In this episode, we discuss:
- New developments of hydrogen sulfide (H2S) in SIBO testing
- Treatment considerations for H2S
- Diet recommendations (and problems with the low-FODMAP diet)
- Update on SIBO medications
- Kids and SIBO
- Improvements in SIBO research
Hey, everybody, Chris Kresser here. Welcome to another episode of Revolution Health Radio. This week, I’m really excited to welcome back Dr. Mark Pimentel for, I believe, his fourth appearance on the show. Dr. Pimentel is currently the head of the Pimentel Laboratory and executive director of the Medically Associated Science and Technology, or MAST, program at Cedars-Sinai. This program focuses on the development of drugs, diagnostic tests, and devices related to conditions of the microbiome.
Dr. Pimentel has been very active in research and has served as principal investigator or co-investigator for numerous basic sciences translational and clinical studies in areas like [irritable bowel syndrome] (IBS) and the relationship between gut flora composition and human disease. He’s widely known and sought out for major scientific developments that he has pioneered including the discovery that IBS is a condition of the altered intestinal microbiome.
I’ve talked to Dr. Pimentel, as I mentioned, three times now on this show. He’s one of the foremost experts in the world on [small intestinal bacterial overgrowth] (SIBO). And that’s primarily what we’ve discussed and mostly what we’ll be discussing today. SIBO is a quite common condition. It’s also one that is difficult to treat and has been relatively poorly understood, up until the last five or 10 years, and even within the last few years, there have been a lot of changes and developments in our understanding of the condition and how to properly diagnose and treat it. So there have been a few new developments that I’m eager to talk about with Dr. Pimentel. So, without further delay, let’s dive in.
Chris Kresser: Dr. Pimentel, [it’s] a pleasure to have you back on the show.
Mark Pimentel: It’s great to be back with you, Chris. Thanks.
In this week’s episode of RHR, I sit down with Dr. Mark Pimentel to discuss the new and developing small intestinal bacterial overgrowth (SIBO) research, treatment, and diet recommendations. #chriskresser #SIBO
New Developments of Hydrogen Sulfide in SIBO Testing
Chris Kresser: All right. I want to just dive right into talking about hydrogen sulfide. So this is kind of the new kid on the block in SIBO land. Not for you, probably. You’ve been thinking about it for a while and we’ve been aware of it for some time as clinicians, but we haven’t really been able to test for it. We’ve suspected that it might be there, especially when hydrogen values were zero or low on a test. So tell us a little bit about hydrogen sulfide [H2S], [and] why it’s important when we’re diagnosing SIBO and thinking about it. And then the new test that you came out with, the trio-smart, or that you were involved with.
Mark Pimentel: So this has been a two- to three-year effort, actually more than that, trying to get to the point where we can have an instrument that can measure all three gases, plus carbon dioxide. There’s a lot of logistical issues with [H2S]. It’s a very reactive gas, meaning it can have chemical reactions. So a lot of things needed to be worked out. For example, how do you transport the breath so that [H2S] remains stable? So you have to develop a system of collection and the right kind of material to collect it in. And then the instrument has to be totally different because [with] conventional instruments, you try and wick the water away before putting it into the instrument. But the drying columns that are used in conventional instruments also take out H2S and [water], so you can’t measure it. So we had to reengineer the entire instrument in order to get this to work.
And then, of course, you have to do a clinical trial to show that it actually makes a difference. And so we’ve done all those pieces, which gets us to this point.
Chris Kresser: So what difference does it make? What does it add? Previously, we were just testing, of course, for hydrogen and methane. What are the kind of clinical case[s], use cases where this really makes a difference in the treatment that we might select or the outcome that we might expect?
Mark Pimentel: So I think, I don’t know if you recall; you’re probably too young. But back in the ‘90s, methane was on breath testing, but nobody actually knew what methane meant. So why is it there? But, of course, it was important, which we learned in the 2000s, that it was correlated with constipation, and so forth and so on. I think we’re a little farther ahead with adding H2S, meaning that the clinical trials that we’ve done show that if the H2S is elevated, it’s associated with diarrhea.
And the cutoff for, and this is very important, the cutoff of five parts per million is for the bag collection system, the transportation, meaning sent to the lab, and time in the bag, and the instrument itself. And that system, the five parts per million cutoff was the determinant or the switch point where people were more likely to have diarrhea. The question I get is, yeah, but my patient has constipation. Well, there [are] going to be patients like that; there’s no doubt. Because it’s not 100 percent universal, but yes, that’s what we’re seeing.
Chris Kresser: Yeah, just like we sometimes have patients with methane that have diarrhea rather than constipation or loose stools. Or maybe they have hydrogen and methane.
Mark Pimentel: Right.
Chris Kresser: The studies looked at the likelihood that hydrogen sulfide appears by itself, with hydrogen, with methane, do we know anything about that yet?
Mark Pimentel: So in our first study using sort of the first generation of a bag collection system, which wasn’t ideal, we saw an overlap of some people where they had hydrogen sulfide, methane, and nitrogen. And that occurred in a small percentage. But we’re trying to get the exact breakdown with the new collection system. But an abstract has been submitted to the [Digestive Disease Week] (DDW) meeting and I will be revealing a lot of data around the second study that we did that validates the new instrumentation for the five parts per million.
But yeah, there are people who have just hydrogen sulfide, [and] there are people who have all three. But what it does add is, we estimate about 25 percent more people that wouldn’t have otherwise tested or known that they had a problem without doing the test.
Chris Kresser: Right. Yeah, we’ve already started to see that. We’ve had test results coming back with only hydrogen sulfide positive, which is super helpful because now we’re catching someone that we might have missed otherwise with that test.
So the last time you came on, we talked about the IBS smart test and the pathology of SIBO in a subset of patients where they had an episode of food poisoning, and then they developed antibodies to [tuberculosis] and vinculin, and that is what slows down the migrating motor complex and leads to SIBO in those cases. And we know from your studies that that’s associated with people with hydrogen overproduction, but not with methane. Do we know about hydrogen sulfide and where that fits in with this idea?
Mark Pimentel: Yeah, that’s a fantastic question because we don’t think that food poisoning leads to methane or C, we think it leads to D, and then [Escherichia coli] (E. coli) and Klebsiella. And we had a paper over the summer, which probably wasn’t part of our previous conversation, that was published that really, in the animal model, nailed [the] concept that that’s what happens. And E. coli and Klebsiella are the two bad characters when it comes to SIBO. More E. coli than Klebsiella. And so now we know what SIBO is exactly on the hydrogen side, we know what organism is contributing to it, and we also know where it lives.
So it’s allowed us to help move forward with developing new drugs that will target and get into those locations. And we’re in the midst of some trials to really come up with a new answer. Hydrogen sulfide, it’s brand new, we’re still looking into it. But we just finished an animal study; it’s a very, very large study. And animal studies are a terrible thing to do. I hate doing them. But we have to do some of them. But it requires a lot of work to get the answer. And we’ll be able to see hydrogen sulfide in that animal study. And we’ll get some answers in the coming weeks or months.
Chris Kresser: Right, so you can, with methane, the migrating motor complex can slow down, but it’s a different mechanism. It’s not related to food poisoning and antibody production. With hydrogen, it can sometimes be related to that. And hydrogen sulfide is still a question mark; we don’t really know.
Mark Pimentel: A question mark we’ll be able to answer in the coming weeks, we think.
Treatment Considerations for H2S
Chris Kresser: Great. Okay, so what about treatment considerations for hydrogen sulfide? You mentioned that with hydrogen, we now know it’s mostly E. coli and that’s leading to some drug discovery and ideas about other options aside from rifaximin that might be useful. Do we know anything about that with hydrogen sulfide? Does it require a different approach? Or are you just using rifaximin and the typical approach with hydrogen so far?
Mark Pimentel: So we don’t know exactly how to treat hydrogen sulfide yet. We know from the historical literature that hydrogen sulfide could reduce, for example, with bismuth. So there are people who are trying bismuth or other therapies with some success. But I can’t give you a conclusive answer on what’s the ideal treatment for hydrogen sulfide yet. We’re working on that. And hopefully, we’ll have some answers again in the coming weeks or months, because we’re avidly treating these patients and trying to see what works.
Diet Recommendations (And Problems with the Low-FODMAP Diet)
Chris Kresser: Right. I would say we’re in the same boat. And we’re trying things like a low sulfur diet and molybdenum, which has some sulfur-reducing properties with unknown efficacy yet. Have you heard anything, [have] you yourself tried anything with diet or any other clinicians that you’ve worked with, with diet or supplements that’s been useful so far?
Mark Pimentel: Well, I’m glad you brought up diet because I’m almost feeling like, at this point, we could recommend or at least come close to suggesting that there might be actually three diets for SIBO: one for hydrogen, one for methane, and one for hydrogen sulfide. Because a low sulfur diet would reduce hydrogen sulfide production. Homocysteine [and] cysteine are two amino acids that if you eat in high concentrations will fuel more sulfur. Yet molybdenum’s story is interesting. I don’t have any outcomes from post-treatment with molybdenum. And bismuth, we’re definitely trying a number of patients and should have some low-level, or I should say high-level, answers on the efficacy of bismuth in that.
Chris Kresser: And along with the low-sulfur diet, one of the things we’ve been exploring, of course, as well, it’s like there are certain supplements that have a lot of sulfur production capacity, like [methylsulfonylmethane] and some in the methylation cycle glutathione and things like that. Would you also recommend avoiding really anything that can lead to high-sulfur production?
Mark Pimentel: Yes, that is true. Also, wines, for example, red wines contain a lot of sulfites, which are or may be a problem for these patients. So we’re going to be searching for sulfur everywhere now.
Chris Kresser: Patients are going, “Oh no, more things that I can’t eat or do.”
Mark Pimentel: My whole philosophy in terms of diets, and this is why I’m not a non-advocate for low [fermentable oligosaccharides, disaccharides, monosaccharides, and polyols] (FODMAP), but I’d like to see a less restrictive diet and that’s why we developed a low fermentation diet. Clearly, low-FODMAP works, but the key is lifestyle, and if we can create the diet such that a patient can reasonably go out and eat and socialize, not [during the] COVID[-19 pandemic], but just someday, that’s the diet I’d like to choose rather than being so overly restrictive that life is miserable. And so, hopefully, we’ll have some non-miserable recommendations.
Chris Kresser: Yeah, and sometimes the diet is just what you’re doing until you can get properly treated, too. And maybe not necessarily a long-term thing you’re going to have to do for the rest of your life. I’m with you on diet, and I think my other concern with the low-FODMAP diet, since we’re on [the] topic, and I know you specialize in the microbiome, not just SIBO, is some of the studies that have been published suggesting that there may be a negative impact on the beneficial microbiome with an extended low-FODMAP diet. Because it’s obviously not just feeding the bacteria in the small intestine that we don’t want to feed, it’s also feeding the bacteria in the large intestine that we do want to feed. Right?
Mark Pimentel: Exactly. And so diet is very complicated. And again, I can’t spill the beans, but we have, from the REIMAGINE study, a very, very interesting abstract that was submitted to DDW where we compared various diets, and I got a lot of surprises from there, like, contrary to what I would have thought, also. And so, just one thing about a scientist, you take your punch to take your knocks on the chin when you say something that you thought was right, but it’s not, and the data speaks for itself. So you’ll see, it’s pretty interesting what the different diets do and what kind of changes occur in the microbiome. That was surprising to all of us.
Chris Kresser: I really welcome that. And one of the issues is, I’m sure you know, and one of the reasons you did this study, and there haven’t been enough studies on diet and the impact it has on conditions like SIBO and the microbiome, it’s been mostly anecdotal, and coming from clinical experience, but that’s not always a reliable guide.
Mark Pimentel: Right, exactly. And we have some really provocative data, I think. It will be very interesting. Hopefully, in May, that will be accepted to DDW and we’ll be able to share some of those interesting findings.
Update on SIBO Medications
Chris Kresser: Great. I look forward to seeing that. So this may or may not be quick, but I just wanted to also get an update on SYN-010. So, for people who haven’t heard our previous episodes, this is a medication that you’ve been working on for methane-predominant SIBO that is a form of a statin, non-absorbable statin, [a] form of lovastatin that I guess interferes with an enzyme in archaea that prevents them from reproducing. I was just thinking about this and imagining that maybe that trial slowed down with [the] COVID[-19 pandemic]. But I’m just curious what stage that’s in and (crosstalk 13:05).
Mark Pimentel: So the company decided to do what’s called a futility analysis with the [U.S. Food and Drug Administration]. And so they registered that analysis, which is you’re halfway through, and basically, the futility analysis says if you were to continue, would you be successful in showing [there] are trends? And the reality was, there wasn’t a trend. So the study was discontinued.
I think the problem, so in the lab, clearly, lovastatin blocks [the] synthesis of methane. What we were trying to accomplish with the formulation was to make it non-absorbed. But I think where the problem was with the product was that it didn’t quite formulate as we had hoped. So I think the drug was being released and wasn’t staying in the gut. But we can make a bunch of excuses. The bottom line is, this is one that didn’t work for us. And again, the data is the data. We have to be honest and move on and try and figure out what to do next.
Chris Kresser: Yeah. And any updates on your end in terms of how you’re approaching methane-predominant SIBO? Are you favoring metronidazole now or still neomycin or along with rifaximin, any changes there?
Mark Pimentel: So we’re using rifaximin with neomycin. We’re substituting the neomycin with metronidazole depending upon the patient’s circumstances. And that still seems to be working well. On the natural side, we do use things, I’m just blanking, like allicin.
Chris Kresser: Allicin.
Mark Pimentel: Allicin has been effective in some of my patients. I’ve even seen some patients where Atrantil is somewhat effective, although that’s a commercial product, which for some patients, that works. In all cases, it seems like the methane comes back quite quickly. Allicin works for a month, two months, three months for some patients, and then maybe they become resistant to it because it comes back. And I think a lot of people have noticed that. That’s unfortunate, but I guess the bugs are smart, smarter than us.
Chris Kresser: I guess, yeah, they don’t call them archaea for nothing. They’ve been around for a very long time, right?
They’ve evolved some sophisticated survival strategies, I think. Yeah, we have the same issue and we end up having to rotate things to get the best results, and often just retreating people. On the subject of retreatment, I think we touched on this briefly in the last episode. But you had mentioned, I believe, some studies suggesting that rifaximin use even serially over time doesn’t seem to have a negative impact on the beneficial gut microbiome. Is that still how you see it?
Mark Pimentel: So we published one study a number of years ago on digestive diseases and sciences where we looked at up to six treatments, the primary treatment plus five retreatments, and we saw that it worked equally each time, on average. So we weren’t seeing what was called clinical resistance. In the target three trial that was published, I’m blanking on the journal. It might be Elementary Pharmacology and Therapeutics, but don’t quote me.
Chris Kresser: I won’t quote you, yeah.
Mark Pimentel: But anyway, it’s in the literature that after three treatments of rifaximin, the microbiome resistance really didn’t develop. So we have pretty good evidence for up to three treatments looking specifically at the microbiome and microbial resistance. We didn’t see it. The one interesting thing that was noted in that paper is that we didn’t see a rise in yeast in stool. And so, that’s a good thing. So even though we’re giving antibiotic[s], we’re not seeing a shift over to higher, which is typical of more broad-spectrum systemic antibiotics.
Chris Kresser: Has there been anything new in the literature on [small intestinal fungal overgrowth]? [The] last time we talked, there were just three kinds of pretty preliminary trials. But anything new there and anything new in terms of diagnostics? Is that something you’re planning on pursuing or any other group that you know of is looking at for a commercial test?
Mark Pimentel: Well, Satish Rao was working avidly on this. Talking to my colleagues around the country this year with COVID[-19] has been a dire year for research. And so I don’t know whether, I know Satish had been planning things like this. But to my knowledge, a lot of funding and other things were diminished because of COVID[-19] and there’s not as much research going on. So we’ve continued to plow ahead. Our funding has been pretty good. So we haven’t really lost a step. And so we’re very proud of that. But others have had more problems.
Chris Kresser: Yeah. And just for the listeners, that was small intestinal fungal overgrowth. So yeast overgrowth in the small intestine rather than bacteria. Prokinetics. So we talked a lot about them on the last show. For the listeners, go back and listen to that one. We won’t go into detail here. But just wondering if you have any updates and any that you’re favoring now? Prucalopride seemed like the most promising of the newer ones that were available. Any lessons learned, clinical pearls on the prokinetic side?
Mark Pimentel: Yeah, I mean, we still love prucalopride. The challenge with prucalopride as more people are using it is insurances are creating higher firewalls for getting it. And so we’re having some challenges. [We] have to get a lot of prior authorizations to get it. But we still find that that’s the strongest. Strongest doesn’t always mean good, because if it’s too strong, it’s causing diarrhea. And so, we’re gravitating more and more toward the prucalopride.
We still use low-dose erythromycin and occasionally low-dose naltrexone, although we don’t use that as much as the other two. Other people in the sphere of this treatment are using low-dose naltrexone more often successfully.
Kids and SIBO
Chris Kresser: Okay, I want to talk a little bit about kids and SIBO. As this has gotten on more people’s radars, and as adults are getting tested, they’re seeing their kids with similar symptoms. They’re wondering if they should get their kids tested. And I haven’t done a deep dive in the literature on this for a couple of years since I put together a training module on it. But at the time, it seemed like the testing, the breath testing at least, was more problematic because of the higher transit time that kids have on average. So how do you approach kids? And you can define age ranges if that’s helpful. When do you start thinking that breath testing is helpful and accurate in kids or adolescents with SIBO? And yeah, we’ll start there and I’ll just ask a couple [of] follow-ups.
Mark Pimentel: Even here in our program, we don’t generally test individuals younger than 10 years old, just because the breath test has not been validated well in that age group and we don’t even know exactly how much lactulose to give because of the smaller body, the difference in transit, and all of that. So my general recommendation is that if you are suspecting, let me just backtrack and say, when we started doing SIBO testing for IBS and when that became a very prominent finding, what was interesting is the pediatric gastroenterologists and pediatricians are very well recognizing and have always well recognized SIBO in pediatric populations as a cause of functional problems.
The adults were more grumpy about the finding and were more gravitating toward psychological and made it a little more challenging for us to move the idea forward. It’s different now, obviously; it’s well-accepted now. But [pediatricians] generally understand SIBO occurs in pediatrics and can account for symptoms. The difference in pediatrics, what’s interesting is that the children generally describe more pain than a change in bowel function. So their phenotype is a little different. And maybe that’s because that’s what they can express. Like, if you ask your five-year-old child, what are you feeling, well, they don’t feel diarrhea, they feel pain.
Chris Kresser: They say, “Ow.”
Mark Pimentel: And that’s what they tell you about. Yeah, ow, exactly. And so that’s the challenge. But most pediatricians and pediatric gastroenterologists are very well-versed in this and maybe they might treat it empirically. And we have some pediatric [gastroenterologists] that we work with here in town.
Chris Kresser: Are they using the same treatment at just different doses, weight-adjusted?
Mark Pimentel: Yeah, weight-adjusted and it really is the comfort level of the pediatrician in terms of what they might want to use. And certain antibiotics, for example, are not safe in children or may cause graying of the teeth or other things, as you know, related to the growth of different parts of the body. Tetracyclines may not be a wise choice [for] young children. And so having that knowledge as a pediatrician helps in guiding the therapy.
Chris Kresser: Right. Yeah, sounds like probably, if someone has a child who they suspect has SIBO, it’s really good not to put too much stock into the test results for all the reasons that we both mentioned. And I’ve seen this happening a little bit and it concerns me because it can put you down a rabbit hole that may not even be the right rabbit hole. It’s a rabbit hole enough when it’s the right one. But if it’s the wrong one, you definitely don’t want to be going down it. Yeah.
So we can keep this relatively short because I just wanted to do a quick update show and I know you’re overwhelmingly busy [with] a lot going on in the hospital right now. Just [one] last question, anything else? You mentioned earlier some new drug development that you’re working on for hydrogen-predominant SIBO. Anything else on the horizon that you’re excited about or on the SIBO front or the gut front, in general?
Improvements in SIBO Research
Mark Pimentel: You know, to be honest, this was a bad year; 2020 was a bad year for COVID[-19] and all the other things everybody’s experiencing. So obviously, to your listeners, I wish everybody well. But on the SIBO front, this has been a fantastic year because we had the SIBO guidelines in February. We have the huge paper from the Australian group summarizing that patients [with IBS] have SIBO. Full-stop, definitive 25-page study meta-analysis, and that really has been a major factor in swaying the medical community again.
We had the cover of a journal article. I’m not boasting about our particular findings, but we finally know what the small bowel microbiome looks like. And this was over the summer that made the cover of the journal because it’s such a provocative first-time-ever finding of what is the small bowel microbiome. And then this all helps with the development of new drugs. So knowing what bugs we’re talking about and where they’re located is a game-changer for how we develop the drugs of the future. And we’re working on that right now. I can’t give you pie in the sky promises yet because we’re just doing some clinical trials and we don’t know until we know. But I’m very optimistic for next year. I think we’re making amazing progress now.
Chris Kresser: So the idea with that new drug development is to make the drugs both more selective and more effective as a result?
Mark Pimentel: Yes, exactly. I mean, we have a lot. Rifaximin has been fantastic. But only 44 percent of people respond to rifaximin among the [patients with] IBS, at least. We can improve on that. We need to improve on that, and that’s our goal. So stay tuned. We’ll have some stuff coming.
Chris Kresser: Okay. And then on the methane archaea front, that seems like maybe a little bit harder of a nut to crack since we don’t have as much of a history in developing therapeutic approaches for archaea as we do for bacteria. But any just big picture views on what [the] next steps there might be?
Mark Pimentel: Well, I think we’re starting to think philosophically about, do we really need to get rid of the archaea? Or if we just get rid of their hydrogen source, would that be good enough, and then they can’t use their energy? So it may be a different tactic that we take next year, especially with knowing what we know about that study with the lovastatin. Or if we can reformulate the lovastatin in a different way that’s more effective and specifically make it for methane, those are all things we’re contemplating and 2021 will be a lot of thinking.
Chris Kresser: Great. Well, thanks again, Mark, for taking time out of your busy schedule to give us a quick update. And for clinicians, practitioners listening, the test is called trio-smart. It’s been very helpful for us in the clinic, and it’s our go-to now for any SIBO testing. So just give them a call and you can get set up. And Mark, [I] would love to have you back maybe in a year or so once you’ve got some more to tell us about the new things that you mentioned on the show.
Mark Pimentel: I always enjoy being on your show, Chris. And thanks for all the hard work you do for educating people, and I’d love to be back. Thank you.
Chris Kresser: All right, take care.