IBS And The Microbiome

Mark Pimentel, M.D.

I mean, it’s not that long a story, I wanted to do medicine. And early on in medicine, I knew I wanted to do gastroenterology, so that part got squared away, but remarkably, I wanted to do the function of the gut. But more, people said, well, what do you wanna do? And I said, well, I wanna do esophagus because esophagus seems interesting to me, the physiology of the esophagus, but in hindsight, good decision I didn’t. It’s a small little organ, a little bit boring. But I think the moment that it hit me was when there was a patient, I think she was about 65 years old, she came into the office. And we had seen her, she had irritable bowel syndrome. And we treated her with antibiotics because we saw the breath was abnormal. 

And she came back and she had this brown paper bag she brought in and she literally had, I don’t know, 10 or 15 pill bottles in there. And she dumped them on the table and she says, “I can’t believe how good I feel and I don’t need any more of this garbage anymore.” And the pill bottles were tricyclics and other antidepressants that people were throwing at her, saying it was psychological or stress. And I realized that, wow, I mean, we did something to her that made her 90% better, none of this stuff could, there’s something here, and we need to do the science because you need the science to prove it. So I think that that was a real big turning point for me.

Eric D. Gordon, M.D.

Yeah, and you did the science, which I think makes it, lots of us think we need the science, but you actually turned around and did it. So tell me about, you know, just how you began to understand the role of the bacterial overgrowth in IBS.

Mark Pimentel, M.D.

Well, I think about 1999, I mean, I finished fellowship in 99, I was already starting the research in my third year of fellowship, but 1999, people thought IBS was a psychological condition, it was listed in the DSM book, which is a psychological sort of catalog, psychiatric catalog, and that’s where IBS stood. Even the term irritable bowel syndrome is derogatory, that means you’re irritable and you’re a syndrome because we don’t know what the heck is going on. And that’s where it was, and that stress and anxiety were causing it, and then I come out with a paper that says, well, it could be bacterial. 

Well, first of all, two things happened. The paper got a lot of attention in the media. Second thing happened, the scientists said, “Are you kidding me? It’s a psychological disease.” And for about a decade, there was sort of a, I wouldn’t say it’s a war or a battle, it was more of a intellectual conversation in strong terms of traditionalists versus the new microbiome area of IBS. And in the end, you know, as I say often, science is a regression to the truth. So I may be wrong, somebody else may be right, but it’s all about the patient, and at some point in the future, we’ll have all the facts and know the truth. And so fortunately, the truth continues to move in the direction of the microbiome in my case. But I assure you, we’ll get to this. We don’t have all the answers yet, but we have a lot of them.

Eric D. Gordon, M.D.

Yeah, yeah. It’s been so exciting, especially, you know, that you are bringing science to it because those of us in the, you know, alternative world or now we call it functional medicine and integrative medicine, you know, we’ve always, you know, we learned from the naturopaths, you know, a long time ago that the gut was at the heart of what was happening in the body for so many, so many illnesses. But, you know, and we looked at a few bugs and, you know, I don’t know if you’re familiar, I’m sure you are familiar with all testing companies that are out there that look at the microbiome now. 

But when what’s now Genova first started, even before it became Great Plains, it was started by a guy in New Jersey who was just looking at stool tests and measuring a handful of bugs, and that’s what we had, and we were playing with them. But you’ve taken this to a whole, just a whole new level of sophistication and information. And are there, but with all that, do you have any families of bacteria that you think have more to do with developing of irritable bowel?

Mark Pimentel, M.D.

Well, you know, again, we’re continuing to learn, and you’ll hear more about some of the new categories that we’re seeing, but at the current moment, we think SIBO breaks down into really three clusters. Cluster one is the hydrogen-producing SIBO, and now we’re jumping to 2021 a little bit here.

Eric D. Gordon, M.D.

Right.

Mark Pimentel, M.D.

But the hydrogen producing organisms, we thought and we still think, are E. coli and Klebsiella. Those are the bad actors in the small bowel. And we see that the higher E. coli is in the small bowel, the more it inhibits all the organisms around it and creates this, you know, as we sometimes term it, dysbiosis. But dysbiosis can, it has many definitions, but what we’re seeing is it’s almost like they’re a gang and people are leaving the community because the gang has taken over.

Eric D. Gordon, M.D.

Yeah, it’s a bad neighborhood now, yep.

Mark Pimentel, M.D.

It’s a bad neighborhood and E. coli has forced people out of the neighborhood. And so there’s a disruption, as we call it, so E. coli is a disruptor. There’s a second cluster which is based on methanogens. So when methane is elevated, it creates a different situation where it triggers constipation, methane gas triggers constipation, and those bugs, which are not even bacteria, they’re archaea, they produce methane. The new kid on the block is sulfate-reducing bacteria or hydrogen sulfide producers. And they are turning out to be super interesting because they relate to the E. coli and Klebsiella in the sense that they’re getting hydrogen from there to make hydrogen sulfide. And when hydrogen sulfide goes up, you get diarrhea, so now we’ve figured out how these fiefdoms of bacteria, when you have one neighborhood, you get diarrhea, when you have another neighborhood, you get constipation. And that’s where we’re at currently, but there’s some really nifty new things coming out later this year that just expand that notion, it doesn’t, it’s not gonna be an apocalyptic finding, but it’s a big sort of shift in understanding the complete picture of those three categories.

Eric D. Gordon, M.D.

Wow. Yeah, okay, and that’s come a long way from, yeah, years ago, we were just doing hydrogen breath testing and, you know, if that was normal, you know, well, you really had a functional problem.

Mark Pimentel, M.D.

Well, I still have one of the old hydrogen machines from the 1980s. Someday, we’ll have a little museum over here that has all these old instruments ’cause there wasn’t even CO2, there wasn’t methane, there was nothing, it was just hydrogen being measured, so.

Eric D. Gordon, M.D.

Yeah, yeah, yeah. And it’s just interesting like, ’cause as an aside, the Klebsiella, is there, do you find a significant relationship when you see elevated Klebsiella in a stool test, since that’s, you know, quite a bit far away from your small bowel?

Mark Pimentel, M.D.

So what we know about stool microbiome, and I don’t wanna get too far in the weeds for your viewers, but when you talk about the, let’s talk about the colon first. There’s Klebsiella in some people’s colon, but that falls in the category of the phylum Proteobacteria, the Klebsiella. But the two phylum in the colon that are literally taking up 80-90% of the colon are Firmicutes and Bacteroidetes. That’s not Klebsiella, that’s not E. coli. So while there’s E. coli and Klebsiella in the stool, they are by no means dominating anything, they are minor contributors, and yes, you can see them on stool tests, but they’re minor contributors. But now fast forward to the small intestine in bacterial overgrow, when you add Klebsiella and E. coli in a SIBO patient, it’s taking up 50% of all the bugs there. 

That’s how it’s dominating everything, so can you imagine that two bacteria are encompassed, if you counted all the cells, 50% of them are those two bacteria. It’s remarkable what SIBO does. And you don’t have an example of that in the colon. Now, some people use stool tests to say, well, there’s E. coli or Klebsiella there and maybe that’s an abnormality and maybe that’s where your question was going. There is some spillover effect, so you will see some of the SIBO E. coli and Klebsiella spill over to higher levels in the colon. But nobody said, this is the level, that’s SIBO, that would be a certain-

Eric D. Gordon, M.D.

Right, yeah, that would be-

Mark Pimentel, M.D.

So there isn’t, that line has not been drawn correctly yet. So I don’t know, what I’m saying is stool testing, I’m not saying it’s bad, I’m saying I don’t know yet exactly.

Eric D. Gordon, M.D.

I think that’s a fair statement, I mean, just to reiterate, I mean, to our listeners, is that I said I’ve been doing stool tests since, now since about 1992. And I can tell you that they’ll give you an idea of a neighborhood vaguely. But don’t hang your hat on them. ‘Cause even now that they’ve gotten much more exact, we still don’t know what it means.

Mark Pimentel, M.D.

Well, that’s the thing, I mean, look, 15, I’m sorry, I’m sort of cutting across you, but 15 years ago, the Human Microbiome Project was created. And at that time, they thought, oh, we know everything about the colon and therefore, the whole gut. We’re now 15 years past that. I can tell you, there’s, besides the methanogens which we found and the E. coli and Klebsiella which we found, there are no one bug, one diseases that have ever been found from stool. Except for C. diff, right, but that was found in the 80s using the old school microbiology, so despite all our technology, we haven’t been able to say, aha, this bug causes colon cancer, aha, this bug causes Crohn’s or aha, this bug causes ulcerative colitis. That was the pie in the sky in 2006, everybody thought, here we go, we’re gonna unlock the mysteries of human health. And it’s way more complicated than that.

Eric D. Gordon, M.D.

Yeah, well, I mean, just, once again, I’ve said this I think on almost every, for every episode, is that chronic disease is an illness of the patient, not of the pathogen. So you’re gonna find multiple pathogens are gonna wind up with similar-looking diseases, and if we, because it’s our body’s response that’s causing this chronic inflammatory state, whether it be in your intestines or in your brain or anywhere in your body, it’s your body that’s running this show. And so we’re just gonna get hints, we’re gonna get hints, and this is where I thank Dr. Pimentel because, you know, this is a far cry from, you know, the total pin the tail on the donkey work we were doing 20 years ago. You know, I mean, and this is a lot of improvement, but right, we’re not gonna probably find, you know, the one. But we got the neighborhood. So this, in, you know, just for our listeners again, so when you went through this, the methanogens, as you call them, and the Archaea, these are really primitive bacteria, is that, what’s the…

Mark Pimentel, M.D.

I mean, from a lay perspective, you could say that, but they’re not even bacteria. So they’re more primitive single-celled organisms than bacteria are and they don’t share a lot. So they’re really their own kingdom, you know, so you’ve got the different kingdoms of characterizing organisms and they’re their own kingdom and bacteria is its own kingdom, so they’re really completely separate. But remarkably, they’ve been around a lot longer and they’re survivors ’cause they’ve been here since the primordial soup in some way, shape or form. And they’re in us to a greater or lesser extent, so.

Eric D. Gordon, M.D.

And they like our small intestine.

Mark Pimentel, M.D.

They like our small intestine and the methanogens also like our colon, which is why we can’t use the term SIBO for methanogens, we’ve changed it to IMO, intestinal methanogen overgrowth, to encompass it could be colon or it could be small bowel, and that came up in the new SIBO guidelines we published just over a year ago.

Eric D. Gordon, M.D.

Oh, okay. So yeah, these guys have been around I guess literally since the dawn of biological time on this planet. Okay. And so, and these seem to be more tied with constipation patterns?

Mark Pimentel, M.D.

Yeah, absolutely, I mean, so the more methane you produce, the more constipated you are. And that is a direct correlation, which is really very few direct correlations like that in medicine. But we see it absolutely that way with methanogens. Something else that, I’m, again, I may be getting a little off topic. It also correlates with heart rate, interestingly, we just published that just three months ago, that the higher methane is, the slower your heart is, which is really fascinating, so methane has properties that could be vagal, properties that could affect muscle function in the gut. And so there’s a number of downstream effects of methane.

Eric D. Gordon, M.D.

Oh, that is fascinating. And, well, while we’re on gases, let’s talk a little bit about hydrogen sulfide ’cause that’s especially interesting ’cause I mean, that all, I’m not, actually, before we get to that, you know, many of these gases like, you know, we know carbon dioxide, carbon monoxide even, you know, these are neuro, they function as neurotransmitters, they function as in communication molecules in the body. Is the same thing possible, is that happening for methane that we know of on any other level other than in the gut?

Mark Pimentel, M.D.

Well, methane was recently sort of characterized as what we call a gasotransmitter. So it’s a gas that actually has a physiologic neuromuscular effect. In the case of constipation, slowing the gut down. It’s not slowing the gut down in the way you think, it’s not paralyzing the colon, it’s actually causing the colon to squeeze on both sides to hold things back, so it’s an active slowing of the gut that methane does. Hydrogen sulfide, that’s the new kid on the block. That one does all sorts of creative things to the wall of the intestine, including changes in secretion, changes in the nerves of the gut in terms of their sensation to pain. And it also has consequences on blood vasculature in terms of arterial tone. And these are things that have been known effects of hydrogen sulfide for a while.

Eric D. Gordon, M.D.

Right, yeah, no, ’cause I mean, we’ve always, I mean, not always, but we’ve known that it was a gaseous communication molecule, I’ll say. But yeah, I just didn’t realize that it also, up until recently, that it had its relationship to causing loose stools. And it’s the pain, the increased pain of irritable bowel.

Mark Pimentel, M.D.

Yeah.

Eric D. Gordon, M.D.

That’s, that is-

Mark Pimentel, M.D.

One of the things that, you know, was frustrating to me is that we were seeing all these SIBO patients, and then there were patients with this flat line breath test. And what was that, because there’s nobody with no bacteria in their intestine such that you should have no hydrogen at all ’cause there’s so many hydrogen producers in the gut. And it always, you know, perplexed me, and then there were patients where you would treat them and their hydrogen would go up. And you’re like, well, what is that? I mean, I just gave them antibiotics, I would’ve expected, there’s no way it goes up. So what was happening is, first of all, the flat liners, many of them turn out, they’re hydrogen sulfide producers. Secondly, when the hydrogen goes up, it means we got rid of the hydrogen sulfide producers and now all this hydrogen is there, nowhere to be eaten. So, you know, it’s all those mysteries that we’re trying to solve. But I can tell you, doing a three-gas breath test was a challenge and I was waiting for somebody to do it, they didn’t, so we went ahead and helped to develop this new test that can do all three plus CO2 stably because hydrogen sulfide is difficult to transport.

Eric D. Gordon, M.D.

Yeah, I would imagine these are-

Mark Pimentel, M.D.

Well, it’s just, it decays, the reactive compound, so.

Eric D. Gordon, M.D.

Yeah. So, you know, now that you have these, when you start seeing the patterns, I mean, what about the one that you see some patients who start off at very high levels or moderately high levels right from the first breath? I mean, and they really haven’t been eating. You know, what do you think about those?

Mark Pimentel, M.D.

So Dr. Rezaie, my partner, he actually, we both felt that the patients, now, if you’re just talking about hydrogen, now, methane, if it’s positive, it’s positive right out the gate, zero time point, methane’s high. Hydrogen sulfide has same property, if it’s positive, it’s positive right out of the gate almost always. Hydrogen can be, usually, it’s low at the beginning ’cause you’re fasted and then goes up with time. But we do have an occasional patient, as you point out, that they start up as high hydrogen and we thought, hmm, maybe that’s poor prep, they ate breakfast, they didn’t tell us, snuck in a little bagel. But they assure us they hadn’t. And we do see that it is associated with some symptoms and can respond to therapy, so I think some people aren’t telling us the truth about their snack for breakfast. But there are truly some people where it’s high at baseline for hydrogen and it’s real. So I think it’s up to the clinician to sort of figure it out in their, case-by-case-

Eric D. Gordon, M.D.

Right, right, right. And so for the patient, I mean, people always wanna know, how did this happen to me? I mean, you know, are there any, you know, stories that you have found that fit good proportions of these folks?

Mark Pimentel, M.D.

Yeah, I mean, I think that’s where the vinculin weaves in because we have now animal models that actually do exactly this, we give them Campylobacter food poisoning and then three months later, they have SIBO, they have IBS, they have everything that humans have just like IBS and the SIBO, as I mentioned. So it starts with food poisoning, we’ve actually identified the toxin CdtB, which is the culprit. In fact, now we don’t give rats food poisoning, we just give them CdtB injections in the arm and they develop IBS and SIBO. It’s pretty remarkable that we found the toxin that’s causing this. But the toxin, CdtB, makes you form antibodies to yourself. And that’s to a protein called vinculin.

And the specific subtype of vinculin that it reacts to is present on the nerves and the muscles of the gut, particularly the nerves. And so sequence is food poisoning, exposure to the toxin, you develop antibodies to the toxin that cross-react with you. And when that happens, the gut slows down and the patterns of the gut change. And the E. coli and Klebsiella are allowed to bloom because they, for some reason, that part we don’t understand, that because we don’t have these cleaning waves of the gut and other muscular functions, E. coli loves it like that. And they become the bully or make the neighborhood all bad.

Eric D. Gordon, M.D.

Yeah, yeah, no, that’s interesting, I’ve used that same I guess metaphor many, many times to explain, yeah, the gut, that, you know, we just gotta change the neighborhood, it’s urban renewal hopefully in a more positive vein than usually practiced. But what’s interesting is how, you know, the neurovascular system, ’cause we see, you know, so many times when people have had this for a long time, and I always wonder which direction the information is going, we see a lot of people with, you know, they just, poor stomach emptying, you know, gastroparesis, as we say, you know. And also, their necks are usually a mess, you know? And we think that there’s some vagal irritation going on, but obviously, most of the people you see, it’s probably starting in the gut and feeding back to the central nervous system.

Mark Pimentel, M.D.

Well, I mean, because in the animals, this is what we create. So we can create the exact scenario that we see in humans with animals just by giving CdtB. So my feeling is, it starts in the gut because the animal models support that. But, you know, we do know there’s a lot of neurochemicals that are produced by these bacteria in the gut. Serotonin, for example, can be produced by bacteria. So there’s histamines, which is a whole separate topic, probably another hour of conversation, that bacteria can produce, Klebsiella can produce histamine. So what does that do, you know, some patients complain of sinus problems when they have overgrowth, some people complain of brain fog, fatigue. Some people have more anxiety, some people have neck pain as you described. So it could be that their particular subset of bacteria in there are different and leads to this nuances. So there’s the general theme, bloating, diarrhea, constipation, and then there’s the nuanced subsets that are what you describe and what I-

Eric D. Gordon, M.D.

I think what you’re describing that are created by the individual, the person who has irritable mast cells because they’ve probably been chronically infected with something else for a long time, then you introduce a little bit extra in their gut with an overgrowth of Klebsiella, maybe those people are the ones that are gonna start having the mast cell type reactions. I mean, that’s, I mean, you know, the joy of being a physician is being able to like get people better and what really, but the intellectual curiosity of it is finding the different ways that these threads interact, okay, ’cause that’s the thing, is that it’s, you know, like I said, when you have an acute illness, you know, you have to recognize it. But-

Mark Pimentel, M.D.

Exactly, and-

Eric D. Gordon, M.D.

But when have a chronic illness, you have to figure it out.

Mark Pimentel, M.D.

That’s exactly right, one of the things that sort of bothers me and has bothered me about the irritable bowel syndrome’s old story is, you know, morphine is not a treatment for cancer. Morphine makes the pain of cancer go away, but you gotta treat the cancer. And so tricyclic antidepressants while constipating is not a treatment for IBS, it’s covering up symptoms. And a lot of things of what we do in medicine when we don’t understand a condition is simply trying to, you know, sugarcoat or cover up the symptoms that the patients have. And that’s fine when you don’t understand what’s going on, but you sure as hell better try to understand what’s going on and try to get to the root cause and the pathophysiology. And I think that’s where this story is really interesting because it’s not done, we’re by no means at the end of the road, but we’ve come a long way, and think about this. I know that food poisoning causes IBS. 

I sort of know the mechanism of how this happens. There’s been a quarter of a billion dollars given by the NIH to Crohn’s and ulcerative colitis research over the last decade and they don’t know those pieces still. They don’t know what triggers Crohn’s or ulcerative colitis, they don’t know the first, you know, this is what starts it. We do with IBS. We’re way better off than Crohn’s and ulcerative colitis now. You know, 20 years ago, we would’ve said no way, but now we can. So the targets for drug development, for therapy, for trying to understand this further are, the map is there now, and now we just need to keep going.

Eric D. Gordon, M.D.

Yeah, yeah, and one thing, as we’re going, I’m realizing, I believe you have a very, you see SIBO as very much a subset or a secondary effect of IBS, do I have that correctly or am I making an assumption here?

Mark Pimentel, M.D.

So remember, SIBO or IBS is a wastebasket-

Eric D. Gordon, M.D.

Yeah, no, totally.

Mark Pimentel, M.D.

So anything that meets these four criteria get thrown in that wastebasket. So it was never possible to find something that caused 100% of that wastebasket. And that’s the problem. But I sort of look at it like H. pylori and ulcers, right? 100 people with the ulcers, well, 20 or 30 are caused by aspirin or Advil, whatever you were taking. About 60 of them are caused by H. pylori. Well, we still call it peptic ulcer disease, we don’t call it H. pylori disease. And a whole bunch of people have H. pylori that don’t have ulcers. So it’s sort of following that path where, look, it’s IBS for now. And 60% of IBS is SIBO. And that’s good because we can treat that. 

So it’s not so much about changing the name of IBS as much as it is, okay, you need to do a breath test, find out if the SIBO is causing your IBS, treat that, and it goes away or at least it gets better. And I think that’s how we have to work. But remember, there’s still a lot of people out there who still subscribe to the old school of IBS and patients out there are still frustrated by some of their practitioners who say, I don’t think SIBO’s real. I just did a debate, I did a debate, and this was with all academicians, which is really interesting, sort of an academic debate on Saturday. And they did a pretest and they said, you know, do you feel SIBO is the cause of IBS? And I bet you wouldn’t guess what percentage of these doctors feel SIBO is part of IBS.

Eric D. Gordon, M.D.

10%.

Mark Pimentel, M.D.

83%.

Eric D. Gordon, M.D.

Oh, so you, okay.

Mark Pimentel, M.D.

That’s really good, right?

Eric D. Gordon, M.D.

Yeah, that’s a way, I was thinking they were still in the stone age, okay.

Mark Pimentel, M.D.

I was shocked, and so the point is, yeah, there’s still 17% of doctors who are out there frustrating patients with old, you know, but my point is-

Eric D. Gordon, M.D.

That’s really good.

Mark Pimentel, M.D.

My job is not to be an evangelist, my job is to keep putting papers out until the proof is so convincing that the last 17% are there too.

Eric D. Gordon, M.D.

Yeah, okay, but I’m just really, that’s overwhelmingly exciting and good news ’cause I, you know, I always compare medicine to one or two aircraft carriers, you know, one, you have the academics and the other one, you have like the FDA. And they’re both designed to be very slow moving, you know, and probably for good reason ’cause we don’t wanna flip on a dime. But it’s impressive when you moved one of them quite, that’s a big turn. So, you know, on just one thing, I realized that we should give your definition or the Rome definition of irritable bowel syndrome. ‘Cause I always get confused, I forget part of it, so.

Mark Pimentel, M.D.

Well, the definition changes with every iteration of Rome.

Eric D. Gordon, M.D.

Right-

Mark Pimentel, M.D.

But, so, and this is, I can tell you, this is frustrating probably to the FDA as well because each definition creates a different cohort of patients, and so if you approve a drug with Rome III, is it even approved for Rome IV IBS patients because the cohort is different? But generally speaking, you have to have abdominal pain. They refuse to put bloating in the Rome criteria, which is really quite a shock since 90% of IBS patients complain of bloating.

Eric D. Gordon, M.D.

Yeah.

Mark Pimentel, M.D.

But this is a Rome bug that we can’t get out of the ointment. And then they have to have alterations in stool pattern. And then there’s other minor criteria such as incomplete evacuation, urgency, you know, those types of things. So that’s it, I mean, the Rome criteria are so vague that if you took a Crohn’s patient, 70% of Crohn’s patients meet the Rome criteria. So not helpful. You know.

Eric D. Gordon, M.D.

Yeah. No, no, no, no, no, but you know, I mean, this is, I don’t think people, I don’t wanna waste a lot of time here, but this is something that, again, for patients to understand is that nosology or the way we organize diseases is such a mishmash, okay. And the idea that there is definitive diagnosis is largely a fantasy, I mean, there are things, you know, pneumonia, we can, you know, especially now with the CT scan, we can see it, an MI, we kind of agree on the EKG changes, you know. But, you know, a broken bone, we’re cool. But when it comes to, you know, again, chronic illnesses, it’s very vague on what you wanna name it, you know-

Mark Pimentel, M.D.

Well, you know, in all fairness to Rome, at the time it started in late 1980s, you know, you have to have an anchor. And the anchor is for the FDA to say, okay, we buy it. This is some nebulous thing called irritable bowel syndrome. And if you take those patients and you put them on placebo or a drug, we can track that. And then you get drugs approved. Without an anchor or at least being able to identify patients, you know, but we’ve moved on a lot since then and now there are sort of new targets. And so it creates a little bit of chaos when we’re trying to do new drugs based on true physiology because we’re stuck with antiquated anchors.

Eric D. Gordon, M.D.

Right, and so where are you with treating these gases? I mean like, you know, what’s the, I mean, A, what are you doing? And B, how is the FDA and the, not so much the pharmaceutical industry, but actually the insurance industry which has to, we have to get to pay for these things. How is that working out?

Mark Pimentel, M.D.

So, well, I’ll tell you what I do first. So rifaximin is FDA-approved for IBS with diarrhea on the basis that IBS is a microbiome condition. Fantastic, FDA acknowledges IBS is in part a microbiome condition, which is a huge victory. And it works and it’s been terrifically successful. We use that for the hydrogen overgrowth part of IBS. And the breath test for hydrogen predicts response to rifaximin, so that’s been published. On the methane side with the methanogen overgrowth, we use rifaximin plus neomycin on the basis of one small randomized control trial that we’ve done. So that’s where we hang our hat there. In the context of hydrogen sulfide, that’s the new kid. So we don’t know what works best there yet, but I can share with you that we’ve already completed one randomized control trial, which is not publicly available yet, on something completely new. But in the clinic, we’re not using that ’cause we don’t have it. And what we’re doing is rifaximin with bismuth-

Eric D. Gordon, M.D.

Okay, yeah, good old-

Mark Pimentel, M.D.

Yeah, 1990s, bismuth inhibits hydrogen sulfide production. So weakens those organisms and maybe the antibiotics slugs them across the head with, you know, and reduce these things. But we’re still using a sledgehammer for a small nail using antibiotics, so hopefully over time, we’ll have better, more boutique laser-like ability to get rid of these things.

Eric D. Gordon, M.D.

Yeah, well, what I’d love to talk a little about is what, again, getting back, the nervous system, the structural musculoskeletal system and the nervous system have always intrigued me ’cause I think they’re the stepchild of medicine since, you know, we really have been trained to ignore them unless broken. But anyway, so I think gut motility, you know, and since, you know, and I know you’ve done some work with improving gut motility, can you give us a little more information about how you look at that and how you think about it?

Mark Pimentel, M.D.

Yeah, well, there’s sort of three arms to treating overgrowth, there’s the arm of the antibiotics, which I’ve just described, there’s the arm of diet, which, you know, we may or may not have time to get into, and then there’s the arm of motility, which is, you know, we basically know that the motility is slow. We know that the majority of that problem is a lack of cleaning waves in the small intestine, or otherwise we call them phase three. And we know drugs that trigger that phase three, like low-dose erythromycin, prucalopride, which is another prokinetic. 

So in patients where the SIBO recurs, we want to try to make the cleaning wave go as best as we can possibly do it. But going even further back to the root, if we can get rid of the anti-vinculin antibodies from the bloodstream, we might be able to get everything cured. And that’s where, you know, our head is at for let’s say the 5 to 10 year plan on this. Now, I know that may disappoint some listeners because damn, I gotta wait 5 to 10 more years. But that’s, I mean, I’ve been doing 5 or 10 year plans for a long time. And it’s a 5 or 10 year plan.

Eric D. Gordon, M.D.

Ah, okay, you can see it. Well, I have a few things, one thing, I’d just love you to tell the story, describe the difference between normal peristalsis and the cleaning waves, ’cause I think people confuse that, they often wonder, I have diarrhea, why do I need more of a cleaning wave?

Mark Pimentel, M.D.

Yeah. So peristalsis is just a really simple generic term for the gut is moving forward, forward meaning from mouth to anus. But in fact, the small bowel is way more complex than that simple, you know, notion. So the cleaning waves or the phase three only occur when you’re not eating. So here’s the analogy, you’re sitting, you went to work, you didn’t have time for breakfast, you got up late, didn’t even have coffee. And you’re sitting in the meeting room and your stomach is grumbling. 

That’s a cleaning wave. That’s a good thing. It may be embarrassing to you because it’s very loud and obnoxious, but it lasts about 10 minutes and then it disappears and you won’t hear it for another hour and a half. That’s the cleaning wave. So you eat your dinner last night, you have some lettuce and pieces of things you can’t digest. That small bowel is like your dinner plate, it needs to go in the dishwasher, it needs to be washed before you use it for breakfast. So every 90 minutes, the cleaning waves come through and strip everything out to the colon. And if you don’t do that, it gets dirty in the small bowel. And that dirtiness means E. coli, Klebsiella, and those characters.

Eric D. Gordon, M.D.

Wow, okay. And the important thing is, if you’re eating all the time, it’s harder for that to happen.

Mark Pimentel, M.D.

If you’re eating all day, you never have cleaning waves. So, you know, when back thousands of years ago, we killed the buffalo, you ate the buffalo, if you didn’t eat it today, it was rotting tomorrow and you couldn’t. No refrigerator, no taco chips, you know, from the cupboard, you didn’t have bagels, you didn’t have Grubhub, you know. You ate and you didn’t eat for two or three days. And that’s the way the human body was designed, I mean, it evolved that way. So people who are constantly eating, it’s not the right way, it’s not what the body physiologically is meant to do.

Eric D. Gordon, M.D.

Yes. Yeah, that’s a whole other wonderful discussion I’d love to go off on one day, is just especially how that affects when we take in, you know, sugars and fructose all the time and why we wind up with fat and diabetic and gaudy and, you know, just ’cause the very things that were designed to keep us alive in times of no food really do us in when there’s too much to eat. Yeah, and getting back to the anti, the cytotoxic whatever, BDP, I can never remember ’cause I wanna make the last thing an eight and it’s a B, the CD.

Mark Pimentel, M.D.

CdtB.

Eric D. Gordon, M.D.

CdtB, okay, cytotoxic, okay. Anyway, are these antibodies, I mean, have you looked into the idea in people with severe cases of using things like plasmapheresis or is that too way out?

Mark Pimentel, M.D.

Well, we’ve done it, but we don’t wanna perpetuate the notion of doing it. So because it’s, you know, plasmapheresis, we’ve done it in about five patients, but these are the extreme patients.

Eric D. Gordon, M.D.

Yeah, that’s what I’m talking about, this is not garden variety, yeah.

Mark Pimentel, M.D.

No, these are not patients, these are patients that are in and out of the hospital, they’re so distended and their anti-vinculin antibody is as high as we’ve ever seen it and it’s a mess. And then, but you put a catheter in the neck, you gotta filter the blood like dialysis three times a week. And then a month later, all the antibodies come back, so the disease comes back. But we, so you can’t do it in a run of the mill IBS patient.

Eric D. Gordon, M.D.

Well, actually, but it doesn’t sound like a good idea if they’re back, you know, it’s not like some illnesses, you remove them and this system kind of resets, in this one, it comes right back.

Mark Pimentel, M.D.

I know it comes back, because I’ve seen it in the patients. But it does go away. So there’s the optimism, is that, if we get rid of these antibodies, I think we have a shot at curing this, it’s complicated to get rid of these antibodies, but-

Eric D. Gordon, M.D.

Right, okay, but that’s the exciting news that, when you did get rid of the antibodies, the symptoms went away during that time.

Mark Pimentel, M.D.

Correct.

Eric D. Gordon, M.D.

That’s very exciting ’cause as I said, it’s proof of concept, at least you know that this is doing it.

Mark Pimentel, M.D.

Yeah, exactly.

Eric D. Gordon, M.D.

Yeah, no, I like that, I like that, that’s very exciting. I’m just interested because, you know, in our field, we have found IVIG to be one of those surprising last ditch treatments, you know, that work often when we’re not even sure why, we’re never sure why it’s working ’cause that’s another thing that we don’t really understand why it helps, at least with the plasmapheresis, it’s a little cleaner, just a little bit, okay. But, and so your, just talk a little bit about diet because I know that that’s, my own experience has been that it’s been so individual in what’s gonna work for the people, but do you have some broad strokes that you’ve found with these different subgroups that you feel comfortable about people starting?

Mark Pimentel, M.D.

Yeah, I mean I think the, what we term the diet now that we use is called the low fermentation eating diet, LFE. So it is basically, and we came up with this long before low FODMAP, we just didn’t, you know, do the low FODMAP approach where we, you know, commercialized it, at least not at that time. It’s basically, the premise that you don’t eat between meals, what we talked about with the cleaning waves, so it’s not just what you eat, it’s how you eat. And then what you eat is, my goal at that time was, I want patients with IBS to live a normal life. So they could show up with friends to a restaurant and almost be guaranteed there’s something on the menu that they could tolerate. 

So it’s not as restrictive as the low FODMAP diet and not as, you know, doesn’t have the risk of malnutrition or other things that the low FODMAP diet has because that’s been demonstrated. But, and it allows you to be more liberal. Like onions and garlic are not, you take onions and garlic off the list, which is the low FODMAP, and suddenly, almost every Italian restaurant in the country you can’t eat at because everything has onions in it. So it really limits you immediately. But there’s many other things that are restricted in the low FODMAP that we allow. But basically, none of those are bad sugars, you know, the artificial sweeteners. What always makes me laugh is they call it sugar-free. It’s not sugar-free, sucralose is a sugar. It’s just not for you, the bacteria get 100% of it, you get 0% of it. It’s not sugar-free, that’s not a correct term. So there’s certain things that are absolute noes-

Eric D. Gordon, M.D.

So you mean like most of those alcohol sugar things are all just food for your bacteria, for your-

Mark Pimentel, M.D.

Yup, you’re just, it’s like a, I don’t like the word prebiotic either because I think prebiotic suggests it’s good. It is feeding the bacteria, that’s for sure.

Eric D. Gordon, M.D.

Okay, okay, so that explains a lot of people’s problem. And just going back to the onions and garlic, you do find that you just have that, a good number of your patients do do fine with small amounts or is it quantity?

Mark Pimentel, M.D.

How much onion are you gonna actually eat in a meal, truly?

Eric D. Gordon, M.D.

Right, no, that’s what I mean, not very much, or-

Mark Pimentel, M.D.

Not like you’re eating an apple, so I think it’s minuscule, the problem with onions and garlic, in terms of concentration. I think if you have a packet of Splenda, that’s a really bad thing, and certainly sucralose, I should say, I’m not gonna pick on a brand, sucralose. And those sweeteners are fine if you don’t have SIBO, it’s just, you have SIBO, you can’t be eating that stuff.

Eric D. Gordon, M.D.

Right, right, right. Any other really no-go foods?

Mark Pimentel, M.D.

Yeah, beans. Beans are awful, I mean, so those are really almost blacklisted for these patients. And hummus, which is a bean, it’s peas, chickpeas, right?

Eric D. Gordon, M.D.

Garbanzo, yeah.

Mark Pimentel, M.D.

Yeah. And those are frequently put in things. I mean, even in Indian restaurants, and I love Indian food, often, they use chickpea flour as a thickener for gravies and for sauces. So you, it says no dairy, it says this or not that, but the thick sauce that’s on the chicken is actually with a chickpea base instead of a flower base, like a whole wheat flour or a white wheat flour.

Eric D. Gordon, M.D.

Yeah.

Mark Pimentel, M.D.

So that’s a problem, and then, you know, miserable.

Eric D. Gordon, M.D.

Yeah. And just, and where do you see gluten in this world, I mean, how much do you, ’cause in my world, they tend to blend together because most of our patients, because of chronically inflamed gut, have wound up with some kind of wheat sensitivity in America, but where is your world?

Mark Pimentel, M.D.

You know, I mean, you know, we’re not always right. I was very, I was not a believer of gluten-free for the longest time, unless you have celiac disease.

Eric D. Gordon, M.D.

Right, right.

Mark Pimentel, M.D.

And I’m generally not prescribing gluten-free to my SIBO patients. But we just recently did a study and we found that, if you compare people who are gluten-free to all the other diets, including veganism, vegetarian, you know, lacto-ovo, et cetera, the only group that had a low TNF, tumor necrosis factor, a lower inflammatory score, was people on low gluten. Which, I was scratching my head, I said, look, I got to eat this one because I was a naysayer and now the science tells me I’m wrong. And again, it’s about the patient, it’s not about me.

Eric D. Gordon, M.D.

Yeah, yeah, there’s something there. I mean, we still have, yeah, we don’t wanna make a religion, but it’d be really interesting to do that with a group from Italy, you know, where many of us who have trouble with gluten or wheat products can get away, you know, we don’t have celiac, but we just, you know, if we eat a lot, for myself, I eat a lot of gluten, I’ll get that heavy fatigue, like I feel like I have to slap myself to stay awake, which to me is real food allergy kind of response.

Mark Pimentel, M.D.

Yeah.

Eric D. Gordon, M.D.

And yet in Italy, I can eat the stuff and it doesn’t happen, I keep always afraid and then I keep doing it ’cause it tastes good. And I’ve heard this from many, many, many, many, many, many patients.

Mark Pimentel, M.D.

You don’t have to convince me, my IBS patients, when they go to places like Italy or Greece or, you know, the food is coming from a farm just down the road, maybe no GMOs, I don’t know what’s going on, but they go to Italy, they have no problems.

Eric D. Gordon, M.D.

Yeah.

Mark Pimentel, M.D.

And then yet here, they eat the same pasta. What I’ve been telling patients is, you know, Italy, I know I’m now I’m telling you a brand, but there are other places, Italian markets, that actually source flour from Italy and make your own pasta and you won’t have as much trouble, and a lot of patients do well that way, but-

Eric D. Gordon, M.D.

Yeah, no, these are the mysteries that would be nice to be solved but, you know, I mean, like I said, as you said, that NIH budget is aimed and targeted at ways to make more money for the people who, I mean, unfortunately, it didn’t, you know, I always tell people, medicine is generally manned by, manned and womaned, by people with good intentions, there are very few evil people out there in this field. It’s just that, you know, just habit patterns and like the funding does seem to depend on funding. And so…

Mark Pimentel, M.D.

Yeah, absolutely, and that’s been our biggest challenge over these 25 years, it’s better now. But we had to be scrappy because there is no funding for IBS. And we got scrappy and did big things with little dollars. I mean, the first neomycin study we did, which wasn’t, you know, now we’re sort of wrapping up with this little comment because it’s so, it’s cute. You know, a randomized control trial, like a target trial for rifaximin, which is about, you know, couple hundred patients, or 600 patients it was actually, this is like $30 million trial if you combine both of them. We did the neomycin and placebo trial for 2,000 bucks. We paid for the neomycin, we paid for the placebo, the pharmacy blinded it and that was it, the whole trial was $2,000. And that was the start of this whole story.

Eric D. Gordon, M.D.

Wow, wow. But it took, you know, how many hours of your time and your staff’s time that you didn’t assign dollar value to?

Mark Pimentel, M.D.

That’s true. Blood, sweat, and tears, a lot of blood, sweat and tears. But it was worth it because patients benefited, and I think that’s-

Eric D. Gordon, M.D.

Oh yeah, no, no, I mean, your work has transformed this world, I mean, you know, we were throwing stones at this, you know, like I said, you know, we threw some of the right stones, you know, we kind of knew in the 90s, we would treat people. But we would, you know, like I said, a lot of what I do I always say is like, pin the tail on the donkey, we’re blindfolded. And with your help, we’re not blindfolded anymore when we’re treating this, you know, we really have some good, some ability to, you know, have a pretty good idea what the target that we want is rather than just, we’re gonna kill something, see what happens.

Mark Pimentel, M.D.

Exactly, exactly.

Eric D. Gordon, M.D.

Yeah. So I just wanna thank you so much, this is great, I hope people didn’t mind our meandering, that is my style, so they’re used to it, if they’re watching this, they’re used to it, I like to explore ideas and you’ve given us a bunch. Just, the thing is, I can do this, I don’t about you, but I’m allowed. Trio-smart, if people are looking, you know, for the breath test, that’s the place to go. And we’ve been very impressed and we said the results are helpful, I mean, clinically, we really like them. And also, I’ve been using the ibs-smart, which is the one that looks at the anti-vinculin antibodies, you know, and again, I think is gonna give us insight and hopefully be able to help us direct therapy over time.

Mark Pimentel, M.D.

Yup, one step closer, moving step-by-step.

Eric D. Gordon, M.D.

Yeah, so again, thank you so much, I look forward to chatting with you again. And stay healthy, don’t give up.

Mark Pimentel, M.D.

Nope, we’ve not given up yet. Thank you so much, Eric.