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Lin Chang, MD: Hello. I'm Dr Lin Chang. Welcome to Medscape's InDiscussion series on irritable bowel syndrome (IBS). Today we'll be discussing the role of the microbiome in IBS and the related topics of postinfection IBS, post-COVID IBS, and long-COVID IBS with Dr Madhu Grover. Dr Grover is an associate professor of medicine and physiology and consultant in the division of gastroenterology and hepatology in the department of internal medicine at Mayo Clinic in Rochester, Minnesota. Welcome to InDiscussion. Madhu, thanks so much for joining us today. It's so great to have you. You're an expert in this field, and I'm sure our listeners will love to hear what you have to say and your expertise on this complicated topic of IBS.
Madhusudan Grover, MBBS: Thanks for having me.
Chang: How did you become interested in IBS?
Grover: This dates back now almost 15 years ago. I was an internal medicine resident, and I chose to work with Doug Drossman and Bill Whitehead at the University of North Carolina (UNC). I was interested in neurogastroenterology — the biopsychosocial context addressing how we think about these disorders and how we address and treat them. I wanted to push the envelope and get into understanding these disorders to design more effective treatments.
Chang: You also started getting more involved in the mechanisms or pathophysiology related to microbiome and IBS. How did you get interested in the microbiome part?
Grover: After spending time at UNC, I decided to come to Mayo Clinic, where we have unique opportunities to engage in translational research. One of the phenotypes that intrigued me clinically was a phenotype of postinfection IBS. When we talk about IBS, we always wonder how a person gets it. I thought looking at this phenotype would be intriguing because it gives us an opportunity to identify individuals who were healthy before the infection. If you get hit by a foodborne illness, 80%-90% of folks are expected to recover, and 10% do not. They develop long-term symptoms that can be pretty disabling. That was my journey. I worked in that niche where I could identify patients over the long term and follow them to understand the mechanisms driving the IBS. At that time, the microbiome was still emerging as a key player. This was 7 or 8 years ago when we were getting some initial understanding of how the microbiome changed in IBS. It was unclear how these changes could affect how IBS may develop. The question of cause and effect comes into the picture whether the changes in microbiome are a result of IBS or vice versa. With postinfection IBS, since we were able to identify these individuals early on right away after infection and follow them over time, we could longitudinally understand how the microbiome is changing and tie it more closely to the development of postinfection IBS.
Chang: To clarify, postinfection IBS is where an individual doesn't have any IBS symptoms. Initially, they get this infection in the gut, and then the infection clears. Even though they may think they still have the infection, they often don't. They get symptoms of IBS, and they can last a fair amount of time. What's the natural history of postinfection IBS? A lot of patients don't have a previous infection. That's just one of the risk factors of getting IBS. Do patients with postinfection IBS have a different trajectory and natural history than patients who have just IBS?
Grover: With postinfection IBS, there have been studies that followed these individuals up to 8-10 years after infection, and we have learned a few things about postinfection IBS. Over the years, a fraction of patients clear their IBS symptoms. For example, in the Walkerton outbreak cohort from Canada where sewage contaminated the water supply, a lot of individuals unfortunately developed acute gastroenteritis and have been followed all the way up to 10 years. What we are learning is that more and more patients clear their IBS over time. We also have natural history studies looking at viral-related postinfection IBS. And there the observation is that within the first 1-2 years, the IBS phenotype clears, whereas bacterial- or protozoa-related postinfection where the symptoms can last for a very long time. It is not to say that every person with postinfection IBS would recover after 8-10 years, but some of them would. We still don't have good ways of telling who will continue to have symptoms vs those who clear their infection or their IBS. We have an observation from a recent study of folks who have preexisting IBS, particularly IBS with constipation. If they get an infection, they sometimes develop diarrhea. So not only can new-onset IBS happen after infection — even for folks who had previous IBS, their IBS can change. Many times, their IBS can become more severe after having an infection. A number of things can happen as a result of infection.
Chang: I see that in patients who have IBS and then get an infection their family gets. They say their family has gotten better but they're not better. This is because they have an underlying gastrointestinal (GI) infection. It's interesting that people with predominant constipation switch to diarrhea postinfection. Is your observation that they keep having diarrhea for a while, or do they switch back to constipation eventually?
Grover: We haven't followed these folks for that amount of time or since the first identification of their IBS. What we do know is that with postinfection IBS, constipation is extremely rare. We have thousands of patients in our cohort, and I would say only 2%-3% have constipation. The rest have either diarrhea or a mix of both. And often clinically, as you know, many times folks with diarrhea tend to have a mixed phenotype when they have alternating diarrhea and constipation. Sometimes it can come back to that diarrhea phenotype. But I have not seen constipation being a predominant issue after infection or in the postinfection IBS subtype.
Chang: A lot of us have had GI infections such as food poisoning, but we all don't get IBS. What are the risk factors of getting postinfection IBS?
Grover: A few years ago we did a meta-analysis looking at a number of studies over the last 15 years or so, and we concluded that females, for example, are at higher risk of developing postinfection IBS. And younger individuals are at higher risk, which also is true for more garden-variety IBS where we see females and young folks getting it more commonly. Patients who are hospitalized during infection or who have a greater severity of infection are also at higher risk. We do know some of these factors. There was also some interesting work looking at the effect of stress during or in the preceding months before infection — things like anxiety, depression, and suicide ideation. These factors were associated with an increased risk of development of postinfection.
Chang: It shows the importance of the brain-gut axis and how there is an interplay and a dynamic process between them. You can have environmental factors like stress or anxiety, and they increase your risk when the insult is really in the gut or it started in the gut. Do you approach the management of patients with postinfection IBS differently than patients who have garden-variety IBS? Is there any evidence for a different treatment?
Grover: I'll answer that question with a two-pronged approach. The first instance is when I see an individual with postinfection IBS. You may wonder how I know the individual has postinfection IBS because, often, an infection is not proven by laboratory testing. It's often in the history. For example, somebody was traveling or ate something strange, and they got sick for 2-3 days. They distinctly remember they were quite miserable. That's often a clue that the infection episode may have led to their postinfection IBS. I always try to find out if they remember something about how their symptoms of IBS started. Often, when you ask that leading question, you will get the answer. When I see that in a patient's history, I try to explain the concept of postinfection IBS to them. It's reassuring to the patients and helps them put their symptoms in context when they know there is a connection between their gut getting injured at the time of that infection, and how a small percentage of patients can develop long-term symptomatology. I also share with them these data we talked about, which tell us that in some patients, particularly if the injury is driven by a virus, symptoms may disappear over the course of 1-2 years. I tell them we don't know whether that's going to be the case for them, but there is a chance that over time, their symptoms may improve or even resolve.
As far as treatments are concerned, there have not been a lot of clinical trials that have looked at postinfection IBS as a unique entity for enrollment, except for one recent study by researchers at Tulane. Colleagues looked at glutamine, for example, and how that can influence symptoms in folks who have postinfection IBS. They measured their urinary excretion of sugars, which is an assay for intestinal permeability, and they selected for patients who had increased intestinal permeability. When you take that specialized cohort of patients and put them through a randomized trial of glutamine, you see there is a very high success rate. We need more studies replicating that original pivotal trial. What we are looking at on the horizon if we think about post-infection IBS? There have been some smaller studies looking at anti-inflammatory agents like mesalamine, which is used for inflammatory bowel disease. Again, not everybody with postinfection IBS gets better, but there is clearly a group within postinfection IBS that shows remarkable improvement in symptoms. Not to say we are there yet with some of these agents, but data are emerging slowly. Clinically, I still tend to treat these patients as routine IBS where I look at the influence of pain in their symptomatology and the predominant bowel phenotype. If it's diarrhea, I might start a patient off on regular antidiarrheals. Often, we try a low-FODMAP diet in a selected group of patients over a short course to see if their symptoms might improve.
Chang: You touched on something really important that you and I both learned from Doug Drossman, which is conveying information to the patients so they understand more about their condition. I like glutamine a lot. I've used that and also for patients with IBS with diarrhea not only postinfection because there were some original data showing it could work in that subgroup as well. I want to move on to post-COVID IBS, which is newer. That's a virus that's been associated with IBS-like symptoms. Can you explain that to us?
Grover: We are getting that as a question a lot in the clinic, where folks who had COVID are experiencing either new-onset of GI symptoms or worsening of their preexisting GI symptoms. A number of studies have looked at the prevalence of these symptoms over the next 1-2 years after COVID. I would say the literature is a bit mixed. When you look at uncontrolled studies where you ask a bunch of people who had COVID about any GI symptoms, there's a big range at the moment — anywhere from 3% all the way to 50% of patients report some sort of GI symptoms. Recently, there was a meta-analysis that looked at around 10 studies and close to 4000 patients, and they found that in an uncontrolled setting, about 13%-14% were reporting IBS or IBS-like symptoms. If you look at controlled studies, which happens quite a bit as you know, where you take individuals with infection and without infection and you try to understand an odds ratio, the data are a bit more mixed. I think it varies from setting to setting. There was a recent study published by Giovanni Barbara and colleagues when they looked at hospitalized patients. Within COVID patients, this was a specialized group that was hospitalized. They had close to 600 cases, close to 300 controls, and got an odds ratio of around 1.8 for IBS development. They also, interestingly, found that constipation was less frequent in those who had COVID vs the controls. So, again, this brings back that point that diarrheal symptoms are likely to happen more often. There was another study from India that found that close to 7% individuals after infection were endorsing symptoms of IBS. So as we learn more about this and we get larger studies representing a variety of different geographic settings, we will be able to make conclusions a bit more definitively. I won't be surprised if there is a risk that is present as compared to controls. But I also think honestly, just like what we experience with norovirus or some of these other viruses, it's also likely that COVID-related IBS may be shorter lasting than what you might experience with E coli or Campylobacter infections. Again, I have no data at this moment to be able to conclusively say this, but this is extrapolating experience from other viruses.
Chang: Let's discuss the risk factors for getting post-COVID IBS. I've seen data where if you have GI symptoms at the time of COVID, you're more likely to get post-COVID IBS. Are there other risk factors, and what do you think about that? Are there other risk factors like we've seen in postinfection IBS?
Grover: That's a great question. Again, in all the studies I have looked at there has been a consistent theme: GI symptoms at the time of infection seem to emerge as a consistent predictive factor for developing long-lasting GI symptoms consistent with IBS. Again, some of the studies also found that females are at higher risk. Another study found that if individuals required oxygen or they had dyspnea as a symptom during COVID, they were at higher risk, and had higher C-reactive protein (CRP). So again, we see some similarities where if patients are sicker, they are more likely to develop postinfection IBS. An intriguing study also found that if patients have higher blood levels of procalcitonin, it was an indicator of development of postinfection IBS. So again, we're going to learn more about this, but we are seeing some similarities with postinfection IBS. But as you said, GI symptoms at the time of infection should be our top-line symptom as we think about a person who is suffering from IBS-like symptoms after COVID.
Chang: It definitely sounds like the more severe illness you have in general, the more at risk you are for post-COVID IBS. It's interesting that you said patients can have post-COVID respiratory symptoms and not necessarily post-COVID GI symptoms. We talked a lot about postinfection causes of IBS, but what is your thought about the microbiome in general in health and in disease? It's not only related to infection. What's your perspective on that?
Grover: Microbiome science has really evolved within the last decade. Back when we were doing studies that were cross-sectional looking at disease vs controls, we were in an era of trying to understand how the microbiome is changed in a disease such as IBS. Then over the last 3-4 years, we have started to learn how a single timepoint assessment may not give you the complete picture. So in IBS, through work done by Purna Kashyap and colleagues, where they collected stool samples longitudinally, we learned there is a lot of fluctuation from month to month in the microbiome in IBS patients. Perhaps more sampling can be more conclusive or a better framework can help us think about what's really changed. We know that's not enough. Over the last 4-5 years, studies are now trying to ask the question of how this relates to the pathophysiology of IBS. When we think about pathophysiology of IBS, we know that folks have either changes in their sensation or sensory system. What we also tend to describe as visceral hypersensitivity, there are then a subset of patients who have altered transit that may result in them experiencing diarrhea or constipation. And we are also learning about increased intestinal permeability and how that may affect how symptoms are experienced and generated. In our studies with postinfection IBS patients, we do all three of these tests in these individuals in our clinical research. One of the messages we are getting from these studies is that there is evidence of increased colonic permeability in these patients. In our case, we take Campylobacter infection because we want to keep our studies a bit more focused toward one infection type. There have been other studies that have looked at other infections as well. What we are doing as an extension of that work is trying to link these microbes and changes to the intestinal permeability changes we see. One of the themes we have discovered over the last few years is regulation of molecules called proteases in the gut. These are molecules that eventually are harmful to the colon, or they disrupt the colonic barrier or increase permeability. If you have a healthy microbiome that has all the healthy members, it really is able to suppress those proteases or those microbes. What happens in postinfection IBS is that some of those key microbes are lost, most likely as a result of that injury. These individuals are not able to regain those microbes. We know from longitudinal studies that once lost, they are not coming back. We know then what happens is those proteases don't get suppressed like they do when the gut is healthy. This is just one example of how some of the recent studies have been trying to link infection and the resulting changes in microbiota, and how they may influence some of these molecules in the gut that can cause a long-lasting injury.
Chang: This tells you how complex it is because people think that the microbiome in IBS is related to too much bacteria, like small intestine bacteria overgrowth, which a lot of people are very aware of. What is your take on SIBO, or small intestinal bacteria overgrowth, and utilizing breath tests for IBS?
Grover: That's been a question that has been in the field for a long period of time. The small bowel is very, very important. That's where the nutrients go first before they make their way into the colon. I believe that a subset of patients perhaps do have small bowel dysbiosis. That's the term I like to use — not overgrowth. What that means is that microbiota composition in their small bowel is not the right kind. It's not talking to the host the right way, which influences symptoms. The way we test bacterial overgrowth right now with breath testing is perhaps not the right way of doing it. Studies have shown that, for example, if you take microbes from the small bowel and sequence them, you are much more likely to get a better clue about true dysbiosis, rather than just measuring them and their amount, which is what some of the breath testing does. Breath testing is also a bit flawed because it can be affected by the transit or the motility of the gut. A lot of what we interpret as a positive breath test is, in fact, those sugars reaching the colon and the colonic flora causing the breath test to turn positive. It's an entity that exists in a very small percentage of IBS patients, but I don't think we have the right tests that are clinically available at this time to diagnose it.
Chang: That's helpful. What do you envision as possible microbiome-targeted therapies in the future?
Grover: I think the microbiome targeted therapies, particularly for IBS, are going to be personalized. We are not going to be able to have a one-size-fits-all approach. We do know the microbiome varies from individual to individual. Trying to use one kind of microbiota to treat all IBS patients is likely not going to be helpful. We know this from IBS studies in general. It's a heterogeneous disorder, and it's likely that different alterations drive symptoms in different subsets of IBS patients. I think the future is going to be identifying those subsets of patients who have a microbiome-driven mechanism and try to give them the right microbiome. We are seeing this with some of the fecal microbiota transplantation studies where if you take selected microbiota as the donor, it works much better than taking unselected microbiome from just anybody. We are also learning that only a subset of patients show an improvement after any of these therapies. I think the future is going to be looking at what microbes are being given and to whom are they being given. I am intrigued by some of the advancements made in prebiotics. When we think about microbiota and how we can alter it, we always think about giving microbiota. You can also give nonviable things, particularly dietary interventions like fructo-oligosaccharides and galacto-oligosaccharides, which interface with unique microbes and produce things that can be helpful for the host. In the future, we're going to learn more about prebiotics, which are dietary components used by certain microbes along with probiotics. This is the idea of symbiotics — when you look at what microbe you are trying to replace or provide, what the right kind of diet is for that microbe, and how they can both interact to help the person.
Chang: It's really fascinating to think of what's going to be out there in the future. There's so many possibilities, which makes it exciting for research and also for clinical care. Thank you so much to Dr Grover for discussing the microbiome and its relation to IBS, particularly postinfection IBS, post-COVID IBS, and the future in research and treatment. Thank you for joining us. This is Dr Lin Chang for InDiscussion.
Resources
Post-Infection Irritable Bowel Syndrome
Sex-Gender Differences in Irritable Bowel Syndrome
The Role of Stress on Physiologic Responses and Clinical Symptoms in Irritable Bowel Syndrome
Systematic Review and Meta-analysis: Efficacy of Mesalamine in Irritable Bowel Syndrome
Low-FODMAP Diet Improves Irritable Bowel Syndrome Symptoms: A Meta-analysis
Postinfection Irritable Bowel Syndrome
COVID-19 as a Trigger of Irritable Bowel Syndrome: A Review of Potential Mechanisms
Incidence and Predisposing Factors for De Novo Post-COVID-19 Irritable Bowel Syndrome
Longitudinal Multi-omics Reveals Subset-Specific Mechanisms Underlying Irritable Bowel Syndrome
Serine Proteases as Luminal Mediators of Intestinal Barrier Dysfunction and Symptom Severity in IBS
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Cite this: Treating Postinfection and Post-COVID Irritable Bowel Syndrome - Medscape - May 16, 2023.
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