Free Virtual Trainings with SIBO Researcher, Dr. Mark Pimentel

Course Content

1:34:25

Hello, and welcome. I'm Siobhan Sarno, your host today, founder of Siebecker SOS, and I am honored to have you join us and these 2 incredible people, Allison Siebecker, doctor Alison Sebecker, my cohost today, founder of SIBOinfo.com, world advocate for SIBO patients and practitioners, the creator of Siebecker Course, the cocreator with me of the SIBO patient recover recovery road map course. It's a mouthful. It's better on paper. And the incredible doctor Mark Pimentel, who is our featured Siebecker, and he's gonna be talking to us about the developments revealed at the American College of Gastroenterology 2022 research updates to share with us today.

He is the, person who I think is gonna cure SIBO in our lifetime ASAP. No pressure, doctor Pimentel. Like, you don't already feel that anyway. And he has, he's the one, okay, who told us about rifaximin for SIBO. He's the one who elemental diet for SIBO.

He's the one to that's, you know, driving forward this differentiation of emo, versus SIBO.

Anetics for SIBO. The diet for Siebecker. On and on and on.

As well as, his new book that we'll, be telling you about and sharing a link with as well as, working tirelessly with his team at the mass program at Cedars Sinai and on and on and on, but I think you get the idea. Let's get started. Hi, doctor Pimentel. Hello, Allison.

Hi. Great to see you both. Good to see you, Allison.

Welcome. Welcome. Alright. I know you've got a a fantastic, presentation for us and, a lot of hope in store for us as well.

So thank you so much for being here.

That's what I try to do. Try to inspire hope because I think we're close. We're always close, but we're always closer. Right?

Right.

Shall I go ahead and share my screen then?

Yes. Share and scare. Thank you.

Alright. Perfect. Hopefully, you see it okay.

Yeah. Looks great.

Okay. So, I sort of titled this evolving understanding of SIBO and IBS because it continues to evolve. So, you know one thing that I start my lectures with especially on this kind of platform is that you know I think I get feedback whether it's on social media or from folks out in the community, patients Sarna so forth, that you keep saying things are coming, things are coming, things are coming. And I and I know that sometimes I say that a lot, that the next thing is going to be even more interesting and it always is. But it's as we develop things for SIBO IBS, it's critical that we understand everything, to its fine detail.

Because by understanding the fine detail, and as you'll see in the lecture, understanding some new things in their fine detail, will refine the treatments to be correctly better, not just better. And so, I hope that sort of perspective makes you realize that, I mean, we're doing a ton of work, and it just, it has to be done correctly, scientifically, in order to do it right when it comes to treatments. And and so, what that prefaces is the MAST program here at Cedars Sinai, which is, actually in front of me. I'm looking at it, and behind me is sort of the window out to the lobby of this building. But, you know, we have 22 people here, 6, 7 PhD scientists, 3 MDs, all working to try to help the patients who have this condition to find and unlock their their small bowel microbiome signals that are giving us the problems in in human health and disease.

And we have some very interesting stuff that we published this year, not related to SIBO, but also amazing stuff in Cboe that I'll share with you in this presentation. For those of you who've heard me talk before, this is the template that I use. Now it's not changed much over the last 2 years. What's changed is our understanding of every single step here. And so we now know that IBS, SIBO, and food poisoning are linked.

And they're linked in that food poisoning is the trip the trip wire or the trigger for the development of these problems in most cases of SIBO. And the CDTV toxin, which is the second, plaque here, is the culprit from the food poisoning that leads to an autoantibody or autoimmunity to a protein called vinculin. And that these 2 then set up a nerve damage of the gut. And that nerve damage leads to a reduction in migrating motor complex, which leads to bacterial overgrowth that I'm Sarna show you is now proven by multiple means and techniques. And then IBS being an, part of Siebecker, and that the SIBO and IBS are in some sense synonymous at least 60% of the time.

So I'm gonna use the term 60% because you're gonna see that over and over and over again through the presentation that it's about 60%. So go back to h pylori and ulcer disease. H pylori causes ulcers in about 60% of the time. The other 40% is your your NSAID or your aspirin or Advil or other causes of ulcers. But that's huge.

60% of explaining 60% of IBS is huge, considering this is a 40,000,000, in the US patient disease or condition. So I'm gonna break it down a little bit differently this time as I've done as I have not done previously. And I wanna break down what the evidence is. How did we get to this road map that I showed you? And first step is, does food poisoning cause IBS?

What's the evidence? Well, there's one paper to lean on. It's the CLEM paper. And it's not one paper of evidence. It's, as you see down here, 45 studies of evidence, all saying the same thing in a meta analysis that was published in this one paper.

And a meta analysis means you put all the papers together and say, is this true or not? And the answer is it's absolutely true. And that if, you know, if 9 people got food poisoning, one would develop bowel syndrome. That's how, likely you are to develop IBS after a case of food poisoning. So, we now know for a fact that food poisoning trips you into developing IBS.

The question is how. And and that's what we'll continue to take that journey. But here's that 60% number at the bottom you can see in the right lower corner. Don't fret on the details of this slide. What we did though is we said, let's pretend 307,000,000 adults are present in the United States today.

0 have IBS or SIBO. 0. And then we take the Center For Disease Control, rates of food poisoning in the United States and say, well, now let's pretend food poisoning's happening on an ongoing basis where it didn't before. And we know how IBS develops from food poisoning. And we use all the data that was available from the research literature.

And then at about 10 years or 9 years, we reached steady state, which is it flattened out. At that point, 9.1% of every human in the United States would have IBS slash Siebecker you wanna call it that, which is about 60% of IBS, which was at the time 15% of the population. So 60% of IBS could be explained mathematically from food poisoning. Okay. So it's very clear from the clinical data that food poisoning triggers IBS, because I showed you a paper that summarized 45 studies.

But how does this fit into bacterial overgrowth? Does food poisoning cause the bacterial overgrowth we now know overlaps with IBS? So we can't food poison humans because that's unethical. So we had to use animal studies. And so in this study, this was way back in 2008, we gave campylobacter, which is the most common bacterial food poisoning agent in the United States, 2 33 rats, and the other 33 got nothing.

They just got placebo. And then we waited for them to clear the campylobacter. And then 3 months after they recovered from campylobacter, we were looking to see if did they develop weird bowel movements? We didn't know if they had Zbor or not. We just wanted to check if they had weird bowel movements and quantify that.

And then we were able to see if they had bacterial overgrowth. And it turns out the rats that got campylobacter, in contrast to the control rats, 27% of these rats got SIBO. So a model of post infectious IBS, the rats developed bacterial overgrowth. Not only that, if they got C plus, which is campylobacter, and they developed SIBO, those rats, 84% of them had basically IBS like stools, altered stool consistency pattern. And this bottom one is the only thing ever found in humans with IBS, which is a little bit of increase in a special type of white cell in the rectum.

And so these rats, why is this important? It basically proves food poisoning causes SIBO and causes IBS. But what's more important is for the first time, we have an animal model where we can study the whole link all the links in the chain of how this happens. And we have. And I'm gonna skip some of the papers because there's so many to go over now, but sort of, touch on the highlights.

But now I Sarna to fast forward to 2022 before I kind of get back into the more nitty gritty. Now in 2022, this is a paper we published with Will Takakura, our fellow, and Mark Riddle, who's an infectious disease expert. And this is called the Bradford Hill criteria. So the Bradford Hill criteria is cause and effect with regards to bacteria. So if if you if you had tuberculosis bug and you gave it to somebody, what is the likelihood that that's a Allison, and how do you prove it?

This is a very complex approach. You have to have all these things for you to say cause and effect, and we have them, to varying degrees of certainty. And so the point of this paper is, full stop, 2022 campylobacter causes IBS, at least one of the pathogens that cause IBS. Okay. So now we get into the nuts and Allison, and this gets into some deep, heavy, basic science.

But I don't dumb things down. It's not about dumbing things down. It's about explaining it in a way that you'll understand what we did. I'm gonna show you the actual science and explain it so that it's very clear to you how we got to this point. This took 10 years, in some parts of it 5 years.

It's a lot of work and and steady work. But what we started to realize early on is that, okay, food poisoning causes IBS, but shigella can do it, salmonella can do it, campylobacter can do it, E. Coli can do it. Well, they don't they're not you can see they're not the same. They're different organisms.

But what do they have in common? What toxin do they have in common? And they all had this only this one toxin in common called CDTV, cytolethyl distending toxin B. So we did a study where we knocked that toxin out of the campylobacter and gave the rats campylobacter, and they didn't develop IBS. So we knew this toxin was important.

But what is the toxin doing? And so here in this study, it's a lot of colors here, but I'm gonna just describe this, the, what I'm, what we're seeing here. Forget about the top row for a second. These round circles of green are the interstitial cells of cajal. These are the pacemaker cells for your gut.

These pacemaker cells make you have cleaning waves of the gut. That sound you hear when you're hungry, that's your gut cleaning itself, your small bowel cleaning itself. You need those because if you don't have those, you get overgrowth. So I want you to focus on these round cells. This big glob of cells is the ganglia, or the nerve hub within the wall of the small intestine.

And so that ganglia is also, in this case, green. The it's green because we used antibodies to the CD TB toxin and put it on the the tissue from the rats who had got campylobacter or didn't get campylobacter. So what we see here is in fact, weirdly, the rats who never got campylobacter, so they don't have the toxin. So, the antibody to the toxin is binding to a rat's nerves who never saw the toxin, doesn't have the toxin. So what that means is that the antibody to the toxin is by for some reason is tricked into binding something that's you in these nerves.

So what is it that's you in these nerves that is getting confused after recognizing the toxin? And so this took a lot of work over many years, and we've isolated the protein vinculin. Vinculin 117 is in these nerves and in these ganglia, and the antibodies to CDTB are tricked into binding to your nerves of your gut, causing changes in those nerves. So what is vinculin? So vinculin is this.

So if you look at the green lines, these are cells in our lab, and the green lines are actin. This is the skeleton, almost like a scaffolding on a building to hold the building structure in place. And the little red things at the end, really at the tips of all of this, are like a little motor that's on the end of this chain of actin that makes the cell stretch out and grab onto the cell next to it. So think of it like this when you talk about nerves. You've got you've got the nerve nerve cell, which is controlling electricity, and you got the wires going out to the next cell.

So the electricity can go from cell to cell to cell to cell, coordinating the muscle function of the gut. So you need these things to be connected. And vinculin is the the the process that stretches the wire to connect to the electrical outlet so the electrical outlet works, and can conduct it to your computer or to whatever you're using. Okay. So what we did see is that if you gave rats campylobacter and they developed SIBO, the number of these special cells that conduct the electricity for the cleaning wave are are markedly markedly reduced.

So here are all the cells here. Beautiful. This is normal. They're all lined up one after another, one after another, all interconnected. And down here is if they had campylobacter, but have and have SIBO.

So they're very few in number, as you can see here, compared to the control group. And you can see they're hard to see, they're very far apart, and you just they're just not connected. So you're not getting the cleaning lights. So is that what's happening in humans? So now we go back to 2,002.

I know it's backwards, but we already knew that in 2,002, the cleaning waves weren't working. Why were they not working? I just showed you because the nerves are reduced. But here's the study from 2002. Look at the healthy people.

This is the number of cleaning waves they got in a, 4 to 6 hour window of fasting measurement, where we put a catheter in the small bowel. Look at in the IBS patients with SIBO. In fact, 50% of IBS patients with SIBO, we detected 0 cleaning weights. This is the average, but we detected 0 in half the patients. And even when they occurred, they were these weird, weak, inefficient cleaning waves.

So we've known that cleaning waves are important in IBS CBOW connection for a while. And then going even further back, 1977, I'm not going back there to say this is the proof, but I'm going back to say there that we've known this for a long, long time, that if you don't have cleaning waves, you get overgrowth, because you're not cleaning your small bowel properly. And so all the debris builds up and the bacteria builds up. So this is a this is a well known phenomenon and is occurring in IBS and is causing the Siebecker, we believe. Okay.

So now let's integrate all of this to try to understand what's happening. So if you wanna prove we proved it's campylobacter. I showed you the Bradford Hill criteria. Campylobacter causes IBS. Now we Sarna prove it's not campylobacter.

It's the toxin CDTB in campylobacter. That's all you need to cause IBS. And so that's what we're gonna show here. We took the toxin out, purified it, and injected it into the arm of the rat, like a vaccine, like a COVID vaccine. It's not going in the gut.

It's going in the arm. If c DTV is causing the gut to be a problem, it doesn't matter where it goes. If it's an antibody issue, it doesn't matter where you put it. If you develop antibodies to c d t b, it's causing the problem. Well, sure enough, after You didn't get vinculin.

You got CDTB, and the rats developed anti vinculin antibodies. So CDTB exposure created autoimmunity in the rats to vinculin, a protein that the rats have in the nerves of their gut. So this is an autoimmune disease. Not to mention, if you focus on the on the graphs on the right, the rats who got the antibody developed SIBO and got the CDTV inoculation. They developed SIBO as compared to the control rats.

So the CDTV toxin all by itself causes IBS. So it works like this. You have CDTV. You you form antibodies to it after you've gotten an infection, and you form antibodies to a lot of it because you don't like any of it. It's not, it's a foreign substance.

But one of these areas looks a little bit like vinculin on purpose to cause this autoimmunity and mess you up. And then this antibody starts to affect the nerves of the gut because it's attacking vinculin. Okay. So now this was a DDW abstract. This is in publication process now, but it's public information because it was presented at DDW.

The this is the next step in this whole CDTV process. We did the study again. We gave CDTV to rats, just like a vaccine. And, of course, again, as we saw in the first experiment, this antibody goes up. Now we had a larger number of rats, and we were able to see the stool wet weight of these rats went up.

And while it looks like it's only 3%, believe me, 3% of 8 liters that are in your gut during digestion is a whole heck of a lot of water coming out of diarrhea. So this is a lot of increase in stool wet weight. And the higher the anti CDTV antibody was in response to that toxin, the worse the rat was in terms of diarrhea. So we're we're proving cause and effect again. Sarna get really deep in the weeds.

I'm sorry. Forgive me. And if you if you, if this is just too much for you, just cover your ears and go la la la la la, and you don't have to hear it. But here's the here's the the part that's interesting from a scientific perspective. So we took the blood of these rats, and they have all sorts of cytokine changes, in particular, these 4, IL 2, IL 5, IL 18, TNF alpha.

You don't need to know what they do. You just need to know that these are signs of particular types of inflammation. But if there's a, a computer, software that if you just didn't know anything, you just put these changes into the software. The software says, I can predict what this rat would look like if they had these 4 like this. And so it's a way of double checking your math So we plug these 4, cytokines into that software, and it gives you what's called an, an up stream and downstream, analysis of what these cytokines are doing if they were to be seen, let's say, in a human.

Okay. So here we are. This is 1, 2, 3, and 4. And if the direction of change of these 4 happened in a human, it would be because the human was seeing too much lipopolysaccharide, which is a toxin or a chemical from E. Coli and klebsiella and coliforms, which are the organisms of SIBO.

Number 2, if you had these 4 in the direction they are, it would predict, you have an autoimmune disease. Number 3, if you had these 4, it would predict, you have diarrhea most likely. And that's exactly what we saw in the animals. So backwards and forwards, looking at the data, the CDTV toxin is predicting the development of SIBO, the development of diarrhea, the development of autoimmunity, and the cytokines affirm that. We also did sequencing of the microbiome.

And people say, well, how do you know the breath test is not in the colon problem versus small bowel? Well, in the animal models, nothing's changing in the col in the cecum. Nothing's changing in the stool with CTB. All the changes are in the duodenum and the ileum, which are the small bowel. So the small bowel is changing because of this toxin and all of these effects.

It is not changing the colon bacteria. But here's what we learned, and this is really important as we get into the breath testing part of this presentation. The rats that got c d t b drifted after they got c d t b into 3 directions. Direction 1 is the green. So after 3 months after the c d t b vaccine, green dots lined up with orange dots, which are healthy rats.

So a group of rats who got c d t b, no change. A group of rats that got c d t b went into a cluster here, the blue dots, and those turned out to be elevated E. Coli in the small bowel, which is the hydrogen producer of the small bowel. And then a group of dots, purple dots, was another cluster. So cluster 3, and they are linked to the elevation of desulfovibrio in rats, which is the hydrogen sulfide cluster.

So even with this, we're seeing that the diarrhea development in IBS D rats is either a hydrogen cluster or a hydrogen sulfide cluster. And as you will see, we need a 3 gas breath test to be able to sort this out in humans. And finally, so how do these antibodies stack up with humans? So we developed a sort of a first generation test and then improved it. This is the 2nd generation blood test now.

It's called IBS Sarna. This is the one that's validated with the, what we call epitope optimization to give you a better separation between IBS d in red and other people with diarrhea. So this is really important. When you develop a blood test for IBS, and people have, some of these blood tests were, well, it's up in IBS, but not up and healthy. Well, if you have a normal bowel movement, you're not seeing me.

If you have diarrhea, I need to figure out what's causing your diarrhea. So it's more important that the tests so just to be clear, the test separates from healthy. But a more important result is that it separates 2 people with diarrhea. You have IBS, and you don't because the test is negative, or you might need further testing because your antibodies are negative. So that's a really important separation, and that's what we get here, IBS versus other conditions.

This is for anti vinculin, and this is for anti CDTV. So we measure both of these antibodies. But here's what's really important is that if these antibodies are positive, you're over 80% for either marker. If both are positive, it's 98% certainty you have IBS. For those of you who don't know, anything over 80% is considered medical certainty in post test probability testing.

So we reach medical certainty if these markers are positive. And so this test is very valuable. But I'm going to show you this part. So if you look at either either one, it's 43 42%. If you do either or, which is the way the test works, it's 56%.

56% of IBS patients will test positive on this test. What did I tell you at the beginning? 60% of IBS is post infectious IBS, we believe. So 56% is right there. The point is your sensitivity will never be greater than 56 percent because there's another 40% of IBS we still need to figure out.

But 60%, that's the important number. Okay. And then finally, this is sort of my last slide on this whole CDTV vinculin story. But I think it puts it in a in a in a sort of a summary slide that's a little bit more colorful and interesting. This is your microbiome in the small bowel.

Beautiful colors. All sorts of different bacteria are present here. Look at the nerves. These are the interstitial cells of Cajal that we were talking about, those round circle cells that were in green. This is the nerve plexus, the ganglia here, And then you've got these green guys who come in, which is campylobacter, and they produce a toxin called cDTP.

And then you start to develop antibodies to cDTV. And we have a case report that we published, I'm not showing it here, that shows exactly how this works. You first start to form antibodies to cDTV after food poisoning. And then about 3 months later, you start to form anti vinculin. So it comes later as the cells open and the vinculin is exposed, you start to increasingly form antibody until you reach a plateau.

And as you get the vinculin antibodies, the nerves start to diminish, we believe. And then you also get some inflammation around the nerves as well. Because of that and the poor motility, we think that's why you get SIBO. And the SIBO is these lots of blue and not a lot of those nice colors we saw before everything started to take a turn. Okay.

So the last part of this, which is, you know, little past the halfway point of this presentation is breath testing, SIBO and IBS, that relationship. So it's pretty clear now this meta analysis kinda settles it that, look, if you did a breath test in an IBS patient and a healthy control, it's way more likely the IBS patient has a positive breath test. And and this Australia really kinda sells it. It's 25 studies. We can put this to rest now.

The breath test findings we described 25 years ago are correct that IBS has more SIBO by breath testing. But SIBO is complicated. In 1996, when we first started doing research in this, all we had was data on hydrogen. Some of the tests had methane on the breath test, but nobody ever told us what to do with methane. We didn't know what the why were they even why was methane even on the breath test?

We don't know. But what we learned very quickly was that when methane was present, patients were constipated, as you can see here. But the problem is methane bacteria or not bacteria. These are archaea. They use 4 hydrogens to make one methane.

So if you have methanogens in your gut, they're sucking up all the hydrogen. So if you only measured hydrogen on your breath test, you can't rely on the number because you don't know if there's methane there. Because the the hydrogen could be 0 because the methane bugs are eating all the hydrogen. So hydrogen is a fuel for other bacteria, and we never found a good correlation between the level of hydrogen and symptoms. All we know is if hydrogen's elevated, you have SIBO, you have symptoms.

But if the hydrogen's a 100 or 50, both are abnormal, those two patients don't really have different symptoms. They just have symptoms. So, and it's because the things that are producing the symptoms, are mostly the hydrogen sulfide and the methane. But now we know hydrogen sulfide produces diarrhea. Now 5 hydrogens to make 1 hydrogen sulfide.

So hydrogen sulfide is even worse. But we are learning that E. Coli and klebsiella do produce symptoms by themselves. And it's more complicated than even the story that's shown here, but I'll show you that later. But now so breath testing is one thing, but let's culture the bowel because there are purest scientists out there that say, well, breath testing, you know, it's an indirect measure.

Show us the meat and potatoes. Like, what's going on literally in the gut? And so this study in 2007 said, yep. Absolutely. IBS patients, if you use this cutoff, 5 times 10 to the 3, 43% of IBS has SIBO.

Now that's 5 times 10 to the 3. But the new North American consensus says, no. No. That's still too too high a cutoff. Use one times 10 to the 3.

And if you use 1 times 10 to 3, there's that magic number again. 60% of IBS d meets SIBO by culture, as compared to non DIBS patients who are sick undergoing endoscopy. These are not healthy controls. But, again, 60%, we keep getting 60%. Okay.

Now we then started to unravel. Okay. Who's who are the bad characters? Now, in those days, back in the early part of the last decade, we were, you know, taking a stab at it. We know E.

Coli and klebsiella were the hydrogen producers, and we measured them by qPCR, which is just single organism PCR. Is it there? How much is it? And E. Coli was 10 times higher.

This is every number is 10 times higher than the previous number. It's sort of like an earthquake scale. So this is a huge difference, 10 times and 10 times versus healthy for these two bugs. But we we had to go further. And and this is where the reimagine study is so important.

The reimagine study, we started about 4 years ago now. And we wanted to collect juice from the small bowel with biopsies, with the blood of the patient, with all their information. And and to be able to put it all together to understand how is the patient's intestine responding to the bacteria. We we need to know all of this because there could be many ways to develop drugs to treat SIBO and IBS, not just antibiotics. And we needed to unravel this.

And we're, of course, using this data to look at obesity and other diseases and conditions. But I will focus on SIBO. One of the early papers, this is seems early for me now because we have so much more data, but this was in 2020. And we published this paper showing greater than 10 to the 3 in the small bowel, less than 10 to the 3, meaning non SIBO. But look at what this one one category of bacteria is taking up 45% of everything in the gut.

But it's even more interesting than that because when you go down to these last rings, this is the genus Sarna this is the species. Back then, we did 16 s sequencing, which can only get to genus roughly, maybe some species. We're now doing shotgun sequencing. We see everything to the strain level. And I'll just say, DDW 2023, I'm gonna tell you exactly what strains of these bacteria we're talking about.

And I think you'll be even more shocked when I tell you what's going on there. But I'll leave that for now. But look, klebsiella and escharithea or or E. Coli are are the majority of that orange ring at the beginning. Literally, 40% of every you have 500 to a 1000 species in the small bowel, and 40% are just a couple.

They're literally have taken over. It's almost like an infection. This is an important part of the study. Really complicated to understand every single column here. But the the point of this is we did breath tests on some of these reimagined study patients.

And 20 parts per Allison by 90 minutes on a lactulose breath test is your best test for SIBO as an indirect measure when you compare it to culture, when you compare it to sequencing. And when you have that cutoff positive, it it is associated with upregulation of hydrogen producing pathways in the juice of the small bowel. So for people who say the hydrogen is coming from the colon, that's not lining up. This hydrogen is coming from the small bowel. And then finally, with our sequencing, we're able to show that really the 10th of the 3 cutoff, the 1,000 if your bacteria on a McConkie agar plate suck juice from the small bowel grows more than 1,000 colonies per milliliter, that's the tipping point.

Because as soon as you go over 1,000, this is over 1,000, the microbiome, you can see by the colors, they suddenly change. So that's the tipping point. Okay. I'm not gonna spend as much time on intestinal methanogen overgrowth because that's a whole shebang that takes a long time to talk about because we have so much data now. But, you know, hydrogen is in the gut from other organisms, and then m smithii, that's the methanogen.

We now know that's the the main character, that's producing methane. And now we know methane is associated with constipation. Not only that, more methane, more constipated. More methane than that, even more constipated. So it's proportional.

So this is what we call a gasotransmitter. The more you have, the worse it is for you. And, again, DDW 2023, we're going to present the entire archaome, which is these this category of organisms from duodenum, dejejunum, ileum, and colon. For the first time in human history, we will know the full archaome of the human intestinal tract. And that's all I can say.

That's my teaser again. But we thought for a long time that E. Coli, klebsiella, those 2 hydrogen producers were the ones producing the hydrogen for the methanogens, but that is not the case. And I'll show you why with our new study. Hydrogen sulfide is really the new kid on the block.

Fusobacterium is one of the key hydrogen sulfide producers of the gut. We do believe E. Coli lines up with this and that these 2 are working in partnership, and the sulfovibrio is the other one. But the important thing is this is the hydrogen sulfide producing bugs, and they cause diarrhea, urgency, and pain. So how do we measure hydrogen sulfide?

This took years to to to perfect because the problem is hydrogen sulfide is a reactive gas. So you have to have the right system to carry the gas. You have to be able to keep it in that system, whether it's a bag or whatever, for up to 7 to 10 days to get it to a lab so that it can be measured and that you can then you gotta develop sensors that are aligned absolutely perfectly in an instrument to optimize that you're measuring those 3 gases correctly, and they're not interacting with the other sensors and data, etcetera. And then you need to do some research studies to prove that, hey, this works. This is the cutoff and so forth.

And so that took years, of course, and now it's available. But just to put it in perspective of previous instruments, the new instrument that's measuring the 3 gases is more precise, is the right word. So if it's 20 parts per million, it only deviates plus or minus 0.2. So it could be 19.8, could be 20.2. Previous instruments are plus or minus 2.

So if it's 20, it could be 18 as the real number, or it could be 22 as a real number. Well, that can be really important, that difference, if you're right on the cusp of either Cboe or non Cboe. So having more precision is really important around that 20 PPM. So new instrument, more precise. But overall, they line up for hydrogen and methane pretty well as you can see here.

But in the first study, we set the cutoff at 5 because we all all we had was really sort of diarrhea patients, not IBS d, which are milder diarrhea, but diarrhea. And surely over 5, you have over 5 for hydrogen sulfide. It lines up with those bad diarrhea patients. We now know that IBS d, it's 3, but it could even be lower. So, you know, it's better to be conservative when you're launching a test than to make everybody hydrogen sulfide positive Shivan then say, oh, oops.

You know, we got that wrong. Because the data is we do the severe diarrhea first. We do the IBS d next. And then we look at the milder patients to see where the cutoff could be even more precise. So but higher hydrogen sulfide, higher, symptoms.

So that's real. So the more hydrogen sulfide you have on your breath test, the more severe your diarrhea appears to be. Okay. So how do we treat SIBO IBS in this context context? Well, we know rifaximin is FDA approved for IBS.

And it is approved for IBS on the basis that IBS is a microbiome condition in Mark. That's a mechanism of action. And so, you know, it's not called out as approved for SIBO, but as an understanding that the microbiome is abnormal in IBS and that rifaximin corrects that abnormality. But if you look at breath testing in the target 3 study, if you just flat out gave rifaximin, didn't think, put a blindfold on, your IBS D, you're getting rifaximin, 44% of people respond without any testing at all. But if your breath test was negative to begin with, almost half of those patients responded.

So it really suggested that breath testing was important. And certainly, if the breath test was positive, you're more likely to respond. If the breath test was positive and the rifaximin really got rid of that overgrowth, 76% met that really difficult FDA endpoint, which is amazing because there's no drug that I know of that can get you 76.5% of FDA endpoint improvement, but it really depended on knowing they had a positive breath test. Okay. For methane, it's different.

Methanogens are archaea. We developed antibiotics for bacteria, not archaea. Now archaea are single cell organisms, and so some of the antibiotics do have some effect on those organisms. But I can tell you neomycin by itself, not much. Rifaximin by itself on that bug, not much.

We happen to find out in the lab that when we combine Rifaximin with neomycin, wow, it had an effect. So we actually did a human study, double blind study, where we gave real drug neomycin, and then real drugs, neomycin plus rifaximin. And as we saw in the lab, if you combine these 2, you got a better improvement in constipation. And if you can get the methane less than 3, those patients did the best. Now we're a little bit stuck yet with hydrogen sulfide.

And when I say stuck, I mean we have something coming. It is looking very promising for hydrogen sulfide, but it is not FDA approved and won't be FDA approved for a couple of years, probably, if it continues along a path of success. But we do have bismuth. And bismuth has been known for a few decades to be or have an effect on hydrogen sulfide. And there was a paper earlier this year, interestingly, I don't have it in my deck, from Eamon Quigley, where they use a, bacteria.

That's a hydrogenotrophic bacteria. And this bacteria, I brought the paper because it's relatively new. But, basically it's eating hydrogen. The bacteria eats hydrogen, but it doesn't it produces it's in a cetogen. So it doesn't produce meth.

It doesn't produce hydrogen sulfide, and it gets rid of hydrogen. And it shows promising results, We're not quite statistically significant, but it shows you that the field is paying attention to hydrogen, hydrogen sulfide, and methane. And it's all declared in this paper. So things are coming that are gonna be able to treat hydrogen sulfide. And, so stay tuned.

But we use bismuth right now. And I'll show you how you we do that later. But the final piece of science I really wanted to highlight here is because this really puts sort of everything collectively that I've showed you today together. And that is that this was a study where we took really amazing patients with IBS D who were part of a randomized controlled trial. When I say amazing, that means they had to meet the FDA sort of guidelines for being enrolled in a clinical study.

They had to have really, really IBS d. And we took another group that were IBS c from another trial. And in both trials, breath tests were done. And in both trials, stool was taken for those who were enrolled in the study. So this paper just got published, in the American Journal of Gastroenterology and was presented at DDW.

But it really kinda brings the breath test to the forefront in terms of understanding IBS. So looking at methane. So this is methane first. If you do a methane breath test, if you're IBS D, uh-uh, there's no methane. You can see it's down here.

If you're IBS C, 56% of IBS C patients had Shivan, and that methane was up here. So these patients went on to have stool, and the IBS d patients went on to have stool. But before we go to the stool stuff, look at hydrogen. IBS d has hydrogen. That's the blue line.

Of course, you know that with lactose, it goes up, whereas methane, it doesn't matter. You're either methane or not. So it's even at the beginning of the breath test. It can be positive or over 10. But here's here's what I wanna point out.

The diarrhea patients at 90 minutes, this is 20 and this is 90, on average, the diarrhea patients were more than 20 by 90 minutes. But here's what I wanna show you that's really interesting. Look at the IBS C with methane versus the IBS C with no methane. No methane is here, didn't meet the 20. Methane is here.

It's lower than even non SIBO patients because the methane is eating the hydrogen. So the hydrogen levels in these patients are even lower than everybody else, because the methane's eating it. And that's why you have to measure 3 gases, because you can't tell what the hydrogen is when you have these other gases eating hydrogen. Okay. And then finally, hydrogen sulfide.

So it's very clear here. If you're d, your hydrogen sulfide is elevated. The diversity of the microbiome is much lower in d, but here's here's the important thing. And I know I've said this already, but it's so good to see it in the best trial yet that in methane with constipation, it's this bug. Methanobrevibacter smithii.

We can stop. I mean, we really know it's this bug. And the higher this bug is, the higher your methane is on your breath test. The higher this bug is, the lower your hydrogen is on your breath test. So again, it's more bugs.

Eating more hydrogen means less hydrogen on your breath test, and and all of that just continues to line up. But this is something new and maybe a little bit too much for the audience, but I'm gonna say it. It's not E. Coli and klebsiella when it comes to methane. These are the 2 hydrogen producers that are partnering with M.

Smithii to make methane. These are the 2 hydrogen producers we need to think about attacking if we want to treat methane or to just go after the m smithii. But we know the cast of characters for the first time. This is the cast of characters. We either attack these 2 as the source of hydrogen, or we attack this character.

One way or another, we're getting gonna get them down. So now that we know. On the d side, it's about hydrogen. Yes. But it's about hydrogen sulfide Mark importantly.

Because the and and these are the 2 bugs that correlated with the breath test hydrogen sulfide. So these so this is the character. Msmithi is the character for methane on breath test. These 2 are the characters for hydrogen sulfide on breath test. Again, we know the cast of characters.

We didn't know that a year ago. Okay. I'm gonna skip this. And so IBS D, it's all about hydrogens hydrogen and hydrogen sulfide production. IBS C, it's all about methane production.

And we were able to show that these pathways for producing these gases were also elevated in the stool. And this is sort of a summary of all of that. So my last 2 or 3 slides is really just kinda saying, look, things have changed. We now have the North American consensus, which was 2018. Ali Rozay, who some of you may know, my partner here at Cedars, who does breath testing and is head of motility now at Cedars.

So we set the standard for how you should think of SIBO and breath testing so that the field would be standardized. Well, guess what? The Europeans came out with their guideline. This was in 2021. And they line up very closely with the Europe the North American guidelines.

And a few weeks ago, the Asia Pacific consensus occurred. And when I say Asia Pacific, that included, experts from Australia. So the entire world now understands that Cboe is important, that SIBO needs to be, evaluated and diagnosed accurately, and that they've set the standards for how to do so across the globe, as you can see. And most of those experts around the world now agree of the importance of SIBO and how to diagnose it. Most of them agree how to dose the substrate, and most of them agree that SIBO and IBS are interlinked and interrelated, which is really, a super important, sort of development in the whole SIBO, phenomenon.

So I come back to this slide. It's not as simple as hydrogen. I know I'm you know, the more you know, the more complicated it gets, but the more you know, the more you know how to treat it properly. And so hydrogen is the starting point, but you got these 2 characters eating hydrogen. This is driving diarrhea.

This is driving methane. These guys do produce symptoms, but it's a little bit, difficult to quantitate how that works with just a breath test. I've shown you evidence for every step. I've cut corners because I can't show you everything. It's 2, 300 papers.

It would be to show you all the details of how we got from here to here, but I tried to give you the sort of the key nuggets of how this has been proven that food poisoning leads to IBS. But what I'm gonna show you today is this is how I do it. So this really kinda just settles in on how I treat my patients. And so if I have a patient with chronic diarrhea or mixed, mixed diarrhea and constipation, my first step is I measure the anti CDTV and the anti vinculin because we now know that tells me and the patient, you got this from food poisoning. And the higher the antibody, the harder they are to be treated.

It's harder to keep the placebo away. And we we we know that now because we've been doing this for a little while. I do the 3 gas breath test now, basically routinely because of the importance of hydrogen sulfide. If it's hydrogen, I give rifaximin. If it's hydrogen sulfide, I give rifaximin and bismuth.

I had a patient who took 3 courses of rifaximin from their doctor. We did a breath test. It turned out it was hydrogen sulfide. We give rifaximin and bismuth One of the first patients. And the reason I'm quoting the first patients, because treated with rifaximin and bismuth, a year later, she's still normal.

I saw her in clinic recently. So normal in terms of her symptoms, not in not just her hydrogen sulfide. So knowing is important because rifaximin alone doesn't seem to work. So the other thing is, if the antibodies are positive back here, I give travel prophylaxis because I and they have to be very careful because the more food poisoning they get, the higher the antibodies go. And for some people, I follow these antibodies over time because the CTB will go down.

The vinculin will either stay the same or go down extremely slowly over 5 or 10 years. So sad to say that this guy is really important as a therapeutic if we can get rid of it, as we move forward here in terms of our research. But when this goes up, as I had a patient yesterday, it went up from 1.8, which is abnormal, now to 2.99, and she is beside herself more unwell and difficult to treat. We now know why she had some form of poop poisoning in between a year and a half ago and now. So I use that as a sort of a thermometer.

If they're constipated, I don't measure routinely those antibodies because they're only present about 25%. Only if a patient says, oh, you know, this all started after food poisoning, would I measure it? But I don't find that it's all that useful in the cost of patients. But I do the 3 gas breath test because, occasionally, I see people with methane and hydrogen sulfide. When you have methane and hydrogen sulfide together, methane wins, so you can be constipated, but you have to treat all 3.

But for the methane positive, I give rifaximin plus neomycin based on that randomized controlled trial. Methane negative, you need to figure out why they're constipated. Something else is going on. And, again, knowing that they or not tells you who to investigate and spend more money on and spend more time on to figure it out. One caveat here, neomycin, the generic company that was making neomycin stopped making it.

So it's almost impossible to get now in the US. So we know from our clinical experience in metronid and from our basic science experience in metronidazole seems to work as well as neomycin with rifaximin. So I give rifaximin with metronidazole. Unfortunately, we don't have a double blind study of neomyofaximin plus metronidazole, but my our lab and clinical experience tells us that this works just as well as newness. So in conclusion, IBS is commonly a small bowel microbiome disease, full stop, even the even the global consensus, suggests that.

SIBO is an important contributor to that process. The most important organisms of SIBO are e coli, klebsiella. You're gonna hear a lot more about that at DDW. Methane and methanogens are the culprit in constipation for the most part. Hydrogen sulfide is becoming the big culprit in diarrhea.

Getting these things down improves constipation or diarrhea depending upon which gas you have. You know, knowing if you have these antibodies is really important in my view because it really tells the patient they have an organic disease. You have a real disease, not it's not in your head. This is where what happened. And they need to be more careful because if these antibodies go up, they get worse.

And so we're if if I were to say one thing sort of to conclude, which is number 9, we now know the the actors. We didn't know them even a year ago, not as completely as we do now. We now have already started developing the treatments, and they are already in clinical trial. So and some of those clinical trials are done. I just can't speak about it yet.

So we're a lot further down the road than I can reveal today. And I I want you to have some optimism that we have a lot of things coming. And it's not just us, which is really the most important thing. I I highlighted this paper about this hydrogenotropic bacteria, which I didn't have time to put a slide in because it's relatively new. People besides us are thinking about ways to manipulate hydrogen and methane and hydrogen sulfide, which is even better.

I mean, it doesn't have to it should be everybody working on this because then there's gonna be something for you all or people with these conditions faster. So I'm really excited about the future because now that the road map and the the the cornerstones are now very well laid, I think we're we're gonna see some really interesting things in the coming years. So thank you. Sorry. Maybe I went a little too long, but I hope fully that was helpful.

It was extraordinarily helpful and absolutely not too long. So thank you so much, doctor Pimentel. Doctor Seabecker, I know you have a lot of questions. I do too. But I need to ask the one question that I know is on everyone's mind.

When is DDW 2023?

It's in the 1st part of May. I don't have the exact date. Okay. I can get No.

But the countdown is on. Okay.

And PDW stands for Digestive Disease Week for people who don't know, and it's the biggest, gastroenterology conference. It's international. And it's typically held isn't it always held, though, in the US even though it's a a worldwide conference?

Yeah. It's it's held in the US, and it's, it's, gonna be in Chicago.

Okay. Alright. Alright. Thank you. We I'm sure we'll be keeping people posted about what happens there.

And, so I wanna hand things over to you, doctor Siebecker, because I know you had some questions already prepared as well. That

was great. Yeah. Thank you so much, Mark. That was fantastic as always. Some of that information that you gave us is so brand new that that the official publication of it just came out, like, October 27th, I think, was when the paper was published.

So really brand new, some of that. And, on that paper I just had a couple of questions I wanted to ask. It was great that you clarified that now that you know these bacteria that are making the hydrogen that then goes to feed, like, the methanogens, for example, that that is a place we could target our treatment. And, I'm sure you're working on that. But I just wondered, do we know does rifaximin Sarna, because we always give rifaxanin and neomycin or rifaxanin and metronidinol together.

Do they target these syndromes? And let me see if I can say them. Rumino ruminococcaceae and Christian senesenaliciae.

So, the answer is yes. Rifaximin should work on those. The question is, does it work on those? And and why am I saying it that way? So E.

Coli klebsiella, Rifaximin is amazing for it. But, some of the problems we have with rifaximin is it's not water soluble. So it can't penetrate some of the deeper parts of the small bowel fluid, that where these bugs are sort of hiding, including the mucus. And so then if you go to Christensenal ACA and ruminococc Sarna, they are often so the methanogens can be in the small bowel and or the colon. In the small bowel, the rifaximin has more effect.

In the colon, it doesn't have as much of an effect. And so it may not as thoroughly diminish those organisms in the colon as if they were in the small bowel. But in clinic, we see it works about 70% of the time if you combine it with rifaximin and metronidazole. Maybe that's why it works because metronidazole has a better solubility and maybe it they're sort of working in tandem. You're sort of, you know, slugging them in different ways and and, and you get the same effect or the good effect.

Great. And, can you tell us if that is one of the things you've been working on is finding, treatments that target those?

Yeah. That is that is many Okay.

So we have that to look forward to.

That's soon.

Excellent. Okay. I was wondering if you could talk, I don't know that it was in your presentation, but it was in the paper, about the the cofactor f 420 that's involved in methanogenesis. And, you know, if you could just describe its role and also if, that is what is being targeted by the statins that that can turn it on.

So, a Sarna of traditional approach to medicine is that you find, an enzyme or sort of the protein that makes something happen, as part of the machinery of cells and bacterial cells in this case. And one of the last steps in making methane in is the f 420 protein. And the f 420 protein is, the reason that one's important is because there's a lot of ways of making methane. But in almost all bugs that make methane, they use f 420 as the final step. So So if you wanna get rid of methane and make sure that it's not, you know, if it just happens to be you don't have Smithy eye, you have one of the other ones, f 420 is still there.

So it's a good target. And so lovastatin, we showed in a paper a number of years ago, sticks in the socket of that protein and blocks the protein doing what it's supposed to do. So we did one study, actually, 2 studies with lovastatin and tried to create a lovastatin that doesn't get absorbed. But it wasn't that successful mostly because what the statin did was reduce cholesterol and didn't really stay in the gut as it's supposed to. So, but in the lab, we put lovastatin in a dish with these methanogens.

They don't produce methane much. So it works in the lab, and it works in the stool of humans, but it has to stay in the stool and not get in the bloodstream. And so those are some of the things we're looking at in the future.

Thank you. Really interesting. Do you have any new thoughts on why we see constipation so often clinically when someone's positive for hydrogen sulfide and they're not positive for methane. Like, it's not like they're both methane and hydrogen sulfide are positive. Clinically, I know many of us have seen the constipation.

It's surprising to us. And, also, my group did a did a a study, a community study, and and we saw that we saw that result as well. Many people seeing it positive. Any new thoughts on why that would be when a study so clearly show diarrhea is linked with hydrogen sulfide?

So, studies are one thing, but real world is different. So, for a lot of reasons. I mean, in our practice, for example, we see hydrogen sulfide. We see it once every couple of weeks, and we treat it. But our practice is maybe more of the extreme cases, maybe not as mild diarrhea.

So it can vary across across the the country depending upon pockets of, and how you know, I mean, I don't do breath tests necessarily in somebody with a one out of 10 symptoms, but 8 out of 10 symptoms, I might, you know, maybe diet works enough for the 1 out of 10 patient rather than antibiotics. So it just depends on who you're testing, the severity of their condition, and so forth. So if a patient has diarrhea once every 2 weeks, they may not have much hydrogen sulfide or the threshold for positive for that patient is a little bit lower and we just haven't got to the granularity of that research. But if methane's present with hydrogen sulfide, methane wins. So these patients are often constipated.

But we had one patient like that where we treated the methane, and all of a sudden, the hydrogen sulfide came up because the methane was gone, and now they have diarrhea. So you have to be that's why it's sometimes important to monitor all 3 gases.

I've definitely seen that. I've seen the switching back and forth between methanate methane and hydrogen sulfide and the clinical correlation going back and forth. Thanks. Okay. And then let's see what I have in this.

Oh, yeah. This paper, you know, made such an excellent clear correlation between the IBS types and the SIBO types, really linking them together. And I just wanted to know, what are your thoughts now on whether or not basically, like, Cboe should just be considered IBS? Like, should these 2 should Cboe and IBS be separate? Should they be joined?

What are your thoughts?

You know, it it's a tough question for a lot of reasons. First of all, if you go back to h pylori and peptic ulcer disease. So h pylori causes ulcers 60% of the time. So peptic ulcer disease means you have an ulcer in your stomach. Hey, we don't know why.

But they never changed the term peptic ulcer disease to h pylori disease. And so they just basically said, you know, you have peptic ulcer. 60% of people can have h pylori as a cause and look for it and treat it when it's there. I I think the challenge with IBS is IBS, and and this is the historical part of IBS, has always been a clinical diagnosis. You must meet the ROMA criteria.

Well, if if we take so there's 2 ways to handle what your question is. Anybody with any diarrhea should have a breath test. If it's positive, then don't apply the Rome criteria. That that's gonna be hard to convince people because, you know, that basically pulls the carpet out from Rome. Nobody's left.

Maybe 30 or 40% of people are left, which cuts IBS, true IBS down instead of 40,000,000 people in the country, maybe 5 or 6 because the rest are Siebecker know what I'm saying? So, it's I I don't know what the answer is in in some of the, you know, the people who do the criteria and all that will have to wrestle with that. To me, those things don't matter as much as, you know, if you have a breath test, you're determining the microtype and you're treating it. And I I think people are starting to well, people have gotten it. They understand what they need to do for the most part.

Most gastroenterologists are starting to understand this whole story, how it how it's playing out. And so maybe the Rome criteria are becoming less important, more important for clinical trials still, but less important going forward. But, you know, time will tell.

Yeah. Yeah. That it I'm the same. I don't care what it I don't care what you call it. I know what it is I'm looking forward to treating and I and

know how it behaves.

Right. You can name it

whatever you want. Yeah. Exactly.

Okay. Oh, yeah. The last time you were chatting with us, which, was, you know, I don't know, 5 months ago or something, You told us about something so interesting, and I was wondering if you could give us an update on it. It was a prevention, basically a vaccine, for preventing food poisoning that would then prevent the development of IBS. Can you give us an update on that?

Can't say much, but yes.

Is there anything you can add to what I just described?

Mostly no. But because I can't I can't talk about it.

Okay. Alright. There we go.

But, yes, I mean, we the the whole point is if we could prevent this from ever happening. You know? I I gotta tell you, people are vaccine fatigued. So I'm not sure everybody wants an IBS vaccine. But but, the point is if you're, somebody who, for example, is a missionary work, and you're working in underserved populations in the world, and you're going there, and you're getting food poisoning, and you're gonna get IBS, or the military, or people who travel a lot.

This is where the vaccine may be extremely important because they're gonna get IBS for sure. And then people at home, if they if they just have they love to eat street food and, or catch squirrels in their backyard and roast it on the barbecue. I'm joking. Joking. That that doesn't happen.

Or maybe it doesn't. Not in Los Angeles anyway.

I've been watching the show alone where people are like, have you seen this show?

That's where I got it from. That's where

I think I I was like, he's watching alone.

It's It's kind of gross, but, anyways. So do

they actually do that in alone? Yes.

They do. They're just on and you know, they're by themselves. They're alone. It's like survivor to the 100th degree.

I've heard about it. I just

Anyway, it's kinda disturbing and kind of inspiring. Moving on. Okay. Moving on.

Alone could all get a vaccine as far as I'm concerned.

Oh my god. Yeah. Yeah. You know, this is the thing. I mean, I understand people are vaccine fatigue, but, you know, what we see in clinic is day after day is people who you know, they've just gone on a vacation, you know, to some to some place.

You know? I don't wanna say one country or another because I don't wanna say but just it's so common. You go on vacay you know, you're having vacation in the sun and fun, and then this is what happens. So common. And, also, I saw tons of people who just eat, like you said, eat out all the time, and and that's how they got their sleep.

So I need

to If you think about it, I mean, it's a little different than COVID kills people. So let's let's be clear. If when it when COVID if and when COVID is a milder illness, then maybe vaccines are less important. But for IBS, if you get one bite of food poisoning and you have lifelong IBS, I think, people might think, hey, I don't want that. And people with IBS need to be a little bit more vocal.

It shouldn't be sort of a humorous disease. It's a real condition that's that people suffer with immensely.

True. Well said. True. Okay. Another thing that was fascinating about what's what's been brought out in this research with this paper is that that difference between the small intestine microbiome diversity that changes between the hydrogen type of E.

Coli Mhmm. And the hydrogen sulfide type. The the hydrogen type of the E. Coli, you saw decreased diversity. And that is what I hear all of my colleagues always talking about is the diversity in the microbiome, whether they're talking small or large, is is too is too diminished, and we need to build it back up.

But what is fascinating is that you found this second type, you know, the hydrogen sulfide type. It's increased diversity. And, you know, as as you've explained previously in the paper, it's it's with, bugs that are typically found in stool. And I was just wondering if you can comment on that and particularly any thoughts on treatment for correcting that. Is it just a matter of, you know, getting the bacterial overgrowth down?

Any any thoughts?

Well, you know, so one of the it's it's a it's a challenging question from 2 two angles. But but, if you slow the gut down, you have more time for diversity, more time for bacteria to grow. So maybe that's the explanation for methane, why the diversity is higher there and lower in diarrhea. If I took a laxative every day, my diversity would be diminished just because you're taking a laxative and you're just washing out the bugs constantly. So diarrhea in and of itself might lead to lower diversity.

But we're gonna show at DDW, the small bowel, exactly how diversity is truly destroyed by the ecolis and the klebsiellas. So I will I will give you more information on that.

But Okay. That's But

basically, we now know how that's occurring and who the species and the strains are that are doing it. We're gonna get down to that level. So, that's gonna be really exciting. But, yeah, diversity is important. But the the problem is, you know, when we treat well, let me say it another way.

When we treat with rifaximin and we get rid of the SIBO, we have data on this, You look at the small bowel again, all the diversity came back. It's sort of like a gang moved into your neighborhood, and all the neighbors just say, I'm out. They move out of the neighborhood. And then when the police get rid of the gang, everybody moves back in, and everything's back to normal. And and that's exactly what, what it's like with, with SIBO.

So once they're gone, the healthy microbiome just recovers. It's pretty amazing.

Yeah. And what is so amazing about that, what you just explained, is that rifaximin's an antibiotic. So with an antibiotic, you can actually restore diversity.

That's the brilliance of it is that, you you know, people say, oh, you're taking an antibiotic. You're gonna destroy the diversity. It's exactly not what's happening. You're getting rid of the bullies. And the bullies are gone, and now the the kids are playing in the yard again.

Okay. Now what's interesting is you were just talking about how with methane, there's increased diversity. But what I was pointing out here is how in this paper, it said in hydrogen sulfide type, there's increased diversity. So is that the part you can't talk anything about?

Well so yes.

Okay. Got it.

But but but I'll say one thing that is published. You know, e coli or or hydrogen producers, when they produce a lot of hydrogen, that hydrogen can intoxicate other organisms. So anything that eats hydrogen or reduces hydrogen in the environment will allow other organisms to be more successful. So I think I'll say it that way and leave it at that. So hydrogen is sort of like you're pickling the environment for other organisms.

So if you can get rid of the hydrogen, whether it's through methane or through hydrogen sulfide pathways, you might give some organisms a chance to stay. And that's sort of how we see it.

Jaiman, did you have your hand up to say something? Oh, you're muted.

Hi. I was coughing a little bit. I do have some questions, but wanna make sure you do you wanna take a break, Allison? I've got a couple, or do you wanna keep going?

You go right ahead. I've only got, like, 4 or 5 months, but you go ahead.

I only got, like, 35. It's fine. No.

I only have I only have 2.

Okay. These are kind of, just different than what we've been talking about, but I was wondering what your opinion was when you, talk to a patient who's going to go have a colonoscopy, and they are a constipated patient. Do you have any tips for them for the prep? Oh, and I do have an agenda because, hello, December 14th.

Oh. Yeah, baby. A egg bottle.

Yeah. Yeah. Can't wait. Any tips? Because I know I'm not alone.

Right? I know I'm not alone.

Yeah. The you gotta pinch your nose when you're drinking it. No. I'm kidding. No.

You gotta drink it all. Otherwise, it does you know, the worst I can tell you the worst day of a patient, they come in. They did the prep last night. They kinda cut corners. The doctor goes in.

It's full of you know what. They can't see anything, and and they tell you we're gonna reschedule it in 2 weeks from now and you start over. So don't make that you, because you don't wanna do that twice. That's that's the most important thing. Just take the whole part.

Okay. And, we were talking to somebody else who said, like, the day before you do the prep, a lot of people sort of gorge because they're thinking yeah. So he he was like gorge. Don't don't yeah.

Go light meals that day or just clear fluids just so that there's not a lot of things to come out. And, yeah. So Easy. I'm excited for you.

Well, it's my 3rd. Right? Because I before I knew you and doctor Siebecker and then I what SIBO was, I was convinced I was dying, and I had cancer. So as so many people can relate, like, I see it all the time in the Facebook group. Well, I I, you know, I my colonoscopy showed nothing.

Right? That was a big discovery for me. Like, SIBO doesn't show up on typical colonoscopies unless you're doing the aspirate like you do or, you know, with all

the It's an amazing point because we we see this all the time. I I use this example that I'm gonna say now. I had a patient in my practice. She's 25 years old, and she comes in. I said, have you ever had a colonoscopy?

She said, yes. I've had 3. And I'm I've just blew my mind.

Yeah.

Why would a 25 year old young woman, after the first one's negative, why would anybody want another one? And then another one after that. I I mean, so, yes, abusive colonoscopy. And and then colonoscopies are negative. You don't have anything.

There's nothing there.

It's a desperation that so many patients experience, and bless the GI doctor who's like, you know, my doc my doctor Michael Schulman in, Florida, he I, like, begged him for the second one. Right? Because I was like, it's a flare. And now I look back and I was just having a flare, but I was his last colonoscopy on the last day before their Christmas break. They just, like, really moved heaven and earth for me.

Bless them. And he's like, you got nothing, sister. Like like, yeah.

But I but the severity of the symptoms are such that the patient's like, look. Something's gotta be wrong.

Exactly.

And but now but now we know. Now we know all these different things.

And then I would hope that

gastroenterologists and and primary carers across the whole world, not just our country, really understand that, yeah, you you run the colonoscopy, but understand about the IBS Mark test and placebo breath test. You know?

So Right. There's your there's your great trifecta. And then, any thoughts on a diet for methanogen overgrowth?

Yeah. So I've been so busy with so many other things. I keep saying there's gonna be a diet for all three types, and I think there will be. We're trying to sort out that, but, we haven't made a lot of progress there, I have to say. Okay.

No teaser on that one because we've

darn it.

Trying you know, the big there's a lot of big questions, and that one is sort of on the back burner.

Okay. And then last but not least is the correlation, I guess, might be the word connection, relationship between diabetes and SIBO. Do you see do you see that happening a lot?

We we do. We don't have any teasers there either, except that we're investigating a lot of areas there because there's something connecting the microbiome to diabetes and high blood sugar. And we have some lead, bugs and things, but but we need to we need to spend a little bit more time in that direction and try and sort through that. But what we do know is that IBS patients do have weird inflections of blood sugar that are difficult to explain. So, yeah, more need more work needs to be done there.

Do you see a pattern as more hypoglycemia or hyper?

So it depends. In the beginning, in younger people, we see a more hypo, especially if we do a a sugar to glucose tolerance test. Partway through the test, they usually go down to, like, 30 or 50. We published that about 15 years ago. But if they're older people, then they tend to go high.

So whether it's something the bugs Sarna doing or something you're doing in adaptation to the bugs over time. So it's this is the challenge with diabetes is because it changes in time. And so some conditions you know, if you have staph aureus in your skin and effect it creates an infection, it's like there and now. What what we're starting to see is that if you have a bug, it does one thing now, and you continue to react to it, and it does something a little bit different as you age. And so when you start to add age as a factor, it increases the complexity of our associations.

I'm not talking about SIBO, but I'm talking about all these different diseases for which your microbiome might be important.

What do you think about, since we're talking about other conditions, psoriasis and SIBO, IMO?

There's definitely a connection between, what we so psoriasis, ankylosing spondylitis, Reiter's syndrome, scleroderma, all have microbiome connections. For example, campylobacter can precipitate psoriatic arthritis Sarna Reuter's and ankylosing spondylitis. And so you can see that there's a connection with campylobacter causing IBS, campylobacter causing another autoimmune disease. Campylobacter is just a nasty figure. It can also cause Guillain Barre.

So campylobacter is a nasty organism that can lead to some of these autoimmune conditions, including psoriatic arthritis. So how that works? Not clear. I do have some patients where some of their, skin manifestations go away when Siebecker gone. Like rosacea patients tend to get better when they get their SIBO treated.

I have 2 psoriatic psoriasis patients with psoriatic arthritis who claim that when the SIBO is gone, their psoriasis and psoriatic arthritis are Siebecker, but it's small numbers, so I can't really

Yeah.

Make this another.

It's interesting. They've been also doing some figuring out about how staph and psoriasis work together. So it's another another thought on that, but, obviously, more to come. And last, this really is my last one, and that is fatty liver and, and, SIBO.

Yeah. You gotta wait for that one.

Oh. New info coming.

Yeah.

Well and I've I've always appreciated the fact that Rifaximin does such a nice job for fatty liver and that, you know, it's, like, very efficient.

Yep. We gotta wait.

Yeah.

Okay. I just have,

like I'm on to something, Allison. You know, I love that.

Oh, yeah. You you're always asking about that. So It sounds like we are gonna get answers. Okay. I think I just have, like, 3 questions.

Boy, that was really interesting about neomycin. I didn't realize. I've been hearing people say that it was being hard to get, and I didn't understand why, that it's the the generic manufacturer.

Yep. They stopped.

There's no it's all it was only generic. There's no brand in the US?

No. It's it's been generic for a long, long time. So, you know, the problem with generics and, you know you know the story with insulin. You know the story with some of these generics. They disappear for a while, and then the company brings it back or another company buys it and brings it back and gives it an explosively high price, and says, well, it's not good for this, and we're bringing it back.

We're starting a whole new manufacturing line. And so insulin k is, like, it's generic. Come on. It's been around for, what, a 100 years? Not a 100.

You know what I'm saying.

Mhmm.

50, 60 years. And why is it so expensive? So what are your shenanigans?

Well, on that front, I just wanted to ask a clinical question about it. I mean, you know, maybe not as relevant now that it's not so accessible. But I was wondering, how often you might have seen tinnitus or tinnitus, however people like to pronounce it, develop. And, like, how how common is that for you to see? And when and if you've seen it, was it temporary or not?

So you can imagine how many people I've given rifaximin and neomycin to. It's a lot. It's it's over a 1,000. Let's put it that way. And I have never, in a human in my clinic, seen tinnitus.

I have seen tinnitus in one patient in a clinical trial. In the clinical trial, there's a whole section on tinnitus because the FDA want us to make wanted us to be very careful about tinnitus. So they required for that trial, this was the lovastatin trial, actually, that all the patients get ear testing before they start the drug for 2 weeks. And then if and when they described anything, we repeat the test. So sure enough, the first patient in the trial says, oh, I think I got ringing in my ears.

So we say, oh my god. So we stop the drug and, you know, and we stop the Dr., and then one day later, they have sniffles, they have runny nose, they have a sore throat. They basically, a cold was coming on. And then 2 weeks later, still, they're out of the trial. We repeat the ear testing, and it was better than the first one.

So, yeah, that's it.

I heard this story before. You know, I thought that was in the context of, whatever one gets so afraid about with, neomycin is is deafness.

I didn't

realize it was tinnitus.

Well, it's both.

Yeah. Obviously.

On it long enough, it becomes it becomes deafness. But you have to be on neomycin. The neomycin studies that suggested that that happened were back in the day when we used to treat cirrhosis with encephalopathy with neomycin. And for that, you take it every day for years. And for about a year, you start to get these things.

And and we know from Neomycin is an aminoglycoside antibiotic. Gentamicin is an aminoglycoside antibiotic. If you take gentamicin intravenously, directly in your blood for 3, 4 weeks for, like, endocarditis, then you can have tinnitus and ear changes. So it's a category assignment of tinnitus. It's not neomycin doesn't get absorbed for the most part.

So you have to take it a a long, long time to see anything. But it's there, and the FDA wants us to be careful and just monitor.

Thank you. Thanks for answering that.

Okay. And then anymore. So we don't have you can't get neomycin anymore.

Right. It doesn't now. Okay. And then this is a question that comes so often. We just had it recently again from, from those who listen to us, is can you help explain why someone could bloat from drinking water?

So, you generally, you have 2 types of receptors in the gut, that turn on digestion, mechanoreceptors. So if you stretch the stomach and you drink, like, half a liter of water, you'll stretch the stomach and inhibit the cleaning of it. You gotta stretch the stomach, though. It's gotta be a good amount of water. If you have a couple of sips, it's not gonna do it.

So that's why you can have you know, when we're doing our low fermentation eating, if you just drink a little water, sip a little coffee, it's not gonna get you out of a clean mix. But if you really like Doug Guzzle, like people do when they're drinking, you see these athletic young people who have these cylinders beside them full of water, and they're just drinking that stuff. There you go. Right there. You're the athletic young person that I'm talking about.

I'm the sipper.

And, and so, you you know, you drink that. You'll activate mechanoreceptors, and then the gut will start moving. And if we know patients with SIBO have air in their gut cause they're fermenting even at night, you'll get a consolidation of that air, and it will feel like a pressure point in the gut. So it's more that the the air is moving around and suddenly becoming in these pockets instead of being just sort of spread out over 15 feet. So that's how I see it.

Some people say, well, what happens is you get a emptying of your ileum into the colon, and the residual stuff might cause a little bit of gas fermentation. So I don't I don't I I sort of believe the first one more than a lot of. And the other receptor is chemoreception. So it's detecting food and turning on your system. You don't get that with water.

You just get that with food.

Thanks. Yeah. Do we people ask that.

I just wanna ask that again.

It's detecting food. And so the back turns on as it starts to detect it's real food coming.

Okay. Okay. And then my this is my last question. I saw you had a, an article that you just published just recently with email on biolasses and IBS with doctor Rosai. And and, you know, there was a comment comment in there about ruminococcacia and bile acids Sarna IBS diarrhea.

And just anything you would wanna comment on, just, you know, the nature of this article is very interesting.

Yeah. I mean, I think, the thing about bile acids has been much much ado about something in bile acids. But there's no randomized controlled trial, none, of treating bile acids in diarrhea IBS. There are open label 20, 30 patient studies that say, hey. This might do something.

But overall, the bile acid story is a bit complicated. I was at DDW, and I went to a bile acid lecture. And the this is from a group in San Diego, and they do mass spec of bile acids in stool. They detected 2,000 different bile acids in stool. I'm like, I'm done.

I can't deal with 2,000 bile acids. I you know, it's bile acids are so complicated that to unravel the mystery of bile acids is gonna take a decade. And, maybe I'll retire by then. So it's it's gonna take too long to to really understand the mystery of bile acids. But, yes, bacteria degrade bile acids into these toxic bile acids, which can lead to diarrhea.

That we know. So, but in my view, it's the bacteria that are the problem, not the bile acids that are the problem in most instances. So that's really what the paper was trying to say is that, you know, you have bile acids, now you have a whole bunch of bacteria in the gut, and they're converting the bile acids prematurely to things that are more harmful to your colon and to your gut, and then you get this diarrhea effect. So the diarrhea effect of SIBO might be multifaceted. It's not just the the gas or the hydrogen sulfide.

It's the bile acid changes and other things. So that's what we're was really the point.

Thank you. Okay. Wait. I'm gonna do Siobhan and have one last one.

Okay. Because I just got, like, 3 more, but that's We'll we could go forever. But And then we'll wrap it up.

Measuring stool. And that's a question we get a lot, from clinicians. They they wanna know how useful stool analysis is for SIBO. And I I feel like there might be a changing landscape because now we know methanogen overgrowth can be, you know, in the large intestine, so can hydrogen sulfide. And we do have, in functional medicine, many of our labs offer m SNPi and DesoccoVibrio sampling.

They, you know, they'll measure. So I don't know. Do you use it? What do you think of it?

Well, you they must have a sneak peek at our data for the Mark for DDW because we're publishing presenting that. What I'm saying is I don't even know that information yet of what almost everybody has methanogens in their small in their colon. Almost everybody. What's normal? What's abnormal?

What's causing IBS c? I mean, we're still trying to figure that out. So I guess what I'm trying to say is and I'm gonna say something really controversial. It's sort of like the yeast story. K?

Everybody has a little bit of yeast in their stool, but what really is true yeast overgrowth? Because I believe there's a clinical true yeast thing. But we we wanna treat those who have the true story rather than those because the colonizing is happening all the time. So I I just wanna make sure that when companies say you have methanogens, that it is really truly a pathogenic level. Not just that it's above their whatever so called normal range because so what?

If I had, you know, 6 burritos yesterday, maybe my methanogens would be a little higher today, but it's not high tomorrow. What is the pathogenic range? So, you know, publish. Come on, guys. Publish some papers.

Show me. I'd be happy to use these tests. And it frustrates me when people are make making money on things, but they're not publishing the data so we can see how they got to this point, how they know this is abnormal, how they know that we should be doing x, y, and z because of what they're finding. You know? It's the same with the probiotic companies.

A lot of them are selling probiotics. They've ever done published science. Some of them have. You know, maybe they don't wanna take a chance, take a risk. I don't know.

Okay. These are just some hot topics in the in the Facebook group, Siebecker community. And so even a couple of sentences, the, COVID and SIBO.

Yeah. There are a couple of papers. I I can tell you, I have thousands of SIBO patients. I can't find one that got worse because they had COVID. I really can't find one that can truly just she or he says, look.

The COVID really wiped me out. My my SIBO is not going away now. I'm having a tougher time. I I I I'm not I'm being honest. I haven't seen it.

And Okay. So I've sort of let that put that to rest.

Okay. And then SIBO and iron levels, serum iron levels and ferritin?

Yeah. There can be some changes. It depends on the organisms. We're trying to look at that. The other thing we're trying to look at is folate Mark importantly because folate is a really strong marker for SIBO, and what organisms Sarna responsible for making that full leg go higher in SIBO.

And then b 12 can go down. So there's a few things that can be markers of SIBO and who's who's making that happen.

And it was weird for me. I had very high b 12 levels, like 8,000 or something ridiculous. And they're like, oh, well, you must have been supplementing. I'm like, no supplements.

Yeah. So there's weird things weird bugs that can produce stuff, folate b 12. Some use iron, some use b 12. You know, so it's it's all sorts of things that we're learning just as we continue to look.

It's the wild west, in there. And then last this really is the last one. Gallstones. Any relationship? Do you ever see any?

Haven't looked. Haven't looked. Yeah. It's

Plenty of other things to look at right now.

An interesting question, but we haven't haven't looked.

Okay. Thank you. Allison, parting thoughts?

I'm done. I said I was done. I'm done. We we have pest what is what does it ever do with questions?

And a little pestering, but we love we love it. That's our favorite thing to do, and we thank you so much for it well.

As usual, you've poured it so well.

I'm I'm glad to be with you, and, I hope this was helpful to your to you and your audience. So

Oh, thank you so much.

So helpful. Incredibly helpful. And so we will look forward to talking to you after DDW.

I'm sure you will.

Can't wait.

I'd be very I'd be delighted to do it. You're doing good work. So it's it's

Thank you.

You get the information out there. You.

So important. Yep. Not worth it to to do anything less than that for sure. It's a disservice. Anyway, we are in our thoughts and prayers.

Continue with your beautiful work. And, doctor Siebecker, thank you so much for all of your insights and questions as always, and we will see you next time. Can't wait.

Alright. Perfect. Bye, guys.

Thanks. Bye. Doctor Siebecker, wow. That was awesome. Amazing.

Fantastic.

Yes. I'm so excited. I think that was a really hopeful session full of a lot of science. I wanna encourage everyone to go back and watch it over again because it's obviously dense in a good way with, you know, material for us to ponder and figure out and to start smart conversations with our practitioners and to not give up. He's not giving up.

We're not giving up. We're gonna keep giving the information out to you. And, I think we've got some really good news on the horizon coming sooner rather than later. So, I mean, he's he's talking about, you know, 2023 midyear, so that's fantastic.

That sounds like there Sarna lot of treatments that he's been studying. So that because that's our next step is is hearing about new and more effective treatments. Very excited

about it.

Excellent. Thanks, doctor Siebecker. We'll talk to you later. Thanks, everyone.

Bye.

Bookmarks