Immunity and virus infections

Impression of the publications on the relevance of the microbiome

The gut microbiome plays an important role in the education and function of the immune system (1,2). The gut bacteria partly determine the basic tone of the immune system (3) and thus influence the crucial balance that exists between sufficient resistance and sufficient inhibition of inflammation (4-6). The gut microbiome thus plays a role in the acquired immunity and how effectively the immune system can respond to pathogens, but also in the extent to which immune responses remain within limits (7). It is striking that many non-communicable diseases such as type 2 diabetes are characterized by an overactive immune system in the form of low-grade inflammation (8-10), while at the same time there are indications that the acute immune response in viral infections is insufficient (11,12). Finally, research into the effect of antibiotics (13) and probiotics (14) on the immune response to vaccinations endorse the role of the microbiome in immunity. In short, a disturbed microbiome can lead to the immune system not being able to respond effectively enough to infections and to the inflammatory response being too strong or too long.

Virus infections
It is not surprising that virus infections affect the intestine and thus the intestinal microbiome, given the often occurring intestinal complaints. Although the research is still in its infancy, there is also evidence of an inverse relationship, in which the microbiome helps determine the response to and the course of viral infections (15). Treatment with different types of antibiotics in laboratory animals has shown that the composition of the gut microbiome influences the course of an infection with the flu virus (16,17). On the other hand, laboratory animal and human research show that certain probiotic strains can favorably influence the course of influenza virus infection (18).

Recent research focuses on the so-called gut-lung axis, which is the result of a complex interaction between micro-organisms and with, among other things, the immune system of the host (19,20). In this light, it is interesting that a Cochrane review concludes that there is cautious evidence that probiotics can reduce respiratory infections and have a beneficial effect on the course. Another Cochrane review concludes that there is some evidence that probiotics may reduce the risk of ventilator-associated pneumonia, although the quality of the included studies is low (21). Collectively, these findings suggest that the gut microbiome may affect infections and inflammation in the lungs.

In light of the current pandemic, the literature has been examined to see whether the aforementioned influence of the gut microbiome on immunity and infections may also play a role in the disease caused by infection with the SARS-CoV-2 coronavirus.

Gastrointestinal complaints
In more than 200 Covid-19 patients admitted to three hospitals in China, more than half had gastrointestinal complaints (22). Below the authors also counted decreased appetite, which is not very specific for gastrointestinal complaints. If only diarrhea, vomiting and abdominal pain are considered, these complaints occurred in 19% of the patients.

Virus in the stool
In several studies, the SARS-CoV-2 virus has been found in stool samples (23, 24). The fact that the RIVM has also found the virus in sewage water confirms the presence of the virus in faeces (25). Detection in feces leads to suspicion that infection with the virus could occur not only via airborne droplets but also via the fecal-oral route (26), implying that infection can also pass through the gastrointestinal tract.

Smell and infection of neurons
The UK Association of ENT Physicians published a notice on March 21 mentioning loss of sense of smell as a possible symptom of Covid-19 (27). The report mentions that in South Korea (where a great many people have been tested) in about 30% of the infected individuals, reduced sense of smell was the main complaint with an otherwise mild clinical picture. One possible cause of this reduced sense of smell is that the SARS-CoV-2 virus can get into the brain (28). Researchers also think this may be related to the breathing problems found in severe cases, because the respiratory center in the brainstem may be affected (29). Antigens against SARS-CoV-2 have been found in the brain stem, and in SARS-CoV (the coronavirus that was circulated in 2003) and MERS-CoV (the coronavirus that broke out in 2012), the brain stem was also among the most infected part of the brain (29).
The blood-brain barrier is an important anatomical layer that protects much (but not all areas) of the brain by selectively allowing or blocking substances (30). As in the intestinal epithelium tight junctions play an important role in this. The tight junctions in the gut epithelium are regulated by zonulin (31), which is also used as a marker for increased gut wall permeability (32,33). The gut microbiome has an important role in regulating the permeability of the gut wall, including through expression of tight junctions (31,33). Intriguingly, recent research shows that tight junctions in the blood-brain barrier also respond to zonulin (34). Increased intestinal permeability can also lead to bacterial substances, such as LPS, in the circulation that themselves, whether or not via an inflammatory reaction, also adversely affect the blood-brain barrier (33,35,36).


1. Hooper LV, Littman DR, Macpherson AJ. Interactions Between the Microbiota and the Immune System. Science. 2012; 336: 1268–73.

2. Shulzhenko N, Morgun A, Hsiao W, Battle M, Yao M, Gavrilova O, Orandle M, Mayer L, Macpherson AJ, McCoy KD, et al. Crosstalk between B lymphocytes, microbiota and the intestinal epithelium governs immunity versus metabolism in the gut. Nat Med. 2011; 17: 1585–93.

3. Belkaid Y, Harrison OJ. Homeostatic immunity and the microbiota. Immunity. 2017; 46: 562–76.

4. Wiesner DL, Klein BS. The Tipping Point between Lung Immunity and Inflammation. Science. 2017; 357: 973–4.

5. Taams LS. Inflammation and immune resolution. Clin Exp Immunol. 2018; 193: 1–2.

6. Cicchese JM, Evans S, Hult C, Joslyn LR, Wessler T, Millar JA, Marino S, Cilfone NA, Mattila JT, Linderman JJ, et al. Dynamic balance of pro- and anti-inflammatory signals controls disease and limits pathology . Immunol Rev. 2018; 285: 147–67.

7. Blander JM, Longman RS, Iliev ID, Sonnenberg GF, Artis D. Regulation of inflammation by microbiota interactions with the host. Wet Immunol. 2017; 18: 851–60.

8. Saltiel AR, Olefsky JM. Inflammatory mechanisms linking obesity and metabolic disease. J Clin Invest. 2017; 127: 1–4.

9. van Greevenbroek MMJ, Schalkwijk CG, Stehouwer CDA. Obesity-associated low-grade inflammation in type 2 diabetes mellitus: causes and consequences. Neth J Med. 2013; 71: 174–87.

10. Oguntibeju OO. Type 2 diabetes mellitus, oxidative stress and inflammation: examining the links. Int J Physiol Pathophysiol Pharmacol. 2019; 11: 45–63.

11. Karlsson EA, Sheridan PA, Beck MA. Diet-Induced Obesity Impairs the T Cell Memory Response to Influenza Virus Infection. J Immunol. American Association of Immunologists; 2010; 184: 3127–33.

12. Akmatov MK, Riese P, Trittel S, May M, Prokein J, Illig T, Schindler C, Guzmán CA, Pessler F. Self-reported diabetes and herpes zoster are associated with a weak humoral response to the seasonal influenza A H1N1 vaccine antigen among the elderly. BMC Infect Dis [Internet]. 2019 [cited 2020 Mar 27]; 19. Available from: https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-019-4214-x

Hagan T, Cortese M, Rouphael N, Boudreau C, Linde C, Maddur MS, Das J, Wang H, Guthmiller J, Zheng N-Y, et al. Antibiotics-Driven Gut Microbiome Perturbation Alters Immunity to Vaccines in Humans. Cell. 2019; 178: 1313-1328.e13.

14. Lei W-T, Shih P-C, Liu S-J, Lin C-Y, Yeh T-L. Effect of Probiotics and Prebiotics on Immune Response to Influenza Vaccination in Adults: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Nutrients. 2017; 9: 1175.

15. Denny JE, Powell WL, Schmidt NW. Local and Long-Distance Calling: Conversations between the Gut Microbiota and Intra- and Extra-Gastrointestinal Tract Infections. Front Cell Infect Microbiol [Internet]. 2016 [cited 2020 Mar 27]; 6. Available from: http://journal.frontiersin.org/Article/10.3389/fcimb.2016.00041/abstract

Ichinohe T, Pang IK, Kumamoto Y, Peaper DR, Ho JH, Murray TS, Iwasaki A. Microbiota regulates immune defense against respiratory tract influenza A virus infection. Proc Natl Acad Sci. 2011; 108: 5354–9.

17. Abt MC, Osborne LC, Monticelli LA, Doering TA, Alenghat T, Sonnenberg GF, Paley MA, Antenus M, Williams KL, Erikson J, et al. Commensal Bacteria Calibrate the Activation Threshold of Innate Antiviral Immunity. Immunity. 2012; 37: 158–70.

18. Zelaya H, Alvarez S, Kitazawa H, Villena J. Respiratory Antiviral Immunity and Immunobiotics: Beneficial Effects on Inflammation-Coagulation Interaction during Influenza Virus Infection. Front Immunol [Internet]. 2016 [cited 2020 Mar 27]; 7. Available from: http://journal.frontiersin.org/article/10.3389/fimmu.2016.00633/full

19. Enaud R, Prevel R, Ciarlo E, Beaufils F, Wieërs G, Guery B, Delhaes L. The Gut-Lung Axis in Health and Respiratory Diseases: A Place for Inter-Organ and Inter-Kingdom Crosstalks. Front Cell Infect Microbiol [Internet]. Frontiers; 2020 [cited 2020 Mar 27]; 10. Available from: https://www.frontiersin.org/articles/10.3389/fcimb.2020.00009/full

20. Budden KF, Gellatly SL, Wood DLA, Cooper MA, Morrison M, Hugenholtz P, Hansbro PM. Emerging pathogenic links between microbiota and the gut – lung axis. Nat Rev Microbiol. 2017; 15: 55–63.

21. Bo L, Li J, Tao T, Bai Y, Ye X, Hotchkiss RS, Kollef MH, Crooks NH, Deng X. Probiotics for preventing ventilator-associated pneumonia. Cochrane Database Syst Rev. 2014; 10: CD009066.

22. Lei Pan. Clinical characteristics of COVID-19 patients with digestive symptoms in Hubei, China: a descriptive, cross-sectional, multicenter study. Am J Gastroenterol [Internet]. 2020; preprint. Available from: https://journals.lww.com/ajg/Documents/COVID_Digestive_Symptoms_AJG_Preproof.pdf

23. Xie C, Jiang L, Huang G, Pu H, Gong B, Lin H, Ma S, Chen X, Long B, Si G, et al. Comparison of different samples for 2019 novel coronavirus detection by nucleic acid amplification tests. Int J Infect Dis. Elsevier; 2020; 93: 264–7.

24. Wang W, Xu Y, Gao R, Lu R, Han K, Wu G, Tan W. Detection of SARS-CoV-2 in Different Types of Clinical Specimens. JAMA [Internet]. 2020 [cited 2020 Mar 26]; Available from: https://jamanetwork.com/journals/jama/fullarticle/2762997

25. New coronavirus found in sewage | RIVM [Internet]. [cited 2020 Mar 26]. Available from: https://www.rivm.nl/nieuws/nieuwe-coronavirus-aangetouden-in-rioolwater

26. Hindson J. COVID-19: faecal – oral transmission? Nat Rev Gastroenterol Hepatol. Nature Publishing Group; 2020; 1–1.

27. Loss of sense of smell as marker of COVID-19 infection [Internet]. [cited 2020 Mar 26]. Available from: https://www.entuk.org/loss-sense-smell-marker-covid-19-infection

28. Baig AM, Khaleeq A, Ali U, Syeda H. Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host – Virus Interaction, and Proposed Neurotropic Mechanisms. ACS Chem Neurosci [Internet]. American Chemical Society; 2020 [cited 2020 Mar 26]; Available from: https://doi.org/10.1021/acschemneuro.0c00122

29. Li Y-C, Bai W-Z, Hashikawa T. The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients. J Med Virol [Internet]. 2020 [cited 2020 Mar 26]; n / a. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1002/jmv.25728

30. Daneman R, Prat A. The Blood – Brain Barrier. Cold Spring Harb Perspect Biol [Internet]. 2015 [cited 2020 Mar 16]; 7. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4292164/

31. Fasano A. Zonulin and Its Regulation of Intestinal Barrier Function: The Biological Door to Inflammation, Autoimmunity, and Cancer. Physiol Rev. American Physiological Society; 2011; 91: 151–75.

32. Fasano A. Zonulin, regulation of tight junctions, and autoimmune diseases. Ann N Y Acad Sci. 2012; 1258: 25–33.

33. Wells JM, Brummer RJ, Derrien M, MacDonald TT, Troost F, Cani PD, Theodorou V, Dekker J, Méheust A, de Vos WM, et al. Homeostasis of the gut barrier and potential biomarkers. Am J Physiol – Gastrointest Liver Physiol. 2017; 312: G171–93.

34. Rahman MT, Ghosh C, Hossain M, Linfield D, Rezaee F, Janigro D, Marchi N, van Boxel-Dezaire AHH. IFN-γ, IL-17A, or zonulin rapidly increase the permeability of the blood-brain and small intestinal epithelial barriers: Relevance for neuro-inflammatory diseases. Biochem Biophys Res Commun. 2018; 507: 274–9.

35. Mayerhofer R, Fröhlich EE, Reichmann F, Farzi A, Kogelnik N, Fröhlich E, Sattler W, Holzer P. Various action of lipoteichoic acid and lipopolysaccharide on neuroinflammation, blood-brain barrier disruption, and anxiety in mice. Brain Behav Immun. 2017; 60: 174–87.

36. Cryan JF, O’Riordan KJ, Cowan CSM, Sandhu KV, Bastiaanssen TFS, Boehme M, Codagnone MG, Cussotto S, Fulling C, Golubeva AV, et al. The Microbiota-Gut-Brain Axis. Physiol Rev. 2019; 99: 1877–2013.


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