How Do Gut Bacteria Affect COVID-19 Severity?

John Whyte, MD, MPH; Siew C. Ng, PhD

Disclosures

February 04, 2021

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  • The gut, which regulates immune response, is one of the largest and most essential organs in the body. COVID-19 patients have been found to have poorer gut microbiome compositions compared with those without the disease.

  • Dysbiosis — abnormal gut microbiome — may account for long-term COVID-19 symptoms. In studies, elderly patients and those with chronic conditions were more likely to have dysbiosis, which might explain their increased risk for severe disease.

  • COVID-19 is not just a lung disease. Anywhere from 30% to 40% have gut manifestations too. Stool samples are now being used to test for COVID-19.

  • The best way to promote good gut bacteria and reduce inflammation is to eat a healthy diet, with less processed food and food additives, and more fiber. Exercise is also important.

  • Select probiotics carefully; they are not all created equal.

This transcript has been edited for clarity.

John Whyte, MD, MPH: Welcome, everyone. You're watching Coronavirus in Context. I'm Dr John Whyte, chief medical officer at WebMD. We think of COVID-19 as a respiratory virus, but there is an emerging set of data that talks about the role of the microbiome. There was a fascinating article in The BMJ recently that talked about the gut microbiome predicting severity of disease for COVID and the immunologic response.

To find out what's really going on, I went straight to an author: From the Chinese University of Hong Kong, I want to welcome Professor Siew Ng. Dr Ng, thanks for joining me.

Siew C. Ng, PhD: Thank you, Dr Whyte, for this invitation.

Whyte: Let's talk about this study because it's creating some discussion about the role of the microbiome (our gut bacteria) in terms of impacting the severity of COVID. Is it because of the immunologic response of the microbiome? Is that what's going on here? Remind us the role of the gut.

Ng: We know that the human gut is one of the largest organs in our body that actually regulates our immune response. In fact, it helps protect us against different infections, including SARS-CoV-2. Each one of us has trillions of bacteria in our guts, and they play a lot of roles.

Whyte: Trillions?

Ng: Trillions, that's right. And it's like an organ on its own. It controls our immune system; it controls how we work our metabolic system, how our brain functions, the hormones in our body. I think in this context of COVID-19 it's fascinating, but we found that patients with COVID-19 have very different composition of the gut microbiome to those without disease. But what's more important, what is missing in those with COVID-19, are the good bacteria that help generate a very good immune response.

I think this is going to be a long story because we now know that some patients have very mild disease and no symptoms whereas others with COVID-19 end up in the ICU and require cytokine syndrome support — they have this storm due to a very inflammatory state. It's likely that some of the gut bacteria that are good in helping us to prevent such an immune response are actually missing. During the third wave of COVID in Hong Kong, we found patients with and without disease, and we were able to follow them up over a period of time to look at what's happening to the gut microbiota.

Whyte: Because some people could argue, well, maybe those persons that were hospitalized with COVID, it wasn't that they had lots of bad bacteria to begin with, but rather the infection gave them that — kind of like a chicken-and-egg issue in terms of which came first, that patients with SARS didn't have good bacteria to begin with or that SARS got rid of the good bacteria. How do we know which one comes first?

Ng: I think that's a really important question, the cause and effect. Is it being so sick that caused them to have such bad bacteria or the other way around? I think our study right now shows the association. What's remarkable is that after the patient has recovered from COVID-19, you would have thought that they would have cleared the virus and the body would have come back to a normal state. But their missing bacteria continues. The good bacteria have never been novelized, what we call as dysbiosis, and we are very concerned because it is likely that dysbiosis may account for some of the symptoms of long COVID that we now hear: Fatigue, mental problems, people who can't sleep, loss of taste, and loss of scent continue. It's quite clear that this multisystem inflammatory state may actually relate to our gut microbiome.

To answer your direct question about which is the chicken and which is the egg, I think we are now currently conducting animal experiments. We are finding that without the good bacteria, you generate a bad immune response. And that could prove the causality. But what's important is that we looked at the blood of these patients in the blood marker, and when you have dysbiosis, your blood inflammatory response is higher. That might account for you ending up in the ICU because your lung is just not functioning so well.

Whyte: Remind us what you were looking for in the blood.

Ng: We are looking at certain markers that are known to generate a hyperimmune response (eg, bad cytokines ─ we called them the chemokines ─ and proinflammatory blood markers).

Whyte: Interleukin 6, some of the others.

Ng: That's right. IL-6, TNF alpha — these are the markers that are known to be associated with the cytokine storm and mortality in these patients.

Whyte: How realistic is it for us to start doing fecal samples to look at the microbiome? Is it something we need to be doing? Is it something that maybe we'll do in a few months? How urgent is it, do you think, that we should add this to our diagnostic strategy? Who needs more care? That could help us in the guidance of monoclonal antibodies earlier on in disease. It could help us in terms of therapeutics. Should we be looking at fecal samples?

Ng: That's a question that is very close to my heart. In fact, I see this as three levels in terms of stool testing of microbiome testing. In fact, at the Chinese University of Hong Kong, we have other centers using stool to test for SARS-CoV-2. We have now tested close to, I think, 6000 children. We found positivity of 0.2%, which is much higher than nasopharyngeal or deep-throat saliva because it's noninvasive. And we now know that SARS-CoV-2 is not just a lung disease because many people (about 30%-40%) get gut manifestation and gut symptoms as well.

Whyte: Diarrhea.

Ng: That's right, and abdominal pain. We are able to detect the breakdown product of the virus within the stool. We use PCR, and right now, apart from deep-throat saliva, we complement testing with stool testing to diagnose the virus itself. I think the second level you're talking about is can we use this as a marker to predict response or to look at people's severity?

Whyte: Individual patients. We actually did a story several months ago about, for epidemiologic purposes, looking at sewage in the city and trying to determine what the percent positivity may be. But here, you could be talking about, almost as we do in cancer therapy sometimes, in terms of using information, not necessarily pharmacogenomics, but the same principles of using the microbiome to determine the therapeutic agents that one would choose. Is that right?

Ng: Oh, absolutely, because what's fascinating is that when we tested about 1000 healthy people in Hong Kong, we found that 40% actually had dysbiosis, abnormal gut microbiome. These are the people who are at higher risk of having the infection: diabetics, the elderly, the obese, those with chronic disease, or those who have abnormal gut microbiome. And this may, in fact, explain why they are more susceptible but, more importantly, why when they are infected, they have worse outcomes. Epidemiology studies have shown that.

So, if we have that as a clue, one day we may be able to test them to identify the type of outcome that they may have and the type of treatment. In the future, I believe that the gut microbiome also affects the vaccine response. We're seeing this data with flu vaccine, that some people may generate longer-term immunity and antibody while others don't. The personalized way will be with a simple stool test — we know that COVID will be here for a long time — and we might be able to personalize to see which type of people may respond better to the vaccine.

Whyte: Based on their gut. When do you think we'll see that? In the next few months? End of the year?

Ng: I think probably by the end of this year. Right now, we are already generating a lot of different collaborations, and in mainland China stool testing and in-nose swab testing have been put in place as one way to complement what we have now.

Whyte: Well, Dr Ng, you know what everyone is thinking while they're listening to you. They're thinking, do I need to start taking probiotics or prebiotics? Maybe you can explain the difference for us, probiotics vs prebiotics. Should people start taking them to make sure they have good gut immunity?

Ng: This is a very important and commonly asked question. The difference between probiotics is probiotics are live bacteria. They are known to generate a beneficial effect on our body. Prebiotics are purely food components. For example, asparagus has prebiotics in it, the byproduct. They help to induce the growth of the good bacteria. Both are generally safe.

During the COVID pandemic, my personal advice is threefold: First is that we know that our diet influences our gut microbiome. So the easiest thing for our citizens to do is to have a very healthy diet. What I mean by that is less processed food, less food additives, emulsifiers — these are known to cause inflammatory response to our bacteria. And increase fiber intake and exercise, because ample data show that this generates really good bacteria in the gut.

Right now, based on the data analysis from a large COVID-19 cohort, we developed a microbiome immunity product that is targeted to what is missing in COVID-19 patients. Not all probiotics are the same, as we believe. What is important as we move forward in this probiotics era is targeting what is missing and understanding the functions. It may not just be the bacteria. It's what does the bacteria do? We did a pilot study in COVID-19 patients, and we were intrigued to find that they developed more antibody. They were also discharged from hospital more rapidly and they had less symptoms. So it is quite a bright and promising future in alleviating some of these detrimental effects of the virus.

Whyte: You're looking at a person whose gut you've already analyzed and then you're helping them decide what they may need? For the general population listening, should they consider taking probiotics? Should they talk to their doctor first? You know, everyone wants to figure out how to help their immunity.

Ng: I would say that because we well know that probiotics are generally safe, it depends on what your role is in doing it. For example, in people who are known to have dysbiosis, chronic disease, and in the elderly, we found that the good bacteria definitely are much lower than those of children. In this cohort, I would think that it's important to talk to your doctor to make sure there are no contraindications for you in taking a specific probiotic. But in the general healthy cohort, my advice is to select them carefully. I think it should be scientifically driven, the probiotic that one uses. Because which ones should you choose? There are so many different types. We now know from the data that there are types that contain certain probiotics that are aim to regulate our immune response.

Whyte: We've been talking about the microbiome for the past few years in various disease conditions: heart disease, rheumatologic disease, and diabetes. Are you surprised at all that we're seeing in this relationship to severity of COVID?

Ng: Absolutely not. We now know that our gut microbiome is a central organ that really influences many of the outcomes. Like you said, John, even in cancers or therapeutics. If I were to predict, I think our gut microbiome is going to have a huge, long impact on our future partly because of the hygiene hypothesis. We know that when you lack a lot of the good bacteria in your gut, you're more likely to get immune-mediated diseases, such as multiple sclerosis and rheumatic diseases. Less than 50 years ago, we were seeing a large surge of this immune-mediated disease because the surrounding was much more hygienic. Ironically, what's going to happen is that right now, because of the disease, the environment, and the social status, we are actually having a very different behavior. Over time, we may be wiping out some of the ancestral gut microbiome that is related to us in the healthy state. So, I think in the next 50 years, there's going to be a change in the epidemiology of different chronic diseases because of what COVID-19 has brought.

Whyte: I don't think it's going to be that long. I think we're going to figure that out sooner. Dr Ng, I want to thank you for taking the time, for sharing your insights, and for helping remind us about the role of the gut, one of the largest organs in our body. It really plays a pivotal role in our immunity.

Ng: Thank you.

Whyte: And thank you for watching. If you have a question about COVID or the role of probiotics, drop us a note. You can email it to me at drjohn@webmd.net or post it on our social properties, Facebook, Twitter, Instagram. Thanks for watching.

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