The Gut Microbiome in Systemic Sclerosis

In this podcast, Elizabeth Volkmann, MD, discusses her research into how the gut microbiome of patients with systemic sclerosis may be associated with the pathogenesis of the disease, how environmental influences may affect gut dysbiosis, and what treatments are available or being tested to address the gastrointestinal manifestations of systemic sclerosis. Read the full transcript here.

Additional Resources:

Elizabeth Volkmann, MD, is the founder and director of the Connective Tissue Disease-Interstitial Lung Disease (CTD-ILD) Integrative Clinic Program and director of the Scleroderma Program at the University of California Los Angeles. 

For more content on systemic sclerosis, visit our Resource Center.


TRANSCRIPTION: 

Rebecca Mashaw: Hello everyone, and welcome to another installment of Podcasts360, your go-to resource for medical news and clinical updates. I'm your moderator, Rebecca Mashaw, with RheumatologyConsultant. Today, we'll talk with Dr Elizabeth Volkmann, the founder and director of the Connective Tissue Disease-Interstitial Lung Disease (CTD-ILD) integrative clinic at the University of California Los Angeles (UCLA). She's going to give us an overview of her recent research into the relationship between the gut microbiome and systemic sclerosis.

Thank you so much for being here today, Dr Volkmann. In your review published last year in the European Journal of Rheumatology, you state that the therapeutic options for treating systemic sclerosis have increased in recent years, but they primarily target symptoms and don't really modify the course of the disease. You've conducted research into the gut microbiome in systemic sclerosis and in effort to discover new treatment targets. What differences have you found in the gut microbiota of systemic sclerosis patients compared with those of healthy controls?

Elizabeth Volkmann, MD: Oh, that's a great question. In the review, we were really highlighting looking for treatment options for the GI disease of scleroderma. Some of the other manifestations of scleroderma, like the lung disease and the skin disease, we do have some options for, but the GI disease is really something where, as you said, the treatments just target symptoms and don't really get at a cure or modifying the disease course. So this is what initially sparked my interest to look at the gut microbiome as potentially being an important mediator of the pathogenesis of this disease. And in the first study that was ever done to investigate the microbiome in scleroderma patients at UCLA, we compared scleroderma patients with healthy controls. And what we found was that patients with scleroderma had higher levels of what we call pathobiont bacteria. These are bacteria that have been found in prior studies to be associated with more inflammation and more symptoms in other disease states. And then we found lower levels of what we call commensal bacteria. And these are bacteria that we think may actually be protective against inflammation and contribute to more of a healthy gut microbiome. And in this study, we also found that the extent of the dysbiosis, or the imbalance, was associated with symptoms. So patients who had more GI symptoms actually had greater imbalances in their gut bacteria.

Rebecca Mashaw: Your research has also looked at how external environmental influences could contribute to these alterations in the gastrointestinal microbiota. What have you found to date in this respect? Is this an area that warrants more and more in depth research?

Dr Volkmann: Another great question. So absolutely. This is definitely an evolving area of research and I think it's important to consider external environmental factors when you're doing this type of research. So for example, we did a follow up study where we looked at scleroderma patients, not only from UCLA, but also scleroderma patients from Norway. And we found significant differences between the 2 groups and probably most of those differences could be explained by external environmental influences. So one of the areas that I'm particularly interested in is nutrition and diet, because this is one way to modify the gut microbiome which doesn't have a lot of side effects like taking a drug but really can have a substantial effect on the balance of gut bacteria. So we recently did a study, which we hope to present at our upcoming American College of Rheumatology meeting this fall, where we looked at a particular diet called the FODMAP diet, the low FODMAP diet. And we looked to see whether this had any impact on the gut microbiome. So I think a lot more research is needed in this area, but that first study we did comparing 2 different scleroderma populations really showed us that there's probably a whole lot of other factors that we need to consider when we do this research,

Rebecca Mashaw: You also noted that most studies of the gut microbiome have focused on studying bacteria in part because the analysis of viruses and fungi is more challenging. You and your colleagues have taken the course of examining the role of gut microbiota in systemic sclerosis, patients by analyzing 16S rRNA meta-genomics sequencing. What have you learned? What else needs to be clarified in further research?

Dr Volkmann: Yeah, so this is kind of a complicated issue but there's different ways to characterize the gut microbiome. And obviously most people look at bacteria and this is what you use the 16S sequencing for, but then there's other inhabitants of the gut microbiome that could be contributing to these disease states and that could include viruses and fungi. So what we're trying to do now is expand our research efforts, doing something called shotgun metagenomics, which you reference and in this will be able to also look at viruses and fungi. In addition, we're also taking the steps to look at what's called metabolomics. So this is looking at the metabolites that are basically produced by the gut bacteria. So it may not be that just the bacteria alone is what's causing inflammation, but it could be the products of the bacteria that interface with the immune system that could cause inflammation. So the next step of this and what we're doing right now, and we hope to have results for in the coming year, is to look not only at the bacteria, the viruses, and the fungi but also to look at the metabolic products.

Rebecca Mashaw: Some research has shown that up to half of all patients with systemic sclerosis who also have esophageal disease and about 20% of those who have small bowel involvement remain asymptomatic until severe damage to the tissues has already taken place. Are there any clinical signs or tests that could help identify these conditions before they manifest as more serious and complex disease?

Dr Volkmann: Yeah, this is a very important clinical issue because oftentimes patients are diagnosed with their GI complications at a later disease stage. And this could be for a variety of reasons. One is that sometimes patients aren't always comfortable disclosing problems they have with their gut. You know, sometimes these are very personal things like diarrhea, fecal incontinence, and they may not be things that someone would voluntarily talk about unless the physician asks the patient. So I'd say first and foremost it's really important to have an open dialogue with patients about these symptoms. Otherwise the patient may not even relay that they're having the symptoms. Another important point is that some of the symptoms that they do have, for example cough, someone will say, well their cough is just due to their lung disease. But in fact, what we've found in studies is that in patients with chronic cough about half the time it's due to their lung disease but the other half of the time it's due to their esophageal disease because cough is a very common symptoms of reflux disease.

So again, it's really important to not only ask the patients about their symptoms, but also really tease out what is the cause of the symptoms. But then the second part of your question that I think is really important and timely is, well how can we test these patients? That maybe even when they're not having symptoms, even when we ask them about symptoms, we could do tests. And I think this is another evolving area of research because at present we don't have great imaging tests like we do for the lungs or other parts of the disease where we can screen for this manifestation. So again, I think that this is an ongoing area of research. I have a really productive collaborator right now at Johns Hopkins and she's looking at motility studies in patients to be able to characterize how the gut moves in different parts. So this could be potentially something that we do in the future in all patients.

Rebecca Mashaw: Systemic sclerosis is an extremely complex disease. In one of your papers, you write about how combining therapies to address the individual manifestations of systemic sclerosis is a cornerstone to the comprehensive management of this condition. What kinds of combination therapies are you using now in your patients and what newer therapies are showing promise in treatment of systemic sclerosis?

Dr Volkmann: Absolutely. So combining therapies is something that we've done in a lot of different diseases throughout the field of rheumatology. So for example, in rheumatoid arthritis and in lupus, we often combine therapies. In systemic sclerosis, I would say that because we didn't have a lot of therapies available there weren't even therapies to combine. But fortunately the pipeline for this disease state is really expanding quite rapidly. And we do now have an opportunity to test the combination of therapies.

So one example of this is the treatment of interstitial lung disease or pulmonary fibrosis, where traditionally we used immunosuppressant therapy such as mycophenolate mofetil or cyclophosphamide to treat this dimension of scleroderma. But now recently approved is the antifibrotic agent nintedanib. And this is a medication that works in a little bit different ways than immune suppressants. So studies are being done now to look at the combination. So combining an antifibrotic like nintedanib or pirfenidone with an immune suppressant, to see that you can get an even greater treatment response. And I think this is really the future of this field is to figure out how to combine these therapies and really how to personalize it to the patient. So some patients may do just fine with 1 therapy, but in other patients, they may need 2 therapies to achieve an adequate treatment response. So I do believe that this is really the future of clinical research in this disease.

Rebecca Mashaw: You've written that you believe this research into the gut microbiome may perhaps shed light on the pathogenesis of systemic sclerosis and may lead to the discovery of biomarkers that can predict the development of specific features of this disease, including interstitial lung disease, which is 1 of your specialty areas in treatment and research. What do you think needs to happen next in research to make progress in these areas?

Dr Volkmann: So this is a really interesting topic. And I would say that in terms of interstitial lung disease, we know that this is the leading cause of death in these patients, but it's often diagnosed at a later disease stage because patients may not be screened adequately or they may not have symptoms early on. And so 1 of the things that we're very interested is using the gut microbiome as a screening tool to be able to detect interstitial lung disease. And this could then prompt the physician to then order a high resolution chest CT to make the firm diagnosis. And what we found when we actually compared the UCLA cohort of scleroderma patients and the Norwegian cohort of scleroderma patients, was that in addition to patients residing in completely different countries, we found that a significantly greater proportion of patients at the UCLA site had interstitial lung disease and a much lower proportion had interstitial lung disease in the Norway site.

Dr Volkmann: And so this made us think, okay, well maybe there's really differences that relate to lung disease. And now what we've endeavored to do is look within our own cohort and we've increased the size of this cohort. And indeed we found that the presence of interstitial lung disease is associated with alterations in the gut microbiome. So I have a large grant now that we're just starting to look at this issue in 2 independent cohorts, both at UCLA and in Sweden, to be able to figure out, can we use the gut microbiome to screen for the presence of interstitial lung disease? And can we use it to also predict the severity of interstitial lung disease?

Rebecca Mashaw: Again, thank you for joining us today to talk about this very interesting topic. And we certainly look forward to hearing more about your research in the future.

 

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