key: cord-0875733-5ritt75u
authors: Zhou, Dan; Wang, Qiu; Liu, Hanmin
title: Coronavirus disease-19 and the gut-lung axis
date: 2021-09-10
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2021.09.013
sha: 98fbcbdec87c8f6614791b824212db4f0ea87e4a
doc_id: 875733
cord_uid: 5ritt75u

Gastrointestinal and respiratory tract diseases often occur together. There are many overlapping pathologies, leading to the concept of the “gut-lung axis,” in which stimulation on one side triggers a response on the other side. This axis appears to be implicated in infections involving severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has triggered the global pandemic of coronavirus disease 2019 (COVID-19), in which respiratory symptoms of fever, cough, and dyspnea often occur together with gastrointestinal symptoms such as nausea, vomiting, abdominal pain, and diarrhea. Besides the gut-lung axis, it should be noted that the gut participates in numerous axes, which may affect lung function and consequently COVID-19 severity through several pathways. However, in this article, we mainly pay attention to the latest evidence and the mechanisms that drive the operation of the gut-lung axis, as well as discuss the interaction between the gut-lung axis and its possible involvement in COVID-19 from the perspective of microbiota, microbiota metabolites, microbial dysbiosis, common mucosal immunity and angiotensin-converting enzyme II (ACE2). Raising hypotheses and providing methods to guide future research on this new disease and its treatments.

Turner-Warwick and Kraft reported the first evidence of pulmonary-intestinal cross-talk nearly 50 years ago, who noted the development of severe, chronic bronchopulmonary disease in patients diagnosed years before with inflammatory bowel disease (Turner-Warwick et al., 1968 , Kraft et al., 1976 . Microbes seem to play an important role in this cross-talk by affecting normal and pathological immune responses in the gut and lung ((Budden et al., 2017 , He et al., 2017 , Dang et al., 2019 , Enaud et al.,2020 . For example, some studies have linked changes in the gut microbiome with changes in lung immunity (Barfod et al., 2013 , Chen et al., 2014 , Olszak et al., 2012 , Russell et al., 2013 . Similarly, the lung microbiota also acts through the blood and affects the gut microbiota (Sze et al., 2014) . This communication between the gut and lung has given rise to the concept of the "gut-lung axis" (Schuijt et al., 2016 , a feedback loop that can be stimulated from either side to induce a response on the other side (Dumas et al., 2018) . In addition to microbes, microbiota metabolites and common mucosal immunity are also extensively studied in the gut-lung axis ( Figure 1 ). Gastrointestinal disorders of nausea, vomiting, abdominal pain, diarrhea (Guan et al., 2020 , Huang et al., 2020 and respiratory tract disorders of fever, cough, dyspnea often occur together in coronavirus disease 2019 (Zhang et al., 2021) , and SARS-CoV-2 was not only detected in oral swabs , but also in anal/rectal swabs and stool specimens , Holshue et al., 2020 , Tang et al., 2020 , which may indicate a cross-talk between gut and lung in COVID-19 (Dhar and Mohanty, 2020 , Ahlawat S et al., 2020 , Allali I et al., 2021 .

The need to clarify whether the gut-lung axis contributes to COVID-19 is critical given studies suggesting the presence of the gastrointestinal disorder in COVID-19 patients might be related to a more aggressive clinical course, including acute respiratory distress syndrome, liver injury, and shock (Luo et al., 2020 , Jin et al., 2020 . In addition, the risk factors for severity and mortality in COVID-19 (such as diabetes) are known to be associated with disorders of the intestinal flora (Singh et al., 2020) . This is especially true for patients with metabolic syndrome such as high blood pressure, obesity, and diabetes who exhibit severe viral infections, including respiratory infections (Badawi et al., 2018, Honce and Schultz-Cherry., 2019) . So these raise the possibility that assessing activation of the gut-lung axis may be a way to stratify COVID-19 patients by risk of severe disease and that regulating this axis may be an effective treatment for COVID-19. So in this article, we particularly pay attention to the latest evidence and the mechanisms that drive the operation of the gut-lung axis, as well as to discuss the interaction between the gut-lung axis and its possible involvement in COVID-19 from the perspective of microbiota, microbiota metabolites, microbial dysbiosis, common mucosal immunity and angiotensin-converting enzyme II (ACE2). Raising hypotheses and provide methods to guide future research on this new disease and its treatments.

Gastrointestinal and respiratory tract diseases often occur together, and there are many overlapping pathologies (Roussos et al., 2003 , Rutten et al., 2014 , leading to the concept of the "gut-lung axis" (Budden et al., 2017 , Schuijt et al., 2016 . Indeed, the two tissues arise embryonically from the primitive foregut (Shu et al., 2007 , Ramalho-Santos et al., 2000 and are similar in structure (Mestecky et al.,1987 , Mestecky et al., 1978 . Both tissues provide a physical barrier against microbial penetration and are colonized by the normal microbiota, thereby providing resistance to pathogens. These two tissues are extensively vascularized and present a substantial epithelial surface area to the external environment (Kuebler, 2005 , Labiris and Dolovich, 2003 , Mason et al., 2008 , Takahashi and Kiyono, 1999 . In both cases, the epithelial surface is covered with the submucosa of loose connective tissue and mucosal-associated lymphoid tissue where the lymphocytes are. This lymphoid tissue regulates antigen sampling, lymphocyte transport, and mucosal defense (Holt,1993, Forchielli and Walker, 2005) . In this way, it can serve as the primary innate and adaptive immune response against invading pathogens (Tulic et al., 2016) . Therefore, it is not surprising that these two sites interact in health and disease despite the different environments they face.

There is a mutualistic relationship between the microbial community and the host. Microbes benefit from a stable, nutrient-rich microenvironment. In exchange, they have an essential role for the host, including the fermentation of dietary components to produce nutrients, vitamins, and metabolites (Krajmalnik-Brown et al., 2012) . A growing body of evidence support the importance of constitutive sensing of microorganisms and their metabolites in adjusting the immune system toward a healthy homeostasis (Samuelson et al., 2015 , Maslowski et al., 2009 ).

The gut microbiota shares a mutually beneficial relationship with its host, where it produces various metabolites that can further signal to remote organs in body through neural, endocrine, immune, humoral, and metabolic pathways, regulating the body metabolic homeostasis and organ physiology (Schroeder et al., 2016 , Feng et al., 2018 . The complex interactions between the gut microbiota and the different organs result in the formation of the "gut-organ axis" between them, such as the gut-lung axis, gut-brain axis, gut-heart axis, gut-liver axis, gut-kidney axis, gut-liver-kidney axis etc. (Nicholson et al., 2012 , Ahlawat et al., 2021 , Budden et al., 2017 , Cryan et al., 2019 , Trøseid et al., 2020 , Tripathi et al., 2018 , Evenepoel et al., 2017 , Raj et al., 2020 . Within these axes, any alterations in gut microbiota composition and diversity may not only trigger gut disorders, but also influence other organs and cause associated diseases ( Figure 2 ). Thus, a better knowledge of gut microbiota and the "gut-organ axis" will encourage the development of innovative diagnostic and therapeutic modalities for associated diseases.

Gut-lung axis is an important part of the "gut-organ axis" , the influence of microbiota and its metabolites on the gut-lung axis has recently been reviewed , Trompette et al., 2014 , Mcaleer and Kolls, 2018 (Table 1 ). An example of the influence of microbiota on the gut-lung axis includes Segmented Filamentous Bacteria (SFB) in the gut can stimulate the lung T helper 17 (TH17) response and protect it from Streptococcus Pneumoniae infection, and enhance the lung mucosal immunity (Gauguet et al., 2015) . In murine studies, antibiotic-driven depletion of certain bacteria in the gut microbiome increases pulmonary viral infections (Ichinohe et al., 2018 ).

Short-chain fatty acids (SCFAs) are the most widely studied metabolites, including butyrate, propionate, and acetate, which have anti-inflammatory and immune-modulatory functions on lung homeostasis and immunity (Trompette et al., 2014 , Koh et al., 2016 . For example, SCFAs produced by Bacteroidetes or Clostridium can enhance influenza-specific CD8+ T-cell function and type I interferon (IFN) signaling in macrophages, thereby improving protection against influenza infection (Atarashi et al., 2013 , Tanoue et al., 2016 . Similarly, a high-fiber diet increased the relative abundance of SCFA-producing Lachnospiraceae Spp. The SCFA acetate protected mice from respiratory syncytial virus (RSV) infection by producing IFN-β in lung epithelial cells through G-protein-coupled receptors (Antunes et al., 2019) .In addition to SCFAs, another microbial metabolite that affects lung response is desaminotyrosine, which can protect mice against influenza virus infection by enhancing type I interferon response (Steed et al., 2017) . Taken together, these studies have proved the importance of symbiotic gut microbes and their metabolites in regulating lung homeostasis.

As discussed earlier, the presence of the gastrointestinal disorder in COVID-19 patients might be related to a more aggressive clinical course (Luo et al., 2020 , Jin et al., 2020 , including acute respiratory distress syndrome, heart failure, renal failure, liver damage, and even multi-organ dysfunction (Rabb., 2020 , Jothimani et al., 2020 , Zaim et al., 2020 , Mokhtari et al., 2020 . So it should be noted that the gut-lung axis may not be the only axis involved in COVID-19, other axes may also be involved. Thus, the gut may affect lung function and consequently Covid-19 severity through several pathways. In COVID-19, upon attack of SARS-CoV-2, innate and adaptive immune system responses trigger inflammation and cytokine storm in various organs such as the lung, gut, heart, liver and kidney, causing several organ dysfunctions (Rabb., 2020 , Jothimani et al., 2020 , Zaim et al., 2020 , Mokhtari et al., 2020 . The gut dysfunction may change the composition and diversity of the gut microbiota , Han et al., 2020 , Zuo et al., 2020 , Aktas B et al., 2020 . According to the "gut-organ axis", any alterations in gut microbiota composition and diversity may not only trigger gut disorders, but also influence other organs such as the lung, heart, liver and kidney through neural, endocrine, immune, humoral, and metabolic pathways, therefore explaining the presence of the gastrointestinal disorder in COVID-19 patients might be related to a more aggressive clinical course.

Consequently, understanding in depth the exact mechanism of the gut and associated microbiota with derived metabolites interact with various organs in health and disease is crucial to counteract pandemics such as that caused by the ongoing SARS-CoV-2 infection.

The human body is colonized by a variety of microbes, including bacteria, fungi, virus, archaea, and protozoa (Grice and Segre, 2012 , Sender et al., 2012 , Debarbieux et al., 2017 , Eckburg et al., 2003 , most of which are found in the gastrointestinal tract (Shreiner et al., 2015) . Healthy lungs were long considered to be sterile. Until recently, studies using culture-independent methods have shown that even healthy lungs harbor bacteria, viruses, and fungi (Harris et al., 2007 , Huang et al., 2010 , Nguyen et al., 2015 . These microbes seem to be important in nutrition, metabolism, and defense against foreign pathogens (Sommer and Backhed, 2013) , as well as epithelial homeostasis and ontogeny of innate and adaptive immunity . Changes in the composition and activities of these microbes termed microbial dysbiosis or imbalance, can affect health in many ways, such as allowing opportunistic bacteria to grow, altering metabolic processes and immune responses, and triggering inflammation (Trompette et al., 2014 , Craven et al., 2012 , Qin et al., 2012 . For example, dysbiosis of intestinal flora has been associated with respiratory diseases such as asthma (Dharmage et al., 2015 , Ranucci et al., 2017 and cystic fibrosis (Bruzzese et al., 2014 , Manor et al., 2016 . A study has shown that endogenous Bifidobacteria intestinal flora caused by fatal influenza infection can enhance resistance to the virus . Conversely, lung inflammation can affect the intestinal flora (Budden et al., 2017 , Dang and Marsland, 2019 , Dumas et al., 2018 : respiratory infection of influenza virus in mice can increase the number of Enterobacteria and reduce the number of Lactobacillus and Lactococcus in the gut (Looft and Allen, 2012, Tirone et al., 2019), and after lipopolysaccharide (LPS) is administered to mice, the dysbiosis of the lung microbiota will be accompanied by the disturbance of the intestinal flora due to the movement of bacteria from the lungs into the bloodstream (Sze et al., 2014) . These studies have shown that microbes play an essential role in the cross-talk between the gut and the lung, and that microbial dysbiosis in the lung may affect the homeostasis of the gut, and vice versa. It is also possible that a continuum of microbiota lines the entire length of the mucosal membrane of the gut and lung, and that the composition of the microbial communities changes throughout the mucosal compartments, dysbiosis in one compartment may affect the stability of the other compartment.

Several studies have shown that microbial dysbiosis is significant in COVID-19 , Han et al., 2020 , Zuo et al., 2020 , Aktas B et al., 2020 . It has been shown that some COVID-19 patients suffer from microbial dysbiosis, and the levels of Lactobacillus and Bifidobacteria are reduced . Severe microbiota dysbiosis was also found in COVID-19 subjects, including a large number of pathogenic bacteria, such as Klebsiella Oxytoca, Lactobacillus, Faecalibacterium Prausnitzii, and Tobacco mosaic virus (TMV) (Han et al., 2020) . In addition, the severity of the disease may have a positive correlation with the abundance of Clostridium Hathewayi, Clostridium Ramosum, Coprobacillus, and a negative correlation with the abundance of Faecalibacterium Prausnitzii (Zuo et al., 2020) . The elderly are at greater risk of SARS-CoV-2 infection, and severe COVID-19 (Goyal et al., 2020 , Lake, 2020 may reflect that their intestinal flora is less diverse and contains a smaller population of beneficial microorganisms such as Bifidobacterium (Nagpal et al., 2018) . These studies indicate the urgent need to restore the balance of microbiota in patients with COVID-19. There is scientific evidence to confirm the role of probiotics and prebiotics in restoring the gut/lung microbiota balance and reducing the risk of secondary infection due to bacterial translocation (Santacroce et al., 2019 , Kanauchi et al., 2019 , Chan et al., 2020 . All these considered, the use of probiotics and prebiotics in preventing COVID-19 is increasing, to eliminate the virus and preclude disease progression to severe stages (Bottari et al., 2021 , Sundararaman et al., 2020 , Khaled JMA., 2021 , Angurana et al., 2020 , Santacroce et al., 2021 .

On the basis of the available evidence, the possible benefits of probiotics and prebiotics administration in the Covid-19 infection, may be through immunomodulatory actions on systemic inflammation or by indirect interaction with the lung through the gut-lung axis. Although the immune benefits of the probiotics and prebiotics are unquestionable, their potential roles against COVID-19 infection still warrant more clinical and laboratory investigations.

Further work is needed to clarify the apparent relationship between microbial dysbiosis and COVID-19. This work should examine whether dysbiosis is the cause or consequence of the disease, and whether prebiotics or probiotics can be used to reduce the burden and severity of this pandemic.

Mucosal tissues are located at the interface between the external world and internal tissues, so they act as the primary innate and adaptive defense against invading pathogens (Abt et al., 2012 , Abrahamsson et al., 2014 , Donaldson et al., 2016 . Different mucosal parts in the body may act together as a system-wide organ to protect the host from foreign invaders (Gill et al., 2010, Wang and Tian., 2015) . This concept of "common mucosal immune system" was put forward by McDermott and Bienenstock in 1978, who found that after adoptive transfer of donor-derived B cells into mice, B cells of mesenteric lymph nodes distributed in most mucosal tissues, while B cells of peripheral lymph node returned to their original peripheral positions (Bienenstock et al.,1978) . This concept may explain, for example, why vaccination in one mucosal site leads to protection in another mucosal site (Gallichan et al., 2001) . Antigen exposure in the gastrointestinal can lead to the production of specific antibodies in the respiratory tract (Artenstein et al., 1997 , Kang and Kudsk, 2007 , Man et al., 2004 .

Available evidence suggests that the gut and lung are part of the common mucosal immune system. The system mainly comprises gut-associated lymphoid tissue (GALT) and bronchial-associated lymphoid tissue (BALT) (Mcghee and Fujihashi, 2012) . GALT, which is rich in innate and adaptive immune cells, has a more significant contribution to mucosal immunity (Deitch et al., 2006, Fagarasan and Honjo, 2003) . The blood and lymphatic vessels can transport these immune cells and factors from GALT to BALT (Qi et al., 2006; Samuelson et al., 2015) , thereby providing and enhancing resistance to respiratory infections. In a mouse model, activated intestinal 2 group innate lymphoid cells (ILC2s) were found in the lung injected with IL-25 in the gut (Huang et al., 2018) . Therefore, lymph and blood can link the site of primary immunization in the gut to the site of action in the lung. Whether immune cells and factors can be transferred from the BALT to the GALT through blood and lymph, needs to be checked in future work.

Although the transfer of sensitized immune cells from GALT to BALT can enhance the immune response in the respiratory system, the overreaction of COVID-19 patients in the form of excessive inflammation can lead to acute lung injury, acute respiratory distress syndrome, and multiple organ failure (Senthil et al., 2006 , Dickson et al., 2016 , Wang and Ma, 2008 , Channappanavar and Perlman, 2017 , Mehta et al., 2020 . It may also cause the intestinal mucus layer to be thin, reduce the surface area of the lumen, and impair the integrity of the intestinal barrier (Osband et al., 2004 , Rupani et al., 2007 , Ng and Tilg, 2020 , Ong et al., 2020 . Such damage will recruit more immune cells from the extra-intestinal space, exacerbating excessive inflammation and damage. These extra immune cells can then translocate from GALT to BALT, exacerbating excessive lung inflammation. This may explain why gastrointestinal symptoms are associated with more severe COVID-19 (Luo et al., 2020 , Jin et al., 2020 . Future research should examine whether these gastrointestinal symptoms are useful for identifying COVID-19 patients at high risk of severe respiratory manifestations.

Immune cells express homing receptors that target them to certain tissues so that wherever they encounter antigen, they will subsequently migrate back to these tissues (Campbell and Butcher, 2002) . This may contradict the idea that immune cells in the gut can be translocated to the lung and affect the inflammatory response. One explanation for this apparent contradiction is that lung and gut tissues come from the same embryonic tissue to share similar homing receptors. Another explanation is that during an inflammatory response, especially an overreaction, immune cells from one compartment can migrate to their target tissues and migrate to other tissues through interactions with surface molecules that the cells normally cannot recognize. For example, T effector memory cells activated in the gut during an inflammatory response may enter the systemic circulation and then interact with lung endothelial PNAd through L-selectin/CD62L, thereby causing them to trigger an inflammatory response in the lung (Golubovskaya and Wu, 2016) . Given the noticeable inflammatory changes in the gut and lung during COVID-19 , Channappanavar and Perlman, 2017 , Ye et al., 2020 , the homing and tissue targeting of immune cells may be altered in a way that supports a common mucosal immune response. Exploring these possibilities is an exciting and vital task for future research.

Angiotensin-converting enzyme II (ACE2) was firstly reported in 2000 by Tipnis and Donoghue (Tipnis et al., 2000 , Donoghue et al., 2000 . It is a homolog of the classic enzyme ACE, but unlike the ACE, it is a negative regulator of the renin-angiotensin system (RAS) (Verano-Braga et al., 2020) .

RAS has an intricate interlinked system that regulates physiological and pathological functions of cardiovascular, renal and pulmonary system including a dynamic control over systemic and local blood flow, blood pressure, natriuresis, and trophic responses to a wide range of stimuli (Iwai et al., 2009 ). So as a counter-regulator of the RAS, ACE2 may be crucial for maintaining tissue homeostasis. In COVID-19, ACE2 has been identified as a functional receptor for SARS-CoV-2 pulmonary infection (Gheblawi et al., 2020) . However, It should be note that ACE2 is not only expressed on the surface of the lung alveolar epithelial cells, but also presents in most other tissues including heart, vessels, kidney, brain, and gastrointestinal system (Tipnis et al., 2000) . The diverse functions and widespread distributions of the ACE2 are critical to our understanding of the varied clinical symptoms and outcomes of COVID-19.

In gut, ACE2 physiologically regulates amino acid transports and has been related to gut immune and microbial homeostasis. Studies have shown that the lack of ACE2 in mice can damage the homeostasis of local tryptophan, change the intestinal microbiome, and make animals more susceptible to inflammation, leading to diffuse alveolar damage and a sharp increase in bacterial load in the cecum, as in acute lung injury (Hashimoto et al., 2012) . It is reported that SARS-CoV-2 can down-regulate the expression of ACE2 (Verdecchia et al., 2020) , which may further limit the function of ACE2, impair the homeostasis of intestinal tryptophan, and cause gut dysbiosis, thereby affecting lung homeostasis through gut-lung axis.

This article described the origin of the gut-lung axis and the latest progress in mediating, maintaining, and regulating the gut-lung axis, and also investigated the potential involvement of the gut-lung axis in COVID-19 from the aspects of microbiota, microbiota metabolites, microbial dysbiosis, common mucosal immunity, and ACE2. The following are some perspectives and suggestions that may guide future research on the mechanisms of COVID-19 and novel treatment and management strategies for COVID-19.

Firstly, the microbiota and microbiota metabolites are necessary for immune homeostasis and may play an essential role in the gut-lung axis. Microbial dysbiosis may affect the homeostasis of the gut and lung, which has also been reported in COVID-19. Since probiotics and prebiotics can shape the intestinal flora to regulate the host's immunity significantly, it seems reasonable to employ probiotics and prebiotics treatment and specific strains of bacteria through fecal transplants to prevent and treat a bacterial or viral infection such as SARS-COV2. Therefore, probiotics, prebiotics and fecal transplant treatment methods will be explored with a great prospect in COVID-19.

Secondly, according to the common mucosal immune system concept, different mucosal sites of the body function together as a system-wide organ to protect the host from foreign invading organisms. Like a gut-lung axis, an inflammatory response in the gut may be reflected in the lung and vice versa. So any disease should not be treated separately because organs interact with each other through various methods. When it comes to COVID-19, it is not simply a disease of the lung, but disease that may affect the organs of the entire system. Targeting system-wide organs affected in COVID-19 may be a critical step in treating COVID-19 in the future.

Thirdly, regarding ACE2, it may play an essential role in COVID-19 through several aspects. It acts as a main invade route for SARS-CoV-2, because it is expressed on the surface of lung alveolar type II cells and upper esophageal cells, stratified epithelial cells, and absorptive enterocytes in the ileum and colon. In addition, its expression in the enterocytes can be used as a regulator of dietary aminoacids uptake. If any, it may be related to fecal-oral transmission. Thus, the containment of viral spreading, and more importantly, affects the gut immune and microbial homeostasis, may affect the lung through the gut-lung axis. So understanding the role of ACE2 in the gut-lung axis and COVID-19 is crucial for developing novel therapeutic strategies.

Last but not the least, we must know that current understanding of the gut-lung axis has only just begun to be deciphered, mainly based on epidemiological and clinical observations, and lack of basic research. In addition, so far, there is no direct evidence to support the notion that acting on the gut-lung axis may affect the course of SARS-CoV-2 infection. However, this remains a fascinating hypothesis due to the possible implications in clinical practice. So future work should combine basic research on the gut-lung axis and COVID-19 to clarify the progression of the disease and how to treat or even prevent it.

The microbiota, microbiota metabolites, and common mucosal immunity might have an essential role in mediating, maintaining and, regulating the gut-lung axis, and the gut-lung axis might be involved in COVID-19. However, the exact mechanism between the gut-lung axis and the COVID-19 is yet to be defined, needing further basic research and improved interventional experiments to elucidate the role of the gut-lung axis in COVID-19.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

This research was supported by the National Key R&D Program of China (2017YFC0211705) and the Science & Technology Department Program of Sichuan Province (2019YFS0144).

No human subjects were involved in this work and therefore ethical approvals were not required for the development of this manuscript.

Dan Zhou and Hanmin Liu conceived the study, Dan Zhou and Qiu Wang wrote the manuscript, Hanmin Liu and Qiu Wang revised the manuscript. All authors revised the manuscript and approved the submitted version.

Bidirectional gut-lung axis. The gut microbiota and microbiota metabolites can regulate the lung immune through the lymphatic or circulatory systems, when the composition and diversity of the gut microbiota are changed, which termed microbial dysbiosis, can affect the lung immune through the lymphatic or circulatory systems. Similarly, the lung microbiota may also affect the gut microbiota through the lymphatic or circulatory systems, the dysbiosis of the intestinal flora can be caused by the lung microbial dysbiosis and inflammatory cytokines through the lymphatic or circulatory systems. Figure 2 The gut-organ axis. The gut microbiota shares a mutually beneficial relationship with its host, where it produces various metabolites that can further signal to remote organs in body through neural, endocrine, immune, humoral, and metabolic pathways, regulating the body metabolic homeostasis and organ physiology. The complex interactions between the gut microbiota and the different organs result in the formation of the "gut-organ axis" between them, such as the gut-lung axis, gut-brain axis, gut-heart axis, gut-liver axis, gut-kidney axis, gut-liver-kidney axis etc. Within these axes, any alterations in gut microbiota composition and diversity may not only trigger gut disorders, but also influence other organs and cause associated diseases. 

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Gut-lymph hypothesis of systemic inflammatory response syndrome / multipleorgan dysfunction syndrome: validating studies in a porcine model

Fibrosing alveolitis and chronic liver disease

Detection of Novel Coronavirus by RT-PCR in Stool Specimen from Asymptomatic Child

Gut as the largest immunologic tissue

Lung-gut cross-talk: evidence, mechanisms and implications for the mucosal inflammatory diseases

The gut microbiome in coronary artery disease and heart failure: Current knowledge and future directions

The gut-liver axis and the intersection with the microbiome

Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis

Development and maintenance of intestinal regulatory T cells

Gut and lung microbiota in preterm infants: immunological modulation and implication in neonatal outcomes

A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase

ACE2 in the renin-angiotensin system

The pivotal link between ACE2 deficiency and SARS-CoV-2 infection

Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan

How lung infection leads to gut injury

The Cytokine Storm and Factors Determining the Sequence and Severity of Organ Dysfunction in Multiple Organ Dysfunction Syndrome

Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding

COVID-19): the Zhejiang experience

The Pathogenesis and Treatment of the `Cytokine Storm' in COVID-19

COVID-19: gastrointestinal symptoms from the view of gut-lung axis

Molecular and serological investigation of 2019-nCoV infected patients: implication of multiple shedding routes

Influenza infection elicits an expansion of gut population of endogenous Bifidobacterium animalis which protects mice against infection

COVID-19 and Multiorgan Response

Alterations in gut microbiota of patients with COVID-19 during time of hospitalization