Gut Check: Update on SIBO With Dr Mark Pimentel

Drs Brian Lacy and Mark Pimentel provide an update on the progress in diagnosing and treating small intestinal bacterial overgrowth and a similar condition, intestinal methanogen overgrowth (IMO).

Brian Lacy, MD, is a professor of medicine at the Mayo Clinic in Jacksonville, Florida. Mark Pimentel, MD, FRCPC, is director of the Gastrointestinal Motility Program and Laboratory and director of the Medically Associated Science and Technology program at Cedars-Sinai Medical Center in Los Angeles, California.

TRANSCRIPT:

Any views and opinions expressed are those of the author and/or participants and do not necessarily reflect the views policy or position of Gastroenterology Learning Network or HMP Global, their employees and affiliates.

Welcome to Gut Check, a podcast from the Gastroenterology Learning Network. My name is Brian Lacy. I'm a professor of medicine at the Mayo Clinic in Jacksonville, Florida, and I'm absolutely delighted to be speaking today with Dr. Mark Pimentel, who is professor of Medicine and director of the MAST Program, Medically Associated Science and Technology program at Cedar-Sinai Medical Center in Los Angeles, California.

Our topic today is one that routinely comes up for every practicing gastroenterologist and internist as well: symptoms thought to represent small intestinal bacterial overgrowth. Dr. Pimentel, welcome. What a pleasure to have you on this podcast today. SIBO or small intestinal bacterial overgrowth is a topic that resonates with both patients and providers. How common is SIBO and is this more common in certain people or different disease states?

Mark Pimentel:

Brian, it's great to be on the podcast with you. SIBO is extraordinarily common. I think we are now getting the best sense we ever have and I think the last 2 years things have really changed in terms of the science. I believe it's quite common. For example, we've been doing the REIMAGINE study, which you may or may not be familiar with, which is taking consecutive patients who come in for upper endoscopy for foregut symptoms. So they're not specifically IBS or GERD, but they're everybody. And approximately 25% of those patients who are simply coming for upper endoscopy on culture of the small bowel meet the definition for SIBO. So SIBO is very common in patients with bloating, distension and abdominal pain. And I know we're going to get into those symptoms, but we were surprised that 25% of all comers, even though they hadn't had a prediagnosis of SIBO, are still testing culture positive, suggesting it's more common than we actually think.

Brian Lacy:

Wonderful. Well, we're looking forward to the results of that study when you finally publish that. So Mark, since our conversation 2 years ago, there have been significant changes in the field and the term IMO or intestinal methanogen overgrowth, is now being used. What's the difference between SIMO and IMO?

Mark Pimentel:

Well, small intestinal bacterial overgrowth is an old terminology that dates back even as early as the 1980s. And SIBO means small intestinal bacterial and overgrowth. And when you talk about methanogens or methane, methanogens are not bacteria, so the B in SIBO doesn't work. And methanogens are distributed throughout the gut in excess in IMO. So it's really intestinal overgrowth, not small intestinal overgrowth. So we took out the small intestine part. And the methanogen overgrowth, so it's intestinal methanogen overgrowth, and we now know these methanogens are overabundant both in the small bowel and in the colon based on what we presented at DDW just recently.

Brian Lacy:

Wonderful. So you already mentioned symptoms and what are the classic symptoms of SIBO and are these symptoms accurate at predicting underlying SIBO or IMO, and could we just use symptoms to make the diagnosis or do we really need supportive testing?

Mark Pimentel:

Well, I guess I get this question in 2 ways. I get it in this way or in the opposite way. Do we really want to give antibiotics to everybody who has symptoms on the premise it might be SIBO and therefore is there an overuse of antibiotics as a result of empiric therapy? I'm sort of flipping the question on you, Brian. I'm sorry. But getting the breath test gives you 2 things. It tells you that you have SIBO and therefore you should or more likely you'll respond to antibiotics and that's been published already.

The second is we don't know what type of overgrowth you have. Maybe you don't have SIBO, maybe you have IMO. And the treatment for that is different. And of course we'll get to later in the podcast is hydrogen sulfide. Maybe you have that and the treatment for that is different also. So I think doing a test actually strategizes whether or not you deserve or should get antibiotics and what antibiotics or treatments you should be put on. So that's very important.

Brian Lacy:

Wonderful. I think that emphasizes, as you nicely pointed out, the need for testing and how that can really point us in a better therapeutic direction. So thank you. And thinking about testing whether SIBO or IMO, there are lots of questions that come up about testing. And to begin, we know that some alternative health care providers use stool tests to diagnose SIBO or IMO. Are these accurate?

Mark Pimentel:

Well, so it's hard to call something small intestinal bacterial overgrowth if you're checking stool, which is not the small intestine. So I think that answer in and of itself sort of summarizes what my answer will be. But there are signals in stool of changes that are abnormal. There are changes in diversity, changes in the composition of the stool in patients with many GI disorders. The problem is we still don't know in stool what is normal. So if we don't know what is normal, how can we define abnormal in stool? Stool is very complicated.

Brian, as you know, stool is the stagnant part of the gut. Three feet of the gut, half of the weight of stool is bacteria. The bacteria in the stool may have no metabolic consequence to the host. It's simply due to the stagnation because the colon is less absorptive. So there's a lot of factors in stool that make it less than ideal, especially for looking at small intestine. And to be honest, it's never really been validated, as breath test for a long time was not really well validated even though we suspected it was accurate. Stool as a surrogate for disease, using the microbiome as markers isn't really well validated and especially for SIBO that's true.

Brian Lacy:

Wonderful. Mark, we began, and you mentioned this great study you're doing right now looking at the prevalence of SIBO in patients just coming in for endoscopy and doing aspirates. Can you comment on duodenal aspirates? Is this something we should be doing more of? Do you think it's an accurate test? Should we be doing duodenal aspirates and is this a good way to really diagnose either SIBO or IMO?

Mark Pimentel:

Well, the aspirate in and of themselves are controversial in this whole arena as well. And to be honest, your paper was the best paper to point this out, you and Dr. Cangemi. Because the gold standard at one point in time for a small intestinal bacterial overgrowth was aspirate and culture. And so what people have done in response to that is they take a single lumen catheter, pass it through the channel of the scope. As it's going through the scope, the scope which has just passed through the mouth, the esophagus in the stomach is contaminated and that open lumen catheter comes out into the duodenum, all contaminated, and then you're trying to aspirate juice from there. And then what people have done is they've taken the juice and put it on MacConkey and blood agar because those are the 2 predominant agars and then they add the colony counts from both.

The problem is e coli grows on both. So if you're counting e coli twice, how is that reliable? So as we were developing the REIMAGINE study, it took us literally 2 years to perfect the catheter system and the systems for doing culture because we were not getting accurate results without doing it correctly. So we had to create a double lumen catheter with a cap so that it was sterile as it went in, the cap is dispensed with and then the inner lumen comes out, gets the juice. Then we realized in a study we just published in Clinical Gastroenterology and Hepatology is that MacConkey is the way to go. You don't need blood agar because you're double counting. But MacConkey correlated with symptoms. MacConkey correlated with the microbiome, MacConkey correlated with SIBO and all the factors associated with SIBO. And we were able to identify the individual 2 species that are responsible for SIBO, which is e coli and Klebsiella, which was a surprise to us. And by identifying only those 2 organisms were correlating with the symptoms of abdominal pain, bloating, urgency, and diarrhea.

We've sort of made it more complicated, but now we understand it and then we were able to more accurately determine SIBO. One final thing about culture, we learned that half of the e coli lives in the mucus and so we have to add a mucolytic to the sample in order to liberate all the e coli and Klebsiella that's there in order to quantitate correctly. So culture can be done, but there are methodologies now that have been published that more accurately use this technique. So if you don't do it this way, I think there's problems with culture as well. Long answer.

Brian Lacy:

No, it's a great answer. And this points out the controversy in the field and how we probably can do things better and then maybe get more accurate data. And again, I think very excited to hear about the results of the REIMAGINE study. So we'll all keep tuned for that and we'll look-

Mark Pimentel:

Your study in and of itself, Brian, showed that there's a lot of false positives or contamination. And so one of the things I point out from your study with Dan Cangemi is that how can the culture be a gold standard in that technique that's been used if 2% are contaminated? So it's only a 78% gold standard, which isn't all that great.

Brian Lacy:

No, wonderful, highlighting the need for a better technique. And it sounds like you've got one which is great for the field. So Mark, let's talk a little bit about breath tests. And again, there's controversy here too and there's been a lot of progress made in the field over the last few years. And a first question about breath tests is a lot of patients are now doing home breath tests, and are those as good as the tests we do in an academic center or a hospital?

Mark Pimentel:

Well, as you know Brian, I have a conflict of interest with one of the breath tests companies, but what I'll tell you is just like we did for REIMAGINE, we understood that there was a growing need for home breath tests for a lot of reasons. It saves money for patients. Getting a diagnosis early in a patient's course saves money as well. So home breath tests can save money. The problem is it has to be done in a way that the breath can be harvested and collected and kept in a stable condition for a period of time. And so we worked hard to develop that, but when we validated that test, we validated it at a distance and in person at the same time so that we would show that the exact same numbers are obtained using that technology versus in person, in our lab testing, and they matched with a correlation coefficient of around 95%. So we were able to validate that home kit testing is exactly the same as in-person testing, at least for the technology that we were responsible for. I can't talk about the others because I don't have their data.

Brian Lacy:

Wonderful. So it sounds like this next and newest generation home test is reliable and providers should accept that, and that's really useful. You mentioned too in terms of breath testing, and we've talked about hydrogen and methane and you mentioned hydrogen sulfide. So is it important to measure hydrogen sulfide in all these tests?

Mark Pimentel:

Well, that's the most exciting thing because... And you know this as well, Brian, but maybe the audience doesn't, that hydrogen by itself doesn't correlate with symptoms, ironically. Even though the higher the hydrogen are, the more e coli and Klebsiella you might have in your gut, but the hydrogen gas itself is being used by other organisms as a fuel source. So when you see a hydrogen on a breath test that's 40, and then you give an antibiotic and then it's 50, you're scratching your head, you're saying, well, I just gave them an antibiotic. Why did it go higher? Well, why it went higher is because there are hydrogen sulfide organisms there that if you kill them, all of a sudden you see all the hydrogen that they were using that they're no longer using. So my point is there are 3 gases in the gut and only 3 gases that that are of fermentation origin. It's hydrogen, methane, and hydrogen sulfide. And we were always missing the third gas, hydrogen sulfide, but our paper from American Journal of Gastroenterology just before the new year, it's the first time that we've taken in IBS-D and IBS-C a breath test with 3 gases, correlated it with the symptoms that the patients were presenting with, and compared it to culture and deep sequencing in the same individual. And we were able to show that the breath test, the gases on breath test correlated quantitatively with the organisms in the gastrointestinal tract.

And we were able to show that when the higher the methane is, the more methanogens you have in the gut. The higher the hydrogen sulfide is, the more fusobacterium and desulfovibrio you have in the gut. And that hydrogen sulfide correlated with diarrhea and methane correlated with constipation. All of that in one paper. And that really is the first paper in history where you took breath testing and correlated with symptoms and next generation sequencing all in one paper. So it really is sort of a landmark thing that should have been done many, many years ago, I guess is what I'm trying to point out.

Brian Lacy:

Mark, that was a wonderful study, as you mentioned, published late in 2022 in the American Journal of Gastroenterology. So for our listeners on Spotify or Apple, make sure you look that up. So another controversy because I think this field still has a lot of controversy, which makes it exciting and challenging. Let's go back to the substrate. And we know that many institutions use lactulose, but there's still this debate about do you use a lactulose breath test or a glucose breath test? What do you think?

Mark Pimentel:

Well, as you know, glucose gets absorbed very readily, so it will get absorbed very quickly in the duodenum. So if you had overgrowth, perhaps more distally in the small bowel, you won't see it because the glucose will all be absorbed by you. But I have it even more because we see so many people ordering glucose breath tests and they're negative. Many ways to answer this question. But rifaximin we believe works on the basis of a microbiome principle in irritable bowel syndrome. If you used glucose breath testing to predict who would respond to rifaximin, you would miss probably 20% of the patients who would've benefited because out of 100 IBS patients, only 20 to 25% will test positive on a glucose breath test, but rifaximin works in 44%. That's one way to answer it. So you're missing people who could benefit from therapy and it's a waste of money if you miss people as well and not good for the patient.

The second part, and this is something that I learned more recently. When you are diabetic and you have hypoglycemia, you take a glucotab and you put it under your tongue because glucose is absorbed in your mouth. It's absorbed in the mucus membranes of your throat, your esophagus and the stomach. I'm 6'4", how much of that glucose load for the breath test got absorbed by this extreme foregut before it ever got to the duodenum? And what dose is getting to the duodenum in me versus the 4'10" female patient where she's drinking the same amount? Lactulose doesn't have that problem. It's a nonabsorbed carbohydrate. So there's a lot of problems with glucose. You don't know what dose is getting to the small intestine.

Brian Lacy:

Mark, I love that answer and I've never thought of you as an extreme foregut person. So for our listeners, want to think about that.

Mark Pimentel:

I'm the 95th percentile for length of foregut.

Brian Lacy:

Wonderful. So we've talked a little bit about a reading breath test and sometimes reading a breath test can be tricky. And for our listeners, we don't need to go into lots of examples, but are there examples, common examples where maybe a breath test is read and it's actually a false positive reading or conversely a false negative reading?

Mark Pimentel:

So again, substrates can give you a false negative. So for example, the glucose that we just discussed, yes, false positives can occur and in a number of circumstances, one of which is becoming more and more common. I'll get to that in a moment. But of course, if you have rapid transit, true rapid transit, you might get lactulose to the colon prematurely. Now, one of the arguments against lactulose is that, well, it's just determining transit. Well, we have now proven that in multiple papers that what the hydrogen that is seen on the breath test is coming from the mechanics and the enzyme elevated pathways that are found in the aspirate of the duodenum. So when you have a positive hydrogen breath test, those enzymatic pathways are present and higher in that individual. So we truly believe the hydrogen's coming from that part.

But as you know, in gastroenterology, we're suffering with a problem with all these patients on GLP-1 agonists when the stomach isn't moving, it's full of food and maybe even full of bacteria. And we see a lot of these high baselines no rise in the carbohydrates. So we think is it overgrowth because it's such a high baseline? Or is it that they're on the GLP-1 agonist and the lactulose has never left the stomach. So we're seeing a lot of unusual breath tests in the era of GLP-1 agonists, and we're wrestling with that in the GI lab also with food in the stomach when we do endoscopy. So for the audience, bear that in mind as you're interpreting these tests now.

Brian Lacy:

Mark, great, great teaching point. Thank you. Because so many people are using GLP-1 agonist to help reduce weight, but we know that they do have significant effects on gastrointestinal motility and therefore could affect breath tests. So great teaching point. Thank you. So one thing I've seen too for some patients who bring in their results from outside is that some providers look at breath test results and then they add the levels of gases and they might add the levels and PPM, parts per million, of hydrogen to that of methane and even to hydrogen sulfide. Is that appropriate? Is that the right way to read the test?

Mark Pimentel:

Well, this is why we had the North American consensus and the North American consensus, we set the standard for how to interpret breath testing. There is, to my knowledge, no study in which you add hydrogen to methane to get a positive test. And it's irrational, because for 1 methane you need 4 hydrogens. So if you really want to do it right, and maybe it's not even right, is you got to take the hydrogen, multiply it by 4, and then add methane to get the right answer. So even their addition is incorrect as to the stoichiometry of what's going on in the gut. So it's wrong and it has no basis. And in fact, it's doubly wrong.

Brian Lacy:

I think we can put this issue to rest and don't add the numbers. So Mark, kind of a big question, but this is a controversial area too, and let's just think about treatment and you can educate our audience. So well, unfortunately we don't really have large head-to-head comparison trial, but you've got 20 years of experience, maybe 25 in this field, and you really are the international expert. Can you give us your opinion about an antibiotic regimen that might be most appropriate for SIBO or IMO? And then I really want you to tell us about some of your exciting work looking at combination therapy and lovastatin.

Mark Pimentel:

Perfect. Yeah, I'm happy to talk about all those topics. So in general, rifaximin is a nonabsorbed antibiotic and because it creates almost no resistance in the gut and you're going to see some more data from REIMAGINE showing, we can't even find resistance genes for rifaximin in the gut. So that's a good thing and gives us a little more breathing room with that drug. But rifaximin, the breath test predicts response to rifaximin that was published by Ali Reza a few years back now.

So I think for the hydrogen patients, what I do in my practice is I give them simply rifaximin. For intestinal methanogens overgrowth, we have one randomized control trial that we did where we compared neomycin to neomycin plus rifaximin, and neomycin plus rifaximin was superior. And thankfully neomycin is back on the market and we're able to get it again. But a substitute for neomycin, in my experience, not by study, is metronidazole. So if the patient doesn't tolerate neomycin, metronidazole at low dose 250, not the 500, just to avoid side effects.

Hydrogen sulfide is a different animal. We do have data from back in Michael Levitt's time where he used bismuth to reduce hydrogen sulfide producers in the gut, and it was very successful. So we give rifaximin with bismuth, but on all fronts, we are developing new therapies. One of them, as you mentioned, is lovastatin. The formulation wasn't great, the trial we did, the most recent trial. But we're reconstructing this story and developing new analogs that we think will be far superior to lovastatin by itself. So you'll see more of that coming in the next 6 to 8 months, more data and more science there. Now that we understand where e coli lives, half in the gut and half in the mucus layer, we've got some interesting techniques for improving the benefits of antibiotic therapy for hydrogen as well. So stay tuned. A lot's happening. Like anything else, the more you understand it, the more you understand how to develop treatments for it. And I think we're on the edge of a number of therapies.

Brian Lacy:

Yeah, Mark, very exciting. This is exactly how science advances and with kind of your logical, precise series of experiments, this really has shed so much light in the field. So thank you. Mark, this has just been a great discussion. I know I've learned an awful lot. I know our listeners, whether on Apple or Spotify, have learned an awful lot. Any last comments for our listeners?

Mark Pimentel:

Well, I think one of the things that we didn't have a chance to do in the IBS guidelines is whether SIBO and IBS are related. I think the Indian guidelines came in just recently and had the benefit of all the new data that's just emerged, and they were able to say that SIBO and IBS are related in their guidelines. And so I think maybe eventually we move away from symptom-based diagnosis in motility disorders to pathophysiological based diagnoses in functional GI disorders. I'd like to see that before I retire, but maybe I need to stay around a lot longer to see it all. But that's my final word.

Brian Lacy:

All right. We would love to see pathophysiology, but that indicating disease states and then treatment regimens. And that means that of course you may not be retiring for quite some time, which would of course be wonderful for the field.

So again, this is Gut Check, a podcast from the Gastroenterology Learning Network. I'm Brian Lacy. I'm a professor of medicine at the Mayo Clinic in Jacksonville, Florida. We've all greatly enjoyed listening to Dr. Mark Pimentel, professor of medicine and director of the MAST program at Cedar-Sinai in Los Angeles, California, an international expert in small intestinal bacterial overgrowth, SIBO and IMO as well. And for our listeners on Apple and Spotify, thank you for joining in. We're looking forward to having you join us for other future podcasts and all of you stay tuned. You're going to hear lots of more exciting things from Dr. Mark Pimentel and his colleagues at Cedar-Sinai. Thank you so much.

Mark Pimentel:

Thank you.