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Potential Effects of SARS-Cov-2 on the Gastrointestinal Tract and Liver

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Potential Effects of SARS-Cov-2 on the Gastrointestinal Tract and Liver Biomedicine & Pharmacotherapy 133 (2021) 111064 Contents lists available at ScienceDirect Biomedicine & Pharmacotherapy journal homepage: www.elsevier.com/locate/biopha Review Potential effects of SARS-CoV-2 on the gastrointestinal tract and liver Han-Yu Lei a,b,1, Ying-He Ding a,b,1, Kai Nie a,b,1, Yin-Miao Dong a,b, Jia-Hao Xu a,b, Meng-Ling Yang a,b, Meng-Qi Liu a,b, Le Wei a,b, MI Nasser c, Lin-Yong Xu d,*, Ping Zhu c,*, Ming-Yi Zhao a,* a Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, Hunan, PR China b Xiangya School of Medicine, Central South University, Changsha, Hunan, PR China c Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, PR China d Xiangya School of Life Science, Central South University, Changsha, Hunan, PR China ARTICLE INFO ABSTRACT Keywords: COVID-19 is a pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Early re­ COVID-19 ported symptoms include fever, cough, and respiratory symptoms. There were few reports of digestive symptoms. Liver injury However, with COVID-19 spreading worldwide, symptoms such as vomiting, diarrhoea, and abdominal pain Gastrointestinal tract have gained increasing attention. Research has found that angiotensin-converting enzyme 2 (ACE2), the SARS- Gut-lung axis CoV-2 receptor, is strongly expressed in the gastrointestinal tract and liver. Whether theoretically or clinically, Inflammatory cytokine storm Liver transplant many studies have suggested a close connection between COVID-19 and the digestive system. In this review, we summarize the digestive symptoms reported in existing research, discuss the impact of SARS-CoV-2 on the gastrointestinal tract and liver, and determine the possible mechanisms and aetiology, such as cytokine storm. In- depth exploration of the relationship between COVID-19 and the digestive system is urgently needed. 1. Introduction the original underlying conditions can impact patient treatment and prognosis not only in COVID-19 cases but also in gastrointestinal COVID-19, which is caused by SARS-CoV-2, is a significant global diseases. public health problem. As of 29 October 2020, there have been The liver is the body’s largest digestive gland for biligenesis and approximately 44,380,000 confirmedcases of COVID-19 and 1,170,000 detoxification. Liver damage is sometimes identified as a typical deaths worldwide [1]. SARS-CoV-2 belongs to the beta coronavirus occurrence in COVID-19 patients. Through pathology and blood tests, family, which enters cells through the ACE2 receptor [2]. Symptoms the mechanisms of liver injury mainly arise from direct viral infection, involving the digestive system were not evident among patients drug cytotoxicity, and inflammatory immune response. Alternative ex­ suffering from the initial disease in Wuhan, China. Only 2.6 % had planations include hypoxic hepatitis, hepatic congestion related to me­ diarrhoea and 2% had chronic diseases of the liver [3]. As the case chanical ventilation (PEEP), and gut barrier dysfunction [4]. Indeed, complexity grows, more and more patients have reported digestive notable facts include the identification of ACE2-positive cells in liver system symptoms. The disorder, with diarrhoea arising most often, is tissues, which turn the liver into a potential target for SARS-CoV-2 marked by diarrhoea, anorexia, nausea, vomiting, abdominal discom­ infection. Moreover, it has been shown that the associations between fort, and gastrointestinal bleeding. Several potential mechanisms for the prior liver diseases and COVID-19 will contribute to worse clinical development of gastrointestinal problems have been suggested. These outcomes and should be taken seriously during care. Specifically, we include virus-induced cytopathic impacts through ACE2, focus on liver transplant recipients with COVID-19 due to their altered immune-mediated inflammatory cytokine storm, the function of the immune state and disease susceptibility. Further studies in COVID-19 gut-lung axis as well as drug-related harm. These pathways can also patients call for a better understanding of pathogenesis and for contribute to sepsis and acute respiratory distress syndrome (ARDS), optimal treatment of COVID-19. which are the leading causes of death in COVID-19 patients. However, Based on the above statement, we propose that the development and * Corresponding authors. E-mail addresses: [email protected] (L.-Y. Xu), [email protected] (P. Zhu), [email protected] (M.-Y. Zhao). 1 Hanyu Lei, Yinghe Ding, and Kai Nie contributed equally. https://doi.org/10.1016/j.biopha.2020.111064 Received 22 July 2020; Received in revised form 7 November 2020; Accepted 20 November 2020 Available online 28 November 2020 0753-3322/© 2020 Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). H.-Y. Lei et al. Biomedicine & Pharmacotherapy 133 (2021) 111064 progression of COVID-19 are closely related to the gastrointestinal tract COVID-19 patients, which means that gastrointestinal symptoms could and the liver. However, there are currently few studies available; thus, be correlated with viral infections in patients with COVID-19. In nearly this article summarizes the relevant views and suggests potential half of the COVID-19 patients with digestive symptoms, viral RNA can mechanisms. be detected in their stool for determining the diagnosis and transmission [12]. The possibility of faecal–oral transmission of SARS-CoV-2 has 2. Gastrointestinal tract involvement in COVID-19 patients important implications and needs further study. Research has shown that SARS-CoV-2 enters cells through the ACE2 2.1. Gastrointestinal symptoms in patients with COVID-19 receiver [2]. Immunofluorescencedata have shown that ACE2 protein is abundantly expressed in gastric, duodenal, and rectal epithelial glan- COVID-19 typically develops in patients as a respiratory disease, dular cells, which promotes the possible entry of SARS-CoV-2 into host with some patients reporting gastrointestinal symptoms during disease cells [8]. Moreover, a study has suggested a possible mechanism for the episodes such as diarrhoea, anorexia, nausea, vomiting, stomach digestive symptoms in COVID-19 patients. ACE2 expression on the small discomfort, and gastrointestinal bleeding. We analysed COVID-19 clin- intestine surface cells can mediate viral invasion and expansion, trig- ical data to show gastrointestinal symptoms and their incidence in pa- gering gastrointestinal inflammation [13]. SARS-CoV-2 invades intesti- tients with COVID-19 (Table 1). Diarrhoea, with a rate ranging from 2.0 nal cells expressing ACE2, causing malabsorption, intestinal disorders, to 47.9%, is the most commonly reported gastrointestinal symptom in activation of the enteric nervous system, and, ultimately, diarrhoea. COVID-19 patients [3,5–9]. Even though the first COVID-19 clinical Interestingly, a previous study on other coronaviruses found that human article reported that only 1 in 38 patients had diarrhoea [3], the fre- intestinal epithelial cells’ high sensitivity to coronavirus increases their quency of diarrhoea is usually greater in later stages. A cohort of 73 replicative capacity [14]. Moreover, this gastrointestinal tropism can COVID-19 patients reported by Xiao et al. showed that diarrhoea was explain the frequent onset of coronaviral diarrhoea (Fig. 1). observed in up to 35.6 % of patients [8]. Similarly, the incidence of diarrhoea was up to 47.9 % in a cohort of 305 patients reported by Fang 2.3. Immune-mediated inflammatory cytokine storm et al. [6]. Although rarely reported, anorexia can occur frequently once diag- The pathogenesis of COVID-19 is not yet clear at the moment. nosed. Wang et al. reported an incidence of up to 39.9 % and Fang et al. Cytokine storms and cellular immune responses are believed to play a reported 33.1 % [6,7]. According to data, patients with nausea account key role in disease occurrence and development [15]. Cytokine distur- for 1.0–19.3 % [5–7,9]. Vomiting, stomach discomfort and gastroin- bance is an abnormal, dynamic pathogenesis inflammatory reaction to testinal bleeding can also be observed in COVID-19 patients, though external stimuli. SARS-CoV-2-infected cells release large numbers of with a low incidence. Regarding the available clinical studies, gastro- inflammatory mediators and chemokines that cause neutrophil aggre- intestinal symptoms are relatively common in patients with COVID-19, gation. While neutrophils mainly have an antiviral function, their se- even though they only manifest in some cases [10]. cretions, cytokines, and chemokines also promote the accumulation of In terms of pathology experiments, Xiao et al. [8] showed that H&E immune cells, which leads to over-reaction. The immune system of staining of the oesophagus, stomach, duodenum, and rectum showed no COVID-19 patients is, therefore, abnormal. Approximately 34.5 % of substantial mucosal epithelial harm. Occasional lymphocyte infiltration 197 patients showed neutrophilia [16], which is known to be a trigger was observed in the oesophageal squamous epithelium in this study. for ARDS and sepsis growth in COVID-19 patients. Secondary hemo- Although the lamina propria of the uterus, duodenum, and rectum were phagocytic lymph histiocytosis (SHLH), an underrecognized hyper- found to display an excess of infiltrating plasma cells and interstitial inflammatory syndrome, could also
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