This Podcast Will Kill You - Ep 87 C. diff: Fighting poop with poop

Episode Date: December 28, 2021

In this week’s episode, we cover a bacterium whose recent emergence and rapid spread has been largely an epidemic of our own making. Clostridium difficile isn’t your typical pathogen - in many cases it’s not even considered a pathogen, just a normal member of our gut microbiota. But when something disrupts our gut microbiota, like antibiotics, C. difficile is given the freedom to spread its wings, wreaking deadly havoc on our bodies especially when it refuses to leave. We explore the characteristics of this bacterium that make it such a terrifying public health threat, delve into its recent-but-not-as-recent-as-you-might-think history, and chat about the current status of C. diff before asking the question, “what can poo do for you?” That’s right, we’re taking this opportunity to talk about one of our all-time favorite medical interventions, fecal microbiota transplantation. Helping us navigate the ins and outs of fecal transplants is Dr. Majdi Osman, Chief Medical Officer at OpenBiome, a nonprofit stool bank that aims to expand access to safe fecal microbiota transplantation and fund research into the human microbiome. By the end of this episode, we think you’ll find yourself in awe at the healing powers of poop. See omnystudio.com/listener for privacy information.

This is exactly right. There are already enough things charging your card every month. Dinner should not be one of them, which is exactly why Blue Apron is now subscription-free. You heard that right, Blue Apron no longer requires a subscription. You can order meals when you want them and skip when you don't without adding another recurring charge. Blue Apron meals are designed by chefs and arrive with pre-portioned ingredients, so there's no meal planning and no extra grocery trip. Order now at Blue Apron.com. Get 50% off your first two orders plus free shipping with code this podcast 50.

Terms and conditions apply. Visit blue apron.com slash terms for more information. Busted appliance? This is your sign to upgrade. Shop at Lowe's to get up to 35% off and next day delivery on hundreds of major appliances. Lowe's, we help. You save. Valitha 318, wall supplies last.

Selection varies by location. Order by 4 p.m. Available Monday through Saturday. subject to availability. Fees, exclusions, and restrictions apply. See Loos.com slash appliance delivery for more details. Visit your nearby lows on Renier Avenue South in Seattle. The worst part about loving cars might just be buying them and all the parts. But on eBay, behind every car in part is a story waiting to be shared.

There was a guy who bought a 2021 Porsche Cayman that was well loved. I mean, there are plenty of Caymans in great condition on eBay. But this one needed some more. work. This guy buys it and rebuilds the whole thing, all with parts he found on eBay. And now, that nearly scrapped Kamen is out tearing up the track. From Toyotas to Aston Martins, eBay has thousands of cars and the largest online selection of vehicle parts and accessories. eBay, things people love. Hi, I'm Laney. So in August of 2019, I started having wild bowel movements. That's about the only way that I can put it. I have celiac. I have irritable bowel. And these stools were nothing like I had

ever encountered before. They were coming every hour to half an hour. It seemed like I couldn't be more than 10 feet from my bathroom in any given time. I went to our little local first aid station kind of at my husband's job. And they had medical staff. And I said, look, 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 gone through everything, was going to just basically say, if it's still not okay in a couple 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 C-DIF. Sure enough, I came back positive.

From there, we went through basically the standard first steps, and I was put on a course of metronidazole or flageal. I saw a little improvement, but once the course of antibiotics was finished, it was all right back. So then he called in oral vancomycin. Thankfully, that cleared it up. After the fact, we were trying to do a little research on how I acquired my C-Div 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 syprofloxasin about two months prior. Fast forwarding to March of 2021, 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 dog's muzzle slipped off when the owner was placing its lead on. It lunged at me, tackled me. into a snowbank and I had puncture wounds in my arm and had to go seek medical attention where they put me on clindomycin and syproflexicin. I mentioned to urgent care, I have a history of C-DIF. Please help me. That's not what we should be doing. And instead of her directions for having a yogurt every day, she suggested to take to have two yogurts every day. That was a little insulting to

the least. A few days later, my armhead abscessed. 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 IV vancomycin, IV metronidazole, and IV is Trinam, which is a pretty kind of novel antibiotic that they only use in real serious cases. From there, my bite wound cleaned up. I was messaging my doctor, like, every day, at least a couple times a day, freaking out about having C-diff again, sure that I was probably

going to have it again. And he agreed that I was probably going to have C-diff 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 Estrinam, so they put me on LevaFloxysin. another broad spectrum antibiotic. My heart kind of sank, knowing what the future held. It was about 10 days after I was home from the hospital, had gone back to work, those urgent loose stools that when you feel it, you need to sprint to the bathroom, but don't sprint too fast.

And I called my doctor and I said, look, I think I've got C-DIF. He ordered the test. I came down and I was positive for C-Div. So they started me on oral vancomycin right away. And finally, after it was a month on the vancomycin 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 C-DIF again. I had a recurrent C-Diff infection. That meant my doctor was calling infectious disease specialists. And I spoke to infectious disease specialist, and they referred me immediately.

to 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. We'll schedule you for, it was June 30th. It was my transplant date. And I had it circled and starred on the calendar, but it was still a month out. So it was exhilarating, but also unnerving knowing that I had to deal with this infection.

So we started another vancomycin taper. I stayed on the dose that basically kept my stool solid. From there, I waited until my transplant date. My transplant was colonoscopy guided, so they did a colonoscopy, and then they came in and applied the fecal transplant matter. I remember wheeling in to the colonoscopy 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 bowel, probably on top of normal. irritable bowel, 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 C-DIF is 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. And 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. C-diff 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 colonoscopy prep. It can't be worse than colonoscopy prep. And I can officially say after doing both that C-diff is much worse.

Wow. Thank you so much, Lainey, for taking the time to share your story with us. That's intense. Yeah, wow. Thank you. Hi, I'm Aaron Welsh. And I'm Aaron Alman Updike. And this is this podcast will kill you. Welcome, everyone. We're excited about this episode. As we are about all our episodes, but it's genuine excitement. It always is. Today we're talking about Clostridium difficile, aka C-diff. C-diff. That's how I'm going to talk about it for the rest of the episode. But we're not talking just about this problematic pathogen. We're also. We're also, talking about one of my favorite solutions to infection.

Yeah, one of my favorite solutions to a problem. Yeah. Yeah. I simply love it. And of course, we are talking about fecal microbiota transplantation. AKA fecal transplant. We have talked about this. Like, we've dabbled in it and several other episodes and been like, ooh, someday, ooh, someday.

That day is finally here, everyone. Yes. This is not going to be like a full takedown of the microbiome and all the impact that it has on different conditions or whatever in this associations. But we are going to do somewhat of a deep dive into fecal transplants or FMTs. And we are very excited to bring on a special guest, an expert guest, to help us out with that. But that's jumping way ahead of ourselves. It is because first, it's quarantini time. It is. What are we drinking this week? This week, Erin, we're drinking the slurry.

We're sorry. Isn't that what everyone wants to drink? Okay, so the thing is, it was either make a gross recipe or a gross name and not both. And so... One or the other had to happen. Yeah, exactly. I mean, like, we are but human. So what is in the slurry? The slurry contains mango, pineapple, lime, tamarind, and tequila, all delicious things.

And of course, you got to blend it up. You got to. You've got to blend it up. But it tastes good, right? And it's like, yeah. I mean, it's like very fruity. It's a lot of flavors. We promise it's worth it.

Yeah. Yeah. And we will post the full recipe for the slurry quarantini as well as the non-alcoholic placebo-rita. On our website, this podcast will kill you.com, as well as on all of our social media channels. Yes, we will. Erin, what other business should we tell everyone about? Well, how about our website? Okay.

It's my turn to do the rundown of things on there. I'm nervous. You can do it, I believe in you. Okay, here we go. We have all of our references to all of our episodes on each episode page. We have transcripts. We have links to our bookshop.org affiliate page and our Goodreads list. We have links to Music, Bloodmobile, now on Spotify.

We have links to our merch, which we have very incredible merch. We really do. We really do. And we have a promo code page. I mean, I think that's got to be most of the things on there. It's most of the things. Definitely check it out. This podcast will kill you.com.

So does that mean we're ready to talk about C-DIF? Yeah, I think so. Thanks also to everyone who has requested this over the years. Yeah. And we hope you like the episode. Yeah. So let's get right into it after this break. Dinner shows up every night, whether you're prepared for it or not.

And with Blue Apron, you won't need to panic order takeout again. Blue Apron meals are designed by chefs and arrive with pre-portioned ingredients so there's no meal planning and no extra grocery trip. There, assemble and bake meals take about five minutes of hands-on prep. Just spread the pre-chopped ingredients on a sheet pan, put it in the oven, and that's it. And if there's truly no time to cook, dish by Blue Apron meals are fully prepared. Just heat them in the oven or microwave, and dinner is ready. And here's the exciting news.

Blue Apron no longer requires a subscription. You can order meals when you want them and skip when you don't without adding another recurring charge. Order now at blueapron.com. Get 50% off your first two orders plus free shipping with code this podcast 50. Terms and conditions apply. Visit blueapron.com slash terms for more information. Anyone who works long hours knows the routine. Wash, sanitize, repeat. By the end of the day, your hands feel like they've been through something. That's why O'Keefe's working hands hand cream is such a relief. It's a concentrated hand cream that is specifically designed to relieve extremely dry, cracked hands caused by constant hand washing and harsh conditions. Working hands creates a protective layer on the skin that locks in moisture. It's non-greasy, unscented, and absorbs quickly. A little goes a long way.

Moisturization that lasts up to 48 hours. It's made for people whose hands take a beating at work, from health care and food service to salon, lab, and caregiving environments. It's been relied on for decades by people who wash their hands constantly or work in harsh conditions because it actually works. O'Keefs is my hand cream of choice in these dry Colorado winters when it feels like my skin is always on the verge of cracking. It keeps them soft and smooth, no matter how harsh it is outside. We're offering our listeners 15% off their first order of O'Keefs.

Just visit O'Keefscom. This Podcast and code this podcast at checkout. A timeless wardrobe starts with pieces that are built well from the beginning. From the fabrics to the fit, everything needs to last beyond one season. And that's how Quince approaches design. Quince has all the staples covered, from 100% organic cotton sweaters to premium denim made with stretch for all-day comfort and luxe cotton cashmere blends, perfect for the changing seasons.

The quality shows in every detail, the stitching, the fit, the fabrics. Every piece is thoughtfully designed to be your new wardrobe essential, and each piece is made with premium materials in ethical trusted factories and priced far below what other luxury brands charge. I recently got a pair of Quince's Bella Stretch Wide Leg jeans, and they are now in constant rotation. They are so comfortable, the fit is amazing, and they come in a bunch of different washes, so I'm about to go order some more. Refresh your wardrobe with Quince. Go to quince.com slash this podcast to get free shipping on your order and 365-day returns, now available in Canada, too. That's Q-U-I-N-C-E.com slash this podcast to get free shipping and 365-day returns, quince.com slash this podcast. So I don't know if anyone but me would notice this, but I think it's funny.

I'm going to start this episode almost identically to anthrax, I think, our anthrax episode. I don't remember this. This is good. That's fine. Nobody will. But as I was typing it, I was like, this sounds familiar. And then I opened my anthrax notes. And I was like, ah, okay.

Clostridium difficile infection is caused by an anaerobic, gram positive, rod-shaped, spore-forming, toxin-producing bacterium. Yeah. Hold on. Okay. A quick question already. Already. Betty. What a sentence in? Is that also how you started the botulism episode?

Oh, probably. Yeah, probably. Okay. I genuinely forgot that we ever did botulism, Erin. It was a long time ago. I loved that. I loved that episode. It was a good episode. I forgot. It'll also be probably the way that I start Tetness whenever we do that. So, you know. So for the remainder of this episode, like we said, I'm probably just going to refer to this as C-DIF because it's easier and shorter, and that's how we're going to say it. So C-DIF causes an infection that most of the time, very commonly, is what's called a nozocomial infection, which means hospital or

health care acquired. So the way that I've tried to organize this biology section is to first focus on the disease that Clostridium difficile can cause how it's transatl. 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 C-diff infection. Because as a spoiler, that, Erin, I know you probably already know, and many listeners may know, but C-diff doesn't always or necessarily cause infection. Yeah, it's like a, it's got to be one of our first, besides Mercer, maybe like opportunistic, super opportunistic pathogens. Yeah, we haven't covered a lot of opportunistic pathogens on here.

This is definitely one of them. But we'll get there eventually. First of all, transmission of C. diff at like the most basic level, the way that anyone in the world gets exposed to C. diff in the first place is fecal oral. So poop in mouth. It's a common mode of transmission, especially for GI bacteria. and C. diff, like I mentioned, is a spore-forming bacterium like our friend, Basilis Anthracis, and Clostridium-Tetanai. And also botulinum. And Clostridium-bottelinum. Anyways, C-Diff is also an anaerobic

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 C-diff 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. And then once we ingest them, these spores can easily survive the acidic environment of our stomach, travel through our guts, and then these spores are activated in our small or large

intestine when they come into contact with our bile acids. Hmm. Isn't that fascinating? Yeah, okay, I have a question about how long these spores can last. Oh, good question. I don't have an exact timeline, but definitely on the order of months, possibly years, depending on the conditions. I really hate that about these things. It's very, it makes it very scary and like it feels a bit challenging. Oh, very, very challenging. Okay, so the bile acids, like what about them? Yeah, what is bile acid? I'm so glad that you asked, Erin. Let me tell you. So bile acids are basically cholesterol derivatives. Our liver makes bile and secretes it into our gallbladder where it's stored. And then whenever you eat something, it sends signals to our gall butter to contract,

squeeze out the bile, and that goes into our small intestine. And these bile acids help support digestion, especially the digestion and eventual absorption of fats. Huh. Okay. And it's a little bit more complicated. There's like, multiple kinds of bile acids, and they're converted in our small intestine from like primary into secondary. And it seems like when C-diff spores come into contact with some types of these bile acids, especially in higher concentrations, that's when they very easily reactivate into a live, replicatable, mobile C-diff bacteria, which can then replicate and replicate and kind of beat out other bacteria in our guts and eventually cause infection.

Are there other bacteria that are activated or inactivated by bile? Like, do the bile acids kill a lot of potentially foodborne bacteria? Or are other foodborne bacteria resistant to bile acids? That's a good question. I don't fully know the answer to. But I'm going to put a pin in it because I want to kind of get back to bile acids in a minute. Okay. As it relates to our gut microbiome.

Okay. So now the spores are activated. C. diff is replicating. And then somehow this leads to disease. How? You may ask, Erin, if you wanted to? I do. Okay, good.

Okay. some species of C. diff, not only do they form these spores in adverse conditions, but they also have the ability to produce toxins. And it turns out that it's these toxins, not the bacteria themselves, that are capable of causing infection, aka C-diff colitis. So let's talk about what that actually looks like. Predominantly, C. diff, the toxicogenic strains, the strains that produce toxins, produce two major toxins, 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-ulceration.

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 pseudomebranes, which sounds gross and it looks gross. It's essentially just hordes of these dead cells mixed with bacteria and white blood cells

and inflammatory gunk. And it forms this kind of membrane that then lines your gut, which even further prevents your colon from doing its job, right, of absorbing water, etc., which then leads to even more diarrhea. Okay, so I'm assuming that the benefit that C-DIF gets from these toxins is that it can sort of wipe out the competition and even further and colonize as much as it wants to, your intestines. Yeah, that's a good question. Maybe, probably, I would guess so. I mean, certainly it makes it hard for anything else to exist where these pseudomebranes exist. Okay. So it might not be necessarily helping with the colonization, but it helps clear the

competition? Yeah, it's interesting because C-DIF is actually not a very good competitor to begin with. Right. Whether it's toxicogenic or non-toxicogenic. So maybe these toxins are helping a little bit and making it a little bit more competitive, but I don't know for sure. Okay. Toxins are costly to make. So you would think there would be some sort of benefit from the toxins. I mean, kind of like we've talked about in a lot of our bacterial pathogens that cause diarrhea, people who are having massive watery diarrhea because of C. diff are spreading billions of spores. Okay. So transmissions. Yeah, are very environmentally hardy. And so perhaps that's the major advantage. is that you're able to spread. Okay.

I don't know if it's that satisfying, but. But that's kind of the main end result. There's a lot more detail on these toxins. They're very interesting. There's also another toxin that is present in some strains that seems to, when it's present, cause even more severe disease. 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 C-DIFs.

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. Is it only the toxicogenic strains that? cause disease? Okay. Yeah. And there are a lot of studies looking at, do you have to have both of these toxins because it's toxin A and toxin B? Or could you have just one of these toxins? There's still some question as to that. It seems like in some models or in some clinical studies, they've seen that strains that only produce toxin B can still cause disease.

So A might be kind of like a benefit but not necessary to cause disease. 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 C. diff, 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 100 times, but I think the only thing I've said so far is diarrhea. And that is the hallmark symptom of a C-Diff infection, massive, watery, maybe mucusy diarrhea. Generally, it's not overtly bloody diarrhea like we see with dysentery.

And that's largely because C-Diff 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 C-DIF infection to severe life-threatening colitis. That is the inflammation of your colon. 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 infection in inflammation, a lot of abdominal pain with this infection, fevers, nausea, vomiting, generalized weakness because you're having diarrhea of 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 megacolon, which sounds horrific. We've talked about this, didn't we? I think we have on Shagas. Ah, was it Shagas? Yeah.

Essentially, toxic megacolon is where your colon gets so inflamed. It's a very different mechanism here than in Shagas disease. but it becomes very, very distended and is unable to move any contents down your gut the way that it's supposed to. So gas and fecal contents just keep building up and that can lead to perforation of your bells, which is, of course, a life-threatening emergency. Yeah. I mean, all of this sounds not only like painful and really unpleasant, but very life-threatening. Very, yeah. So the mortality rate directly due to C-DIF infection is estimated. to be about 5%, but that's just for death directly due to C. diff infection. So C. diff colitis

causing death. If you look at overall mortality that's associated with C. diff infection, which includes like downstream complications, but also just the fact that a large proportion of people who get C. diff infection are often already sick with underlying conditions. And so, the kind of associated mortality rate is often up to 15 to 25 percent or if you look at people who are already in the ICU so already like very sick it's up to like 30 percent which is horrific yeah yeah yeah and scary it's really really scary yeah c diff is like the scourge of hospitals but like i said at the top as severe as the infectious as the infectious that C. diff causes can be, it doesn't always make us sick. It's an opportunistic

pathogen. And Aaron, 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? 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 C. diff and who lives with C. 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 C. diff produce those toxins. And because it's the toxins and not the bacterium that causes the damage, if you are colonized with a non-toxicogenic strain, you're very unlikely to get C-dif colitis or C-Diff 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-toxicogenic from toxicogenic strains. But the data that does exist suggests that if you're colonized with a non-toxicogenic strain, it might actually be protective against infection with a toxicogenic strain. But what's interesting is it doesn't seem to be an immune-mediated response necessarily. Oh, so it's like competition?

Uh-huh. Let's talk about it a little more. I mean, does that just have to do with like the fact that it's a bad competitor and it's needs like an open playing field? Yeah. So the other major thing other than strain that affects whether somebody gets Clostridium difficile infection or just is colonized with C. diff or has neither, like doesn't get C. diff infection and isn't colonized with C. diff is their microbiome 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 C. diff, 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 looked at people colonized with C-DIF versus not colonized with C-DIF versus infected have found that people who test positive and have symptoms of infection with C-DIF. So people sick from C-DIF with C-DIF colitis have a significant reduction in their overall all microbial diversity and species richness. So for lots of people who don't know, because I even had to re-google 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 C-DIF have both low numbers of bacterial species. 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 clustered am diffi still 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 do you know what? It seems like the effect of this microbiome composition on the amount of bile acids that make it all the way to your gut likely play a role. Interesting. I know. Okay. So, but I have questions about this. Uh-huh. So this is what I think is difficult a lot about microbiome research, is that there's still so much

we don't know and so much is not necessarily about the species identity, but like the species role. So like what's the functional role of those? Like you might have two different species, but they might play a similar functional role. Right. And so that's why they think that at least they've been able to identify some of that in that the functional role of some of these species might be to decrease the amount of bile acids that activate C. diff spores and therefore allow C. diff colonization, activation and colonization. So then my second question is about the effect size. So like when you say reduce the amount of bile, like how much? Good question. I don't know. Okay. Yeah. Yeah. It basically just shifts the ratio of primary bile acids to secondary bile acids, but I don't know by what numbers. Okay. Yeah. Interesting.

But it is really interesting. Yeah, I agree. Even though I agree, we really don't know. And so it's also like how do we then translate that into something that can then, you know, prevent infection? It's still hard to do, right? Mm-hmm. Right. But what's important is that the biggest risk factor for C-DIF colitis is antibiotic exposure, right?

And it's not surprising when you look at that. Studies that have looked at even very short course exposure to antibiotics rapidly reduces the diversity of your 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. Right. Because remember, antibiotics are, some are more targeted than others. Right. But none of them are like, this will only kill this species. There are going to be bystanders that are wiped out just as a result of taking antibiotics. Right.

And any antibiotics that you take through your mouth are going to make it to your gut. So they're going to have some kind of an effect on your gut microbiome, even if the antibiotics are for a kidney infection or a skin infection. Like it's going through your gut. Yeah. Yeah. The other risk factors for infection, of course, are things like exposure itself. And so the reason, one of the reasons, that C-DIF infection is so pervasive in health care environments is because these spores exist in really, really high concentrations in the feces of people with C-Diff infection,

which means that they exist in really high concentrations at health care facilities, and they're so environmentally resistant that they're really hard to get rid of. and so they're really easily transmitted throughout health care systems. It's like a nightmare. Yeah. Yeah. That's how my grandmother got sick from C-DIF after having a knee replacement. And it was horrible.

I mean, it was absolutely, it's just horrific. Yeah. Yeah. Older age is also a really big risk factor. Yeah. So, yeah. But it's not just health care. This just is getting more.

and more depressing because there are some studies that suggest that like 30% of people who end up with a C-DIF infection don't actually have any risk factors, which also means that this isn't a problem only in hospitals or care facilities. This is also something 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 C-diff, 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 campllobacter or salmonella. So it's a really important cause of diarrhea that not only can be fatal, but also often causes recurrent infection.

Yeah. So like 10 to 25% of people will get at least one recurrent infection after an initial infection. And of those people who get it twice, something like 40 to 65% of them may go on to have another and another. Just like Mercer again. Yeah, exactly. Right. I think with C. diff, it's one of those infections that it has become so clear how important the gut microbiome is to the establishment and persistence of an infection like this. or to the establishment and the susceptibility to an infection like this is.

Yeah, it's kind of like the perfect example of like, oh, hey, this thing that we didn't really think all that much about turns out that there's a very important balance and delicate balance and the disruption of that is deadly. Yeah, yeah, or it can be. Yeah. That's all for the biology, Erin. I mean, it is still a treatable infection a lot of the time, but again, because of the recurrence. And the resistance.

And the resistance. Well, the good news is that later in this episode we are going to get to talk about fecal transplants. Fecal microbiota transplants. aka FMT, putting healthy bacteria back into your colon. We'll talk more about it later as well as other novel treatments and prevention strategies. But first, Erin, tell me what's up with this? Where did it come from? Has it always been with us?

Why is it making us so sick? Good questions. Good questions. I will try to answer them right after this break. Anyone who works long hours knows the routine. wash, sanitize, repeat. By the end of the day, your hands feel like they've been through something. That's why O'Keefe's Working Hands hand cream is such a relief. It's a concentrated hand cream that is specifically designed to relieve extremely dry, cracked hands caused by constant hand washing and harsh

conditions. Working Hands creates a protective layer on the skin that locks in moisture. It's non-greasy, unscented, and absorbs quickly. A little goes a long way. Moisturization that lasts up to 48 hours. It's made for people whose hands take a beating at work, from health care and food service to salon, lab, and caregiving environments. It's been relied on for decades by people who wash their hands constantly or work in harsh conditions because it actually works. O'Keefs is my hand cream of choice in these dry Colorado winters when it feels like my skin is always on the verge of cracking. It keeps them soft and smooth, no matter how harsh it is outside. We're offering our listeners 15% off their first order of O'Keef's. just visit o'Keefscompanic.com slash this podcast and code this podcast at checkout.

Why have I asked my age-fat guy I found on Angie.com to change my grandpa's tracheat tube? Because I was so amazed by how quickly he replaced our air ducts. I knew I could trust him to change Pop-Pub's tube while I was on vacation. Make a quick, young man. Aw, see, Pop-P trusts you. I think we should call it, Doctor. Connecting homeowners with skilled pros for over 30 years. Angie, the one you trust to find the ones you trust.

Find pros for all your home projects at Angie.com. Success starts with your drive, and American Public University is here to fuel it. With affordable tuition and over 200 flexible online programs, APU helps you gain the skills and confidence to move forward. Whether you're changing careers, starting fresh, or pursuing a lifelong passion, our programs are designed for people who never stop.

You bring the fire, APU will fuel the journey. Learn more at APU.apus.edu.edu.edu. The story that I want to tell for this history section is really more like two stories, each with a central main character, two kind of origin stories, to rise of the villain or hero stories, and then only closer to the end to 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 ample 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, too, since we've also already talked about it.

But I wanted to talk a bit about the history of fecal microbiota 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 anthropomorphizing to cast C-DIF in the villain role, and that, you know, these bacteria might be more accurately described as pawns without motive or guile,

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 in the symbolic language that we use, like battle and war on microbes, whatever. It would be an interesting. I would like to read a paper about that. That would be really interesting. Yeah.

What words do we use? Because words matter. Anyway, C-DIF, where did it come from? Well, the group Clostridium itself is incredibly ancient. It's estimated to have diverged from the bacterial domain about 2.34 billion years ago, which is what I saw. And that's right around the same time that the atmosphere began to contain more and more oxygen. And while I don't know the exact specific origin of C-DIF 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 analyses of C-DIF also support this. The genome of a particular strain of C-DIF, I think one of the most predominant ones, was fully sequenced and annotated around 2006. And this analysis, this 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 C-DIF 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 C-Diff that we've talked about before, Clostridium-Bachalinum. So Clostridium-Bachilinum, 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 C-DIF has to humans. It's not necessarily just a pathogen. Right. So. Yeah. And it's, and I mean, it's not just a pathogen. Right. So it's a little bit, it's a little bit deeper than that. Secondly, and one of the things that I find super interesting is that the species itself, like all the isolates and strains and whatever that make up C-DIF that we know about, they are incredibly diverse, even when compared to other bacterial species that have high genetic variability. So according to one paper I read by Knight at all from 2015, the amount of shared core genome of C-DIF, so in my understanding,

that's the amount of genome shared across all isolates of C-diff, like the core genome or whatever, is as low as 16%. 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 C. diff 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 C. diff's designation as one species with more researchers suggesting that we take a new approach to the taxonomy of C. diff. So for instance, by recognizing certain strains as subspecies or separate species entirely. Like the non-toxicogenic versus toxicogenic? Right.

Something like that. Mm-hmm. Yeah. And so what does that mean in practice? Right. I don't know. But I think it could have a lot to do with, like, I don't know, the evolution of this, trying to predict the evolution and the geographic spread.

Right. Which ones to worry about? I don't know. It's interesting to think about. Well, it would really change the way that we've gotten estimates for things like C-Div colonization in the past. because, right, that it's been like all of these strains lumped together. Yeah, so it would definitely change like the disease burden or how we look at those numbers.

Yeah, yeah. So let's go back to when our villain C. diff was first discovered, or as it was first named, bacillus Deficilis. And so as you mentioned, Aaron, yes, this happened a long time ago, back in 1935, specifically. The name was changed to Clostridium Difficil in 1938. And it happened when these two researchers in Denver, which I wanted to shout out because I don't think I've told everybody here on the podcast, but I moved to Denver this year. And I love it. It's incredible. It's the best. But these two researchers were named Ivan Hall and Elizabeth O'Toole. And they collected the maconium and feces of 10 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? And 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 there 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 O'Toole 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 10 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. Man, what riveting reading. Rividing is right. And they named this new species Bacillus difficile, because of how difficult it was to isolate and study under lab conditions. It's just like a finicky guy. Finicky. It's anaerobic, you know? Yeah, they're finicky. Then to see if they could figure out more about the role of this bacterium, they infected rabbits and guinea pigs with it to see, you know, what would happen. And they were surprised to find that it seemed quite pathogenic to them, or at least that the bacterium produced a toxin that could lead to death

or severe disease in these lab animals. Although the toxins wouldn't be described until 1974, when Green et al all isolated it from the stools of guinea pigs treated with penicillin, although even then it was thought to be a virus and the connection to C-DIF wouldn't be made until later. And that's all kind of like part of the theme of C-DIF. 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 C. diff. And so this paper that I talked about, the Hol and O'Toole paper, where C. diff was first described, that came out in 1935. And between the years

1940 and 1962, there were only two mentions of C. diff infections in humans in the medical literature. And in both of these studies, C. diff was not suspected to be pathogenic to humans. Like it wasn't written about as a potential pathogen. And Hol and O'Toole did, like based on their rabbit and Gitty Pig 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 C-DIF during that time. So like since HoloTool described it to, I don't know, the 1950s or something.

And if anything, you know, I think I'm all side with you in being surprised at how early C. diff was described. Like 1935, at first I was like, wow, that's so recent. And then I was like, wait a second. Yeah. Based on its biology, no, that's like very surprisingly early. Right. Especially because it was, yeah, not causing disease. Mm-hmm.

Mm-hmm. Yeah. And I definitely didn't find anything or read anything about historical infections of C-DIF or ancient writings describing the disease. I mean, you know, of course, there's plenty to choose from in terms of ancient writings of diarrhea. It's always been a part of human existence. And I'm sure that C-DIF took on the role of pathogen occasionally in human history.

And the first description we have of pseudomemberness colitis, for example, which is that horrible sounding condition caused by C. diff is from 1893, reported in a 22-year-old woman who had recently undergone surgery for a gastric tumor. She later developed severe diarrhea and died. Okay. And so maybe that was caused by C-DIF, but we have no way of knowing for sure. But beyond, you know, cases like that, C-DIF 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 1940s with penicillin. and it continued to grow and grow as more antibiotics such as vancomycin were discovered and then administered. By the 1950s, 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's sick and you don't know what it is and you need to try something.

Yeah, it's still very important that they exist. I'm not, I am so many lives. Yeah, we are still pro-anibiotic. Right. This isn't like antibiotics are not part of the villain. They're not, they're just, yeah. They're just a supporting character. Yeah.

But this is an inevitable consequence. We are pro-good antibiotic stewardship. That is what we are pro. Mm-hmm. Mm-hmm. That's a very, very important. Yeah, caveat there. Yeah.

Okay. So shortly after the rise of antibiotics in the 1950s and 1960s, doctors began to notice a rise in pseudomembrenous colitis and a rise that seemed to be tied to antibiotic use. Surgeons had observed rates as high as 14 to 27 percent among people who had recently undergone surgery, which is high. That's very high. Yeah. And of course, the prescription of antibiotics after surgery was and continues to be a very common practice, and it's important to prevent secondary infections.

But even when people started to recognize the link between pseudomemberous colitis and antibiotics, C-DIF wasn't really on the short or even long list of suspects. Most people actually thought that Staph-Oreus was the likely culprit. since it was often isolated from the patient's stool. And because of this, vancomycin, which was used to kill the staff, began to be given as the standard treatment for pseudomemberness colitis starting in the late 1950s. But over the next couple of decades,

Stafforeas seemed less and less likely to be the cause, since it wasn't really reliably found in the stool of many people with pseudomemberness colitis. and the disease itself, like the rates of the disease, didn't really seem to go down at all. A study in the 1970s firmly displaced Staff Aureus 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 200 patients at a hospital who had been given clindomycin, 21% developed diarrhea and 10% developed pseudomemberous colitis, but stool cultures were all negative for staphoreas. 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 Dr. John G. Bartlett, who was then at Tufts University. So he had begun investigating antibiotic-induced diarrhea and pseudomebrinous colitis in the mid-1970s. And in 1978, he and his team published a series of papers in which they finally revealed the link between a toxin-producing clostridium and pseudomemberous colitis. And then he followed up this research by showing that he had found C-DIF in the stool samples of cell. several of the individuals in that first study of 200 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 the samples and was like, C diff's 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 C diff, which also hugely opened up the field for other researchers to characterize its toxins, to examine strain diversity. to understand transmission dynamics. Like, from the late 1970s 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 1970s studies from Bartlett and his group, the field of C. diff 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 C-diff is intrinsically resistant to during the 1980s and 1990s, it led to a huge rise in C-DIF 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 C-DIF 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, Erin, 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 foodborne,

which has led to many people calling for a one health approach for this pathogen. Oh my gosh. Oh, I know, one health always. Well, yeah, but this like the numbers that I saw on like ground meats being contaminated was terrifying. Are you going to share them? Oh, I didn't write them down, but I should pull them back up because it is awful. Okay. Yeah, because also the other thing, and we touched on this in I think our antibiotics episode we had to have, maybe the second one, the overuse of antibiotics in both livestock and like other animals has led to increasingly resistant and difficult to treat strains of C. diff. C. diff is now like quite expectedly an enormous global problem, which I know you'll get into more later. It had this dramatic rise from zero to villain that was made

possible only by antibiotics. So maybe it's time we looked for an out. out-of-the-box solution? Or out-of-the-bowl solution? I don't know. Ew. No. No? Okay. Oh, goodness. So, you know the saying, like, fight fire with fire?

Oh, sure. What about fighting poop with poop? Oh, Aaron. You know, I can't resist. Come on. I love it. I do. Introducing fecal microbiota transplants. So at the end of this episode, you'll get to hear a whole lot more about the how and the why of fecal microbiota transplants, and I can't wait to get into it. But I wanted to first provide a bit of context, a bit of the where did this come from and how did 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 to kind of get things back to normal. Like unplug it and plug it back in again. Exactly. And it works in many cases, like remarkably well. It's beautiful.

Like it's a beautiful thing. I love it. I get chills when I think about FMTs. They're just so satisfyingly wonderful. It's so elegant. Yeah, it is. It's weird to say because it's poop, but it is. I think it's the simplicity of it and the logic of it is so, of course.

Yeah. Yeah. So who first came up with this idea that healthy poop could cure someone's bad poop? Yeah, I don't know. Tell me. It actually goes way, way back, all the way back to the fourth century in China, CE. Yeah, fourth century CE. I love that, Aaron, and it is somehow shocking and also not surprising at all, if you've ever listened to this podcast, I feel like. Exactly. Yeah. Yeah. So it was described in the first Chinese handbook of emergency medicine. And in this book, it was recommended. It was recommended. that if you had food poisoning or severe diarrhea, you should ingest fecal suspension by mouth. Wow.

Mm-hmm. And it was described as not just being somewhat successful, like, oh, try this and it might work, but like miraculous, bringing back patients from the brink of death. And this isn't 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. You'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, about ancient or medieval cures and how ridiculous they are. I know. I know. And it struck me that if we had done this podcast, this episode 20 or 30 years ago, we may have similarly laughed at yellow soup, at actually eating poop. But we're not laughing now, except that ourselves maybe. That's, yeah, that's hard, Aaron. I know. And that's not to say, but like, I'm not saying that, hey, maybe we should look into how effective saying, my wark be with you is for treating HPV or like mice tails for rabies or something. 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, ha-ha, look at these cures. These are ridiculous. I know. We all need to be more open-minded, don't we? We do. I think so. And even if they are clearly not based in any sort of medicine or like clearly they would not be effective, I think it also is still useful to, at the very least, try to understand the logic or reasoning behind them. Why mice tails ground with wine? Or, you know, pigeon heart and beer or something like that. Like, 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 and 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? I think that almost every day, Erin. Ah, yeah. And the, examples of this, I think, are endless, like our limited understanding of autoimmune disorders, or the mechanisms behind different mental health issues, or some of the ways that we treat cancer, or how we overuse antibiotics. Like, there's a lot there that people will have, there's ample material for people to laugh at us in the future. But we think we know it all now. We're all just doing

our best. We're all just doing our best. But my point is, I think that like we can look back and see how far we've come with these things, with our knowledge and technology and maybe feel okay laughing a bit about my warp be with you, just because it's such a great saying. But I think we also need to recognize that there is still so far to go and that scientific or medical advancements are rarely, if ever done in leaps and bounds, but rather the accumulation of years and years and centuries sometimes of shared knowledge being built. All right.

So a soapbox moment over. 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 17th century, there was an Italian anatomist who wrote, quote, I have heard of animals which lose the capacity 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 trans fondation. And also, like I just want to point out that many animals regularly consume feces for probably a variety of reasons. My dog loves him. Yeah. Dogs love poop. And then later on, in the 17th century also, a German physician recommended fecal transplant for humans in a book whose title translates to either healing mud pharmacy or salutary filth pharmacy, depending on the source.

Okay. I found it translated both ways, so I don't know. I also saw it mentioned that Bedouin groups historically consumed camel stools as a treatment for bacterial dysentery, something that seems to have been picked up on during World War II 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 besieged. silas subtilis, which they cultured and administered to decent success, like it seemed to work

to a certain extent. So that's kind of cool. This is 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 1958, when Iceman and colleagues successfully used fecal microbiota transplants to treat four people with pseudomemberous colitis associated with antibiotic use. This time, fortunately, using an enema rather than oral application. 1958? Yeah. Wow. Yeah. And this kind of just goes to further show that developments are not made in Isolate. Like a lot of, there's a lot of background to things.

Because in this study, he wrote that, quote, most of the recently reported cases of pseudomembrenous colitis have followed the use of oral broad spectrum antibiotics, suggesting that the intestinal flora was thus altered to permit the overgrowth of antibiotic-resistant micrococcus pyogenes within the gut. Huh. And so, yeah, he didn't get the bacterial species right, necessarily. But all you have to do is swap out microchoccus pyogenes for C-DIF.

And he's absolutely right in this mechanism of how broad-spectrum antibiotics, like, perfectly set up the gut for something to take over. Yeah. But decades would pass before the idea of the fecal microbiotic transplant would gain any real traction in human medicine, especially as more antibiotic classes were discovered, being like, oh, well, we can fix that. oh, we can fix that this way, you know. It kind of reminds me a bit of like how phage therapy dropped out. Yes. Yeah. And it was used again, fecal microbiototransplants were used again in 1989 to treat someone with

refractory ulcerative colitis, and it was remarkably successful with lasting recovery. But for the most part, reports of people successfully using fecal microbiota transplants, were kind of like one-offs, these, you know, case studies of people trying out fecal microbiota 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 2013 that the first randomized clinical trial was conducted in the Netherlands to look at fecal mycorrhioda transplant as a treatment for C-DIF infections. Here is where our two, our villain and our hero meet. It took a while, but hey.

And you'll see that it soon is resolved. Because in this study, the participants all had recurrent C-DIF, and they were all randomly assigned to one of three groups, either receiving vancomycin alone, vancomycin with bowel lavage, or bowel lavage, and then fecal microbiota transplant as treatment. And although the study was initially supposed to include 120 people with 40 people in each group, it was stopped early with only 43 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 microbiota transplant showed such incredible cure rates. Wow. Yeah. So of the 19 people in the fecal microbiota transplant group, 94% were cured of C-DIF infection. Wow. After a couple rounds of treatment of like 80-something were cured after one. 94% cured. Cured.

Right. And that means like no more recurrences. No more recurrences compared to 31% of those in vancomycin only groups and 23% of those in the vancomycin-only-plus bowel lavage. groups. So like, yeah, I mean, leaps and bounds beyond the ability of antibiotics. So that's, I just, I love that. What a clear indication of like, hey, there's real promise here. Yeah. And after the study was stopped, the people who were in the vancomycin groups were treated with fecal transplants and they 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 microbiota transplants? Are there long-term consequences? We have so many questions about fecal microbiota transplantation, and thank goodness we have an actual expert to help us answer them. But before we get to that, I think that, Erin, I want you to tell me just how much the world needs creative solutions like fecal microbiota transplants for this incredibly enormous global C-DIF problem. I would love to right after this break. So we're starting off this season, two episodes in a row with not great numbers when it comes to, we, We should have thought this. We didn't know.

Listen. Of all of the diseases, I would have expected C-DIF to have good numbers. Yeah. I would have. Let me tell you what I've got. Estimates in the U.S., and from what I can tell, these numbers that get thrown around seem to be from, like, 2011 is where they're getting these estimates. That's a long time ago, like in C-Diff. It is 10 years ago.

Yeah, but that's what we're working with here, Aaron. The U.S. estimates about 500,000, half a million cases a year, and 29,000 deaths due to C. diff infection. Now, that number in the studies that I read, was thought to be a huge underestimation, but that's still the number that the CDC cites on their website, for example, today here in 2021. I was going to say that sounds lower than I would have thought. Yep. The European Center for Disease Prevention and Control in the same year, 2011, was estimating 124,000 cases a year and didn't have a real estimate on deaths that I found.

Wait, all across Europe? That was, yeah, the European Center for Disease Prevention and Control. Now, I obviously wanted to get better numbers than that, so 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 C-DIF infections for every 1,000 hospital admissions worldwide. and they calculated an average, a global average, of 2.25 cases of C-DIF infection for every 1,000 hospital admissions worldwide. And I was like, wait a second, that number doesn't make a lot of sense. And if you look in that paper at the ranges with which they calculated this average, the range,

The ranges are bananas. They're from anywhere from one case per 1,000 to 37 cases per 1,000 hospital admissions, depending on which geographic region you look at. North America by far has the greatest number of cases reported compared to other places. And even though this study looked at 41 different countries, there was no data whatsoever from South America or from South America, or from Africa or from a lot of countries in Asia. So still we don't have great numbers.

We still don't have great numbers. Okay, but the 29,000 deaths and half a million cases in the U.S. in 2011 was an underestimation then and likely continues to be an underestimation. Yes. I did a little bit of Aaron Math, you know, my trademark. I love Aaron Math. Me too. trademark erin math don't trust these numbers so according to the american hospital association and that's just in the u.s

there are over 36 million hospital admissions every year in the u.s alone so if you look at those estimates of like maybe it's as low as two and a half it isn't cases of c diff per 1,000 hospitalizations or as high as 37 per 1,000 that's anywhere from 80s. thousand to over 1.2 million cases in U.S. hospitals alone each year. It's quite a range. Plus, it's not just hospitals. Like, what about long-term care facilities? Exactly. Exactly. That's the problem. And we just, with a lack of surveillance in a lot of places, and sometimes even a lack of definitions on how are you testing or screening for C-DIF infection versus colonization, how are you even defining a C-Diff infection. It makes global estimates really, really difficult. Well, I think we can come up with a qualitative metric based on the biology of the disease, as well as our medical practices of, you know, using a lot of antibiotics for a good reason.

Right. And that it's probably been only increasing since it was very first seen. I mean skyrocketed in terms of numbers, and now it's everywhere, and it's a huge problem. It really is. So because of that, there are a lot of areas of research ongoing when it comes to C. diff. Even though it seems like future areas, a lot of this research is promising enough that there are things that are not future, future directions of research. They're present. The very first thing is probiotics.

Probiotics are an area of research that I think is really fascinating. It all goes back to the whole microbiome, which again, we don't know a lot about. But there was a Cochrane Review from 2017 that showed, with moderate certainty evidence, which is like pretty good for a Cochrane review, that probiotics can reduce the risk of C-Diff infection by as much as 60 percent. in people who are inpatient in the hospital on antibiotics. So giving probiotics concurrently with antibiotics might be significantly protective. This is like opening a huge can of worms, but like, yeah, I know.

I know. And it was a co-briety. What does that mean? Exactly. I don't have data on like what that actually means in practice because, yeah, probiotics, they're not exactly regulated. We don't know enough about the human microbiome to know what are these specific bacteria and which probiotics do you take and how much money are you supposed to spend on these things, etc. And things that are claiming to be probiotics, but like, are they actually

probiotics? Like, what do you need to do to have probiotic on your label? That I don't have an answer too. But things to think about. Things to think about. And they did mention yogurt specifically. multiple times in this. That makes sense. And I'm also, I'm all for probiotics, but I think that like, we got to ask questions. But yeah, so that's kind of a one thing now that seems to be really promising. And I don't think that it's really talked about enough. And it's likely because of all the problems that are inherent, like we already said, with the idea of probiotics, that we just don't have good regulation on them. We don't know a lot about them. But that doesn't mean you can't find places that have live cultures

of bacteria and help yourself. I don't know. Other things, there are, even though antibiotics are still used very commonly for treatment of C-DIF, 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 C-DIF 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 C-DIF rather than just colonization. But yeah, there's a lot of promise both in terms of how we can potentially deal with, especially severe C-DIF infections today, but going forward, how we might be able to prevent them even more down the line. But here on TPDWDKY, we all have our biases, and one of ours is how amazing fecal microbiota transplantation is. Yeah, I don't think we've been enthusiastic enough about it this episode. No, I, it is truly, like the first time that I heard about it, I was just so enthused.

Like, I want to be a donor and or I want a transplant for just because I think it's amazing. I think it's, it is, like you said, it's, it's just like, you know, chef's kiss. Yes. Beautiful. I love it. So we were absolutely thrilled to speak with a true expert from OpenBiom, which is a nonprofit organization that is all about expanding access, safe access to fecal microbiota transatlore. plant and increasing research into the human microbiome. We'll let them introduce themselves right now.

I'm Mastie. I am the chief medical officer at OpenBiom. And I'm a physician trained in infectious diseases, as you could probably tell by the accent, trained in the UK. And my first encounter with FMT was about 10 years ago now and a patient who, an elderly woman who had Cedophysal infection after a hip operation and 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 is before stool banks. We had to do the FMT ourselves from a related donor of the patient. And within three days, the patient had fully recovered from their C diff 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 and met the team at Open Biome just as things were getting started that I ended up embarking on this adventure. That's amazing. So talking now about OpenBioam, can you tell us a bit about the project and sort of what a non-profit stool bank is? You know, how did it get started and what are some of its missions? Yeah, yeah. So OpenBion, we're a nonprofit stoolbank, as you said. You know, our first mission is to enable safe access to this treatment, fecal microbiota transplants or FMT.

And the second half of our mission is to catalyze research in the human gut microbiome using FMT, but also other tools in our toolkit to support new ways of understanding and treating diseases, especially those in areas of unmet need. And we started really because of our executive director, Carolyn, she had a relative that, you know, a young guy in his early 20s just out of college, you know, had a gold ladder infection, had surgery and then some antibiotics after that, and developed C-difacil 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 the 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 Cidifacin 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, you know, grown to the point now where we, you know, work with over a thousand hospitals across the US. And 99% of the US population is within a four-hour drive of a hospital. Of a

hospital using open biome FMT. That is amazing. What an origin story. I can't believe that. But I mean, it's it's clear that over the years, the need for FMTs is more and more pressing. And so it's an incredible thing that you guys are doing. And so before we get further into the transplant aspect of this, I want to talk about donation. Like, what is a stool bank? And also, So how does one become a donor? What are the criteria for acceptance? Like, I have a lot of questions, but we'll start there. Yeah, I sure think. So the stool bank is, you know, a bit like a blood bank, really, but for poop. So what we do is we screen our donors. Yeah, we're based in Boston. And so all of our donors come from around this area. A bit like with a blood transfusion, we would screen our

donors to make sure that they aren't potentially passing on any risk of either infection to a recipient, or potentially some of these other diseases that we seem to see in association with the gut microbiome. 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 200 questions related to their health physical assessment. And then if they pass that, they go through a blood and a stool 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 stool sample. And then every 60 days, they undergo the same three-step screen, so the clinical, the blood and the stool. The pass rate for becoming a donor is less than 3%. And so we often say that it's harder to become a donor at open biome than it is to say get into MIT or Harvard, because we are sort of screening these folks really rigorously. Wow, that is very interesting.

what a thorough process. I mean, it completely makes sense. So now I want to switch to transplants. What are FMTs, fecal microbiota transplants, and how do they work? Could you walk us through like the entire process from the patient's perspective? Sure. So a fecal microbiota transplant or an FMT is a very simple treatment in a lot of ways. It's essentially taking stool from a healthy donor and transferring it to a patient who's got a disease, in this case, Cidifacil infection. And, you know, when a donor who's been screened and gone through that very rigorous process provides a sample, that sample is inspected and tested, and then simply we add a saline glycerol buffer so that it stays stable once it's frozen. We homogenize it or blend it,

and then filter it to remove 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 upper 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 an open biome is prevention of C-DIF. And so 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 C-DIF. 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 C-DIF. So, yeah, you know, the treatment itself is surprisingly straightforward in many ways, but I think the complexity is around the donor 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. Gotcha, yeah, that is fascinating. I love the idea of pills, just like a little capsule of, and here's a new microbiome for your gut. Like, that's, it just feels like the future. And so that actually, your last comment there leads me to my next question, which is about eligibility. As you mentioned, unfortunately, not everyone who has a C. difficile infection is eligible

for an FMT. So I wanted to ask, like, what are the criteria for eligibility and who decides it? So FMT is recommended for. or patients with pseudifacil that haven't responded to antibiotic therapy. And that's the only patient group that this treatment is recommended for at the moment. And so, you know, 460,000 Americans experience Cedophysal every year. Of those, about 20 to 35 percent of them will experience a recurrence of that infection. And then potentially, you know, from that population, about 40 to 60 percent will experience

is the second recurrence. And it's on that second recurrence of their Cedophysal infection that they are eligible for an 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 remain 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 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. Yeah. And so, you know, you mentioned that there are some risks associated with FMTs, both short term and potentially long term. For instance, there's a lot that we still don't know about

how our gut microbiota affects our risk of developing some chronic conditions, right? Like cancer, diabetes, heart disease. I mean, many studies have shown a link, but what that link actually means. is it correlative, is it causative? 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? Yeah, absolutely. So I think when it comes to a risk of FMT, you know, it's always quite context specific. You know, in the case of Cidifacial 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 C-diff and perhaps has more options left on the table such as antibiotics or Bezlootoxymab 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, you know, we have to continuously be evolving our, criteria for screening for infections to, you know, 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 store. The second sort of category of risks, I'd say, are the, as you said, the potential association with non-infectious diseases. You know, 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, you know, potentially resection of their bowel or long-term antibiotics or, you know, even, even worse development of, you know, 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 Gastroenterology has set up a patient registry to follow a, were recipients of FMT for up to 10 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. Yes, absolutely. And so you mentioned that this is still pretty new. And those early studies,

like when I talk about the early studies of FMT, we're talking less than 10 years ago. And, you know, those did show incredible effectiveness in curing C. diffusil infection, has that success been maintained since those early studies and as the number of FMTs performed has increased over the years. Yeah, that's been a really interesting thing. So, you know, at OpenBiom, we follow the clinical outcomes of each patient that receives an FMT. A few years ago, we presented data on over 2,000 patients who had received an open biome treatment and observed a clinical curate of 82%, which is pretty consistent with the findings in clinical trials, but also the American College of Gastroenterology or ACG have been running a patient registry as well that I mentioned.

And they've to date followed up 259 patients and observed clinical curates of 90%. And so, you know, we're seeing these findings from these randomized control trials being replicated in a 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, you know, 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 optimized. 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. Yeah. Yeah, that's really interesting. those are incredibly high cure rates. It's just an amazing, it's just an amazing thing. And for this amazing, potentially amazing, life-saving treatment, there have got to be, I assume, some barriers in terms of cost or access.

So what are some of those barriers? So, yeah, at Open Biom, you know, our goal was to reduce the costs of treatment so that patients can access this at their needs. nearest hospital. And so we've got over a thousand hospitals now that are able to provide open biome treatments. And the way that we've reduced the cost of the treatment is by centralizing all of that donor screening. You know, if only 3% of donors pass the clinical screening, you can imagine that 97% of that for a clinician to be able to screen donors who may not be eligible is really expensive. And so, you know, if for a clinician to do this themselves can range from 4,000,

to up to $20,000 per single treatment. In an open buy, and we charge just over $2,000 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 alternatively, you know, the clinicians are having to eat up the cost themselves. And so that obviously creates a barrier to access, especially if we're thinking about coverage in some of the more rural areas or centres that might not be near a large gastroenterologist 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. Right. Yeah. So in this episode so far, we've largely been focusing on FMTs in the context of Clostridium difficile, but they have been found to be an effective treatment for a number of other conditions, or at least there's been early explorative research looking at FMTs for other conditions.

So can you take us through some of the research that OpenBiom is working on in terms of other applications of FMT beyond C-DIF infections? Yeah, sure thing. So I think one example that's really interesting and potentially points us to how the field might move in the future is a clinical trial that we did looking at fecal transplants in hepatic encephalopathy. So hepatic encephalopathy is a condition that is

associated with late stage liver disease, so 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 buildup of nitrogenous waste products that, you know, accumulating the systemic circulation and part of the role of the gut bacteria is to break down some of those waste products. And so working with a colleague of ours, Dr. Jasperjjj at University of Virginia, we conducted a randomized control trial that showed that FM. was able to effectively treat this, basically in this trial of about 20 patients, 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 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 this study that I think is really interesting is Dr. Bejarge 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 in these patients. And 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 microbiomes 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 personalised medicine approach to this may be 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 have 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 37% of patients are in clinical remission after FMT, which compared to about 18 to 20% for standard of care is really exciting. And then, you know, as a non-profit, we are also exploring, you know, the role of this in disease areas that are perhaps neglected by, pharma companies in the U.S. and Europe to support clinical trials in low and Lincoln countries. And so we're actually working with the University of Kiketown at the moment, looking at the role of fecal transplant in children with severe acute malnutrition who fail 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.

That is so incredible, though. That is. I mean, yeah, like you said, very broad, but promising and it just seems like such an incredible potential solution. So what do you see as the future of FMT? What hopes do you have for FMT in the future? Yeah, so I think we are at such an early stage of our understanding of the microbiome and the potential and the way that we should be using FMT. and what I hope is a few things, I think. Firstly, that we've accumulated more and more data on patient outcomes in a more systematic way across the world for all patients that are receiving this treatment. I think the second piece is that aspect of personalisation and can we do more to potentially increase the curates for patients who are receiving FMT for conditions like C-DIF.

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? And this is already being explored in some patients, some patients, some of the patient's, some, patient populations who are, you know, receiving lots of antibiotics like stem cell transplant patients,

but we, I think at 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 Biom 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, C-DIF is likely to become more and more of a burden as we see wider antibiotic use

and wider occurrence of risk factors that are associated with C-DIF, 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 could still access this treatment when they need it. I think COVID has highlighted.

said more than ever the importance of sort of health equity in 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. Thank you so much, Dr. Osman. That was just so enlightening. And I think I somehow, I didn't know it was possible, love fecal microbiotot transplants that much more. Even more. Oh, Aaron, what a fun episode this was. This was, This was very interesting. I mean, it did have its frustrating moments. Oh, yeah. Mm-hmm. Yeah. Like, I really wish that we had better numbers. And yeah, there's a lot of frustrations. But this was, I mean, I think C-DIF is a very remarkable pathogen and that it's not necessarily a pathogen. And its recent emergence and how much our existing medical structures kind of facilitate the growth of this back. bacterium and the spread of it is, is terrifying.

Absolutely. Yeah. Well, okay. Should we do sources? Yeah, let's. Okay. So I'm just going to shout out a few. I have a bunch of papers, but a couple that were key for the history and genomic aspects of C-DIF.

One is by Bartlett from 2008. And the other is the one that I already mentioned by Knight at all from 2015. And then in terms of the fecal microbiota transplant stuff, I contain multitudes by Ed Yong, a very fun book about the human microbiome, check it out, and by DeGrut at all from 2017. And I have to shout this out also because it doesn't just have great information, but it also contains an amazing figure, one of my favorite that I've seen, of the most important developments in the timeline of fecal microbiota transplants, but it's marked along intestines. Like it's like starting in one part of the intestine and going to the other. It's beautiful. Oh, that's so cool. I loved it.

Yeah. One of my favorite papers that I read was actually it was by Krobok at all 2018 called Understanding Clostridium difficile colonization. I found that one just really, really interesting. But there was a number of other review papers on sort of C. diff infection. and a couple at least including the global burden of clostridium difficile infections, a systematic review and meta-analysis that we're trying to get at the global distribution. Yeah, so we'll post a list of all of those sources on our website. This Podcast Willkillyou.com under the episodes tab.

Thanks again, Lainey so much for providing the firsthand account. We really appreciate you taking the time to chat with us. Yeah, thank you. Thank you also to Bloodmobile, who provides the music for this episode and all of our episodes. And thank you to exactly right, of whom we are a very proud part. Mm-hmm. And thank you to you, listeners. You make this podcast possible, and we love you for it.

We really do. Especially thanks also to our patrons. You guys are absolutely amazing. We love you. We appreciate you. it's just incredible. A joy. It is. Okay, well, this feels quite relevant. It does. Until next time, wash your hands. You filthy animals with soap and water and not just an alcohol-based hand sanitizer. I like that. Success starts with your drive, and American Public University is here to fuel it. With affordable tuition and over

200 flexible online programs APU helps you gain the skills and confidence to move forward whether you're changing careers starting fresh or pursuing a lifelong passion our programs are designed for people who never stop you bring the fire APU will fuel

the journey learn more at APU dot APUS.edu me made sure a resume of that I'm a difficult, rockoso and impirado what you'd expect? The next Every time I'll say, no if you manage a Toyota truck. We know what we're doing on

Hecht. Truck Month is going on now at your local RAM dealer. Hurry in for great deals and exceptional offers on a powerful selection of RAM trucks. And right now purchase and get 0% financing for 60 months on 2026 RAM 1500 Big Horn and Laramie models. Don't miss this great offer. See your local RAM dealer. Not compatible with any other offers. 0% APR financing for 60 months equals 1667 per month per 1,000 financed for well-qualified for well-quited.

Qualified buyers through Stalantis financial services regardless of down payment. Not all customers will qualify. Contact dealer for details. Offer ends 3-2.