Is the Health of the Gut Microbiome Linked to the Severity of Covid-19?

On April 25, 2020, the results of a study looking at the connection between the gut microbiome and Covid-19 were published.  This research adds depth to the new discovery that an unbalanced, unhealthy gut microbiome promotes inflammation that may result in higher susceptibility to Covid-19 and a greater risk of progression into more severe disease, especially in older individuals (1).  Though this study has not yet been peer-reviewed, it cannot be dismissed as unimportant.  Further study is necessary however to substantiate its findings.

 

The coronavirus outbreak known as Covid-19 has spread around the world at an alarming rate.  Its clinical features are gradually making themselves known and its treatment has evolved as physicians discover therapies that seem to lead to better outcomes.  Still, little is known about why some people with the disease are hardly aware they have it and others become gravely ill.

 

What is now well understood is that SARS-CoV-2, the virus that causes Covid-19, enters the body by attaching to angiotensin-converting enzyme 2 receptors (ACE2) that are present in many parts of the body including the lungs, heart, arteries, kidney, brain, small intestine and colon (2).  ACE2s are known to play a major role in the regulation of intestinal inflammation and also have substantial impact on the composition of the microorganisms that live in the gut (3,4).  Covid-19 patients demonstrate the ACE2 intestinal link.  Over 60% of patients with Covid-19 experience gastrointestinal symptoms such as diarrhea, nausea and vomiting and having these symptoms has been found to predict a worse disease outcome overall (1).

 

Putting this evidence together, the authors of the April 2020 study wanted to look into the potential of the gut microbiome to alter the susceptibility to Covid-19 and its subsequent severity.  Earlier observations of Covid-19 patients identified a set of inflammatory proteins in their blood that act as biomarkers, predicting more serious Covid-19 infection.  In this investigation, the link between the gut microbiome and the inflammatory biomarkers was studied with the goal of learning if these biomarkers could predict susceptibility to Covid-19 in healthy, non-infected individuals and whether or not the gut microbiome might play a role in regulating Covid-19 disease (1).

 

 

What are the results of this study?    

Every 10% increase in the blood level of these inflammatory biomarkers in Covid-19 patients was associated with a 57% higher risk of progression to a much more critical form of the disease (1).

 

The presence of these biomarkers was also associated with concentrations of other well-known inflammatory markers in the blood such as hsCRP and TNF-α, especially in individuals over the age of 58 (1).

 

The concentrations of certain microorganism species in the gut microbiome could explain an average of 21.5% of the risk of contracting Covid-19 in healthy people, indicating that the gut microbiome had a stronger influence on the progression of Covid-19 disease than other risk factors of the disease such as age, BMI, blood pressure, blood lipids or gender. Researchers found that they could predict higher levels of inflammatory biomarkers when a microbiome was out of balance, demonstrating that an unhealthy gut microbiome may predispose healthy people to increased inflammation, higher susceptibility to Covid-19 and higher risk of progression to a more serious form of the disease.  Importantly, these results were successfully replicated in another independent group of participants, supporting the conclusion that changes in the gut microbiota precede the change in biomarkers.  In other words, poor health of the gut microbiome is a potential cause of severe Covid-19 (1).

 

To further clarify the effect of the balance of species within the gut microbiome on Covid-19, a separate group of 366 subjects was examined for the relationship between gut microbiome species and inflammatory cytokines.  Cytokines are small proteins important for communication within the immune system.  Accumulating evidence is suggesting that excessive production of inflammatory cytokines resulting in a “cytokine storm” may be an important mechanism leading to serious Covid-19 and increased risk of death from the disease, actually causing more damage than the direct effects of the SARS-CoV-2 virus itself.  Cytokines produced in the inflammatory environment of a damaged gut microbiome can provide a running start to a cytokine storm and increase its potential to cause serious harm in a Covid-19 patient (5,6,7).  Results from this group of subjects revealed that inflammatory gut microorganisms were significantly associated with the production of cytokines (1).

 

 

What are the conclusions of this study?

Wide variability in the susceptibility of healthy people to Covid-19 has been observed during the course of the Covid-19 pandemic.  This study shows that, among healthy non-infected individuals, gut microbial features are highly predictive of elevated levels of biomarkers for severe Covid-19 disease.  Disruption of the gut microbiome may predispose healthy individuals to higher levels of inflammation and increased Covid-19 susceptibility (1).

 

Evidence from this study adds to previous research that illustrates that the balance of species making up the gut microbiome plays a fundamental role in the function of the host immune system.  Making positive changes in the composition of the gut microbiome through encouraging the growth of beneficial microorganisms and discouraging harmful ones may be both a potential preventative and a treatment for Covid-19 disease (1,8).

 

 

What can be learned from this study?

Further research is needed to corroborate the outcomes of this study, however, there is already ample evidence of the importance of a healthy gut microbiome for health in general.  With indications of the potential of a robust gut microbiome to lessen the severity of Covid-19, the time to encourage a healthy  balance of gut microorganisms is now (1).

 

 

Fostering healthy gut microorganisms

What we eat is inevitably what our gut microorganisms eat.  Is it possible to eat in a way that satisfies us but also provides the food to help the beneficial species in our gut thrive?  Not only can we do this, but it is not difficult to achieve.

 

Our tiny beneficial gut inhabitants flourish on fiber of all kinds. and there are literally thousands of different kinds of fiber to be gleaned from the foods that we eat.  But fiber is not present in just any food.  There is absolutely no fiber in animal-based foods such as meat, eggs and dairy products.  Conversely, every plant-based food provides fiber of some kind.  Different gut microbes prefer different types of dietary fiber, and, because every type of plant contains its own mix of fibers, it is best to consume a wide variety of plants in order to keep all the various healthy microbes satisfied.

 

The largest study of the gut microbiome to date includes more than 11,000 people and illustrates that the most important factor for a healthy gut microbiome is the diversity of plants in the diet.  Simply being a vegan (eating a diet made up of only plant-based food) is not enough if the same foods are eaten all the time.  This study recommends including more than thirty types of plants in the diet to provide great enough diversity of fiber and resistant starches to support a more varied microbial community in the gut.  This may sound daunting but modern grocery stores easily provide year-round access to many more varieties of plants than this (9).

 

Fiber is made up of long, complex chains of carbohydrates that our bodies are unable to digest on their own.  Consequently, fiber from food makes its way mostly unchanged to the colon (large intestine), where beneficial gut microorganisms break it down through fermentation and produce short-chain fatty acids (SCFAs) such as butyrate, acetate and propionate.  SCFAs not only promote the health of the cells lining the gut but also reduce the risk of many diseases.  Higher intake of dietary fiber is associated with lower risks of cardiovascular disease, diabetes and metabolic syndrome, cancer and even mortality from all causes (10, 11, 12, 13, 14, 15, 16, 17, 18, 19).  In addition, fiber can help with weight control by triggering the stretch receptors in the stomach, alerting the eater that they are full before too many excess calories have been consumed (20).

The majority of people in the developed world do not eat nearly enough fiber.   Health Canada and the American Institute of Medicine recommend that women need 25 grams of fiber per day while men need 38 grams.  It is estimated that most Canadians are getting about half that much (21).  National consumption surveys in the US show that only about 5% of the American population meets dietary fiber recommendations (22).  If you eat lots of plants, you will easily consume higher fiber levels than these recommendations call for, but this is not harmful.  Our human ancestors consistently ingested somewhere between 70 grams and 150 grams of fiber daily (23).

 

When fiber is lacking, the fiber-loving beneficial gut bacteria grow weak and allow more inflammatory, detrimental species to dominate.  This can lead to “leaky gut” in which the tight spaces between the cells lining the gut open up and allow bacteria and other toxins to enter the bloodstream causing havoc throughout the body.  The immune system is of course called upon to right this situation, leaving less of its power to rally against other threats such as the attack of a coronavirus.

 

In practical terms…

Gaining the health advantages of fiber means including the following food groups in your meals every day;

• Vegetables
• Legumes (beans, lentils, peas, soybeans)
• Fruits
• Whole grains (grains such as brown rice, hulled barley, and oats as well as whole grain breads, cereals and pasta)
• Nuts and seeds

 

Significantly reduce or completely avoid animal-based foods.  The more of these you eat, the less room physically in your stomach for the high-fiber foods you are striving to eat lots of.

 

Avoid processed foods.  Many of them are completely stripped of their fiber.

 

Promoting a healthy gut microbiome is one more step towards protecting yourself against Covid-19 and many debilitating chronic diseases as well as supporting good health in general.  On your next trip to the grocery store, try adding one or two new and unusual vegetables to your cart.  You may find it an adventure worth repeating.

 

 

SOURCES:

1  Gou, W., Fu, Y., Yue, L, Chen, G.-D., Cai, X., Shuai, M., Xu, F. et al. Gut Microbiome May Underlie the Predisposition of Healthy Individuals to COVID-19. MedRxiv, April 25, 2020, 2020.04.22.20076091.

2  South, A.M., Diz, D.I., Chappell, M.C.   COVID-19, ACE2, and the Cardiovascular Consequences.  Am J Physiol Heart Circ Physiol. 2020 May 1; 318(5): H1084-H1090. doi: 10.1152/ajpheart.00217.2020.

3  Hashimoto, T., Perlot, T., Rehman, A., Trichereau, J., Ishiguro, H., Paolino, M., et al.   ACE2 Links Amino Acid Malnutrition to Microbial Ecology and Intestinal Inflammation.   Nature. 2012 Jul 25; 487(7408):477-481. doi: 10.1038/nature11228.

4  Cole-Jeffrey, C.T., Liu, M., Katovich, M.J., Raizada, M.K., Shenoy, V.  ACE2 and Microbiota: Emerging Targets for Cardiopulmonary Disease Therapy.  J Cardiovasc Pharmacol. 2015 Dec; 66(6): 540-550. doi: 10.1097/FJC.0000000000000307.

5  Mehta, P., McAuley, D.F., Brown, M., Sanchez, E., Tattersall, R.S., Manson, J.J., et al.   COVID-19: consider cytokine storm syndromes and immunosuppression.   Correspondence to The Lancet. March 28, 2020; 395(10229): 1033-1034.  Doi.org/10.1016/S0140-6736(20)30628-0.

6  Vaninov, N. In the eye of the COVID-19 cytokine storm. Nat Rev Immunol 20; 277 (2020). https://doi.org/10.1038/s41577-020-0305-6

7  Tisoncik, J.R., Korth, M.J., Simmons, C.P., Farrar, J., Martin, T.R., Katzea, MG. Into the Eye of the Cytokine Storm.  Microbiol Mol Biol Rev. 2012 Mar; 76(1): 16–32.

8  Purchiaroni, F., Tortora, A., Gabrielli, M., Bertucci, F., Gigante, G., Ianiro, G., Ojetti, V., Scarpellini, E., Gasbarrini, A.  The Role of Intestinal Microbiota and the Immune System.  Review Eur Rev Med Pharmacol Sci. 2013 Feb; 17(3):323-333.

9  McDonald, D., Hyde, E., Debelius, J.W., Morton, J.T., Gonzalez, A., Ackermann, G., Aksenov, A.A. et al.  American Gut: an Open Platform for Citizen Science Microbiome Research.  American Society for Microbiology. mSystems: Host-Microbe Biology.  May/June 2018; 3(3): e00031-18.

10  Aune, D., Chan, D.S., Lau, R. et al.  Dietary fibre, whole grains, and risk of colorectal cancer: systematic review and dose-response meta-analysis of prospective studies.  BMJ. 2011; 343: d6617.

11 Ye, E.Q., Chacko, S.A., Chou, E.L., Kugizaki, M., Liu, S.   Greater whole-grain intake is associated with lower risk of type 2 diabetes, cardiovascular disease, and weight gain.  J Nutr. 2012 Jul;142(7):1304-1313.

12 Threapleton, D.E., Greenwood, D.C., Evans, C.E., Cleghorn, C.L., Nykjaer, C., Woodhead, C., Cade, J.E., Gale, C.P., Burley, V.J.   Dietary fibre intake and risk of cardiovascular disease: systematic review and meta-analysis.  BMJ. 2013 Dec 19;347:f6879.

13  Liu, L., Wang, S., Liu, J.  Fiber consumption and all-cause, cardiovascular, and cancer mortalities: a systematic review and meta-analysis of cohort studies.  Mol Nutr Food Res. 2015; 59: 139-146.

14  Zong, G., Gao, A., Hu, F.B., Sun, Q. Whole Grain Intake and Mortality From All Causes, Cardiovascular Disease, and Cancer; A Meta-Analysis of Prospective Cohort Studies.  Circulation Jun 14, 2016; 133(24): 2370-2380.

15  Aune, D., Keum, N., Giovannucci, E., Fadnes, L.T., Boffetta, P., Greenwood, D.C., Tonstad, S., Vatten, L.J., Riboli, E., Norat, T.  Whole grain consumption and risk of cardiovascular disease, cancer, and all cause and cause specific mortality: systematic review and dose-response meta-analysis of prospective studies.  BMJ. 2016 Jun 14;353:i2716.

16  Aune, D., Giovannucci, E., Boffetta, P., Fadnes, L.T., Keum, N., Norat, T., Greenwood, D.C., Riboli, E., Vatten, L.J., Tonstad, S..  Fruit and vegetable intake and the risk of cardiovascular disease, total cancer and all-cause mortality-a systematic review and dose-response meta-analysis of prospective studies.  Int J Epidemiol. 2017 Jun 1;46(3):1029-1056.

17  Kyrø, C., Tjønneland, A., Overvad, K., Olsen, A., Landberg, R. Higher whole-grain intake is associated with lower risk of type 2 diabetes among middle-aged men and women: the Danish Diet, Cancer, and Health Cohort. J Nutr. 2018;148:1434-1444.

18  Yang, Y., Zhao, L.G., Wu, Q.J., Ma, X., Xiang, Y.B.  Association between dietary fiber and lower risk of all-cause mortality: a meta-analysis of cohort studies.  Am J Epidemiol. 2015 Jan 15;181(2):83-91.

19  Slavin, J.  Whole Grains and Human Health.  Nutr Res Rev. 2004 Jun;17(1):99-110.

20  Tucker, L.A., Thomas, K.S.   Increasing Total Fiber Intake Reduces Risk of Weight and Fat Gains in Women.  The Journal of Nutrition. March 2009; 139(3):  576–581.

21  https://www.canada.ca/en/health-canada/services/nutrients/fibre.html

22 Quagliani, D., Felt-Gunderseon, P.  Closing America’s Fiber Intake Gap.  Am J Lifestyle Med. 2017 Jan-Feb; 11(1): 80–85.

23  Eaton, S.B., Eaton III, S.B., Konner, M.J.  Paleolithic nutrition revisited; A twelve year retrospective on its nature and implications. Eur J Clin Nutr 1997; 51: 207-216.