A New Understanding of SIBO and IBS, with Mark Pimentel

In this episode, we discuss:

• The link between food poisoning, SIBO, and IBS
• IBS and autoimmunity
• Available treatments for people with IBS-D
• Getting treatment for IBS-C and methane-predominant SIBO
• Pimentel’s upcoming study on lovastatin
• Small intestinal fungal overgrowth (SIFO)
• The low-fermentation diet (and problems with the low-FODMAP diet)
• New findings from Dr. Pimentel

Show notes:

• MAST program at Cedars-Sinai
• “RHR: SIBO Update—An Interview with Dr. Mark Pimentel,” by Chris Kresser
• More information about joining Dr. Pimentel’s upcoming study
• “Small Intestinal Microbial Dysbiosis Underlies Symptoms Associated with Functional Gastrointestinal Disorders,” published in Nature

Hey, everybody, it’s Chris Kresser here. Welcome to another episode of Revolution Health Radio. This week I’m really excited to welcome Dr. Mark Pimentel back on the show as my guest. 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 served as a principal investigator or co-investigator for numerous basic science, translational, and clinical studies in areas like IBS and the relationship between gut flora composition and human disease. He’s widely known and sought out for major scientific developments that he’s pioneered, including the discovery that IBS is a condition of altered intestinal microbial activity.

I’ve had Dr. Pimentel on this show before to talk about SIBO and the many outstanding questions and things that we’re still exploring about that mysterious condition, and I wanted to have him back on to discuss that same topic because there have been some new developments in the field and some exciting new announcements that Dr. Pimentel recently made at a conference, as well as some other papers published by different researchers that I wanted to get Dr. Pimentel’s opinion about.

So this one might get pretty technical, but I know that many of you are following this topic closely and I hope you find this to be valuable. Okay, let’s dive in.

Chris Kresser:  Dr. Pimentel, thanks so much for coming back on the show. I’ve been really looking forward to this.

Mark Pimentel:  Chris, it’s great to talk to you again.

Could IBS and SIBO be linked to food poisoning and autoimmunity? Find out in this episode of RHR with microbiome expert Dr. Mark Pimentel. #functionalmedicine #chriskresser

The Link between Food Poisoning, SIBO, and IBS

Chris Kresser:  So let’s start with kind of a 30,000-foot view. How has your understanding of SIBO shifted, if it has, over the past few years?

Mark Pimentel:  Well, it’s a very broad question, but I think my understanding of SIBO has shifted quite substantially in a number of areas. First of all, we now better understand why SIBO is occurring. For example, we’re measuring new antibodies that are derived from food poisoning that can actually be the cause of SIBO. So these are the anti-cdtB and anti-vinculin antibodies, and that can now tell patients what was the mechanism. What started the whole thing? In some cases, or in a lot of cases, it’s food poisoning.

Of course there are other causes of SIBO. Another touch point that’s relatively new, literally just this week, we presented the first deep sequencing of the small bowel at the DDW course, which is our G.I. national meeting. And we were able to show for the first time exactly who were the culprits, particularly in SIBO, of the hydrogen type. The evolution of methane as a component of constipation and the organisms and bugs that are involved there, plus treatments around that are completely changing. So I could go on and on.

Chris Kresser:  Yeah, but that’s a good starting place. Yeah. Let’s dive in to each of those a little bit more because I know we had talked on the last show about the antibody testing. At that time it wasn’t yet available, and it is now. I think it’s called the ibs-smart blood test.

Mark Pimentel:  Yes.

Chris Kresser:  Is that correct?

Mark Pimentel:  That’s correct.

Chris Kresser:  So tell us a little bit more about that particular line of research, where you discovered that after a bout of food poisoning, the body produces antibodies to these proteins vinculin and cbtB. And then that has an impact on the motility of the small intestine that can lead to the development of SIBO. That’s my understanding, is that correct?

Mark Pimentel:  That’s right. So basically, you get a case of food poisoning, usually it’s bacterial like Campylobacter, Salmonella, E. coli, Shigella, those types of things that can happen at restaurants or eating tainted food. And then after that, that diarrhea episode, the diarrhea kind of settles, but there’s a particular toxin that we discovered that is important for you to go from just having that old food poisoning to now developing a motility disorder of the gut.

And while it’s on, it’s been relaunched as ibs-smart because this is a new generation test much more specific. In fact, just dive into the specificity. Both markers, the anti-cbtB and anti-vinculin, are over 90 percent predictive of irritable bowel syndrome with diarrhea. But if both markers are positive, you have a 98 percent certainty.

Chris Kresser:  Wow.

Mark Pimentel:  Well, there’s a lot of, I know we’ve talked about it before, but there’s a lot that this helps patients with. Because you go to your doctor, the doctor says you have IBS. They don’t know why you got IBS. This will tell you why. The doctor says you have IBS, but that’s based on experience, not on any kind of biological marker. This is really a biological marker. And we think these markers are the cause of IBS, particularly the anti-vinculin, that antibody that goes against yourself, which makes the gut slow down. Which makes the bacteria build up. So you’re going to go to your doctor and you’re going to talk to them about the test and they’re not going to know about it because it’s so new.

That doesn’t mean you can’t get it; you just have to tell your doctor you want it. But I’ve been using it in practice now for six months, and it’s helped me immensely to establish that diagnosis and confirm it. And having an organic biomarker means you have a real disease.

Chris Kresser:  Right.

Mark Pimentel:  It’s not in your head. And I think that’s even the most compelling.

Chris Kresser:  Validating for patients. I mean, this is taking IBS out of the realm of being a diagnosis of exclusion where you just exclude other structural conditions like inflammatory bowel disease or diverticulitis or something like that, and then you meet certain criteria and then you just labeled with IBS. Now it sounds like this is not only now a specific diagnosis. I mean, would you go as far as to call it an autoimmune condition, given that the body is attacking itself?

Mark Pimentel:  That’s a great question, Chris. Because the reality is, maybe in a couple of years we’ll rename the condition because it could be an autoimmune disease, IBS, that’s what we’re thinking.

Chris Kresser:  Right.

Mark Pimentel:  At least in the subset that are positive. But another way to look at this is if you end up in a gastroenterologist’s office with IBS or with diarrhea of unexplained etiology or understanding, your doctor’s going to want to do a colonoscopy. You have a copay of $500-plus on that. They’re going to want to do an ultrasound. You’re going to have a copay on that.

They’re going to want to do stool test, blood test. And by the time you ratchet up all those costs, you’re out a couple thousand dollars. Why? Why, if you’re 25 years old, why waste all that effort? You’re going to be taking time off work to do the colonoscopy. If the blood test is positive on both markers, you’re more than 98 percent certain you have the condition.

Chris Kresser:  Right.

Mark Pimentel:  So it’s going to save money in the healthcare system, but also the hassle for patients. Anyways, lots going on there.

Chris Kresser:  Yeah, and I’ve got more questions. So, anecdotally, I don’t know if you did any research on this. I mean, it’s hard because people’s memories are not reliable, but anecdotally, just from your own work, do you find that this is even more likely in people who recall becoming ill after food poisoning, where their symptoms started after an episode of food poisoning? Because I know in some cases that some of these pathogens, we can actually even have them and not have a serious episode of diarrhea and be almost asymptomatic.

I mean, I do a fair amount of stool testing, DNA, PCR stool testing, and sometimes I’ll see Campylobacter, other organisms like that, and the person doesn’t have symptoms. So is it possible that someone could have even had a food exposure to one of these bacteria that can cause this condition and not even known it?

Mark Pimentel:  For sure. And so the thing is, if you’re coming into the doctor with diarrhea, day one of diarrhea, it could’ve been the same, it could’ve been the food poisoning, you don’t know. The other thing is, most food poisonings are marginally eventful. And so you had a little diarrhea, you went on a trip somewhere and you kind of brushed it off. It was one day.

Chris Kresser:  Yeah.

Mark Pimentel:  That would’ve been enough. And so you don’t have to remember some apocalypse of events in your life for it to be triggering IBS or SIBO. So that’s why the markers are so important because it could’ve been something that really didn’t even affect you all that much.

Chris Kresser:  Didn’t register, yeah. So I want to clarify something for the listeners because it might be a little bit confusing. So when you have these antibodies, my understanding is that decreases the motility of the small intestine, the orocecal transit time. So the time it takes something to get from when you swallow it to when it gets to the large intestine, which might be a little counterintuitive. Because someone is saying, “Hey, wait, I have diarrhea. I have frequent stools. So how could this be a condition of decreased motility?”

Mark Pimentel:  Yeah, so, there’s a lot of things that are going on in this process. First of all, one of the things that happens is, as you say, the motility is diminished, but I think it’s even more specific than that. I think it’s actually diminishing the cleaning wave of the gut. So then the bacteria build up, and they, of course, have all sorts of chemicals like lipopolysaccharides that can cause some inflammation. There’s inflammation around the nerves and the actual flow of the gut is different. The absorption of liquid is different.

And so while things may be moving in a different way through the small bowel and may be on a gross level, slowly, if more fluid gets into the colon, you can’t absorb it all and you end up with diarrhea. Not to mention the bloating and the gas and the distention from all the extra bugs that are there from this. So it’s more complicated than simply how slow or how fast the small bowel moves. Some of the … and I’m just going to say one more sort of random thing.

Chris Kresser:  Yeah.

Mark Pimentel:  But there are patients, for example, who have other diseases that are not related to what we’re talking about today, where the gut is very stiff. And so the gut is moving extremely slowly, but it acts like a tube, like a funnel, and doesn’t hold anything in and they have lots of diarrhea. So how fast and how slow the small bowel moves doesn’t really predict diarrhea as a phenotype because things could just be washing through, which is diarrhea.

Chris Kresser:  Right, right.

Mark Pimentel:  I hope that sort of answers.

IBS and Autoimmunity

Chris Kresser:  Yeah, yeah, definitely. So again, just in the interest of helping listeners understand this, so we could say—and I’m not going to hold you to this—but in the subset of people who test positive for these antibodies, especially people who test positive for both, one way of looking at this is that IBS in those situations, or what we’ve been calling the condition previously known as IBS, perhaps it will be at some point, is an autoimmune condition that is affecting the nerves in the small intestine, or in some sense causing nerve damage in the small intestine, and that is what is leading to these symptoms of gas and bloating and altered stool frequency.

Mark Pimentel:  Yes, that’s the hypothesis we’re working with.

Chris Kresser:  Ah, that is a big paradigm change.

Mark Pimentel:  Yeah.

Chris Kresser:  It’s hard to even get my head around all of what that means for approaching this condition. But another question that came up, I think, on the last show when we talked about this—I know that so far this test has only been validated for people with IBS-D, or IBS-diarrhea. So tell me more about that. Why do you think this is not the case for IBS-C, constipation? And do you think it has something to do with, and as an extension do you also, how does this relate to people who test positive for methane-predominant SIBO?

Because for the listeners that are not aware, people who have methane-predominant SIBO, or an overproduction of methane in the small intestine, more often will have constipation than diarrhea. So is this test useful for people who have IBS-C, or methane-predominant SIBO? Or just IBS-D and IBS mixed?

Mark Pimentel:  So, we published one study looking at this, and what we’re able to see is that the test is very helpful, of course, most helpful if there is a component of diarrhea to the condition. So mixed and D is where it’s most fruitful. If you compare IBS-C to healthy people, more people with IBS-C have the antibody than healthy people, although we didn’t have enough numbers to make it, to reach statistical significance. But its power is much less. And we know this from food poisoning outbreaks, that food poisoning outbreaks generally precipitate or result in the diarrhea flavor of IBS, if you’d want to call it that, or the diarrhea or mixed IBS. So really, two-thirds of IBS could benefit from the test.

In regards to your second part of the question, is the mapping, we don’t understand why the methane blooms in this way. Or you get this overabundance of methane organisms and methane production, leading to constipation. And maybe the mechanism is different. So some of the things that I say in lectures now is I’m starting to think that there’s sort of this group of IBS-D and mixed which are the post-infectious and the autoimmune-type markers. And then there’s the other group which maybe the path of physiology is different and the methane just increases for reasons we don’t yet understand, leading to the constipation, then maybe they’re two separate disorders. But we’re still working on that.

Chris Kresser:  Okay, and we’re getting pretty deep into the weeds here, but I’m so sorry, listeners, if you’re not following. But I know a lot of my audience is clinicians and practitioners. So want to get into this. Is there a correlation between breath test results and the ibs-smart test? So, for example, if somebody has only elevated methane on a breath test and not elevated hydrogen, would they be a lot less likely to test positive on the blood test? Or is there not really, have you not looked at that, or is there not a correlation between hydrogen and methane in the blood test results?

Mark Pimentel:  Well, I’ll answer your question and then I’ll sort of lead into sort of a little bit of a different flavor of what I think is important for the audience—

Chris Kresser:  Sure.

Mark Pimentel:  Is that, we think that the hydrogen part of the story is more the diarrhea part and the methane is more the constipation part. And we basically, in our clinic, tend to see that the methane-positive would be less likely to be positive on the blood test. But I think I would look at the breath test and the blood test in a different framework.

It’s sort of like you have a heart condition and you do an EKG and you do an ultrasound of the heart to look for the structural changes. The two tests complement each other. So let me start with the blood test. Your blood test is positive. As a clinician and in my clinic, I’m going to tell you why this all started; I’m going to tell you you’d better avoid food poisoning from here on as best as you can. And I’m not saying don’t travel, I’m saying travel much more cautiously than others.

Because number one, you’re more likely to get food poisoning if these antibodies are positive. Two if you get food poisoning again, the antibodies go higher and you’re harder to treat. You do see, and again, we haven’t published this yet, but we absolutely see a difference in somebody whose vinculin level is super high in terms of their response to treatment, they’re less likely to respond. So the biomarker gives you some prognosis of success of therapy or why therapies are failing. So there’s a lot of value in the blood test.

Chris Kresser:  Right.

Mark Pimentel:  Breath test tells you what to use to treat. So if you’re hydrogen, you’d want to use something more along the lines of rifaximin, which is what we do in our clinic.

Chris Kresser:  Yeah.

Mark Pimentel:  If you’re methane, methane doesn’t respond well to rifaximin alone, and our published double-blind study suggests you should give rifaximin plus another antibiotic like neomycin or even metronidazole.

Chris Kresser:  Right.

Mark Pimentel:  So it stratifies the algorithm of treatment when using the breath test. But the biomarker is extremely valuable at counseling the patient and validating the illness.

Available Treatments for People with IBS-D

Chris Kresser:  Okay, good. I think that’s much, that’s clear now. Thanks for that. So let’s move on to talking how this affects, this really significant paradigm shift in understanding the ideology and pathogenesis of IBS-D, at least, and mixed as being a post-infectious, autoimmune condition that impacts the nerves of the gut. So how is this shifting treatment and how you approach treatment?

Mark Pimentel:  Well, so the treatment is the other part, which is sort of alluded to with the complement of the blood test and the breath test. The other part about the blood test is the higher the anti-vinculin, that’s the auto-antibody, or the autoimmune antibody. The higher that is, the more likely you are to relapse, is what we’re seeing in the clinic now.

Again, where early days we have to do objective publications, peer-reviewed publications on how this works. But but we are seeing this in our clinic, these high-level anti-vinculins tend to require prokinetics to keep the bacteria away once you’ve succeeded with antibiotics. So the marker also gives us some guidance that a prokinetic might be important as a follow-through after antibiotics. A little complicated to go there right now because we haven’t really touched on that.

And the antibiotics we use though, still again, if you’re hydrogen on the breath test, we still give rifaximin. You could simply give rifaximin by itself if the patient has diarrhea because the likelihood is that it’s hydrogen. And you can skip the breath test for hydrogen, but even that’s changing, since hydrogen sulfide is coming soon.

Chris Kresser:  Yeah, yeah. Yeah, I wanted to ask you about that. So yeah, let’s talk a little bit about prokinetics because again, my audience is pretty, they’re pretty sharp on this stuff. So prokinetic, kinetic meaning movement, pro, stimulating movement. So these are medications that increase that cleansing wave that you were talking about that is probably decreased or dysregulated by the antibody production, the autoimmune condition.

Mark Pimentel:  Correct.

Chris Kresser:  And we know that some of the earlier versions of these drugs were eventually pulled from the market because of side effects or adverse effects. So what’s new here? What are you using these days? And what kind of results are you seeing? I know it’s still early days.

Mark Pimentel:  Yeah, so once we’ve given the antibiotic, let’s say the patient responds very well. The person has SIBO, their antibodies are positive, they’ve responded very well to antibiotics. Maybe we put them on a diet, and again, that may come up later in the conversation. But we have to decide, do we use a prokinetic now or do we not use a prokinetic now?

Obviously there are patients where they take the antibiotic and they don’t come back for two years. They’re doing fine. So I don’t want to give somebody a prokinetic if they’re not going to have a relapse for two years. That’s a waste of money and energy on the patient’s part, and also a drug being taken for no reason.

Chris Kresser:  Yeah.

Mark Pimentel:  So sometimes I will wait until the first relapse to see what is the time between instances of SIBO relapse to dictate. So if it’s more than six months, I may not give the prokinetic. If it’s greater than six months, I may give the … if less than six months, I may give a prokinetic. The antibodies are telling me now that if they’re really high I’m going to jump to a prokinetic sooner, maybe even after the first treatment.

But the prokinetic that I generally use following a successful treatment with antibiotics is erythromycin, is a prokinetic at very low doses. And for example, 50 milligrams or a quarter of 250 milligrams, which would give us 62 and a half milligrams, which is cheaper. So that’s what I use sort of as a first line because it’s cheap and it’s safe and it’s been around forever.

But there are two new kids on the block. One is prucalopride and the other is tegaserod and their trade names here in the US are Motegrity and Zelnorm. Now, some of you may remember Zelnorm.

Chris Kresser:  Yes.

Mark Pimentel:  Zelnorm was a drug we had in the last decade. It was a very successful prokinetic, and then there was some suspicion that maybe there was an association with cardiovascular risk or cerebrovascular, meaning stroke or heart attack.

Chris Kresser:  Yeah.

Mark Pimentel:  Well, that was later found to be, there’s no “there” there. And so a company brought the product back, did further safety, and now it just recently got FDA approved. Now, I don’t think you can get a prescription quite yet. I think they’re stocking pharmacies and gearing up production. But prucalopride can be obtained. Now, just to put the context on the two products, they are both, both prucalopride and tegaserod are serotonin agonists. So they basically bind to the serotonin receptors and make the gut move more correctly.

Chris Kresser:  Most people don’t know that. They’ve heard of serotonin as a neurotransmitter in the brain, but there’s actually 400 times more serotonin in the gut, which is why these drugs work in this way.

Mark Pimentel:  Right. And as long as the drug doesn’t cross into the brain through the blood–brain barrier, there is limited or no side effects to the patient. And studies have shown that some of the thoughts around these products were incorrect and that they didn’t create these problems. And so the FDA has reviewed more than a decade of study in Europe because the drug was never taken off the market in other parts of the world.

Chris Kresser:  Right.

Mark Pimentel:  And prucalopride has been available in Europe, I would say, almost a decade. And so all of that data was available for the FDA to review, and certainly they were comfortable with what they learned about the product on the market in other parts.

Chris Kresser:  Okay, so a few questions about these prokinetic options. So erythromycin is an antibiotic, of course, but this is using it at a much lower dose. Do we know anything about the impacts that it has on the colonic microbiome, our beneficial bacteria, when it’s taken at a low dose like this?

Mark Pimentel:  Yeah, so what we’ve seen in the context of erythromycin is that erythromycin at this tiny dose literally is below any MIC, or minimum inhibitory concentration is the acronym, for bacteria. So it really isn’t an antibiotic in any true sense.

Chris Kresser:  At that dose. Yeah.

Mark Pimentel:  So I think what we’ve learned over the years is that it really has had no impact on, it’s not acting like an antibiotic, despite its name. It’s too low a dose. It’s acting like a prokinetic.

Chris Kresser:  Okay. And then I know from some correspondence that we’ve had and other sources that I’ve read that prucalopride is a little bit tricky to take as a prokinetic in the context of this condition and trying to deal with it. My understanding from what I’ve read, and correct me if I’m wrong, is that you have to take it a minimum of four hours after your last meal and then do a 12-hour fast after that. So let’s say if you go to bed at 10 o’clock, you’d have to finish dinner by six and then take it at 10 and then you couldn’t eat until 10 the next morning. Is that how you’re using it? And if so, how many patients have you got to actually use this regularly?

Mark Pimentel:  So it’s not quite that stringent.

Chris Kresser:  Okay.

Mark Pimentel:  Generally what we do is we—say it’s two hours after the last meal of the day or at bedtime. So if you eat at 8 p.m. and you go to bed at midnight, that’s perfect.

Chris Kresser:  Okay.

Mark Pimentel:  At 8 p.m. and you take it at 10:30, that’s fine too. As long as you don’t take any calories in the two hours preceding the dose. And it’s not that that’s going to hurt you by taking it closer. It simply means that you’re not in a fasting state, you’re not going to trigger the cleaning waves. And to be honest, erythromycin only has, I would say, six hours of activity anyway. So you don’t need to fast for 12 hours after any of the prokinetics. I think if you’re fasting overnight and you’re just sleeping for eight hours, that’s plenty of time.

Chris Kresser:  Yeah, okay. That certainly seems easier. When I read that, I thought man, there’s going to be some complaints issues with this medication. But what you’re saying here is just pretty much what was recommended in general. Don’t eat too close to bedtime and don’t eat during the night. I think most people could probably handle that. Do you see any meaningful difference in terms of efficacy between these medications? And I know you mentioned that you’ll tend to use erythromycin first because it’s cheaper and readily available. Is there any difference in efficacy that you’ve witnessed? Or is it mostly just a question of cost and convenience?

Mark Pimentel:  In terms of choosing which one?

Chris Kresser:  Yeah, exactly.

Mark Pimentel:  So erythromycin, funny things are happening with drug companies—and I don’t want to get off on too far a tangent—but we’ve gotten into this situation, and I think Congress is even looking into this, where generic drugs that have been around for decades generally were lower cost because they’ve been around a long time and manufacturing has been nailed down and it’s easy to make and all of that. But once generics start dropping drugs and then there’s only one or two manufacturers, they can take the opportunity to increase the price.

Chris Kresser:  Yeah.

Mark Pimentel:  So I’ve seen erythromycin in the days where it was five dollars to buy a whole month of erythromycin, and now the prices have all been jacked up. And so erythromycin still is anticipated to be cheaper than prucalopride or tegaserod, but those gaps are changing because the makers of erythromycin have increased the price.

Chris Kresser:  And what about insurance approval? Like, I know one of the main issues clinically that we have with rifaximin is that it’s only approved for IBS-D if they failed other treatments, and it’s not actually technically approved for SIBO. So if you prescribe prucalopride or tegaserod or even erythromycin in this situation, are patients getting insurance coverage?

Mark Pimentel:  Yeah, I mean, that’s a fantastic question, and again, the answer is a little complicated.

Chris Kresser:  Yeah.

Mark Pimentel:  But let me start with rifaximin because I think your audience needs to sort of  understand how this is framed out. So let’s go back to the 1980s. A condition called peptic ulcer disease. So you have an ulcer in your stomach or in the first part of your small intestine, you scope, you see this ulcer, it’s like a crater, and that’s called peptic ulcer disease.

And then a gentleman by the name of Dr. Barry Marshall discovered that H. pylori, Helicobacter pylori, was a bacteria that causes peptic ulcers. And so all of a sudden ulcers were being treated with antibiotics. And then, now ulcers are going away because—but where I’m getting to with all this—we didn’t change the name “peptic ulcer disease” to “H. pylori disease.”

Chris Kresser:  Right.

Mark Pimentel:  It’s still peptic ulcer disease. But 70 percent of peptic ulcer disease was caused by H. pylori. It’s the same thing here. So we have irritable bowel syndrome, which is the constellation of symptoms by which you present to your physician, and by definition you are IBS-D. Now we now know that IBS-D, 70 percent of it is caused by SIBO. But it is still IBS-D.

So it is fully legitimate in my mind to say that despite SIBO being the cause of your IBS-D, you have IBS-D and should be qualified for rifaximin. And using that terminology, but your physician has to qualify you as IBS-D but that SIBO is the cause.

Chris Kresser:  Yeah.

Mark Pimentel:  So that should clear up the issue because as long as you put IBS-D there, 80-plus percent of patients are covered to a greater or lesser extent by their insurance. So maybe a co-pay.

Chris Kresser:  Right.

Mark Pimentel:  When it comes to the prokinetics though, it’s a bit of a free-for-all because both of the two more modern prokinetics, the tegaserod and the prucalopride, are totally brand new. And because they’re totally brand new, insurance companies are still trying to figure out the product and where it’s going to be placed in their algorithms.

Chris Kresser:  Right.

Mark Pimentel:  So almost universally they’re being denied without petition, and the doctor has to get the prior auths in and push the insurance company to pay for it. And we’re getting insurance to cover some of it, but we’re getting a lot of pushback early on, even a few months.

Chris Kresser:  Yeah, yeah. And then the erythromycin, I mean that’s obviously been around for a long time. But this is an off-label use, I would imagine. So is that also typically pushback from insurance companies?

Mark Pimentel:  Yeah, we’ve gotten a lot less pushback from erythromycin simply because it’s an older product and insurance companies don’t pay attention to that as much.

Chris Kresser:  Yeah.

Mark Pimentel:  But 80 percent of drugs used by clinicians are off label. So being off label and an old drug doesn’t really create a lot of stress or concern by insurance companies.

Chris Kresser:  Yeah, yeah, okay.

Mark Pimentel:  It’s a typical thing.

Getting Treatment for IBS-C and Methane-Predominant SIBO

Chris Kresser:  So, I want to circle back to the use of these drugs in the context of IBS-C and methane-predominant SIBO, which, I mean, it’s interesting to me because these drugs are being again used in a condition where, just when someone’s thinking about their overall motility, they have diarrhea. And then they’re taking prokinetics.

I mean, you’ve explained very well why that is necessary and helpful. But is the converse also true that even though you would kind of assume if someone’s motility, overall motility, is decreased, as in the case of constipation, that pro-motility drugs would be effective that they’re actually not? Because, you know, especially if the antibodies aren’t positive?

Mark Pimentel:  So I guess I’m trying to understand the question. Are you suggesting, well, why not just do prokinetic versus treating …?

Chris Kresser:  Well, let’s say someone comes in and they have IBS-C and they test positive for methane-predominant SIBO, but they don’t have antibodies. Would prokinetics still be effective in that situation? Or are they not because there the mechanism isn’t the same as the decreased motility in the small intestine? Or we don’t at least know that it is?

Mark Pimentel:  Got it. Yeah, I got it. So again, it’s complicated.

Chris Kresser:  That’s all right. I’m not trying to give you a hard time. It’s just—

Mark Pimentel:  No, I mean, your questions are amazing, to be honest, and they’re really sophisticated and kind of the things that we’re working through. Because these are questions we ask ourselves as we go through what’s the next step in the science to prove this and then the next thing and the next thing.

Chris Kresser:  Yeah.

Mark Pimentel:  But if you get rid of methane—and if I can get rid of methane in that person down to a very low level, their bowel movements are normal. So obviously they do not need a prokinetic.

Chris Kresser:  Right.

Mark Pimentel:  The problem we have is that antibiotics, like the cocktail that I mentioned earlier, rifaximin plus neomycin, it will reduce your methane to a normal level 80 percent of the time. The problem is, the methane keeps wanting to come back.

Chris Kresser:  Yes.

Mark Pimentel:  Often, unlike the other side, the diarrhea side, where you can take rifaximin, you could go a year or two years without any recurrence, methane is generally recurring a month or two later. Because those bugs are hard to get rid of. Remember, methane bugs are archaea, they’re not bacteria. We didn’t design antibiotics for archaea.

They’re just designed as antibacterials, and it’s only fortunate that we can get some cocktails that have some influence. But they’re not really killing the bugs as much as we want. So we’ve been trying to come up with better ways, but in the meantime, yes, we give the antibiotic and we give the prokinetic hoping that the methanogens don’t relapse. But it isn’t because of the autoimmunity.

Chris Kresser:  Right.

Mark Pimentel:  It’s a different sort of mechanism.

Chris Kresser:  So there’s some possibility that prokinetics, just by stimulating that cleansing wave, make it harder for the archaea to reestablish themselves. But it’s not by the same mechanism.

Mark Pimentel:  Right. That’s a trickier proposition for, because … So, I’m not of the mindset that diarrhea is a treatment for constipation. I’m not of the mindset that laxatives are what patients should be on the rest of their life to treat constipation.

Chris Kresser:  Yeah.

Mark Pimentel:  I’m of the mindset of “Why do they have constipation?” and treat the why, and then the bowel movements become normal. And methane is part of that story of you get rid of the methane, you don’t get diarrhea, you just feel good and you feel normal.

Chris Kresser:  Yeah.

Mark Pimentel:  And that’s where we’re heading. But that’s where lovastatin comes in. We haven’t gotten to that yet.

Chris Kresser:  Yeah, well, let’s get to that. But Mark, I have to say, you’re a Functional Medicine practitioner at heart. Always looking for the underlying cause. That’s what I appreciate about you.

And I think I mentioned this in our previous interview, but I, for the listeners, I saw Dr. Pimentel as a patient. This has got to be 20 years ago now, when I had gotten back from Indonesia and had my episode of serious food poisoning, which is what started all of my symptoms. So this is, of course, of great personal interest for me as well.

But I’ve always appreciated your relentless pursuit of what’s the real cause of what’s going on here, instead of just being content to use antibiotics for the rest of the patient’s life. I mean, sometimes you need to do that over and over, but ideally we get to a place where we better understand these conditions and we can develop treatments that don’t have as much potential for harm.

Mark Pimentel:  Well, and thank you for that very gracious commentary and also sharing your story. But I hate, and I’ve always fought against personally in my own personal career, single-mindedness. Because—and I’m not picking on Functional Medicine per se—but there are people who are very pro-yeast being a problem. But then every patient that comes in the door is a yeast problem.

Chris Kresser:  You’ve got a hammer, everything looks like a nail.

Mark Pimentel:  Everything looks like a nail. Now I’m not saying yeast isn’t a problem in a subset of patients. It think it is, actually, and we could discuss SIFO at some point during this.

Chris Kresser:  Yes.

Mark Pimentel:  But I do believe that there is, but a lot of scientists, and this isn’t a Functional Medicine thing or a science thing, but a lot of scientists themselves are looking at everything as a nail once they find something.

Chris Kresser:  Yeah.

Mark Pimentel:  I have seen too many people get in trouble and trapped in those kinds of mindsets. Not everything’s going to be a nail, and we have to find a different solution for a different problem. And I recognize that antibiotics are not going to work for IBS-C and methane requires a different hammer, because it’s a different animal. Maybe a screwdriver.

Chris Kresser:  Right.

Mark Pimentel:  And you have to move on.

Chris Kresser:  Yeah. I agree with that 100 percent. One of my mentors in medicine used to also say, “If you look for something hard enough, you usually find it.”

Mark Pimentel:  Yeah.

Chris Kresser:  So that kind of myopic focus doesn’t really serve anyone. So a couple things you had mentioned, well, you just mentioned lovastatin, and I was going to ask you about other treatments for methane-predominant SIBO that you’ve been investigating. So maybe that’s a good segue.

Dr. Pimentel’s Upcoming Study on Lovastatin

Mark Pimentel:  Sure. Should we talk about lovastatin?

Chris Kresser:  Sure, yeah.

Mark Pimentel:  Okay. So lovastatin—and this is something that was derived from some data we were seeing coming out of animal literature, veterinary world—but lovastatin appears to reduce methane in animals, in cows and other ruminant animals.

And what we started to study in our lab is, okay, well, let’s study all the statins that are out there. Well, first of all, we looked in our database and we couldn’t see a pattern where statins were associated with less constipation. The problem was what we didn’t realize until we did the research in the lab is that a statin is not a statin is not a statin.

When we tested lovastatin, we got immediate reduction of methane. But every time that lovastatin molecule was broken or readjusted to make your cholesterol go down, it was ruining what nature developed, which was lovastatin. And so going back to the original thing I said, we couldn’t find a pattern because most people are on contemporary statins that are human made, meaning the molecules have been modified specifically in a way that makes cholesterol go down. But it’s ruined the natural lovastatin’s ability to drop methane.

So back to the story is that you’ve got to get the original lovastatin from the fungus that’s called Aspergillus and that lovastatin blocks an enzyme in the methane-producing organisms so that they stop producing methane. We saw it in the lab, then we partnered with a company to develop one that’s non-absorbed, that stays in the gu,t and that currently is coded as SYN010 or SYN10 and that product is in clinical trials right now.

The first clinical trial showed that it dropped methane, and when methane dropped, constipation got better. Small study, but now we’re in the midst of a big phase two study. And we’re recruiting right now. So if any of your viewers are in California and they’re constipated and methane, we’re looking for folks. Sorry for the plug.

Chris Kresser:  No, we’ll put that in the show notes on the website.

Mark Pimentel:  We’re hopeful that it’s going to help a lot of people with C IBS, or constipation, who have methane.

Chris Kresser:  Great. Yeah, so after, I’ll follow up and get the link and we’ll put it in the show notes. So anyone that wants to participate in that can. And just let me clarify. So in this case, this SYN010 new derivative of lovastatin, or old perhaps, is not being systemically absorbed, you said? So it’s not going to have any impact on cholesterol or would not be expected to have some of the potential side effects that statins have?

Mark Pimentel:  Correct. So what we saw in the first trial is really essentially little or no side effects from the statin. Not at the rates you would expect from absorbed statins—

Chris Kresser:  Right.

Mark Pimentel:  Muscle aches and liver tests and all those changes, because it’s not absorbed. And the studies of absorption of this modification of lovastatin show that it hardly gets absorbed into the bloodstream. Which is again, it’s sort of like rifaximin, where rifaximin is antibiotic but doesn’t get absorbed. And lovastatin is a statin that doesn’t get absorbed. So cholesterol is not going to go down with this.

Chris Kresser:  Right.

Mark Pimentel:  If you’re looking for cholesterol, this is not the right thing.

Chris Kresser:  Right.

Mark Pimentel:  Clearly a drug for bugs.

Chris Kresser:  Right. Okay, so, and then would this be a situation where people would take it for a certain period of time, almost like an antibiotic, and then just if it recurs, take it again? Or would they take it continuously to keep the archaea and the methane production inhibited? Because it’s not, is it actually killing the archaea by disrupting the enzyme? Or is it just decreasing the methane production of the archaea?

Mark Pimentel:  In the study we’re doing currently, we’re going to get those exact questions.

Chris Kresser:  Right.

Mark Pimentel:  What we saw in the first trial, we didn’t do all the microbiome stuff in the stool. But what we saw on the first trial is that in some patients, and there was a handful of patients where methane disappeared after the drug for a long period of time after. Even though you stopped the product, they continue to have no methane recurrence. And I think some of those are still methane free.

So I don’t know what it, obviously, if the methane organisms are not producing methane, they’re not producing energy. If they’re not producing energy, they’re weakened and maybe they can’t multiply.

Chris Kresser:  Right.

Mark Pimentel:  And I think what happens is a new world order of the microbiome takes over, and so in that vacuum of the methanogens, other organisms fill in the gap, and then the methanogens can no longer kind of—

Chris Kresser:  Right, they get outcompeted.

Mark Pimentel:  Yes, exactly.

Chris Kresser:  Yeah. Survival of the fittest in the microbiome, yeah.

Mark Pimentel:  Game of Thrones in the gut.

Chris Kresser:  Yeah, that’s right. Hopefully a better outcome in the gut.

Mark Pimentel:  Yeah, we don’t want to repeat Season 8 in the microbiome.

Small Intestinal Fungal Overgrowth (SIFO)

Chris Kresser:  You don’t want the Drogon torching effect of Westeros. But yeah, so you mentioned SIFO. I’m glad you brought that up because I somehow had forgotten to include that in the bullet points I sent you for questions that we might cover. But I’m really glad you reminded me. Because I’ve been curious about this.

There have now been, I think, two, or is it three, studies that have been published in the literature about this? And for the listeners, this is small intestinal fungal overgrowth as opposed to bacterial overgrowth. So what do we know about this condition so far? And as far as I understand, there’s still no commercially available testing for it that clinicians can order.

Mark Pimentel:  Yeah, so SIFO is a little complicated. Dr. Satish Rao, a very good friend of mine, I saw him just this past weekend at the meeting, he studies SIFO. But again, it’s a very complicated approach. He has to do a scope, get in the small bowel, take the juice out and then specifically culture using his lab to find out if the fungi are there.

And then in that group, and if I’m correcting what he’s previously presented at these meetings, it’s a small minority of patients with IBS-D or presumed IBS-B in patients with bloating that have SIFO. But obviously when it’s identified and he identifies it, the patients respond very well to antifungals. I think we’ve all seen this in our clinic. We do have patients where if we give an antifungal, nothing else is working, that they benefit.

Chris Kresser:  Yeah.

Mark Pimentel:  It’s going to be a subgroup of this population, and I don’t know what it has to do with the antibodies yet and how all that fits together, though.

Chris Kresser:  Yeah. Yeah, I’ve often wondered in a subset of patients who we treat with antibiotics for SIBO who get worse, I’ve found myself wondering if they have SIFO and if reducing the bacterial levels in the small intestine actually makes it easier for the fungal organisms to win the “game of thrones,” so to speak, in there. And that’s why they’re getting worse. But, I mean, we don’t have, obviously, the research we need yet to answer those questions. But it has crossed my mind.

Mark Pimentel:  The data are coming. One of the things that we received a lot of attention this past weekend was our new effort here in the MAST program, is the REIMAGINE study. So, the REIMAGINE study, for your listeners, is any patient coming for scope, an upper scope—not a colonoscopy because we don’t want that clean washout—we’re taking juice from the small bowel and doing—and genetics and blood and all the characteristics of the patients and questionnaires—and we’re compiling it into a massive data set to associate what bugs are there with what disease.

So our hope, of course, is to characterize SIBO, which we presented this past weekend. And SIBO is characterized, at least the hydrogen SIBO, by excessive proteobacteria, which are E. coli, Klebsiella, and those types. And that was a big finding. It was a plenary session at this meeting. But that session showed deep sequencing correlated with culture, correlated with breath test, and correlated with patient symptoms.

So for the first time we were able to say with great certainty that the breath test is absolutely valid and absolutely predictive of the bugs that are in the small intestine. And now we know what bugs are there. But the reason I went into this whole tangent on the REIMAGINE study is because we will be looking at fungus at some point from this juice we’ve taken out.

Chris Kresser:  Right.

Mark Pimentel:  And we will be looking at associations between all these microbiome in the small intestine and human diseases like diabetes, Parkinson’s, and all of that kind of stuff. And so we’re at the beginning. We only have about 400 patients on our way to 10,000. But we’re going to keep plugging along. We’re already finding connections.

Chris Kresser:  Yeah, that’s exciting and definitely seems like the next step here, especially drawing the connection between what you see with the DNA PCR testing and the breath test and symptoms. So that there’s a clear line between those things. Now, to that end, there was a recent paper in Nature which I know you have seen that had findings which, at least on the surface, seemed to contradict what you just said. So I’m curious to hear your take.

They found an inverse correlation between microbial diversity in the small intestine and G.I. symptoms and intestinal permeability. But they found that the presence of bacterial overgrowth in the small intestine, as I think they measured by aspirate, didn’t correlate with symptoms. So essentially they were saying that bacterial overgrowth wasn’t connected to symptoms, but reduced diversity, or we could say dysbiosis in the small intestine was. So first of all, did I characterize that correctly? And second of all, what did you make of these findings?

Mark Pimentel:  Yeah, so this is a study from the Mayo Clinic. And, I mean, I don’t want to go all off on the study, but the first problem with the study is nearly 50 percent of patients in that trial had SIBO. Which no study has ever shown that that many people have SIBO.

So first of all, in culture specifically, so the population is a little bit suspicious. Either these patients were hand chosen because of symptoms, because what we’re doing is we’re just taking all comers. The second thing is there’s a lot of concern in how they determined SIBO. Because they added the anaerobic culture to the aerobic. They added all the cultures together. We don’t do that because that isn’t traditionally how SIBO is defined. SIBO is defined as using MacConkey agar, or a particular type of growth on a particular type of media that cultures colon bacteria. And those are the bugs that are predictive.

And the final thing is, to my knowledge, they don’t describe the catheter they used, which can get contaminated as you push it through the scope. What we do—or they don’t use a catheter at all. They don’t describe it. We had to develop a catheter that had two lumens. One tube inside another with a cap on it, that as we push it through the scope, it’s not getting any of the junk that was sucked in the scope as they were passing it through, so no oral flora, no esophageal flora, no stomach acid or juices.

And then we had to validate that. We spent a year validating the techniques for isolating bacteria from the thick mucusy juice from the small intestine. And you can’t use the sequencing technology or sequencing methods from stool because it doesn’t work well in the juice. So once we did our, validated our technique, then we applied our statistics. And we found much less SIBO than they did. And we also identified the specific organisms that they didn’t.

And so I have a lot of things to say about that paper that don’t quite add up. And I think others are finding the same thing.

Chris Kresser:  Yeah. Oh, we’ll look forward to more of your findings. Because it sounds like you’ve got a great model now set up to collect these data.

Mark Pimentel:  Yeah.

Chris Kresser:  So the other thing that that paper suggested or that they found, and I’m not, I have to go back and look at the exact methods. I’m not recalling them off the top of my head. But they found that a low-residue diet or low-fiber diet, what we might characterize the Standard American Diet as, which is also what’s often recommended for patients with SIBO, may cause dysbiosis in the small intestine and worsen symptoms. So I wanted to ask you about your take on that, and I imagine that a lot of the things you just said would probably impact your answer to this. Because if the way that they collected the data wasn’t sound, then this would all not be really reliable anyways.

Mark Pimentel:  Well, I think that’s the big problem is, is how did they collect all of this? And was their methodology correct? And just based on what we know from the North American Consensus and information that we currently know, that they’re not using, they never validated their techniques to begin with, in my opinion. So that’s a problem, first and foremost.

But taking it in a little slightly different direction, we do know, for example, that the low-FODMAP diet, which is the extreme low fermentation, I mean, it’s the ultimate low-fermentation diet, it does reduce diversity in the intestinal tract, at least in the stool. I mean, people haven’t studied the small bowel until the paper you just described. But it does reduce diversity, which can potentially be something harmful. But we have to study what happens in the small bowel using a bit more rigor, and hopefully that’ll come in the coming years.

The Low-Fermentation Diet (And Problems with the Low-FODMAP Diet)

Chris Kresser:  So since we’re on the topic of diet, is there anything else that’s changed in that world for you, especially related to just the overall shift in the understanding of SIBO, at least with IBS-D and IBS mixed, as an autoimmune condition that’s affecting the nervous system of the gut? Or are your recommendations still pretty much the same?

Mark Pimentel:  I think, so we, just to be clear, we tend to use what’s called a low-fermentation diet. Something that we put together. The intention of the low-fermentation diet is that you can take this diet and eat in almost any restaurant in the country. My goal in life, as I said before, is to find the cause of a disease and treat it.

But my secondary goal is I want patients to live a normal and live their best life. And if all they do all day is not want to go to restaurants with friends because they have to ask the waiter 20 questions before they order anything, that’s embarrassing for them. So the diet is less restrictive than the low-FODMAP diet. But I think what we’re learning is that—and this is relatively new to the last year—is that the low-FODMAP diet may not be the be-all and end-all that we thought it was.

Certainly, and this is for your viewers, and I’m going to emphasize this, you should not be on the low-FODMAP diet more than three months. Because we know that you get nutritional deficiencies from it. It’s too restrictive. That means you should be managed by a dietician or by somebody who’s experienced with it because you have to reintroduce foods with time. It also reduces diversity of the microbiome, which may be harmful in the long run.

Chris Kresser:  Right.

Mark Pimentel:  Sometimes I see these patients in my clinic and they’ve done a low-FODMAP diet for a year. And I’m like, wow, that’s—

Chris Kresser:  Or longer. I mean, yeah, I mean, is it possible that the low-FODMAP diet for an extended period of time could reduce diversity in the microbiome, which then leads to decreased capacity to digest FODMAPs? Or process them?

Mark Pimentel:  Yeah, it’s not clear. Because if you change your diet so dramatically, it may create an imbalance that, like I said with the methane, we just impact one organism and all of a sudden the methane doesn’t come back, that may create that new world order that’s beneficial. But if you reduce 500 different organisms or 100 different organisms, you’re changing metabolic pathways in many ways that we don’t quite understand.

Chris Kresser:  Right.

Mark Pimentel:  And so, like everything else, I think your mother probably, my mother taught me this, do everything in moderation, and actually take that to heart.

Chris Kresser:  Yeah.

Mark Pimentel:  You shouldn’t be extreme in anything. You should eat broccoli, but that shouldn’t be all you eat.

Chris Kresser:  Right. Yeah, I mean, it’s, I mean, we know from other studies that, like, for example, people in Japan who live in certain parts of Japan, especially where they eat a ton of seaweed, their gut microbiota changes from that to actually produce more of the compounds that help to digest those typically non-digestible polysaccharides. So it makes sense to me that if you cut foods out of the diet for too long, that we might actually start to lose the production of enzymes and other compounds that are required to digest those foods. Because the body’s pretty ruthless when it comes to that kind of thing. From an evolutionary perspective, if it’s like, “Hey, if we’re not needing to digest these things, we’re going to conserve energy or the bacterial microbiome as well.”

Mark Pimentel:  Yeah, and the question is, once you’ve lost that organism in your gut, how easy is it to get it back if you do bring those diet—

New Findings from Dr. Pimentel

Chris Kresser:  Yes. If it’s, yeah, dropped to a point where you can’t get that. And that leads to a whole other conversation about things like probiotics and FMT, which we don’t have time for. But I just wanted to finish up by giving you a chance to talk about any other findings. I know we’ve talked about some of the new findings, maybe all of them that you announced at the conference. Anything else that you want to tell us about?

Mark Pimentel:  There were two other big things that we presented at the conference that may be important to your listeners. Number one is the proton pump inhibitors, they really don’t change the microbiome and they don’t really cause SIBO or a change in diversity. This is part of the REIMAGINE study. And this was a huge number of patients, over 150 patients in that study.

Chris Kresser:  Wow, that really contradicts some of the previous ideas or findings there.

Mark Pimentel:  Yeah. And it’s very definitive. And then the second thing is using these new techniques that we’ve been spending more than a year validating in our lab, we’re now able to assess the microbiome, the DNA from bacteria, in samples that are informal and sitting in the pathology department for years.

Chris Kresser:  Wow.

Mark Pimentel:  So we were able to go back and look at old appendectomies from appendicitis, and we found that between 30 and 45 percent of appendectomies are for food poisoning. So it turns out Campylobacter was sitting in the appendix causing the inflammation. Or that’s what we believe. And maybe you could have been treated with antibiotics, didn’t need to take the appendix out.

But the important aspect of that is for all the years of appendicitis, the number one surgical procedure in the U.S., nobody knew what caused it. And maybe Campylobacter is the cause of appendicitis in at least a third. So that’s pretty exciting.

Chris Kresser:  Wow, yeah. That doesn’t surprise me at all and it is, because it’s, like, why would the appendix just go crazy all of a sudden? And now I always wondered about it, a possible infectious agent. And, yeah, that’s quite an amazing—

Mark Pimentel:  Imagine what we could do with all the different tissues from different things that happened in the body.

Chris Kresser:  Right.

Mark Pimentel:  And now we can start.

Chris Kresser:  Well, it makes me wonder about gallbladder.

Mark Pimentel:  Yep, that’s on our list.

Chris Kresser:  Yeah.

Mark Pimentel:  Stay tuned.

Chris Kresser:  Yeah, great. Well, so, you seem to be a busy guy, Dr. Pimentel, and it’s all great work. But what’s next in the most immediate future? I know we touched on hydrogen sulfide earlier and then on the last show. So I gather that those findings aren’t quite ready yet. But must be coming in in the near future.

Mark Pimentel:  Oh, it’s coming very soon. And I always say that, and people are … but that’s not tomorrow. And the problem is, things are out of my hands sometimes.

Chris Kresser:  Yeah.

Mark Pimentel:  And those commercial, the commercial people, do things in a particular way or order, and it’s one of the benefits of doing it right. But it just takes longer than I wish it could.

Chris Kresser:  Sure.

Mark Pimentel:  So that clinicians can have access to it.

Chris Kresser:  Are you able to tell us whether this is related to diagnosis or treatment or both?

Mark Pimentel:  The delays?

Chris Kresser:  No the, what’s coming.

Mark Pimentel:  Oh, no, it’s for diagnosis and, we believe, treatment.

Chris Kresser:  Okay.

Mark Pimentel:  So hydrogen sulfide is, we think, the cause of the diarrhea side. And it’s supplementary to the hydrogen. So it’s going to be, make a big impact. And so I’m looking forward to that.

Chris Kresser:  Yeah, definitely. I am, too, of just having a way to test for that and be certain. I mean, we have just a suspicion at this point based on sometimes certain presentations with clinically and with the blood test, or with the breath test. But it’ll be great to be able to pack that up with perfect valid tests.

So, Mark, thank you so much again. I know that people are going to love this show. We covered an amazing amount of ground in a relatively short period of time. But very much appreciate your time and just your life’s work here in this field. It’s enormously helpful for clinicians and for patients because I don’t need to tell you that so many people are affected by this condition.

I mean, IBS is now the second leading cause of people missing work. It’s really an epidemic. And so finding answers here is just going to help so many people. So thank you for continuing to do this work.

Mark Pimentel:  Oh, thank you for having me on the show, and I know that what you’re trying to do to disseminate accurate information is very valuable. And patients are much more important than they were before, and we just want to make sure what’s out there makes sense and it is true to data, and not just because there’s a lot of misinformation. Thank you.

Chris Kresser:  Yes, absolutely. Yeah, it was my pleasure. And I hope to have you back at some point for all of the latest discoveries. There’s always, it’s always moving forward, and that’s what’s great to see.

Mark Pimentel:  Yeah.

Chris Kresser:  All right.

Mark Pimentel:  Thanks again, Chris.

Chris Kresser:  Take care. Bye-bye.