An important contributing factor to irritable bowel syndrome (IBS) and small intestinal bacterial overgrowth (SIBO) is a food poisoning incident (and subsequent antibodies to a toxin called cytolethal distending toxin B, or CdtB). CdtB looks like a protein made by the body and can trigger autoimmunity that disrupts motility in the intestines. Dr. Mark Pimentel and his colleagues developed a blood test that tests for these antibodies, called IBS-smart. This blood test can be ordered by your doctor as a first-step to screen for IBS. It is designed to be covered by insurance. If you’re suffering from IBS-like symptoms, this test may save you time and money by verifying your IBS. As well, your level of antibodies (if present) can help inform you as to the severity of your condition and may inform treatment.
Dr. Michael Ruscio, DC: Hey everyone, welcome to Dr. Ruscio Radio. This is Dr. Ruscio. Today I’m here with Dr. Mark Pimentel, who is one of the preeminent researchers in IBS and SIBO, so we’re very lucky to have him here today. Mark, thank you so much for taking some time to be on the show.
Dr. Mark Pimentel, MD: Oh, it’s a great pleasure to be here. Thanks for inviting me.
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Dr. R’s Fast Facts Summary
IBS Smart Test
- Measures anti-CdtB and anti-vinculin
- Determines your likelihood of having IBS-D or IBS-M
- If test is positive – there’s a 98% chance you have IBS and can go on to treat it
- Does not diagnose constipation IBS
- Must be ordered by a clinician
- Normal: if both markers are less than 1.6
- Abnormal: between 1.6 – 3
- Challenging cases: when results are 3 or above
- Very high (over 3) on vinculin, may increase the risk of scleroderma (1) which can be assessed via the ScleroSmart test
How should it be used?
- As a screening tool to diagnosis IBS and prevent additional testing for IBD
- Might predict tough cases – The higher the anti vinculin the more bloated the patient is and more likely they’re dealing with a tough case of IBS and/or SIBO
- May predict if more likely to get food poisoning.
- Be wary of getting food poisoning again because the autoimmune symptoms will be worse the next time around
- High risk patients – Use Rifaximin prophylactically, ½ pill with each meal
- Rifaximin does not change the antibodies it minimizes the bacteria
Low FODMAP Diet
- Low FODMAP Diet does not change the antibodies it minimizes the bacteria and can reduce symptoms
Where to learn more?
DrMR: Absolutely. Can you tell people a little bit about your background? As far as advancing the bacterial hypothesis of IBS, you’re the guy who really advanced that agenda farther than anybody else I can think of. I’d love to have you get people up to speed on your background in case they haven’t heard of it.
DrMP: Yeah. I got interested in the function of the gut—which is called GI motility—more than a couple of decades ago. One of the areas that was of interest to me initially was irritable bowel syndrome. People had neglected that area and thought that IBS was a psychological disorder. Meanwhile these patients were bloated, they didn’t seem like they had any altered psychological profile compared to other patients, and I got the thought that maybe this was microbial.
My mentor at the time was interested in this area as well. So we really started to examine bloating as the common feature to all these functional illnesses. It led down a very complicated path of trying to prove that a disease that had initially been thought of as psychological is now organic due to bacteria building up in the gut. That was sort of the initial nidus. And we took a lot of criticism for that, because when we were making these assertions, the word “microbiome” hadn’t even come out. Nobody had even used that word. That came out in 2003.
What we then began doing is to explore, well, why does this happen? What are the steps and the mechanisms? That’s what I spent the last 20 years of my life doing. It’s been a great journey.
DrMR: It has.
Autoimmunity Link to IBS and SIBO
Watching some of what you’ve uncovered has really been this new autoimmune component to IBS. I’m sure people listening to or reading this have heard about this in one shape or another. Can you give people the short primer on, really, what it is you discovered and how we’re now realizing that autoimmunity to the motility apparatus is one contributing factor to IBS and to SIBO?
DrMP: Right, so there are three components that we had to fuse together to try to understand. First, we had the term irritable bowel syndrome. Then we had the term small intestinal bacterial overgrowth. Then there was a third term called post-infectious IBS (where you got food poisoning, and ever since then you have IBS). How do those three concepts fit together? As I mentioned in my introduction, over the last 20 years we’ve been trying to work out the steps of how these all fit together.
What we now know in 2019 is that food poisoning starts the process. Now, some people say, “I haven’t gotten food poisoning.” If you’ve had your overgrowth or your IBS for 20 years, you may not have remembered that first day, maybe it was a mild diarrhea. There’s a toxin on food poisoning called cytolethal distending toxin B, and all the major foodborne illnesses—E. coli, Salmonella, Shigella, and Campylobacter—have that one toxin and they’re almost identical between the organisms. That’s the one toxin in common.
We tried to identify the toxin, see what it was doing. It turns out when you get exposed to that toxin, you develop antibodies to you. Your body sees this CdtB, it looks similar to a protein you have, and now it starts reacting to you, and you create this autoimmunity. Measuring these two antibodies, (the antibody to the toxin anti-CdtB, and the resulting antibody, the antibody to vinculin) we’re able to diagnose IBS. But it’s part of the cascade to the development of SIBO and IBS as well.
DrMR: As you’ve discovered this, you’ve developed a test that can now be used for this underlying autoimmunity. And you’ve recently updated this test. Can you tell people, in case they haven’t heard about what is different about the newer version of this test, what improvements or modifications have been made?
IBS Blood Test and Updates
DrMP: Yes, great question and I appreciate looking at it that way. When we first brought the test out and patients were using it, they were concerned the sensitivity was a little low or the specificity maybe could have been better. We’re always anticipating improving the test, but we learned a lot about those two proteins, CdtB and vinculin. There are ways to improve our ability to detect antibodies, by manipulating the protein slightly before applying them on the wells where we do this test. We’re able to actually optimize that. By doing so, now, if both antibodies are positive, you’re 98% sure you have irritable bowel syndrome as compared to Crohn’s disease or ulcerative colitis.
It’s like this… you show up at a doctor’s office. You have chronic changes in your bowel pattern, more on the diarrhea side or mixed patterns. And the doctor is a primary care physician. They’re alarmed. They’re thinking, “It could be Celiac disease, it could be Crohn’s, it could be ulcerative colitis. I need to send you to a gastroenterologist.” But if you did this test, you’re 98% sure, if both markers are positive, that it’s IBS. And you can go on to treatment or start to think about the treatment.
One of the things we know—this is super important for patients—is that the sooner you get a diagnosis, the less nonsense the patient has to go through. Less colonoscopies, less blood tests, less ultrasounds, less cost to the patient, co-pays, insurance. The flip side of it is that patients run around the block trying to figure out what they have, and a lot of times the doctor says, “Well, I can’t figure it out. I don’t know what it is. I’m sorry, do some relaxation therapy or something,” when really, this test could tell the doctor very quickly.
The patient is validated by this test, because the patient says, “Look, I know something’s wrong and now the test says, ‘Yeah, something’s wrong and this is where it started from.’”
DrMR: Yes, and I just want to echo that. Because that really struck me as quite the savings on both the poking and prodding to the patient and also expense to the healthcare system. Just like you said, those who have diarrhea will be subjected to many more evaluations. Whereas for someone with constipation, there tends to be maybe a laxative or two or three rendered, but there’s not the same, “Let’s check off these other potential boxes,” like inflammatory bowel disease and celiac.
Saving that time and expense to the patient is significant. So as a screening tool, I think this test has a lot of great merit. Just to clarify for people, if they do have constipation, I don’t believe the new version of the test offers any diagnostic utility there. But I just want to pose that question in case there’s something that I’ve missed.
DrMP: Yes, so we did publish a paper looking at the mixed IBS, diarrhea IBS, and constipation IBS as compared to healthy. There is a little higher percentage of patients who are constipated who have a positive test, but it’s nothing near what we see with diarrhea IBS. That’s the group (and mixed IBS) that benefits most from this test.
Going back to your cost comment, we’ve done a cost analysis and it literally saves $800 per patient who does this test as a first step. People were still getting colonoscopies, we weren’t getting to colonoscopy zero. If we did, it would save an extraordinary amount of money. We basically modified the pattern of practice slightly, by maybe fewer patients getting colonoscopies (because they’re 22, there’s no reason to do a colonoscopy, and the test is positive). Even that conservative approach saved a lot of money for healthcare and for the patient.
How to Order an IBS Blood Test
DrMR: Now, is there something a patient should say to their doctor? Let’s say their doctor hasn’t heard about this. And rightfully, many doctors are a bit circumspect with things that their patients are telling them. I tend to be open-minded, but I also look for some evidence. Some doctors are a bit more closed-minded. How would you recommend a patient bring this information to the attention of their doctor, so as to have the best probability of them running this test, rather than doing a colonoscopy or further IBD screening?
DrMP: Obviously the test just launched, so the awareness of the test takes time. It doesn’t happen overnight. I apologize to patients who are trying to get the test, they go to their doctor, and the doctor says, “I have no idea what you’re talking about.” I’m sorry that that will still happen for a while. It just takes time for doctors to find the time to educate themselves or for the literature or the papers that we’re writing to reach their offices. We’ve written manuscripts that demonstrate the essential component of these tests and how valuable they are. We’ve written the cost-analyses papers. They’ve already been published. All of this has been published, it’s just that doctors are very busy and they can’t read every paper that comes across the journals.
This kind of thing we’re doing here today educates physicians and patients. But if you want to know, you talk to your doctor, and there is a website to acquire the information as to where to get the test, how to obtain it. Generally speaking, the kit for the test can be mailed to the doctor’s office. The doctor draws the blood from the patient, sends it in to the laboratory, and we’ll get results in a handful of days.
DrMR: Okay. Is this also available direct-to-consumer?
DrMP: It’s currently not, because it’s a test that needs to be ordered by a clinician. So doctors order. Within the kit, the doctor has to sign the form and check the appropriate check boxes on it. Because if the patient does it direct-to-consumer then the patient may have to pay for the test. And the initial offering of the test is that the insurance is billed first, then if there’s any small balance the patient would then get billed for the remainder. The test is very reasonably-priced. This isn’t meant to gouge patients, as some new tests often do.
DrMR: Sure. Do you mind if I ask what the cost is, because I’m sure people are going to inquire?
DrMP: The total cost is $220 for the test. But the insurance is billed first, as I’ve mentioned. In a lot of instances, the insurance pays a significant share of that and then there might be a small balance for the patient.
DrMR: Yes, it’s absolutely reasonable. We’ve alluded to the best way to use this test. There’s the component that I think has fantastic applicability, which is as an early diagnostic screening tool to prevent unneeded additional follow-up testing, poking, and prodding.
There’s also a use to diagnose IBS, so that the patient knows what the underlying cause of their symptoms are. Do you have any further guidelines? I know clinicians are always trying to get the most mileage out of any marker. So some of the hypotheses, I think, that are out there I’m curious to hear your commentary on: predicting responsiveness to antibiotics, predicting responsiveness to prokinetics, potentially predicting relapse rate after antibiotic therapy.
Observations on IBS Blood Test Results
How do you see this fitting the clinical practice? If you could provide both what you feel to be the most conservative and then any inferences or thoughts you’re currently tinkering with in your clinical practice, I’d be curious to hear both sets of those.
DrMP: Our goal is to publish as much information as we can as it arrives. But I understand the drive for information even before publication. What we see in our clinic—and this isn’t top secret or anything—is basically the higher the anti-vinculin (we mean that auto-antibody) the more bloated and distended the patients appear to be in our clinic. It’s as if the autoimmunity is deeper, denser. And we know that the anti-vinculin antibodies bind to the nerves of the gut, impair the nerve function of the gut, and even perhaps reduce the number of nerve cells there (specifically the interstitial cells of Cajal, which are the special pacemaker cells of the small bowel).
We think that the higher the antibody, the worse the neuropathy, the worse the migrating motor complex, the denser, deeper the small intestinal overgrowth in IBS might be, and the harder it is to treat. That’s what we see in our clinic every day.
We like to see that the antibody is positive, giving us an indication. We don’t like it when the antibody is very high, because it means we’re going to have a tougher time with that individual case. The other part of the story is, if you have a positive test, irrespective of the levels, it means that when you get food poisoning, you are autoimmune-tending. Meaning, you tend to get these auto-antibodies, and they will go higher and higher with every food poisoning. We see this in some of our lab experiments that we do. And the higher it is, the sicker the patient gets.
One of the other benefits of knowing that you have these antibodies is, we can counsel you when you travel on what you eat. You’ll want to try to be more careful in your food choices and restaurant choices, because you don’t want to get food poisoning again. To the final part of your question—does it dictate what therapy you get—the higher antibodies, we think, predict a greater degree of bacterial overgrowth. But breath testing is a better predictor of what to give. Because the problem is, if you’re methane, you need two antibiotics, if you’re just hydrogen, you need one antibiotic. The tests, somebody said to me the other day, are sort of like doing an EKG and doing an ECHO of the heart. The EKG tells you part of the story, the ultrasound or ECHO of the heart tells you the function of the heart. You need the two tests together to really get a clear answer on what to do.
Anti-Vinculin Antibody Levels
DrMR: First, I want to take a step back and say, what are you considering high? Do you stratify this to a moderate elevation of antibodies to high antibodies? And if so, is there a specific number that you’re using to distinguish those two?
DrMP: It’s a little tricky, because what I should say is normal is less than 1.6 for both markers in this new version of the test. If the anti-vinculin is greater than 1.6, it’s abnormal. Generally, we start to see the really challenging patients if it’s over 3, as a result. Again, it depends on the size and physique of the person as to how high these levels are and what sort of implications they have. However, generally speaking, if you’re over 3 it’s more trouble for the patient unfortunately. But there’s hope. What we now know is, if we can get those antibodies out of the blood, we might be able to cure these patients for the first time. We know the culprit and knowing the culprit is half the battle. Now we need to figure out how to wipe these antibodies out of the blood so that we can make this all go away, and maybe you don’t need anything else.
DrMR: I’m assuming that’s a question you’re taking steps to answer currently?
DrMP: We are. It’s a complicated technique to do this, but we’re working on that every day in the lab.
DrMR: Great. And when people have this elevated marker, and they’re more at risk for food poisoning upon travel, are you recommending some prophylaxis like rifaximin? I’ve heard varying things in terms of how effective that is, but curious what you’re recommending there.
DrMP: We know that prophylaxis works, in patients who are at high-risk. I know that, for example, my colleagues who treat Crohn’s disease will recommend prophylaxis, because IBD can be flared by food poisoning too. Let me give you a story, because it’s a very nice story. It’s half nice, half not nice, maybe. I had a patient who had positive antibodies, had taken rifaximin for her IBS, had done phenomenal. She says, “I’m going to Costa Rica for a big trip, what do I do?” I said, “You’re going to take half a pill of rifaximin with each meal.” This is not an FDA-approved use of rifaximin, but this is what we do for our patients who travel to areas where we think food poisoning is at a higher rate.
She went to Costa Rica and they were touring the country in a bus. There were about 20 of them in her family reunion, I think. And 19 people on the bus were stopping every few miles because they had diarrhea, except for the IBS patient, who had perfectly normal bowel function.
DrMR: That’s great.
DrMP: The good part of that story is, the IBS patient was the healthiest person on the trip. And we see that time and again. I think that’s what we try to do, especially for these ones with high antibodies. Because we really don’t want them to get another case of food poisoning.
DrMR: I apologize if I missed this. I’m taking some notes here for our audience. Were you saying that the antibody score tends to predict a higher degree of positivity on the SIBO breath test?
DrMP: We’re studying that currently. Anecdotally, we see that they’re more likely to have SIBO with the higher antibodies. Again we’re studying this prospectively, and the test has only been out for a few months. But we’re seeing that pattern. We see that in our experiments in the lab, these are animal experiments. But here in clinic we have to study it over a long period of time to get enough patients.
That’s what the theme looks like. The higher the vinculin, the more the overgrowth, but also the more challenging the overgrowth is to treat, because the vinculin is what we think is creating the neuropathy. The more anti-vinculin, the more neuropathy that we think is happening. More neuropathy means tougher to treat, it becomes deeper motility disorder that maybe even a prokinetic won’t overcome. Again, all of this stuff is being studied over the next year or two to try and get more granularity around the comments I’m making and that we’re seeing anecdotally.
DrMR: If prokinetics didn’t have enough oomph, is there an escalation of therapy that you’re using in its place?
DrMP: Well, there are some patients who are tremendously distended, to the point where sometimes they’re in and out of the hospital, because we see extreme cases here as well. Some of those patients, nothing is working. Hopefully, this happens very infrequently. It’s infrequent in our clinic, but hopefully across the country this is a very infrequent finding. My point of describing these extreme examples is that we think these extreme cases are on a spectrum. In other words, the higher the antibody, the worse things are for the patient.
Benefits and Uses of the Low FODMAP Diet
DrMR: Does a low FODMAP diet have any influence, by the results of the test?
DrMP: That speaks to a couple angles on the question, and I get this a lot. If the antibodies are positive, and let’s say you take rifaximin and it works, the antibodies don’t change. Rifaximin doesn’t make the antibodies go down. It just makes the bacteria go down that are caused by the neuropathy that are caused by the antibodies. Same thing with a low FODMAP diet. The low FODMAP diet’s going to reduce the bacteria of the gut, making things a little less symptomatic for the patient. But the neuropathy remains, the risk for the overgrowth recurring remains, and maybe is predicted by the level of the antibody and how quickly the overgrowth might come back after treatment. Those are the kind of questions we’re trying to answer with this new research.
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We’ve had a gastroenterologist from Norway on the podcast, Tarek Mazzawi, and his group has published a few really fascinating papers where they’re showing the ability to increase serotonin and PYY cell densities in IBS patients after using a low FODMAP diet. Which begs the question, could a low FODMAP diet have the ability to—at least to some extent—resurrect or improve motility? Have you seen any of this? Do you have any comment on this potential therapeutic option?
DrMP: Well, I know what you’re talking about. There are always two ways to look at data. For example, there are bacteria in the gut that can produce serotonin themselves. There are bacteria in the gut that can produce insulin-like peptides. There are bacteria in the gut that can produce androgens and estrogens. So it’s as if the gut has almost the same capabilities in their collective as our own human metabolism, in some ways. If you go on a low FODMAP diet, and you shift the balances and the flora, can you shift, number one, the chemicals that they produce? The answer is yes. Can you affect the integrity of the lining of the gut? I think the answer there is also yes. There’s some data emerging that if you treat overgrowth, the gap junctions between cells go back to normal, so the gut becomes less “leaky”. It may be that bacterial overgrowth is responsible for part of that leakiness.
I think the answer to your question is, all of it is possible. The question is, is it what the bacteria are producing that are having this effect, or is it the diet itself? I think in the case of the low FODMAP diet, it’s the change in the flora that changes things in either a beneficial way or a harmful way depending upon the patient and circumstances.
DrMR: Are you thinking the reason why, when they look upon a histological sample, the cell density of serotonin cells goes up is because there are less serotonin-producing bacteria? So you’re seeing a tissue adaptation to maintain the same level of serotonin? Is that what you think is happening?
DrMP: We definitely know that can happen. For example, if you’re bathed in serotonin, you downregulate serotonin production. The question is, if you downregulate the bacteria that produce serotonin, will the human lining then respond by increasing serotonin production? I don’t think anybody’s studied that. I’ve never seen a paper on that, but those are all possible. And certainly in the drug world, if you give too much serotonin, you’ll downregulate endogenous, or your own, production of serotonin. So if the bacteria are doing the same thing, it should be the same phenomenon.
DrMR: Okay. So getting outside of the academic conjecture, a low FODMAP diet is still squarely an option on the table for people, perhaps irrespective of what it’s doing mechanistically.
DrMP: Yes, exactly. And I use the low FODMAP diet fairly routinely. It’s very effective in patients with IBS and SIBO because it’s restricting the calories. It’s just challenging in the reintroduction phase… how to bring foods back, that’s the difficult part of the low FODMAP diet.
DrMR: A question here while we’re on the low FODMAP. There’ve been, to my knowledge, two longer-term studies, I believe they were 18-month and 24-month roughly, and they didn’t show any long-term negative side effects in terms of quality of life or gastrointestinal symptoms.
I’m wondering how you feel about the use of a modified lower FODMAP diet in the longer term? When I say modified, the goal there would be to have the patient expand their diet to the broadest array of foods possible. But knowing some cases are more severe than others—the spectrum you alluded to earlier—some patients may have to adhere to a greater degree of FODMAP restriction in the longer term.
I’m assuming you would be okay with that, as long as someone’s trying to get to the broadest diet possible? Just wondering if you have any trepidation about using the diet like that in a longer-term approach.
DrMP: I have trepidation in the long-term use of the low FODMAP diet, more than three to six months, in the purest form of the low FODMAP diet. So I agree with you in reintroducing foods, to the best of the ability of the patient to find a good balance. It’s sort of the reason we developed a low-fermentation diet, which is a much less restrictive diet that focuses only on the most fermentable products. It’s not as well-publicized, it’s not as well-studied as a low FODMAP diet, so not as well-recognized or known. The goal of that diet was to say, “Okay, look, this has to be balanced, this has to be healthy in the long run. How do patients keep going?”
I appreciate the two papers that you cited, but there are two studies that contradict a little bit of what those studies showed. One is a study by Bill Chey, that looked at micronutrient measurements in the bloodstream of patients on a low FODMAP diet greater than three months. It appears the thresholds for starting to develop micronutrient deficiencies on pure low FODMAP is three months. The second is a study that showed that the diversity of the microbiome in stool—not in the small bowel, in stool—on the low FODMAP diet during an extended period of time goes down. And we all know that low diversity can lead to consequences. A lot of diseases like inflammatory bowel disease and all these other conditions are also associated with low diversity. I am not saying low FODMAP diet portends development of these other GI conditions, but in general, low diversity is considered an unhealthy microbiome. There are a couple of things that are suggesting you need to reintroduce.
But back to your point, if you can reintroduce enough foods that under guidance of a dietitian, there is the perception that there’s a balanced enough diet and that things aren’t going off the rails, I think it’s perfectly fine.
DrMR: I’ve felt that there’s a balance there. I’m very curious to get your thoughts on this… Let’s say—and I think it’s an arguable point that the low FODMAP diet is “bad” for the microbiota—for conversation’s sake that low FODMAP is bad if adhered to too strictly in the longer term. When we weigh that against the ability of the low FODMAP diet to lower inflammatory cytokines, and potentially even improve disease activity as in inflammatory bowel disease, I wonder what is leading to the best net effect for the patient? If they see a small decrease in diversity but they also have less disease activity in IBD, then I would look at that as an overall positive. Again, under the important caveat of the person trying to move to the broadest diet possible.
But are you weighing those pros/cons a little differently in your mind, or how do you look at those?
DrMP: I’m not. So in my clinic I have patients on a spectrum of diets. And in medicine, as you know, it’s a balance. You have to weigh two evils. You’re giving a drug to a patient with a disease. The drug has side effects. You weigh the side effects of the drug against the disease for which the patient’s suffering.
Obviously there are patients who suffer immensely and we weigh the consequences of low diversity of the stool (which we don’t know necessarily means any long-term consequences, besides the belief that low diversity is a bad thing). I think the patient will say, “Look, I’d rather be on the low FODMAP diet than not, given the fact that my life is absolutely miserable without it.” You weigh the pros and the cons in all situations.
I agree, and I’m not a purist about diversity. I think diversity is a little overrated in the microbiome world. I think if somebody’s having florid diarrhea from Crohn’s disease, they’re washing out all the microbiome from their disease, so diversity would be low. It doesn’t mean the low diversity is the cause of the disease, and that’s why I sort of said that earlier. I guess my answer is the same as your comment: if a patient needs it, they need it. That’s just the way it is.
DrMR: Yep, agreed. What about small intestinal fungal overgrowth? Have you looked at any of the prevalence data? People with the autoimmunity of their motility apparatus, I’m assuming, will be at higher risk for small intestinal fungal overgrowth, but have you looked at that at all?
DrMP: I’m just going to regress back to rifaximin a little bit. We’ve given rifaximin to a large number of patients over the years. Certainly, in the target three trial, it was given to 2,500 patients. We didn’t see any increase in yeast in the stool of those patients. Now, we didn’t do small bowel, but considering how many people respond to rifaximin versus yeast therapy, I think yeast is a minor player. I know that Dr. Satish Rao in Georgia has done a lot of really amazing work looking at yeast and the possibility of SIFO (small intestinal fungal overgrowth) in a subset. I do believe there is a subset like that. It’s just challenging to find labs that will measure yeast in the way that you need to do it.
Mapping the Microbiome of the Small Intestine
What I can tell you is that we’re in the middle of a trial called the Reimagine Trial. I can’t give you results of that, but there are going to be a whole lot of presentations at the DDW, which is the big GI meeting coming up in May. We’ve got a lot of things accepted from that trial. We’re looking at all the microbiome of the small bowel for the first time, top to bottom, so this will be the first cut of those data. We’re planning to get about 10,000 patients in that trial, to look for the association between yeast, bacteria, archaea, and human disease. We think stool has been interesting, but really hasn’t found any smoking guns. And we’re already finding smoking guns in the small bowel, so we’re really excited about that project.
DrMR: Are you using some kind of small capsule to assess that, or are you doing direct sampling? How are you assessing?
DrMP: We’re doing direct sampling, because we want to get a biopsy as well, to look at mucosally-associated bacteria. We want to look at cytokine-signaling in the tissue, serotonin, blood, genetics, and of course, the human phenotype in each instance, whether they have neurological disease or diabetes or obesity. We’re assessing all those factors. We’re really excited about what we already found, what we’ll be presenting in May, and what’s to come.
DrMR: Oh, that’s fantastic. I can’t wait to read the summary.
DrMP: Yes. Some of it’s going to be press-released because they’re such dramatic findings, but I have to bite my tongue on that one for now.
DrMR: I’m sure it’s hard to do, but I understand why you’re doing it!
Probiotics Acceptance (or Lack Thereof) by Doctors
And one question I’ve been wanting to ask you for a while is regarding probiotics. Sometimes I’m at a bit of a loss, because I see most gastroenterologists don’t seem to be too keen on the use of probiotics. But when I look at the evidence, I know there’s been more than one meta-analysis in the treatment of IBS, and even a meta-analysis going as far as using Rome III as diagnostic criteria, looking at 21 RCTs, and showing a favorable impact in IBS patients with probiotics.
I know looking at number-needed-to-treat comparisons across different therapies isn’t necessarily an apples-to-apples comparison. But at last check, the NNT for probiotics was eight to nine and rifaximin was 11 (we can double-check that while we’re on the line here). But essentially, the number needed to treat for probiotics was lower than that of rifaximin, plus we have at least 20ish RCTs. Why do you think that probiotics haven’t been more widely accepted? And do you think that there’s no evidence there? Or is it another issue of, maybe there’s not one probiotic that’s showing this effect, so people are a bit tenuous for that reason?
DrMP: Wow, that’s a loaded question. Only because there’s so many facets to answer that question. The number needed to treat for tricyclic antidepressants for IBS is even lower than eight. But if you take all nine double-blind, randomized control trials for tricyclics, two out of the nine were statistically significant. In other words, seven trials failed, two succeeded, and the largest trial failed. The largest trial failed by a long shot. In total, of all the nine double-blind trials, 120 patients on drug, 120 patients on placebo, less than 300 total patients in the trials.
To do one FDA-approved trial for alosetron or rifaximin, you’re talking between 300 and 600 patients per arm, to conclusively use the really challenging FDA endpoint. That hasn’t been done with any other products, except for the ones that are FDA-approved.
There’s a study that we presented last year at DDW, looking at this. There’s a metric of how well a drug works. It’s not meta-analysis, because positive trials get published, negative trials do not. There’s a tendency towards journals publishing trials where a drug works and rejecting trials where a drug doesn’t work… that’s called publication bias. The way you get around that and figure this out is, you take trials. Let’s say you want to look at peppermint for IBS. And we showed this in the study… there were a number of trials, and the larger the trial, the lower the P-value for peppermint. That means that the more you get to a trial that is like the FDA, the more you get to the true result, which is that the P-value doesn’t hold weight.
The smaller the trial, the bigger the P-value, the better the P-value. That means that it’s more statistically significant. Should be the opposite. It should be the more people you put in a trial, the stronger the statistics get. If it’s getting weaker, it means that it was publication bias. And this is a problem with probiotic trials is the larger the trial, the less effective we’re seeing the probiotics and that goes to the PLACIDE study. The PLACIDE study was a 3,000 patient trial looking at probiotics. It wasn’t for IBS. It was looking at it for prevention of antibiotic-associated diarrhea, and the only thing the probiotic gave that was statistically greater than placebo was bloating. People on probiotics got more bloated.
That was one probiotic. People will argue, “Well, but you didn’t try this probiotic. You didn’t try that probiotic.” The problem is, there isn’t enough data on every single probiotic in your grocery store or in your nutrition centers. I’m not knocking probiotics. There could be a probiotic that’s brilliant, but the trials just aren’t strong enough, aren’t large enough yet. I wish they were. I wish I could hang my hat on one of them.
DrMR: You think we have a number of small RCTs, and we haven’t really seen the power yet—with the sample size—to make the probiotic therapy you’re one comfortable getting behind, essentially?
DrMP: Yeah, because what they’re doing with the meta-analyses that you mentioned was they’re taking 10 different probiotics and saying they’re all equal and stacking them up with each other. It’s like me saying, “Well, drugs work for IBS,” and you combine tricyclics, alosetron, and rifaximin all in one meta-analysis and say, “Allopathic drugs work for IBS.” It’s the same thing with probiotics, you’re adding the Bifido to the Lactobacillus trials, to the VSL trials, to the Saccharomyces trials and you’re saying they’re all equivalent probiotics. By doing that, you get a P-value that says probiotics work. You can’t compare apples and oranges in one meta-analysis, it doesn’t quite make sense. Those are the things that I’m trying to clarify.
DrMR: Gotcha, okay. And this is kind of a nerdy question, pardon it. When there is adequate homogeneity between the trials—and enough to where they can be fused together in the meta-analysis—you still feel that if the probiotics are of different strains, it detracts from the strength of what’s been seen in a given meta-analysis?
DrMP: What I’m hoping for, and again I’m not anti-probiotic, that isn’t the point of my arguments. I would be thrilled to see more probiotic trials, because I’d love to know which one is the ideal probiotic. I do have patients come to my clinic and swear by a probiotic they’re on. And I say, “Well, I can’t get you better than that, that’s amazing. I’m glad for you, but one probiotic may not fit all.” I think even the probiotic companies would agree with that. There is no one fit. I wish we had more data, to be able to get those answers of what shoe fits on what person. Maybe our trial, where we’re looking at the small bowel microbiome—and figuring out all the uniqueness of that individual and what’s missing—may help answer that question. Which probiotic would be best for you because of your profile?
DrMR: I’m hoping eventually we’re going to get there. I think that’ll be a fantastic day, when we can do some sort of assessment and say, “This will be the best probiotic for you,” with a strong margin of confidence.
Different Categories of Probiotics
One final question on probiotics. What I’ve been doing in the clinic is essentially using three different types of probiotics that break down into what some of the research papers are calling the three different categories of probiotics. What I like about the category system is, it somewhat simplifies the landscape to like probiotics being able to be grouped together. So if there are different formulas that all have this like formula, or constitution, you can classify them as either a category one, two, or three.
The way some of the researchers have broken this down is, you have your Lactobacillus-Bifidobacterium predominated strains, that’s category one. Category two would be a Saccharomyces Boulardii. Then category three would be your soil-based probiotics, your Bacillus licheniformis, Bacillus coagulans, what have you. Have you seen any of this? Do you have any thoughts on if maybe we can start to partition these probiotics into different groups, and then say, “Okay, you’ve done bad on VSL-3, so that likely means you’re not going to do good on a Lacto-Bifido blend probiotic of any stripe, but perhaps a trial on Saccharomyces Boulardii would be a good idea”?
DrMP: Yeah, I mean, that’s the kind of thinking we need with probiotics, tailoring it in a way that fits the individual, sort of like what I was saying. I don’t disagree with that approach. If I can tease you with just one aspect of the small bowel microbiome that we’ve revealed in the last year: there are almost no bacteroides in the small bowel. I mean, bacteroides is not there. So there are things that don’t belong in the small bowel.
I’ll be curious, as we start to unfold all this data, as to whether probiotics companies may think it may be more beneficial for the capsule to release in the colon, where some of these bacteria do belong and need to be balanced out, versus other bacteria that maybe are more preferably released in the small bowel, because that’s what the balance looks like there. The small bowel looks completely different from the stool. So you shouldn’t have Lactobacillus up and down the entire bowel, for example. There are specific things about the small bowel, where it doesn’t belong there.
I hear you and I agree with you. I think the biggest difficulty we’ve had is, the final frontier of the microbiome is the small intestine, nobody’s looked at it until now. Once we unravel that, I think these probiotic cocktails will be tailored according to that. I’m very optimistic about that.
DrMR: Yes, agreed. I think the small intestine has not been given nearly the attention that it needs. And if you consider its anatomical relevance—being the longest portion, the most ostensibly immunoactive because it has the thinnest, most permeable, most leaky-gut-prone membrane—then it’s like we know the least about the most important section of the intestinal tract.
DrMP: You said it better than I did, that’s exactly the way I feel. That’s exactly the way I feel. It’s amazing, that one section. If you’re obese, you’re obese because of the small bowel, you’re not obese because of the colon, because you hardly absorb any nutrients from there. That’s just one example of the importance of the small bowel and the microbiome there, and nobody ever looked.
DrMR: Yes, totally agreed. Thank you for being one of the people who pointed that out to me earlier in my career through some of your work. As I started pulling on that string, I started saying, “Gosh, so much of what we do is colon-centric, yet the small intestine looks to be a lot more important.” As I started shifting my clinical practice to use interventions that, at least we think are more reparative or balancing to the small intestine, that was when I really started seeing better results.
Just a quick aside on this, there was this huge boom in the interest of the microbiota starting from maybe 10ish years ago. But really it felt to me like five years ago was when this whole “fiber, fiber, fiber, feed your gut bacteria” was really coming into full swing. Yet I was seeing so many patients where, when we tried to do that, it would just decimate their gut. That’s the observation I pieced together, which is, “Well, that observation is probably good for improving someone’s colonic health, but at the same time they’re probably not really doing favors for their small intestinal health.” Then we look at the outcome of the individual, which is quite a marked regression in symptoms. It would logically suggest that we need to be more attentive to the SI.
DrMP: I agree. Probably gave the same speech to a patient this morning in my clinic. All the years of fiber, and what have we gotten today? We’re doing colon cancer screening now at 45 years old instead of 50 years old. It’s more complicated, because we don’t know what we don’t know yet.
DrMR: Right. Well, to shut this off on the probiotics, and thank you for your indulgence there…
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Hydrogen sulfide: I believe you’re getting ready to hopefully release a test on it. At least that’s what I’ve heard through the grapevine. I’m curious if there’s anything you can discuss there?
Hydrogen Sulfide Test in Development
DrMP: Well, IBS smart, the blood test, is an exciting development. But another exciting development is hydrogen sulfide. We really hope that before this half year is up, there’ll be an offering of being able to get the hydrogen sulfide. Because hydrogen sulfide is the final gas; there’s no other gas that bacteria produce that can be measured. It’s the missing piece in terms of diarrhea, because we could never correlate hydrogen. You could have a hydrogen of 100 or a hydrogen of 50 and you wouldn’t have necessarily more diarrhea at 100. What we now know is methane correlates with constipation and hydrogen sulfide correlates with diarrhea. Hydrogen is purely the fuel for one or the other. If methane’s the winner, you’re constipated, if hydrogen sulfide is the winner, you have diarrhea. There’s really a balance of gases that dictate the phenotype of the patient.
The next question people ask me is, does it mean that you’ll respond better to this drug or that drug? The test isn’t even out yet, so we don’t have enough data to say, this is going to predict whether you should be on these antibiotics. For methane, we know you need the double antibiotic. But for hydrogen sulfide, we’re just beginning. It’s exciting and we look forward to being able to offer that later this year.
DrMR: Yes, same here. Will you tell people again about the test, where providers can go to get kits, and any other logistics of getting started for clinicians who want to start offering this in their clinics?
DrMP: Well, for the blood test, because the breath test isn’t out yet–
DrMR: I’m sorry, for the autoimmunity blood test.
DrMP: Yes, IBSsmart.com is where you can get the blood test. Interestingly, the site is designed so that patients can ask questions if you want. Not meant to provide medical advice. But if you want to know if your doctor offers it, I think the company does a little homework for the patient if they’re in an area that’s a little off the path. Or they’ll be able to provide the nearest location. Physicians can order the kits right there on the web page, and they’ll be delivered to the physician for their patients.
DrMR: Awesome. And the insurance coverage has been pretty good, I take it, from what you said earlier?
DrMP: Now they have a contract with Medicare so that’s a good sign, because you can’t get anything paid without that. And it looks very good so far. Think about it… if I was an insurance company, insurance companies know this formula: the sooner you get a diagnosis for any disease, the less money it costs. The last thing the insurance company wants is two colonoscopies instead of a blood test that costs $220. I think the last thing a patient wants is the same answer.
DrMR: Right, and that’s why I love the cost-analysis that you publish. Unfortunately a lot of this is just cost-dependent, so if we can display a cost savings to an insurance company, that seems like a great way to facilitate new therapies or tests being accepted and covered. Of course, that allows more doctors to be able to sanction this in their offices. I think it’s challenging to convince a patient to do a test that they don’t have insurance coverage for, so that was a smart study for you to have done and I’m really glad that you did it.
DrMP: Yes. The whole goal is to help patients. This isn’t about anything else but making sure patients get the right answer, that they feel empowered, and not to gouge.
DrMR: Yes, well said. Any closing thoughts that you want to leave people with?
DrMP: No, I was just very glad to have done this podcast with you. I think you’re doing amazing work by allowing people like me to talk about these important concepts. Look, there’s one billion people in the world with IBS. This is not a small disease, this is a super important disease. It deserves the respect that it hasn’t gotten and just happy to be a part of that story.
DrMR: Well, Mark, thank you again for being on the show and also just the fantastic research that you’re doing. You truly are one of the pioneers in IBS and SIBO. So again a very hearty thank you for the work that you’re doing and the massive contributions you’ve made to the field.
DrMP: I appreciate that. Thank you again.
What do you think? I would like to hear your thoughts or experience with this.
Dr. Ruscio is your leading functional and integrative doctor specializing in gut related disorders such as SIBO, leaky gut, Celiac, IBS and in thyroid disorders such as hypothyroid and hyperthyroid. For more information on how to become a patient, please contact our office. Serving the San Francisco bay area and distance patients via phone and Skype.