THE MICROBIOME SUMMIT : The New Path to Health
Fecal microbial transplant, a novel approach to treating C.difficile infection
Dr. Talia Zenlea, PhD
Dr. Talia Zenlea, a gastroenterologist at Women’s College Hospital discusses C. difficile infection as an example of dysbiosis. C. difficile infection can be life-threatening and it is unique because it is an example of how gastroenterologists can effectively treat a patient by manipulating the microbiome. Patients with refractory disease (resistant to standard treatment with antibiotics) respond very well to fecal microbial transplant (FMT). Dr. Zenlea explains what FMT is and how and when this therapy is currently being used.
- Tracey:
- We’re here at the University of Toronto with Dr. Talia Zenlea, a gastroenterologist. Welcome!
- Talia:
- Thank you. Thanks for having me.
- Tracey:
- Can you discuss how alterations in the gut microbiome, or dysbiosis, may lead to disease?
- Talia:
- Sure! Dysbiosis basically refers to the difference between the gut microbiota in a healthy person vs. a disease state, or a condition state. As we’ve characterized the microbiota of people, so we’ve looked at general healthy people, we’ve looked at vegetarians, and we’ve looked at people with certain illnesses. So cardiovascular illness, inflammatory bowel diseases, and what we’ve found is that there are similarities, and everybody’s microbiome is different, but there are more similarities than differences in certain groups of people. So, healthy people tend to have more similarities to each other, whereas people with certain illnesses are more similar to one another than to healthy people – and that is called dysbiosis. So, what we can say, for some of the illnesses or conditions that we’ve looked at, we’ve identified dysbiosis, which is really interesting, because why would that be? So, why would somebody with heart disease have different organisms in their stool than a healthy person, because it implies a role, which is why I think this area of research is so fascinating and promising, particularly because it might have implications for treatment down the road. Is their dysbiosis what caused them to develop that condition? Or did that condition cause them to have dysbiosis? We don’t know, because this is just observational, so all we can say for sure is that this phenomenon of dysbiosis exists. We don’t know what caused it, we don’t know if the chicken came before the egg, and it’s hard to manipulate it, with one exception, which is a condition called C. diff. So, this is really promising research in this field and it sort of helped us to understand the role of the microbiome in mediating health and disease. So, what we found, and I’m going to back up again, I talked before about how there are certain organisms that live healthily in the GI tract and then there are other organisms called pathogens which cause illness. So, there’s an organism called C. difficile that live in the GI tract. Babies, for example are colonized with C. difficile, so in small amounts, in certain hosts, it’s not a problem. But when that organism is allowed to overgrow, and take over that area, meaning that it’s becoming a more predominant strain in that area where it should be one in a million, then it becomes problematic, and the reason it’s problematic is that is causes a really severe diarrheal illness that can be so severe that it can actually cause the gut to perforate, which means a hole, or it can cause something called “toxic megacolon” where the gut just stops working. It can lead to a lot of morbidity or can often even necessitate a surgery to take the whole colon out as a treatment, so it can lead to a very, very severe diarrheal illness, so it is important to recognize it and be able to treat it. Even at its mildest, it can cause really significant symptoms that impact people’s lives greatly. So, what do we know about C. diff? So, one of the common ways that people can get C. diff is by taking antibiotics, and again I alluded to this before, but antibiotics are great when you have a bacterial infection because they kill the bacteria that’s driving that infection, and a good example is strep throat. So, if you have strep throat, you have too much strep, it’s causing pus, it’s causing an infection in the back of your throat, if it goes untreated – 100 years ago this used to kill people and the reason it doesn’t anymore is because we have antibiotics, and those antibiotics are strong medications. Even though they are readily available, and we think of them as “vitamins” they’re not. These are very potent, strong medications that kill bacteria. The side-effect, or a downstream consequence of that is that they’re not completely selective. We try to have them be as selective as possible meaning they’re targeting towards this strain, or this type of organism but they’re not perfect and they often impact organisms that they’re not meant to kill and that can happen in the GI tract. They can kill some of those good bacteria, and when the good bacteria are dead, it allows some of these other bacteria to overgrow and cause problems, and one of those is C. diff. So that’s one of the reasons that people can sometimes get C. diff infections. Now it’s not the only reason, so its clearly more complicated than that, but that a simplified overview of what we understand.
- So, people have theorized, so if the reason why C. diff developed, or was allowed to overgrow, was because of a lack of good bacteria, maybe putting the good bacteria back would allow the C diff to not be so predominant, and to help people be able to clear the infection. So, a first-line therapy to treating C diff – it sounds counterintuitive – but it’s with a different antibiotic that’s more selective against the C difficile. That works for a lot of people and when it does- that’s great. But there’s subset of people of whom that doesn’t work. So, you can give them rounds and rounds of increasingly more potent antibiotics, and unfortunately, they continue to get C. diff. Meaning it might be supressing the amounts and they feel a little bit better, but then a few weeks later they come back with symptoms because that C. diff is growing and growing and growing. And those are the people in whom we’ve said well maybe that’s because their microbiota aren’t favorable, so that environment in their gut isn’t favorable to allowing the C. diff to just… go away. It’s favorable to having it continue to grow and that’s why they have persistent symptoms, so we’ve actually tested, and sometimes this sounds like sci fi when I talk about it, but it’s actually reality in 2016 that people who have refractory C. diff infection, the most effective way for us to treat them is with something called fecal microbial transplantation – or stool transplant, and it’s exactly what it sounds. It’s taking poop from a healthy host, and putting it in a host who has disease and we’ve shown that this is extremely effective in treating C. diff. So that has a lot of implications, because that’s one of the first times that we’ve shown that actually altering the microbiome in a very tangible way, has a huge impact on disease. And it’s led gastroenterologists to wonder “well, what other conditions could this treat?” So, an obvious one, and again you’ve alluded to this before, was the inflammatory bowel diseases. So we’ve said ok, well, could there be, we sort of have thought that, we know that these auto immune diseases are driven by the immune system, and we know that the microbiome plays a role in innate immunity in teaching our immune system how to function, so if we alter that in the same way that taking the appendix out we’ve shown, is associated with lower rates of inflammatory bowel disease – could altering the microbiome by means of a fecal transplant, actually help to treat inflammatory bowel disease? Unfortunately, the results in that domain are less promising, and probably because it’s a different illness, but our knowledge is still evolving, so for every trial that shows that it doesn’t work, there’s always going to be another trial later that shows that it does, and this is what’s confusing about the human body, we’re not mice in a lab, we’re people, and there’s a lot of different things that impact us in terms of our success in response to therapy, so I just think it just needs more time. We need more studies and larger studies, and then we can generalize. So, I think there is promise using stool transplant to treat illness, we’re just – aside from C. diff – we’re not there yet, in terms of saying like, this is the gold standard.
- Tracey:
- Right. So, if I were a patient that had C diff, I would say, “why can’t I have that fecal transplant first? Why do I have to take all these antibiotics?”
- Talia:
- Yeah. So, there’s a couple of reasons why that’s true, and the first and most important is that fecal transplant hasn’t been studied or proven as first line therapy for C diff. So, this is not something we’ve looked in people who’ve come with a first presentation of infection. We’ve only studied it in refractory disease, and though it seems obvious, like “well if it’s works for the people with refractory disease, wouldn’t it just work a thousand times better for me if I have it for the first time?” and like everything in medicine – that would be common sense, but often our bodies don’t listen to common sense, and that’s not how they act. So, sometimes in medicine something seems so obvious, and such a clear an assumption to make, and until we’ve shown it to be true, it’s very dangerous to assume that it is true, because it’s just an assumption and often times doesn’t prove to be the case – so that’s the most important reason. The other reason, which is equally as important is that of a risk So, as I said before, we always have to mitigate risk, and benefit. So, you might say, “well, fine, antibiotics – we know have risks!” but the truth is, we’ve shown that in treating C. diff, there are very few risks with the antibiotics. Most people with C. diff, take this treatment – a targeted antibiotic – and do much better. They get better, and that’s the end of it. They never have any other problems, it’s a short course of antibiotics, there are very few side effects. They’re not taking these antibiotics forever, they’re just taking them for a course and they often do better. So you’ll think, what’s the risk of a fecal transplant, and the truth is, or the answer to that question is that we’re still a/ still learning but b/I’ll tell you why I’m hesitating about this in a minute, but the way we do a fecal transplant is with an endoscopic procedure, and any endoscopic procedure – this is an invasive procedure, and again: is it worth is for somebody with refractory C. diff? 100% because their potential risks of refractory disease and the morbidity, meaning the impact on their lives, is great – astronomical! And to them it’s worth a small 1 in 1000 risk of a perforation in a colonoscopy for example. Now I that same risk worth it if the alternative is just to take an antibiotic for 14 days? Of course not, so I can’t justify the risks of that procedure. The reason I was hedging is because they are working on potentially being able to do fecal transplant through a pill. So, if we can package poop in a pill, then it’s very comparable to taking an antibiotic and maybe we can do head-to- head studies and compare the safety of both of those things. Again, my gut – forgive the pun – is telling me that it is probably safer to take the poop pill than to take the antibiotic, but again that’s an assumption. So, I need to have a head-to- head study to tell me that. We need to look and someone who has C diff, if we randomized some people to conventional therapy and other people to the poop pill – who’s going to do better and we have to follow them for some time and see if there are any downstream consequences down the road, so 6 months later is one group more likely to have a recurrent infection? Those are some of the questions we need to answer.
- The other question that’s been raised, is there anything bad about getting poop from someone else, and what about risks of infection, like HIV or hepatitis? So, at the moment we are very carefully screening our donors and getting a poop transplant isn’t something you can just walk into any gastroenterologist’s office and do. So, when you ask me like a day in my life as a GI – is fecal transplant any part of it? And the answer is no – these are very highly-regulated procedures that can only really done at the moment with a research protocol. So, they’re not front and centre as part of routine therapy even though we know they work. We have to be careful because we’re using sensitive human product, and it’s hard to know, you know, we have to be sure that’s safe and we’re not going to contaminate people with something bad.
- Tracey:
- Thank you.
- Talia:
- Thank you. Thanks for having me!
