Podcast: Faecal microbiota transplantation: indications, evidence and safety
Is one person’s faeces another person’s therapy? David Liew interviews Dr Sam Costello about the indications, evidence and safety of faecal microbiota transplantation.
Read the full article in Australian Prescriber.
Listen to podcast here.
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Faecal microbiota transplantation or FMT. At first, it evoked surprise and mirth among some, but that was quickly replaced by the excitement about the possibilities that FMT might bring. It suddenly escalated as a potential power of the microbiome became better known, but what’s the current state of play and where does FMT really belong in practice?
I’m David Liew, your host, and we’re in for a fascinating one in today’s podcast. I’m joined by Dr Sam Costello, a gastroenterologist at the Queen Elizabeth Hospital in Adelaide, and the founder of Australia’s first public stool bank, BiomeBank. He’s written an article about all of this in the latest edition of Australian Prescriber, and we’re lucky to have him on the program here today to tell us a little bit more about it. Sam, welcome to the program.
Thank you, David. Thanks for having me.
Now, before we start, let’s get something out of the way. This area is rich in childish puns, but we’re all professionals here at Australian Prescriber, so we’ll refrain. You must get them a lot.
Yeah, it’s a topic that’s ripe for humour, that’s for sure. Yeah.
Well, you’ve probably had a gut full and the last thing you want is for the quality of this to go down the toilet, so I’ll stop and get to some of the facts. I think the idea of FMT is mysterious to most people. To talk us through this, where does faecal microbiota transplantation, what does it mean in practice, where does it sit, and why might this be something that works?
Faecal microbiota transplantation or FMT, as it’s commonly referred, is the transfer of faecal material from a healthy individual to a person with disease, with the aim of treating that disease. At the moment, where does it sit? It’s an effective therapy to treat Clostridium difficile infection. It is now in most national and international guidelines for the treatment of recurrent or refractory C. difficile infection and really plays a role when patients have at least two recurrences, or have a severe episode of C. diff or C. diff that’s not responding to traditional antibiotic therapy, so vancomycin or metronidazole. There are also emerging indications, so there is evidence that you can induce remission of ulcerative colitis using FMT also. And there are trials under way in a number of other areas now.
I mean I think for most people when they first hear about this as an idea, it seems fairly incredible that you can transplant someone else’s faecal microbiota and change the disease process so dramatically. How does this even work? What’s involved and why might this have some plausibility behind it?
Well it really is a revolutionary therapy in some ways. Traditionally bacteria have often been thought of as the enemy. I suppose now we realise more and more that the microbiome, the organisms that live on and within us, play critical roles for our health. They help us digest our food, maintain the lining of the bowel, they educate our immune system. In that sense we’re a composite of human and microbial cells that work synergistically together.
Loss of these organisms through antibiotics, poor diet or other exposures related to modern living can impact our health. FMT is really a demonstration that replenishing the gut microbiome can be beneficial and can be therapeutic. I do think that there is a huge amount of more research needed in this area, but it’s hugely promising also.
Can you tell us a little bit more about the microbiome and what it means in terms of regulation within the body and how it evolves?
The microbiome collectively are all the organisms that live on and within us. The majority of these are in the gut and the gut microbiota consist of bacteria, fungi, protozoa, archaea, viruses, and that includes phage that are viruses that infect bacteria. A really diverse array of organisms and these organisms have really co-evolved with humans and the microbiome is really established early on in life.
There is some evidence of transplacental transfer, in utero, but the majority of the organisms are acquired during the birthing process and then shortly after through exposure to the mother. Breastfeeding plays a very important role. There are organisms within breast milk. There are also a number of important prebiotics within the breast milk that really shepherd the microbiome into a healthy state and allow the acquisition of organisms from the environment. The environment itself.
There is evidence that say having a pet at home will result in a more diverse microbiome and reduce your risk of subsequent development of allergy and atopic disease. Diet plays a critical role as well. High-fibre foods are really important. A number of the bacteria within the gut rely on fibre, so essentially resistant starches, as their primary food source and they use that to produce short-chain fatty acids, which are important for gut health. Then there can be some deleterious things. Early antibody exposure can have a long-lasting effect on the microbiome in reducing its diversity.
We know that early exposure in the first three years to antibiotics is correlated with subsequent development of diseases including obesity, inflammatory bowel disease and others. That early window appears critical. Then after the first three years, the microbiome is relatively stable.
Once you’ve got that imprinting of risk, I guess, from the microbiome, I guess beyond that there’s the idea that perhaps we can manipulate that in the future to change disease and I guess this is where FMT comes in. How did this evolve as an area in terms of trying to understand how the introduction of a different microbiome might affect diseases?
The study of the microbiome has really evolved quite rapidly recently. Traditionally microbiome was assessed with culture-based methods and these were initially quite limited. We could culture a range of organisms, things like lactobacilli and bifidobacteria are quite easy to culture, but they really make up a very small sliver of species that are present in the gut. Then really with the advent of sequencing, so molecular methods to sequence the genome and the genetic material within the gut, that allowed a bigger picture of what was there and it’s opened the field of research up to everyday researchers to assess the microbiome and different disease states and in health.
Actually the research has now gone full circle in a way. The really cutting-edge research now into the microbiome again involves culture of organisms. There are groups who have developed methods that can really almost culture any organism in the gut now. Dr Sam Foster, who’s at the Hudson Institute in Melbourne, is one of the world experts in this area, and his and other groups have been able to culture widely in the gut microbiome and then using the… and actually sequence the genome of each of these isolates and then put all of those genomes into a reference library, which allows them to get a much better coverage in other sequencing studies, might be much more precise in their identification of organisms. Now actually culture and sequencing go hand in hand in these later studies.
How did all of this come to Clostridium difficile? Because I guess on a broad level it seems that maybe this is a disease where there is some dysbiosis of the microbiome and even to a lay medical person like myself, but how did we start to realise that there might be potential with this specific indication?
I mean, the first clue is that C. diifficile really does often rear its head after antibiotic exposure. We know that people who develop C. diff infection have a rarely reduced microbial diversity. They don’t have the breadth of organisms that you would expect to see. We think that there are a lot of organisms that provide colonisation resistance, so their presence wards off pathogens such as C. diff. But really the FMT for C. diff is not a new therapy. The first cases were reported in the Western literature in the 1950s and then there were sporadic case reports over probably the next 50 years until 2013 when there was a paper published in the New England Journal from a Dutch group who showed in a randomised controlled trial that faecal transplant was superior to vancomycin therapy, so they were looking at sort of 80 to 90% cure versus 30% with traditional antibiotic treatments.
Let’s talk a bit about how this happens in practice because those numbers are fairly stunning and it sounds like the kind of thing which we’d like to be using often. It sounds like it might be logistically not straightforward, even though you hear about people trying to do it on following recipes on the internet at home. I get the sense that this isn’t the kind of thing that you’d necessarily want to do that way.
No, I mean if you go online, there are a large number of reports of people doing this. Yeah, it is happening and there is no point putting your head in the sand about this as a doctor, because unlike a lot of other treatments, prescribed medicines, if you don’t think someone should have the treatment, you can withhold it. Whereas this anyone can access stool really. I think it really is important to have access for people who do need it so that we can provide it as safely and as reliably as possible because, with proper methodologies, you can certainly deliver it in a more safe way than doing it at home without proper screening.
You do this on scale professionally now, tell us a little bit about how it works for you in practice. How do you select an appropriate donor for your BiomeBank?
Donors are healthy volunteers who don’t have active medical problems and they are screened really with a four-step process, so they have a medical interview, a physical examination. If they pass those steps, they then proceed to have a blood test and a stool test. Each of those steps, we’re really looking to reduce the risk of disease transmission. This includes infectious disease. Often tests that we would do would be similar to the blood bank for blood donors, but we also have additional tests, so the stool test obviously is different.
We know that the microbiome is involved in a number of diseases that are not transmissible infectious diseases. Obesity would be one of these. There is evidence that you can transmit obesity in animal models. Into germ-free animals you can transfer the microbiome and then cause animals to gain or lose weight just with microbiome changes. We would screen people for that condition just to name one.
Yes, the screening process is quite a bit broader than with blood donation. As a result, really we have less than 10% of people who apply to be donors do qualify in the end and that donation process then starts after they’ve passed the screening and they typically donate over an eight-week period. We like to have multiple donations during that period of time. Then we do what we call a tail screening. We screen again using the same tests and, if donors pass both those tests, the stool that’s been collected during that period is acceptable to be used to treat a patient.
Right. Okay. What do we do once we’ve got those samples? I can imagine the preparation is not necessarily straightforward as well. Then of course the actual delivery requires a bit of sophistication as well.
Yeah, so we process the stool in our laboratory. We have a purpose-built clean room, which we’re looking to comply with the latest guidelines that are coming out from the TGA. There are a lot of protocols involved in that. Essentially the stool comes into an anaerobic chamber. This is a chamber that’s filled with nitrogen, hydrogen and CO2 gas to exclude oxygen because a lot of the bacteria are sensitive to oxygen and we want to maintain their viability.
We then add saline and glycerol and then that’s then all mixed up in a bag using a device called a stomacher that’s then transferred to syringes. They’re then capped and taken out of the chamber and frozen. We store those at –80 degrees. The stool sits in the freezer during the eight-week period until the donor has their second screen. Then it can be released to the hospitals.
Right. Then so once it gets to the point where a patient perhaps, say, has Clostridium difficile and needs FMT therapy, then how do we go about delivering? I get the sense it’s become more and more sophisticated in terms of delivery as well.
FMT is most commonly given via colonoscopy at present. There’s the most evidence for that delivery method and it does have a high success rate via that method. Typically, the patient would be on vancomycin. They would have a course of that between say five and 10 days, and then they would hold the vancomycin for a day, have a bowel preparation, which is probably less than would be required for a standard colonoscopy, largely because they often have diarrhoea from the C. diff infection and they would come in and really the experience for them would be similar to having a colonoscopy for any other reason. They would have a sedation and have the colonoscopy.
The FMT is flushed down the biopsy channel of the scope so it’s delivered through the scope into the bowel, right into the right side of the bowel, usually into the cecum. They would then stay on their side for about an hour afterwards to try and retain the FMT and then go home and usually patients will feel a lot better quickly. Cure, we’d expect about 90% with one treatment and in patients with severe disease or those who are unlucky, they may relapse, or exposed to antibiotics again, that’s a risk factor and in those 10% of patients we would typically retreat them.
You can also give FMT via enema and success rate with that is lower, but if you use repeated enemas you can get a high success rate and we would use that in patients often who are say high risk. They might have a colonoscopy and follow it up with a couple of enemas, or in patients who are too high risk to have a colonoscopy, for other medical reasons, they might just have enema treatments. FMT is also been given via nasogastric tube or capsule in some studies also.
All of this sophistication, I guess speaks firstly to the fact that you can’t do this at home, but there’s a lot that’s gone into trying to make sure that this is a procedure which is well tolerated and doesn’t cause harm.
Absolutely. Screening is very important. We have Head of Donor Screening at our organisation, Dr Emily Tucker who’s an infectious diseases physician. She has put together our screening document, which tries to assess the epidemiological risk of donors and also the best test to use. That continually evolves. I mean we’ve seen with COVID-19, the coronavirus, that has implications for donors and that was nothing that we’d heard of six months ago when we wrote the protocols.
Because that death in the US, was it with multidrug resistant E. coli, really that’s the thing that you go to great lengths to avoid and that’s why that protocol and that level of screening is so important.
Which do you think of the next diseases that… Where is it showing promise? Where are the areas where FMT is looking like well maybe this might help solve some difficult problems?
I suppose the second indication really with the most evidence is ulcerative colitis. We do know that FMT can induce remission in ulcerative colitis. What we need, we need further evidence regarding maintenance of remission because this is a disease that relapses and remits. The other issue would be safety, of course. I’m sorry. Yes, so long-term safety data is needed as well.
I think that’s probably something to keep in mind as we talk about other indications. I know that perhaps Crohn’s may well be the next cab off the rank. What would you say in terms of trying to interpret those emerging data and indications?
There are trials coming out all the time now. With regards to irritable bowel syndrome, there are four randomised controlled trials, two have shown benefit and two have shown no benefit. In fact, one of the trials showed that placebo was actually statistically better than donor FMT, so donor FMT was worse. So it’s certainly conflicting. With the irritable bowel, the two studies that used upper gastrointestinal delivery, including capsule, they seemed to perform worse and the ones that used lower GI delivery were positive studies. It’s really a bit difficult to know how to interpret that.
The take home is that there is not strong evidence that FMT is effective for irritable bowel syndrome and then for Crohn’s disease there is far less evidence. There are no randomised controlled trials. There were case reports and case series and people have reported benefits certainly in those, but it’s really, it’s very difficult to interpret them without a control arm. The only other thing I’d say is I really think that in the long term FMT will not be the primary microbial therapy. I think FMT will be used to demonstrate clinical efficacy and prove that by modifying the microbiome you can improve disease.
But then I hope that the science progresses so that we can determine what are the elements within faecal transplant that are having the effect and distilling those down into a more defined therapy. So second-generation microbial therapies where we know what the composition is. And then I think you could expect potentially improved efficacy, but also improved safety and a more predictable response with a more defined consortia of organisms. And there is certainly a lot of research that’s going into that now and I think that’s really exciting.
Well, it’s an exciting time for manipulating the microbiome. Thanks very much for talking us through it today, Sam.
Thanks very much David.
The views of the guests and the hosts on this podcast are their own and may not represent NPS MedicineWise or Australia Prescriber. I’m David Liew and, once again, it’s been a pleasure joining you on the Australian Prescriber Podcast.