Meeting News

Fecal transplant shows promise in IBD, other chronic conditions

Jessica R. Allegretti
Jessica R. Allegretti

BOSTON — Fecal microbiota transplantation has emerged as a highly effective treatment option for Clostridium difficile infection, but as the understanding of its effects on the gut microbiome increases, research is expanding to evaluate the approach in other chronic conditions, according to a speaker at the Interdisciplinary Autoimmune Summit.

Healio Gastroenterology and Liver Disease spoke with Jessica R. Allegretti, MD, MPH, director of the Fecal Microbiota Transplant Program in the division of gastroenterology at Brigham and Women’s Hospital, about her presentation on current FMT best practices and its potential application in conditions like inflammatory bowel disease, primary sclerosing cholangitis and obesity.

Healio: In your talk, you likened the human gut microbiome to a rainforest ecosystem. Can you explain this comparison?

Allegretti: One of the ways we describe the gut microbiome is alpha diversity, or how many different species of bacteria there are. We know that greater diversity is associated with healthier microbiomes, and in contrast when you look at various disease states you often see a depletion of that overall diversity. This is similar to a rainforest, where diversity of species is sort of a marker of its wellbeing. The same goes for your gut microbiome; you want many types of organisms present, because each type of bacteria that live within us perform different functions, so the more variety you have the better the performance overall. You can think of your microbiome as a living organ that provides function for your overall health, so the more diverse it is, the more function it provides.

Healio: What are the current indications for FMT? Have there been any recent changes in its regulatory status and guideline recommendations?

Allegretti: FMT is not FDA-approved for any indication, but the FDA still holds enforcement discretion for recurrent and refractory C. difficile infection, so that is the only indication for which you can perform FMT clinically under this umbrella of enforcement discretion. This policy states that you have to provide informed consent to the patient to explain that it’s an investigational therapy. For any other indication, or if you’re doing a trial or any research even within the realm of C. diff, you have to hold an Investigational New Drug license.

The FDA did issue a draft guidance in 2016 indicating that they may start to institute an IND requirement for providers that use stool bank material, but they still have not enacted that yet. This brief came out over a year ago and they have not enacted that further, so the regulatory status of FMT really hasn’t changed since 2013.

The new IDSA guidelines just came out, and I’m very excited about them. It was a much needed update, and in addition the European guidelines also came out last year, which recommended FMT for recurrent C. diff with high quality evidence, so it was exciting to see FMT recognized as a recommended and well researched procedure. The IDSA guidelines further validate this, showing we have done a lot of work in this area, that we have a lot of high-quality data including randomized controlled trials to show the efficacy of this treatment, and that it is a therapeutic option that really should be offered.

Healio: What are the 5 Ds of FMT, and why is this framework useful?

Allegretti: My colleagues and I work in fairly high-volume centers and we have learned a lot in our experience, so we wanted to develop a practical framework for providers who want to perform FMT or set up an FMT program at their center. The 5 Ds are an easy way for providers to remember the important things you need to be thinking about before you perform an FMT.

First is Decision: Is the candidate appropriate, meaning do they meet those requirements of confirmed recurrent or refractory C. diff? In my own experience and in the literature about 30% of patients who were referred for FMT do not actually have recurrent C. diff, and I’ve diagnosed many other conditions in candidates for whom FMT would not have been appropriate. So really making sure you have those confirmatory tests. Ensuring that FMT is the appropriate therapy is paramount.

The second D is Donor: Where is your donor material coming from? There are two methods for this: a patient-directed model in which the patients select a donor themselves and the provider screens the material, and a universal donor model, whether you partner with a stool bank like OpenBiome, or your institution has its own stool bank that stores material from a pool of healthy donors. You have to decide which model is right for your patient and the institution. I personally use OpenBiome almost universally for my FMTs because of the convenience, and they’re able to do a much better job of aggressive screening that I was not able to provide on my own, so I have a lot of faith in the safety of that material.

The third D is Discussion: The FDA enforcement discretion insists on good informed consent with the patient, so you should discuss both the real and theoretical risks and benefits of FMT with them before the procedure. This includes acute risks like infection transmission or allergic reactions, which are very rare, and the long-term risks, which are still largely unknown. However, we’re certainly concerned about putting patients at risk for these now known microbial-associated diseases like obesity, metabolic syndrome, and some other autoimmune conditions. Even if we screen the donor for these conditions now, and they don’t have anything, what if they develop something later in life? Would we be putting the patient at risk for developing the same condition? We just don’t know.

Fortunately, the NIH has sponsored the national FMT registry that I and many of my colleagues are participating in, which will allow us to start collecting good long-term data, so we will be able to answer a lot of these questions in the future.

The fourth D is Delivery: How are you going to deliver the material? There are many ways you can do it. The most common in the adults is lower endoscopy, so either colonoscopy or flexible sigmoidoscopy, so you can do an assessment of the mucosa to make sure there’s nothing else going on, and then deliver the material. Capsules are now more popular and available, so I will often use those as well. In pediatrics they tend to use a lot of enema preparation to avoid procedures in young children. Providers should have a discussion with their patient about which modality might be more appropriate for them.

The fifth and final D is your Discharge and follow-up plan. We know that the risk of FMT failure is highest within the first 4 weeks. I follow-up with patients for 8 weeks just to make sure the FMT has worked, and if they do experience a failure I will repeat the FMT. Then I generally follow the patients long-term for safety follow-up but also to provide counseling on avoiding unnecessary antibiotics so that patients can advocate for themselves if they need antibiotics in the future.

So that’s a rundown of the 5 Ds, and we hope they will help clinicians simplify what many view as a complex process, so that more providers become comfortable performing this important procedure.

Healio: What is currently the most efficacious mode of delivery, and why are capsules "the future of FMT," as you said in your talk?

Allegretti: We know that the highest efficacy is achieved when the material is delivered to the right colon. The literature shows that the overall C. diff cure rate is about 93% if you deliver the material to the right colon. The most common way to do that is with a full colonoscopy.

Also, in general, if you do a lower GI delivery as opposed to an upper endoscopy or NG tube where you’re delivering the material to the stomach or to the upper small bowel, the efficacy rates are higher. So, where you deliver the material does matter. They all work but lower GI delivery works better.

Regarding capsule delivery, the older formulation capsules were more of an upper GI delivery, meaning they opened higher up in the GI tract, and so you’d lose a bit of efficacy with those. With some of the older data you see around a 70% or 75% efficacy rate with older versions of capsules. Newer versions of capsules are coming down the line with directed colonic release and we’re presenting some of that data at DDW later this year. These new capsules have shown almost equivalent efficacy to colonoscopy. These are promising, because wouldn’t it be great if we could avoid doing a procedure and bowel prep?

I think capsules are the future, partly because for a lot of chronic diseases and in clinical trials you’re not doing a single transplant like you do with C. diff. What we’re learning is that in other chronic diseases like IBD, one FMT does not seem to be enough; you really need to do multiple therapies, whether it’s weekly or daily dosing, we don’t really know yet. We just know that more is better, and when you’re talking about patient quality of life, you can’t be asking patients to get a colonoscopy every week. Even doing an enema that frequently is not ideal, so if we can do capsule dosing, that will improve patient outcomes and QOL. Capsules will make it easier to do better research and will also be much easier on the patient.

Healio: What is the rationale for the use of FMT in autoimmune conditions, and in what conditions beyond C. diff does it show the most potential?

Allegretti: There’s been a lot of mostly cross-sectional research looking at microbial differences between patients with a certain disease compared to healthy controls, and we are starting to see a lot of differences, and every disease is different. My work focuses on IBD, but even in subsets within IBD, for example primary sclerosing cholangitis, we see these very distinct microbial signatures that are very different from healthy controls.

We often see a lack of organisms that produce butyrate, a short-chain fatty acid that is known to be anti-inflammatory. So, there are these key organisms and key functions that might be missing, and perhaps we can replace those functions with FMT. By doing so, we can also learn about the microbial link to the pathogenesis of some of these diseases.

For example, Colleen Kelly, MD, of Brown University, is looking into FMT for alopecia areata right now, an autoimmune condition characterized by hair loss. A lot of what we’ve learned in C. diff is what led us here, so she noted anecdotally that in two patients with alopecia for whom she performed FMT for C. diff had this remarkable hair growth post-FMT. So, in doing so many FMTs for C. diff, we’re starting to notice some of these links to improvement in other conditions. I’m also currently enrolling for an obesity trial so we can start to understand what role the microbiome plays in both weight loss and weight gain.

Healio: Why is the patient perspective on FMT so important?

Allegretti: The patient perspective is critical, and I can tell you now that I’ve done this for many years, the patient perspective has really changed. When this was just emerging patients were a bit squeamish about FMT, but now the “ick factor” has decreased because it’s so prevalent in the lay media; there are books written on it, YouTube channels dedicated to it, and it was even the focus of an episode of Grey’s Anatomy in 2008, which always kind of blows my mind because the first clinical trial wasn’t published until 2013. So, I think the public perspective has shifted.

There was a study by Stacy Kahn, MD, and her group at University of Chicago where they interviewed all their patients who came through their IBD waiting room and they asked just a simple question: “Do you want an FMT to treat your disease?” Not surprisingly 100% of patients with very severe disease wanted it because those are the patients who really need alternative therapies, but more interestingly more than 30% of patients in remission who were doing well on their current therapies also wanted an FMT for their disease.

Healio: What ongoing studies should we keep our eye on?

Allegretti: The work going on in IBD is very exciting, and there are many studies underway that I think will push this even further. I also think the work my group is doing in PSC, a disease that has no currently approved therapies, is really exciting. We’re starting to see some promising data, so we’re working toward the next step there. Another area of interest is obesity, which is obviously a much more prevalent condition, so I think many people are very interested in the results of the trial we are performing.

I think in the next year or two we’re going to have a lot of exciting new data and for these chronic, hard-to-treat diseases, which will really help us understand how to treat them more effectively.

I don’t think this will be a universal magic bullet for all that ails you, but I do think we can learn a lot from FMT about what the microbiome is doing and what role it is contributing to the pathogenesis of a lot of these disease with the hopes that we can engineer better, more targeted therapies based on what we’ve learned, and I assume in a few years from now we probably won’t be doing FMT in its current state anymore. We’ll have better, more directed therapies for each individual disease. – by Adam Leitenberger

Reference:

Allegretti JR. “Fecal Microbiota Transplantation and its Emerging Role in Immune Mediated Inflammatory Diseases.” Presented at: Interdisciplinary Autoimmune Summit; April 27-29, 2018; Boston, Mass.

Disclosures: Allegretti reports she is a scientific advisor and receives research support from Finch Therapeutics.

Jessica R. Allegretti
Jessica R. Allegretti

BOSTON — Fecal microbiota transplantation has emerged as a highly effective treatment option for Clostridium difficile infection, but as the understanding of its effects on the gut microbiome increases, research is expanding to evaluate the approach in other chronic conditions, according to a speaker at the Interdisciplinary Autoimmune Summit.

Healio Gastroenterology and Liver Disease spoke with Jessica R. Allegretti, MD, MPH, director of the Fecal Microbiota Transplant Program in the division of gastroenterology at Brigham and Women’s Hospital, about her presentation on current FMT best practices and its potential application in conditions like inflammatory bowel disease, primary sclerosing cholangitis and obesity.

Healio: In your talk, you likened the human gut microbiome to a rainforest ecosystem. Can you explain this comparison?

Allegretti: One of the ways we describe the gut microbiome is alpha diversity, or how many different species of bacteria there are. We know that greater diversity is associated with healthier microbiomes, and in contrast when you look at various disease states you often see a depletion of that overall diversity. This is similar to a rainforest, where diversity of species is sort of a marker of its wellbeing. The same goes for your gut microbiome; you want many types of organisms present, because each type of bacteria that live within us perform different functions, so the more variety you have the better the performance overall. You can think of your microbiome as a living organ that provides function for your overall health, so the more diverse it is, the more function it provides.

Healio: What are the current indications for FMT? Have there been any recent changes in its regulatory status and guideline recommendations?

Allegretti: FMT is not FDA-approved for any indication, but the FDA still holds enforcement discretion for recurrent and refractory C. difficile infection, so that is the only indication for which you can perform FMT clinically under this umbrella of enforcement discretion. This policy states that you have to provide informed consent to the patient to explain that it’s an investigational therapy. For any other indication, or if you’re doing a trial or any research even within the realm of C. diff, you have to hold an Investigational New Drug license.

The FDA did issue a draft guidance in 2016 indicating that they may start to institute an IND requirement for providers that use stool bank material, but they still have not enacted that yet. This brief came out over a year ago and they have not enacted that further, so the regulatory status of FMT really hasn’t changed since 2013.

The new IDSA guidelines just came out, and I’m very excited about them. It was a much needed update, and in addition the European guidelines also came out last year, which recommended FMT for recurrent C. diff with high quality evidence, so it was exciting to see FMT recognized as a recommended and well researched procedure. The IDSA guidelines further validate this, showing we have done a lot of work in this area, that we have a lot of high-quality data including randomized controlled trials to show the efficacy of this treatment, and that it is a therapeutic option that really should be offered.

Healio: What are the 5 Ds of FMT, and why is this framework useful?

Allegretti: My colleagues and I work in fairly high-volume centers and we have learned a lot in our experience, so we wanted to develop a practical framework for providers who want to perform FMT or set up an FMT program at their center. The 5 Ds are an easy way for providers to remember the important things you need to be thinking about before you perform an FMT.

First is Decision: Is the candidate appropriate, meaning do they meet those requirements of confirmed recurrent or refractory C. diff? In my own experience and in the literature about 30% of patients who were referred for FMT do not actually have recurrent C. diff, and I’ve diagnosed many other conditions in candidates for whom FMT would not have been appropriate. So really making sure you have those confirmatory tests. Ensuring that FMT is the appropriate therapy is paramount.

The second D is Donor: Where is your donor material coming from? There are two methods for this: a patient-directed model in which the patients select a donor themselves and the provider screens the material, and a universal donor model, whether you partner with a stool bank like OpenBiome, or your institution has its own stool bank that stores material from a pool of healthy donors. You have to decide which model is right for your patient and the institution. I personally use OpenBiome almost universally for my FMTs because of the convenience, and they’re able to do a much better job of aggressive screening that I was not able to provide on my own, so I have a lot of faith in the safety of that material.

The third D is Discussion: The FDA enforcement discretion insists on good informed consent with the patient, so you should discuss both the real and theoretical risks and benefits of FMT with them before the procedure. This includes acute risks like infection transmission or allergic reactions, which are very rare, and the long-term risks, which are still largely unknown. However, we’re certainly concerned about putting patients at risk for these now known microbial-associated diseases like obesity, metabolic syndrome, and some other autoimmune conditions. Even if we screen the donor for these conditions now, and they don’t have anything, what if they develop something later in life? Would we be putting the patient at risk for developing the same condition? We just don’t know.

Fortunately, the NIH has sponsored the national FMT registry that I and many of my colleagues are participating in, which will allow us to start collecting good long-term data, so we will be able to answer a lot of these questions in the future.

The fourth D is Delivery: How are you going to deliver the material? There are many ways you can do it. The most common in the adults is lower endoscopy, so either colonoscopy or flexible sigmoidoscopy, so you can do an assessment of the mucosa to make sure there’s nothing else going on, and then deliver the material. Capsules are now more popular and available, so I will often use those as well. In pediatrics they tend to use a lot of enema preparation to avoid procedures in young children. Providers should have a discussion with their patient about which modality might be more appropriate for them.

The fifth and final D is your Discharge and follow-up plan. We know that the risk of FMT failure is highest within the first 4 weeks. I follow-up with patients for 8 weeks just to make sure the FMT has worked, and if they do experience a failure I will repeat the FMT. Then I generally follow the patients long-term for safety follow-up but also to provide counseling on avoiding unnecessary antibiotics so that patients can advocate for themselves if they need antibiotics in the future.

So that’s a rundown of the 5 Ds, and we hope they will help clinicians simplify what many view as a complex process, so that more providers become comfortable performing this important procedure.

PAGE BREAK

Healio: What is currently the most efficacious mode of delivery, and why are capsules "the future of FMT," as you said in your talk?

Allegretti: We know that the highest efficacy is achieved when the material is delivered to the right colon. The literature shows that the overall C. diff cure rate is about 93% if you deliver the material to the right colon. The most common way to do that is with a full colonoscopy.

Also, in general, if you do a lower GI delivery as opposed to an upper endoscopy or NG tube where you’re delivering the material to the stomach or to the upper small bowel, the efficacy rates are higher. So, where you deliver the material does matter. They all work but lower GI delivery works better.

Regarding capsule delivery, the older formulation capsules were more of an upper GI delivery, meaning they opened higher up in the GI tract, and so you’d lose a bit of efficacy with those. With some of the older data you see around a 70% or 75% efficacy rate with older versions of capsules. Newer versions of capsules are coming down the line with directed colonic release and we’re presenting some of that data at DDW later this year. These new capsules have shown almost equivalent efficacy to colonoscopy. These are promising, because wouldn’t it be great if we could avoid doing a procedure and bowel prep?

I think capsules are the future, partly because for a lot of chronic diseases and in clinical trials you’re not doing a single transplant like you do with C. diff. What we’re learning is that in other chronic diseases like IBD, one FMT does not seem to be enough; you really need to do multiple therapies, whether it’s weekly or daily dosing, we don’t really know yet. We just know that more is better, and when you’re talking about patient quality of life, you can’t be asking patients to get a colonoscopy every week. Even doing an enema that frequently is not ideal, so if we can do capsule dosing, that will improve patient outcomes and QOL. Capsules will make it easier to do better research and will also be much easier on the patient.

Healio: What is the rationale for the use of FMT in autoimmune conditions, and in what conditions beyond C. diff does it show the most potential?

Allegretti: There’s been a lot of mostly cross-sectional research looking at microbial differences between patients with a certain disease compared to healthy controls, and we are starting to see a lot of differences, and every disease is different. My work focuses on IBD, but even in subsets within IBD, for example primary sclerosing cholangitis, we see these very distinct microbial signatures that are very different from healthy controls.

We often see a lack of organisms that produce butyrate, a short-chain fatty acid that is known to be anti-inflammatory. So, there are these key organisms and key functions that might be missing, and perhaps we can replace those functions with FMT. By doing so, we can also learn about the microbial link to the pathogenesis of some of these diseases.

For example, Colleen Kelly, MD, of Brown University, is looking into FMT for alopecia areata right now, an autoimmune condition characterized by hair loss. A lot of what we’ve learned in C. diff is what led us here, so she noted anecdotally that in two patients with alopecia for whom she performed FMT for C. diff had this remarkable hair growth post-FMT. So, in doing so many FMTs for C. diff, we’re starting to notice some of these links to improvement in other conditions. I’m also currently enrolling for an obesity trial so we can start to understand what role the microbiome plays in both weight loss and weight gain.

PAGE BREAK

Healio: Why is the patient perspective on FMT so important?

Allegretti: The patient perspective is critical, and I can tell you now that I’ve done this for many years, the patient perspective has really changed. When this was just emerging patients were a bit squeamish about FMT, but now the “ick factor” has decreased because it’s so prevalent in the lay media; there are books written on it, YouTube channels dedicated to it, and it was even the focus of an episode of Grey’s Anatomy in 2008, which always kind of blows my mind because the first clinical trial wasn’t published until 2013. So, I think the public perspective has shifted.

There was a study by Stacy Kahn, MD, and her group at University of Chicago where they interviewed all their patients who came through their IBD waiting room and they asked just a simple question: “Do you want an FMT to treat your disease?” Not surprisingly 100% of patients with very severe disease wanted it because those are the patients who really need alternative therapies, but more interestingly more than 30% of patients in remission who were doing well on their current therapies also wanted an FMT for their disease.

Healio: What ongoing studies should we keep our eye on?

Allegretti: The work going on in IBD is very exciting, and there are many studies underway that I think will push this even further. I also think the work my group is doing in PSC, a disease that has no currently approved therapies, is really exciting. We’re starting to see some promising data, so we’re working toward the next step there. Another area of interest is obesity, which is obviously a much more prevalent condition, so I think many people are very interested in the results of the trial we are performing.

I think in the next year or two we’re going to have a lot of exciting new data and for these chronic, hard-to-treat diseases, which will really help us understand how to treat them more effectively.

I don’t think this will be a universal magic bullet for all that ails you, but I do think we can learn a lot from FMT about what the microbiome is doing and what role it is contributing to the pathogenesis of a lot of these disease with the hopes that we can engineer better, more targeted therapies based on what we’ve learned, and I assume in a few years from now we probably won’t be doing FMT in its current state anymore. We’ll have better, more directed therapies for each individual disease. – by Adam Leitenberger

Reference:

Allegretti JR. “Fecal Microbiota Transplantation and its Emerging Role in Immune Mediated Inflammatory Diseases.” Presented at: Interdisciplinary Autoimmune Summit; April 27-29, 2018; Boston, Mass.

Disclosures: Allegretti reports she is a scientific advisor and receives research support from Finch Therapeutics.

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