The role of gut microbiota in SARS-CoV-2 infection: Focus on angiotensin-converting enzyme 2

Nata Pratama Hardjo Lugito; Andree Kurniawan; Vika Damay; Henny Chyntya; Natasya Sugianto

doi:10.4103/cmi.cmi_80_20

LETTER TO THE EDITOR

Year : 2020 | Volume : 18 | Issue : 3 | Page : 261-263

The role of gut microbiota in SARS-CoV-2 infection: Focus on angiotensin-converting enzyme 2

Nata Pratama Hardjo Lugito¹, Andree Kurniawan¹, Vika Damay², Henny Chyntya², Natasya Sugianto²
¹ Department of Internal Medicine, Pelita Harapan University, Tangerang, Banten, Indonesia
² Department of General Medicine, Faculty of Medicine, Pelita Harapan University, Tangerang, Banten, Indonesia

Date of Submission	12-May-2020
Date of Decision	27-May-2020
Date of Acceptance	04-Jun-2020
Date of Web Publication	10-Jul-2020

Correspondence Address:
Mr. Nata Pratama Hardjo Lugito
Department of Internal Medicine, Faculty of Medicine, Pelita Harapan University, Boulevard Jendral Sudirman, Lippo Karawaci, Tangerang, 15811 Banten
Indonesia

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/cmi.cmi_80_20

How to cite this article:
Lugito NP, Kurniawan A, Damay V, Chyntya H, Sugianto N. The role of gut microbiota in SARS-CoV-2 infection: Focus on angiotensin-converting enzyme 2. Curr Med Issues 2020;18:261-3

How to cite this URL:
Lugito NP, Kurniawan A, Damay V, Chyntya H, Sugianto N. The role of gut microbiota in SARS-CoV-2 infection: Focus on angiotensin-converting enzyme 2. Curr Med Issues [serial online] 2020 [cited 2021 Jan 18];18:261-3. Available from: https://www.cmijournal.org/text.asp?2020/18/3/261/289426

The microbiota and probiotics affect the function of the human body in many ways through various mechanisms.^[1] The pathogenesis of SARS-CoV-2 through angiotensin-converting enzyme 2 (ACE2) would seem to be an important way of intervention against the infection. Many proteins and drugs that modulate the renin-angiotensin aldosterone system (RAAS) mainly affecting the ACE2. The gut microbiota has been showed to affect the RAAS, especially the ACE2.

Mechanism of Sars-Cov-2 Cell Entry

The S protein of SARS-CoV-2 binds to ACE2, and mediate membrane fusion and virus entry.^[2] The SARS-CoV-2 uses ACE2 to enter human cell, similar to SARS-CoV. A study showed the presence of ACE2 in Type II alveolar (AT2) cells of lung, esophagus upper and stratified epithelial cells, absorptive enterocytes from ileum and colon, myocardial cells, and kidney proximal tubule cells thus resulting clinical manifestations.^[3] Interaction between SARS-CoV-2 and the RAAS is shown in [Figure 1].

Figure 1: Interaction between SARS-CoV-2 and the renin-angiotensin aldosterone system. After binding to its functional receptor, ACE2, the SARS-CoV-2 enters into cells, primarily AT2 cells. After endocytosis of the viral complex, surface ACE2 is further downregulated, resulting in increased angiotensin II that will mediate bronchoconstriction, acute lung injury, and acute respiratory distress syndrome, vasoconstriction. ACE: Angiotensin-converting enzyme; AT1R: Type 1 angiotensin II receptor; AT2: Type II alveolar.

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Role of Angiotensin-Converting Enzyme 2 in Pulmonary Virus Infection

ACE cleaves Ang I into angiotensin II (Ang II). The ACE2 cleaves Ang I into angiotensin-(1-9), and angiotensin II (Ang II) into angiotensin-(1-7), which counterbalances each other in the Ang II production. However, ACE2 has a preference for Ang II compared to Ang I. Ang II then binds to the type 1 angiotensin II receptor (AT1R) to initiate vasoconstriction and type 2 angiotensin II receptor (AT2R) to initiate local vasodilation.^[3] In the lung, Ang II activation of AT1R induces bronchoconstriction, pulmonary hypertension, and pulmonary fibrosis, which is opposed by ACE2.^[4]

The ACE2 is downregulated in SARS-CoV infection, and as the viral infection continues, the ACE2 expression on the cell membrane is reduced. The ACE2 downregulation leads to a local increase of Ang II levels and worsens lung injury and also started neutrophil infiltration. The ACE2 is hypothesized to protect against lung injury.^[5]

Potential Role of Gut Microbiota on Sars-Cov-2 Infection

Increased prevalence and severity of SARS-CoV-2 infection in the elderly might be associated with decreased gut microbiota diversity. Studies found a general decrease of Bacteroides, Prevotella, Bifidobacteria, and Lactobacillus spp. in the elderly.^[6] Inflammageing which is affected by changes in gut microbiota composition makes the elderly susceptible to morbidity, disability, frailty, and premature death.^[7]

In SARS-CoV-2 treatment, probiotics were widely used for patients with diarrhea.^[8] However, probiotics usage was based on the knowledge of the dysbiosis of gut microbiota caused diarrhea. There are some ongoing clinical trials on the use of probiotics in SARS-CoV-2 patients and their caregivers. These studies were based on the beneficial effects of probiotics on the immune system.^[9]

The mechanisms of probiotics' antiviral effects are still unclear. Possible mechanisms, among others, were hindering the adsorption, blocking the virus-cell internalization process, binding to and blocking further infections, and suppressing virus replication, which is associated with ACE2.^[10] During the fermentation process by microbiota, ACE inhibitory peptides are released into the intestinal lumen into and bloodstream.^[11] These peptides block the cleavage of Ang I into Ang II. Ang II induces bronchoconstriction, pulmonary hypertension, and pulmonary fibrosis. Thus, ACE inhibitory peptides would prevent them.

The interplay between microbiota and the RAAS in the gut could counterbalance the ACE2 deficiency. Segmented filamentous bacteria, a probiotic that proved effective to prevent and cure rotavirus infection, resulted in the increase of ACE2 expression. Lactobacillus acidophilus and Bacillus clausii could preserve ACE2 expression in the murine small intestine post Salmonella ^{More Details} infection.^[8] The potential role of gut microbiota associated with ACE2 on SARS-CoV-2 infection is shown in [Figure 2].

Figure 2: Potential role of gut microbiota associated with ACE2 on SARS-CoV-2 infection. The potential gut microbiota and probiotics role in the SARS-CoV-2 infection are (1) release of ACE inhibitory peptides, which blocks the ACE action; (2) block the SARS-CoV-2 internalization; (3) increase ACE2 expression which is downregulated in SARS-CoV-2 infection. ACE: Angiotensin-converting enzyme; AT1R: Type 1 angiotensin II receptor.

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In conclusion, microbiotas and probiotics could provide an option in the treatment of SARS-CoV-2 infection.

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Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Hamady M, Knight R. Microbial community profiling for human micro-biome projects: Tools, techniques, and challenges. Genome Res 2009;19:1141-52.
2.	Ou X, Liu Y, Lei X, Li P, Mi D, Ren L,et al. Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nat Commun 2020;11:1620.
3.	Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B,et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med 2005;11:875-9.
4.	Vasileiadis IE, Goudis CA, Giannakopoulou PT, Liu T. Angiotensin converting enzyme inhibitors and angiotensin receptor blockers: A promising medication for chronic obstructive pulmonary disease? COPD 2018;15:148-56.
5.	Vaduganathan M, Vardeny O, Michel T, McMurray JJV, Pfeffer MA, Solomon SD. Renin-angiotensin-aldosterone system inhibitors in patients with Covid-19. N Engl J Med 2020;382:1653-9.
6.	Ferrucci L, Fabbri E. Inflammageing: Chronic inflammation in ageing, cardiovascular disease, and frailty. Nat Rev Cardiol 2018;15:505-22.
7.	Woodmansey EJ, McMurdo ME, Macfarlane GT, Macfarlane S. Comparison of compositions and metabolic activities of fecal microbiotas in young adults and in antibiotic-treated and non-antibiotic-treated elderly subjects. Appl Environ Microbiol 2004;70:6113-22.
8.	Feng Z, Wang Y, Qi W. The small intestine, an underestimated site of SARS-CoV-2 infection: From red queen effect to probiotics. Peer J. Preprints 2020;2020030161. doi: 10.20944/preprints202003.0161.v1. Available from: https://www.preprints.org/manuscript/202003.0161/v1. [Last accessed on 2020 May 11].
9.	Sacramento: Internasional Scientific Association for Probiotics and Prebiotics; c2002. How some probiotic and prebiotic scientists are working to address covid-19; 2020. Available from: https://isappscience.org/how-some-probiotic-and-prebiotic-scientists-are-working-to-address-covid-19/. [Last accessed on 2020 May 23].
10.	Li N, Ma WT, Pang M, Fan QL, Hua JL. The commensal microbiota and viral infection: A comprehensive review. Front Immunol 2019;10:1551.
11.	Dave LA, Hayes M, Montoya CA, Rutherfurd SM, Moughan PJ. Human gut endogenous proteins as a potential source of angiotensin-I-converting enzyme (ACE-I)-, renin inhibitory and antioxidant peptides. Peptides 2016;76:30-44.