With the outbreak of coronavirus disease 2019 (COVID-2019) by SARS-CoV-2 infection in Wuhan (Hubei province), the whole world is undergoing an invisible war. By 1 April, the WHO’s daily outbreak report showed that there were 823 626 confirmed cases of COVID-19 and 40 598 deaths around the world, and the numbers are still climbing. The main symptoms of COVID-19 are respiratory symptoms while some confirmed patients developed gastrointestinal symptoms or even initially presented digestive symptoms. Maybe it was not an accident that patients had COVID-19 complicated with gastrointestinal symptoms. The link between pneumonia and gastrointestinal symptoms caused by SARS-CoV-2 focused our attention on the concept of ‘gut–lung axis’. In this article, we discuss the inevitability and possible mechanisms of the occurrence of intestinal symptoms or intestinal dysfunction in COVID-19 from the perspective of the gut–lung axis, as well as the influence of the imbalance of intestinal homeostasis on the respiratory symptoms of COVID-19.
The underestimated gastrointestinal symptoms of COVID-19
The common symptoms of COVID-19 are fever, cough and fatigue . However, the gastrointestinal symptoms (vomiting, diarrhea, and abdominal pain) were overlooked in the early stage of the outbreak in China. According to the latest reports, few confirmed patients who initially presented only gastrointestinal symptoms. As a case report of a family cluster of COVID-19, there were two young (36, 37 years old, respectively) confirmed patients initially had diarrhea . What is more, it noted that a female patient initially had diarrhea, anorexia and asthenia in another case report . In some cases, pregnant women and children also presented diarrhea as their chief complaint [4,5]. A clinical retrospective study showed that 3% of the infected patients had diarrhea . Later, an analysis of 1099 COVID-19 cases indicated that 3.8% confirmed patients with diarrhea . Moreover, the severe acute respiratory symptoms (SARS) in 2003 and Middle East respiratory syndrome (MERS) in 2012 also presented digestive symptoms. These atypical symptoms make it more difficult to separate patients with COVID-19. Once the suspected patients were admitted to the digestive ward instead of quarantine ward, it would threaten the lives of medical staff and other patients considering high infectivity of SARS-CoV-2 , or even cause widespread transmission. Therefore, it is urgent to pay attention to patients with gastrointestinal symptoms, especially accompanied by fever. It is favorable to quarantine such suspected patients and their close contactors and administrate nucleic acid testing to diagnosis.
The lung and intestine be treated as a whole in COVID-19
The growing evidence indicates the key role of inter-organ crosstalk in disease progression. The link between pneumonia and gastrointestinal symptoms caused by SARS-CoV-2 refocused our attention on this issue. Specifically, the ‘gut–lung axis’ refers to the crosstalk between these two mucosal sites of the body. As is known that the tracheal and lung cell progenitors were originated from foregut endoderm in the early stage of respiratory system development, which may be the structural basis of the theory. Besides, the epithelium of the airway and intestinal is part of the mucosal immune system, an integrated network composed of tissues, cells and effector molecules, protecting the host from environment infections. Multiple evidence showed that cross-mucosal interaction between intestinal mucosal and respiratory mucosa. For example, Ruane et al. have proved that murine lung dendritic cells recruited T cells to the gastrointestinal tract, demonstrating the functional evidence of mucosal cross-talk . Respiratory tract viral infection can indirectly cause the imbalance of intestinal microecology. In clinical observations, patients with influenza virus-mediated respiratory diseases are often accompanied by gastroenteritis-like symptoms . Interestingly, it was proposed that respiratory influenza infection caused intestinal injury, which was not due to direct intestinal viral infection but the alteration of intestinal microbiota composition mediated by lung-derived CCR9+CD4+ T cells . Additionally, Groves et al. found the infection of the virus in lung altered the murine gut microbiota and was associated with gut inflammation . Similar mechanisms may be responsible for the gastrointestinal symptoms associated with COVID-19. In line, the newest treatment guideline published by the National Health Commission mentions the role of intestinal microecological regulator in regulating the dysbiosis of intestinal flora in patients with COVID-19 . However, further research is needed to understand how SARS-CoV-2 infection shapes the intestinal flora.
In turn, intestinal flora also regulates the immune response of lung after virus infection. A team from Yale University reported that the composition of intestinal flora played a key role in regulating the production of virus-specific CD4+ and CD8+ T cells and antibody response when influenza virus-infected the respiratory tract . Besides, the lungs were generally believed to be sterile, but a recent study had identified microbial organisms in the lungs . Similar to the gut microbiome, the microbial organisms in the lungs were considered of great importance for host immunity by priming the immune system. What is more, studies have revealed that gut bacteria would migrate to the lung in vivo. Acute respiratory disease syndrome (ARDS) is characterized as a partial cause of death in patients with COVID-19. It was known that the lung microbiome of patients with ARDS was enriched with gut bacteria, which might indicate the disorder of the gut–lung axis. Therefore, in the body’s inflammatory response, the interaction between lung and intestine might lead to a vicious cycle of pulmonary and intestinal inflammation [14,15]. Therefore, the intestinal symptoms may be a predictor of COVID-19 and it is beneficial for the recovery of pneumonia to maintain the homeostasis of intestinal microbiota and immune. Based on the evidence, the lung and gut should be treated as a whole in the diagnosis and treatment of COVID-19.
Moreover, Chinese Traditional Medicine (TCM) plays an important role in the treatment of COVID-19 in China. According to the State Administration of Traditional Medicine, the participation rate of TCM was 91.05% in Hubei province and 96.37% outside the Hubei area. In the theory of TCM, lung and large intestine being interior-exteriorly related. With the development of science and technology, amounts of evidence verified this ancient theory from different angles and raised the concept of ‘gut–lung axis’. Its existence opens up new possibilities for therapeutic approaches to SARS-CoV-2.
Potential risk of fecal–oral transmission
The transmission of SARS-CoV-2 is mainly through contact transmission and airborne . However, some laboratories from China declared that they had isolated live SARS-CoV-2 from the stool of patients recently , and in the stool of asymptomatic infected child or even patients with virus-negative in respiratory samples [18,19], There exists potential transmission probability from the aspects of etiology and epidemiology though there is no direct evidence that the SARS-CoV-2 can be transmitted by the fecal–oral route. The pathogenicity of coronavirus depends mainly on the interaction of transmembrane spike glycoprotein (S-protein) receptor binding domain, specific cell receptor (ACE2) and host cellular transmembrane serine protease, with a binding affinity of SARS-CoV-2 about 73% of SARS virus . Recently, bioinformatics analysis of available single-cell transcriptomes data from normal human lung and gastrointestinal systems found that ACE2 is not only expressed in AT2 cells of the lung, but also in the upper and stratified epithelial cells of esophagus and the absorptive enterocytes of the ileum and colon . Fei Xiao et al. found that the epithelial cells of gastrointestinal visualized positive with ACE2 staining and viral nucleocapsid protein staining . This suggests that the digestive system may be susceptible to SARS-CoV-2 infection, which may explain the gastrointestinal symptoms of COVID-19. Abundant evidence from former studies of SARS and MERS indicated that the gastrointestinal tract was vulnerable to the coronavirus of SARS and MERS by the viral detection in biopsy specimens and stool [18,22]. Furthermore, researchers found high concentrations of SARS virus in the stool of infected patients in the case of a large community outbreak of SARS in Hong Kong which might provide evidence that the virus from feces may form aerosol to infect respiratory tract through airborne route . It demands further study to confirm whether the SARS-CoV-2 can transmit by fecal–oral or fecal-airborne because lower fecal concentrations of SARS-CoV-2 compared to the SARS virus . Therefore, we suggest washing hands carefully before eating and after defecating, do not use central air-conditioning, ventilate and sterilize the house frequently. Last but not least, flush the toilet with the lid on to prevent the aerosol from leaking in. In summary, safety first, any reasonable efforts to reduce the risk of infection need not wait for scientific proof.
In this review, we discuss the inevitability and possible mechanisms of the emergence of gastrointestinal symptoms in COVID-19 from the view of the gut–lung axis and put forward a holistic viewpoint of treating the lung and gut together. Given the atypical gastrointestinal symptoms and potential possibility of fecal–oral transmission in patients with COVID-19, the gastrointestinal symptoms should be paid more attention in the prevention, diagnosis and treatment of COVID-19.
We acknowledge the financial support from the National Natural Science Foundation of China (J.L., No. 81472735) and the National Basic Research Program of China (973 program, J.L., Grant #2015CB932600).
Conflicts of interest
There are no conflicts of interest.
1. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020; 395:497–506.
2. Chan JF, Yuan S, Kok KH, To KK, Chu H, Yang J, et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet. 2020; 395:514–523.
3. An P, Song P, Lian K, Wang Y. CT manifestations of novel coronavirus pneumonia: a case report. Balkan Med J. 2020; 37:163–165.
4. Zhu H, Wang L, Fang C, Peng S, Zhang L, Chang G, et al. Clinical analysis of 10 neonates born to mothers with 2019-nCoV pneumonia. Transl Pediatr. 2020; 9:51–60.
5. Wang D, Ju XL, Xie F, Lu Y, Li FY, Huang HH, et al. Clinical analysis of 31 cases of 2019 novel coronavirus infection in children from six provinces (autonomous region) of northern China. Zhonghua Er Ke Za Zhi. 2020; 58:E011.
6. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al.; China Medical Treatment Expert Group for Covid-19. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020; 382:1708–1720.
7. Novel Coronavirus Pneumonia Emergency Response Epidemiology Team. The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) in China. Zhonghua Liu Xing Bing Xue Za Zhi. 2020; 41:145–151.
8. Ruane D, Brane L, Reis BS, Cheong C, Poles J, Do Y, et al. Lung dendritic cells induce migration of protective T cells to the gastrointestinal tract. J Exp Med. 2013; 210:1871–1888.
9. Wang J, Li F, Wei H, Lian ZX, Sun R, Tian Z. Respiratory influenza virus infection induces intestinal immune injury via microbiota-mediated Th17 cell-dependent inflammation. J Exp Med. 2014; 211:2397–2410.
10. Groves HT, Cuthbertson L, James P, Moffatt MF, Cox MJ, Tregoning JS. Respiratory disease following viral lung infection alters the murine gut microbiota. Front Immunol. 2018; 9:182.
11. National Health Commission of the People’s Republic of China. Notice on printing and distributing the diagnosis and treatment plan of pneumonia with new coronavirus infection (trial version 7). http://www.nhc.gov.cn/yzygj/s7653p/202001/f492c9153ea9437bb587ce2ffcbee1fa. Shtml
. [Accessed March 4, 2020]
12. Ichinohe T, Pang IK, Kumamoto Y, Peaper DR, Ho JH, Murray TS, Iwasaki A. Microbiota regulates immune defense against respiratory tract influenza A virus infection. Proc Natl Acad Sci USA. 2011; 108:5354–5359.
13. Huang YJ, Nelson CE, Brodie EL, Desantis TZ, Baek MS, Liu J, et al.; National Heart, Lung, and Blood Institute’s Asthma Clinical Research Network. Airway microbiota and bronchial hyperresponsiveness in patients with suboptimally controlled asthma. J Allergy Clin Immunol. 2011; 127:372–381.e1.
14. Marsland BJ, Trompette A, Gollwitzer ES. The gut-lung axis
in respiratory disease. Ann Am Thorac Soc. 2015; 12 (Suppl 2):S150–S156.
15. Fink MP, Delude RL. Epithelial barrier dysfunction a unifying themo to explain the pathogenesis of multiple organ dysfunction at the cellular level. Crit Care Clin. 2005; 21:177–196.
16. Lai CC, Shih TP, Ko WC, Tang HJ, Hsueh PR. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): the epidemic and the challenges. Int J Antimicrob Agents. 2020; 17:105924
17. Tang A, Tong ZD, Wang HL, Dai YX, Li KF, Liu JN, et al. Detection of novel coronavirus by RT-PCR in stool specimen from asymptomatic child, China. Emerg Infect Dis. 2020; 26:1337–1339.
18. Gu J, Han B, Wang J. COVID-19: gastrointestinal manifestations and potential fecal-oral transmission. Gastroenterology. 2020; 158:1518–1519.
19. Xiao F, Tang M, Zheng X, Liu Y, Li X, Shan H. Evidence for gastrointestinal infection of SARS-CoV-2. Gastroenterology. 2020; 158:1831–1833.e3.
20. Huang Q, Herrmann A. Fast assessment of human receptor-binding capability of 2019 novel coronavirus (2019-nCoV). bioRxiv. 2020:930537.
21. Zhang H, Kang ZJ, Gong HY, Xu D, Wang J, Li ZF, et al. The digestive system is a potential route of 2019-nCov infection: a bioinformatics analysis based on single-cell transcriptomes. bioRxiv. 2020: 927806.
22. Leung WK, To KF, Chan PK, Chan HL, Wu AK, Lee N, et al. Enteric involvement of severe acute respiratory syndrome-associated coronavirus infection. Gastroenterology. 2003; 125:1011–1017.
23. Yu IT, Li Y, Wong TW, Tam W, Chan AT, Lee JH, et al. Evidence of airborne transmission of the severe acute respiratory syndrome virus. N Engl J Med. 2004; 350:1731–1739.
24. Holshue ML, DeBolt C, Lindquist S, Lofy KH, Wiesman J, Bruce H, et al.; Washington State 2019-nCoV Case Investigation Team. First case of 2019 novel coronavirus in the United States. N Engl J Med. 2020; 382:929–936.