Dr. Mark Pimentel Presents New Perspectives on SIBO and IBS

Dr. Mark Pimentel. We all know him as the clinician/scientist who understands the varied pathogenic underpinnings of IBS/SIBO/IMO. In my recent conversation with him, we cover the definition of terms, causes, when to use a stool test. We discuss the Pimentel low fermentation diet, intervention (including botanicals), and diagnosing hydrogen sulfide (a test is coming soon, but wasn’t available at time of recording). Probiotics: any utility? Elemental diet, and so much more. Grateful to have Dr. Pimentel on the podcast, and know you will benefit from this insightful convo. Thanks for listening, please leave a review if you can! ~DrKF

Dr. Mark Pimentel Presents New Perspectives on SIBO and IBS

Functional GI conditions like IBS and SIBO are increasingly common in the United States and across the world. Dr. Mark Pimentel is the world leader in developing both testing and treatment options for SIBO and IBS. Dr. Pimentel is the Professor of Medicine at Geffen School of Medicine and an associate professor at Cedars-Sinai Medical Center in Los Angeles, California, the developer of the first blood test for IBS on the basis of IBS being derived from acute gastroenteritis, and the person who discovered rifaximin as treatment for IBS. In this episode of New Frontiers, he talks with Dr. Fitzgerald about the latest developments in testing and treating IBS, SIBO, and other functional GI conditions

In this episode of New Frontiers in Functional Medicine, you’ll learn about:

Mark Pimentel, M.D., is Professor of Medicine, Geffen School of Medicine and Associate Professor at Cedars‐Sinai Medical Center in Los Angeles, California. Dr. Pimentel completed 3 years of an undergraduate degree in honors microbiology and biochemistry at the University of Manitoba, Canada. This was followed by his medical degree, and his BSc (Med) from the University of Manitoba Health Sciences Center in Winnipeg, Manitoba, Canada, where he also completed a residency in internal medicine. His medical training includes a fellowship in gastroenterology at the UCLA Affiliated Training Program. Active in research, Dr. Pimentel has served as a principal investigator or co‐investigator for numerous basic‐science, translational and clinical studies in such areas as IBS, and the relationship between gut flora composition and human disease. His work has been published in the New England Journal of Medicine, Annals of Internal Medicine, American Journal of Physiology, American Journal of Medicine, American Journal of Gastroenterology and Digestive Diseases and Sciences, among others. Dr. Pimentel has been invited to present his work at meetings, grand rounds, and advisory boards in the United States and Internationally. He is diplomate of the American Board of Internal Medicine (Gastroenterology) and a fellow of the Royal College of Physicians and Surgeons of Canada. Dr. Pimentel is also a member of several medical associations including the American Gastroenterological Association, the American College of Gastroenterology, and the American Neurogastroenterology and Motility Society.

A few of Dr. Pimentel’s most significant accomplishments include:

1. The discovery of rifaximin as a treatment for irritable bowel syndrome (IBS)
2. He developed the first blood test for IBS on the basis of IBS being derived from acute gastroenteritis
3. Described the association between IBS and bacterial overgrowth which forms the basis for microbiome therapies in this condition
4. Uncovered the methanogen (M. smithii) as an agent for causing constipation in humans.
5. Discovered the use of lovastatin as a microbiome treatment for constipation on the basis of inhibiting methane production by methanogens

ACG Clinical Guideline: Small Intestinal Bacterial Overgrowth

Pimentel Lab: Cedars Sinai

DrKF FxMed Resources

DrKF FxMed Clinic: Patient consults with DrKF physicians

Clinician Professional Development: DrKF FxMed Clinic Immersion

DrKF FxMed Nutritional Residency Program

Dr. Kara Fitzgerald: Hi everybody. Welcome to New Frontiers in Functional Medicine. I am your host, Dr.  Kara Fitzgerald and we are interviewing the best minds in functional medicine, and today is no exception. I am thrilled to be talking to Dr. Mark Pimentel. I know he doesn’t need any introduction in our world, but let me give you some of his background because it’s really impressive and he continues to do cutting edge work.

He’s Professor of Medicine at Geffen School of Medicine and an associate professor at Cedars-Sinai Medical Center in LA, California. His background is in microbiology and biochemistry at the University of Manitoba, and then he received his medical degree also from the University of Manitoba. He came to UCLA and completed a fellow in gastroenterology. He’s continually active in research and he’s the principal investigator or co-PI for a lot of studies from basic science and translational to clinical studies in areas such as IBS, and really looking a SIBO and defining SIBO, looking at the gut flora, et cetera.

He’s been published in all of the top tier journals from New England Journal of Medicine and on to Gastroenterology and Digestive Diseases and Sciences. A little bit of the accomplishments of Dr. Pimentel include the fact that he discovered rifaximin as treatment for IBS. He was one who put that on the map for all of us, just a really remarkable finding.

He developed the first blood test for IBS on the basis of IBS being derived from acute gastroenteritis. He described the association between IBS and bacterial overgrowth, which forms the basis for microbiome therapies in this condition. He uncovered the methanogen, Methanobrevibacter smithii, as the agent for causing constipation in humans. He’s currently, well, he discovered the use of lovastatin in treating constipation created by the methanogens and he’s also actually involved in researching that now. They’re still recruiting for that study. Dr. Pimentel, welcome to New Frontiers.

Dr. Mark Pimentel: Thank you so much for that introduction.

Dr. Kara Fitzgerald: It’s just great to have you here. I want to just start by defining SIBO and IBS.

Dr. Mark Pimentel: Well, I look at SIBO and IBS differently, although they’re the same. The way I describe it to people now is it’s sort of like peptic ulcer disease. You had peptic ulcer disease back in the 80s, where you’d find an ulcer in the stomach. The patient’s having pain, and you scope and there’s an ulcer. Then it was later discovered that about 60% or 70% of ulcers in the stomach were due to H. pylori which was a bacteria. We didn’t change the name from peptic ulcer disease to H. pylori disease. It’s still peptic ulcer disease, except what we can say now is that H. pylori is the cause of 60% to 70% of ulcers.

Now, IBS, same thing. Irritable bowel syndrome is a group of patients who have these unexplained symptoms of abdominal pain, alternating bowel patterns, sometimes more diarrhea, sometimes more constipation. Nobody knew what was going on, and now with SIBO we think we can explain 60% to 70% of IBS with SIBO. The other reason why IBS, the name, should stay is because, first, similar to H. pylori and peptic ulcer disease, there’s a lot of people who don’t have IBS who also have SIBO, because they have adhesions or because they have stasis of the bowel or other reasons.

It’s kind of important to keep the nomenclature but understand that SIBO is a cause of things but may not be the primary diagnosis.

Dr. Kara Fitzgerald: What are the various SIBOs?

Dr. Mark Pimentel: We’re starting to subdivide SIBO into various types. First of all, small intestinal bacterial overgrowth by its definition is that the small intestine which ordinarily shouldn’t have very many bacteria now has too many bacteria mostly from the colon in the small bowel. That’s the traditional and still the definition of SIBO. That’s where you get your positive hydrogen breath test.

The second SIBO is no longer SIBO. It’s now called IMO, intestinal methanogen overgrowth. When methanogens, which are not bacteria, are elevated in the intestines, and they’re elevated not just in the small bowel but also the colon in those patients, so we can’t really call it small intestinal, and really we can’t call it bacteria because it’s archaea, it’s not bacteria, because methanogens are archaea. We had to change the term, otherwise it wasn’t really proper. It’s intestinal methanogen overgrowth.

The third type of “overgrowth” which we don’t have a really defining term for yet is hydrogen sulfide excess. Hydrogen sulfide are bacteria, and they are excessively present in some patients, and that leads to diarrhea. We don’t have a breath test available for that yet, and we don’t have an exact understanding of where these organisms are proliferating, small bowel, colon, or both.

Dr. Kara Fitzgerald: Is it a rule out diagnosis at this point? How do you actually tease through the various imbalances to conclude somebody has hydrogen sulfide overgrowth?

Dr. Mark Pimentel: Hydrogen sulfide overgrowth is a little tricky. We used to think, “We think this is hydrogen sulfide because the breath test is flat, or a flat line.” A flat line means you have one, one, one, one for hydrogen all the way across. Nobody has zero hydrogen in their gut, so that doesn’t make sense. Something must be consuming the hydrogen. If there’s no methane, it’s not the methanogens. The other alternative is the sulfate reducing bacteria, which produce hydrogen sulfide. Those would be the ones that are likely present to account for the flat line.

Dr. Kara Fitzgerald: A flat line coupled with symptoms.

Dr. Mark Pimentel: Yes. Correct.

Dr. Kara Fitzgerald: Hydrogen sulfide.

Dr. Mark Pimentel: Correct.

Dr. Kara Fitzgerald: I just want to circle back to just to SIBO itself, the excess production of hydrogen. The main players involved are. Go ahead.

Dr. Mark Pimentel: I didn’t understand the question.

Dr. Kara Fitzgerald: The main bacteria implicated in being present in primary SIBO.

Dr. Mark Pimentel: Primary SIBO. Recent studies that we’ve been presenting at major meetings are we’ve actually through the REIMAGINE study been able to start to dissect what are the bacteria that are part of the small bowel. In SIBO, the characters that are excessive are E. coli, Klebsiella, and Aeromonas. We published a small paper, or smaller paper a number of years ago mentioning those as apparently higher in SIBO. Now with the REIMAGINE study we have more patients and we have more clearly defined that those are the characters.

The way I used to call it, and I think I can say it again, because I think that’s really the truth is that when you don’t have good flow of the small bowel, it’s like you’re not mowing your lawn. The grass looks great when you’re mowing your lawn, but as soon as you stop mowing your lawn the weeds out-populate the grass, and suddenly you didn’t realize how many weeds you had in the garden, or on the grass because they’re growing higher than the grass.

I think that’s the case here is that these bugs, the E. coli, Klebsiella and Aeromonas are opportunistic. If there’s poor flow, they latch on and they just proliferate.

Dr. Kara Fitzgerald: I’ve got a few questions on that. What are the top causes in your experience of this particular pattern of overgrowth?

Dr. Mark Pimentel: Without a doubt, the number one association with SIBO is going to be irritable bowel syndrome, purely by the fact that IBS accounts for about 12% to 14% of the entire US population or world population. It’s 40 to 60 million Americans suffer from irritable bowel syndrome. Again, as I mentioned, that’s probably the bulk. We know that IBS is associated with various muscular or neurological and muscular abnormalities of the small intestine, which I think we’re going to get to later with the antibody testing.

We know that there’s a neuropathy of the gut in IBS. That’s what’s causing the slowing or the poor flow of the gut. Of course, there’s many others. Scleroderma patients, which is a rare condition, but it’s an autoimmune disease, they tend to have very bad overgrowth. Then narcotic users, they’ll slow their gut down enough to get this. Those are really some of the common ones, adhesions is another one.

Dr. Kara Fitzgerald: What about acid blocking therapy?

Dr. Mark Pimentel: The irony of that is we presented that at the meeting last year. The REIMAGINE study, when we looked at the small intestinal microbiome, the presence of SIBO and any changes in the microbiome, in the small bowel and even the stool we tested, there were some subtle changes, but it wasn’t overgrowth. There was just some redistribution of bacteria.

The way I can explain that is that if you were to wipe your counter once a day with Mister Clean, or with your favorite counter cleaner, or Windex, the counter would be clean. You don’t have to wipe it all day. It’s the same thing with acid. These acid blocking medications are blocking acid for about 90% of the day. 10% of the day acid is being produced, and when it’s produced it’s enough to kill most of the bugs that are susceptible. That’s how I explain it.

There’s another explanation and that is that lack of acid makes the cleaning waves of the gut occur more frequently. It’s well-known that as the acid production in the stomach diminishes after the completion of a meal, because you need a lot more acid when you’re eating, as that diminishes, the cleaning waves return and the two are run together.

People on PPIs have more cleaning waves sooner after a meal, which is kind of interesting because we think cleaning waves are the cause, not having enough cleaning waves are the cause of SIBO.

Dr. Kara Fitzgerald: That’s so fascinating. Then you would consider this maybe as an intervention, I’m sure.

Dr. Mark Pimentel: We could take it one step further. One step further is that the methanogens, and this was the paper we published on PPIs a number of years ago, if you’re on a PPI you have less methane, because the PPI prevents hydrogen from getting into the gut. Acid hydrogen is also a source for methanogens to produce methane. If you’re on a PPI, you produce less methane. What’s the twist on this? The twist on this is that a lot of practitioners use betaine HCL or apple cider vinegar, a mechanism of treating SIBO. If you have methane SIBO, you’re basically putting gas on the fire. You have to know what kind of SIBO you have before using these acid containing products.

Dr. Kara Fitzgerald: Or antacid, or turning acid off. That’s really quite interesting. In the REIMAGINE study, you did a deep dive into the mucus layer and revolutionized the diagnosis or what you were actually seeing in terms of quantity of organisms. Can you talk a little bit about that study?

Dr. Mark Pimentel: We’ve learned a tremendous amount just in the last two years. The study’s been going on for about two and a half years. The first year was just nobody was taking juice from the small bowel correctly. People weren’t using a protected catheter. They weren’t doing it sterilely. They weren’t even amplifying all the bugs that were there, because as a paper we just published just before, just in December, the mucus is so thick you can’t get the bugs out to amplify their DNA.

You have to first of all thin the mucus. Once you do all these steps, there’s so much more bacteria there than we imagined. The point I’m trying to get at is we’ve had to validate all the techniques. Now that they’re validated, we’re seeing a lot more than we used to. What we see is that the small bowel microbiome, just as a first observation, is nothing like the colon microbiome.

If you do stool studies, and I’m not knocking stool studies, I just want you to understand what you’re getting. When doing stool studies, you’re measuring the bugs in stool. You are not measuring the bugs in the small bowel. The stool is not a reference to the small bowel whatsoever, because it’s literally another planet. Let me give you an example. Bacteroidetes is present in very high numbers in that category in stool. It’s almost nonexistent in small bowel.

In the small bowel, it’s Firmicutes and Proteobacteria. When you’ve lost an entire category, anyways, the shift and the difference is night and day. You can’t use stool as a surrogate for small bowel, period. That we showed and that’s coming out in a paper. We already presented it so it’s public information. The second is that these organisms, these E. Coli, Klebsiella and Aeromonas, they really are driving things. It’s almost like flipping a switch. Once they start to grow in high numbers, they almost tip the bacteria over like a seesaw into another state which is hard to get out of.

They are self-motivating, if you will, and when they’ve taken over the environment, it’s hard to flip back. That’s something we’ve also noted, and many other things. I don’t want to take too long to answer your question.

Dr. Kara Fitzgerald: It’s actually really interesting. The fact that they can survive in this thick mucus layer explains these chronic SIBO patients, I’m imagining.

Dr. Mark Pimentel: Think about yourself. If it was you, and would you want to live in a trashcan or live in a four or five star restaurant with fresh food, where would you want to live? The small bowel’s fresh food coming in. By the time it gets to the colon it’s just a trash bin. These bacteria don’t want to let go. They want to be there. Once they’ve established themselves, they really realize it’s much better up here.

Dr. Kara Fitzgerald: This understanding, then the REIMAGINE study you’ve been doing over time, how has that shifted your thinking with regard to interventions?

Dr. Mark Pimentel: Well, it’s shifted my thinking in terms of the complexity of what’s going on up there and the breath. One of the things that we’ve done some calculations on is people talk about the Gut Microbiome Project, which was a publication in Nature about 12 years ago. It was like this big victory lap that we’ve now determined the gut microbiome. In 2020, I’m saying, “No you haven’t, because the small bowel, you didn’t look at the small bowel and it’s completely different.”

The second part of it is if you look at the colon, which is only three feet long, and, granted, there’s chunk of stool in there, so that looks impressive, but the small bowel is 15 feet long and has the surface area of a tennis court. If you were to smear a thin layer of peanut butter on a tennis court, that’s a hell of a lot of peanut butter.

The question is, is there a larger microbiome in the small bowel than even the colon, and who’s really the big impact or player, not to mention the small bowel’s where everything is absorbed. Whatever bugs are in the small bowel are affecting you more than what’s in stool in the center of a piece of stool. I think we have to bend our focus again towards the small bowel.

Dr. Kara Fitzgerald: That’s fascinating. All of these points you’re making are just prompting more questions in me. What kind of tools do we have as clinicians to evaluate this beyond the breath test? You say stool is of no utility. If you see the presence of Klebsiella which is relatively common, or certainly E. coli’s a big player in the stool, or Aeromonas. Regardless of how elevated they are, there’s no inference you can make. There’s no surrogate.

Dr. Mark Pimentel: Well, I guess, let me restate so it’s clear. If you find abnormal things in stool that aren’t supposed to be in stool, you can make inference that that may be abnormal. What people are tending to do and what I’m trying to clarify is that you can’t look at what’s in the stool and say, “Aha, that’s what’s in the small bowel.” That’s what I’m trying to say is that don’t use stool as a surrogate for what’s happening in the small intestine and say they have SIBO or that they have some kind of small bowel condition.

We’re the first to even look at small bowel and stool in the same patients with a detailed analysis like this. If we haven’t said anything about it, it doesn’t quite exist. I don’t mean that in an arrogant way. It’s just that not a lot of people are studying the small bowel. My point is, don’t use stool to imply the small bowel. Use stool to imply stool.

Dr. Kara Fitzgerald: Good. I got it.

Dr. Mark Pimentel: You got a lot of Klebsiella in the stool and it’s not supposed to be there. That’s not normal, but it doesn’t mean you have Klebsiella in your small bowel. We can’t make those connections yet.

Dr. Kara Fitzgerald: Perfect. Listen, I have to ask you one more in this arena even though you’re being very clear. What about archaea and a really high M. smithii? Any inference then or no?

Dr. Mark Pimentel: That’s different, because M. smithii which is why we changed the name to intestinal methanogen overgrowth is because M. smithii lives in the colon and in the small bowel in cases. While you can’t infer that if it’s high in the stool, it’s high in the small bowel, what you can infer that it’s high in the stool, it’s probably causing the methane on the breath test. Remember, the breath test …

Dr. Kara Fitzgerald: Got it.

Dr. Mark Pimentel: … from methane doesn’t need lactulose, doesn’t need glucose to prime. You’re either methane positive or you’re not. You’re producing it all the time. M. smithii in the stool is probably okay, and we’ve published one paper on that showing that the levels of M. smithii by PCR in the stool correlate with symptoms. I think there’s data to substantiate that comment.

Dr. Kara Fitzgerald: Good. Well, thanks for that important distinction. The breath test is currently our best tool. Would you agree?

Dr. Mark Pimentel: It’s the easiest tool. One of the things, and this is something that I’ve been writing a paper, another paper just recently. Every time I look back at the literature on this, breath testing was never validated. We had to basically take the breath test, turn it on its head upside down, shake the coins out of the pocket to try and figure out … The breath test just gradually emerged without a true validation.

We finally in last year’s DDW presented the validation of the breath test against sequencing of the bowel, against culture as well. The breath test is related to SIBO. In other words, if by 90 minutes the hydrogen is more than 20, which is what we’ve been arguing is the cutoff, that is the best cutoff for SIBO. Actually, it works. It’s ironic. What we were doing was correct, but there was no data to prove that it was correct until last year. That’s good to know. It’s reassuring that we haven’t been completely foolish all these years.

It’s an indirect test, so it’s not perfect. It’s the best thing we have and it’s easy, it’s cheap. It’s easy for patients. What I don’t want to see happen is that people start putting tubes into the upper gut and sucking juice on hundreds of thousands of patients a year to see if they have SIBO. I don’t think patients would want that and it’s just too invasive.

Dr. Kara Fitzgerald: Absolutely. Incidentally, folks, we will link to as many of these papers as possible. The most recent February publication, or, excuse me, January of this year, the ACG clinical guideline on SIBO, we’ll link to that. Actually it lays it out pretty clearly, the evidence for using the breath test, the utility of it. What about the smart test? When are we going to be using the IBS-smart test? Just talk about that a little bit, and the benefit of that in clinical practice.

Dr. Mark Pimentel: I think the IBS-smart test has changed my practice. Now, I’m biased. I helped develop it, but obviously what we’re trying to do is find things that help our practice. That’s what we’ve been doing the whole last 23 years. Patients come in. They have either IBS or SIBO and we’re talking about the diarrhea side now. They can’t understand why.

They don’t know why. They’re not confident that they even have IBS. They say, “Doctor, I’m not responding to everything. Are you sure you’re right?” Those are the kinds of comments we get over many years. The point is that we now know more about the cause of IBS diarrhea than we do even Crohn’s disease or ulcerative colitis, because food poisoning starts IBS.

About 12 years ago, maybe even longer, we were on a mission to say, “How does food poisoning cause IBS? Could it cause SIBO in IBS? Could it be the cause of the SIBO of IBS?” The answer is we proved all of that. Using Campylobacter in infecting animal studies, and we showed that it caused SIBO. It caused IBS in animals. It allowed us, those animal models allowed us to dissect the path. It turns out that the toxin CdtB, which is the toxin from most food poisonings of bacterial origin, causes an autoimmune reaction in a subset of humans, and that autoimmunity is to a protein that’s important for gut nerve integrity, among other things.

When that protein’s elevated or when that antibody is elevated in the blood, we can use it as a diagnostic test for IBS. Why is it important? There’s a number of reasons why it’s important. First of all, a blood test that can tell you have IBS and it’s from food poisoning means you get a diagnosis of IBS, and we understand exactly what’s going on in you in two or three days, instead of the six years that was previously published. That’s how long it took for a patient to feel comfortable that this was their diagnosis.

Second of all, we can move to treatment faster, because once we make the diagnosis, we don’t have to mess around with colonoscopies in 25-year-old people and get to treatment. More importantly for the patient, this is not in your head. When the blood test is positive, it’s a real disease. Number two, food poisoning caused it and you better not get food poisoning again because if you do, you’re going to get a worsening of the antibody and a more difficult disease to treat.

Three, when the anti-vinculin is up it usually means there’s a motility problem. In our practice, what we do is we are more likely to reach to prokinetics to treat it. I’ll give you one example of a case which is super-interesting, and I’ve been talking about this particular patient. This is a person who got food poisoning about two years ago, and developed anti-CdtB antibodies just to the toxin, not to the autoimmunity. He was a little hard to treat, but we were successful. We were treating him for about two years and then he came in in December, and he says, “I’m doing great.”

I said, “What do you mean?” He says, “Well, I’ve stopped all my medications about six months ago. It seems like everything drifted off and I’m fine now. I’m back to normal.” We measured the anti-CdtB again and it’s gone. We know that if you develop the anti-CdtB only that you’re more likely to just simply resolve as the antibodies drift away, as all antibodies do, sort of like vaccines. You have to get vaccines every five or ten years because the antibody will drift away if you don’t get food poisoning again.

It’s completely changed how we manage our patients using this test. We use it in all of our diarrhea patients. People say, “Well, the patient had food poisoning. I ordered the test.” I’m like, “Well, that’s great. That’s good to do it there, but you should be using it in the ones that you don’t know or they don’t remember food poisoning, because they just don’t remember.” That way you can identify them and take them out of the mix. We’re doing it routinely in diarrhea cases.

Dr. Kara Fitzgerald: That is interesting. It’s nice to hear that he was able to move through it over time. What about “SIFO” or small intestinal fungal overgrowth, what is your thinking on that?

Dr. Mark Pimentel: The challenge with SIFO, so I do believe SIFO accounts for a certain percentage of these patients. If somebody responds, let’s say, to rifaximin, then it’s very unlikely they have SIFO because taking an antibiotic, well, at least by convention, means that more opportunity for yeast, and they should actually be worse because of the antibiotic. I don’t see a lot of patients getting worse with rifaximin, but if they do get better with rifaximin that usually is a rule out for SIFO for me. There are patients who don’t respond.

The problem with SIFO is how do you test for it? Now, Dr. Satish Rao is not an advocate, but he’s a scientist studying SIFO, and he sees it in a small percentage of patients, but it’s through culture. He basically gets the juice from the small bowel and then proceeds to culture it to demonstrate that it’s there. Then when it is there and he treats it, the patients do better.

Dr. Kara Fitzgerald: What would be the history of somebody vulnerable to SIFO? Use of steroids, like chronic steroid exposure. What do we think about as risk factors for it?

Dr. Mark Pimentel: Well, because we don’t have large, like, for example, Dr.  Rao is doing research in this, but we’re not systematically doing it across the country. To look for risk factors, let’s say in this case PPI maybe, or in this case steroids for asthma, maybe you’re swallowing steroids, or just that you took a recent antibiotic or something for a dental procedure. Those are the kinds of things we would look for if we had a large population to do a multivariate analysis, but we don’t have enough data yet to say those are true. What I just said, we don’t have proof. It’s something to think about.

Dr. Kara Fitzgerald: Let me ask you this, knowing that I know you won’t be able to speak specifically to it, but any kind of distinguishing clinical features? I guess they haven’t responded to rifaximin but how would a SIFO … Anything you can say about how they might present?

Dr. Mark Pimentel: What I see from the literature and what I experience in my patients is that they may have more upper gut symptoms is what I see. They still have the bloating and the distension, but a little more sensitivity to foods and a little bit more higher in the abdomen type symptoms. That’s my experience. Generally I have a few patients with SIFO, and they respond to fluconazole or an antifungal medication.

Dr. Kara Fitzgerald: Good. I do a lot of organic acids in my patients. I actually was in a clinical lab that looked at organics, organic acids and amino acids, and so forth, at the beginning of my career. D-lactate was an interesting marker. You could see it extremely high, if somebody after a course of antibiotics or with some … Back then, we weren’t doing breath tests, but we would diagnose or think about dysbiosis in a more general sense. Not everybody had short bowel, so it wasn’t the classic cause of D-lactic acidosis. What’s your thinking about the utility of it, if anything?

Dr. Mark Pimentel: I guess the challenge with D-lactic acidosis and this is the number one challenge is handling of the blood sample. It requires a special tube, a special thing on ice. It’s a process to do it right. It’s easy to get a false negative from a D-lactic acidosis in a hospital or in a clinical setting. If you’re in a private practice somewhere, and you’re measuring D-lactate, it’s tough. Urine organic acids, maybe it’s easier. It tends to be unstable, D-lactate.

Let me just say this, some of these patients do have elevated D-lactate. Again, Satish Rao has done some of the papers on this. I can’t take credit. He’s really been championing this. In some of his patients he finds it, and they have a lot of brain fog if they have D-lactic acidosis. He’s seen them get better with therapy, for whatever overgrowth that they had that was causing that production of D-lactate.

Organic acids is interesting, because it may be a way of … It’s pie in the sky still, so I don’t want to get everybody too excited. Maybe five to ten years from now we do a different kind of breath test. Maybe we do a breath test with hydrogen/methane, hydrogen/sulfide, and we add some organic acids in there which can give you a signature of what’s going on in the small bowel. I think those are things that are coming, but it’s really hard to dissect that out yet. We don’t have a good technology that’s inexpensive and easy.

Dr. Kara Fitzgerald: That is pretty provocative. That would be very exciting, and really be able to do a little bit of a drill down to stratify who’s making what. Certainly indican is something in my world as a naturopathic physician that was our forefathers in this profession measured it in-office. There’s some nice research coming out around it.

Dr. Mark Pimentel: Indicans is still a published and validated as a technique for overgrowth.

Dr. Kara Fitzgerald: There was some sort of a little in-office test that docs were doing years ago. That’s all I know. I don’t know anything about it, but I think just a little color metric change. Let’s talk about diet. What is your thinking with regard to pulling people off of FODMAPs or keeping them on, and long-term eliminations? Just in general, what is your thinking around using some of the dietary interventions for these various?

Dr. Mark Pimentel: The extreme thing that I say is if you eat nothing, your bacteria will go away. Because they’re no longer getting the five star meal or any meal. They will die because the lack of nutrition, meaning less food, less bacteria. That’s just how it works. Taking advantage of that extreme way of looking at things, if you can restrict calories to the bacteria by providing calories that are very easy for humans to just grab and put into their bloodstream leaving very little for bacteria to harness or use, you will reduce bacteria.

This is the mechanism of the low FODMAP and the diet we use which we call the low fermentation diet. The problem with doing that is you can take one extreme which is the low FODMAP diet where you overly restrict. There’s no denying that the low FODMAP diet will make you less bloated. The question is what’s the end game? This is not a lifelong diet. You can only be on it for two or three months because there are nutritional deficiencies that occur, and those are now well characterized studies that show that. You have to get back on some balance of nutrition.

We came up with the low fermentation diet, which doesn’t have those challenges, is more liberal with food, not as restrictive, and as a result maybe not as effective or maybe not as remarkably effective. We don’t use diet to treat the condition. We use rifaximin and prokinetics. Diet is a means of extending the remission. Some people will just give people low FODMAP diet from the get go. We do the opposite. We treat the overgrowth first, get them to a good place, and use the diet as a way of keeping them in remission longer. I think that’s a more effective way to use diet.

Dr. Kara Fitzgerald: How do you transition them off of diet?

Dr. Mark Pimentel: Anybody who has, for example, the anti-vinculin antibodies on IBS-smart, they need to be on this diet until those antibodies disappear, because it’s likely as soon as they stop these measures they are going to be relapsing. That’s our experience. We have to find a diet that they can do in a more long term that isn’t so socially isolating. Because the low FODMAP diet with its extremes make it almost impossible to eat at restaurants or to go out with friends and live your life.

Whereas the low fermentation, our whole, and I’m not comparing, saying we’re better or they’re better, but the whole mantra of the low fermentation diet is you can eat at any restaurant and you can find something with the low fermentation diet. You don’t have to spend an hour with the waiter in front of your friends trying to figure out what has what. We want to make people live as normally as possible, and that’s our goal.

Dr. Kara Fitzgerald: Have you published on that? Is it accessible for folks to use, to find?

Dr. Mark Pimentel: People ask me that a lot, and I don’t know why we haven’t. Actually, I do know why we haven’t, because we’ve been focusing more on pharmacological therapies and keeping extremely busy on that side, and diet studies were just not on our radar. I think considering the circumstances we talked about in our research meeting lately that we really need to publish on our diet, so that it’s more transparent, and also more objectively proven.

Dr. Kara Fitzgerald: Good. That would be great. Can you rough out, give me a rough outline of what it might look like?

Dr. Mark Pimentel: Basically, the way we do it is we want people to eat things that are more readily digestible. In the vegetable category, you’re allowed to eat the roots and the fruits but not the plants. You can eat the eggplants, the zucchinis, the squash, et cetera, the root vegetables, which are beets, carrots, so forth, potatoes, but not the plants. We don’t want you eating Brussels sprouts or broccoli, or any of those things which would be more bloating. Of course, no legumes, no lentils, no beans. Those are pretty much out forever for these patients, because they’re just so gas producing.

Then in terms of sugars or carbohydrates, so it’s really a modified carbohydrate diet, not a low carbohydrate diet. No non-digestible, no Stevia, no Splenda. You can do Equal because it’s a protein, it’s not a sugar, but anything that’s a sugar that’s not absorbed, sorbitol, et cetera, would be off the list. You could not use it. We have what we call red lights, yellow lights and green lights. If you wanted to cheat and have a salad, even bacteria don’t like spinach or arugula. If you want to have a spinach and arugula salad, go for it. Other salads, maybe not. Coleslaw definitely not, because it’s gas. These are just some of the highlights of the diet.

Dr. Kara Fitzgerald: You treat first. Are you using elemental diet in your practice at all? Any times you might think about that?

Dr. Mark Pimentel: Well, the whole elemental diet and SIBO started from a paper we published about, oh my gosh, 14 years ago now. It works extremely well. We do use the elemental diet in patients where nothing is working and they’re absolutely miserable. The challenge with the elemental diet is not, to be honest, if I were to choose one therapy for every single patient, the elemental diet works better than antibiotics. Psychologically it’s hard.

Dr. Kara Fitzgerald: It is.

Dr. Mark Pimentel: I talked to my patients and I tell them, I said, “This is how the diet’s going to go. The first three days you’re going to hate me, and then you’re going to get used to the diet. The last three days you’re going to hate me more because you can’t wait to finish.” It’s true. They’re just scratching till the end of the diet as they get near the end, because they can’t wait till it’s done. It’s just hard.

Dr. Kara Fitzgerald: Well, let me ask you this, why are you prescribing it still? They will get some symptomatic relief, but they also hate you in the process. Is it important in the treatment journey?

Dr. Mark Pimentel: It’s important because it makes the patient better. The treatment journey is never about me. It’s always about the patient. If they’re willing to do it and they want to do it, and they have the motivation to do it. We’ve probably done, over the 15 years, 3,000 patients on the elemental diet, so a lot of patients. It works 80% of the time. It’s very effective. I still have patients who twice a year that’s what they do, and they just reset themselves and they do fantastic. They don’t like it, but they know that’s the one thing that gets them to their best place, and they continue to do it.

Dr. Kara Fitzgerald: That makes sense. I guess what I was wondering is that it’s not going to be lasting. The E. coli in that deep mucus layer are still going to be there after an elemental, so you need to do concurrent antibiotic therapy as well.

Dr. Mark Pimentel: I never do concurrent with elemental. It’s purely elemental. The bugs that are in the mucus, first of all, mucus will be less produced during elemental diet, because of conservation. The gut conserves itself and starts to produce less mucus, even less villi. The villi get shorter because they’re saying, “Look, your arm’s in a cast for two weeks.” The muscles under the arm get a little atrophied because you don’t need energy making it. Truly, the E. coli’s of the world and those bugs go down dramatically.

The challenge with elemental diet for those of your viewers who may be considering it is you have to have a post-elemental diet plan. You can’t just give an elemental diet and say it’s going to be magic and have no plan coming out of it. Coming off the elemental diet you have to have a diet plan. I almost always use a prokinetic in those patients, because you don’t go through two weeks of hell on an elemental diet and then have no plan.

Because if it comes back in two weeks, that’s when patients really are frustrated because they went through that effort and it just reemerged so quickly.

Dr. Kara Fitzgerald: It makes them though, just what you’re describing, dropping the mucus layer down. They’re going to be more responsive than to pharmacotherapy.

Dr. Mark Pimentel: Possibly, but I don’t use antibiotics concurrently with it.

Dr. Kara Fitzgerald: No. I get that, but after in your follow-up plan.

Dr. Mark Pimentel: I haven’t done that. There are people who do that. They think it does work better. I haven’t done that. I haven’t traditionally given antibiotics right after the diet.

Dr. Kara Fitzgerald: What about addressing the mucus layer with other interventions? Have you thought about that? Just trying to liberate some of the bugs to have better treatment outcome?

Dr. Mark Pimentel: We’re thinking about all sorts of things. One of the things that we’re thinking about is can we get rid of the vinculin antibody and just make the gut wake up, and then everything’s gone. That would be the cure. That’s one of the things we’re really focusing on among other things. There’s many different angles to this. You’re on the right track, let’s put it that way.

Dr. Kara Fitzgerald: How are you thinking about disappearing the vinculin antibodies?

Dr. Mark Pimentel: There’s a number of ways we can do it, but because we haven’t published it yet we can’t really disclose all of it yet.

Dr. Kara Fitzgerald: Can you pantomime it? No. I’m just kidding.

Dr. Mark Pimentel: I could right now, but you can’t see me.

Dr. Kara Fitzgerald: Laughing…right.  Talk to me about lovastatin and it working as effectively as it does for methane. What’s the mechanism?

Dr. Mark Pimentel: Well, so lovastatin, if you know a lot about lovastatin, was discovered in Japan. It was discovered, it’s red rice yeast. When things are in a bog, in the swamp like rice is, it gets fungus-y and some of the fungus in swamps and bogs are Aspergillus. Aspergillus lives in a swamp. In a swamp, methanogens live in a swamp. That’s why lots of methane comes off swamps.

The lovastatin comes out in these little granules out of the Aspergillus fungus, because the Aspergillus fungus doesn’t like methane, because it sort of intoxicates it. Lovastatin, as I understand it, is not produced for human cholesterol. Obviously we know that. It was an accidental discovery. Lovastatin is secreted into the swamp to reduce methane. It blocks that enzyme perfectly. We’re taking advantage….

Dr. Kara Fitzgerald: That’s interesting. Go ahead. I’m sorry.

Dr. Mark Pimentel: No. We’re taking advantage of that mechanism. It goes in, blocks that enzyme in the archaea, in the methanogens that make it produce methane, so they stop.

Dr. Kara Fitzgerald: How did you put that together?

Dr. Mark Pimentel: That’s a fun story. Just piecing it together, there was some … Let me start over and say the veterinary literature has a lot of information about methane. Cows, for example, were given steroids and statins because the steroids help the cows, and antibiotics. Anabolic steroids increase meat on the animal. Antibiotics also increase the weight of the animal. These are called STAT antibiotics, low-level antibiotics. Then statins keep the meat lean.

These were things that were being done to cows to make the meat “better.” Environmentalists and activists for animals and for food quality are upset about steroids in the meat, antibiotics to cows, and so forth. One of the arguments that the cattle industry said is, “But statins reduce methane and so we’re helping the environment,” in cows. Cows who are taking lovastatin had less methane production. It’s things like that that cued us up to all of this, and that’s how the story started.

Dr. Kara Fitzgerald: That’s fascinating. It reminds me of the Atrantil story. Just similar looking at methane production and some botanical agents. I can’t remember specifically which ones. Are you using probiotics? Are you prescribing probiotics? I know it’s mixed, but it can be helpful.

Dr. Mark Pimentel: I don’t disbelieve in probiotics. I just haven’t seen the study that tips me over into using probiotics routinely. There are meta-analyses, which you’re familiar with this technique, where you smush studies together. The meta-analyses show that probiotics categorically help IBS, for example. There are some also meta-analyses in SIBO. There is some benefit. If you break it down into Lactobacillus, Bifido, or cocktails or Saccharomyces, none of them categorically help. Meaning the meta-analysis of the categories don’t help. Most of them are small studies.

This is the problem with probiotics is that the studies are tiny for the most part, and so it’s hard to know for sure which probiotic to use, what’s going to work and if they work at all. I’m still mixed on probiotics.

Dr. Kara Fitzgerald: Well, I think it’s going to require at least to some extent understanding all of the various subcategories and who’s producing what in a given condition to actually have a successful probiotic intervention. Wouldn’t you think?

Dr. Mark Pimentel: That’s the thing.   To be honest with you, if a company stepped up and did a large randomized control trial, it would be to their great benefit. Look at the peppermint story. Peppermint, I think peppermint works a little bit, but it really doesn’t work as well as it’s touted. I’m not trying to knock peppermint. I’m saying, “Look, I use it.” I do use it in some of the patients where nothing else is working. I don’t use it first line.

They did one small double-blind study and showed that it worked in a double-blind fashion. It’s helped that peppermint product be very successful. Doing a proper study is a good thing. Now, we analyzed peppermint and I don’t want to get off the rails or on a tangent here, but the larger the study of peppermint, the worse the P value got. Meaning the larger the study they did, the less statistical significance. That’s a bad sign for a product.

Because the larger study you do with rifaximin, the P value gets better, and better, and better. It means that the drug is working. If you study it in the larger populations, it’s even working better, in the larger populations even working better. That’s why you do bigger and bigger trials for the FDA because the FDA looks for that pattern.

Peppermint’s the opposite. The larger trial they do, the worse the numbers get. It makes you wonder if you did a thousand patient study like an FDA study, whether peppermint would work. It’s stuff like this we just have to wrestle with what data we have.

Dr. Kara Fitzgerald: Again, there may be a certain subtype of SIBO for whom peppermint is more effective.

Dr. Mark Pimentel: Exactly. If you do a larger study, you can figure that out and be targeted. It’s just the money isn’t put on the table to do that.

Dr. Kara Fitzgerald: Not for peppermint. Are there any other botanicals that you’re using?

Dr. Mark Pimentel: I do use Allimed or allicin in some cases, because of its effect on methane. I do use Atrantil in some of the refractory patients, and I get some good results in some patients. I can’t say it’s universal. Nothing’s universal. I do use some of those and sometimes Berberine as well.

Dr. Kara Fitzgerald: We’re at the end. I could keep pinging you with questions all day. Just one final question on FMT. It seemed like it was a godsend, or it had the potential early on and now perhaps that’s a little more equivocal.

Dr. Mark Pimentel: Well, it reminds me, and I was saying this all along, FMT reminds me of the days of blood transfusion in the 70s and 80s. People were getting what was called non A-non B hepatitis. They linked it to blood transfusion, and they finally found out that that was hepatitis C. You don’t know what you don’t know until you know it.

You’re taking stool from some other human, and you’re putting it in another human. There are a lot of things we don’t understand about the microbiome. On the positive side though, if you think about probiotics, probiotics is just one bug. It’s hard to imagine putting one bug into an environment of a thousand bugs and saying that that’s going to just magically make things better. It’s sort of like saying we’re going to add a thousand lawyers to Los Angeles every day and Los Angeles will be a better city.

We need lawyers. We don’t need a thousand every day. That’s the probiotic notion is that if you put something good into a city, or into an environment, that even though it has beneficial properties is it going to fix the situation? The answer is probably not. Now, probiotics was you’re adding a city to the city, so it has the right mix, and maybe it will repair the city by putting the right mix into the city. Very promising.

My worry with SIBO is that they already have too many bacteria, why are you adding a second city to the city that’s already overpopulated? My worry was people were going to get worse. Sure enough, they got worse. In three out of five studies there was evidence that the placebo was working better than the FMT, which means that the FMT was making people worse.

More significantly and more worrisome is the deaths from FMT. Now there are some superbugs that were transmitted from one person to another. We ourselves published a case where FMT came from a person with methane into the person with C. difficile, and now the recipient of the stool has one bowel movement a week and is absolutely bloated and miserable and can’t believe how bad they feel. Then what do you do at that point?

They had C. diff. Do you give them antibiotics to get rid of the methane? Can you give antibiotics to get rid of the … It was a learning experience. It works for C. diff, there’s no doubt, but I think we didn’t know what bad things could be in the stool of somebody else. I’ll add one more flavor to that. Women’s stool is different than men’s stool. There are some who believe that you should not be cross gendering stool as well, just because of some of the hormones and other things that the gut bacteria produce and contribute to the overall environment of your particular gender. Because your hormones influence the microbiome and vice versa. We’re starting to learn a lot about that as well, even in our lab.

Dr. Kara Fitzgerald: That makes a lot of sense. Well, Dr. Pimentel, it’s just been a pleasure talking to you and just having this opportunity to pick your brain today. Thank you so much for joining me. We’ll continue to pay attention to all of the good work you’re doing.

Dr. Mark Pimentel: Lots coming out, so I look forward to talking to you again if that’s convenient. Thank you so much for the interview. It was a pleasure.

Dr. Kara Fitzgerald: Absolutely. Take care.

Dr. Mark Pimentel: Bye-bye.

Dr. Kara Fitzgerald: And that wraps up another amazing conversation with a great mind in functional medicine. I am so glad that you could join me. None of this would be possible, through the years, without our generous, wonderful sponsors, including Integrative Therapeutics, Metagenics, and Biotics. These are companies that I trust, and I use with my patients, every single day. Visit them at IntegativePro.com, BioticsResearch.com, and Metagenics.com. Please tell them that I sent you and thank them for making New Frontiers in Functional Medicine possible.

And one more thing? Leave a review and a thumbs-up on iTunes or Soundcloud or wherever you’re hearing my voice. These kinds of comments will promote New Frontiers in Functional Medicine getting the word on functional medicine out there to greater community. And for that, I thank you.