Dr. Pimentel has been very active in research and served as a principal investigator or co-investigator for numerous basic sciences, translational and clinical studies in areas like IBS and the relationship between gut flora composition and human disease. He is widely known and sought out for major scientific developments that he’s pioneered, including the discovery that IBS is a condition of altered intestinal microbial

In this episode, we cover:

7:36 What is small intestinal bacterial overgrowth?

11:20 Testing for SIBO

18:42 The future of SIBO treatment

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Chris Kresser: I’m Chris Kresser and this is Revolution Health Radio.

Hey, everyone. Chris Kresser here. Welcome to another episode of Revolution Health Radio. I’m really excited about our guest today. We have Dr. Mark Pimentel, a global expert on small intestine bacterial overgrowth, and I’m going to talk to him all about some unresolved questions and problems or issues with SIBO, the SIBO hypothesis, diagnosis and treatment of SIBO, and I’m really looking forward to this, and I hope it’s going to be useful for you as well.

Mark Pimentel is an associate professor of medicine at Cedars-Sinai Medical Center in Los Angeles, California. His medical training includes a fellowship in gastroenterology at the UCLA Affiliated Training Program. He’s been very active in research and has served as a principal investigator or co-investigator for numerous basic sciences, translational and clinical studies in areas like IBS and the relationship between gut flora composition and human disease. Dr. Pimentel is widely known and sought out for major scientific developments that he’s pioneered, including the discovery that IBS is a condition of altered intestinal microbial balance, which we’ve talked about before; the recognition that antibiotics improve IBS, irritable bowel syndrome, and this officially legitimized IBS because before these discoveries, IBS was often considered to be a psychosomatic condition; the discovery that methane produced in the gut by specific microbes produces constipation, which we might talk about today; and then his work linking SIBO to IBS and other conditions.

So again, I’m really, really excited about this episode, and without further ado, let’s get to it.

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OK, now back to the show.

Chris Kresser: Dr. Pimentel, thanks so much for being here. I really appreciate it.

Mark Pimentel, MD: It’s my pleasure. Thanks for inviting me.

Chris Kresser: Maybe you could start by telling us a little bit about how you got interested in SIBO in the first place. I’m always curious to hear how people get involved in their field.

Mark Pimentel, MD: Well, it’s interesting. I mean, when I was in residency and planning my fellowship and my career, obviously IBS was not on my radar. I think what I learned very quickly when I started to learn gastroenterology is that IBS was an area not too many people were interested in, and as I started to see these patients, I was fascinated by the fact that they all had distention and bloating, and it seemed to me that bacteria and fermentation in the gut could be an important aspect of that. I also began to notice under the tutelage of my mentor that these patients often had positive breath tests, and we began treating them with antibiotics, and we got some remarkable results, and so this really was the beginning of a long journey into trying to help a group of patients that really were outcasts in medicine. Doctors just didn’t want to see them, didn’t know what to do with them.

Chris Kresser: Right. For all the listeners, at that time, IBS was largely considered to be a psychosomatic condition, right? Antidepressants — or maybe no treatment at all — was what was offered at that point.

Mark Pimentel, MD: Yeah, I mean, in some of the early days and some of the early patients that I saw, I remember distinctly this one retired lady who had IBS. She brought out a paper bag full of six different psychotropic medications, and she said, “I no longer need these medications,” but that was the therapy she was given, to no avail, and it didn’t help her.

Chris Kresser: Yeah. You were definitely ahead of your time now because I would say it’s pretty universally recognized — well, maybe I’m getting ahead of myself! — but at least within the scientific community, that altered intestinal microbiota is a major player in not only IBS, but a whole range of other diseases, both gastrointestinally and even extra-intestinally. Things like fibromyalgia and even depression now are being linked to altered intestinal microbiota, so you were a real pioneer there, and I just want to thank you for your contribution to that.

Mark Pimentel, MD: Well, it’s humbling to actually see this evolution because even before the term ‘microbiome,’ we were kind of yelling in the wilderness and saying, “You know, microbes may be important in some of these functional disorders.” It wasn’t very well accepted, obviously, in the beginning, but it’s really nice to see the evolution of the science, and really it’s come such a long way. Very exciting.

Chris Kresser: It has, yeah. We were chatting before. Most of my listeners know that I struggled with a long chronic illness that started with an infection in Indonesia, and I saw you at some point early on in that journey, and that was enough to convince me that some alteration of the gut by a viral infection or a parasitic infection or antibiotic use — all of which were actually historically present for me — was something that could create so-called IBS or potentially even IBD. There wasn’t much research on that at that time, but my own personal experience of it was enough to convince me!

Mark Pimentel, MD: Yeah, it’s very interesting how a lot of these patients are describing exactly the scenario you had, and we’re learning a lot from that, actually. I have to say just briefly, my largest group of researchers are my own patients because they teach me the answers. You have to listen to your patients because they’re telling you what they’re feeling and their experiences.

Chris Kresser: Yeah, I feel the same way. I’m so glad to hear you say that.

So let’s move on to SIBO. This episode, since we have Dr. Pimentel here, I really want to focus on, not some of the basics of SIBO, which we’ve already covered at some length, but I want to talk to Dr. Pimentel about some of the unanswered questions, at least in my own mind, and get his take and opinion on those. But before we dive in, maybe we can just start with what should be or would seemingly be a straightforward question but maybe is not, which is, what is SIBO? How are you defining it now?

What Is Small Intestinal Bacterial Overgrowth?

Mark Pimentel, MD: I think the term SIBO is evolving in a sense because initially we used the term small intestinal bacterial overgrowth based on breath testing, and I think breath testing has a lot of merit, but SIBO does not equal SIBO does not equal SIBO, and I think both from a breath testing standpoint and even a microbiology standpoint we know there are different forms. But essentially the bottom line is that it’s an overcolonization of specific bacteria, usually the colon bacteria, into the small intestine, where they don’t belong. Ruminating animals, for example, like cows and sheep and horses, they have a lot of bacteria through their small bowel in order to help them absorb and digest grass, which they don’t have enzymes for. Humans don’t need that. Our small bowel is almost sterile — on purpose — because we’re sophisticated, we can digest many different things, and we have all the enzymes for that. And when all this bacteria builds up in the small bowel, then you get this bloating, gas and distention, and a lot of changes in bowel function.

But the reason I started by saying, “SIBO is not SIBO,” is because as we move forward, we’re seeing that if you have methane type of organisms in the small bowel, you’re getting constipated, and if you have hydrogen type, you get more of the loose bowel movements or mixed IBS. And it’s going to get even more complicated because we think that the type of bugs may be associated with different diseases. Maybe fibromyalgia has a different type of overgrowth than, say, just simple IBS. So those complexities are emerging.

Chris Kresser: Right. And I’ve seen some studies that show that apparently healthy controls — and of course, I always wonder about that because the definition of a healthy control has certain assumptions that I’m not sure are correct, but let’s just assume that they are healthy — up to 20% can have SIBO, at least according to breath tests or other testing methods, so what do we make of that? Is it possible to have SIBO and be completely asymptomatic, in your opinion?

Mark Pimentel, MD: That’s a great question. The breath test, of course, has its limitations, and that may be part of the reason why some of the healthies are positive, but I like where you’re going, and you’ve obviously put a lot of thought into this, because healthy is not healthy. Even the definitions of what is a normal bowel habit in textbooks were based on studies that didn’t exclude IBS patients.

Chris Kresser: Right.

Mark Pimentel, MD: The range is three times a day to three times a week as a normal bowel function, but after treating overgrowth in thousands of IBS patients and all of a sudden they’re having a perfect bowel movement every day, some of the IBS patients are better than healthy people that I’ve seen.

Chris Kresser: Right!

Mark Pimentel, MD: So it really speaks to the question, OK, so what is true normal? And if we don’t know what true normal is, then it’s really hard to define healthy and then to compare breath tests between healthy and unhealthy. So it’s complicated, and the answer to your question is, if we take super-healthy people who are spot-on perfect, the chances of having an abnormal breath test are very low, less than 5%. But people might critique that and say, “Well, super-healthy is not normal either.”

Chris Kresser: Well, yeah.

Mark Pimentel, MD: It’s splitting hairs.

Chris Kresser: Yeah. It may not be common, but I would like to think it’s normal for humans. It’s, perhaps, our default state if we don’t get in the way of that.

Mark Pimentel, MD: Right.

Chris Kresser: And certainly everyone listening to this show is looking for that super-healthy state, so I appreciate that distinction.

Testing for SIBO

Let’s talk about breath testing next because that’s something I really wanted to go into some detail on. As some listeners will know, there are different kinds of breath tests. There’s a lactulose breath test and a glucose breath test, and I want to talk to you about some of those distinctions. At this point, do you look at breath testing as being kind of the best compromise available, in the sense that other test methods are invasive and if you’re sampling a part of the small intestine, if SIBO is patchy, you may miss it because you’re getting a portion of the intestine that doesn’t have the overgrowth? Tell us just kind of in a general sense where you’re at in terms of looking at breath testing as a whole category.

Mark Pimentel, MD: Well, I think this is where is gets confusing for patients because, for example, Mayo Clinic doesn’t like breath testing, so they do a lot of aspirates. They tend to want to take the sample. Taking a sample is very expensive. The validity of that is questionable, too. I mean, we don’t really know what part of the bowel to culture for your best result.

Chris Kresser: Right.

Mark Pimentel, MD: You hit the nail on the head. It could be patchy. We don’t culture everything, so maybe we should be doing PCR or sophisticated genetic techniques to look at the bacteria. Mayo Clinic doesn’t do that for their aspirates. All they do is culture, so they’re missing stuff. So there’s no perfect technique, but I have to say that what we’ve seen in the papers and in our own experience is that breath testing is kind of a compromise. It’s extremely easy to do. Patients can do it even at home, in some circumstances, with some of the kits that are available, and it’s convenient.

But what I will say is that when the breath test has methane in it — and I suspect we’ll be talking about that a little bit later — that’s super accurate.

Chris Kresser: Yeah.

Mark Pimentel, MD: So in that context, when you have methane on the breath test, that’s extremely predictive. Hydrogen is a little bit more challenging.

Chris Kresser: OK. Let’s talk a little bit about methane detection now. I know this is an area where you’ve made big contributions, and up until fairly recently, a lot of commercial labs weren’t even offering methane as an option. Methane has some specific effects and characteristics compared to hydrogen, so maybe you could tell us a little bit about why it’s important to test for methane overgrowth and if you’re still using 3 parts per million at baseline as the cutoff there.

Mark Pimentel, MD: Yeah, so methane is intimately related to constipation. In fact, there’s now a large series of studies, various investigators around the world proclaiming the same results, and a meta-analysis. But essentially, if the methane is present on the breath test at greater than 3 parts per million at any part during the test, the association to constipation is over 90%. The other very interesting aspect of methane is that methane is proportional. So the higher the area under the curve on the breath test for methane, the greater the patient’s constipation severity is. And we know from animal studies that giving methane, just the gas itself, constipation or slows transit remarkably by about 60%, so getting rid of the methane is key. The breath test is very accurate at picking up methane, and I think, to be honest with you, there’s almost no argument about methane and breath tests in terms of the utility of breath tests in that particular circumstance.

Chris Kresser: And is it the same difference there between lactulose and glucose in terms of detecting methane? Is lactulose more likely to detect it for the same reasons?

Mark Pimentel, MD: The interesting thing about methane is that methane is not driven by the lactulose or the glucose; it’s driven by the presence of hydrogen, because hydrogen gas from fermentation of other bacteria fuels —

Chris Kresser: It’s the food for the methanogens, right?

Mark Pimentel, MD: Right, exactly. I would say more than 90% of the time, just at baseline, the methane is already elevated, whether you’ve given the glucose or the lactulose or not. So it really doesn’t matter which breath test you use because the methane will be there, and you don’t see, necessarily, a rise in methane all the time.

Chris Kresser: OK, I have a bonus question for you, and this is just selfish clinician-to-clinician from a test result that I saw the other day. It might be a little over everyone’s head, but we have a patient, and we treated them for SIBO. They had high hydrogen levels and methane levels. Then on the retest, their hydrogen was actually zero at nearly every time interval, but their methane was still a little bit elevated. How is that possible since the methanogens require hydrogen to produce the methane?

Mark Pimentel, MD: There are different methane profiles, and this gets a little complicated. There are methane profiles where methane is elevated throughout the test and hydrogen is zero all the way across the board. The only way that can happen is if the methanogen organisms are colocalized precisely where all the hydrogen organisms are. In other words, the methanogens are eating up every bit of hydrogen that you find on a breath test because they’re sitting beside each other throughout the gut.

Chris Kresser: Interesting.

Mark Pimentel, MD: When you see hydrogen on the breath test, it means that the methanogens are not all localized to where the hydrogen producers are, and we call that ‘hydrogen escape.’ It’s kind of a term we made up. Let’s say there’s 3 or 4 feet of bowel where there are hydrogen producers, but there are no methane producers in the area, so you’re getting this hydrogen release and you’re picking it up on the breath test. So maybe you’ve gotten rid of the hydrogen in that area and therefore you’re only left with areas with some methanogens colocalized with hydrogen.

Chris Kresser: Yeah, that makes sense.

Mark Pimentel, MD: That’s kind of hypothetical. It makes sense, but of course, you can’t dissect humans to prove that. You can only kind of theorize how it works, but that’s how we think it works.

Chris Kresser: It’s a reasonable theory, yeah.

OK, great. Before we move on to treatment, let’s talk a little bit about what’s on the horizon in terms of testing. I’ve read a few papers that talk about electronic nose or metabolomics. Is there any methodology that you’re aware of or excited about that might help us to have more accurate testing without being invasive or costing too much money?

Mark Pimentel, MD: Well, I think that there are a number of people looking at volatiles in the breath for detection of cancer, for detection of getting bacterial signatures. There’s a lot of excitement around that. The problem is I haven’t seen anything that is kind of an aha moment yet.

Chris Kresser: Right.

Mark Pimentel, MD: I think it’s a matter of time because so many people are working on this, so I’m very excited, but I’m waiting for the aha moment that somebody says, “OK, this is very predictive of X, Y, and Z, and this is how you treat it.” And I think those are the connections that will be made in the next few years.

Chris Kresser: Maybe we’ll have SIBO-sniffing dogs.

Mark Pimentel, MD: No doubt!

Chris Kresser: We have cancer-sniffing dogs, mold-sniffing dogs now. I wouldn’t be surprised!

Mark Pimentel, MD: With YouTube, it’s only a matter of weeks.

Chris Kresser: Right!

The Future of SIBO Treatment

All right, so let’s talk a little bit about treatment now, and specifically, along the same theme here, not the treatment that goes well and works perfectly as advertised, but some of the issues that we see with treatment. The first thing I want to talk about is some of the studies that have shown recurrent rates of up to 45% in people that have been successfully treated. They go breath test negative, and then almost half of those people are getting SIBO again. Do you accept that number, is that your experience, and what do you think is happening there?

Mark Pimentel, MD: The TARGET 3 Study, which is the latest rifaximin study, is the only study, really, that’s blinded and controlled for treatment and retreatment. And what I was shocked at when I saw the results of the trial is it almost mirrors what happened in my clinic back when I started using rifaximin. You can’t say that in my clinic now because I basically see the patients that fail, because everybody in the community is using it this way, and so I’m seeing the tougher cases. But back when I started using rifaximin, this was exactly the rate.

We see about 72% of people have some response to rifaximin, for example. Using the FDA endpoint, the patients who responded by FDA criteria, over 18 weeks 36% of them never relapsed, and they just dropped out of the study because they were done. They didn’t relapse. And then the 64% who did relapse then were randomized into the double-blind phase of the trial and responded again and again versus placebo, which was good.

But the point is that pretty much mirrors what I see. I see about 70% of patients with IBS or SIBO — however you want to frame it — but definitely with the breath test, more than 70% respond to rifaximin. What we then are looking at is relapses, and I think for sure I’m seeing about a third of patients that I don’t see them for months and months and months, and they never have a relapse, maybe more than a third. But then the rest of them, they will have relapses. And it depends. Some of them relapse in six months, some of them relapse in three months, and some of them relapse in a week, and those are the tougher cases.

Chris Kresser: So what do you think is driving the relapse? I know you’ve done a lot of work on intestinal motility and impaired motility and its contribution to SIBO and relapsing SIBO, so maybe you could talk a little bit about that and if there are any other factors that you are investigating right now in terms of the propensity for relapse.

Mark Pimentel, MD: Well, this speaks to kind of food poisoning triggering everything because this starts to get into that area, but we think food poisoning causes some kind of neuropathy or motility disturbance of the intestinal tract, and then you get stasis or slowing, and then the bacteria start to accumulate. I would say that probably 70% or 80% of patients who come to me with overgrowth, that’s the mechanism of action, or at least that’s what we feel is the mechanism, and that it’s a reduction in the migrating motor complexes as a result of some insult in the past.

Where it gets tricky is that depending upon how bad that is or how bad the motility is will probably predict how quickly the bacteria will return. The problem is we don’t have a good grading system for how bad the motility is, so I can’t tell a patient, “Look, you have this test; you’re going to relapse in two months.” We don’t have that kind of sophistication yet. I’d love to see that come.

When the patients relapse in one week or two weeks, then we start to be concerned that it isn’t just a motility disorder, that maybe it’s an adhesion or some other mechanical cause for the overgrowth to begin with and not just the motility disorder.

Chris Kresser: When you say ‘impaired motility,’ is that always clinically evident, like delayed transit time, or is it possible to have a defect in the migrating motor complex, but still have regular bowel movements?

Mark Pimentel, MD: The migrating motor complex is responsible for cleaning the gut — or the small intestine, specifically — when you’re not eating. The intestines have kind of like two computer programs. One is eating mode, one is cleaning mode, and usually it’s the cleaning mode that goes bad in terms of the bacterial overgrowth. If you were to ingest a meal, for example, and you measured stomach emptying, stomach emptying is perfect. But that’s not telling the whole story, so if we really want to know what the patient has, we do a manometry of the upper gut. We put a tube in that detects motor function, and we’re able to see how many migrating motor complexes, what happens when they eat, how are the mechanics of the gut working, and we can diagnose these things. But if you have no migrating motor complex in 6 hours, is that severe, or do I have to do it for 24 hours to know how severe it is? The patients don’t want to have a tube in their nose for 24 hours, so it’s really hard to grade these things.

Chris Kresser: Mm-hmm. What do you think of the idea that dysbiosis or changes in the microbiota in the colon could be a predisposing factor to SIBO and SIBO recurrence?

Mark Pimentel, MD: I can’t discount changes in colon in terms of a response to antibiotics, although I will say with rifaximin, specifically, I think this has probably convinced some of late critics who were saying, “Well, maybe it’s the colon, maybe it’s the colon,” the stool study that we did and microbiome work that has been described at meetings but will be fully presented at the ACG meeting in Hawaii, there really is no change in the flora of the colon in these patients with overgrowth or IBS after rifaximin. So rifaximin is not doing anything to colon bacteria, at least in stool. I can’t tell you the cecum or the higher parts of the colon. And no increases in yeast and other things in the case of rifaximin — in the stool, again, specifically looking at that area.

Chris Kresser: Right.

Mark Pimentel, MD: We think that all along, as we’ve been saying rifaximin dissolves in bile, will work mostly in the small bowel, not in the colon when the bile is gone, rifaximin crystallizes — I think we’re all on the same page with that now. But I can’t totally dismiss the possibility that it is a dysbiosis in the colon. We’re going to require more work there.

Chris Kresser: Right. OK.

Mark Pimentel, MD: One more point on that, though.

Chris Kresser: Sure.

Mark Pimentel, MD: I will say in our animal models where we give food poisoning, Campylobacter, to the rats and then we follow them over time, they develop overgrowth. But when we do PCR of the colon, we see absolutely no differences between the colon, the cecum, or any part of the colon in the rats who got Campy and the rats who never got anything and are normal. It’s all in the small bowel, the detrimental events.

Chris Kresser: Yeah, that’s really interesting and would definitely seem to support your argument there.

Mark Pimentel, MD: Yes.

Chris Kresser: Let’s talk a little bit about diet. Within the, let’s call it, allied health professional world, functional medicine, alternative medicine community, it’s common to prescribe a low-FODMAP and even low-starch or no-starch diet during treatment for SIBO, and the thinking there is that these are carbohydrates that are poorly absorbed and can become food for the bacteria that are overgrown in the small intestine. We ourselves at our clinic have been doing that for some time, but I have a couple of questions about that in my own mind, and I’m curious to get your take on it.



Number one is I saw a study recently — I’m sure you saw it — that showed that rifaximin plus partially hydrolyzed guar gum was more effective than rifaximin alone, and that’s essentially a prebiotic that would seemingly be expected to feed the bacteria in the small intestine, but yet this study showed that it significantly improved the treatment.

And then the second thing is that, as far as I know, there’s been no study yet that has examined the efficacy of a low-FODMAP or low-residue diet during treatment other than an abstract that was presented at Digestive Disease Week a couple of months ago, and I haven’t been able to track down the full paper, so I’m curious to hear your thoughts on that.

Mark Pimentel, MD: Well, I can say you’re extremely well read because, yes, these are issues, and these papers are very, very interesting and hard to put into the context of this. You’ve opened up a lot of things to talk about, and I’m just trying to figure out where to start, but let me start with the guar gum aspect. I have told my patients from day one of rifaximin or treating with antibiotics — and this goes back to the 1980s; this is an old microbiological concept — happy bacteria, happy and well-fed bacteria, are more sensitive to antibiotics and are easier to kill. What that means is that most antibiotics work on the replicating cell wall of bacteria. When bacteria are in hibernation, starving, distressed, they wall off, don’t replicate, and they just sit there, waiting for conditions to improve. That’s a survival mode. So when the bacteria are in survival mode, antibiotics won’t penetrate and won’t work as well.

Chris Kresser: Mm-hmm. I have heard you say that.

Mark Pimentel, MD: If you give guar gum or you augment their eating — so now you’re feeding them, they’re thrilled, they’re enjoying all that food — they’ll be more sensitive to rifaximin. So when I treat with rifaximin, or antibiotics, in general, for these IBS patients, I don’t want them to be on a low-FODMAP diet simultaneously or any kind of carbohydrate restrictions. I want those bacteria happy and fed because they’ll respond better, in my experience, and the guar gum study kind of supports that notion.

Now, speaking to low-FODMAP diets, for example, it’s kind of a joke I tell patients, and I don’t mean to be flippant, but it you don’t eat any food at all, the bacterial overgrowth will be better.

Chris Kresser: Right!

Mark Pimentel, MD: Looking at the entire spectrum of people publishing papers and/or books about diets for SIBO or for digestive health, the more restrictive you make the diet, the less the bacteria is going to be happy, or you’ll starve the bacteria out, but you want to do it within a rational and a reasonableness for the patient because we all want a relatively normal life, we all want to walk with our friends into a restaurant and at least be able to get something and not be so difficult, so that’s kind of how I start my conversation in the clinic. The low-FODMAP diet works. I mean, there’s no question. Studies show it works. I’ve experienced its benefit. It’s just difficult for patients to maintain in the long term.

Chris Kresser: Mm-hmm. I’ve also seen some studies — I’m curious to get your take on these — that the low-FODMAP diet over the long term may actually decrease bifidobacteria production in the colon, which would make sense, given that that’s the substrate that those bacteria use, and therefore, there may be some disadvantage to doing a really strict low-FODMAP diet. Maybe it’s helpful for SIBO or IBS recurrence, but maybe it’s not great for the colon. What do you think about that?

Mark Pimentel, MD: I agree. Sometimes I think the paleo folks have it right because when we think about how we evolved, we didn’t have potato chips and various refined carbohydrates back then that we have now. And eating whale blubber and seal meat and so forth, those were the staples, and a few berries off of the plains or whatever. It was a very different time, and the question is, is our digestive tract honed into that type of diet more than it is to what we’re currently doing? It’s so hard to know, but what I tell my patients is carbohydrates feed bacteria. You can leave the bottle of oil on the counter for cooking, and it will never become contaminated because bacteria cannot live on oil alone. You can leave your protein powder in the cupboard, and for the most part, it’s going to be fine. As soon as you put carbs in something, if you take a teaspoon of sugar and put it in that olive oil, that olive oil’s done in 24 to 48 hours.

Chris Kresser: Right.

Mark Pimentel, MD: It’s carbohydrate related. Now, I don’t tell my patients zero carbs. I tell them try to eat the carbs that humans easily absorb and digest, so white bread, of all things. It sounds like I’m telling them to eat Wonder Bread, but French, sourdough, and Italian bread are white breads, and they’re a little bit better than just Wonder Bread or the off-the-shelf, in-the-bag bread.

Chris Kresser: So you’re talking about higher glycemic carbs that would be absorbed further up in the digestive tract and less likely to feed bacteria.

Mark Pimentel, MD: Kind of like a glucose breath test versus a lactulose breath test. You want to feed them less, as less as you can, and patients tolerate that well. I call it kind of our low-fermentation diet as opposed to low-FODMAP.

Chris Kresser: Yeah.

Mark Pimentel, MD: But everything becomes individualized over time. Patients will come in and say, “Well, yeah, that diet works great except for onions,” and they’ll tell me, but at least they can go to any restaurant in the country and get a meal and not feel so socially isolated.

Chris Kresser: Right. It seems so tricky because I totally get how that diet is better for SIBO recurrence possibly and even symptomatically. I’ve seen that in our patient population. But I do get concerned about the longer term. You mentioned paleo, and it’s definitely true that our ancestors ate a lot of fermentable carbohydrate, like starchy plants and non-starchy vegetables and all kinds of stuff that would provide food for that beneficial bacteria in the colon, so my dilemma is, in fixing one problem, are we causing another one? That’s what I’m always worried about. It would be helpful if we had any studies at all to guide us in this area, but as far as I know — and correct me if I’m wrong — there haven’t been any studies specifically about a low-FODMAP or low-fermentation diet related to SIBO. I know there have been a ton with IBS, but nothing that actually characterizes, does a low-FODMAP diet reduce the recurrence of SIBO after it’s been successfully treated? for example. I’d love to see that question answered.

Mark Pimentel, MD: Yeah. It’s not been answered, but if you want to add another layer of complexity to this whole thing, just to touch on methane briefly for a second, the highest population of methane colonization in the world is Sub-Saharan Africa. And methanogens, it turns out, based on the microbiome work that’s being done on that particular organism, are super important to help liberate calories from nondigestibles. So let’s say you have a high-fiber diet. Humans generally can’t eat fiber. Cows and ruminating animals have a lot of methanogens because the methanogens help facilitate digestion of fiber. So what does that mean? That means that you can get more calories from a meal if you’re a methane producer because you’re liberating calories from things that people who don’t have methane can’t get.

So where am I going with this? What I’m saying is if you take a population from Africa and immigrate them into the United States, and those folks, for genetic reasons or environmental reasons, have methanogens flourishing in their gut, which is an evolutionary advantage for getting and harvesting nutrients, it’s not an advantage when food is abundant and food is so processed and easily digested that you get more calories, and we’ve seen signals between methane and obesity. The question then becomes, does one diet fit all? And the answer is, no, it’s not going to be that way, and maybe it does have to do with your microbial profile benefits from this diet, and your microbial profile benefits from that diet, and it’s not as simple as one suit fitting all.

Chris Kresser: Yeah, I completely agree with that. I’ve often said there’s no one-size-fits-all approach, and it’s really interesting to hear you say that about Sub-Saharan Africa because I know Jeff Leach and some other people who are down there studying the Hadza hunter-gatherers and looking at their gut microbiome because they’re one of the last cultures on Earth that is really still living a paleolithic lifestyle. They’re down there trying to sequence the microbiome. It’s the last kind of intact, normal human microbiome.

Mark Pimentel, MD: Right. At least for that area.

Chris Kresser: Right, and what they’ve found are some really interesting things, which is that some of the bacterial species that we associate with ill health in the West are actually quite prevalent there in healthy populations, and vice versa. Bifidobacteria, which is kind of universally considered to be a beneficial species in Western people, is virtually absent in those people. So I think that really just supports what you were saying, that a great microbiome imprint for someone living in Sub-Saharan Africa could be a total disaster for someone living in the industrialized world.

Mark Pimentel, MD: Which is probably why probiotics have been challenging to prove effectiveness in certain diseases, is because it isn’t all that simple.

Chris Kresser: Right.

Mark Pimentel, MD: I think probiotics are the way of the future, but it’s just trying to find the right key for the right lock. Science is on to this. This is a very exciting time in terms of the microbiome, and I have a great deal of optimism for the future in terms of characterizing it and then finding the key and locks for populations.

Chris Kresser: Yeah, exactly.

I want to step back to something you mentioned when we were talking about eating prebiotic fibers during rifaximin treatment to kind of make the bugs come out to play so that they will be killed. Different antimicrobials work in different ways, for the listeners’ benefit, and rifaximin appears to work when the antibiotics are multiplying or splitting. Is that correct?

Mark Pimentel, MD: That’s always the way antibiotics are best effective, is when the bacteria are happy. For example, some bacteria form cysts or they sporulate, and once they’re sporulated, it’s done. You can’t get an antibiotic to go into the cell or do anything. Those are the kinds of concepts I’m talking about, is that stress or starvation will force those events in bacteria.

Chris Kresser: Spore forming. Right.

Mark Pimentel, MD: Yeah.

Chris Kresser: Given that, I suppose the same would be true for some of the botanical antimicrobial protocols. I know there’s been at least one study, which you may have seen, that compared the efficacy of rifaximin with a botanical protocol and found that they were roughly equivalent. We use both in our clinic. We will tend to start with a botanical protocol, and if that’s not effective, we’ll go on to rifaximin, or rifaximin plus neomycin if it’s methane. But would you guess the same thing is true for the botanicals?

Mark Pimentel, MD: You’re referring to the study from Johns Hopkins?

Chris Kresser: Yeah, they had the four different botanical supplements.

Mark Pimentel, MD: Yeah, that’s the one. I think botanical supplements have some benefit, and I’ve seen some of the studies like that one which show some interesting results. I’ve done a couple of programs for the naturopathic college, and what I’ve learned from them is incredible because — you know, the funny thing is the naturopathic physicians are giving rifaximin, and when I first met them, it kind of befuddled me. It would seem counterintuitive, but the scientists in their group — because they have a scientific core — they say, “Well, natural antibiotics are still antibiotics. Bacteria still get resistant. That’s where we get our penicillins: from the plants.” So the plant effects and side effects are identical to the pharmaceutical effects and side effects, and that really spoke to me in a way.

So I think, yes, there are botanicals — garlic, for example — that can have effects or anti-methanogen effects, and they’ve been studied. I think the big challenge with the botanicals is not their lack of efficacy; it’s a lack of funding and ability to get good studies out in the public domain and prove their efficacy. I think the Johns Hopkins study is a great study, it helps to demonstrate that these things are possible, but we need more like that.

Chris Kresser: Yeah, I would agree.

Let’s talk a little bit about methane treatment. I believe it was one of your papers that showed rifaximin alone is only effective about 45% of the time — I could be getting numbers wrong — but when you add neomycin, it goes up to 80-something percent. Is that your current treatment of choice for methane, still the rifaximin-plus-neomycin combo?

Mark Pimentel, MD: Right. With methane, rifaximin alone or neomycin alone are relatively ineffective or modestly effective, and with then the combination of the two both in vitro, meaning in the lab, and in humans, we see a dramatic effect. That is the cocktail we’re using now. We sometimes substitute the neomycin for metronidazole, although that’s not published, so that’s mostly anecdote. The neomycin-rifaximin combination was a small double-blind study we published about a year and a bit ago.

The new kid on the block, although it’s not available yet, is we’re in phase II trials of a product that just inhibits methane production. It doesn’t kill the bacteria — or I should say ‘archaea’ in the case of methane. It doesn’t kill them. It gets in and shuts down the machinery that makes methane, because we think the methane it what’s causing the constipation. You don’t need to get rid of the bugs. Just stop them from producing methane.

Chris Kresser: Right.

Mark Pimentel, MD: In preliminary work, that’s highly effective. We should have some top-line results in the late fall, so you can look forward to hearing that. I don’t have results yet. The study is halfway through.

Chris Kresser: Right. Yeah, I definitely will.

Since you mentioned that, any other future avenues that you’re looking into or excited about? Prokinetics, we haven’t really touched on that yet, but what have you been looking at doing lately in terms of prokinetics for people with the impaired MMC, migrating motor complex, and who are highly likely to relapse?

Mark Pimentel, MD: There’s a variety of prokinetics on the market. I don’t like to use domperidone because of the side effects with the heart. Generally we resort to two potential prokinetics. One is erythromycin at a very low dose. It has prokinetic properties at a very low dose and no antibiotic properties at that does, so that’s what we use. Sometimes we get Resolor, which is prucalopride from Canada, a very potent prokinetic based on serotonin. It doesn’t have any real side effects except for headache in some patients. Those are the two.

The problem with prokinetics is we’re kind of hitting a wall. The circuitry of the gut is not connected well, and you’re kind of forcing it to do something that — and again, it depends on how severe that is in a patient, as to whether the prokinetic will work well enough, so we’re shifting gears almost entirely. We’ve spent the last six years kind of trying to figure out, well, why is this happening from food poisoning? And that led to the next blood test for IBS that was just launched about eight or nine weeks ago. Are you familiar with that?

Chris Kresser: Yes.

Mark Pimentel, MD: There are two antibodies that get created after an infection like you described in Indonesia, and these antibodies, when they go up, they’re the ones that are causing the damage of the nerves. We, in fact, did a study in animals where we just gave the CdtB toxin from food poisoning, not the food poisoning, and the rats get bacterial overgrowth, so we know the toxin that causes bacterial overgrowth and IBS, and we can measure the antibodies in the humans now to that toxin.

So what does that mean? First of all, it will tell us why you have the overgrowth, what the mechanisms are, and that it is likely this neuropathy. Two, the antibodies, the higher they are, the worse the patient is. Three, our entire focus now for the next two years is trying to get that out of the bloodstream and make the nerves come back to life, so really kind of essentially curing the disease. Will it mean a drug in two years? Drug development takes time. But can we prove that that will reverse the disease? I think in two years we’ll prove that that will reverse the disease, which means drugs will be developed around that concept. That’s the exciting part, and then you don’t have to worry about whether you’re disturbing the microflora. We’re basically treating it at the root.

Chris Kresser: Right.

I’m kind of skipping back here. There’s a question I wanted to ask you before we finish up. I saw a study recently that suggested that the length of treatment with rifaximin should be correlated with the severity of the breath test results. I believe in that study, they used a course of treatment as long as 12 weeks with no adverse effects. What do you think of that notion, and are you using longer courses of rifaximin in people who have very severely elevated breath test results?

Mark Pimentel, MD: I’ve seen various groups or research groups around the world trying different cocktails for their patients with overgrowth. I think that in my experience, and again, I haven’t studied longer-duration therapies, except I will say just in the phase II studies of rifaximin, there was a longer arm, and the longer arm did not work well. It was really short-term therapy.

I don’t have a problem with longer therapies. Again, this will be described at the ACG and was briefly described at DDW. Rifaximin does not cause microbial resistance of any magnitude. In fact, if there’s any resistance whatsoever, it disappears within a week or 10 days after stopping the rifaximin, and so rifaximin really doesn’t create any kind of superbugs or any kind of resistance, and this was epic amounts of culture, stuff that even Cipro and other antibiotics that are true antibiotics didn’t have to go through. Rifaximin did. And it’s not apocalyptic on the microbiome, rifaximin, compared to, like, Cipro.

Chris Kresser: Yeah.

Mark Pimentel, MD: But what I was saying is that I think using these longer therapies is fine, very experimental. I haven’t seen the need for it in my practice so far.

Chris Kresser: Right. I’m mostly a natural medicine guy myself, but I’ve always felt like my standard is whatever works and causes the least harm, and if that happens to be a drug, then I’m all for it, and rifaximin certainly does seem to fall into that category.

Mark Pimentel, MD: Yeah.

Chris Kresser: Well, is there anything else, before we finish up, that if you could tell folks — let’s say we have folks out there listening to this who have SIBO and it’s recurrent, any words of wisdom or advice or even just a way for them to frame it in their mind that is helpful for them to think about?

Mark Pimentel, MD: Anything specific you want me to?

Chris Kresser: Well, part of it for me is just educating patients about the things that we’ve already talked about, so I think that this will help a lot, that SIBO is not necessarily a one-time thing. I think it helps patients. It’s not easy to hear that, right? Most of us would like to be able to just treat it and move on. But once they do hear that and they accept that, I think it helps with the outcome because then they know that they have to stay a little more vigilant and it’s something that they may have to treat repeatedly, and if they understand the safety profile of rifaximin, that’s a little bit easier to accept as well.

Mark Pimentel, MD: Right.

Chris Kresser: So nothing in particular. I guess the question was more like, is there anything else you want to say? We’ll put it that way.

Mark Pimentel, MD: Well, I think I know exactly what you’re getting at. Let me give you an example of something that happened in one of the clinical trials which kind of speaks exactly to your point.

As a patient in phase II studies of rifaximin, you take rifaximin, if you got better, you move on and get followed through the whole trial. If you didn’t get better, you’re out. One of my patients went into phase II. She got rifaximin, it turns out, after the unblinding, and she came to my clinic, and I said, “Well, it looks like you didn’t do well in the trial.” At the time, we thought she got placebo. It turns out she got rifaximin. She says, “No, no, I’m doing great!” I said, “Well, what do you mean? If you did great, you’re supposed to stay in the trial. How much percent improved are you?” She says, “Well, I’m 80% better.” I said, “Well, that’s terrific,” and I said, “Why aren’t you in the trial?” She said, “Well, they asked me if I’m all better,” and she interpreted it as, “If it’s an antibiotic, I should be cured. I should be 100%.”

Chris Kresser: Right.

Mark Pimentel, MD: And 80% wasn’t like her urine infection in the past. That’s a point for your listeners to kind of appreciate, that rifaximin is going to make you better when it works, it’s going to make you a lot better than anything we’ve had before, but it’s not like a urine infection where you’re cured, because the motility disorder underlying this is still there and you’re still going to have a little bit of gas and you’re still going to have poor clearance of the bowel, and it’s a bit of a lifestyle change until we have something that gets at the root.

Chris Kresser: Yeah, that’s really helpful.

Well, Dr. Pimentel, this was certainly educational for me, and I think my audience is really going to appreciate it as well, so thanks so much for joining me.

Mark Pimentel, MD: Thank you for your time. This was a lot of fun for me as well.

Chris Kresser: That’s the end of this episode of Revolution Health Radio. If you appreciate the show and want to help me create a healthier and happier world, please head over to iTunes and leave us a review. They really do make a difference.

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Thanks so much for listening. Talk to you next time.

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