Gut microbiome and severity of COVID-19: what are the advances in research in this area?

The COVID-19 epidemic, caused by infection with the SARS-CoV-2 virus, which emerged in late 2019 in Hubei in the Chinese province of Wuhan and spread rapidly to the rest of the world, is characterized, in its most serious forms, by severe acute respiratory distress syndrome, or SARS. A number of arguments soon prompted the medical and scientific community to question the involvement of the gut microbiota in the severity of infection.

In fact, research conducted in the 2000s had already shown that SARS is associated with gastrointestinal symptoms (diarrhea, vomiting, abdominal pain, nausea, anorexia)¹, symptoms also observed in SARS-CoV-2 infections². However, it is not yet clear whether these gastrointestinal symptoms point to the severity of infection. Indeed, various studies, including one recently published on the medRxiv website, which analyzed the results obtained in different patient cohorts (from Italy, the United States, and Europe), even suggest the opposite, since they found that gastrointestinal symptoms associated with SARS-CoV-2 infection correlate with a reduction in the severity of infection.^3,4.

Irrespective of the presence or absence of gastrointestinal symptoms, other research has shown that the severity of infection is associated with a higher level of viral replication, as detected in the stool samples of hospitalized patients⁵. In fact, characterization of the infectious cycle of the virus (invasion, replication, and dispersion) has revealed that the receptor to which the virus attaches, which constitutes the virus’s point of entry, as it were, is expressed abundantly not only on the surface of the epithelium* of the upper respiratory tract but also on the intestinal epithelium^6,7,8. However, the presence alone of this receptor and of the components required for the virus to enter the cell does not explain why the virus replicates more favorably in the intestinal cells of some patients. Current research is trying to establish whether the gut constitutes a true viral reservoir – that is, a site where the virus continues to multiply – and whether this intestinal persistence contributes to the worsening of patients’ condition, or even to the persistence of the virus in the longer term.

These questions are particularly important since many patients present with recurrent and persistent long-term inflammatory symptoms.

In parallel with a high rate of intestinal viral replication, researchers observed notable differences in microbial composition and function between patients affected severely and moderately with SARS-CoV-2⁵. In particular, the production of short-chain fatty acids, which are products of bacterial fermentation and whose anti-inflammatory properties and contribution to good gut function are well known in the scientific community, is associated with less severe cases⁵. These recent data reinforce previous work on another type of virus, Influenza, which showed that certain gut microbial metabolites participate in the early antiviral response, allowing the pulmonary immune system to control the infection^9,10.

These new avenues of research could make it possible to detect people at risk of developing severe forms or to establish new treatments to prevent an aggravation of the infection. Indeed, the observation of a higher incidence of the severity of SARS-CoV-2 infection in people with pathologies in which an alteration of the microbial balance has been observed, such as obesity, arterial hypertension, and type 2 diabetes, strongly suggests the hypothesis that an initial alteration of the composition of the gut microbiome could be a predisposing factor for the development of severe forms of SARS-CoV-2 infection^11,12. However, due to the difficulty of recovering samples early on, including before hospitalization, it is not always possible to establish whether the initial gut microbial composition, prior to infection, might favor development of the virus.

The use of experimental models¹³will allow for a better understanding of the kinetics of these microbial changes. This will make it possible to identify the determinants that lead to aggravation of the disease, as well as to test whether treatments that support restoration of the microbiome through nutritional interventions and/or supplementation of beneficial microbial products from the beginning of the infection might limit aggravation of the disease¹¹.

*epithelium: cells that line the inside of hollow organs such as the skin, lungs, and gut

1. Leung, W. K. et al. Enteric involvement of severe acute respiratory syndrome-associated coronavirus infection. Gastroenterology 125, 1011–1017 (2003).

2. Cheung, K. S. et al. Gastrointestinal Manifestations of SARS-CoV-2 Infection and Virus Load in Fecal Samples From a Hong Kong Cohort: Systematic Review and Meta-analysis. Gastroenterology 159, 81–95 (2020).

3. Aghemo, A. et al. COVID-19 Digestive System Involvement and Clinical Outcomes in a Large Academic Hospital in Milan, Italy. Clinical Gastroenterology and Hepatology 18, 2366-2368.e3 (2020).

4. Livanos, A. E. et al. Gastrointestinal involvement attenuates COVID-19 severity and mortality. medRxiv 2020.09.07.20187666 (2020) doi:10.1101/2020.09.07.20187666.

5. Zuo, T. et al. Depicting SARS-CoV-2 faecal viral activity in association with gut microbiota composition in patients with COVID-19. Gut 70, 276–284 (2021).

6. Hamming, I. et al. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol 203, 631–637 (2004).

7. Hoffmann, M. et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 181, 271-280.e8 (2020).

8. Zhang, H. et al. Digestive system is a potential route of COVID-19: an analysis of single-cell coexpression pattern of key proteins in viral entry process. Gut 69, 1010–1018 (2020).

9. Ichinohe, T. et al. Microbiota regulates immune defense against respiratory tract influenza A virus infection. Proc Natl Acad Sci U S A 108, 5354–5359 (2011).

10. Steed, A. L. et al. The microbial metabolite desaminotyrosine protects from influenza through type I interferon. Science 357, 498–502 (2017).

11. Zhang, F. et al. Obesity predisposes to the risk of higher mortality in young COVID-19 patients. Journal of Medical Virology 92, 2536–2542 (2020).

12. Tang, Q. et al. A comprehensive evaluation of early potential risk factors for disease aggravation in patients with COVID-19. Sci Rep 11, 8062 (2021).

13. Johansen, M. D. et al. Animal and translational models of SARS-CoV-2 infection and COVID-19. Mucosal Immunol 13, 877–891 (2020).

Emelyne Lecuyer