Ep 87 C. diff: Fighting poop with poop

something's not right, it's not okay. I intentionally withheld the fact that I had celiac disease, knowing that a lot of doctors actually like to just hang their hat on any GI symptom. And at the very end she had had gone through everything was gonna just basically say, if it's still not okay in a couple of days, come back. And somehow the word got out that I had celiac disease. And she said, oh, you must have just had gluten, that's all. And even though I was sure, she said,

have some bananas, drink lots of water. Your stool should firm up and everything will be fine, and all I really wanted to do was go to my normal GP, but in rural Iowa, he was over an hour away and I could not make that trip to save my life. No bathrooms on the way, no gas stations. It would have been like me in a cornfield, So not an option. Finally, when I was having what I would consider a good day, I called my doctor and I said, I'm on my way, I need to come see you, and he submitted a

test for SEDIFF. Sure enough, I came back positive. From there, we went through basically the standard first steps and I was put on a course of metronitisolar flagile. I saw a little improvement, but once the course of antibiotics was finished, it was all right back. So then he called in

oral Vancomyasin. Thankfully that cleared it up. After the fact, we were trying to do a little research on how I acquired my seat of infection, and it wasn't until it was a long thought, afterthought that I had a bug bite before that and it had gotten infected and they had put me on superflexis in about two months prior. Fast forwarding to March of twenty twenty one, I am a vet tech and it was my third week on the job, we were still doing curbside because of COVID.

I went out to go get a dog to bring it into the hospital. Somehow the dogs muscle slipped off when the owner was placing its lead on it, lunched at me, tackled me into a snow bank, and I had puncture wounds in my arm and had to go seek medical attention, where they put me on clintamyasin and zyperflexisin. I mentioned to urgent care, I have a history of cediff. Please help me. That's not what we should be doing.

And instead of her directions for having a yogurt every day, she suggested a take to have two yogurts every day. That was a little insulting, to say the least. A few days later, my armhead absessed. I went to my current doctor's emergency room. I went in and they said, we need to admit you to the hospital. They started me on ivy vankamyasin, ivy metronitisol and ivy is trianam, which is a pretty kind of novel antibiotic that they only use in real serious cases. From there, my bite

moom cleaned up. I was messaging my doctor like every day, at least a couple times a day, freaking out about having sea diiff again, sure that I was probably going to have it again, and he agreed that I was probably going to have seediff again from all of these antibiotics. Finally, when I was discharged from the hospital three days later, they don't have an oral version of as tree and am, so they put me on leva floxis, in another broad

spectrum antibiotic. My heart kind of sank, knowing what the future held. It was about ten days after I was home from the hospital, had gone back to work, those urgent loose tools that when you feel it you need to sprint to the bathroom, but don't spread too fast. And I called my doctor and I said, look, I think I've got sea diiff. He ordered the test. I

came down and I positive for SEEDFF. So they started me on oral vank commiasin right away, and finally, after it was a month on the bank commosin and doing a taper, things were starting to kind of finally feel normal. I finished my antibiotics and it wasn't three days later before I was at work and I realized, in the last hour and a half I've gone to the bathroom three times. I messaged my doctor while I was at work.

I said, I need another test. I don't think it's gone, And sure enough I went over our lunch break, I took a longer lunch than we normally have and went down and by the time we were done. That night at work, I had my results that I had seediff again. I had a recurren seed if infection. That meant my doctor was calling infectious disease specialists and I spoke to infectious disease specialists and they referred me immediately to you

a research trial for fecal transplant. They didn't even want to see me and they just sent me straight there. Then I get the phone call and I tell them my story. They said, you absolutely qualify for a fecal transplant with your recurrent infection. Will schedule you for. It was June thirtieth. It was my transplant date, and I had it circled and like starred on a calendar, but it was still a month out. So it was exhilarating but also a nerving knowing that I had to deal

with this infection. So we started another Vincimizon taper. I stayed on the dose that basically kept my stools solid. From there, I waited until my transplant date. My transplant was colon ascapy guided, so they did a colonoscopy and then they came in and applied the fecal transplant matter. I remember wheeling it in to the colon ass could be room and seeing a jar with brown liquid in it, and I took a selfie with it. I was so excited. I screamed, that's my poop, that's my new poop, and

the doctors laughed at me. I was just so excited. Thankfully, post transplant, things are going well. I have post infectious irritable bewel, probably on top of normal irritable bell, but they're still calling it post infection. So day to day

life things are going pretty well. However, every time I feel like a little gas bubble or I get a funny little cramp, my heart sinks and I'm worried that the seed off his back because the doctors did notify me that my infection was relatively severe and that I might have to kind of get what they call little tune ups as far as just additional fecal transplants in the future, and so every time I get a funny little feeling I'm instantly worried, and my doctor even associates

that with a little bit of PTSD. Honestly, from the whole event, it's interesting to think that I have more trauma from the medical fallout from my dog bite than the actual dog bite itself. Seed Iff has really stuck with me for anyone who's comparing it, because my mom was trying to put a label on it. She was saying, it can't be worse than kolonoscopy prep. It can't be worse than kolonoscopy prep. And I can officially say, after doing both that seed Iff is much worse.

hospital or healthcare acquired. So the way that I've tried to organize this biology section is to first focus on the disease that Clusterdium difficiale can cause, how it's transmitted, how it makes us sick, and then take kind of a bigger picture view and talk a little bit about the microbiome as it relates to sea diff infection.

Bascillas anthrasis and Clusterdium tetani and also Botulinum and clusterdrium bochculainum. Anyways, see diff is also an anaerobic bacterium. Like a lot of our gut bacteria are either entirely or facultatively anaerobic, which means that they survive without oxygen. So what happens in the case of seedff is that on contact with oxygen, like when we poop out this bacterium, it forms spores, and these spores are very highly environmentally resistant inactive forms

of this bacteria. They really can't easily be killed by heat or cold or alcohol, and they can persist in the environment, not dying or desiccating, just hanging out until they're ingested by another human or animal, because animals can also get infected.

intestine from like primary into secondary. And it seems like when sea diff spores come into contact with some types of these bio acids, especially in higher concentrations, that's when they very easily reactivate into a live, replicatable, mobile sea diff bacteria, which can then replicate and replicate and kind of beat out other bacteria in our guts and eventually cause infection.

So let's talk about what that actually looks like. Predominantly, se diff the toxogenic strains, the strains that produce toxins produce two major talks, very creatively named toxin A and toxin B. Keeps it easy, and essentially, what these two toxins do is they work together to ultimately disrupt the membranes of the cells that line your gut, and this results in little micro ulcerations of our gut wall, little

little holes. It also disrupts the junction between cells which are supposed to be you know, a nice tight line of cells lining our gut. Basically, these toxins get in there and kind of shred the lining between them, leaving holes, which increases permeability, and that is what leads to watery,

massive amounts of diarrhea. These toxins also then induce apoptosis and kill the cells that line our gut wall because of all of this disruption, and that leads to a lot of inflammation that can cause the formation of what are called pseudo membranes, which sounds gross and it looks gross.

There's also another toxin that is present in some strains that seems to when its present cause even more severe disease. Uh, But I'm not going to get into all of the specific biochemistry of it, because there's a lot more that I want to talk about with zetiff. But the end result of these toxins and the disruption that they cause in the lining of our colon, the death that they cause of the cells that line our colon, and all of this inflammation is what really causes the symptoms that we see.

But then in other studies it looks like, no, you really have to have both, and if you only have one or the other, you don't really see disease from sea diiff, even though you might have colonization. So it's still a little bit I think up in the air. But it is really interesting the way that these two toxins kind of interact to then cause the actual symptoms

that we see. Okay, so I've said the word symptoms like one hundred times, but I think the only thing I've said so far is diarrhea, and that is the hallmark symptom of a sea diiff infection, massive watery maybe mucis diarrhea. Generally, it's not overtly bloody diarrhea like we see with dysentery, and that's largely because seadift doesn't invade through our cells and it's very rare that it causes

disease outside of the intestine. But because it is causing all of this inflammation and this damage to the lining of our gut, you can see like micro amounts of blood in the diarrhea, but usually not like what would look like bloody diarrhea. And otherwise symptoms can really really range. You can have very mild diarrhea with a set off infection to severe life threatening colitis that is the inflammation

of your colon, of your gut wall. And even though it doesn't usually go outside of our colon and cause

actual infection anywhere else. It can generate such a strong inflammatory response in our body that you see a lot of other signs of infectionate inflammation, a lot of abdominal pain with this infection, fevers, nausea, vomiting, generalized weakness because you're having diarrhea of all of your anything you're trying to eat, and so in severe cases, if this goes untreated, it can lead to significant dehydration, which can then lead

to shock and death. It can also lead to something called toxic mega colon, which sounds horrific and talked about I think we have on shagus ah.

colitis causing death. If you look at overall mortality that's associated with sea diff infection, which includes like downstream complications, but also just the fact that a large proportion of people who get sea diff infection are often already sick with underlying conditions, and so the kind of associated mortality rate is often up to fifteen to twenty five percent, Or if you look at people who are already in the ICU, so already like very sick, it's up to

like thirty percent, which is horrific.

It's an opportunistic pathogen and aarin. You'll probably talk more about this in the history section, So I hope I'm not stepping on your toes, but Claustridium difficile was actually first identified as just like a normal component of the microbiome in a healthy infants and neonates, what like, yeah, yeah, so this is a bacterium that might exist in me, or you, aaron, or in quite a lot of you listening, just as one of the I don't know how many

hundreds of species happily coexist inside of our gut microbiome. Right, So then the question becomes who gets sick from sea diff and who lives with sea diff without ever getting sick and why? And the answer relates to two major things, one of which we've kind of already touched on. So first and most obviously, is is this a toxin producing strain or not? So not all strains of sea diiff

produce those toxins. And because it's the toxins and not the bacterium that causes the damage, if you are colonized with a non toxogenic strain, you're very unlikely to get sea diiff colitis or seadiff infection. And there's actually some interesting studies, and I think this might be a little bit controversial because there just isn't a ton of data on it where they separate non toxogenic from toxogenic strains.

But the data that does exist suggests that if you're colonized with a non toxogenic strain, it might actually be protective against infection with a toxogenic strain. But what's interesting is it doesn't seem to be an immune mediated response necessarily.

and the composition of their microbiome to begin with. So I'm going to preface this by saying that all of the studies on the human microbiome, at least the ones that I read in specific how it relates to sea diiff, they're limited and have low sample sizes, So like, keep that in mind. But there's still some really interesting things

from some review articles. So let me tell you what I found studies that have low at people colonized with sea diff versus not colonized with seed diff versus infected. Have found that people who test positive and have symptoms of infection with seed diff, so people sick from SEEDFF with seed diff colitis have a significant reduction in their

overall microbial diversity and species richness. So for lots of people who don't know, because I even had to regogle, this species richness is just the actual number of different bacterial species that are present, and diversity is a measure of both that richness, so the number of species and the abundance of these different species. So people who get infected and get sick from seedediff have both low numbers of bacterial species in their gut and low diversity of

those microbes. That's not surprising, right because we already said these are generally people who might be sick or that this is not a good competitor. But even people who are colonized with cluster named diffy Stiel without any overt signs of infection also have decreased species richness and diversity. But the distribution of species is different in these two groups.

So it seems like there are certain species that are more protective against infection, and you know what, it seems like the effect of this microbiome composition on the amount of bio acids that make it all the way to your gut likely play a role.

microbiome in your colon. And this diversity, this reduction in diversity rather can persist for months and months, leaving you potentially susceptible to something like an opportunistic pathogen.

like exposure itself. And so the reason one of the reasons that seadiff infection is so pervasive in healthcare environments is because these spores exist in really really high concentrations in the feces of people with sea diiff infection, which means that they exist in really high concentrations at healthcare facilities, and they're so environmentally resistant that they're really hard to get rid of, and so they're really easily transmitted throughout healthcare systems.

that exists in the environment at large. So, and there are some studies in Europe, in places like the Netherlands that suggest that this what they're what they call community acquired sea diff aka not from a hospital, actually has a higher incidence than other causes of diarrhea that we think of that we might think are more common, like Camplobacter or sale manila. So it's a really important cause of diarrhea that not only can be fatal but also

often causes recurrent infection. Yeah, so like ten to twenty five percent of people will get at least one recurrent infection after an initial infection, and of those people who get it twice, something like forty to sixty five percent of them may go on to have another and another.

right after this break. The story that I want to tell for this history section is really more like two stories, each with a central main character to kind of origin stories, to rise of the villain or hero stories, and then only closer to the end, the two threads of the stories meet, and unlike most straightforward hero versus villain or good versus evil stories, the conflict doesn't drag on and on, although there's still a material for many sequels, but rather

it resolves itself, I think, fairly quickly and in a satisfying way. So who are these two main characters? Tell me, Well, the first is probably fairly obvious because it's the topic of today's episode, and you've already gone in great detail about the biology of it, okay, Clostridium difficile. And the second might be pretty obvious to since we've also already

talked about it. But I wanted to talk a bit about the history of fecal microbiotic transplantations or FMT, which are I think at least one of the obvious heroes in this story. And I also fully acknowledge that it's unfair and you know, anthropomorphizing to cast Seediff in the villain role, and that you know, these bacteria might be more accurately described as pawns without motive verguile, allowed only to cause the damage they do because of a human

invention antibiotics. But I'm getting ahead of myself. And also I don't know how much time we need to spend in this particular episode about like anthropomorphizing of microbes and the symbolic language that we use, like battle and war on microbes whatever. It would be an interesting I would like to write a paper about that.

more oxygen. And while I don't know the exact specific origin of seaediff itself, I would imagine that based on its genome and its ability to coexist with humans and many other animals, it's been a part of our gut microbiota and the microbiota of many other animals for quite some time. And genomic analyzes of seediff also support this.

The genome of a particular strain of seedff, I think one of the most predominant ones was fully sequenced and annotated around two thousand and six, and this analysis is a genomic look told us a lot about the ecology of this bacterium and the type of relationship that it

has with its host like humans. So first, it told us that sea diiff is really well adapted to coexist with its host, not just to kill or pathogenically infect and cause disease, which is in contrast to a relative of seed Iff that we've talked about before, Claustridie and Bochelinum.

So Clustridi and Bochulinum in contrast, contains many unique genes that are involved with like direct disease mortality, which is just I think that's interesting because that does speak to sort of the more multifaceted relationship that seediff has to humans. It's not necessarily just a pathogen.

compared to other bacterial species that have high genetic variability. So, according to one paper I read by night at All from twenty fifteen, the amount of shared core genome of seed iff, So in my understanding, that's the amount of genome shared across all isolates of seed iff, like the core genome or whatever is as low as sixteen percent, what which is lower than has been observed for any

other bacterial species so far. And so what does that mean? Well, so, of course there's like natural genomic variation across members of an individual species like aaron, you and I, we don't share the same exact genome, right, But what this means is essentially that the amount of genomic variation across sea diiff is more along what you might expect for like members of a different genus, rather than among strains within

a species. And so this research and other research has called into question Seaediff's designation as one species, with more researchers suggesting that we take a new approach to the taxonomy of seediff, so for instance, by recognizing certain strains as subspecies or separate species entirely, like the.

Denver this year and I love it. It's incredible, it's the best. But these two researchers were named Elizabeth O'Toole, and they collected the maconium and feces of ten newborn infants at a hospital to see what microbes might be in there. And I thought that was interesting because I guess I didn't realize that the characterization of the microbiome, or at least like the recognition of endosymbiotic bacteria, had

started so early. And it's true that a lot of the early germ theory days were focused on like matching a disease to a pathogen, like, oh, we found a bacterium, it has to cause a disease, what does it cause? So you know, based on that, when people were just like hunting microbes, it does make sense that people would have encountered some over and over again that were not

associated with any inherent or any apparent disease. But I think they're also Around this time, there had been a growing recognition that not all bacteria were bad, and that some might be helpful or at the very least neutral, And basically that's what it seems like Hall and Otool had set out to do with this study, just like find out what was there, and especially the way that these microbe communities changed during the first ten days after birth.

And in their screening they found several species of bacteria that had already been described, but they also found something new in several of the samples. Quote an actively motile, heavily bodied rod with elongate, subterminal or nearly terminal spores of about the same diameter of the rods. Ooh man, what riveting reading riveting is right? And they named this new species Bacillis dificillis because of how difficult it was to isolate and study under lab conditions. It's just like a finicky guy.

isolated it from the stools of guinea pigs treated with penicillin, although even then it was thought to be a virus, and that connection to seed iff wouldn't be made until later. And that's all kind of like part of the theme of seediff. It's like flying by under the radar, not really acting suspicious or you know, earning any suspicion. That kind of makes up a lot of the history of seediff.

And so this paper that I talked about, the Hollino tool paper where seediff was first described, that came out in nineteen thirty five, and between the years nineteen forty and nineteen sixty two, there were only two mentions of seadiff infections in humans in the medical literature, and in both of these studies, seedediff was not suspected to be pathogenic to humans, like, it wasn't written about as a potential pathogen, and Hallan O'Toole did, like based on their

rabbit and giddapig studies, they did say, oh, maybe we want to keep an eye out for this in infants as a possibility of causing disease, but it didn't. There didn't seem to be a whole lot of follow up and there didn't really seem to need to be a whole lot of follow up because it doesn't seem as though, at least from what I can tell, that there was

a silent epidemic of sea diff during that time. So like since Hallan o'tool described it to I don't know, the nineteen fifties or something, and if anything, you know, I think I'm all side with you in being surprised at how early sea diiff was described, like nineteen thirty five. At first, I was like, wow, that's so recent, and then I was like, wait a second, Yeah, based on biology, No, that's like very surprisingly early.

And the first description we have of pseudomembranous colitis, for example, which is that horrible sounding condition caused by seediff is from eighteen ninety three, reported in a twenty two year old woman who had recently undergone surgery for a gastric tumor. She later developed severe diarrhea and died. And so maybe that was caused by sea diiff, but we have no

way of knowing for sure. But beyond you know, cases like that, seedediff was probably just part of the background, like minding its own business, popping up here and there, and it likely would have stayed that way, just like a wallflower on your gut gut flower. But humans intervened, And of course I'm talking about the rise of antibiotics.

So the widespread use of antibiotics began in the nineteen forties with penicillin, and it continued to grow and grow as more antibiotics, such as vankomycin were discovered and then administered. By the nineteen fifties, antibiotics were readily available everywhere and frequently prescribed, and the ones most commonly reached for were broad spectrum antibiotics, the ones that would wipe out not only whatever was making you sick, but a bunch of

other species right along with it. Casualties of the War on Bacteria, and also like it's still reasonable to prescribe broad spectrum antibiotics, especially when you're someone sick and you don't know what it is and you need to try something.

patient's stool. And because of this, vancomycin, which was used to kill the staff, began to be given as the standard treatment for pseudomembranus colitis starting in the late nineteen fifties, but over the next couple of decades, staph orias seemed less and less likely to be the cause since it wasn't really reliably found in the stool of many people with pseudomembranus colitis, and the disease itself, like the rates of the disease didn't really seem to go down at all.

A study in the nineteen seventies firmly displaced staph areas as the causative agent, and through suspicion on antibiotics themselves because they were like, well, if it's not staff, what the heck is it? And this study followed two hundred patients at a hospital who had been given clindamycin. Twenty one percent developed diarrhea and ten percent developed pseudomembranus colitis,

but stool cultures were all negative for staphorus. And so it was this study and another study from New Zealand that linked diarrhea and colitis with antibiotics that kind of caught the wider attention of the medical community, including a doctor John G. Bartlett, who was then at Tufts University.

So he had begun investigating antibiotic induced diarrhea and pseudomembranus colitis in the mid nineteen seventies, and in nineteen seventy eight he and his team published a series of papers in which they finally revealed the link between a toxin

producing class stridium and pseudomembranus colitis. And then he followed up this research by showing that he had found seediff in the stool samples of several of the individuals in that first study of two hundred patients that they could find no staff, they were like, well, we don't know what it is. And so he actually got some of those samples and was like, seadiffs here as well, so

that kind of was just like boom. This clearly made the link, and he went on to uncover a great deal more about seediff, which also hugely opened up the field for other researchers to characterize its toxins, to examine strain diversity, and to understand transmission dynamics. Like from the late nineteen seventies to now, we know an incredible amount about this bacterium. It's pretty amazing, I mean, and that also speaks to the huge public health impact that it has.

With these late nineteen seventies studies from Bartlett and his group, the field of sea diiff was blown wide open. It seemed that once researchers started looking for the pathogen, they

found it everywhere, and in increasingly high numbers. The continued use of antibiotics, especially cephalosporins, which seadiff is intrinsically resistant to, during the nineteen eighties and nineteen nineties it led to a huge rise in seaediff overall, which of course led to a huge increase in the diversity of strains, including the emergence of highly virulent strains, and over time, the characterization of seediff as a hospital acquired pathogen and one

that you have nothing to worry about if you aren't in a hospital, or if you don't work in a hospital setting, or if you aren't taking antibiotics, like you said, Aaron, that's become increasingly less accurate. Community acquired infections have become more common, as I read have animal associated infections, either through direct contact as well as potentially food borne, which has led to many people calling for a one health approach for this pathogen. Oh, I know, one health always well.

we get to where we are today type of thing. Essentially, like you said, Aaron, the idea behind fecal microbiota transplants is that you take the fecal material from a healthy donor and put it in the intestinal tract of someone who has some sort of GI disorder, often because their microbiota is disrupted, and you do this in order to change the gut microbiota, the composition of the microbes in the gut with the hope that this infusion acts like a hard reset and can take out the disease, kind

of get things.

the only reference to early fecal transplants either. In the traditional Chinese medicine book Compendium of Materia Medica, a series of prescriptions are described that are essentially various preparations of human fecal material. I've got your fermented fecal solution, fresh fecal suspension, dry feces, infant feces, take your pick all for the effective treatment of abdominal diseases with severe diarrhea, fever, pain, vomiting,

and constipation, just various things. And so reading about this got me thinking about all of the times that we have laughed and laughed and laughed about ancient or medieval cures and how ridiculous they are.

But it is a good reminder that every generation thinks of themselves as being so advanced and looks down on past generations with scorn like how on earth could they have believed something like that? And so maybe we shouldn't be so quick to dismiss the ideas of the past. And this is I'm super guilty of this, of like, how look at these cures? These are ridiculous.

what about that? Because if there's one thing that's an absolute certainty it's that future generations will look back on us now in our medical practices or scientific knowledge that's widely accepted today, and they'll think, how on earth could they have thought that? Or oh, my god, did they not realize that they were only making things worse?

sometimes of shared knowledge being built. All right, so soapbox moment. Beyond those early descriptions of yellow soup and poop as treatment from China, there are a couple of other examples of what is essentially fecal microbiota transplants from other parts

of the world. In the seventeenth century, there was an Italian anatomist who wrote, quote, I have heard of animals which lose the capait to ruminate, which when one puts into their mouth a portion of the materials from the mouth of another ruminant which that animal has already chewed, they immediately start chewing and recover their former health. And

he called that process transformation. And also, like, I just want to point out that many animals regularly consume feces for oh, probably a variety of reasons.

I also saw it mentioned that Bedouin groups historically consumed camel stools as treatment for bacterial dysentery, something that seems to have been picked up on during World War Two, when German soldiers were dying of dysentery in Africa, Nazi scientists observed that locals would consume fresh camel stools at the first sign of disease, and it seemed to prevent them from getting sick. And so the scientists cultured what they could find in the stools, and they isolated Bascilla subtilis,

which they cultured and administered to decent success. Like it seemed to work to a certain extent, So that's kind of cool. It's like this all goes way back further

than I thought. Yeah, But from then, as far as I can tell, the concept of fecal microbiota transplantation it really only remained mostly in practice or even in experimentation in veterinary medicine until nineteen fifty eight, when Iceman and colleagues successfully used fecal microbiota transplants to treat four people with pseudomembranous colitis with antibiotic use, this time fortunately using an enema rather than oral application.

more antibiotic classes were discovered. Being like, oh, well we can fix that, Oh we can fix that this way.

remarkably successful with lasting recovery. But for the most part, reports of people successfully using fecal microbiotic transplants were kind of like one offs, like these, you know, case studies of people trying out fecal microbida transplants for a variety of infectious and non infectious conditions on one patient, on

a handful of patients, but not like large scale. It wasn't until twenty thirteen that the first randomized clinical trial was conducted in the Netherlands to look at fecal microbiota

transplant as a treatment for sea diiff infections. Here's where our two our villain and our hero meet took a while, but hey, and you'll see that it soon is resolved because in this study the participants all had recurren se diff and they were all randomly assigned to one of three groups, either receiving vancom iosin alone, vancom iasin with bowel levage, or bowl levage, and then fecal microbiota transplant

as treatment. And although the study was initially supposed to include one hundred and twenty people with forty people in each group, it was stopped early with only forty three participants. Why was it stopped because it was so incredibly successful that it wasn't ethical to keep going with the other control groups when fecal microbiotic transplant showed such incredible cure rates.

also showed high rates of cure. But how exactly do they work? How do fecal microbiota transplants work, What diseases or conditions do they seem to be effective against? How does one become a stool donor what makes someone a good candidate for fecal microbida transplants? Are their long term consequences.

I was trying to find global estimates. I found a paper that was a meta analysis from a couple of years ago that looked at a whole bunch of different papers and calculated an average number of SEADIFF infections for every one thousand hospital admissions worldwide. And they calculated an average, a global average of two point two five cases of SEADIFF infection for every one thousand hospital admissions worldwide. And I was like, wait a second, that number doesn't make a lot of sense.

reported compared to other places. And even though this study looked at forty one different countries, there was no data whatsoever from South America, or from Africa, or from a lot of countries in Asia.

one thousand. That's anywhere from eighty thousand to over one point two million cases in US hospitals alone each year.

But there was a Cochrane review from twenty seventeen that showed with moderate certainty evidence, which is like pretty good for a Cochrane review, that probiotics can reduce the risk of seediff infection by as much as sixty percent in people who are inpatient in the hospital on antibiotics. So giving probiotics concurrently with antibiotics might be significantly protective.

don't know other things there are. Even though antibiotics are still used very commonly for treatment of seediff, we know that antibiotic resistance is a huge problem. There are a number of different monoclonal antibodies that have been shown to be beneficial for the treatment of especially recurrent seediff infection. That would be something that's only available, you know, in the case where you're already really, really sick. It's not

necessarily preventing you. There are also a lot of different vaccine candidates that have been studied. Generally these are toxoid vaccines, so vaccines against just the toxins A and B to help prevent infection from seediff rather than just colonization. But yeah, there's a lot of promise both in terms of how we can potentially deal with especially severe seaediff infections today but going forward, how we might be able to prevent

them even more down the line. But here on TPDKY, we all have our biases, and one of ours is how amazing fecal microbiotic transplantation is.

we'd run out of options for her. The sort of next thing on the treatment ladder was surgery, which for a frail patient like this was going to come with a lot of risks, and so this was before stool banks. We had to do the FMT ourselves from a related donor of the patient, and you know, within three days the patient had fully recovered from their seed iff and was eating and ready to go home. So that was

sort of my first encounter with this treatment. It wasn't until I came to the US that and met the team at Opened Biome just as things were getting started that I ended up embarking on this adventure.

executive director Carolyn. She had a relative that, you know, a young guy in his early twenties, just out of college, you know, had a gold badder infection, had surgery and then some antibiotics after that, and developed cedificile infection and eventually, you know, having found out that he would have had to wait several months for an FMT, he would have had to drive hours to one of hospitals in New York to get this treatment, decided to take matters into

his own hands and ended up doing an FMT himself. And so, you know, that was sort of the motivating patient in a way for us to establish Open Biome really to make sure that patients who had seedificil infection, who had failed antibiotic therapy didn't have to go through that process again of having to source their own donor and getting their own treatment arranged, and to make this, as you know, as straightforward as getting a blood transfusion. And so you know, we set ourselves up really to

serve that need. And yeah, we've grown to the point now where we work with over a thousand hospitals across the US and ninety nine percent of the US population is within a four hour drive of a hospital. Using open FMT.

seem to see in association with the gut microbiome. You know, these are things like asthma, diabetes, obesity, even mood disorders like depression or anxiety. And so you know, we put these donors through a pretty comprehensive screening process, which starts off initially with an online form that if anyone is interested in becoming a donor, they go to our website fill out a short form that excludes for the common

reasons that folks are ineligible to become a donor. And so then if a prospective donor completes that form and it's all clear, then they would be invited for an in person clinical assessment led by one of our clinical team that includes a clinical assessment where they run through nearly two hundred questions related to their health, physical assessment, and then if they pass that, they go through a blood and a stall test, and yeah, it doesn't stop

there though, you know. If a donor passes all of that, then they have an assessment each time they drop off a stall sample, and then every sixty days they undergo the same three step screen. So the clinical all the blood in the stool. The past rate for becoming a donor is less than three percent, and so we often say that it's harder to become a donor open biome than it is to say, get into MIT or HAVID because we are sort of screening these folks really rigorously.

Once it's frozen, we homogenize it or blend it and then filter it to remove any anything like food debris

or other things that aren't relevant for the treatment. And so then that treatment gets frozen, either as a liquid preparation that is instilled via colonoscopy or via a par endoscopy or nasogastric tube, or alternatively we prepare it into capsules, and these capsules can be taken by the patient at their doctor's office, and the patients are observed for several hours afterwards, and then they can usually start eating four

to six hours afterwards as well. And then in many cases, patients are discharged on the same day so they're able

to go home. And you know, one thing we are really keen on emphasizing it open biome is prevention of cediff when patients go home, you know, making sure that their home is clean, making sure that high touch surfaces are cleaned so that they're not re exposing themselves to seediff, and you know where possible, avoiding antibiotics as well, or having a conversation with their physician that they've had an

FMT might be at risk of sediff. So yeah, you know, the treatment itself is surprisingly straightforward in many ways, but I think the complexity is around the donus screening and making sure that the patient is appropriately selected for an FMT and that the risks and benefits are clearly communicated to them as well before performing the treatment.

And it's on that second recurrence of their C. Deficile infection that they are eligible for in FMT. The other consideration is, you know, FMT is still an investigational drug, and what that means is that it has not gone

through the FDA approval process. And there remains some unknowns about the treatment itself, and so at this stage, in a relatively early time in the field, it's important to make sure that patients, especially those who are immunocompromised, for example, children or you know, those in pregnancy perhaps are carefully considered for FMT. And in some patients they may not be eligible because of perhaps one of those reasons that mean the risk benefit of that FMT treatment doesn't make

sense in their case. So, you know, those are the main criteria really for an FMT, and I think over time we'll be refining those, hopefully both to enhance the safety of the treatment and also to improve the efficacy as well of each treatment that's administered.

It's unclear, And so could you walk us through some of the risks of FMT, both short and long term, or maybe what you see as the biggest gaps in knowledge regarding risk.

of FFT, you know, it's always quite concept specific. You know, in the case of c dificile infection, especially severe disease, which carries a very high mortality rate, and where even surgery carries a significant rate of morbidity and poor outcomes following the surgery, that profile, the risk benefit profile in that patient may be very different to someone who is very early in their seedff and perhaps has more options left on the table, such as antibiotics or BES, tuximab

or other interventions. So I think the first thing to emphasize is that it's very context specific and depends on the patient. But more generally speaking, this is a treatment

that relies on instilling bacteria into a patient. And we do all we can, you know, just like a blood transfusion to screen out pathogens and bacteria viruses, but you know, there is always the potential risk that an infection might be transmitted, and you know, COVID has taught us that, if you know, we have to continuously be evolving our criteria for screening for infections to you assess for new infections that might be on the horizon, especially antibiotic resistant ones,

and also, you know, continuously enhancing the tests that we use to screen out pathogens that might be potentially transmitted in stall. The second sort of category of risks i'd say, are as you said, the potential association with non inf

anxious diseases. To date, we haven't seen any evidence to suggest that FMT transmits any of those conditions or increases the risk of those However, I think it's something that we have to be very mindful of that we don't have much evidence on the long term effects of FMT, and so it's really important you know, with the patient that the clinician is having a meaningful conversation around the risks and the unknowns of some of these long term

consequences of FMT. But you know, for a patient who has run out of all of their treatment options and faces potentially resection of their bowel or long term antibiotics, or you know, even worse development of really severe disease, that sort of risk benefit needs to be taken into consideration. You know, there are sort of efforts being made to set up registries. So the American College of Gastroentrology has set up a patient registry to all the recipients of

FMT to ten years. And I think that's going to be really helpful in understanding the risk profile of FMT and also the long term curates as well.

in clinical trials. But also the American College of Gastoroentrology or ACG, have been running a patient registry as well that I mentioned, and they've to date followed up two hundred and fifty nine patients and observed clinical curates of ninety percent. And so, you know, we're seeing these findings from these randomized control trials being replicated in the real world setting, which is very reassuring for the treatment and

its use in clinical practice. But I think what we are going to hopefully learn more about in the coming years is how to improve that efficacy, how to select patients so that we are using this in the right context and the patient's microbiome perhaps is suited to this treatment. I think also, you know, simple questions like dosing for example,

could be potentially optimzed. And so we're still learning so much about you know, what it is that leads to a clinical cure, why is it that some patients don't respond? And you know, hopefully we're going to be gathering more data on you know, the real world evidence over time.

donors who may not be eligible is really extensive. And so you know if for a clinician to do this themselves can range from four thousand to up to twenty thousand dollars per single treatment in an open by and we charged just over two thousand dollars for our treatments, and so that hopefully makes the treatment itself more accessible. But FMT today is still an investigational drug, so it hasn't received an approval from the FDA. It's being provided

to patients under a framework called enforcement discretion. What does that mean to this question? It means that the treatment itself at the moment isn't covered by insurance, and so patients are having to pay out of pocket for it

or altensively. You know, the clinicians are having to eat up the cost themselves, and so that obviously creates a barrier to access as especially if we're thinking about coverage in some of the more rural areas or centers that might not be near a large gastrotrologists or infectious disease practice.

But you know, I think an interesting other lens on this is that, given we are still quite early in the field, is there some justification for potentially building up centers of excellence that can provide this treatment At their centers do all of the really sort of rigorous screening and assessment of the patient and follow up and really you know, gathering the data to understand how effective this treatment is.

did looking at fecal transplants in hepatica and caphilopathy. So, hepatica cathelopathy is a condition that is associated with late stage liver disease liver cirrhosis, and it is characterized by confusion and agitation, drowsiness, loss of consciousness, and can be you know, putting patients into the intensive care unit and is typically quite a challenging condition to treat, especially to

maintain clinical cure. But it's caused by a build up of nitrogenous waste products that you know, accumulating the systemic circulation and part of the role of the gut bacterias

to break down some of those waste products. And so, working with a colleague of others, doctor Chaz Bagage at University of Virginia, we conducted a randomized control trial that showed that FMT was able to effectively treat this Basically in this trial of about twenty vations so a small study, half of the patients in standard of care group were cured and all of the patients in the FMT arm

had a clinical cure. And so that's just a really interesting sort of example of you know, we talk about the gut brain axis, and you know, this is sort of an early example of how potentially FMT and the gut microbiome may play a role in that. The other piece of the study that I think is really interesting is doctor Bajaj characterized the gut microbiomes of these patients before the study to see whether there were some common microbial signatures in the composition or function of the microbiomes

and these patients. And you know, we observed that these patients were particularly depleted in bacteria that play a role in the production of short chain fatty acids. And so what we did was to go back to our donors and we characterized the microbians of our donors and selected a donor that had a particularly high abundance of these

microbes that these patients were depleted in. And so, you know, that sort of rational donor selection or personalized medicine approach to this maybe something that we see more and more in the future. And you know with the sort of falling costs of genomics and the introduction of that into clinical practice, So I think that's a really interesting one.

You know, the other diseases like inflammatory bowel disease, there've been a number of trials now that have shown promise in that, especially in alternative colitis, where you know, we're seeing in patients with this very difficult disease about thirty seven percent of patients are in clinical remission after a FMT, which compared to about eighteen to twenty percent for standard

of care. Is really exciting. And then you know, as a nonprofit, we are also exploring the role of this in disease areas that are perhaps neglected by farmer companies in the US and Europe, to support clinical trials in lonand Lincoln Countries, and so we're actually working with the University of Kicktown at the moment looking at the role of fecal transplant in children with severe cute malnutrition who failed to respond to a nutritional therapy, which is surprisingly

the case in about a third of kids with malnutrition. So yeah, really broad disease areas that we're working on.

patients that are receiving this treatment. I think the second pieces that aspect of personalization, and you know, can we do more to potentially increase the curates for patients who are receiving FMT for conditions like cediff And you know, perhaps in the future, you know, we're treating patients who have failed multiple rounds of antibiotics, But is there potentially

more that we can do in prevention. Is there a world, you know, perhaps you know in a few years time where you bank your stool prior to receiving antibiotics and then you receive your own stool back to restore your gut microbiome after a course of antibiotics. This is already being explored in some patients, some patient populations who are

receiving lots of antibiotics, like stem cell transplant patients. But we I think open Biome are really interested in a public health approach to FMT in the microbiome, and can we prevent diseases as much as treating them when patients are really sick? And you know, i'd say sort of. The last thing really is we started open Biome to enable access to this treatment for patients when they need it.

We know that there's still much more to do for that in the US, but I think globally, SEEDIFF is likely to become more and more of a burden as we see wider antibiotic use and wider occurrence of risk factors they are associated with seed IFF, like inflammatory bowel disease, And so I think we're going to have to be really mindful of making sure that people who may not necessarily have access to the same health systems as we do in the US can still access this treatment when

they need it. I think COVID has highlighted more than ever the importance of sort of health equity and technologies and access to them as quickly as possible, and so I think, yeah, hopefully that's the other piece that gets resolved and we're all working towards over time.

Check it out, and by de Groot at All from twenty seventeen. And I have to shout this out also because it doesn't just have great information, but it also contains and amazing figure. One of my favorite that I've seen of the most important developments in the timeline of fecal microbida transplants, but it's marked along intestines. It's starting in one part of the intestine going together. It's beautiful.

global distribution. Yeah, so we'll post a list of all of those sources on our website, This podcast will Kill You dot Com under the episodes tab.