Today we speak with Dr. Neil Stollman, MD. He was involved in the very first FMTs performed under medical supervision and was involved in establishing the first-ever protocol used. Since then Dr. Stollman has gone on to perform hundreds of FMTs and published several research papers on this topic. He shares his insights with passion and enthusiasm in this episode.
If you want help learning how to replace your gut microbiota, click here.
Dr. Neil Stollman Bio….. 1:37
Early History of FMT….. 2:09
FMT and the FDA….. 9:16
Long-Term Safety of FMT….. 17:36
Mitigating Risk of FMT….. 22:21
FMT and IBD….. 25:42
The Future of FMT and Stool….. 30:22
Cytomegalovirus (CMV), Cdiff, and IBD….. 36:11
Methods of FMT….. 38:22
FMT Donors….. 41:02
Episode Wrap-up….. 48:17
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Dr. Neil Stollman, MD, on Replacing Your Gut Microbiota
Dr. Michael Ruscio: Hey, everyone. Welcome to Dr. Ruscio Radio. This is Dr. Ruscio. I am here with Dr. Neil Stollman, who is a medical doctor here in the same town as I am in Walnut Creek. And he is a very big proponent of FMT. And I thought this would be a great person to kind of add to the discussion we’ve been having on FMT. So Dr. Neil, welcome to the show. Thanks for being here.
Dr. Neil Stollman: Thank you, Michael. I appreciate your having me with you, although I think I have to start off right away by correcting you because there are a lot of people in Oakland who would be very disappointed to hear that I’m in Walnut Creek. I’m an Oakland boy. And whether it’s, say, what’s that basketball team? Oh, that’s right. The Golden State Warriors play. I’m an Oakland boy.
DrMR: Gotcha. Sorry, someone told me that you were in the same town. They must have just meant you were in the same area.
DrNS: We’re close. We’re probably in the same county.
DrMR: Close enough.
DrNS: We are certainly in the same county.
Dr. Neil Stollman Bio
DrMR: Definitely. Definitely. So tell us a little bit about your background, your training, and how you got into doing FMT.
DrNS: Sure. So I’m a gastroenterologist by training and have been for, I guess, 20 years at this point in time. And I’ve had a somewhat varied career including stints at a VA hospital in Miami, at University of Miami. I moved out here to work at UCSF actually. So for many years, I was working at San Francisco General and at UCSF. And then I joined a practice in Oakland, where I’ve been practicing for the last over 10 years now.
Early History of FMT
And the FMT thing started maybe eight years ago now—it’s been awhile—when a very dear friend and arguably the godmother of American C. diff. treatment, a woman Dr. Chris Surawicz who’s up in Seattle, who’s been a friend is really one of the leaders in the C. diff. world—called me and said—or emailed me, I forget which—eight or ten years ago and said, “Hey, Neil. I got this lady in the Bay Area who has horrible, horrible C. diff. And she’s been emailing me. And I really think she needs a fecal transplant.” And I laughed and said, “Okay. Sure. And next?” And she said, “No, no. I want you to do a fecal transplant on her.”
And I had kind of known the concept then. But certainly there had been no recent trials, no recent data. This is an old concept. But it had been languishing for forever basically. And I actually declined. I said, “Chris, I can’t do this. I’m not at the university anymore. I’m in a private practice. How am I going to get permission to do this? The hassle, it seems—” And it seemed insane to put poop in this lady’s tush.
DrNS: So I said no. And I don’t know, three, five days later, she called me back again. And if you knew Dr. Surawicz, you’d know that you don’t easily say no to Dr. Surawicz. And she called me back and said, “No, no, no. You’re doing this.” It was no longer a discussion. I’m taking a little bit of poetic license. But essentially, it was no longer a discussion.
And she said, “I need you to do this. I’ve got a sick lady. And I need you to do this.” So I said okay because that’s how you respond to Chris Surawicz. And I agreed to do it.
And I spent hours and hours and hours and hours getting the hospital to agree to let me do it and filling out a million forms and consents and the like because this was really an unheard of thing eight or ten years ago. And we did it. And I did it myself. I didn’t have a nurse or a tech. I made that milkshake because how do you ask a tech to do this?
DrNS: It’s never been done. No one even knew what the hell it was. And how do I possibly impose on an employee to do this? So I did it myself. I went into this back room under a hood. And I did the poop. And we did the colonoscopy. We put it in. And goddamn if it didn’t work. So now I’m in trouble because I agreed to do this, and it frigging worked.
So I don’t know. A month later, I think it was Chris again, calls me up because a lot of these cases in the West sort of funneled through her. She’s very accessible. She’s very helpful to people. And they find her. Email has been out there. And there’s this whole population of people who sort of funneled into her. And she sent me another one. She said, “Here’s number two. Do it.” And I said, “Alright. Well, if I’m going to start doing this, I may as well set up a protocol and train people and have a whole set-up.”
DrNS: So this is, I guess, eight years ago now. I set up my system at my center where I work and wrote. And the truth is, at that time, there was no template for this. So we kind of made it up as we went. And I will tell you that I and Chris Surawicz, this woman, and Larry Brandt, who’s one of the founders—not founders, but fathers of this for sure, and a woman named Colleen Kelley, and Mark Mellow—we pretty much were at a national GI meeting sometime around this period, very shortly thereafter this period. And we sat in a hotel lobby—it may have been the hotel bar—but having a beer, literally writing on napkins out thoughts as to how to do this because, again, how do you do this? Where do you look it up? There is no “look it up.”
DrNS: It’s not been done. It was done in the 1950s by a guy in the hospital who used interns to do it. It was done in old Chinese medicine texts. It’s been done in veterinarian literature. But there was no human experience with this at all. And how much poop? And how do you prepare the poop? And where do you put it? And what do you put it in? There are a million such questions that there was no experiential answer for. And honest to goodness, this is exactly how unsophisticated science is that the five of us sat in a hotel bar/lobby making some arbitrary decisions. We honestly did. We made some—“alright, let’s try this. Let’s try this.” And you have five smart people and five caring people. And I think in retrospect we made some rational decisions. But it was no more complex than that. And it was certainly no more informed than that. I wish it were, but it wasn’t. And we made some decisions. And then that evolved over time.
Fast forward maybe a year, and I had done 11. I had done—so now, not two, three, four. I had done 11. And Dr. Surawicz, she started after me too. So after I did a couple, she did some. And a year later, we decided to publish our first 20. I think 11 were mine, and nine were hers or some such number.
And we said, “Let’s—’’ And it worked. It was 19 out of 21 or something. A very, very high efficacy rate. I don’t remember the exact data. And we published our paper, which was one of the earlier modern papers. Again, this is an older technology. But we had one of the earlier modern papers. And I was up to 11. She was up to nine. We did our 20.
And then the five people I just mentioned—Mark Mellow and Colleen Kelley and Larry Brandt and Chris and I—all put all of our papers together and got some—or patients rather—and then a longer follow up. So we ended up with—I don’t know—70 patients or some such number between the five of us. And we had follow-up now.
Now, it’s going on two or three years. So we have a longer term follow-up. And we published that, which at that time was by far the largest series of patients that was done. And it’s taken off. Our first paper is cited a lot for the methodology, not for the science. The science was 11 patients or 20 patients or some such number. There is now much larger series of hundreds of patients. But we pretty much wrote along. We wrote a cookbook. We wrote a how-to guide.
DrNS: And that how-to guide has evolved over the last eight or ten years. But we wrote a methodology section. “This is what we did.” And people looked at it. And people evolved it and changed it and revised it. But that was kind of how it all began. And fast forward now, and now this is standard stuff—well, close to standard stuff anyway. It’s certainly not nearly as weird or investigational as it was when we began. That’s a long answer to a short question, Michael.
DrMR: Yeah. No, no. That’s a great answer. And it’s just so interesting to hear how you were really there at the inception of a lot of this. And that’s exciting. I wasn’t aware of that. So just thank you, I guess, for being willing to—
DrNS: Well, it was random. It really was random. Chris called me largely because the patient was in the Bay Area. And she knew me and figured she could steamroll me into doing it. I’m being sarcastic. She and I are wonderful friends. But she did basically. And that was wonderful. And I was not at the time thinking of this. This was not my research interest. I do other things. I was just a guy in Oakland. That sounds arrogant. I don’t quite mean it that way. But this was not something that I was seeing as a career. It was just sort of a random thing that I agreed to do.
DrNS: And it turned as a win-win for everyone. It certainly got me some academic props, if you will, and some publications. And obviously, it’s helped patients. And it’s a different—I’m sure we’ll segue to that. But it’s a different world now than it was eight years ago.
FMT and the FDA
DrMR: Yeah. Yeah, and eight years ago, was this FDA approved at that time?
DrNS: Yeah, so the FDA was completely silent on it. There was no approval. No one knew what to do. And I did file it with my hospital. We didn’t do this under the table. We didn’t hide it. But there was no FDA guidance whatsoever for the first four or five years I was doing this.
DrNS: And you probably know this history well. But now, the FDA ignored it, not maliciously. I think it was kind of under their radar for a period of time. And I’m not sure they knew what to do. And then, as you probably know, at some point—I don’t know—maybe three years ago now, three or four years ago, they came out and said, “Stop. Cease and desist. This is unacceptable.”
DrNS: “You’re using poop as a drug. And you don’t have approval to use poop as a drug. And you’re treating an illness. You’re using poop as a medicine in that sense. And medicines need to go through the FDA. And the FDA needs to say what medicine you can use. And we’ve never said you could use poop. So stop, please.” Which was a really kind of crazy moment. It was April of—you probably know the date. I don’t know the year. It was two or three, maybe four years ago.
So there was this brief complete and utter moratorium where everyone in this country—I certainly, and I think everyone, had to stop doing this and say, “We can’t do this anymore.” And then as you may know, people started screaming and yelling and saying, “Okay, FDA. What’s your plan B? You’re going to tell us not do this.”
DrNS: But recognize for this population of patients—and we can talk about different patient populations for sure—but multiply recurrent C. difficile. And that’s all the patients I do is solely multiple recurrent C. diff. patients. There is not a plan B for that population.
DrMR: Yeah. Yeah.
DrNS: They have exhausted—which is why I think ultimately we all kind of agreed to try this crazy thing because you had, not so much desperate, but you had patients who didn’t have an alternative treatment. There really wasn’t something to do for them. So the FDA said no.
And we said, “Yeah, so now what, dudes?” Well, we didn’t say it quite that flippantly. And pretty much, the FDA—I’m personifying a little bit. But the FDA actually said, “We don’t care” to the doctors. We were not an important voice in this. But more interestingly to me, patients were a very important voice.
The FDA listened, in this particular instance—is my perception—to patients very well, and to their credit. I’m giving them full props because patients stomped their feet and said, “Now what?” And it took about a month, I think. It wasn’t all that long, which in government beaurocractic time—
DrMR: Yeah, very fast. Yeah.
DrNS: Yeah, exactly. A month is a pretty damn fast—and I could be off by a few weeks. But it was in that magnitude of time. The FDA said, “Okay, Neil. You’re right. We don’t have a plan B. So here’s what we’re going to say. We say—” which is still, by the way, the current standard, which will soon evolve again. But it’s still the procedure we’re operating under.
The FDA said, “Okay, Neil and friends. You can do this only for multiply recurrent C. diff., so not for any other indication. And you’ve got to tell people it’s experimental. And you’ve got to tell people there are unknown risks. And they have to have failed conventional therapy.” So end-stage patients who have this one diagnosis of multiply recurrent C. diff. who have exhausted all of their other treatment options with an adequate informed consent, the FDA said, “We will exercise ‘enforcement discretion,’” which I think is wonderful semantics frankly.
DrNS: They’re not saying, “We give you permission.” They actually don’t. The terminology is, I think, very intentional government speak. “We’re not saying, ‘Yes, it’s approved.’ We’re not saying we encourage, authorize, whatever active verb you can come up with.” Instead they said, “We will exercise enforcement discretion,” meaning we won’t come after you if you meet all these criteria that I just outlined.
And that has been the policy for the last, now, three years, which is if you do it in this population in this way, we’ll let you slide until we figure out what really we should do about this because they don’t know. Nor should they. It’s not a given. There’s no template for this. They don’t know. What do you do with poop as a drug? And they’re figuring it out. And they’re figuring it out now.
And there’s, as you may know, a new set of government semantics—not semantics, but government ideas that have come out for public comment. So that’s what the government typically does now. They say, “Okay, we’re going to make some suggestions, and we want to hear from the users, your opinion before we make the final ruling.”
DrNS: So they’ve come out with some new things. And I’ll mention why I think they’re doing that. But they have yet to come out with a ruling. So nothing has changed now. But what has changed is that there’s new public commentary. And I think we’re in the midst of it. Now, it may end at the end of April or May. I’m not sure. But we’re in the middle of a period of public commentary with some new recommendations.
And then the FDA takes those recommendations and listens or doesn’t listen. They do what they do. And at some point, which could be a month or a year, can come out and say, “Okay, here’s our new guidance for this.”
DrNS: So there’s likely to be new guidance. And I think what’s driven that is, as you probably know, there are now stool banks in existence. So when I started this and everyone else started this, the donor was typically a family member of the recipient. So Estelle has bad C. diff.
Estelle’s husband, Stanley, is going to be her donor. And we check Stanley for 18 different things and make sure he doesn’t have hepatitis and HIV and C. diff. of course and all this other stuff. And then Stanley poops in a bucket. I make a milkshake out of Stanley’s poop. And I put it up Estelle’s tush.
DrNS: Not to be too graphic.
DrMR: No, that isn’t.
DrNS: The FDA wasn’t hugely alarmed by that because, god forbid, Stanley had a problem and I put something bad in Estelle, I’m infecting his wife largely, or one person. But now with a stool bank, you could have one donor who is theoretically providing specimens to hundreds of recipients. And if you’ve got a problem, you’ve now got a really big problem. Right?
DrMR: Sure. Sure.
DrNS: There has not been. There has never been. But they, of course, want to avoid there being a problem. Let’s say, god forbid, Donor 17 has hepatitis X. There’s a new hepatitis that we don’t know about. This is theoretical obviously.
DrMR: Sure. Sure, sure.
DrNS: Not actual. But we know about A, B, C, D, E. There’s hepatitis J comes along. And Donor 17 has hepatitis J. But we don’t test for hepatitis J because we don’t know anything about hepatitis J. Now, a lot of people are going to get hepatitis J because Donor 17 is providing poop for a lot of people, not just one person. And that, rationally, is causing more concern, as it should. So the FDA is trying to figure out what to do about that and how to track that and how to follow that up and how to do surveillance on this. So they have asked for some guidance as to how to move forward in this world. And I and others have provided comments.
You can go to the FDA website. And they encourage feedback. And many, many people have done so, myself included. And we give feedback and say, “I think you should do it this way. I think you should do that. Here are my thoughts.” And then again, they tend to be bright, rational people. And they listen to many of them. And some of them, they don’t listen to. And like I said, at some point, there will be a change. And I don’t know whether that’s a month from now or a year from now. But they didn’t go through this exercise for no reason.
DrNS: So they’re going through this exercise to modify their guidance. And I suspect, at some point shortly, there will be new guidance. But right now, we’re still operating under the prior guidance.
DrMR: And I can understand where they’re coming from. “First, do no harm.”
DrNS: Yeah, exactly. Exactly. No, it’s the appropriate thing. And very few of us are against that. To be fair, it’s easy to bash the FDA in general as not particularly mobile or patient centric or whatever. And this is a whole new thing that there was no template. Just like I didn’t have a template for how to do this, they don’t have a template either. So they’re making it up.
And they’re asking good questions. And they’re asking rational people to help them. And they have to. There’s no question they have to. So I’m not against that. In fact, none of us are against that. All of us in this world are very supportive of that. We hope that they’ll listen to us and that rational guidance will come out of this. And perhaps I’ll change my tune if completely irrational guidance comes out of this process. But thus far, they’ve been actually very rational.
Long-Term Safety of FMT
DrMR: Now, one of the things, of course, that I think the FDA is trying to safeguard against—and absolutely, rightfully so—is any kind of unforeseen consequences. And one of the consequences or side effects that I think some are concerned about are things that may happen in the long term.
And that’s where I really love the paper that you published. And I believe the title is “Long-Term Efficacy and Safety of Fecal Microbiota Transplant Therapy for Recurrent, Severe C. Diff.” Can you tell us a little bit more about what you’ve seen in terms of long-term safety for this?
DrNS: Yeah, so I love that I titled it “long-term.” But the truth is that was probably two or three years max. So long-term—again I could look up the exact interval. But it’s not more than three or four years certainly.
DrNS: And ultimately, we’re going to need to know 20 years. But we can’t get there. And again, that was 77 patients. So it’s a relatively small number of people, not followed for 12 weeks, followed for X years, which is more useful than 12 weeks. But it still isn’t really long-term.
DrNS: And we still need better long-term answers. But there are a lot of theoretical concerns. And there should be. And no one should see fecal transplant as a cure-all with no risk, because I’m certain there’s risk, although, to be fair, we haven’t found a ton of risk yet.
There have been reports of—well, there are complications of having a colonoscopy. Most of mine are done with colonoscopy. I have not had a complication. Simply doing a colonoscopy is a complicated procedure. And there have been a couple of cases where people had aspiration pneumonias or other consequences of the colonoscopy proper, not of the actual transplant.
In our series, the one signal we found—so the paper you just referenced—in our series, we found three or four people—I think it’s four people—who in later years developed so-called autoimmune disease like rheumatoid arthritis or something called ITP or Sjörgen’s syndrome, which is an autoimmune attack on your salivary glands. And one of the theories is that, well, we’re putting in all this new stuff inside your colon. Is that new stuff immunogenic? And in fact, it might be. And in fact, it kind of should be, right?
DrNS: You’re putting in all this new stuff. And what do bodies do when they see new stuff? They rev up their immune system. That’s a typical response of our body. And in fact, that may even be part of why it works because it’s revving up the immune system. That may be part of its mechanism of action against C. diff., that by tweaking your immune system, you can better fight off the C. diff.
However, if you tweak your immune system, you can also turn on diseases that are a consequence of a hyperactive immune system like the three diseases I just mentioned. So the key question is, do those women—they’re all three women, interestingly. They’re all middle-aged women as it turned out.
And middle-aged women get autoimmune diseases, to be clear. That’s the demographic that gets ITP and rheumatoid arthritis and Sjörgen’s. So did they just get it because they’re 50-year-old women and that happens to 50-year-old women? Or did they get it because we kick-started their immune system?
That is an unanswered question. There’s no way to answer that question in this population. And it’s going to take us a lot more data to know the answer to that question. But it should give people pause to say, is that a possibility with the transplant? And absolutely it is a possibility with a transplant.
DrMR: What I think is so interesting about that is most of the microbiota literature seems to suggest that you have a window of maybe about three years of age through which most of the microbiota forms.
And that seems to have a pretty strong impact also on the immune system, which is why it seems like the earlier the exposure to dirt and dander and things like that, the higher the protection against autoimmunity. And so it definitely seems like there’s this certain window through which the immune system can calibrate to the microbiota, if you will.
DrMR: And if there are perturbations too late in life, the immune system may not be calibrated to that. And that may cause disarray as you’re describing.
DrNS: Completely correct. I agree with every single thing you just said. And it may be radically different doing it this way. And by the way, kids are often born with C. diff. as a colonizer. C. diff. is not a pathogen, just related to that, in infants. It’s felt to be commensal in infants. And then at some point, you’re right.
Our biome evolves, our gut biome. As you know, there are other biomes, as well. And it may be that an 80-year-old or a 70-year-old with C. diff. is a radically different beast than a one-year-old. In fact, they certainly are immunologically and microbiologically.
Mitigating Risk of FMT
DrMR: Right. And one of the ways that we’ve discussed—and it seems like most are in agreement with this. And I’d be curious to get your thoughts. But one of the ways we’ve discussed to mitigate risk with FMT is using it as one of the last therapies, not making it the first thing that you turn to should you clean up your diet, try a probiotic, and then throw your hands up in the air and say, “I’m going to now try an FMT.”
I would only suggest using this after you’ve really worked through every other available treatment option and hopefully with a few different, very educated clinicians. This way, you position a patient to mitigate risk from the procedure because they’ve kind of qualified for it better, if you will. Would you agree with that?
DrNS: I agree fully, vehemently. I think you said it actually better than I could. I agree fully. People want this. People. Patients. Not people, patients ask, “Why don’t I do it sooner. Why don’t we do this sooner?”
DrNS: “Why do I wait? Why do I have to fail?” So I get referrals. Not shockingly, I get known as this guy now. And I see three, four, five of these a week in my clinic. And they’re ready. By the time they get to me, they want their transplant. And sometimes, they are ready, and we go ahead with their transplant.
But oftentimes, they have not yet been through every kind of therapy. And I annoy them a little bit or disappoint them by making them fail further therapy. And I have exactly that conversation that you just had, Michael. You said really well, better than I would have. I basically say, “I know you want to get fixed. And I know this will fix you with a very high probability. But there could be these risks. And while I have not harmed anyone that I am aware of yet, we must acknowledge that there are potential harms that we don’t know about. This is messing with a lot of important systems in our body. And it is not inconceivable—”
Again, 88-year-old lady in a nursing home, she isn’t worried about the long term. She’s just miserable. She can’t leave the house. She’s incontinent. She’s losing weight. She’s like, “Just fix me. I’m not worried about your long-term risk.”
But what about your 25-year-old? There absolutely could be significant risk/benefit. So you’re right. It is a last—and that’s what the FDA said as well. And that’s very much, I think, any responsible FMT provider’s mantra—this is still an intervention of last resort, largely, as you said, for safety reasons.
DrMR: And as this gains visibility and popularity, people are starting to consider this for other conditions. And this will be a good segue for us to come to some other conditions. But I think it’s going to apply to those also—IBD, IBS, other types of autoimmunity.
I think it’s important for the person maybe listening to this at home and tinkering with the idea of doing a do-it-yourself FMT to really be a little bit reserved. And I know it sucks when you don’t feel well. But invest in the guidance of a good clinician to try to go through the other established therapies for the condition that you have first, leaving this as kind of a last resort.
And that’s exactly what we do in the clinic. We run patients through other therapies first. And it’s usually only a small fraction that needs to be referred out for FMT. But at least by doing that, we’ve made sure that you’ll not suffer, potentially, from any of these unforeseen side effects that we may not fully understand just yet.
FMT and IBD
Neil, with that as a transition, C. diff. we’ve talked about. My thinking is the next condition the FDA will allow this for would be IBD, just looking at the number of studies especially in the past year or so that have been published using this for IBD. So what are your thoughts on FMT and IBD?
DrNS: Yeah, for sure. I think you’re right. I would agree with you that that’s probably the next frontier for a whole bunch of reasons. One is that it is an unmet need, so to speak. There are a lot of sick people who don’t have a plan B, as opposed to IBS. And not to minimize how miserable a patient with IBS can be, IBS is not fatal. And there are therapies. And this should be a last line there. But IBD patients, as you know, can be seriously sick. And interestingly, the current guidelines, of course, are that I don’t ever do a patient with IBD other than in a trial.
However, before that guideline came out, I did a number of patients who were IBD and C. diff. In fact, IBD patients have a higher rate of getting C. diff. So I’ve probably done six, eight, ten patients over time who were C. diff. patients but were C. diff. patients with underlying IBD. And I don’t think I’ve helped any of their IBD actually. I’m certain I’ve helped their C. diff. But my experience has been rather negative.
As you know, there’s tons of data—or not tons of data. There is lots of evolving data. And the data has been very mixed as well. There was one study that was negative. There’s another study that was sort of positive.
There was one study. They went back in and said, interestingly. This is fascinating. They said, “Well, the study was negative. We don’t think—we did 40 people. And we used two different donors. And if you just look at all 40 people, they didn’t get better.” So that was the paper.
So then when they went back a little bit and said, “Wait a minute.” If you look—I’m making up the numbers again. But if you look at Donor A, it was actually 60% effective. And Donor B was 20% effective. So overall, the study didn’t look very effective. But if you peel out Donor A, Donor A was far better than Donor B.
And that’s an unbelievably interesting thing. Why is that? And maybe there are better donors and worse donors. And maybe that’s specific to the disease or the recipient. Maybe Donor A is a great IBD donor but a lousy C. diff. donor.
DrNS: And we don’t know the answer to any of those questions. But this is raising more questions than it’s answering. Circling back to the IBD thing—and we can talk more about donor and recipients and how we’re going to do this going forward because we’re not going to be doing it the way we’re currently doing it for sure. I would agree with you that that it is a needy market. There is some underlying biology to suggest why this might work. And I suspect you’re right, that we’ll see this more and more in IBD.
But I would stress very clearly that there is not a consensus that this is effective at all yet. And my personal experience—this is anecdote, not science—is somewhat skeptical. I am rather skeptical that this is the answer to IBD.
DrMR: And I share your skepticism, although as I’ve been following this, I think there have been now two systematic reviews showing either no effect or overall benefit and no adverse events. So as I’ve seen some of those papers come through, it’s shifting my opinion on this in IBD.
And one of the interesting things that I’d love to hear your thoughts on—when Dr. Mark Davis was on, he was speculating that perhaps the reason why—I believe he had mentioned that we see better results in ulcerative colitis than we do Crohn’s disease, likely because when we do this through colonoscopic administration, we’re going to have predominantly the effect, of course, in the colon.
And we won’t be able to reach the small intestine where a lot of this can occur in Crohn’s disease. So perhaps if we were to use a different method of administration, the poop capsules or something that was more through the other end, we would have more contact with the small intestine and therefore have a better effect on Crohn’s disease and even speculated maybe we could have a positive impact on something like SIBO. But what’s your take on any of that?
DrNS: So Mark is a smart guy. And those are all very cogent theses. But they’re still theses.
DrMR: Sure. Sure.
DrNS: We’re still waiting. We still need to answer that question. And that’s science. And it’s hard science to do. It’s really hard science to do, because you can’t control for all of these variables.
The Future of FMT and Stool
And to segue a little bit further, I suspect stool-based FMT is not our long-term solution either.
DrNS: And we can talk about that. So by the time you get this study done, I’m not quite so sure. We’re evolving already. Now, we’re using stool banks instead of the Estelle’s husband, Harold. Now, using universal donors, if you will, rather than direct donors.
And I’m pretty sure that, in a very short period of time, in single-digit years, we’re not going to be using poop at all. I think poop, as poop itself, is going away, as you know. There will be synthetic stool, if you will. You don’t have to actually use a person’s stool. If and when—not if—when we better understand our biome, we will not be—a stool transplant is the most shotgun thing in the world, if you kind of think about it.
DrNS: I know your biome is messed up. And I don’t really know how to fix your biome. So instead, I’m going to replace your biome. That’s really what it is, sort of biome replacement therapy, if you will.
DrMR: Yeah, yeah.
DrNS: Your biome is messed up. I can’t really tell you how to fix it. So why don’t we flush it all out and just put in someone else’s biome. And that works. We know that works. The data is extraordinary. And we can show that the recipient, of course, adopts the general characteristics of the biome of the donor. We can engraft the donor, if you will.
But we’re not doing that forever. That’s a horrible solution to this. The better solution is absolutely to understand that in C. diff. or Crohn’s disease or ulcerative colitis or IBS or any of these illnesses the biome is altered in the following ways. And to get that patient to a healthier biome, we need to take away some of this guy and put in more of that guy.
DrNS: More custom biome modification, if you will. I just made up that phrase. There’s probably a better phrase for it. But precise biome interventions rather than this shotgun biome intervention. And that’s going to come before too long.
So you can spend five years designing a trial on Crohn’s disease using NG tube versus pills versus colon versus enema with a stool bank versus a direct donor, Donor A, B, C, D, or E. By the time that study is done, we’re not going to be doing that anymore.
We’re going to be doing something different, which is saying that this donor needs two jars—this recipient, rather—this patient needs two jars of Firmicutes and vial of peptostreptococcus and two jiggers of bifidobacterium or something like that.
We’re going to be really understanding what a normal biome is, what an abnormal biome is in an illness and, I think, doing a more directed correction of that dysbiosis. That’s pie in the sky. But honestly, I don’t think it’s that pie in the sky. I think in five or ten years, we’ll be doing that in some way.
DrMR: Yeah, I certainly hope you’re right. I have some reservations about how quickly we’re going to get there, just looking at how many complexities affect the microbiome.
DrNS: For sure. For sure.
DrMR: Like a diurnal variation and a variation from month to month. But that being said—and I’ve been watching the literature pretty closely on this. But there’s just—I think there was one landmark paper published that showed finally a very consistent difference in IBD. And it correlated in a causal fashion to IBD. And that’s the key piece that’s been missing in most of the literature in my mind. If the change is—
DrNS: Absolutely. Cause versus affect.
DrMR: Right. Exactly, exactly. So there was one landmark paper that really showed it looked like it was causal. And that really excited me because then that suggests we can create a custom-tailored treatment to that.
But there has been so much research done. And we’re just getting to maybe a solid causal association, which needs to be replicated. And then once it’s replicated, then we can try treating it. And then we have to make sure we have a treatment that works.
DrNS: There is no question this is an unbelievably complicated system.
DrNS: And the answers are not simple. I wish it were simple.
DrNS: Your cholesterol is up. Take a statin. And your cholesterol goes down. And you have fewer heart attacks. That would be nice. But it’s just not that simple.
DrNS: However, the more optimistic observation is that the amount of time, energy, resources, and really smart people working on this is unbelievably dense now.
DrMR: Yes, yes.
DrNS: I was this first guy ten years ago, doing this clinically. There are 10,000 people working on this worldwide in research labs now. So the microbiome project, if you will—I put something in my Twitter feed yesterday. There was a hysterical little piece in The Onion—that sarcastic news site, The Onion—about cities, ecosystems that “walls in New York have different microbiomes than walls in Philadelphia and walls in Chicago. And we’re going to be doing—” It was taking this argument to an absurdity, as The Onion can do.
But it has become the hottest topic in the world that anyone who’s trying to make a research career—I’m a mid-career guy. And I’m not really a Nobel-level researcher. I’m a clinician more than I’m a high-end researcher. I do, obviously, a lot of clinical research in this world. But that’s not who I am.
There are now thousands of people—not hundreds, literally thousands of people coming at this. So I’m a little more optimistic, Michael, just because—what’s the line—put 5,000 monkeys at 5,000 typewriters; we’ll eventually create the Declaration of Independence.
DrNS: If you have thousands of people working on this, we’re going to figure it out.
DrMR: Sure, yeah. Well said. Well said.
Cytomegalovirus (CMV), C. diff, and IBD
Before we leave IBD, I’d like to ask you—I’ve been seeing some papers about cytomegalovirus as a cause of very resistant IBD. And I’ve been looking—of course, I look for association.
And then I also look for treatment because with the work that we put out, I try to give people not theoretical association stuff that sounds academically interesting but things that actually—here’s something, and here is a treatment for that something. I’ve seen just a couple papers showing that treatment with anti-virals can help in IBD that’s somewhat steroid refractory. Have you seen any cases like this?
DrNS: Yeah, but they’re few and far between.
DrNS: So it is our mantra, when an IBD patient misbehaves—meaning isn’t clinically acting like we think they should act and certainly if they’re not responding to therapies we would expect them to respond to or they’ve historically responded to—you always scratch your head and say, “Am I treating the wrong thing?”
And in IBD, the wrong thing number one is CMV and C. diff. now. It used to be CMV. Now, arguably, we think C. diff. before we even think C—because we know IBD patients get both of those infections at higher risk.
DrNS: So ten years ago, when my IBD patients misbehaved, we would stick a scope in, biopsy them, and specifically send path for viral inclusions, for CMV. The treatment is not so easy. So you wouldn’t treat someone empirically for CMV. You really want to find it before you would treat it.
Now, we just send stool for C. diff. first because that’s common and a really common explanation for a refractory IBD patient. But yeah, both of those are things we think about. CMV is very common. But the CMV treatment is an anti-viral treatment, which is not so trivial. It’s I.V. And it’s often prolonged. It’s not pills. So, to your question, I’m battling. Yes, I’ve seen it. But it’s maybe once every three years. It’s not common.
DrMR: Wow. Yeah.
DrNS: I’ve looked for it 50 times. I probably found it five times. I’m making up those numbers, but somewhere in that ballpark.
DrMR: Gotcha. Okay.
Methods of FMT
We’ve already, I think, bridged on this. But in terms of the best method of administration, do you have any thoughts on what might—
DrNS: Yeah, and I’ve used them all. So I do have a sense of them all. I think there’s probably not one answer to the question. It kind of depends on the patient too. Colonoscopy is what I have done the bulk of, so I’m most comfortable with it. And there’s no question colonoscopic FMT is super effective, 90+% in both the literature and my experience and pretty much everyone else’s experience.
But expensive—colonoscopy costs $1,000 or some such number. And as I mentioned early on, there are potential complications of a colonoscopy. I have not had one. But there are a couple of reports in the literature of C. diff. patients having a complication of the colonoscopy, not of the transplant, per se. So it works. But it costs some money and has some risk. Enemas work, probably not as well, but at lower cost and lower risk. So how do you adjudicate those two?
Pills—I did some of the early research on pills. We’ve been studying pills now. Pills are essentially riskless to administer. Again, the poop may have its risks. That is a separate discussion. But swallowing pills is riskless. And I’ve done now—I’ve probably done 25 pill patients at this point. It is definitely not as effective as colonoscopy. It is maybe 60-70% range, in my experience. However, I did a woman recently who was literally a 500-pound lady. She is hugely at risk for me to do a colonoscopy.
I did another 95-year-old last week who got pills who was also at huge risk for colonoscopy. I have someone else that I’m scheduling now for pills who has critical lung disease—can’t lie flat, is on home oxygen. They’re just a pulmonary cripple in a sense. And I’m deathly afraid of doing a procedure on them. So we’re giving them pills.
So pills are not, in my mind, first line. And if you’re at average or low risk for a colonoscopy, I would not offer you pills. If I was doing you, Michael—god forbid. We shouldn’t personalize this. But I would not suggest the pills to you.
I’d say, “You’re a young, healthy guy. The risk of a colonoscopy is close to zero. Let’s solve your problem with a high likelihood of efficacy and a very low risk.” I would do a colonoscopy. But for a high-risk patient, pills are an excellent plan B. But we still don’t even know. How many pills? How often? How do you take them? That’s in flux as well.
DrNS: So long answer to a short question. Again there’s not a single answer. I think different patients call for different solutions.
And what about donor? Dr. Connelly had remarked that a female in her 20s who, of course, was very healthy and ate a mostly vegetarian diet was what he has observed to be the best.
And he also remarked that if you’re not rejecting 90% of your donors, then you’re not screening closely enough. I’ve heard others suggest that multiple donors is really the way to go. And I think that makes a lot of sense also because if there was a minor imbalance that doesn’t jive with the recipient, if you have multiple donors, you have, hopefully, theoretically, the highest effect to get the microbiome recalibration that you’re trying to get, if you will. So thoughts on donor—
DrNS: Yeah, so we don’t know yet really. Again, like I said, I’ve done at least 200 of these, probably more. The first hundred I did with single, direct donors—spouses, typically a spouse. And it worked. It worked. And I have the data on that—95% efficacy. So those are random donors. They’re not young women. They’re generally older men. In fact, more of my patients are older women than not. And most of the donors were their spouses, sometimes a child. But of that population, I would say—out of that hundred, say, only five of them fit that definition of healthy, young, vegetarian women.
DrNS: Yet our efficacy is over 90%. So it’s obviously not that critical. The stool banks, as you know, have replaced direct donors for a whole bunch of good reasons. But I would say I do the large majority of my transplants now using Open Biome, which is the MIT-based, Boston-based stool bank.
As mentioned, they have an incredibly rigorous screening process. The joke at MIT is that it’s easier to get into MIT, which has a 6% acceptance rate, than to be a stool donor with Open Biome, which has a 4% acceptance rate.
DrMR: Oh wow.
DrNS: So it is easier to get into MIT than to be a poop donor at Open Biome.
DrMR: Oh, man.
DrNS: So they kick out literally 94%. And it’s not gender actually. They don’t believe there’s a gender difference. So it’s not female versus male. But it’s healthy. It’s lack of antibiotics, lack of travel, lack of family history. There are a whole bunch of criteria.
And then they screen these kids for literally—I screen the husband donor for eight pathogens, say. They screen for 70 pathogens. They screen for every pathogen known—any pathogen we can test for, we test for because we have to be hyper cautious.
DrNS: And those donors work great too. We’ve looked at that data. But I’m not sure those donors work any better than my spouses. My first 75 husbands worked just fine, too.
DrNS: And then throw in the fact that, well, my 75 husbands were fresh poop versus frozen poop from the stool bank. Maybe frozen poop is different. It seems not to be. But we don’t know. And again, I hinted earlier at who’s the right donor?
So Open Biome, to their credit, is trying to collect that data anonymously now, not with patients. But they’re getting feedback. You’re supposed to, if you’re an Open Biome client, before you get new poop, you’re supposed to tell them did your old poop work or not.
DrNS: Not the name, nothing identifiable. But sort of yes or no, did it work? So that they can look and say, “Well, Donor 17 is 49 out of 50 successful. But Donor 13 is only 40 out of 100 successful” or some such number. And then it raises a great question.
Well, what’s different between Donor 17 and Donor 20? And why is this working better than that one in this one disease, C. diff., yet alone taking that to a whole other world of a different disease? So we need to know that. And we don’t have a clue. We really don’t have a clue.
DrNS: I am amazed, however, how almost anything seems to work. So we can come up with what we think are the right donor characteristics, as you were mentioning. But it turns out, the wrong donor characteristics seem to work too.
DrMR: It’s great that we have the high efficacy, not knowing.
DrNS: Right. Exactly. Yeah, it’s very lucky, isn’t it?
DrNS: I don’t want to take too much time. But I think about that a lot. How fortunate was it that the test case—because look. I’m going to sound like I’m on a soapbox here. But why is the cool? It’s cool because for this one disease, it’s amazing. And it can be lifesaving and radically life changing for the small population of people who have this disease. But this disease on a global scale is trivial.
However, this is, without a doubt, the first template example of curing an illness with biome manipulation. We have never done that before in a programmatic way. This is really the test case, if you will.
And of course, it was, fortunately, an extraordinarily successful test case. And is that luck or skill? Did we choose the right disease? Or it just was kind of random? Great question. But thank god, in a sense, that this was safe and effective for this disease because it was sort of arbitrary that this is where we began.
DrNS: And knock on wood, it’s working. And it’s not hurting anybody. But it didn’t have to be that way. It really didn’t have to be that way. We could have chosen something else. And it wouldn’t have worked. And this could have gone nowhere.
DrMR: Well, it reminds me of how complicated the human body is.
DrMR: And maybe to play the devil’s advocate to one of the points you were making a little while ago—looking at this, and I thought you said this excellently, it’s really we’re giving them a new microbiome.
DrMR: It’s totally new.
DrNS: Like a replacement rather than a fix.
DrMR: Right. Right, a replacement rather than a fix. And I wonder. It’s been said that the microbiome is pretty much like an organ. And we just don’t have the ability to create, to synthetically make, new organs.
So I wonder if we’ll ever have the ability, the scientific capability to create a new organ. Just like we can’t create a new heart or a new kidney, I wonder if there are just too many intricacies because we have the mycome and the virome. And then we have how all of those interface with each other. And might the complexity be so deep that we’re never able to engineer?
I share your optimism where I really hope that we can so we can deliver people very simple, safe targeted treatments and fix their microbiomes rather than having to replace it. But I wrestle with those two things in my mind because of the complexity of the human machine.
DrNS: You are completely accurate. I’m going to choose optimism rather than—you’re right. And I justify that partly because it’s my career. And otherwise, I couldn’t get out of bed in the morning. But also because of kind of what I hinted at, which is that this works almost no matter how I do it, which is true.
DrMR: Right. Right.
DrNS: That’s true and data supported and factual. So that tells me that maybe there’s—even though it’s complex, maybe it’s a little bit forgiving too. Maybe we don’t have to be perfect.
DrMR: Sure. Well said. Well said.
Well, I don’t want to take too much of your time here. I appreciate you taking the time to speak with us. And any closing thoughts you want to leave people with on this topic?
DrNS: No, just I think my excitement that I mentioned earlier that this is just really, literally the tip of the iceberg. It’s this one illness. And it’s a cool illness. And it happened to be my illness that I started working on. But I think this is like finding the first gene for X and fast forward 50 years later.
And we have a genome that we understand. I think this is just the incredible beginning of a really cool… By the way, I’m kind of embarrassed we missed. That’s a flip argument here. Why the hell did it take us so long to even acknowledge that we have an ecosystem?
DrNS: And by the way, as you know, not just a colonic ecosystem. We have a skin ecosystem and a pulmonary ecosystem—we have lots—and a vaginal ecosystem. And we’ve got a cloud of a biome. We know that. Now, there’s data that we carry our own little biome clouds around with us.
DrMR: Yeah, yeah.
DrNS: So just to make it even more complicated. We focused on the gut biome. But gut biome clearly isn’t our only biome. So how come it took to 2010 to wake up to that?
DrNS: I’m almost embarrassed by that fact. It is what it is. But that’s where we are today.
DrMR: Well, I guess better late than never.
DrNS: Exactly. And we’re going to catch up. We are. We’re very good at playing catch up.
DrMR: So where can people—if they wanted to hear more from you, read from you, try to contact you—where can people track you down?
DrNS: So I have a website, which is NeilStollman.com, which is actually pretty straightforward. So that’s probably the easiest way. It has contact information. That is just my personal website. That’s not my practice website. My practice is East Bay—well, East Bay Endoscopy —is where I do this procedure. That’s my work facility, which is in Oakland. It’s called East Bay Endosurgery, to be precise. And it’s in downtown Oakland. But that’s actually not a good source of information for me. That’s just the place where this is done. So I think NeilStollman.com—which is my name in one word, NeilStollman.com—is the easiest way to get through.
DrNS: And my papers are on there, as well.
DrMR: Oh, right. Right.
DrNS: And you can find my Twitter and the rest of it on there.
DrMR: Okay, cool. And we’ll put that link in the transcript.
DrNS: Yeah, that’s perfect. That’s perfect.
DrMR: Cool. Well, thank you so much for taking the time. And hopefully, if there’s a new breakthrough in the field, we’ll have you back on. And we can hash through it.
DrNS: I’d be pleased to, Michael. It was a pleasure.
DrMR: All right. Same to you. Take care.
DrNS: Take care. Bye-bye.
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