Gastrointestinal Symptoms in COVID-19: a Molecular Approach

Gamma-glutamyltransferase elevation is frequent in patients with COVID-19: A clinical epidemiologic study

COVID-19: Abnormal liver function tests

Epidemiological, clinical and virological characteristics of 74 cases of coronavirus-infected disease 2019 (COVID-19) with gastrointestinal symptoms

Bilirubin levels in patients with mild and severe Covid-19: A pooled analysis

Lipase Elevation in Patients With COVID-19

COVID-19 presenting as acute pancreatitis

Nucleic Acid Detection of Fecal Samples from Confirmed Cases of COVID-19

Detection of SARS-CoV-2 RNA in fecal specimens of patients with confirmed COVID-19: A meta-analysis

Fecal occult blood and urinary cytology tests for rapid screening of inflammatory infection in the gastrointestinal and urological systems in patients with Coronavirus disease 2019

Implications of SARS-CoV-2 infection for neurogastroenterology