Latest SIBO Research 2024 with Dr. Mark Pimentel

It's a big day. We have doctor Mark Pimentel here and doctor Allison Siebecker. I am your host co hosting with doctor Siebecker, Siobhan Sarna. We're lucky enough to have doctor Sarna Pimentel. He's still share your sky slide for a second, doctor.

Let me see your face Sarna doctor Siebecker come on too and say hi. Hello, you 2. Hello. Hi. Hello.

How are you? Such a welcome, Mark. Yes. Okay. Here's for those of you who do not know who doctor Mark Pimentel is, he is the one who has brought the microbiome to GI.

One of the many things we can say wonderfully about him. He's the leading expert and researcher on SIBO, IMO, hydrogen sulfide overgrowth, as well as IBS. And he's going to be explaining his most recent research as revealed at DDW, Digestive Disease Week. Am gonna keep the intro super short so we can get right to it. My cohost, the esteemed doctor, Allison Siebecker is here.

She is also a world renowned SIBO expert. And truly, when we talk about, what the work that doctor Siebecker and I do together about educating the world about research and treatments and the like. Doctor Seabecker always says, it's the mission, and that is exactly correct. So you are here with high, high level, true, true people on a mission to help you feel better through these answers. Welcome to both of you, doctor Pimentel, I'm Sarna hand things over to you and be sure to check out all of his work on Twitter, everybody.

And he is officially the executive director of the medically associated science and technology program known as MAST at Cedars Sinai. So welcome. Thank you both. It's so great to be here. You know, every year I say the same thing.

And every time we do these presentations, I say the same thing. I say 2 things. Lots of exciting stuff has come. And the other thing that I say that's annoying, you should see what we have in the future. And so because we have some papers coming out that really kinda close the book, actually, really close the book on this and, I think, really address any of the concerns that people have about SIBO and its relationship to IBS and just, in general, the importance of SIBO.

But I'm really just heartened by so many people who've gotten better because of the things that that this work has done and, for example, the use of rifaximin and how many millions of people have improved, from the research that we've been able to produce over these decades. But there's so much more to do and so much more to come to make things even Siebecker. And I'm Sarna tease you with some really cool stuff at the end because we have a study this fall. And so I'll pitch that coming up. So I'll get my slides to move.

I'm gonna talk about new developments in IBS, SIBO, and the microbiome. And because this is after DDW, for those of you who don't know, DDW is Digestive Disease Week, and it's our once a year, very it's an international meeting, very intense, a lot of thousands of, presentations. And we had, such a good meeting, and and I'll share some of that with you in the context of things you may have heard from me before. But, you know, I like to build on my slides because the story doesn't isn't different. It's just evolving.

It's the same story. But I just Sarna take us back to 1996. And if you've seen this, forgive me. But but, you know, IBS was thought of as a disease of hysterical women. Imagine that when we didn't understand IBS, We attributed it just like we do with a lot of different conditions, distress, anxiety, depression.

But, you know, an effort was made to develop a criteria, as you can see in the middle. And this criteria, though, initially was considered a diagnosis of exclusion first. Why? Because the criteria are nonspecific. These are the Rome criteria.

You have abdominal pain, and you have diarrhea. Well, Crohn's, you have abdominal pain, you have diarrhea. So you have to get rid of that. You gotta make sure they don't have Crohn's first, the exclusion part, then apply the criteria. But the problem with the Rome criteria is it's a symptom criteria.

So as a symptom criteria, you have diarrhea and abdominal pain as IBS. So what treatments Mark drug companies gonna develop? Drugs that improve abdominal pain and improve diarrhea. Imodium, for example, or a tricyclic reduces abdominal pain. So what ends up happening now 30 years later, sadly, is we treat IBS by treating its symptoms, not by treating its cause except for rifaximin, and that's what we heard him talk about a little bit.

So now the Rome criteria I mentioned the Rome criteria. For IBS with diarrhea, the Rome criteria and diarrhea. The RUM criteria, despite trying to advocate for adding this, doesn't include bloating. But then when you ask a whole bunch of IBS patients what's your most bothersome symptom, they say bloating. So why isn't bloating part of the criteria?

It's very, very strange that that never got added to Rome, But here we are in these two papers, and the one on the right is from Rome, 55,000 patients on the right, and bloating really was linked to the pain, constipation, and diarrhea of IBS and highly related to IBS, all subtypes. So bloating is essentially part of IBS intimately, no matter what type. And and on the left, again, another study this time, 88,000 patients by Brandon Spiegel and and and Bill Shivan Janice Oh. And and they basically show the same thing. Bloating is a huge problem.

So we're gonna talk about bloating in the context of IBS, what could be causing it, and how Siebecker relates to it. This is, from the Rome experts as well, and talks about so this is a published sort of guidance from the society, the American Gastroenterological Association, the our our flag one of our flagship associations. And it says, if you have bloating, you need to consider carbohydrate testing for malabsorption and breath testing, either lactulose or glucose, for SIBO testing, because those are causes of bloating. So we're gonna go through this path and you've probably seen this if you watched anything I've done, this path hasn't changed. This appears to be the sequence of events that leads to SIBO in IBS and IBS, that food poisoning on the left, the toxin CDTB, and the development of anti vinculin antibodies causing a reduction in the nerves of the gut, specific nerves I'll show you, and then leading to stasis of the gut and bacterial overgrowth.

And so we're gonna talk about food poisoning first. So food poisoning causes IBS. This is there is no debate about this. There is some debate about whether we should call it IBS or post infection IBS. But essentially, you get a food poisoning at a wedding.

And ever since then, you've had a change in your bowel function, and they call that irritable bowel syndrome of the post infectious type. But imagine though that 1 in 9 people who get food poisoning or 11% get IBS. And we actually modeled this. And food poisoning in the United States, based on how much food poisoning is out there, could account for about 2 thirds of IBS. So we believe about 60% of IBS d could be accounted for by food poisoning.

Now that 60% number Sarna is gonna carry through this presentation because we keep seeing the 60%, 50 to 60% number over and over again, in terms of how we see IBS. But can food poisoning cause bacterial overgrowth, which we're saying is part of IBS? And the answer is yes, because we did the study in 2008, campylobacter food poisoning to the rats on the right, placebo to the rats on the left, and then we followed them till they cleared the campylobacter and then waited another 3 months of them just being normal, you know, wandering around, and and then we did the dissections. But we looked for bacteria in the small bowel, and we found that the rats who got campylobacter now have Siebecker. So campylobacter, which is the number one cause of food poisoning in the US by the way, we know causes IBS in humans.

It causes SIBO in rats. So we see that here. Not just that, the rats got IBS. They got the diarrhea. 80 plus percent of the rats who got campylobacter and developed SIBO, they even more had diarrhea and also, they had increased rectal lymphocytes.

What that means is a little bit of inflammation in the rectum which we also see in humans with post infection IBS. But this is the other thing we found. Now I put this here, a little out of out of order and kinda a little confusing, but one of the things we saw early on in this research is that the the specialized nerve cells of the gut because we wanted to find out, like, why is why is this happening? Why are you getting SIBO? One of the causes of SIBO is that, you know, the gut doesn't move correctly and the nerves control the gut.

So we studied the nerves and we saw that these these specific nerve cells of the gut called d m p I c c cells, and you can see the arrows on the on the right, were reduced, and they were most reduced in the ileum and the jejunum, which are parts of the small bowel of the rats who got campylobacter. And the ones who developed SIBO, there was even a lower reduction. Now when the pathologists were reading these slides, they didn't know which group the the slides were in. So the slides were randomized. So this was a blinded reading and the counts were obvious that these cells were reduced.

These are the cells that drive the cleaning waves of the gut. They drive the cleaning waves of the gut. Okay. Now there's a thing called the Bradford Hill criteria for those of you who do any kind of science. It used to be called the Cox postulates.

There were 3 postulates. Bradford Hill criteria. Now these days, it's gotta be more complicated and more robust. So the Bradford Hill criteria are the robust way to say, does something cause something else? And it meets all the criteria.

So food poisoning causes IBS, full stop. There's nothing to, you know, there's no argument about this or there shouldn't be because it meets all the criteria. But how does it do it? And so we knew that all of these food poisonings on the left can cause IBS, but they're different. Shigella can cause IBS, salmonella can cause IBS.

We already talked about campylobacter is the number one food poisoning in the US and probably the strongest organism to to to cause IBS. And then e coli, certain strains have, this toxin, CDTV, and could cause IBS. But the point I'm trying to make is all these bugs have the same toxin, CDTV, and that's the only toxin they share. So it must be important. So we actually did a study where we deleted the toxin from campylobacter and gave the rats campylobacter missing this toxin and they didn't get the IBS.

So we said, well maybe it's the toxin. I'll come back to that. Now remember I told you about those little cells that were reduced in the in the gut lining? Well, those little cells are important for the cleaning waves of the gut. So we didn't know about those little cells being reduced when we did this study in 2002, but we did know in 2002 based on this study that if you have IBS and you have SIBO, you have less migrating motor complexes, those cleaning waves of the gut.

So we measured the cleaning waves by putting a tube into the small bowel of IBS patients and compared it to healthy controls. And 50% of IBS subjects with SIBO had zero cleaning waves, like, literally none. But on average, you can see here in in in this panel, there were some, but there were very few. So the point is the cleaning waves are reduced, and we know from way back in 1997 from this very respected European, physiologist, Shivan Trappen, that if you don't have cleaning waves, you get bacterial overgrowth. So cleaning waves are critical for preventing the debris of food you've eaten last night.

It has to be cleaned up. You gotta wash your plate. Your plate is your small bowel so that in the morning, everything's nice and clean, ready for the next meal. And this is missing in IBS. So let's get back to this toxin.

So we decided to do 2 studies. I'm Sarna show you the first one, which was just a very simple study initially, and then the second one, which is a repeat study, bigger but much more complicated in the sense that we did much deeper analysis. So what we did is we took the toxin CDTB, extracted it, and purified it from campylobacter, and gave it to rats. Now if CDTV causes IBS, do you need to give it in the gut, or do you just need to have it in your body? So we actually gave it to the rats as a vaccine so they would develop antibodies to CDTV, and I'll explain why we did that later.

But when we gave the c d t b toxin, this is the rat's blood before. These are the antibodies to c d t b in their blood, and they don't have it. But when we gave the c d t b, you can see the antibodies shoot up very high. So they develop antibodies to c d p like a vaccine. But the rats also develop antibodies to vinculin, a protein that's on the nerves of those little cells in the gut.

That's very important for those cells to connect to each other like wires connecting to each other. And that antibody also went up. And the rats who got the CDTV toxin developed Siebecker, both in the ileum and the duodenum. And the vinculin, was reduced in the gut. So it's interesting that you give a toxin under the Shivan, and the gut proteins change, and the gut bacteria goes up, and you get SIBO.

So we felt it was an immune response to this antibody that was creating IBS or SIBO in these rats. Now I am not gonna go through all the details of this slide because this took 5 years. We had to do dozens of experiments to prove this, but we were able to show that the antibodies to the CDTV, seeing that toxin, made you, as a human or a rat, form antibodies to a protein called vinculin. The hard part was trying to figure out what protein was being attacked, and it turned out to be vinculin. Vinculin's complicated.

There's 5 different vinculins in the body, and this particular one is the only one that this antibody reacts to. So to simplify things, you get food poisoning, you get this reaction or this exposure to this toxin, you form antibodies to multiple parts of this toxin, but one specific part looks like vinculin, and that's where you get autoimmunity. Now I'm showing this slide. I don't usually show this slide, but I'm Sarna show it today just because I want to impress upon you. In this study, we took rats that are alive.

They're just sedated, but they're alive, and we injected the antibody to CDTB in the top panel and the antibody to vinculin in the bottom panel. So you see cDtb antibody, cDt vinculin. And the antibody is labeled, labeled, not radioactive, but labeled with an immunofluorescent marker. And you put these rats underneath a camera and the camera can actually see where the antibodies went in the body of the rats. So that's kinda cool.

And then sadly, we have to dissect the rats and we dissected the rats and showed the gut and then put that under the camera. And what you can see is that the antibody collects in the gut, not in the skin, the fur. And you can see the anti vinculin even more strongly collects specifically in the gut. And and you can see it's going along the lining of the gut. So these antibodies are attracted to the intestinal tract.

Now what is vinculin? So I'm gonna show you, this is sort of a a a picture of cells in our lab. You can see the green filaments. That's the skeleton of the cell that holds the cell shape called actin. At the end of actin, you can probably see it best here.

There's vinculin, this little red thing here. So vinculin is the motor at the end of these strings that stretch the cells out to grab onto each other. So I said that we did this study twice. This is the second study. So we did the CDTP injection in rats again.

More rats though, more power. Again, no antibodies in the rats before we injected them. Lots of antibodies after we injected them. But what happened to the rats is they got diarrhea, more stool water. And the more the anti CDTV antibody was elevated, the more wet their stool was.

So the antibody was proportional to the amount of symptoms the rat had. But this time, because the technology was available, we could do microbiome assessment. And this is the microbiome of the different segments of the gut. The duodenum, the ileum, the cecum, and stool. There's nothing going on in the colon.

Nothing. Which is another argument that you can't really see what's going on in the stool or in the small bowel using stool testing. In the small bowels where everything happened. And what happened in these rats is so think about you, you know, 100 people went to a wedding and a 100 people didn't. Right?

So the 100 people who didn't, their microbiome is normal. They're the control. The 100 people that went to the wedding and got food poisoning, not all of them developed IBS, but some of them did. And that's what happened here with the rats as I show you the next slide. So the people who didn't go to the wedding, or in this case the rats that are controls, this is what their microbiome looked like.

But some of the rats who went to the wedding and got this toxin, they also didn't get worse. They didn't change because they just didn't. But the rats that changed changed in 2 ways, 2 different possible ways. 1 group of rats became e coli, SIBO. Another group of rats became desulfovibrio SIBO.

You can see the two names here. This is a hydrogen producer. This is a hydrogen sulfide producer. So the rats moved into 2, what we call, cluster groups or microtypes. And this is really important because what we're going to show at the end is that the rat experiments exactly mimic what we're seeing in the human studies as I'll show those later.

And what's interesting is in these rats, when we look at the functional, proteins that are produced by the gut after this toxin, etcetera, it's all the stuff that's IBS. Barrier functions affected, serotonin's affected, visceral hyperalgesia, which is pain sensations in the gut systems are affected and circadian rhythms are affected. So it all comes together. I'm gonna throw this in because this is what I'm gonna pitch right at the end. But, we now know where these bugs live, especially e coli.

It likes 50% of e coli likes to live in the mucus, doesn't like to live in the liquid phase. So half and half, basically. So which is probably why rifaximin doesn't work in as many people as we wish it did because rifaximin cannot penetrate the mucus because it's not water soluble. So it can't get in there, and it can't kill the entirety of E. Coli.

So in this rat study, there was another set of arms where we used rifaximin in a new way, in a new combination, in a particular way and ratio of rifaximin to n acetylcysteine. And those are the rats that got better. Those are the rats that had a better bowel movement. Those are the rats where e coli went to normal. Those are the rats that their system biology switched to normal again.

And this was presented at DDW. And I'm not gonna get into all the figures, but, basically, it worked better than rifaximin alone. So the study we're doing in the fall is a phase 2b study with the FDA using a special delivery system for combining rifaximin with NAAC in order to get the bacteria in the mucus and outside the mucus down. And and that's super exciting for patients because we really gotta improve upon what we've done. And that's the next extremely exciting, evolution and hopefully a drug that will be on the market soon.

That's amazing. I Sarna quickly ask you this question. So for people who don't know what, NAC is, is it do you consider it like a biofilm buster? Like, can you just explain a little bit about how it works with the mucus first, please? Shivan acetylcysteine is is well known.

It's a mucus degradator. So biofilm is a is a term for, a film of material. Like, for example, the tartar on your teeth, that hard stuff that the dentist has to scrape off, that's a biofilm. Sarna acetylcysteine wouldn't break something like that down. But it's the mucus in your gut.

So E. Coli likes to swim. It has flagella. And so it can swim through the mucus. And that mucus, most of it you're producing, you call it biofilm because bugs are in it.

And so you could say biofilm buster, but it's buster is implies it's busting something, but it it's basically thinning the mucus. Yeah. That's how I look at it. Thank you. Just wanted to clarify that.

Okay. Back to you. Super cool. Thank you. Okay.

So now let's talk about this antibody. These 2 antibodies now can help us diagnose IBS for the first time. And and the 1st generation wasn't as robust as the 2nd generation. So there's only one second generation test out there, and we can talk about it in q and a. But that's the test that truly differentiates IBS from other diseases.

And you can see here that the anti CTB, we can measure it in humans now, And the anti vinculin head and shoulders above. And it's really important to know this for patients. I do it in all my patients. But I'm not gonna get into all the details, sensitivity, specificity, except to say, look, the pooled sensitivity of this test is 56%, and people say, well, that's a low sensitivity. It's not a low sensitivity because out of a 100 IBS patients, only 60 are likely from food poisoning.

So the highest you can get is 60, and we're at 56. So look at it that way. Don't look at it as sensitivity. We're not diagnosing IBS. We're diagnosing post infection IBS.

And and that's a very important thing when you look at this, but look at the specificity. If you're positive, you got it. Positive to predictive value. If you're positive, you got it. And if you look at every test that's ever been developed for IBS, the IBS Mark test, which which is the one that measures anti CDTV and anti vinculin in the 2nd generation version, is the only test that gets you to medical certainty.

The first generation test you can see is down here. So this is what other other labs are doing is this first generation test, which doesn't quite make the 80% medical certainty. So you're stuck using the one that's most accurate. And so this puts the story together on the antibodies, and then we'll get to breath testing. But basically, your bugs are all normal on the left.

You get food poisoning. You get the CDTB toxin here in the middle. You form antibodies to CDTB, and it isn't initially that you get the anti vinculin. It comes later, usually about 2 or 3 months into it, and then the antibodies start to to affect the nerves of the gut. This is what we believe is happening, published.

Published data, all published science. This is I showed you the papers that have been published on this. Not opinion. This is science. This we presented at DDW, and this proposes something even more exciting.

Okay. Over time, we measure these antibodies, and we see that they go down in time very slowly. So anti c d anti CDTV can go down faster in some patients, but vinculin, really, it's a sluggish thing. You have vinculin in your body, so you're gonna always have the potential to form antibodies. But it goes down ever so slowly.

But I want you to focus on the table on the right. In the patients where the anti vinculin normalized, 75% of those patients, their symptoms improved. So here's here's what the future is. You get this antibody out of your blood, you get better. And so if this is the cause of IBS, you gotta get rid of that antibody.

And that's what we're working on. Like, day and night right now is trying to figure out how to do that. So stay tuned for more on that in the coming months because we are literally we we were we have identified all the antibodies the blood. We've identified the b cells that produce this antibody in humans. We're we're marching fast towards this next thing, which I think will be really important.

Okay. So, now let's talk about breath testing. So this is the meta analysis by an Australian group. We're not part of this. This is a Asia shaw from from Australia, a brilliant, scientist down there, and she shows that it's absolutely true that IBS patients have more positive breath tests.

Only 2 outlier studies here, and this is only a 35 patient study. And this is a very poorly done study, a 166 patients where half of them were IBS, and they were 35 years old. And then they went to the college campus and got 18 year olds for their control group. So there aren't they aren't they're like the obvious patients are double in age. This isn't how you do research, but it's okay.

It's in the meta analysis. And despite having these 2, not so great studies here, the the data's overwhelming that IBS and CBO go together, But it's important that you understand breath testing because when you do a breath test, you have to capture the last half of the breath because you gotta get the breath closest to the deepest parts of the lung. So Sarna second half, you can't take the sum of hydrogen and methane. It's not a thing. The North American consensus says it's not a thing.

You can't add the 2 together. There's no study that says that means anything, and it doesn't actually work that way. I'll show you that later. And going past 2 hours on the breath test, I know people want to look past 2 hours, but we haven't been able to show a study validating that past 2 hours adds Mark. But I understand people still do that.

And, it's very important to prep for your breath test. Mark, can I just jump in here for one second? That's for hydrogen, right? The 2 hours. But for methane, we do look past 2 hours, right?

So we still do 2 hours because methane, 95 percent of the time, even at baseline is already positive. So you don't need all that extra time because it's just you'd have to wait 12 hours for some patients. 6 you know, so and we don't have a 12 hour breath test. So it's, But if somebody is using a 3 hour, we can use the 3rd hour. That's valid to look at that methane.

So any methane over 10 at any point during a breath test is considered positive by the North American consensus, we don't say it can't be past 2 hours for methane. So you are correct. You can use something past 2 hours for methane, but you can't do it for hydrogen. Yeah. At least we don't have data.

It's not that I don't like to say it's wrong to go past 2 hours. We don't have the science to say it's right. And so without the science, we cannot say it's right. So 2 hours is all you need. And that's the same for hydrogen sulfide as well.

Right? We can also use that 3rd hour if it's there. So we don't have a consensus statement on that yet. So you'd only be getting my opinion. My opinion is if it is if it ain't positive within 2 hours, it's probably not going to be positive, but that's just my experience.

Thank you. But there's no test that I know that goes past 2 hours for hydrogen sulfide. So unless you unless you know something I don't know. Okay. We could talk.

Okay. So this is important. So you've got you've got hydrogen producers on the left and you've got hydrogen eaters on the right. So you have and these are the 3 gases, hydrogen, hydrogen sulfide, and methane. That's it.

There's no other gases produced in the gut. There's all sorts of volatiles, but no gases. So, hydrogen sulfide producers use 5 hydrogens from these guys to make 1 hydrogen sulfide. Methane producers use 4 hydrogen to make 1 methane. So I don't Sarna get complicated math here.

It's not terribly complicated, but if you add hydrogen plus methane, that's not even right. You should take the methane, multiply it before by 4, follow that hydrogen and then add it to the methane. If you really wanted to talk about chemical stoichiometry, that would be the way to add the 2 gases together, not 1 +1, because it's 4+1. And and so that's why we say adding hydrogen to methane is not a thing. It doesn't even it doesn't even make chemistry sense.

Okay. So small bowel culture has been done in IBS patients. This is Magnus Simren's study from Sweden. Small bowel culture is more positive in IBS than healthy controls. A very big study, 26 controls, 165 IBS.

Another study from Europe from Polaris, this time, that 60% number comes up. Again, 60% of IBS d have SIBO by culture culture was believed to be the gold standard. But now we have the reimagine study which I'm Sarna talk a little bit about. I don't know why people don't bring this in their presentations. Maybe they don't like it, but this is, such a seminal figure, a table, because this shows that breath test at 90 minutes, the sensitivity and specificity of breath test at 90 minutes is quite good.

It correlates with the gamma proteobacteria, which are e coli, echoricea, which is the cbo bug in the small bowel, that breath test result. It correlates with gas and the breath test, the result on the breath test correlates with hydrogen producing enzymes that make hydrogen that are found in the small bowel juice. So if this doesn't tell you that the breath test is accurate to the microbiome, I don't know what tells you that. But, you know, this is the paper that should be quoted and and just people don't look at this one table. But this is really important.

But now we've gone to shotgun sequencing, which is even more advanced. But we've we've been able now in this year to settle the issue of what is Siebecker. And SIBO is greater than 10 to the 3 or greater than a 1000 bacteria per ml, and you have to use McConkey agar. There are centers in the US that use McConkie and blood and add them together, another thing you don't do in microbiology. The problem with microbiome research in some instances is that you have people who know GI and know microbiome analysis but don't know microbiology.

And microbiology is a whole field in and of itself. I happen to that's where I Sarna. I was a microbiology person, then I became a gastrologist, then I became a microbiome person through study. And so you gotta put the 3 together, and balat agar counts E. Coli and macconkey agar counts E.

Coli. So if you add them together, you're counting it twice. Can't do that. You gotta you gotta keep them separate. So, anyways, 10 to the 3 is the cutoff, and you can see clearly that this is a beautiful microbiome here.

It starts to break apart. The lines are thinner, less bacteria, and the higher you go with the amount of bacteria in the small bowel, the more destroyed the microbiome is. The community is breaking apart because SIBO is destructive to the microbiome, and we see that in our study. But I wanna talk about, you know, deeper sequencing. And, and so we've gone deeper now and we're able to see exactly what bacteria are causing Siebecker, and that's what I'm gonna show you here.

Look at SIBO by itself. Siebecker on the right. So these are culture positive patients. Isn't the breath test These are culture positive. So it's gold standard stuff.

And you can see when you sequence that klebsiella and escharicia are the important genus or genera, in SIBO. But look what happens. It this is remarkable that 18% of all the bacteria in your gut is klebsiella pneumoniae and 28%, if you look here, is Escherichia coli. So SIBO is not what we used to think, just colon bacteria in the small bowel. It's 2 bugs only.

E coli, pudzilloplneumonia. That's it. Encompassing the whole problem of SIBO. But even more interesting, it might be 1 or 2 strains of these bugs. Look at this comparison of k 12 e coli, which is a it's a strain of e coli, and it correlates with all the IBS symptoms that we know of bloating, abdominal pain, diarrhea, etcetera.

So we're really getting down to who are the real causes of this. But I love this slide because it really puts to bed a lot of other things. If you have Siebecker, your ability to ferment in the gut is jacked up by 63 times. 60 3 fold Siebecker versus non SIBO in glucose degradation. So if you eat sugar, patients tell me so, well, 10 minutes after I eat, I'm getting some bloating already.

You know, it takes about an hour to ferment, by the way, to get to peak fermentation. But when you start to see patients saying, like, 10 or 15 minutes, you're like, well, how does that happen so quickly? Because he call is so good at fermenting that and it's taken over that it just starts to produce gas much more quickly than if you had your normal bacteria. And I'm gonna get into all the production details. I'm gonna skip these because I'm getting too complicated.

But let's talk about methane now because methane is not SIBO. Methane is intestinal advantage and overgrowth. We've come a long way with methane, but I wanna take it back. Methane is associated with constipation. That's clear now.

And and what we saw in 2006 is that we when we put methane gas on the left into animal small intestine, the the transit, the speed with which food and material moves through the small intestine slowed by 69%. We're talking 70% slowing. So methane slows the gut, but it doesn't slow the gut by paralyzing. It slows the gut by causing the gut to spasm and not let things move. And that's what the panel on the right shows.

When we put oxygen in an organ bath, the the the ileum tissue, the small bowel tissue, contracts very nicely. You put methane with the oxygen, and it's spasming intensely because the methane is changing how the muscles react, and that's how it slows things down. But now we know intestinal methanogen overgrowth, this is a meta analysis, this is hard science of all the studies that have been done, and you can see that methane is associated with higher constipation and lower diarrhea, which we knew, but this is a summary, that was presented at the ACG meeting just a few months ago. But the new kid on the block, which we're calling intestinal sulfide overproduction because the terminology is important. It's not just in the colon.

It's not just in the small bowel, and it's overproducing the sulfur competing against the methanogens. And it's gonna be get really complicated. But we had to have a breath test that can measure this, and this took about 5 years to develop because hydrogen sulfide is very reactive. You need new sensors. You need to array the sensors so they don't cross react.

Whole new machine needed to be built. Whole new kits needed to be built, and then science need to be needed to be done and is continuing to be done. You can't just put this out there. You have to validate it. You have to find out what the cutoff is going to be, you know, how how many symptoms depending upon what level of hydrogen sulfide, and that's that's still being done.

We're still trying to figure out what is the bottom end of this, but this these two studies I'm gonna show you in the next, in the next couple of slides. When you do the breath test and you measure methane on breath using the 3 gas breath tests, The amount of methane you produce on the breath correlates with the number of methane producers in the small bowel juice. This is a 110 patients. We got we've got now the reimagine study is 1,000 patients, but we've only been doing this 3 gas breath test recently. We have a 110 in this cohort.

This is a huge number of studies with shotgun sequencing, which is extremely expensive. When I talk about the reimagine study, we're talking about 5, $6,000,000 put into this already, into this study, to try and figure these things out for patients. So it's it's expensive, but it's getting us all the answers. But what is important is that it is, again, the methanobrevibacter smithii. That's the character that's causing the methane for the most part in the small bowel.

Hydrogen sulfide, we have now filled cox postulates for hydrogen sulfide. Cox postulates are if you find the gas, it's associated with diarrhea. If you find the bug that's causing the gas and you put it into an animal, do they get diarrhea? That's what this study is. So we took the 2 bugs, the desulfofibril and fusobacterium that are in the colon causing hydrogen sulfide, and we put it into rats, and they got diarrhea in both instances, and they produced more hydrogen sulfide in their stool because we put those bugs in.

So they were alive and kicking. So hydrogen sulfide causes diarrhea. We did the same thing. We measured hydrogen sulfide on the breath of patients, then they were in the reimagine study. The same day we're collecting the juice, and we found a bug that we think is the most important bug in the small bowel, and it's Proteus mirabilis.

So Proteus mirabilis in the small bowel, fuso and desulfo in the colon, these are the bad actors. And you can see that Proteus is driving the entire effect of breath hydrogen sulfide from the small bowel. So not only do we validate that each and every gas on the breath test correlates with the microbiome, we know the bugs that correlate with the breath. So when you do a breath test, that breath test is telling you exactly who the bugs are in the small bowel that are increased. We now know that that's true as of this DDW.

And if all 3 bugs, the prominent hydrogen sulfide bugs Mark there, the breath hydrogen sulfide is dramatically elevated. And we found the pathways that produce hydrogen sulfide. So I'm gonna come back to IBS and then we'll finish up with treatment and then we'll be done. But this is the this again is the 3 gas breath test, hydrogen sulfide, hydrogen, and methane, in irritable bowel syndrome patients in randomized controlled trials. This was not a SIBO trials.

These were double blind FDA trials for IBS d and IBS c. And we did breath tests using the 3 gas breath tests in both instances. If you're diarrhea a diarrhea patient look what your methane is on average. Of all these diarrhea patients that were in this trial, nothing. Doesn't happen much.

Right? People say, oh, I have a diarrhea patient with methane. Well, you better look for something else because it just generally doesn't happen. And that's what we showed here. If you're constipated, not everybody with constipation had methane.

Some didn't, but when they did, this was what the breath test looked like. Look at hydrogen. Hydrogen is lowest in methane positive IBS C patients, because the methane's eating hydrogen. And so the hydrogen will be even lower than normal because it's eating the hydrogen to make the methane. So that's why you can't add gases.

You can't do this kind of stuff. But look at the hydrogen. The hydrogen is on average in the SIBO range for an IBS D patient. And hydrogen sulfide is higher in IBS D versus c. And again, m smithii.

Methanobarbacteria smithii in the stool is the character, and we prove this even shows that every single time point on the breath test is statistically related to the M. Smithy ion stool, and we saw the same thing in the small bowel that it's correlated with M. Smithy ion. So, I mean, when you do a breath test, the breath test accurately determines not just that you have those organisms, but the amount of those organisms is proportional to the amount of breath methane. So, I mean, the breath test in this study is fully validated in IBS.

And in the small in the colon, fusobacterium desulfovibrio. I'm gonna give you a summary slide that really shows all of this once we're done. So with IBS D, which is on the left, humans remember the rat study? You can get either hydrogen or hydrogen sulfide microtypes? It's exactly what we see in IBS D.

Hydrogen microtype or hydrogen sulfide microtype. In IBS C, we see methane Now food poisoning doesn't cause constipation, doesn't cause the methane, so we don't know why these patients get all this methane So that's something that's still a mystery to us. So we've done this very large study, real world study, and we presented one bit of data at DDW, looking at the 3 gas breath tests, and these are the kind of symptoms that they had in order to get the breath test. But what you can see is that the higher the methane is on breath in this nationwide, nothing to do with cedar cyanide. This is, like, across the nation, Every state, people getting a 3 gas breath test.

The higher the methane is, the more constipated these patients were. So this is what's seen across the nation. So I talked about the North American consensus. So the North American consensus, just to give you perspective, these experts who are listed here, and there's a group that are and, beyond the names that are listed here who helped write the actual construct of the paper, These are the people who publish in SIBO. These are the people who do research in IBS and SIBO, that were invited to this meeting to vote and comment on how breath tests are done.

The same thing was done in Europe, although some of these folks have not necessarily done breath testing. And then definitely, Uday Ghoshal has done a lot of work on bacteria in the gut in India but also wrote, this isn't the Indian this is the Indian neurogastroenterology association, but it's an Asia Pacific consensus. So it includes people from Australia and and that region. And basically, they mostly agree about the criteria for SIBO, mostly agree about the dosing, and mostly agree that SIBO and IBS are interrelated. But I wanna point this out because this is the first intern this is an international this is an Indian consensus, but this is the first consensus on irritable bowel syndrome since a lot of the data I've shown you today, the new stuff.

And they say that food poisoning causes IBS. That's the first thing. They they say that's a great recommendation a. They say that methane causes or is associated with constipation. Great recommendation b is still good.

And that, infection oh, sorry. And that, breath test, SIBO and IBS is a grade a. So SIBO and IBS d relationship is a grade a, and food poisoning and IBS is a grade a. So with the new data in scientists who publish consensus statements summarizing the actual complete literature, this is very exciting so here we Sarna. This is what we've got now.

We've got these 3 gases. So what do we do with this sequence? And so I do show you the rifaximin study. So this is a rifaximin in the New England Journal of Medicine in 2011. Rifaximin eventually became FDA approved for IBS d, understanding that IBS D was a microbiome condition.

We felt it was SIBO, but the data needed more work and we've now done a lot of that work in the past 8 years, 9 years. And we feel that it is Siebecker and this study, which came out in 2019, 4 years after the FDA approval, shows that if you did a breath test so if you did no breath test and you just took rifaximin for IBS d, 44% chance you're gonna get better. If the breath test was positive, 56 percent percent chance you're gonna get better. And if Rifaximin made that abnormal breath test normal, those patients, 76% of those were better. So the breath test is telling us something about the microbiome that makes rifaximin more likely to work.

For methane, the only thing we have right now is this double blind study. It's small, but it's a double blind study. Neomycin and rifaximin improve your constipation more than neomycin alone. For hydrogen sulfide, we don't exactly know. However, I told you we're Sarna do a study in the fall and that study in the fall is actually going to be testing whether the new agent is getting rid of hydrogen sulfide.

But right now, we're using rifaximin and and bismuth because of this study here from the 19 nineties. But this is an interesting meta analysis that was done, by Will Takakura showing that if you have a positive breath test in all of these studies listed here, you are more likely to respond to rifaximin. So the breath test is telling us something about the the SIBO being present and that rifaximin will work. So this is what I do in my clinic. This is not a guideline.

This is just me, how I approach things in my clinic. So if I have somebody with chronic diarrhea, I'm measuring those 2 antibodies. I'm measuring anti CTB and anti vinculin because I believe, based on the science that we've published and the science that's out there, that anti vinculin is a cause of IBS and that that that gives you a propensity to get food poisoning more easily because of how it's damaging the nerves of the gut. But it leads to SIBO, so I do the 3 gas breath test. And if it's hydrogen positive, I give rifaximin.

If it's hydrogen sulfide positive, I would give rifaximin with bismuth. And for some patients, I do follow the antibodies with time. I I we're we're in the middle of a publication showing the time changes in the antibodies. So once that's published, others can reflect on that as well. For constipation, I don't measure the antibodies because I don't feel that food poisoning causes constipation.

I do the 3 gas breath test because I wanna see if they have constipation. I do the 3 gas breath test because I wanna see if they have methane. And sometimes people with methane also have hydrogen sulfide. So we don't know if you need to treat both, but we think we do. We have a few cases where we've had to, because methane wins.

If methane is present, you'll be constipated. So I go back to this slide, which I showed you right at the beginning, food poisoning, Sarna, that, you know, back in the 19 nineties, this is what we thought of IBS. This is what we see in the microbiome of IBS now in 2023, and I can change that to 2024 and add a lot more to this now because we know even more than this. So, things have really moved along. But I wanna show you this next slide because it really puts it all together.

So when you do science Sarna I mean deep science, you want to have an animal model if you can because you have to say okay it works like this in humans, it It works like this in animal. It works like this in humans. It works like this in animal. It works like this in humans. It works.

Because if you Sarna prove causation, they've got to be parallel and mimicking each other. So food poisoning and the CDTV toxin are linked in human studies and now animal studies to the development of antibodies. Those antibodies Mark, when they're higher, you have more disease. We see that in humans, and we see that in animals. We see reduced ICCs.

We see a reduced cleaning wave in humans. We have not done that in animals yet. But we see 2 micro types in IBS D in humans, and we see 2 micro types of the exact same nature in the animal studies. We see the transcriptomics, meaning this expression factors in the lining of the gut of animals and then the lining of the gut of humans as being the same. The same IBS phenotypes, the same IBS derangements are happening in these two models.

And rifaximin, but maybe rifaximin with NAAC is better, there's a normalization of all of these factors, And we've seen that in animal studies that we've published and in human studies. So we've really worked out the nuts and bolts of how this all happens. So my conclusion is IBS is commonly a small bowel microbiome disease. SIBO is an important contributor. The most important organisms for SIBO are e coli and klebsiella.

M. Smithii is the most important organism for constipation. It's CIBS. Hydrogen sulfide is key. It was the missing piece to try and put all of these pieces together as you saw on the last slide.

And the through new 3 gas breath test really is the first breath test ever validated against the microbiome. So this last year and a half really has changed the understanding of breath testing, the importance of breath testing, and really put it to the forefront. And these new antibodies really tell us why the patient got this and what to be aware of. Don't get food poisoning again because if you have these antibodies, they can get worse Sarna you can be worse. So we're starting to unravel all of these mysteries, and new treatments are on the way.

The new trial starts in October. We've already got all the paperwork lined up. The drugs manufactured. Everything's good to go. I know I always say these things are coming.

I hope it'll be October, but it could be November, but it I'm I'm pushing for October, the sooner the better. So thank you, and sorry if that took too long. No. No. It was amazing.

Fantastic. Fantastic. Really. Pouring your heart and soul into the work and then revealing it to us. Thank you so much.

Okay. I know, Allison, you have some questions. Of course. I have some too. I just wanna, can I just scoop up a few right here, right now, doctor Siebecker?

Of course. You need a sip of water, Mark Pimentel? I don't know. Coffee is my water. So Okay.

Okay. Perfect. Okay. Pimentel diet. You were talking about rifaximin and and knack and bismuth.

How does the elemental diet play, and does it have different results for which kind of gas you have? Okay. So, I can't tell you the whole story of it because it's not it's the paper is submitted, so it's all, going forward. We did present some of it at DDW. But, essentially, if you if you have hydrogen, almost every single patient, the hydrogen breath test normalized, which is even better than what we saw with the VivaNex study from 2,003, I think.

In terms of methane, we're seeing approximately 70 to 80%, which is also better than the Shivan story. So now it's not a head to head study, so we didn't compare the new Pimentel diet to the Vivenix, but this is pretty darn good. And and and the most important thing, if you're going to take something as dramatic as an elemental diet, it has to taste good. And that's that we've shown diet, it has to taste good. And that's that we've shown that that this taste, it's it's 400 to 0, compared to It's delicious.

Honestly, stretch for me. Super taster. But Yeah. We both got samples of it. Siobhan is a super taster for anyone who doesn't know, which means that, you know, she has it's a genetic thing where, like, she will vomit if something's too bitter.

And she thought it tasted good. Right? I did. I absolutely did. So And I've been I just wanna say I've been hearing Well, everything gets old after 2 weeks.

I mean, you can eat apples every day for 2 weeks. You get you get tired of apples. But but, you know, it consume it at all is a miracle. Yeah. Doctors are telling us their patients think it tastes better than any other elemental diet.

Okay. Then then that was the point because you gotta be compliant. If you don't do it or worse worse than that, you know, if you pay a $1,000 for an elemental diet and then you can't tolerate it after 2 days, that's money down the drain. That's not that's not fair. That's not fair to patients.

So I'm I'm very glad for this. Mark, you do you guys didn't, check people for hydrogen sulfide on that, elemental diet study? I can't talk about everything yet because it's not yet been publicly disclosed. We checked out everything. So Okay.

Good. You'll you'll see I mean, I I can say that, you know, I have a hydrogen sulfide study group with other colleagues, for 3 3 years now. And in our group, we found elemental diet is successful for hydrogen sulfide. So great. I'm not let's just say I'm not surprised.

Okay. Then coming just as a side note here, what is the elemental diet for those of you who are not familiar? Mark, do you wanna take that and just do a little reader's digest version of that in case people are like, No. Honestly, you know, in 2002, I had a patient who had, like, really serious SIBO. It wasn't IBS.

It was caused by, radiation to the vagus nerve. So he had a vagotomy from the radiation for cancer. But Hisibo was so bad, antibiotics weren't keeping it away. And so, I read a paper that said, if you took an elemental diet, they used to do it to prep the colon for colon surgery because it can reduce bacteria in the colon because it starves them out. I said, well, maybe it'll starve SIBO out.

So we did it and this guy who was willing, 2 weeks and it just wiped out his SIBO. And so that's where the story began with that one patient. And then so basically, it's food completely broken. You don't have to do anything. It's completely broken down and it all gets absorbed for you and nothing for the bacteria.

And so they starve to death, basically. They don't have enough nutrients. At least that's how we see it and understand it, at the moment. Okay. And then when someone is coming off the elemental diet, we get so many questions about this.

Like, should I be on basically baby food? What this transition time from being on this liquid diet to regular table food? I know, know, you've talked about this recently, I think, on an Instagram live, but what and when we've asked you this before, but what do you tell patients about the transition from elemental diet to table food? So, it's it's basically s and s, soup and sandwich. You know?

Don't go crazy. Don't go out to, you know, a steak house and have steak and potatoes the 1st night or a big, you know, ribs at, Tony Roma's. That's too much for your gut. You know, you have to just ease into food for a few days. And and the one thing that we do say is that, you know, because when you're on an Pimentel diet, the villi get a little bit shorter because you don't need them as much.

Sort of like putting a cast on your arm for 3 months because you broke your Mark. You take the cast off and you look one smaller than the other. If you don't use something in the human body, the body conserves. So if you go to the Lowry's steakhouse and you get something very rich, you could have diarrhea because you're not absorbing it because the villi have atrophied a little bit and they're not being used. But they grow back really quick.

3, 4 days, you're back to square 1. But the other thing that I really Sarna point out with the elemental diet that we know from doing a couple thousand patients, don't declare victory until 10 days after. Victory or failure. Because you can feel a little grumpy in the stomach just for a few days after Pimentel. So don't say, oh, it didn't work.

I'm I'm bloated. I'm this. I'm that. Wait 10 days. 10 to 14 days after.

That's when you really have to look at it. But this is what this is what I mean, you know. So, you know, some I think patients have been frustrated that we haven't had therapies based on all the science, but you gotta get all the hard deep science to know the therapies. And so here we are now a few years after people said, well, now give us some therapies. Elemental diet's done.

We did it. We we did the science. The patient's breath test improved and their symptoms improved. This is research. This is this is hard.

This is expensive. And now we're publishing it, we presented it, and now it's on the market. The next is this new therapy with the NAAC. We've been working our ass off with these animal studies, these randomized controlled trials in animals And now we're ready for we did a small human trial. Worked great.

Can't talk about it because it's a small human trial. They haven't published it yet, but we're now in phase 2 b with the FDA. And you'll see that in the fall, and then you'll see a product. We have a similar thing for methane coming in behind. We're now that we know, the things are coming fast.

So the patients should be very optimistic that all and we needed the 3 gas breath tests because we couldn't understand a piece. We couldn't understand what's happening with diarrhea. So you had to develop the tools to develop the treatments, to develop the, you know, the things for the patients. And then the vinculin story, we're developing that drug right now. So all the pieces are there and all the all the treatments are coming.

So so this is an exciting time and not a time to be, pessimistic. Exactly. Optimistic with that patience of choice. We haven't said the name of the new elemental diet. It's m biota.

Biotic. M biota. And, doctor Siebecker and I are working behind the scenes to get it on full script, by the way, with our Oh, yeah. I've already written in and multiple times. And then so just so you know.

But the other thing I wanted to ask you is, because this comes up all the time, that hyper vigilance that can come cause you're gonna have to be hypervigilant to be on the elemental diet. Then when you're transitioning off of it, I see a lot of people with a lot of anxiety. I'm not a doctor. This is my general observation about, like, putting table food in your mouth. So I think what I just heard from you is breathe, relax, don't go crazy, and don't overthink that phase.

Allow your microbiome to come back on track. And Dr. Pimentel, after you see the reduction of these bad players, you've told me in the past, there's one I'd be able to say I talked to you about it again. You see the microbiome come back into a homeostasis state of a mbioTA, we from mbio to, we don't we haven't run that data yet. So we haven't actually done the sequencing on this.

We have it all. We have it all. So we we will be doing it. But I think what I've said before is that in the reimagine study, we have some patients who we've done the juice a few weeks after Rifaximin where we knew they had Siebecker. And what we see in the patients is all the normal flora come back.

Once you get rid of the bad actors, everything just grows back. And, again, and I I use this analogy. You just pulled the weeds out of the garden and the tomatoes are now going crazy. So, like they're supposed to. And so I think that's that's the message.

We get rid of these bad actors and then we have we restore the normal microbiome. What most, patients are concerned about, on doctors, is do we need to give probiotics and or prebiotics at this time? I guess using your analogy like fertilizer, you know, do we need to do that? And and everyone is just so concerned about whether they should or shouldn't. Well, so let's talk about prebiotics for a second.

I showed you that when you have SIBO and E. Coli, the E. Coli is so darn good at fermenting. It's competing, outcompeting everything. So you put fish food into a tank with piranhas, and the E.

Coli are piranhas, the piranhas are going to get the food before anybody else Sarna everybody else starts. So e coli is gonna be eating that prebiotic so fast, it's gonna grow, make more babies, and, you know, the usual thing. It it's going to bloom. So I I don't like the and this is why no sucralose, no, you know, because that's just putting fish food on the e coli and making these patients sicker. Probiotics, again, I'm always hedging on this because I don't know the answer, but I haven't seen a probiotic that works yet.

So could a probiotic go in there and outperform or outcompete or inhibit E. Coli, show it to me. I'd be curious. I'd love to have something like that. It could be a thing, but I just don't know what that thing is.

So, but to my knowledge, there's nothing out there that that sort of defeats this yet. Well, that's like during treatment, you know, when the person has the SIBO or emo. But I think what most people are concerned about is after elimination, after eradication, do is it necessary to come in with probiotics? You know, we know with rifaximin in your study, it's not that just removing the overgrowth, the microbiome comes back to normal. But that this is what everyone is wondering.

You know? Should we use them at this time? Yeah. So I mean, look, I It sounds like the jury is still out. It sounds like you haven't committed yet.

The jury is still out. But I think but I think rifaximin is sort of this weirdest drug of all time in a sense that doesn't cause resistance. I don't know why. I mean, I know the mechanisms of why, but but it just seems very fortunate. It just mostly kills the e coli and the club CLN, then you get everything returning to normal and you can use it time and again and it continues to work and so what a blessing.

I mean, you know, because a lot of antibiotics don't work that way and so I'm I'm really grateful that this is the one that we tripped across, because it it really so far has been fantastic and and hope we continue to be able to use it in the future. Doctor Siebecker have 2 more questions and I'll hand things over to you. Doctor Pimentel, with the methane, when you're saying a lot of times people have the hydrogen sulfide as well, have you ever put, like, the bismuth with neomycin and rifaximin and seen the needle move? Yes. I have done that.

Once or twice, and it was successful to get rid of the methane and hydrogen sulfide simultaneously. But again, this is just my experience. There is no research on this, that's published. So I can just tell you what my experience is. And, again, as you know, I'm a scientist, not a here, do this because this is what I do or do this because this is my opinion.

I mean, it's all trying to quote research to to make the right choice. But we're not talking about Oh, sorry. Sorry, Siobhan. I just wanted to say that, you know, in the hydrogen sulfide study group that we have, when we have patients with hydrogen sulfide and constipation, many of us have done that triple combination and had it be effective. Beautiful.

Agree. Glad to hear that. With, this new emphasis, thank goodness, on menopause these days, we're seeing a lot of people who have hormone replacement therapy going on. And I have a lot of people asking, do you see hormone replacement therapy, like micronized, like progesterone, for example, impacting the migrating motor complex or impacting this in any way? Like, I know that's not your main focus of of of study, of course, but what are your just general thoughts on that?

Well, I I can quote the one study that we published on menopause. Doctor I know you had a menopause study. Yay. Thank you. Yeah.

No. This is from the reimagined. So, Gabriela Leite and Ruchi Mathur, they did the study. Yeah. Looking at the reimagined study, premenopause, menopause, menopause on hormone replacement.

You should check it out because it got a lot of media attention. And if if you're menopausal and you're on hormone replacement therapy, your small bowel microbiome looks like the 30 year old. If you're not on hormone replacement therapy, your microbiome looks not so great. So You remember this. Yes.

Right. I do so which we thought was just incredible. I mean, it's so interesting that that that that's the way it is. But that is what it showed. Okay.

Fantastic. Doctor Siebecker, I know you have tons of questions. Take it away. Oh, my gosh. I'm still writing notes from that one.

That's incredible. I I barely remember that study. That's incredible. Okay. You know what I wanna start with is the question we we asked you this, well, starting last year every time, is about semaglutide, tirzepatide, the the, GLP 1, GIP drugs that seemingly everyone's on these days and their effect was SIBO.

So I've I've got a couple of questions I'd like to ask because, truly, so many people are on them who have SIBO or who we Sarna test for SIBO. I know it can be tricky to get an accurate test, for someone on these drugs. Can you describe that and give us your recommendation of how we can accurately test SIBO on these folks? My recommend my recommendation is it's a disaster in a sense for SIBO. You know, it can work for obesity and for weight loss and all the things that is being, you know, supplied for but here's the problem.

So if you're on a GLP since it slows the gut down and we say hey slowing the gut down can cause SIBO, does it cause SIBO? I don't know the answer. Number 1, because I can't do a breath test when you're on Jill P1. Because if you do a breath test the lactulose never gets out of the stomach. So you've got a flat line, not because it's a flat line, but because the lactulose glucose never leaves the stomach.

Part 2 is I can't put a catheter in there to do the reimagine study because you can't be on a GLP-1 Sarna be scoped because your stomach's full of food. Even if I get the catheter in there, I'm gonna get food in the catheter and it's a disaster for the reimagine study. And then the third part is, well, if elemental diet means food is absorbed higher up, does that help SIBO? If GLP-one keeps the food higher up and slower release, maybe gets absorbed earlier in the gut, maybe you reduce SIBO. I don't know the answer to that either because we can't do a breath test and we can't do the aspiration, so we can't check.

So everything is a mystery and probably unsolvable, because and then even if you have GLP 1 and you have SIBO, if you give rifaximin, when does it get out of the stomach? Does it get out of the stomach? Does the acid break it down because it's been sitting there for a day? I don't know. So, yeah, it's a mess.

I have I have one colleague who recommended, well, try testing, you know, the morning of when you were gonna take take it again at 1 week. But the thing of it is is is that I know it takes, you know, a month or more to get to steady state and to clear. So I'm not so sure that's enough time. And then another, another suggestion that I've heard is to just don't take it for a week or 2 and then do your do your SIBO test. I don't know.

What do you think about these ideas? Yeah. So what we recommend people do is to stop it for a minimum of a week if we're gonna do a breath test. But I don't have enough patience that I've done that in to be able to say that that's working or not working for the breath test. So, really, it's still just big question marks.

I'm sorry. I wish I had better answers. I just don't know. We're all trying to figure it out. Yeah.

Do you think it's okay to use a prokinetic in someone on these medicines who are getting symptoms where they would need a prokinetic. So just for people listening, prokinetic is, an agent that can help, you know, move the stomach and intestines in a downward motion. And these drugs stop a lot of that. They slow that. That's part of their mechanism of action.

But yet is it okay to do that if if they're having really bad symptoms? Yeah. So first of all, if a prokinetic like for calipride would do what we want it to do in the GLP one patient, it it would overcome the GLP-one and then be counterproductive to the effect of the GLP-one. So patients probably wouldn't want that anyways because they're you know, buying an expensive drug to lose weight and the, you know, fucalaparide or the prokinetic is counteracting that. But I can tell you that the GLP one agonists are so powerful at inhibiting motility, nothing overcomes it.

They're they they you can take all the Motegrity or procalibride in the world or prokinetics. It's not gonna overcome the power of the GLP 1. So, it's a waste. It's you're wasting money taking it. Wow.

And have you seen many people with, SIBO get worse on these? I mean, obviously, that's a concern. Have you seen it? Yeah. So I've I see so the problem is, again, it's it's it's confusing because what I see are patients who go on the GLP-one.

I had one yesterday, actually, literally in my clinic. And she wanted to know if she could check for SIBO because she feels like the SIBO is starting to come back. She's on the GLP one. She's successfully losing weight. But, and I said, no.

I mean, look, you have to decide when what weight loss you want and when you get to that goal, we pause the GLP one for a period of time and check. But if to say that what happens with the GLP one is that people just aren't eating much because they're not they have no appetite. So that reduction in calories usually means that their IBS symptoms are less because they're just eating less. So they're probably fermenting less. Does it reduce the overgrowth?

I don't know as I said earlier but they're fermenting less because they're eating less. So their symptoms generally don't get worse on the GLP one. Maybe slightly Siebecker, but again, I'm just imagining what what's happening. I'm not I don't have any objective evidence. Yeah.

That's that makes a lot of sense. Well, thank you. And I didn't say the brand names for these are, you know, Ozempic, Monjaro, Zepbound, Wegovy. You know? So for anyone listening, we're using the medical terms.

Thanks. Okay. So okay. This is a perennial one that I get questions about all the time, And it's the difference between glucose and lactulose breath tests Sarna which you prefer and why. And the real question here is is that so many, practitioners will come into this field without any background, and they'll look at studies.

And proportionately, studies seem to favor glucose breath tests. So then they'll run glucose breath tests and everybody comes back negative, and they don't they don't know really you know, you and I favor lactulose, and they don't know about these things. The studies why do the studies seem to show glucose is better when clinically we tend to find lactulose is better. And can you just talk about the difference Sarna why you like lactulose, etcetera? Okay.

So I'm gonna tell you the criteria that I use that makes me convinced lactulose is Siebecker, and then I'm gonna tell you we have a study coming out that's going to finish the story. It will be the defining study that says who's Siebecker. Because when you talk about whether you use lactulose and glucose, the most important thing is, are you by the choice of your substrate, are you finding the patients for which symptoms are correlated with the test? That's the most important thing and that's Sarna be the defining study that's already done but we'll get to that sometime in the next few months when it's published. But when you go back, the lactulose is the breath test that has been validated against the microbiome in the PLOS 1 paper, in the Villanueva paper, in all the papers that I showed you today where we proved that the breath test is associated with the microbiome.

Those were all actual tests. There's no such test for glucose. There's no such research studies comparing the microbiome to a glucose breath test. It doesn't exist. The other part about glucose that bothers me is if I drink glucose I think I said this the last time we talked.

If you put a glucose if you're diabetic and you got hypoglycemia, you put a gluco tab under your tongue, the glucose gets absorbed. And your blood sugar goes up. And hockey players, you see you know, have you seen hockey players in the rink? And they squirt the thing in their mouth and they spit it down on the ground? You know why they're doing that?

It's a glucose drink. The glucose gets absorbed by the mouth to get this charge of glucose and energy. They don't wanna drink because they gotta pee. They can't pee because they're all geared up and, you know, they got all this stuff and gear everywhere. They can't go pee during the 3, you know, 3 periods of a game.

So they can't be drinking that much. It's glucose getting absorbed by their mouth. Okay. My point is, glucose, if you take glucose, part of its absorbed by your mouth, your throat, your esophagus, your stomach, what's actually getting to the colon? What's actually getting to the small bowel?

It's for me, it's gonna be less than somebody who's a smaller individual or shorter esophagus or whatever. And so you may give 75 grams to me and only 50 gets to the small bowel. I may give 75 grams to somebody else, 65 gets to the small bowel. Somebody else, maybe 30 gets to I don't know, right? Black chills, everything.

You give 10 grams, 10 grams is going in, 10 grams is coming out the other end. And that's the problem with glucose and it gets absorbed too quickly so you miss overgrowth. So I have a lot of reasons, There are some scientific publications that lean towards glucose versus lactulose. I will say that that's though there are facts by some people who you could use as argument that glucose is equal to or more specific than lactulose. But we're going to like I said, we're going to cut the tree down finally.

Yeah. I cannot wait for the study by the way, because it's a it's a real problem we have with, practitioners, you know, they what are they supposed to do? They're doing their due diligence. They're looking at the studies, and it's so thank goodness you're having this paper come out. But remember, the North American consensus says you can do glucose or lactulose.

I favor lactulose. I don't push lactulose on people because I understand some believe glucose is better. Yeah. Until we have data and and then we can push the data and until we have another consensus. So we don't make decisions based on me.

We make decisions based on the consensus. And, so And the studies. And this is this is the thing that that always I remember is is that all most well, I guess all of those studies on glucose were when they compared to, culture, were not done with the new gathering techniques culture gathering techniques that you all developed and validated. And so this is the argument that I usually tell people is that the gold standard of culture was not very golden. And that's why a lot of those studies look like they lined up.

But once we got the gold standard to be more of a gold standard, then lactulose lines up beautifully. Yeah. I agree. I agree. So so, again, it's what I was really trying to say is it's not about me.

It's about consensus and it's about the science. So if the science points in a direction, that's where I point. And so Mark, I believe the science points towards lactosel, the hard science. You know, you can always find other papers that say otherwise, but the overall science seems to point in that direction. So I use lactulose only.

Right. Okay. So next, you were talking all about, of course, post infectious IBS, you know, food poisoning as a cause of SIBO and IBS. And, you were talking about your working you know, this is this is the question everyone's wondering about. You know, When when are we gonna have an answer?

Everyone most of us know you've been working on this, and you were saying you're fast and furious working on this. As you said, you're working to get the antibodies out of the blood. But what so many people wanna know, you know, until all that comes out, is if somebody gets food poisoning, do you have recommendations of what they can do, or is there anything they can do to then not get SIBO? And can you talk about that? Because people get, you know, very concerned about that.

So there's only one study ever that was done. It was by a Canadian group from McMaster where they took people who got food poisoning, and then just after the food poisoning, they gave them steroids, which is really kinda like the an intense thing to do to try to reduce the immune response to this to the fact that they got this food poisoning. It didn't change whether they developed IBS or not. And now understanding what we know today, that was about 12 or 15 years ago, that wouldn't work anyway because the antibodies would have formed anyway. And it would reduce the inflammation at the moment you're on the steroids but it does nothing to formation of these antibodies.

So, it makes sense that it didn't work. But, you know, they they figured there's an immune reaction that's causing it. And so that's why they did the study. But there's nothing you can do once once the landscape has been come and come and done, it's done. So what we do believe though is if you can prevent food poisoning, if you're going somewhere on a trip where food poisoning is more common, If you took antibiotics to prevent, that would work the best.

If you just were very cautious, that would work if you don't get food poisoning. If you get food poisoning, maybe you should treat it. You shouldn't let it run its course because the shorter the food poisoning is, the less likely you get IBS. We know that. So these are things that should be considered but again the studies to prove that that's true haven't been done.

And we've discussed doing these kinds of trials in rats to see, you know, give them the campylobacter then give them an antibiotic 12 hours later. Campylobacter is already in there, Can you stop it? And these are very hard studies to do and very expensive Shivan we have a lot of other things that we wanna get at but it is an important question. Okay. So I'd now I really wanna talk about the NAC plus rifaximin study you did.

Because myself and my group had quite a bit of experience with it, and we didn't find it to be very successful. So let me just give you the background here. We were coming at it from a little bit of a different way. We were thinking about, relapse. We were thinking about recurrence.

And, you know, one of the first things, you know, anybody would think about with a chronic relapsing, you know, bacterial condition is biofilm. You know, is it a biofilm infection? And, so we thought, look, if we give antibiofilm remedies, which with H. Pylori just for anyone listening, as an anti biofilm adjunctive therapy, to treat that. So we looked at that and we thought, let look, why don't we give antibiofilm and let's see if it affects relapse?

So for about 2 years, we used NEC and then we used, enzyme based, anti biofilms as well as with EDTA. And we also didn't give it to everybody. This wasn't an official study. So this is just, you know, clinical observation, which can there can be misperceptions. Antibiofilms, we abandoned it because we just thought, look, we're not seeing any help.

We weren't really looking to see, is it making our treatment go better? We might have missed that in our in our perception. The dose I wonder, could it be a dose thing? We gave just this doses that were given for h pylori, you know, 6600 to 1200. Some of those studies use it a week or 2 ahead, and then during, we did that.

We did it during. But what I heard you say is that you have a special delivery system in your lecture, you said. Could this be the difference? I don't know. Anything you wanna tell us.

One of the unique things about N Acetylcysteine is that, when you put it on mucus, Sarna, for example, or the stomach is if you've ever vomited, you know the stringy stuff you get at the end which is kinda gross but that's mucus, right? N Acetylcysteine breaks that up. The stomach is full of mucus. If you just pop a pill of an acetylcysteine, that an acetylcysteine will be used up by the amount of mucus that's just in your stomach. So you gotta get it to where it needs to get to.

And you can't let it just pop open in the stomach and then it gets all used up. There we go. So it has to be yeah. So it's gotta be delivered to where we want the Rifaximin to work. And you know where that is, and hence the term SIBO, small intestine, but in a particular way.

So it's not just there, but in a particular way that it's delivered. We'll see. I mean, the trial has to work. I mean, if it doesn't work, then the delivery system wasn't wasn't good. But, but, yeah, that's that's the problem.

Okay. Thank you. That answers it. Great. And that works for h pylori because it's in the stomach mucus of the stomach.

Right? And so it's like an antibiotic, it can kill one bug and maybe be around to kill another bug and kill another bug and kill another bug. But NaC, once it breaks down mucus, it gets trapped in that dissolving force. So you actually consume the NaC by breaking down mucus. And then you don't have anything left for the small bowel if you just put it in the stomach.

So that's part of the trickiness of neck. Oh, thank you for explaining that. You know, just a side note, I used to recommend it to patients who were wearing a CPAP who had I guess, it would maybe they had allergies or whatever, but they would get mucus accumulating in their, you know, CPAP. And we would it didn't work for everybody. What we would, tell people to take NAC, and then it wouldn't happen.

It would thin out. So that was very that's very and NAC is amazing, you know, for so many things. Yeah. That's great. Eugalytic.

You know? Okay. Gosh. You had so many studies that I mean, there's the NEC was one of them. There were so many studies I wanna talk about.

But, you know, I wanna just go back to a study first that came out, I think, at the very end of last year. Boy, it was fascinating. You know, you've you've been able to elucidate and explain all of these bacteria now and archaea for each form of SIBO, emo, you know, eso, the new term. This one was so fascinating because you talked about hydrogen sulfide and how let me just read what it says that the the sulfvibrio pager and f varium will lead to overgrowth with other bacteria. So the desulfibrio project would lead to subterella overgrowth, and the Fusobacterium varium would lead to lachnospiraceae and bileophilia.

How fascinating. Could you talk about this? Yeah. So, it I guess I guess it I don't I don't wanna make liken it to a gang, but when you have a gang leader, you bring gang members with you. So, it's it's like that.

You know, e coli surrounds it. E coli needs friends because there are factors they can't produce. So it sort of congregates not just itself. It destroys the ones it doesn't want because get get rid of those guys. They're competing with me for food, and it brings along the players it needs.

And the same thing is true for the hydrogen sulfide, and the same thing is true for m. Smithii. You need ruminococcus and cristinsenalaceae or cristinsenella because those are the bugs that make the proper kind of hydrogen or properly associate with methane in the colon. And as you'll see in a paper coming, those are the same characters in the small bowel again that are helping msmithii. So it's a posse.

We call it a posse. You know, on those on those the posse for methane, those are called syntrophs that, you know, you all put that term out and explain to everyone what that is. What I've been wondering about these syntrophs is, is this where the research is gonna go for treatment? Are we now gonna be aiming our treatments at the centros? So it's possible.

You know, bacteria are so amazing that they find a way around what you're doing. So for example, methanogens can use ammonia. The hydrogen donation from NH4 plus which is a hydrogen donating ammonium or ammonia, and then take that hydrogen and make methane. They can take acid and make methane and a lot of bacteria produce acid. That's one of the byproducts of fermentation is acetic acid or vinegar and so or lactic acid as well.

And so, you know, they're creative. So if they don't get it from ruminantoccus and chrysantinella, they might get it from something else. But your point is good. Could we target those 2 and then it impairs the methanogen? Yeah.

Maybe. Haven't tried it, but it's something that to consider. But you you're right. There's no again, knowing the facts gives you multiple avenues for therapy that could be very beneficial. And we just have to choose the best avenues and see which one is, hopefully, the ones we're going after are correct.

Okay. You also did an amazing study this time on the fungal fungiome or whatever, the fungal microbiome basically Yeah. Of the and was this of the small or large intestine? It was a small, wasn't it? Small intestine.

Small intestine. Has never been done. Right? I don't think. So not shot well, we were the first to do shotgun sequencing of the small bowel period.

So and then we were able to see the fungal. And the fungal is interesting. So there is SIFO. It's not common. Among our SIBO patients, it's about 5% of the SIBO patients.

So maybe 1 in 20 might have SIBO and SIFO. But you don't know because you don't then we don't have a breath test for SIFO. We don't have, you know, we don't have a good indirect measurement for SIFO. But, and it is Candida albicans, occasionally glaburata, which is more toxic and more problematic. But it generally went along with SIBO.

So the higher the candida albicans, the higher the SIBO was, which I thought was interesting. But, you know, we need to know more. That's the basic knowledge of what we've discovered so far. And you also had another study that related to that where there was something about anti, antimicrobial resistant resistance having to do with fungus. Wasn't there?

Or like penicillin or something? Yeah. So, so this Sarna an amazing study that we did, which didn't get a lot of as much attention because it's you know, everybody wants to know what we're doing about Cboe. Right? So the other stuff becomes sort of like curiosities.

But this is super important, so we actually identified fungal elements in a normal person's gut that produce Penicillin. We know Penicillin is a fungus right? And we found Penicillin producing fungi in the small bowel and when those fungi are there, there's more penicillin resistance in the bacteria. So again, it's a thing where we blame humans for microbial resistance but it's always been there and it's maybe normal. And so the question is raised which could lead to another therapy, but the question is raised, maybe the fungal elements are controlling SIBO and not allowing it to happen in some patients because they produce penicillin locally and keep the microbes like this instead of like this.

These are questions now we have to answer because we found this stuff. So So fascinating. Well, thank you so much. That's all I wanted to ask. It's enough of, I mean, paraging you with questions for half an hour.

Thank you, doctor Pimentel. Thank you, doctor Siebecker. Oh, oh, gosh. No. There's one more thing I just remembered.

No. No. I told Mark I was Sarna ask him about this at the beginning. In the last 2 months, there was a critical paper that came out about SIBO. It was it was called a critical whatever, something about SIBO.

And, so many are confused when they read this. What what do you Sarna say about it, Mark? Well, it's a it's it's a bit of a sad commentary because it really wasn't endorsed by the society because I'm part of the society. So I don't remember You have to identify a little bit more what it's about. So when people Yeah.

So it's a paper that claims to be endorsed by the American Motility Society, neurogastroenterology, not the AGA, not our flagships, Sarna and it it criticizes the SIBO association with IBS. Doesn't mention any of the science that you see published here virtually. What's interesting is that the the authors, you know, sort of evolve their story. And and if you if you read the article, it's fine. Most of them don't do work in Cboe.

So, okay, you know, it's the critic on the sideline. You know, they haven't spent $5,000,000 on a reimagined study like we to be able to get all this good data. We can't get grants Allison IBS, so nobody has grants, so they're just basically speculating. But I will say one thing, a couple of things. One of the authors, Magnus Simran, which we talked about earlier, he's the one who showed that culture shows Siebecker in IBS.

I showed you that paper from one of the slides. Magnus Shivan recently proves that methane goes along with constipation. Steve Banner showed in his study that methane is associated with constipation. Steve Vanner is studying histamine producing bacteria in the gut, and our SIBO studies show klebsiella is one of the big players of Siebecker that's the histamine producer in the gut. So I don't understand.

But where they end is, Oh, but we're really optimistic about capsules and capsules for diagnosing SIBO. But the capsule studies are not succeeding so far. One of the capsules, which is really a cool technology from Stanford, the capsule comes, they open it, it's brown. I can tell you by sampling the small bowel, nothing's brown. Everything's green.

Everything's bile tinged. There's nothing brown. The only thing that's brown is poop. So the capsule is I don't know where it's getting its sample from, but nothing in the small bowel's brown. So, you know, capsules are coming, but how can they be optimistic about capsules where the data are really poor so Sarna?

And and and then they don't reflect on and they didn't talk about anything at DDW. All this exciting stuff where the breath test correlate with the microbiome. Anyway, I you know, read it if you like. It's fine. And, you know, in science, the thing about science is it's meant to be a debate until it's a fact and or until everybody's convinced.

But in science, even now there are people who believe h pylori doesn't cause ulcers. There really Sarna. It's crazy but that's the way it is and and we'll take it and we'll just move on and continue to do the science and publish the papers and let the facts fall where they may. Which is in our favor and we thank you so much, so very much for spending this time with us and your continued work. So, yes, Mark, thank you so much for all of the work you and your team do.

All of us, all of the SIBO sufferers, IBS sufferers are so grateful for all the work you do. It helps us all so much. Thank you. Glad to be with you and thanks for what you do as well and spreading the information and and just advocating. Our pleasure.

Our mission.

Free Virtual Trainings with SIBO Researcher, Dr. Mark Pimentel

Course Content

Latest SIBO Research 2024 with Dr. Mark Pimentel - recorded July 2024

0 comments

Leave a comment