00:00:00: Hello everyone, welcome to this episode of the UG Talks.

00:00:04: I'm Pradeep Mundra here and i am your host for today now.

00:00:08: fecal microbiome is probably one other most complex concepts to understand at least from my simple mind.

00:00:16: Estimates indicate that there's probably about thirty trillion bacterial cells in the body, which is equivalent to the number of cells we have.

00:00:24: And a variety of them probably explains why it so difficult to understand the rule of microbiome and disease.

00:00:32: I guess imbalance seems to be implicated on almost all diseases and health states.

00:00:38: Sometimes at least some disease states wonder whether this is more chicken-and-egg situation.

00:00:44: where does the imbalance in microbiome leads to disease or the disease leads to the imbalance of microbiome.

00:00:51: Fecal microbiota transplant, let's call it that way for now at least involves transfer of stools from a healthy individual to an individual with disease and I guess they have been intentioned to reset their microbiome within aim to treat the disease process.

00:01:08: considering every other day there is new paper published about implicating the role of gut microbiome in disease states, I feel that fecal microbiota transplant may have a very expanding role in treating various diseases.

00:01:23: But where do we stand currently to discuss this today?

00:01:27: We have our lovely guest Professor Maria Verstschalt who is an infectious disease specialist and head of Infectious Diseases Department at Frankfurt University Hospital.

00:01:39: Maria has published extensively in this field and heads the Cologne microbiota bank.

00:01:44: And is also taught previously at The PGT Programme at UG Week.

00:01:50: Welcome to the podcast, Maria!

00:01:52: Thank you it's so nice to be here.

00:01:54: Excellent So Maria.

00:01:56: I remember a story few years ago about German troops in World War II In Africa eating camel poo To treat travelers decently.

00:02:06: The way I remember it, as i think they followed what the locals said.

00:02:09: Locals used to do.

00:02:10: but surely the concept of fecal microbiota transplant goes before this?

00:02:17: Can you tell us when its all started and who conceptualizes?

00:02:21: Yeah, to my knowledge it was first described in ancient China as yellow soup.

00:02:27: That's what I learned is the earliest description of something similar to a fecal microbiota transfer.

00:02:35: What may be important for us as modern physicians Is that?

00:02:41: The first formal case description Was published in the nineteen fifties by Mr.

00:02:48: I think his name was Steinman from Colorado, and after that FMT was used in case series particularly In the Scandinavian countries.

00:03:03: And then in two thousand thirteen we had The first randomized controlled trial which Was conducted in the Netherlands and i Think everybody is very much aware of the impact Of this trial changed our view on FMT or how it even drew the attention of people to this topic, who were previously not even aware of the existence of FMT.

00:03:27: At the beginning was that same indication?

00:03:30: Was is a completely different let's say in the nineteen fifties?

00:03:35: The physician used it initially.

00:03:38: he did not really understand exactly why his patients suffering from diarrhea.

00:03:45: So he thought that there was a different cause and it only later became clear.

00:03:50: That C diff is actually the cause of this problem, but you did use in for hospital acquired diarrhea

00:03:57: okay?

00:03:57: Okay so that indication still kind of stands.

00:04:00: that brings us on to the next topic.

00:04:03: Maria can explain simple terms how a complex concussion of unknown bacteria and totally unknown substrates, I'm assuming could work in specifically defined disease states such as C. difficile?

00:04:15: I guess IBD is different ball game in its theology extremely complex and unknown.

00:04:21: so what's the pathophysiology behind mechanism?

00:04:26: My interpretation

00:04:30: of the evidence is that when people are exposed to antibiotics, their physiological composition of the microbiota is altered.

00:04:42: The physiological microbiota can down-regulate the transformation from C. diff spores into vegetative cells but also the toxin production.

00:04:57: And now there are different hypotheses how this works.

00:05:01: One very much discussed hypothesis is that primary bile acids are converted into secondary bile acids by components of the physiological microbiota.

00:05:14: and if I then expose my patient to antibiotics, these bacteria manage this transformation.

00:05:22: they're gone.

00:05:26: that stops the clostridia from multiplying and producing toxin is also gone, then they become active.

00:05:34: Our asymptomatic carrier turns into a symptomatic

00:05:38: patient.".

00:05:39: Some people doubt this hypothesis.

00:05:42: other mechanisms have been discussed.

00:05:45: for example phages might play role in regulating bacteria in the gut, then it has been hypothesized that other metabolites may also play an important role.

00:06:02: But I think it's safe to say that regulation of the activity of C. diff

00:06:10: is

00:06:10: somehow connected with composition our gut microbiota.

00:06:16: How would FMT change this?

00:06:19: In terms how does it work for patients at C.Diff?

00:06:22: Yeah, so if your gut microbiota composition is disturbed and you are lacking the bacteria that you need to suppress the CDIF activity then FMT will restore a physiological habitat in your gut.

00:06:40: And re-establish the regulation processes to suppress CDI

00:06:46: In CDIF.

00:06:47: I guess as a physician my aim when I treat these patients is to improve the symptoms and probably prevent mortality, although i personally haven't come across anyone who know what.

00:06:59: any of my patients die from CDF but have dealt with pretty sick elderly patients.

00:07:05: With CDF...I'm assuming that the goals for treatment are in improving their symptoms or reducing mortality?

00:07:11: In terms Drug management, what is lacking with the current use of drugs?

00:07:17: Why was there a need to use FMT for such

00:07:19: patients?".

00:07:20: Yeah.

00:07:20: So we know that when patients are treated with metronidazole or vancomycin, their recurrence rate after having treated first episode is around twenty-five percent.

00:07:32: it's lower if they're treated with Fidexamycin but still has considerable recurrence rates.

00:07:40: and then some do enter a kind of vicious cycle of recurrences.

00:07:47: And FMT, in my opinion is particularly important for these patients who don't respond anymore to any of the drugs or better put they do respond but as soon you stop treatment will have another recurrence no matter which drug use.

00:08:07: And these patients really need their microbiota restored to prevent further recurrences.

00:08:13: So that you've already mentioned, it looks like that's one of the indication for use of FMT in CTF in terms of preventing recurrence.

00:08:22: and can we just allude what are current indications in CT for a whole scheme of CTF management?

00:08:30: Where can we use FMT?

00:08:32: only because patients can be used as primary treatment instead of antibiotics?

00:08:37: How does this fit in, in and amongst various drugs?

00:08:40: You know, vancomycin, metronidazole, fidoxamycin.

00:08:44: So where do we need to consider FMT in our

00:08:47: patients?".

00:08:47: Yeah so current guidelines recommend an FMT as a follow-up treatment to a standard treatment.

00:08:56: I want to explain it well because i think many people are not aware of the fact that Diarrhea current diarrhea episode with an FMT.

00:09:08: what people usually do is that they treat the current episode.

00:09:13: With one of the standard drugs and then when that is finished and patients are free off symptoms, They perform the FMT to stabilize this situation.

00:09:25: but it's not done interchangeably or at the same time its sequentially.

00:09:32: So that's important to understand, so it really is secondary prophylaxis.

00:09:37: That the proper classification for the FMT.

00:09:40: and you are asking when this done at an international level guidelines recommend FMT from multiple recurrent CDI?

00:09:59: closer to treating earlier.

00:10:01: So this is definitely where things are going, but guidelines I'm not there to recommend that already and they're definitely isn't enough evidence yet to say after a primary episode we should perform an FFT in everybody?

00:10:20: We are not there yet.

00:10:21: But i know That people thinking into this direction.

00:10:25: Okay so just let me make it clear to our listeners.

00:10:28: Two recurrences means you get a primary episode of CDIF, you get your first recurrence and second recurrence.

00:10:34: so that's the third time they are having a CDIFF episode with investigations confirming positive CDIFT.

00:10:44: That is when... You would use but also mention it as if you treat them then use FMT to prevent.

00:10:52: Am I correct in that?

00:10:55: Excellent, okay.

00:10:56: And the treatment for that?

00:10:57: you would always use these antibiotics?

00:10:59: The vancomycin at that time or Fidoxamycin?

00:11:02: Personally prefer to use Fidoxymycin because it causes less collateral damage to gut microbiota and as I just explained is all about restoring the gut microbiot.

00:11:16: so i actually don't want to cause any further collateral damage if can prior to the FMT.

00:11:23: On the other hand, you can say well if you're just going to restore it radically anyway You could also use vancomycin.

00:11:30: so I think both works and It's often more an economical question than really a medical Question whether one or the others used

00:11:40: right?

00:11:41: Is that universal rule about second recurrence?

00:11:45: Are there any selected patients who do not want to use FMT depending on their immune status?

00:11:51: Oh, do you mean other contraindications?

00:11:54: Yeah.

00:11:54: I mean there

00:11:55: are definitely patients where the risks associated with an FMT are higher than in others.

00:12:03: so whenever there's significant disturbance of the barrier function off the gut then i would be very careful when performing FMT.

00:12:16: for example let say Neutropinic patient who has received chemotherapy and there's also inflammatory activity due to the chemotherapy in the gut mucosa.

00:12:29: Then this is a patient I have two watch very closely.

00:12:33: when i perform an FMT, i'm not saying you cannot perform it but you do have to be more careful.

00:12:40: that is the clinical trial in steroid refactory graft versus host disease after stem cell transplantation that proves it is possible to administer FMTs.

00:12:53: In quite extreme situation with respect to immune suppression, but of course these patients have to be watched closely.

00:13:02: okay.

00:13:03: so Mary, it looks like you would see diff with reasonably clear when we should use and in my practice as a gastroenterologist.

00:13:11: We mainly deal with IBD patients And most of my IBDP A lot of my OBD patients ask about FMT.

00:13:18: In fact one on my patience.

00:13:20: for years ago I remember He asked me what FMT and i said well there's some evidence but the guidelines do not suggest using FMT out With clinical trials.

00:13:30: And he went home.

00:13:31: I said, oh got some poo from his relative made it into animal concussion and administered itself.

00:13:38: so there are some people who just strongly believe in this.

00:13:40: So i guess i want you to sort of summarize what's the current evidence for use FFMT in IBD?

00:13:50: What am getting at is Am I okay to advise using it right now or should we wait more Evidence to emerge?

00:13:58: That's a very difficult to answer question.

00:14:01: I believe it is safe that FMT generally spoken has an effect on IVD, but in which situation should be used?

00:14:20: Let me try and explain that further... So we now have a moderate number of randomized controlled trials.

00:14:28: They are moderate in size or small, so that doesn't help!

00:14:34: We would actually like very big trial better and if you look at the meta-analyses performed based on these trials there is an effect... favorable effects of FMT on activity of IBD.

00:14:48: But these trials have been performed in very different ways.

00:14:52: So some trials have used multiple donors to produce an FMT, others use just one donor per treatment.

00:15:04: Others used anaerobic conditions for manufacturing the FMT, yet others treated very intensively over longer periods of time.

00:15:16: Are there only ones?

00:15:18: Some use capsule, some administered the FMt endoscopically.

00:15:23: Some used an antibiotic induction treatment prior to FMT and some used additional nutritional preparations like a nutrition regimen in combination with the FMT.

00:15:38: So there are so many factors that might have determined the favorable outcome, but it's really hard to say how should be perfect FMT and this setting look like?

00:15:52: And how long should this be administered?

00:15:54: because many of the trials also show if there is an effect it wanes after certain time.

00:16:03: we need to keep that in mind too, because it means I would have to re-administer the FMT again and again.

00:16:10: So its not a question of if but how do this?

00:16:15: And i see that can be really frustrating for patients who say oh yeah there is an effect...I still cannot give it you..because im not sure what's best way to give it to you!

00:16:32: difficult or I can't really be justified in using this outside a trial setting, maybe on an individual basis you could make that decision explaining the uncertainty to patients.

00:16:45: Is it what your thoughts are?

00:16:47: Yes!

00:16:48: Can give you example?

00:16:49: when first trials came out and showed certain effect we treated around ten patients here at Germany because based our laws.

00:17:02: But then we realized that this is more complicated than we may have thought.

00:17:07: Because, when people responded the effect went away after about three months and... We would have to re-enwrite these people probably every three month To receive these treatments at the same time?

00:17:23: We don't have financial compensation of these treatment in Germany so who will pay for it?

00:17:29: And how is it ethically fair To give this to ten people but not two all the others?

00:17:36: so we stopped it again and decided that we should really wait for the situation to be much clearer.

00:17:43: And four of the possibility to scale up production with financial safety before we would offer this more people?

00:17:51: are there any large studies going on at the moment which will change the scene?

00:17:56: so say, for our IBD patients.

00:17:59: There are many studies going on, but what I'm missing a bit is very large trial that would systematically assess all the different or at least some of.

00:18:18: But I understand the funding landscape also.

00:18:23: It's extremely difficult to get money for such a big trial, but it is less difficult to make money with small or moderate-sized trials.

00:18:33: so we can have all these smaller and moderate sized trials that cannot be answered by the big

00:18:38: questions.".

00:18:39: Right!

00:18:40: Okay... So looks like there are more ways to go about this?

00:18:44: Okay, let's move on to the next one.

00:18:48: IPS always difficult and we as clinicians really struggle to treat patients.

00:18:54: certainly in clinical practice say I'm always advising patients try different probiotics.

00:19:00: so my patient ask me which one should i A lot of times I'm clueless, and say try different things.

00:19:09: which ever works for you.

00:19:10: So i'm assuming giving a concussion or bacteria seems to help some our patients.

00:19:15: so my question is would FMT work?

00:19:19: What should we be considering?

00:19:20: what does the science says?

00:19:23: The science says that you shouldn't offer it at this point because again There is a number of trials that looked into this indication and if you take the meta-analyses, they are quite recent.

00:19:39: You do not see a benefit for FMT overall.

00:19:44: but we must also recognize these statistical assessments by many patients as an average.

00:19:55: It's not exactly an average but I think you understand what i mean.

00:19:59: Yet, from my practical experience there are individual patients that seem to benefit from the FMT but I cannot exclude they benefit because of the placebo effect.

00:20:15: Because when I offer it in an individualized trial setting i can not use a placebo.

00:20:22: so these people benefited.

00:20:26: And also here, I often see the effect that the affect wanes after about two or three months and then you have the same problem as with the IBD People.

00:20:37: how to deal with that on a long run?

00:20:39: Looks like in a people are thinking of different indications.

00:20:42: is there any other disease process That FMT been tried Other than this?

00:20:47: three we discussed just now.

00:20:49: There's very broad range of trials that out right know.

00:20:53: So we have trials in the neurological area on Parkinson's disease, on multiple sclerosis.

00:21:03: We have trials and autoimmune diseases.

00:21:06: there are trials in liver cirrhosis patients who were decompensated.

00:21:12: There are trials of patients taking immune checkpoint inhibitors And we want to enhance their response to these drugs.

00:21:23: I think i could go on forever.

00:21:27: Name the disease, it's very likely you will find a trial!

00:21:32: Okay that is what i thought considering so much was published these days about, you know, microbiome changes in pretty much all disease process.

00:21:43: So I'm not surprised that people are considering this for various disease processes.

00:21:48: Excellent!

00:21:49: On that note can we just move on to safety now?

00:21:51: What could go wrong with these things?

00:21:53: so... Can you highlight from your point of view what could be the safety issues when we do FMT?

00:22:01: Yeah, sure.

00:22:02: The people who manufacture the FMT really need to take very good care in what they do.

00:22:10: so it's important that you have a stool bank that concentrates on just manufacturing FMTs.

00:22:20: these shouldn't be people doing this after their work or weekend.

00:22:26: It should be professional setup And the professional setup includes roles of different people who work in it.

00:22:35: There needs to be a quality management and quality control system, all this need very professional because there are potential safety risks.

00:22:46: I like compared with blood bank transfusions nowadays quite sure but they aren't quite sure.

00:22:55: we learned that if you don't respect safety rules, we do have safety issues and the same is true for FMT.

00:23:04: So if you set up such a system of quality management.

00:23:07: in Quality Control I think it's very safe treatment but really to guarantee that there are EDQM guides describing how substances or human origin should be processed used as treatments and this EDQM guide very clearly describes which quality standards are necessary to properly manufacture an FMT.

00:23:36: So if anyone is interested, you can read that in the EDQ M Guide.

00:23:42: Okay on just to educate our listeners what are safety?

00:23:46: Is it infections or allergic reactions?

00:23:51: What could go wrong?

00:23:52: Yeah okay so Potential pathogens could be transmitted to the recipient from the donor and many healthy people are colonized by potential pathogens.

00:24:06: For example, e-HEC or EPEC—many of us are intermittent carriers.

00:24:11: we don't even notice it but it wouldn't be very wise to have this transmitted to an immunocompromised patient through an FMT?

00:24:21: I think we can agree on that And we really have to check carefully for these things.

00:24:27: So our safety process, or any safety process on FMP usually starts with an interview of the volunteer and similar to an interview in a blood bank risk behaviors asked for prior underlying conditions.

00:24:47: then based off that it is decided whether the volunteer can give the stoolbanks some blood and feces.

00:24:55: that will then be checked for infectious diseases pathogens.

00:25:01: And if it's also fine, this person usually becomes a donor.

00:25:06: but all these tests or questionnaires have to be repeated regularly.

00:25:12: So is it as rigid process of sort-of-blood transfusion?

00:25:19: Can we move on to the roots of delivery?

00:25:23: And if you all have our thoughts on this, I guess.

00:25:27: The easiest would be for somebody to swallow a pill.

00:25:31: so in terms of efficacy and what we should be using let's say give an example of CDEF.

00:25:38: What is your preferred method or root-of-delivery?

00:25:43: So let's start with the available ones, so you can go through the upper gastrointestinal tract.

00:25:49: The early trials they used duodenal tubes to which the FNT was delivered and could use capsules as we just said.

00:25:58: then you could also do lower gastro-intestinol tracts through colonoscopy or by using an enema.

00:26:06: And if now look at evidence would say that the anima is definitely not as efficacious as the other roots.

00:26:18: only if you use it repetitively then they are similar.

00:26:22: but if your own me used once than the other routes are superior.

00:26:27: now i don't really like to work with the tube.

00:26:31: Because u have two places endoscopy curly and then also, have some kind of problem with aspiration, this can be dangerous if there's somehow a way that the infused microbiota comes back.

00:26:49: We don't really want that so I'd rather use capsules or a colonoscopy to see what seems safest for us.

00:26:59: And between the two, the patients definitely prefer the capsules because then they don't need to have their guts prepared.

00:27:07: They don't eat.

00:27:08: the colonoscopy and of course a colonoscopy can also have side effects on these can be spared if you use the capsule

00:27:17: And the capsules are equally efficacious compared to colonoscopic method of delivery.

00:27:22: It's a bit difficult say because there is no head-to-head trial, right?

00:27:27: But if you look at studies that use capsules and studies that used colonoscopy I would say maybe... The evidence for colonoscopy is couple off percentage just better but me it wouldn't really Yeah, outweigh the advantages of the capsule and efficacy is still very high with both methods.

00:27:53: We are around eighty percent after one treatment.

00:27:57: So that brings on to our next point Maria.

00:28:00: How do you source?

00:28:01: You know can I maybe where you work?

00:28:04: Can we get these pills in Frankfurt?

00:28:10: I don't think so.

00:28:12: I have access as far as i know.

00:28:13: Yeah, so access is really different.

00:28:17: when you look at the front countries and regions of different countries it differs radically.

00:28:24: So As I understand access in the UK Is quite good?

00:28:29: And there's also compensation by the insurance companies.

00:28:34: This seems all very thought through and well set up.

00:28:38: The same is true for Denmark.

00:28:41: But then, for example in Germany we don't get recompensation for these treatments and there are only very few centers who actually offer this treatment.

00:28:51: And we're becoming less and less because the process is expensive since it's not covered.

00:28:59: It's hard to maintain.

00:29:00: I can speak for every country but you see that range is broad between situations of different stool banks.

00:29:10: Probably to the conclusion, any final take-home messages for our listeners?

00:29:16: Yes.

00:29:17: I would say that in conclusion if you have a multiple recurrent CDI patient You are really doing this person something good If you find an FMC center For that person because they're really desperate most of the time and They will be very grateful.

00:29:40: concerning all other indications.

00:29:43: I think it's not the time yet, but i'm very optimistic that we will get there in further indication soon!

00:29:51: Thanks so much for your time Maria and effort sitting down this Friday afternoon.

00:29:56: thanks everyone goodbye

00:29:57: thank you.