Nirala Jacobi:                Welcome back to part two of the SIBO Doctor Podcast, and let's jump right back into it. We've arrived at them methane topic, and that's really ... it's a good segue into that. Like I said, myself, I'm very fascinated with methane because it seems to be a different situation. Then the situation that you just described, where we have a case of food poisoning that then results in an overgrowth of these proteobacteria because of a damaged motility issue. Now, as far as I understand it, also looking at your research into this matter, methane operates very differently. Is that right? We don't really see the history of food poisoning as much with methane dominance SIBO as we see with just pure hydrogen.

Mark Pimentel:                Yeah, that's exactly true. I mean, occasionally, patients with methane will test positive, for example, on the ibs-smart, but it's much lower. I wouldn't probably be incorrect to recommend doing ibs-smart as a way of diagnosing constipation IBS or methane overgrowth. So it's different. It's a different animal, and that's what we think the C part of constipation part of IBS where methane is predominant or constipation in general, where methane is predominant, the mechanism of that is unclear except we think methane blooms or is overgrown in the intestinal tract.

Again, methane's a little different too because it isn't necessarily the small bowel only, there's colonic excess of methane too. Everything is a little bit different there, but methane is a problem. The amount of methane you produce correlates with the amount of constipation you have, and that's really important because it's proportional, it's cause and effect with methane.

Nirala Jacobi:                   Right, and yet we have many, many people who would be considered positive on a breath test that don't have constipation, and we have all these odd things ... Naturally, we are more higher in this [inaudible 00:02:52] as we age, and also an entire continent has ... Africa is massively methane dominant. I just wonder if there are other factors that determine whether or not a patient will become constipated under those circumstances, because many people do not have constipation when even though methane levels are high.

Mark Pimentel:                Yeah, and I think it's a matter of circumstances and maybe locations of where the methane is. Yes. I mean, I've spoken about this many times, about African populations having higher [inaudible 00:03:24] But you think about what people are eating in different parts of the world, so there may be less meat consumption, more fiber material consumption in Sub-Saharan African diets than in Western diets where it's all meat all the time. So that may dictate some of the problems that we see, because fiber may offset the constipating effects of methane or it may change some of the physiology.

We're not sure how that all works. But what I can tell you is that, for example, in African American populations, and we see this in our clinic, methane is very high and very constipating. But we think methane though comes [inaudible 00:04:09] actually are acquired from your environment more, so we see methane run in families. If a father has methane, the daughter or son or both may have methane, and it's maybe casual contact that determines the colonization more so than others.

The reason we know that even more so from data is there's a ... Suarez is author from Brazil, and they showed that the proximity of living close to a sanitation facility or a dump, as we call it here in the US, where your garbage or trash is dumped, are more likely to have methane than people who live in more affluent areas. Again, it's an environmental, we think, colonization.

Nirala Jacobi:                   But getting back to the Sub-Saharan Africans and this whole fiber idea, it was always, as you've mentioned many times before in previous symposiums, that it is thought to be an evolutionary advantage, right? To actually have had Methanobrevibacter onboard because it would slow digestion so you could extract more calories from varied undigestible fibers. Maybe it's not really a pathogen per se. I mean, it isn't, it's not a pathogen, it's just something that we find very much correlated.

That's the mystery to me, is are there other colonic circumstances or small intestinal circumstances that then lead to constipation with methane? Because it seems like everything we find out about the microbiome, there are so much interrelationship between different phyla and different situations that it wouldn't surprise me at all that we find a specific circumstance that would lead Methanobrevibacter to become more constipating in some than others.

Mark Pimentel:                Yes, you're preaching to the choir on that. That is exactly how I feel about all of this. I mean, think about it. The microbiome are in balance with you, they want you to survive because you're providing food for them by running around and eating things, and so there's a harmony between the diet and the human and the microbiome. I think in populations in Africa or in situations where there's more feast and famine, methanogens are a competitive advantage. So you are actually super human by having the methanogens and that's a good thing.

But if you move those populations West and there's potato chips on the desk or bagels in the back office all the time and you're just eating all day and candy bowl in front of you, then having all these methanogens and you're harvesting so much energy so easily is not an advantage. It's a disadvantage. I think in the end, it's really a civilization problem. We just have grotesquely too much food in some parts of the world, and undernourished in other parts of the world, and in the disadvantaged. But maybe nature takes care of the disadvantaged, and in the case of methane and some strange but beautiful way.

Nirala Jacobi:                   Well, I mean after all these years in practice and having tested for methane or at least breath testing for SIBO and seeing the patterns and seeing people that have been on very restrictive diets for many years in many cases, and self selected themselves for reducing their FODMAPs, et cetera, because they were told they have SIBO and it's a really methane dominant situation, let's say. I just haven't found that these people don't fit the picture that they over consume calories necessarily.

They are restricting certain foods, they've tried every which way, and methane is just really hard. I think I get most success with my methane is when I just do much more of a comprehensive approach in terms of microbiome restoration in general, which is a whole another topic. But I think it's just such a fascinating thing because we say these people have SIBO, and ... I guess my next question would be since the North American consensus a couple of years ago that set some guidelines in terms of breath testing interpretation, is there any further movement to perhaps even reclassify IBS-C as a different condition from SIBO all together?

Mark Pimentel:                You need to stay tuned there. There are somethings I can't talk about yet because it's not published, but the answer is yes, things need to be reclassified and you should see some of that reclassification in the coming months. But I can't say more than that, I'm sorry.

Nirala Jacobi:                   That's really exciting because I'm just guessing. I was just guessing that something needs to happen because these people do not respond to the same approach that we use with other SIBO patients that are much more straightforward, high hydrogen, et cetera.

Mark Pimentel:                100% agree, and those things are starting to happen among the field. So very exciting times for everybody and for patients mostly, and I think that's the key, is that these patients were dismissed, thought of as psychological problems, but now we're really finding the true pathophysiology, and now we can get to the bottom of it and start to treat it. But I think, but methane, you are absolutely right, it's a bane of my existence and patients' existence because it's the toughest one to treat. I would say that I'm seeing less than less [inaudible 00:09:54] in the clinic than I used to, but I'm seeing more and more of these methane constipated patients because nothing seems to work well for them. So we're looking to try and change that game also.

Nirala Jacobi:                   Are you any closer with the [CIN-10 00:10:09], the lovastatin?

Mark Pimentel:                Well, much closer. So we are right now in the middle of a trial, the phase two trial, which is really exciting because we want ... If this works, then it goes quickly to phase three, and then to approval. S we're thrilled we're part of this trial, and we're partly enrolled for those who might have methane and are still struggling, and we've just announced that we're paying for travel for people to come for the trials, five visits, but I'm certain that Australia would not qualify for the dollar amounts that we're talking about, but within the US, that's doable now. We're able to pay for some accommodation and travel to allow patients the opportunity to get into this trial.

Nirala Jacobi:                   All right. Let's see. We have about 15 minutes left in our very fascinating conversation. I have a few questions about hydrogen sulfide. Of course, we were going to get to that. Everybody's waiting with bated breath on hydrogen sulfide and protesting ability, but also the implications of what it really means. Can you just give us a little summary of what you've talked about this year?

Mark Pimentel:                One of the things we've always known since the beginning of my research with understanding hydrogen and methane and breath testing, the irony of all of that breath testing is that people really didn't dig into the science, and we would have never able to show that hydrogen was proportional to symptoms. So if your hydrogen is 150 or if it's 30, both are positive, but the 150 isn't necessarily sicker than the 30 or the 40. With methane, it's proportional, so the more methane you had, the sicker you were, the more constipation you had.

The missing element with hydrogen was hydrogen sulfide, and so we helped to engineer a machine that can actually measure all the gases, and that machine is now created and is very shortly going to be able to provide that hydrogen sulfide missing element. But in the trials that we did, we showed that hydrogen sulfide really is the cause of diarrhea, or at least as associated with diarrhea. The higher the hydrogen sulfide, the more diarrhea you have. So for the first time, hydrogen sulfide is giving us an answer as to that third element, and there are no other gases.

So this is the complete picture now for the first time, and I'm looking forward to what patient's response is to all of this. It could be the reason why certain antibiotics work and others don't, and it's going to open up a whole new area of trying to understand how to best treat these patients based on their gas profile.

Nirala Jacobi:                   One quick question I have about hydrogen sulfide. It is the one gas that's also endogenously produced though, right? So it's not only a measure of bacterial fermentation that probably definitely not to that degree that we would find it on a breath test, but I know that there are ... high hydrogen sulfide also has been looked into as a Goldilocks concentration where it can even exert a beneficial effect in low levels.

Mark Pimentel:                Yes. I mean, your gut can produce a little bit of hydrogen sulfide. Hydrogen sulfide is a neurotransmitter, so a tiny amounts are produced by the human body. The human body does not produce methane or hydrogen, but yes, hydrogen sulfide is a small byproduct. To counteract some of those discussions is that we do have healthy controls, and the healthy controls do not have elevated hydrogen sulfite. They have detectable hydrogen sulfide, but not elevated. So it's really when the hydrogen sulfide is excessive from the gut that we start to see the illness part of this.

Again, it's just another chapter that we will have a tool to start to unravel the subtleties and the nuances of this. But we know, from the studies, that hydrogen sulfide in parts per million of more than 1.2 is associated with diarrhea. So that's going to be likely to cut off for the final test. The other part of this is hydrogen sulfide is quite toxic, as well, in higher concentrations. As you know, or as most of your audience might know, parts per million over five can kill humans. It's not a good thing to have high concentrations in the body.

The liver detoxifies a lot of hydrogen sulfide, and the reason we get such small amounts on breath is because the liver is constantly trying to get rid of it, even what you produce in your body, so it detoxifies hydrogen sulfides. That's why you don't see 20, 30, 40 parts per million on the breath. Even though locally in the gut, you might be producing a lot more than one or two parts per million.

Nirala Jacobi:                   That makes sense. You and I had this conversation, I'd just thought I'd briefly touch on it that a lot of my research, when I looked into hydrogen sulfide, was more the colonic environment with Desulfovibrio and those types of organisms and Bilophila that are very well known hydrogen sulfide producers. But even in this sequencing that you're doing in the small intestine, I didn't really come across those bacteria. Are we any closer to knowing what bacteria produce hydrogen sulfide in hydrogen sulfide SIBO?

Mark Pimentel:                Yes, closer than you think.

Nirala Jacobi:                   Oh God, this is always going to be like this, is it?

Mark Pimentel:                I think it is. If it wasn't like this, it wouldn't be exciting, right?

Nirala Jacobi:                   That is true.

Mark Pimentel:                Because if we had all the answers, we would have nothing to talk about next year. But the point is, yeah, stay tuned for DDW 2020 because we-

Nirala Jacobi:                   2020. Okay, and-

Mark Pimentel:                [crosstalk 00:16:13]

Nirala Jacobi:                   ... that's usually in May or something, right? May, June?

Mark Pimentel:                May in Chicago because we will be presenting some amazing data that I think will be very provocative [inaudible 00:16:23] in that will get us closer to those lights at the end of the tunnel for all these different questions. I think hydrogen sulfide is so fascinating and the results are unexpected. I love unexpected results because it's just ... When you figure it out, it actually turns out to be more intuitive, but nobody realized how intuitive it was. But anyway, that's my little teaser. But stay tuned, and then we do [inaudible 00:16:51]

Nirala Jacobi:                   Well, listeners, I have tried, I have tried again and again, so we'll just have to keep waiting to hear what we're going to find out about hydrogen sulfide. Now, this is a total non-sequitur, but I thought I'd ask it because I was ... It was something that I heard in one of the interviews, I think it was with [Chavonne 00:17:10] or so, where you talked about a test for vagal function. As integrative practitioners, we're really interested in the vagus nerve because of its massive function in digestive regulation, et cetera.

You talked about a test called the pancreatic polypeptide test where food is chewed and spat out, and I just wondered how often it's used, and can you just talk just a minute about this test? Because it seems like, wow, if there's a test for vagal function that involves the pancreatic output or just a blood test, why are we not talking more about this?

Mark Pimentel:                I think the reason things are not spoken about as much ... excuse me, is because these tests are so old that people have forgotten about them. But these were tests that were discovered or invented in the '70s and maybe even earlier. But basically, physiology is disappearing from medical teaching, and this is something I'm desperately trying to keep teaching our fellows so that they're more abreast of this. But basically when you eat, there's various phases of eating.

There's a cephalic phase. I'm thinking of food, the gut is already turning on. Now you're smelling food from the kitchen and you're already starting to think, "Oh, I've got to eat," and then when you put it in your mouth, it really turns on the vagus nerves because you have to have the pancreas juice already being produced before you start eating, and the vagus nerve controls that. Pancreatic polypeptide is very responsive intermediate or a marker that turns the pancreas on. It was discovered that if your vagi or vagus nerves were cut, you couldn't produce pancreatic polypeptide, that wouldn't go up.

It would be there, but it wouldn't go up with that anticipation of food. The strongest provoker of pancreatic polypeptide is actually physically eating, but you can get pancreatic ... If I were to just have no vagus nerve and put food in the duodenum, pancreatic polypeptide would go up through local signaling, so you have to just chew it and spit it out, and that's the vagus nerve only. It should go up by 50% so if it starts at a 100, it should go to more than 150 on them on the test, and over the period of measure usually it's an hour and a half to two hours.

Nirala Jacobi:                   Maybe that's why it's not so popular because patient has to [crosstalk 00:19:43]

Mark Pimentel:                Yeah, I meant to have an IV, and you have to draw blood [inaudible 00:19:45]

Nirala Jacobi:                   Yeah. Okay. It's not as easy as I thought.

Mark Pimentel:                Yeah, it's not [inaudible 00:19:49] so easy. But it's really meant for people where they had some kind of surgery or they had a recent one was ... I saw a case report at the ACG where they did radio ablation of atrial fibrillation. So they did a cardiac procedure and they burned both vagus nerves and then the patient was vomiting, and it was vagal nerve dysfunction from that. So pancreatic polypeptide is a good way to test that.

Nirala Jacobi:                   Okay. Now, we're going to conclude the interview with a couple of questions that are in the category of how often do you, and are we any closer to, okay? These can be just really fast at all things. Firstly, how often do you see a patient with diarrhea that has high methane on a breath test?

Mark Pimentel:                Very rarely. I can't give you the exact percentage, but I would say it's less than 5% easily.

Nirala Jacobi:                   Okay. How often do you relax for an entire weekend with your family?

Mark Pimentel:                Every weekend.

Nirala Jacobi:                   Do you?

Mark Pimentel:                I do take time off. On the weekdays, I'm working round the clock, but during the time with my family ... My kids are now in college. But when my kids were all assembled, and my wife and I don't do research together so there's more work at home, but 5:30 I was home. When the kids went to bed, I turned it on again. But the kids need my time, and that's important, because family's critical.

Nirala Jacobi:                   Very critical. I just wondered because every day you're somewhere else. Are we any closer to knowing accurately the percentage of IBS that is actually SIBO? Because there's figures 60% to 80%. That's a big difference.

Mark Pimentel:                It is a big difference. I think as we're getting closer and closer to defining what sequencing means SIBO, equals SIBO. I think we're getting closer and closer to that answer. I think the best answer we have so far is the Pyleris study, P-Y-L-E-R-I-S. Pyleris is the first author. That study says 60%, and so I think I'm settling on that for now. Breath testing can be as high as 80% in our trials that we've done in the past, so that's where the 60 to 80 comes from. But culture wise, it looks like it's at least 60.

Nirala Jacobi:                   Okay. Is that US versus global?

Mark Pimentel:                That was actual European studies. That wasn't even the US study.

Nirala Jacobi:                   What about, are we any closer to having ... maybe not consensus is the right word, but I still get a lot of complaints from people that go to their either GP or medical doctor or even their gastroenterologist, and are told that SIBO doesn't exist. Are we any closer to that changing?

Mark Pimentel:                100%. I mean, one of the problem is primary care. I would hate to be primary care. Let me say it a different way. I would hate to be a primary care physician, because primary care has ... Can you imagine the amount and volume of information they have to know to be able to understand the cutting edge of every facet of medicine? It's impossible. I mean, the amount and volume of inundation of data that they get. They can't possibly keep up with the latest and greatest SIBO and so forth. What sometimes is disappointing is that gastroenterologists who meet in 2019 should know food poisoning causes IBS, and that SIBO is a big part of IBS because even the skeptics are saying that now.

That's a little disappointing, and I'm sad for patients where they have that kind of experience. But you could say that if you get that kind of experience with a gastroenterologist, then maybe that gastroenterologist is up to date, not as well on everything, and reconsider. But, those are my words of wisdom there.

Nirala Jacobi:                   Yeah. They're still coming in, in terms of saying that they've been to their specialist and have the breath test was negated, and they're still scheduled for a colonoscopy. That's why I have so much respect for you besides the other aspects of your research, but really to try to reduce costs and medical costs for patients so that we have something a little bit more streamlined and cost effective for people that are looking for answers. So I thank you for that. On that note also, before we go, are you still seeing patients or do they have to see your associates, or how do people find you?

Mark Pimentel:                My practice is so inundated that I stopped seeing new patients. I just couldn't keep up with the patients I had existing already. So it's been really sad for me because I enjoyed the challenge of new patients. But I don't know what to do. I mean, the numbers just don't equate. I just can't keep up with the new patients. So unfortunately, but my colleagues are seeing news. We just hired a new person here at Cedars, and she's amazing. We're continuing to add experts that have the same skill set as I do to our group of doctors to try and see the patients.

Nirala Jacobi:                   Fantastic. Well, Dr. Pimentel, any last nuggets of wisdom from you?

Mark Pimentel:                I'm just always happy to talk to you. I think I learn from your questions and your ideas, and it sounds like every time you ask a question, it's the same question I'm asking here.

Nirala Jacobi:                   Thank you.

Mark Pimentel:                So obviously, we're both on the same wavelength in terms of what the patient needs, and thank you for doing what you do.

Nirala Jacobi:                   Thank you. I really appreciate your time with us and look forward to talking to you at the next conference again. So thank you very much, Dr. Pimentel.

Mark Pimentel:                My pleasure.