Gut-lung cross-talk: a role for the gut microbiota in COVID-19?
Evidence amounts showing that the impact of the gut extends to distant organs such as the brain and the liver. Is it possible then that the lungs and the gut may also be connected? The answer is yes. Individuals suffering from lung diseases including allergy, asthma and lung cancer often have disturbances in the composition and metabolic activity of their intestinal communities.1-3 Likewise, patients with certain intestinal diseases, for instance, inflammatory bowel disease, manifest pulmonary abnormalities such as inflammation in their airway even without necessarily developing bronchopulmonary symptoms.4 The mechanism underlying a gut-lung relationship is not clear. Yet, inflammation and immune responses seem to be the main components of this vital cross-talk.5
The gut microbiota in respiratory infections
It is well known that the gut microbiota has a profound effect on the immune system. This includes, importantly, the ability to steer type I interferon (IFNα/β) signature. These are critical pathways that provide early protection against viruses. As observed in some experimental models, antibiotic depletion of the gut communities facilitates the early replication of the influenza virus in lung epithelia and increases its severity on the host.6 Other studies, in pneumonia patients, show that modulation of the gut microbiota reduces ventilator-associated infection in mechanically ventilated patients with enteritis.7
Underlying microbiota-driven mechanisms in respiratory infections are still to be elucidated. Yet, it is clear already that some microbial metabolites do play a key role. For instance, previous research indicated a correlation between butyrate-producing microbes and protection against viral respiratory infections.8 Butyrate, a bacterial metabolite produced during fermentation, stands out by its immunomodulatory effect. Among the important roles of butyrate, it enhances the integrity of the intestinal epithelium. In addition, it has been shown to reduce lung injury and inflammation during pneumonia.9
What has been found in patients with COVID-19?
In general, patients with respiratory infections report gut dysfunctions including diarrhoea and COVID-19 patients are not an exception. About 5 to 33% of individuals have, besides upper respiratory symptoms, diarrhoea, vomiting, loss of appetite and nausea.10,11 Not surprisingly, the virus can often be tracked in faeces suggesting that it can spread via “faecal-oral transmission”.
Mechanistically speaking, researchers are focusing on a possible modulatory effect of the gut microbiota during SARS-CoV-2 infection.12 The hypothesis is based on the fact that gut microbes are known to influence the expression and activity of ACE-2 (angiotensin-converting enzyme 2). This protein is located on the surface of some cells (including nose, lungs and intestines) and is a key place for SARS-CoV-2 to attach and subsequently infect them. A recent publication indicates that, indeed, SARS-CoV-2 is able to infect enterocytes and can multiply in the gut.13 Moreover, the study also showed the activation of interferon stimulated genes (type I and III) and a broad signature of cytokines. ACE2 is also known to regulate intestinal amino acid transport, including tryptophan. Affecting tryptophan levels has a direct effect on the expression of antimicrobial peptides, especially in the small intestine.11 An event that may not only lead to changes in the composition of the gut microbiota but that may also affect the activity of Paneth cells, the key mediators of the intestinal defence.
Tackling SARS-CoV-2 infection from the gut, a real opportunity?
At the moment, researchers are exploring the potential of modulating the gut microbiota as a therapeutic tool against respiratory infections, including COVID-19. Experts highlight two randomised controlled trials when making a search for evidence to support this endeavour. In both studies, patients who received a probiotic intervention (Lactobacillus rhamnosus GG, live Bacillus subtilis, and Enterococcus faecalis) presented less cases of ventilator-associated pneumonia when compared to placebo.14,15 An effect that might be of importance during this crisis seeing that a range of 2-47% of patients infected require invasive mechanical ventilation.16,17 In addition, a report indicated that COVID-19 patients, in some cases, have decreased abundance of Lactobacilli and Bifidobacteria which constituted a starting point to invite the population to take care of their gut health.18,19
Considering that an optimal immune response is crucial for the control of any disease, it then becomes essential to have a balance in the cells that modulate the immune system. It has been reported that COVID-19 patients show an altered equilibrium in Th17 cells (IL-17) and TREG cells (IL-10).11 Thus, probiotics exhibiting anti-inflammatory effects, such as Lactobacillus rhamnosus and Bifidobacterium lactis HN019, whilst also restoring a patient’s gut microbiota may be of clinical significance during the disease.11 Moreover, besides the use of probiotics, microbial metabolites such as propionate have been also hypothesised to have potential in restoring adaptive and innate immunity.11
The cases mentioned above are of great excitement for many researchers although some others advice to be cautious and have a better understanding of the pathogenesis of SARS-CoV-2 and the impact on the gut microbiota before immediately using probiotics during the pandemic.20 However, some authorities are already ahead on this matter. These include the Chinese National Health Commission and National Administration of Traditional Chinese Medicine which recommended last February the use of probiotics to maintain the intestinal balance and prevent infection.21 And the Vietnamese Ministry of Health government's decision to specifically recommend probiotic consumption as a way to strengthen the immune defences.22
1. Russell et al. (2012) EMBO Reports 13(5): 440-447
2. Du et al. (2020) Journal of Cellular Physiology 235(1): 563-572
3. Tsang et al. (2018) Molecules 23(11)
4. Wang et al. (2013) World Journal of Gastroenterology 19(40): 6794-6804
5. Zhang et al. (2020) Frontiers in Microbiology 11: 301
6. Bradley et al. (2019) Cell Reports 28(1): 245-256.e4
7. Shimizu et al. (2018) Critical Care 22(1): 239
8. Haak et al. (2018) Blood 131(26): 2978-2986
9. Chakraborty et al. (2017) Nature Communications 8: 13944
10. University, S. Gastrointestinal symptoms common in COVID-19 patients, Stanford Medicine study reports. 2020; Available from: http://med.stanford.edu/news/all-news/2020/04/stomach-complaints-common-in-covid-19-patients.html.
11. Di Renzo et al. (2020) European Reviews for Medical and Pharmacology Science 24(8): 4062-4063
12. Fanos et al. (2020) JPNIM 9(1): e090139
13. Lamers et al. (2020) Science eabc1669
14. Morrow et al. (2010) American Journal of Respiratory and Critical Care Medicine 182(8): 1058-64
15. Zeng et al. (2016) Intensive Care Medicine 42(6): 1018-28
16. Guan et al. (2020) The New England Journal of Medicine 382(18): 1708-1720
17. Chen et al. (2020) Lancet 395(10223): 507-513
18. Xu et al. (2020) Zhejiang Da Xue Xue Bao Yi Xue Ban 49(2): 147-157
19. Gao et al. (2020) Journal of Digestive Diseases 21(3): 125-126
20. Mak et al. (2020) The Lancet Gastroenterology and Hepatology 24; S2468-1253(20)30122-9.
21. National Health Committee of the People's Republic of China, N.A.o.T.C.M. Diagnostic and therapeutic guidance for 2019 novel coronavirus disease (version 5). 2020; Available from: http://www.nhc.gov.cn/yzygj/s7653p/202002/d4b895337e19445f8d728fcaf1e3e13a/files/ab6bec7f93e64e7f998d802991203cd6.pdf.
22. Ministry of Health, V. Enhance immunity during the epidemic season. 2020; Available from: https://ncov.moh.gov.vn/web/guest/-/tang-cuong-mien-dich-trong-mua-dich.