The Gut Health Podcast

The Gut Microbiome + Dysbiosis

• Kate Scarlata and Megan Riehl • Episode 22

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Dr. Mark Pimentel, Executive Director of the MAST program at Cedars-Sinai in Los Angeles, shares groundbreaking insights into the small intestinal microbiome that challenge long-held beliefs about gut bacteria. Findings from his team’s REIMAGINE study reveal that the small intestine is far from sterile, as previously thought—instead, it harbors substantial bacterial communities that play a critical role in health and disease, especially in conditions such as IBS and SIBO.

• E. coli and Klebsiella act as aggressive "Ferrari" bacteria that outcompete other microbes and destroy microbial diversity when overgrown inducing a "apocalyptic" disruption of the small bowel microbiome.
• Lactobacillus, commonly found in many probiotics, may act as a disruptor in the small intestine and new research correlates higher small intestinal levels with obesity and unhealthy aging (more research needed)
• The PLACIDE trial found probiotics didn't reduce C. diff or antibiotic-associated diarrhea but did increase bloating
• Food poisoning is the only proven cause-and-effect trigger for IBS, with stress acting as a modifier rather than initiator
• Combining rifaximin with NAC works 10x better for SIBO by targeting bacteria in both intestinal fluid and mucus
• A new compound (CS06) shows promise for reducing methane production and relieving constipation
• Three distinct gas patterns (hydrogen, methane, hydrogen sulfide) correlate with different symptom patterns and respond to targeted treatments

This episode was sponsored by Salix Pharmaceuticals. 

Resources: 

DDW 2025 Abstracts by the Mast Program and Dr. Pimentel

A Novel Microbiome Therapy, CS-06 (MTD Blocker), Reduces Methane Production in Stool Culture

Real World Study of Three-Gas Breath Testing Nationwide and The Association with Symptoms






Learn more about Kate and Dr. Riehl:

Website: www.katescarlata.com and www.drriehl.com
Instagram: @katescarlata @drriehl and @theguthealthpodcast

Order Kate and Dr. Riehl's book, Mind Your Gut: The Science-Based, Whole-body Guide to Living Well with IBS.

The information included in this podcast is not a substitute for professional medical advice, examination, diagnosis or treatment. Always seek the advice of your physician or other qualified health care provider before starting any new treatment or making changes to existing treatment.

Kate Scarlata, MPH, RDN:

This podcast is sponsored by Salix Pharmaceuticals.

Kate Scarlata, MPH, RDN:

Maintaining a healthy gut is key for overall physical and mental well-being. Whether you're a health-conscious advocate, an individual navigating the complexities of living with GI issues, or a healthcare provider, you are in the right place. Or a healthcare provider, you are in the right place. The Gut Health Podcast will empower you with a fascinating scientific connection between your brain, food and the gut. Come join us. We welcome you.

Dr. Megan Riehl:

Hello friends, and welcome to The Gut Health Podcast, where we talk about all things related to your gut and well-being. We are your hosts. I'm Dr Megan Riehl, a GI psychologist.

Kate Scarlata, MPH, RDN:

Hello, and I'm Kate Scarlata, a GI dietitian. Today, on The Gut Health Podcast, we're joined by a true pioneer in digestive science, Dr Mark Pimentel. Renowned across the globe for his groundbreaking work in gastroenterology, Dr Pimentel serves as the Executive Director of the Medically Associated Science and Technology, also known as MAST program at Cedars-Sinai Medical Center in Los Angeles. At the helm of the MAST program, Dr Pimentel leads an innovative team that's unraveling the complexities of the human gut. Their focus conditions like irritable bowel syndrome, IBS, a disorder that affects nearly 1 in 10 people worldwide, as well as the lesser-known but increasingly important small intestinal bacterial overgrowth, or SIBO, and intestinal methanogen overgrowth, or IMO. Today's topic is the gut microbiome and dysbiosis. Welcome back, Dr Mark Pimentel.

Dr. Mark Pimentel:

It's great to be back with you. It's exciting. It's the summertime, but people are still interested in the microbiome. What a thought time, but people are still interested in the microbiome what a thought.

Dr. Megan Riehl:

Well, Dr Pimentel, we want to kick things off today with you with a myth buster and, you know, with summer, whatever it may be. What do you think our listeners need to know in the myth busting world of the microbiome?

Dr. Mark Pimentel:

I think the biggest myth that we deal with on a daily basis is that the magic is really in the dual microbiome only. And if we're going to talk about microbiome, a lot of what I'm going to talk about is the small intestinal microbiome, which is harder to get to. They used to think that the small intestinal microbiome was sterile. There was no bacteria there, or hardly any, and now we know it's abundant, and the bacteria there are giving you things that you don't want, sometimes giving you things you do need, and that's the myth. The myth is that the bugs that we thought were only in the colon are in the small bowel as well, and they can create problems for your health.

Kate Scarlata, MPH, RDN:

I often think like are we going to start looking a little closer at the mouth microbiome, the esophagus microbiome, the stomach microbiome, all these places that seem to be inconsequential but maybe are playing a role, even if the bacteria numbers are vastly different and less, etc. But let's kick it off with what is gut microbial dysbiosis and why should we care?

Dr. Mark Pimentel:

You know, dysbiosis used to be a dirty word or a word that people didn't like to use because it had really no meaning. It just means there's a problem with the microbiome, and that's like saying there's a problem with your arm. That's a diagnosis. No, that's not a diagnosis. There's a problem with your arm. We need something more specific. So I think the term dysbiosis has been thrown around and again still doesn't have any meaning.

Dr. Mark Pimentel:

But I think what we're trying to do, or what people are trying to say, is that it's an overarching term that says there's something wrong with your microbiome and it could be this, it could be this, it could be this, and in each particular instance, it can have different ramifications on your health and your condition. And I think that's really what the term dysbiosis ought to be used for at this point in time, because, like, for example, there are things that are advertised oh, help your gut, dysbiosis. What does that mean? I mean you're selling a product to help dysbiosis, but what dysbiosis are you talking about? So we don't want to use it in that context, but as an overarching term, I think it's fair to say.

Dr. Megan Riehl:

Okay. So it's certainly not specific to just it's too general for the gut.

Dr. Mark Pimentel:

Right, exactly.

Dr. Megan Riehl:

Okay. So when it comes to a diagnosis of something that you are studying every day of your life SIBO, small intestinal bacterial overgrowth, do you believe that this fits the definition of small bowel dysbiosis?

Dr. Mark Pimentel:

So we're doing a study called the REIMAGINE study and you may have heard about it, but basically it's the first and largest now study of the small intestinal microbiome taking aspirates using proper double lumen catheter techniques so that it's sterile. We've been doing this for a while. We have well over a thousand patients on our way to 10,000 patients. When you look at the small intestine in a normal person it barely goes above 10 to the 2, 10 to the 3, or 100 to 1,000 microbes per ml. In the case of overgrowth it's over 10 to the three. But that's not the story. The story is in the reimagined data. This is like over 1,000 patients.

Dr. Mark Pimentel:

The most apocalyptic thing we see is overgrowth, and what I mean by that is nothing is as dramatic, nothing is as obvious as when overgrowth is there, because when the E coli and Klebsiella part of overgrowth blooms or grows, it destroys everything in its path. It's like a bulldozer taking out all the rest of the microbiome. The higher the E coli is, the more destroyed the rest of the natural garden is is destroyed, and so it really is apocalyptic. The only other example of apocalypse on the small bowel is antibiotics. If you take broad spectrum like ciprofloxacin or something like that recently the microbiome is wiped out. So those two instances are the most obvious. Dysbiosis, if you want to go back to that term. Sibo is very dramatic, very obvious when it's there.

Kate Scarlata, MPH, RDN:

Yeah, so you're basically saying I just want to kind of recap this for our listeners that there are certain microbes that you're finding are always there with overgrowth and they're wiping out some of the other populations. So they're the primary microbes in that condition, Right?

Dr. Mark Pimentel:

Exactly, they're the primary microbes in that condition.

Kate Scarlata, MPH, RDN:

Exactly, so are they always the bad guys, like some people have Klebsiella and E coli and they're fine, it's just when they go rogue in the small intestine.

Dr. Mark Pimentel:

Yeah, so it's a little bit tricky. So one of the other myths if we want to go back to myths going backwards in this podcast is that even I, in review articles on SIBO, I used to say, as the textbooks used to say, that it's coliform microbes moving into the small intestine that's overgrowth. Some people even still talk that way. That's absolutely not what it is. We didn't know that then when we were writing these articles. What we now know it's really know that then when we were writing these articles. What we now know it's really there is a slowing of the small intestine and that preferentially favors aggressive bacteria, and E coli and Klebsiella are the two most aggressive.

Dr. Mark Pimentel:

There are others Eremonis and other organisms that are minor parts of SIBO, but the Ferraris are E coli and Klebsiella and they are so good at fermenting and capturing the nutrients from your food that once they've established they're a wrecking ball, and we call them disruptors because as they grow they disrupt the rest of the flora. Sort of like your garden is overtaken by weeds and the weeds will win, the garden will lose, and that's what's happening. So E coli is the biggest one. Klebsiella is less common but worse to the microbiome, it's more disruptive, and then the others are minor. Overgrowth is not coliforms. It's the E coli and Klebsiella that are there that now have the competitive advantage because of the stasis or different changes in the environment in the small intestine at that moment.

Dr. Megan Riehl:

And this is some of the connection then to IBS, post-infectious IBS and SIBO. These microbes are culprits.

Dr. Mark Pimentel:

Yeah, exactly. So we've shown this entire sequence. Like we've given food poisoning to rats and then they develop the stasis of the gut. They develop these antibodies from the toxins of the food poisoning the CdtB and anti-vinculin antibodies, because they react to the food poisoning. So you get this autoimmunity, and then the small bowel slows down from that and when it slows down the bacteria build up, and in rats it's not Klebsiella, it's only they don't have Klebsiella, it's E coli, and E coli goes through the roof. So we've seen this entire sequence in animals. So we know this happens and we know that in humans the only known cause and the only cause and effect cause because this has been proven with the Bradford Hill criteria for IBS in humans is food poisoning. Campylobacter particularly is the worst and so it's been very well characterized. In fact, stress has been shown not to be the precipitant but to be a cofactor. So stress, anxiety and depression is not a cause of IBS but is a modifier of IBS.

Dr. Megan Riehl:

That's right.

Dr. Megan Riehl:

That's right, and many other things too,

Dr. Mark Pimentel:

and many other things blood pressure, heart disease, stroke, you name it. Stress.

Dr. Megan Riehl:

Inflammatory bowel disease.

Dr. Mark Pimentel:

Yes, exactly.

Kate Scarlata, MPH, RDN:

We got to all chill out.

Dr. Megan Riehl:

That's right.

Kate Scarlata, MPH, RDN:

So you also had mentioned lactobacillus as being a disruptor in a former conversation and I'd love you to talk about that, as your group's been really looking at the small bowel. Can you talk a little bit about lactobacillus as a disruptor in the small intestine?

Dr. Mark Pimentel:

Yes, so I mean a lot of our work's been focused on irritable bowel syndrome and the relationship with overgrowth, and that's very exciting and it's really come to the forefront now. But we found some pearls in the REIMAGINE study that are super interesting. For example is the lactobacillus so in patients who have unhealthy aging. So let me backstep. Lactobacillus has been studied. Administering lactobacillus, taking probiotics has been studied on the basis of measuring stool. Nobody ever looked at the small bowel to see the effect of these probiotics on the small bowel. So now fast forward to the REIMAGINE study. We see that when patients have high lactobacillus in their small bowel, it is associated with more obesity and it's very strong association. And then the second thing is we looked at aging and unhealthy aging, and healthy aging and unhealthy aging is associated with higher lactobacillus in the small bowel. Now is it cause and effect? Those things need to be determined. So I can't say that, oh boy, because your lactobacillus is high, you're going to age badly. If you think about it, we give yogurt to our kids instead of fruit cups because we think it's more healthy. Is it right? Is it a good thing? We don't know the answer to it.

Dr. Mark Pimentel:

But the third piece of that lactobacillus puzzle is we did a study looking at the disruptors of the small bowel. The more lactobacillus you have in the small bowel, the more the garden is destroyed the normal flora. So that concerns me a lot because I don't know what the repercussions of that are. But you can imagine it might be similar to the E coli and Klebsiella of IBS. The lactobacillus is not making you have all that IBS symptoms, but is it doing other things? Is it leading to obesity? Is it leading to other things that we need to understand more consequentially, and so more work needs to be done. But I think that's worrisome to me. So I don't really advocate for lactobacillus or probiotics using lactobacillus in my practice.

Kate Scarlata, MPH, RDN:

Would you say that across the board for everyone, like say you were talking to someone just interested in their gut health? Do you think lactobacillus has got a potential problem? I don't know the answer.

Dr. Mark Pimentel:

Now that's really got me wondering what is good about lactobacillus, what could be bad about it? I don't know the answer to it, but it really raises a lot of questions and a few hairs on my neck because I'm worried that it could be harmful. I go back to what our mothers told us too much of anything is a bad thing, and that has always rung true for all of science is that too much of one thing is always a bad thing. Oh, don't eat fat, don't eat any fat. So you know, you swing the pendulum. So now we switch it all to carbs and everybody's getting obese. And now they're swinging back and saying carbs are okay or carbs are not okay, fat is okay. And so the pendulum swings. But if you have a balanced diet, if you have a little bit of yogurt here and there, as a healthy person I think there's no problem with it. But if you want to get 20 billion lactobacillus in your gut every day, is that healthy? I'm not sure.

Kate Scarlata, MPH, RDN:

Yeah, it's that whole notion that more is better. We just can't get away from that. Everyone thinks, well, geez, if 10's good, let's get a million. And see what happens.

Dr. Mark Pimentel:

Yeah, if I can live longer, because a little bit of selenium is good. More is better, right?

Dr. Megan Riehl:

So anyway, it's interesting we have to remain curious and I think that's the thing here is and I think probiotics are a great example right that people are just, they want to feel better. And to your point, which one has the highest? If a little bit is good, then again let me find the probiotic out there with the highest amount of that. And then they stay on it for too long without adequate relief of their symptoms and it becomes a very muddy waters or the garden is very heavily impacted by too many weeds and species.

Kate Scarlata, MPH, RDN:

exactly.

Dr. Mark Pimentel:

But even if you're planting a garden, you don't plant all tomatoes. I mean, you can't expect one organism to correct a thousand, right? So it's like I say, if you add a thousand lawyers every day to Los Angeles, that may not be a healthy thing for the city. We need lawyers, but maybe a thousand every day is too many, you know. So that's the concept of a probiotic, and not to mention the other sad thing about the word probiotic is it has the word or the prefix pro in it, like it's good. And then this notion another myth of good and bad bacteria. That's a myth. There is no such thing as good and bad. There's. Bacteria are all good and all bad, depending on where they are. Lactobacillus in your bloodstream, not good. Lactobacillus a little bit in your gut, probably good, and so it just depends where they are and what circumstance. They all evolved to stay in their place and their niche, and when they are too high or in the wrong place, it's a bad thing.

Kate Scarlata, MPH, RDN:

Moderation in all things.

Dr. Megan Riehl:

That's right. We've discussed and you can correct me if I'm saying this incorrect. Is it Placide trial?

Dr. Mark Pimentel:

Yes.

Dr. Megan Riehl:

Okay, so let's talk about the Placide trial. What did this trial look at and how is this information clinically relevant for us?

Dr. Mark Pimentel:

So this was a study looking at patients that were given antibiotics for whatever a urinary tract infection or some sort of infection at the moment in primary care clinics. And then, as they were given the antibiotics, they were randomized to probiotic or no probiotic and what they found was there were no decreased rates of C difficile or antibiotic-associated diarrhea because you're on the probiotic. That was what they were hoping to see. Is that that would prevent C diff or something like that, and the only thing they found that was statistically different. The only significant thing really was that the probiotic group had more bloating. So this is what I tell my patients If you want more bloating, please take a probiotic, because it will provide that for you, because the Placide trial is the largest randomized control trial to date on this. So it kind of settles the issue.

Dr. Mark Pimentel:

Now, the probiotic world is a plethora of products, so it's very easy for the company says well, that's not our strain, our strain doesn't do that, or that's not bifido, that's lactobacillus. So whether I say this or not in a podcast, and whether somebody hears this or not in a podcast. The product companies are going to say, well, that wasn't my product. And so the story continues as we unfold this. But the problem is that these companies don't have the money or don't want to do these incredibly large trials to prove one way or the other if their product does what they hope it does. So it's a tricky area. I do believe bacteria are important. I do believe there are some that are better than others. I just don't think you've got to over. You know, jack up the system with too much of it.

Kate Scarlata, MPH, RDN:

Especially if the small bowel is not working very well. It just feels like you're just accumulating.

Dr. Mark Pimentel:

I can tell you absolutely. I have patients who have IBS, who've taken probiotics and said, oh my God, I feel so much better. It's rare but it happens, and so I say, great, call me when it's not. Inevitably they call me and it's not working again. And then we go back to square one and we go through the fundamentals again. But you know, I can't deny that there are occasions where patients feel better. But anecdote is not science. We deal with it in the clinic all the time.

Kate Scarlata, MPH, RDN:

Yeah, it's true, especially when you really want to feel better. You're hoping so hard on that little probiotic capsule.

Dr. Mark Pimentel:

Exactly.

Kate Scarlata, MPH, RDN:

So let's talk a little bit about SIBO and new treatments, and I know your group reported at DDW this year about using rifaximin with N-acetylcysteine or NAC and found that this combo worked better than rifaximin alone. I know rifaximin has FDA approval for IBS-D, so kind of used off-label for bacterial overgrowth, but is used commonly. So what led you to looking at NAC and rifaximin together? What prompted that idea?

Dr. Mark Pimentel:

So when we helped develop rifaximin together, like what prompted that idea, so when we helped develop rifaximin in the first place, it is a great drug for IBS. It's the number one drug for IBS worldwide. Now If you go to chat GPT you can ask because it's safe, because two weeks might get you six months of benefit, which no other drug does. So in that context it's been very successful. But I was never satisfied because what I'm seeing in the microbiome of IBS more people should get better from rifaximin. Something didn't add up to me because we're seeing more SIBO in IBS than rifaximin makes better. So, for example, rifaximin target three trial, 44% of people responded to rifaximin but we're seeing 60 to 70% having SIBO. So why are the others not getting better? Or why isn't it as good as it should be? Where rifaximin's characteristic are, it's not absorbed because it's hydrophobic. It's like an oil almost technically. It doesn't have an ability to dissolve in water. So there's that part. And then what we found in the REIMAGINE study in SIBO patients is that E coli and Klebsiella, those two bad disrupting characters, those Ferraris, when we calculate where they live in the small bowel, 50% of them live in the free fluid which rifaximin has access to, and the other 50% live in the mucus, not the mucosally associated with the mucus, the thick, stringy stuff. And rifaximin will never get into that.

Dr. Mark Pimentel:

So we did some studies preliminarily to see if we added a mucus buster or a mucolytic like NAC, does rifaximin work better? And it works 10 times better in that situation. So we are able to get rid of the Ferraris more comprehensively if NAC is present and we can use a much lower dose of rifaximin to get the same effect. And we can use a much lower dose of rifaximin to get the same effect. So we did an initial study which we presented at DDW and it showed that in a very small study rifaximin and NAC is better than rifaximin, the one on the market. And so the phase 2B study. I just had a meeting before this one. We're kicking that off in September. It's the first phase 2B study at our center that isn't pharma funded, it's we're doing the whole thing ourself to see if we can get this better for patients. So it was pretty cool. No pharmaceutical company.

Kate Scarlata, MPH, RDN:

No pharmaceutical company, yep, amazing.

Dr. Megan Riehl:

Why is that important for a listener? What does that mean?

Dr. Mark Pimentel:

You know doctors do a lot of things with pharmaceutical companies. You know we try to get things across the finish line. But I'm not doing this for that. I'm doing this for patients. We want patients to get better. This isn't about pharmaceutical companies. This is about doing the right thing and finding the right answers and getting these things for patients. So I'm hopeful this will amount to something and then make patients better more often. I believe it will. Our data has shown that we even had to use our rat study, the rats who were post-infectious and, sure enough, just giving rifaximin versus rifaximin and NAC. Rifaximin and NAC was completely normalized. Their cytokines normalized, their microbiome normalized their bowel movements, whereas the rifaximin and NAC. Refaximin and NAC was completely normalized. Their cytokines normalized, their microbiome normalized their bowel movements, whereas the refaximin only partially did that. So we're going to the next level and we're doing it alone.

Kate Scarlata, MPH, RDN:

I love that. So just quickly, how much NAC are you using? The same amount of NAC that you used in the trial that was reported at DDW? Can you disclose the amount that you're using in the trial?

Dr. Mark Pimentel:

So it's a different formulation than that trial Now this is the final formulation, where it's delivered in the small intestine, specifically in the locations where the E coli would be expected to be. So it's got a special delivery system. It's different than the other. Okay so we'll see how it goes.

Kate Scarlata, MPH, RDN:

Awesome, we'll be waiting. Yes, we will.

Dr. Mark Pimentel:

And I will have no fingernails left by the end of it.

Kate Scarlata, MPH, RDN:

I bet you won't. We appreciate all the work you're doing, especially in this area, because you're really like it seems like the one and only that's just like really knee deep in it and pushing the bar like really knee deep in it and pushing the bar.

Speaker 4:

Visit Xifaxan. com/ IBSD for the PI or talk to your doctor. Don't use Xifaxan if you have a history of sensitivity to rifaximin, rifamycin antibiotic agents or any components of zyfaxin. Tell your doctor right away if your diarrhea worsens while taking zyfaxin, as this may be a sign of a serious or even fatal condition. Tell your doctor if you are pregnant, plan on becoming pregnant or nursing. If you have liver disease, taking warfarin or other medications, some medications may increase the amount of Xifaxin in your body, most common side effects are nausea and an increase in liver enzymes.

Speaker 4:

Xifaxin.

Kate Scarlata, MPH, RDN:

So let's switch gears to methane, and I know there's been a number of different studies linking high levels of methane with constipation. But I'm wondering, like is this bi-directional at all? Like, if you're constipated, does that contribute to methane being produced or more substrate for those microbes? Like is there any connection with just someone being, say, someone's just constipated doesn't have elevated methanogens. Do they develop elevated methanogens just because they're constipated, or is it just the methanogens are causing the constipation through their methane? Does that make sense?

Dr. Mark Pimentel:

Yes, and that's an argument that's resurfaced recently, and I wonder whether some of those folks hadn't read the earlier papers that have already been done, whether some of those folks hadn't read the earlier papers that have already been done because we've gone through that argument already.

Dr. Mark Pimentel:

So yes, if you have methane you're more likely to have constipation. The higher the methane you have on the breath test, the more constipated you are. It's very proportional, which is really important for cause and effect. But that doesn't mean that the methane is causing the constipation, because if you're more constipated maybe you have more methane, maybe the methanogens love that dry stool environment and they do better in that situation.

Dr. Mark Pimentel:

But we've done the other side of it, where we've given methanogens to animals and they get constipated. So we gavage them with the methanogens. We've done the studies of live animals where we infuse methane into the small intestine and they get 60% slowing of intestinal transit. We've done organ baths of the smooth muscle of guinea pig ileum, adding methane to the bath and the guinea pig ileum the peristalsis goes away, it goes into more of a spastic contractile activity. So it's the methane. And now all of a sudden maybe there's a study that says that I don't know that maybe they're constipated first, then they get methane. I'm not sure it hasn't come out yet, but this is coming back to life. But maybe they should read those papers because I think we pretty much nailed that down that methane is a constipating agent period.

Kate Scarlata, MPH, RDN:

Yeah, I thought so too, but I was on as I do lurk on Twitter and saw a recent paper and I'm like I'm going to ask Dr Pimentel about that.

Dr. Mark Pimentel:

Well, the paper hasn't come out yet, so it remains to be determined.

Kate Scarlata, MPH, RDN:

Yeah, I just saw the commentary.

Dr. Mark Pimentel:

But I certainly hope that they at least reference those papers, because those are the ones that show that it's primarily methane that's causing the constipation and slowing the gut down, but it's okay.

Kate Scarlata, MPH, RDN:

You heard it here first.

Dr. Megan Riehl:

and in more cutting edge research that's coming out of your lab. Let's talk a little bit about CSO6. So you presented a preclinical study looking at the molecule in relation to reducing the methane gas levels, as we've really identified, methane associated with constipation and also IMO in human studies. So what is CSO6 and its potential mode of action? And, based on the timing of the research, if this study proves itself to work in humans, when do you think it's going to come to market?

Dr. Mark Pimentel:

Well, this is more proof for the last question. So we did a double-blind study of rifaximin with neomycin, with methane, and only the humans or most prominently the humans where the methane went down did their constipation resolve for a period of time as the methane was gone. So it wasn't the effect of the drug, it was the effect of removing the methane Again proving that methane is the issue. So now we have CSO6, which blocks an enzyme in the production of methane by the methanobrevibacter smithii bug or archaea that's causing the methane in humans and we see 70% reduction in methane with this drug.

Dr. Mark Pimentel:

And the study we presented at DDW was the controlled trial in animals, where these are animals that we can make constipated, make their methane go up that we spoke about in the last question. And then we give the drug and the methane goes down and the constipation goes away. So again, cause and effect of methane equals constipation. So the animals had less constipation and less methane. So we are about a year away. You got to do all these toxicity studies et cetera, et cetera, to get to humans and so we're hopeful to be in humans within a year and that will be very exciting because then we're really treating the cause right.

Dr. Megan Riehl:

Right.

Dr. Mark Pimentel:

It's not an antibiotic, it's not a sledgehammer. It's just a small molecule to make the bug stop doing what hurts you, and that's it. So that's very exciting.

Kate Scarlata, MPH, RDN:

Very exciting. So back to methane. As a dietitian, you know we're always working with patients with IMO and want to help them. You know we're always working with patients with IMO and want to help them, and there's been some talk that a low-fat diet would help with methane production. Is there any diet interventions that you're finding useful in your patients or that you have data to talk about?

Dr. Mark Pimentel:

Well, we do know that high-fat diet does promote methane production. We see that in animals too does promote methane production. We see that in animals too. If we gavage them with methanogens and give them high fat, the methane goes up a lot more than if we didn't use high fat. Don't know why, except we know that methanogens use bile acids as a fuel source as well. So more fat, more bile, more bile acids. It's possible that those are the connections, but we do see that happening. We don't necessarily see it.

Dr. Mark Pimentel:

On high protein. High protein can cause more constipation as well. We don't necessarily see more methane in a high protein diet. But we haven't gotten around to saying please go on a low fat diet, this will make your methane go away. We haven't done that. It's an interesting exercise. I wonder whether it might help, you know, and when we.

Dr. Mark Pimentel:

If we get to hydrogen sulfide, there may be things that can be done there. I almost see that, because what we've identified in IBS if I can go back a step is three microtypes really. There's the SIBO microtype, with this E coli, klebsiella, two Ferraris racing to get all your food. Then there's the methanogens, which are the constipation side of things and their needs are different, and maybe there's a diet for that. And then, of course, hydrogen sulfide. When it's there, you get more flora diarrhea and they need sulfur. So if you had a low sulfur diet, maybe that would be helpful. So I think diet's going to play a role in all three over time, as we understand their nutritional needs and what's driving their increased metabolism and growth, and so diet may play a big role in all three.

Kate Scarlata, MPH, RDN:

So who's going to do those studies?

Dr. Mark Pimentel:

Well, I can't do all the studies, Kate.

Kate Scarlata, MPH, RDN:

I know, I know, maybe Bill Chey.

Dr. Mark Pimentel:

Maybe Bill Chey. Let's get Bill. You know it's like what do they say Mikey, let Mikey eat it.

Kate Scarlata, MPH, RDN:

All right, we got to find someone to do those studies.

Dr. Megan Riehl:

And it might happen. You know, we've got Dr Prashant Singh, we've got Dr Chey here at the University of Michigan. So, I don't know. Here's our call outs. I'll be knocking on some doors.

Dr. Mark Pimentel:

Bill's an expert in diet studies, so he anyways, I've talked to him and he's got a lot on his plate, but I wasn't trying to commit him to something, but oh, I'll commit him.

Kate Scarlata, MPH, RDN:

No, we'll get Prashant. We go for the younger ones that are coming up.

Dr. Megan Riehl:

All right. So you mentioned the three gases. Right, we've got the hydrogen, the methane, the hydrogen sulfide and we now have testing to look at all three of these gases via breath tests and they're available nationwide. And you did a real world study, you know, with a rather large cohort of people, over 3000, that completed all aspects of the study with questionnaire feedback. So tell us a little bit about what you learned because, again, these things that are available on the market, people are interested in and we want to know what they show us and how it leads to treatment.

Dr. Mark Pimentel:

Well, we do it for the sake of science, trying to understand these different subcategories of gas types. But we also do it for critics, because always there's critics. Uh, you know, people said, well, oh, breath testing is great, but now you got to do culture. Then you do culture to say IBS has SIBO. You publish that. They say, yeah, but next generation sequencing is better. We don't believe it until you do next generation sequencing. Then we do sequencing and we show the same thing and they say, yeah, but you could do shotgun sequencing. And so now we've done shotgun sequencing, we published it.

Dr. Mark Pimentel:

Anyways, the list of the critics' desires never ends. But we keep showing the same thing with the different tests and the same thing with breath testing. So you know, we show that it works in clinics. So methane is associated with constipation, hydrogen is associated with diarrhea. In-person, in-person breath testing at Cedars-Sinai, for example, or at Ann Arbor. But now you're doing mailing, at-home breath testing. Does that work? Can patients actually do it at home? And a 6,000 breath test study says absolutely.

Dr. Mark Pimentel:

Methane's associated with constipation, SIBO and hydrogen sulfide is associated with diarrhea. It all turned out the same way and the results were equally impressive. But what we were able to show is that these gases interact. Because it's such a large study there are some patients have all three and that's pretty remarkable. But what I used to think is that methane is the winner. Like methane will out because of its constipating effect, it will out constipate the diarrhea, but not with hydrogen sulfide. Hydrogen sulfide is the winner.

Dr. Mark Pimentel:

Anytime it's present, it is dominating the symptoms and making all the symptoms more severe and in particular visceral hyperalgesia or pain. So hydrogen sulfide is an activator of pain pathways. Then what we also did at DDW, which I don't think we're going to get into, is we actually looked at the biopsies in the REIMAGINE study of the bowel and the same thing in the animals where we gavage these organisms to test whether hydrogen sulfide is causing diarrhea or not. And of course it does. The changes in you, in your lining of your intestine, when you have these hydrogen sulfide organisms are incredible. It's literally you're killing the cells almost at certain levels, but you're causing visceral hyperalgesia. Intestinal barrier proteins are affected, serotonin is affected, mitochondrial function is affected. So your energy of the cells are affected. H2S is nasty. It's nasty, but anyways, in the 6,000 patient study we were able to confirm that hydrogen sulfide, the higher it is the more diarrhea the SIBO and the methane in this very large-scale study.

Kate Scarlata, MPH, RDN:

So interesting? And wasn't hydrogen sulfide connected with inflammatory bowel disease? Didn't they think that years ago? I haven't really heard a lot recently.

Dr. Mark Pimentel:

Well, what happened with that? So there was this big movement in the early 90s of the relationship between hydrogen sulfide in the colon and the development of ulcerative colitis, for example. It was ramping up, so to speak, and then infleximab came and boom. Everything changed to biologics and it in essence cut off at the pass the continued work on hydrogen sulfide. But maybe now it's going to be reinvigorated in IBD too. I know there's a few studies that are ongoing already looking at ulcerative colitis and other IBD patients with H2S. H2s is toxic, so it's not good.

Kate Scarlata, MPH, RDN:

Interesting and really there's only one test, like most hospital settings are not testing for hydrogen sulfide. It's this meal order.

Dr. Mark Pimentel:

So it depends on the hospital system. There are some Stanford does. I think, Bill Chey is going to start. I'm not sure. Northwestern does all three. So, it just depends, because you just get the kit, you can do it at the academic center and send it, so you can do them in person. Still, you just have to have the kit or you can do it by mail order.

Kate Scarlata, MPH, RDN:

That's amazing. You know, I've been doing this for a long time and in the beginning it was like this big thing request hydrogen and methane, like that was a big deal because they weren't looking even at methane.

Kate Scarlata, MPH, RDN:

You know, back in the day and now it's like okay.

Dr. Mark Pimentel:

I think the biggest problem we had, even in the SIBO, has been around. Breath testing has been around since the 80s and even centers where they you know they're somewhat critical of breath testing they're doing tons of breath tests because it makes money for their institution. To be honest, that's sad that you would be a critic, yet you're still doing these tests. Anyways, the tests do work well in my view. But people started pulling these Quintron instruments out of their basement and turning them on and starting to run them. They need servicing. I mean, these instruments, these gas chromatographs, need servicing and we've experienced some pretty high level institutions where the breath test isn't calibrated properly and they're getting wonky results. So it's a delicate test to do right and therefore get good data. So that's another problem that we've encountered over the years.

Kate Scarlata, MPH, RDN:

Yeah. So listeners ask about what equipment they're using and maybe inquire about the three gas breath test. So as we wrap up, I wanted to just briefly talk about fiber. I know a lot of the work you do is in IBS and SIBO. Is fiber a friend or a foe, or is the answer kind of somewhere in the middle?

Dr. Mark Pimentel:

Like everything else, your mom told you keep everything in moderation. There was a study that was done in Japan where they fed rats kidney beans for two weeks. So that's high fiber. The rats develop SIBO just from eating kidney beans. So beans.

Dr. Mark Pimentel:

If you were to be on an all bean diet as a human, you're going to get SIBO, even if you don't have any underlying reasons for SIBO. That is a just an example of what high fiber can do and the power of high fiber in terms of SIBO without any other medical problem. So too high fiber is not a good idea. Too much of anything is not a good idea. Right? That's the theme today. But with people who already have SIBO, you're basically putting logs of wood on the fire, in a sense, because now you're providing more nutrients for the Ferraris to be able to produce more gas, bloating and distension. So the offset of that is, yes, fiber can make you have more bowel movements. So maybe if you have more bowel movements, you clear some of these bacteria out. Maybe that makes you feel better because you're having diarrhea from the fiber or whatever the manifestation is of the fiber. But all in all, we see that fiber just causes a lot more bloating for these patients, and so we generally recommend low fiber. Not no fiber, just low fiber.

Kate Scarlata, MPH, RDN:

Yeah, incidentally, the kidney beans are very, very, very like probably the highest fructan containing bean, so it's a very high FODMAP, small chain carbohydrate. You know. Even compared to like chickpeas or lentils or black beans or cannellini beans, kidney beans are like the top dog. They're so, so concentrated, so they were giving them a lot, a lot of fiber. And I do wonder, like in bacterial overgrowth, if the smaller chain fibers are more problematic because they're easier, they're rapidly fermentable and, you know, are they going to be in that small bowel a limited amount of time? So those things they can access a little quicker are more problematic. Just, you know, critically thinking, I don't think, in my opinion, I'm not sure that all fibers act the same, or maybe as problematic for SIBO as maybe some that are really quickly accessible by our microbes in the small bowel. But tell me otherwise.

Dr. Mark Pimentel:

So I like to do everything based on science right.

Kate Scarlata, MPH, RDN:

Me too.

Dr. Mark Pimentel:

And I don't know that there's enough science to tell me it's got to be this long, that long, this long, that long. All I know is it's fiber or no fiber, and that's really inappropriate for me to be so dogmatic. But I don't have any data. All I know is if the patient is on fiber, if they're on metamucil or if they're on some product that is fiber containing which is good for some people, it isn't good for SIBO. It's just the patients do poorly. But I would love to see a study where you compare different fibers to see which ones they tolerated. But again, that's not been done.

Kate Scarlata, MPH, RDN:

Prashant Singh calling.

Dr. Mark Pimentel:

We're volunteering him for a lot of studies. We are yes.

Dr. Megan Riehl:

We are yes we are and clearly I love the debates, I love the conversations and clearly I love the debates, I love the conversations. It really is important, as I said earlier we have to be curious about this, we can not just lean into, it's not black and white is the reality.

Dr. Mark Pimentel:

I like to tell you things that I have a ton of data on. But so my overall gestalt is low fiber for now, until we figure it out.

Dr. Megan Riehl:

All right. Well, you told us last year that, in order to navigate the stress of running this massive lab. You are a blues guitar player.

Dr. Mark Pimentel:

Oh my God, did I tell you that?

Dr. Megan Riehl:

You did tell us that and I've been waiting for, you know, an MP3 or something of hearing you play. But what are you doing for your well-being and self-care these days.

Dr. Mark Pimentel:

Well, I have a home up in Banff area in the Banff area, so I go up there and I write papers up there and just spend a little bit of time with nature. It's very good, it's very cleansing. I also have guitars up there.

Dr. Megan Riehl:

Perfect.

Kate Scarlata, MPH, RDN:

That is a magical, magical place. We were in Banff a couple of years ago. It is one of the most beautiful places I've ever been. How lucky.

Dr. Mark Pimentel:

Yeah, now we've gotten to know it quite well, and if you know it quite well, you know the real places because, Lake Louise is beautiful and all of that. But there are places where hikes could be five miles up to a lake where there is literally not a human anywhere. These mountain lakes, and they're just spectacular. The water is like glass and there's nobody.

Kate Scarlata, MPH, RDN:

Love that.

Kate Scarlata, MPH, RDN:

We went when it was freezing. So to be honest, there was really no one there except for us in my poorly dressed attire because I was so cold. But it was kind of nice because we missed the crowds, but it was a little chilly yeah, crowds are too much but that's okay, same everywhere.

Dr. Megan Riehl:

Exactly that's the key. You got to get away in order to kind of clear the brain and just give yourself the space and so a little slice of heaven. It sounds like that's incredible. Yes, you deserve it.

Kate Scarlata, MPH, RDN:

So thank you so much for joining us. We really appreciate your time, and the first podcast that you joined us with is still our top producing podcast. It's got the most downloads, so no surprise, people are really interested to hear your brilliance and expertise and just you're really making a difference in so many people's lives. So thank you and thanks for your time today.

Dr. Mark Pimentel:

No, it's my pleasure. It's good to talk to you both.

Dr. Megan Riehl:

All right, friends. Well, don't forget to like, share and subscribe to The Gut Health Podcast. Your support means the world, our friends.

Dr. Megan Riehl:

Thank you for joining us as we grow this gut health community. We hope you enjoyed this episode and don't forget to subscribe, rate and leave us a comment. You can also follow us on social media @The Gut Health Podcast, where we'd love for you to share your thoughts, questions and experiences. Thanks for tuning in, friends.

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Kate Scarlata

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Megan Riehl

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