Intestinal Flora as a Potential Strategy to Fight SARS-CoV-2 Infection: Review

Owning to its strong virulence, unfavourable prognosis, and lack of definitive treatment, potential prevention and treatment strategies for COVID-19 are required to be urgently identified and developed. The damage to host immune defense and "cytokine storm" - excessive production of inflammatory cytokines, are believed to be important determinants of poor outcomes and even mortality in patients with COVID-19(2)

Considering the vital role played by intestinal flora and its metabolites in regulating immune and inflammatory responses of the host, the prospect of modulating intestinal flora for preventing and treating COVID-19 and related diseases (e.g., viral and/or bacterial pneumonia, acute respiratory infections, influenza, etc.) have managed to attract considerable attention among the medical and research fraternity(3)

The "gut-lung axis" is a concept which refers to the cross-talk between these two mucosal components of the human body, which may take place via blood and lymphatic circulation (1)

It is noteworthy that COVID-19 patients with digestive tract symptoms had more severe disease and these could be used to predict the development of severe respiratory disorders (4). It is also an interesting association that some COVID-19 patients showed microbial dysbiosis with decreased levels of Lactobacillus and Bifidobacterium (5)

SARS-CoV-2 can identify and invade human cells through its interaction of spike proteins with human angiotensin-converting enzyme 2 (ACE2) (6) . ACE2 is expressed not just in the lung tissues but also on the epithelium of the oesophagus and intestines; thus, forming the fundamental basis of SARS-CoV-2 attacking the digestive tract and leading to intestinal flora dysbiosis and gastrointestinal symptoms (7) . Some studies have even reported that SARS-CoV-2 and its nucleic acid were isolated from stool samples of patients who presented with diarrhea (8). These pieces of evidence suggest that SARS-CoV-2 may be harbouring and fostering in the digestive tract of patients and transmitted via the faecal-oral route, affecting digestive health and gut flora.

Microbial metabolites like short-chain fatty acids (SCFAs), including butyric acid, acetic acid, and propionic acid, are the most critical metabolites of the intestinal flora. They are extremely critical in regulating systemic and pulmonary immune and inflammatory responses (9). The most direct function of SCFAs is to reduce the intestinal pH and increase mucin production, which reduces the growth and adhesion of pathogenic microbes and improves epithelial integrity, thereby enhancing systemic immunity of the host (10).

Probiotics and its metabolites such as short-chain fatty acids (SCFAs) are taken up by microfold (M cells) of the intestinal epithelium and presented to the immune system (T cells) as antigens via dendritic cells, leading to T/B cell proliferation and their subsequent activation. Through a series of immune mediators, these immune cells are then localized at the lung infection site, where they enhance antiviral immunity, thus providing protection to the lungs. The intestinal innate lymphoid cells (ILC2 and ILC3) migrate to the lungs to raise the antiviral immunity via lymphatic and blood. Surface IgA is produced and transported from gut-associated lymphoid tissues to the surface of the pulmonary mucosa, which could prevent virus adhesion and help strengthen the integrity of mucosal barriers. SCFAs produced by intestinal flora can be transported to the lungs through the blood, where they could possess anti-inflammatory activity and physiologically cement the lung mucosal barrier. SCFAs can also be mobilized to the bone marrow and help stimulate its hematopoietic functions, further promoting proliferation and activation of dendritic cells and other immune cells (1)

The above rationale seeks clinical testimony of a recent clinical trial which used a combination of multi-strain probiotics including Lactobacillus administered to hospitalised patients positive for COVID-19, and resulted in an eightfold lower risk of developing respiratory failure compared to standard care, thus significantly improving clinical outcomes in COVID-19 infections (11)

Intestinal flora may to some extent, mediate the effects of SARS-CoV-2 on both - local gastrointestinal response and systemic immune response of the host, thus serve to be a promising target for COVID-19 prevention and its treatment. This is consistent with emerging data which suggests that the gut microbiota plays a key role in predicting the blood proteomic biomarkers that determine the abnormal inflammatory state of individuals with severe COVID-19 (4)

Different kinds of probiotics and their metabolites may have different biological effects and may help to modulate the immune and inflammatory responses across a variety of respiratory infections (1), with encouraging evidence in COVID-19 specific infections (11)

Adapted from:

1 He LH, Ren LF, Li JF, Wu YN, Li X, Zhang L. Intestinal Flora as a Potential Strategy to Fight SARS-CoV-2 Infection. Front Microbiol. 2020;11:1388. Published 2020 Jun 9. doi:10.3389/fmicb.2020.01388

2 Zumla, A., Chan, J. F., Azhar, E. I., Hui, D. S., and Yuen, K. Y. (2016). Coronaviruses - drug discovery and therapeutic options. Nat. Rev. Drug Discov. 15, 327–347. doi: 10.1038/nrd.2015.37

3 Belkaid, Y., and Harrison, O. J. (2017). Homeostatic immunity and the microbiota. Immunity 46, 562–576. doi: 10.1016/j.immuni.2017.04.008

4 Gou, W., Fu, Y., Yue, L., Chen, G.-D., Cai, X., Shuai, M., et al. (2020). Gut microbiota may underlie the predisposition of healthy individuals to COVID- 19. medRXiv. 2020.2004.2022.20076091. doi: 10.1101/2020.04.22.20076091

5 Xu, K., Cai, H., Shen, Y., Ni, Q., Chen, Y., Hu, S., et al. (2020). [Management of corona virus disease-19 (COVID-19): the Zhejiang experience]. Zhejiang Da Xue Xue Bao Yi Xue Ban 49, 147–157.

6 Wu, F., Zhao, S., Yu, B., Chen, Y. M., Wang, W., Song, Z. G., et al.(2020). A new coronavirus associated with human respiratory disease in China. Nature 579, 265–269. doi: 10.1038/s41586-020-2202-3

7 Guan, W. J., Ni, Z. Y., Hu, Y., Liang, W. H., Ou, C. Q., He, J. X., et al. (2020). Clinical characteristics of coronavirus disease 2019 in China. N. Engl. J. Med.382, 1708–1720. doi: 10.1056/NEJMoa2002032

8 Lamers, M. M., Beumer, J., Van Der Vaart, J., Knoops, K., Puschhof, J., Breugem, T. I., et al. (2020). SARS-CoV-2 productively infects human gut enterocytes. Science. doi: 10.1126/science.abc1669

9 Budden, K. F., Gellatly, S. L., Wood, D. L., Cooper, M. A., Morrison, M., Hugenholtz, P., et al. (2017). Emerging pathogenic links between microbiota and the gut-lung axis. Nat. Rev. Microbiol. 15, 55–63. doi: 10.1038/nrmicro.2016.142

10 Fukuda, S., Toh, H., Hase, K., Oshima, K., Nakanishi, Y., Yoshimura, K., et al. (2011). Bifidobacteria can protect from enteropathogenic infection through production of acetate. Nature 469, 543–547. doi: 10.1038/nature09646

11 d'Ettorre G, Ceccarelli G et al, (2020) Challenges in the Management of SARS-CoV2 Infection: The Role of Oral Bacteriotherapy as Complementary Therapeutic Strategy to Avoid the Progression of COVID-19. Front. Med. 7:389. doi: 10.3389/fmed.2020.003