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New Developments in IBS and SIBO with Dr. Mark Pimentel: Rational Wellness Podcast 159

Dr. Mark Pimentel speaks with Dr. Ben Weitz and the Functional Medicine Discussion Group meeting about New Developments in IBS and SIBO.

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Podcast Highlights

9:15  The story about SIBO and IBS is similar to the story about peptic ulcers and H. pylori.  We’ve known about peptic ulcers since the 1980s and then they discovered that H. pylori is the cause of 60-70% of cases of peptic ulcers. We didn’t change the name to H. pylori disease. About 60-70% of IBS is caused by SIBO, but just like there are a bunch of people with H. pylori that don’t have ulcers, there are a bunch of patients with SIBO that don’t have IBS.  There could be narcotics or adhesions as the cause or something else.

10:49  Dr. Pimentel discovered that many cases of SIBO have an autoimmune origin. It starts with a bout of food poisoning related to a bacteria like E. Coli, salmonella, shigella or campylobacter. These bacteria can all secrete Cytolethal Distending Toxin, which can create a response from the immune system, creating antibodies. Those antibodies can cross react with a similar structural protein in the intestinal wall called vinculin and this can damage the ability of the nerves to control the Migrating Motor Complex, which produces cleansing waves that help keep the intestines clear of too much bacteria.  Thus by damaging this normal motility, there is an increased likelihood of bacterial overgrowth of the small intestines.  Dr. Pimentel has also developed a blood test to measure these anti-CDT and anti-vinculin antibodies, the IBS Smart Test. The higher the anti-vinculin antibodies, the more difficult the patient is to treat.

17:15  This cross-reactivity of anti-CDT and anti-vinculin antibodies proves that this model of cross reactivity of antibodies can lead to autoimmunity and in the Functional Medicine world we use this concept of immune cross reactivity to explain how reactions to gluten or dairy or to toxins or to infections can result in autoimmunity. Dr. Pimentel remarked that when he was conducting his Reimagine Study, where he and his colleagues mapped the microbiome of the small intestine, he was surprised that they found that patients who went gluten free but did not have celiac disease, tended to have lower cytokines in their blood and that they were less inflammatory.

20:05  In a recent paper, the ACG Clinical Guidelines for SIBO, you list 6 factors that are important for helping to maintain small bowel ecology and for preventing SIBO.  You talk about 1. hydrochloric acid, 2. digestive enzymes, 3. bile, 4. motility, 5. the ileocecal valve, and 6. the gut immune system.  Yes, acid kills bacteria, but acid blocking medications like PPI use is not necessarily associated with SIBO and Dr. Pimentel’s group did not find really significant changes in the microbiome in patients who took PPIs.  If you have IBS and you’re on a PPI, we didn’t see more SIBO. But if you’re a healthy individual with no GI symptoms, just GERD, and you’re taking a PPI, there is higher risk of getting SIBO.  But because methane organisms eat hydrogen, and because hydrochloric acid contains hydrogen, patients on PPIs had less methane SIBO.  Dr. Pimentel has found that GI motility is the most important factor in preventing SIBO.  The Migrating Motor Complex (MMC) refers to waves of peristaltic contractions that occur when you haven’t eaten for several hours and these help keep the intestine clear of too much bacteria. It is like a dishwasher. This MMC is what gets inhibited by vinculin antibodies or by opiate medications. There are drugs that stimulate this motility, like Prucalopride, Tegaserod or Zelnorm, and even erythromycin low dose can do it.

24:53  When intestinal motility is impaired you can have diarrhea rather than constipation. You would think that without peristalsis, without motility, you would have constipation.  But you can actually have diarrhea, since without the squeezing of the peristaltic activity actively slowing things down, the intestinal contents would just pour through. This is the case with scleroderma, where the bowel becomes thicker and the contents just pour through like water going through your plumbing pipes, since there is nothing holding it back. 

26:08  The Migrating Motor Complex controls the cleaning waves and this is separate from the peristaltic activity that happens when you eat food.  The eating mode is grind three times, four times, then stop and wait, let the food absorb, and then grind a little more, and then let the food absorb. Then keep doing that over and over again. The small bowel moves the food forwards and backwards and forwards and backwards getting it all mixed with enzymes and bile, like it’s mixing it up. Each section of the digestive tract–stomach, small bowel, colon–each section moves differently at a different time and each has separate neural control.  The only time they all come together is during the cleaning wave. The cleaning wave starts at the top of the digestive tract and marches down, squeezing things through in a very straight top to bottom way to strip everything out. Patients who are taking a Proton Pump Inhibitor (PPI). like Prilosec, which are acid reducing medications, the bowel thinks you don’t have as much food in the stomach and it goes to cleaning waves prematurely or sooner than you should.  Because when you eat, you’ve got a lot of acid and all that acid prevents the switch from switching from eating mode to cleaning mode. But when you’re on a PPI, you don’t have that signal. You switch to cleaning mode earlier and you actually get more MMCs or cleaning waves, which may reduce the likelihood of SIBO. There are patients who have neuropathies where they switch to cleaning wave mode when their stomach is full of food, which is not good. People think it happens because they get what’s called a gastrocolic reflex where they eat and then they’re running into the bathroom. But that’s not that meal.  But there are also people who never switch to cleaning mode and then that’s a problem because they never clean.

29:26  The Vagus Nerve. There are a number of prominent practitioners in the Functional Medicine world who talk about the importance of stimulating the vagal nerve to help patients with SIBO by stimulating motility.  The vagus nerve is the electricity coming into the house, but the problem is the wiring that goes to the light sockets and having more electricity going to your house will not fix the wires and not all the lights will turn on. Using a prokinetic is also a way to turn up the energy, so that the lights that are working can be brighter, but the only way to get the other lights working, to fix the motility, is to get rid of the vinculin antibodies.

30:57  Dr. Pimentel and his group have mapped out the microbiome of the small intestine for the first time with his REIMAGINE Study.  The Human Microbiome Project was published in Nature in 2007, but this only mapped out the microbiome of the colon.  But the microbiome of the small intestine is completely different from the colon. The density of microbes in the small intestine is much smaller than the colon, but the small intestine has a much larger surface area, so there are probably more total microbes than there are in the colon.  Unfortunately, the Human Microbiome Project has not yielded one bug, one disease, but Dr. Pimentel’s research looks like it will be discovering a number of one bug, one disease associations in the small bowel, which is very exciting.

33:57  Dr. Pimentel used to think that the bacteria that cause SIBO overgrew up from the colon, but now we know that they are likely already in the small intestine and have overgrown since the cleaning wave is not working. It’s basically E. Coli and Klebsiella and possibly Aeromonas. These are the bacteria that cause many cases of hydrogen SIBO.

35:28  While Dr. Pimentel used to think that there potentially was a different variant of SIBO in different portions of the small intestine, regional forms of SIBO, such as duodenal SIBO and jejunal SIBO.  But his study did not really find that there was much of a difference in the bacterial content as you get closer to the colon, as had been theorized, so there does not appear to be regional SIBO.

37:00  Dr. Pimentel and his group have now reclassified methane SIBO as IMO, which stand for Intestinal Methanogen Overgrowth, since it is caused by methanogens, which are not bacteria, and they are not necessarily overgrown only in the small intestine, but also in the colon.  Dr. Pimentel has been studying the beneficial effects of a non-absorbable form of Lovastatin that reduces methane production. 

38:52  The consensus by experts for the cutoff level for a positive for methane on a lactulose SIBO breath test is 10 and while Dr. Pimentel used to prefer a level of 3, he now feels that 10 is probably a better marker.

40:50  Methane SIBO is often more difficult to treat than hydrogen SIBO and Dr. Pimentel pointed out that this may be because the methanogens that cause it tend to be closer to the surface of the mucosa and drugs like rifaximin may not penetrate as well there. This is why Dr. Pimentel is working on possibly using a version of Lovastatin.  Dr. Sam Rahbar of LA Integrative Gastroenterology and Nutrition has noticed that methane SIBO may also have a coexistence of fungal overgrowth and he has pointed out that this may be one of the reasons that Lovastatin helps, since it appears to have antifungal properties as well.  I suggested that perhaps certain nutritional agents that are known to break up biofilms like bismuth and NAC, which is also a mucolytic agent (breaks up mucus) might be helpful, but Dr. Pimentel feels that there is not enough scientific evidence to know if these might work.  Dr. Pimentel also noted that the organisms that cause hydrogen SIBO, E. Coli and Klebsiella also tend to live in this mucosal layer. And this is one of the reasons that the work that Dr. Pimentel and his group did to sample the bacteria in the small intestine was so difficult. 

44:30  Hydrogen Sulfide SIBO. We think that hydrogen sulfide is causing diarrhea in SIBO patients. Methane causes constipation, hydrogen sulfide causes diarrhea, and hydrogen is just the fuel source for either direction.  Dr. Pimentel usually uses antibiotics to kill the bugs that cause SIBO, but he tries to use as few antibiotics as possible. He uses Rifaximin for hydrogen SIBO and Rifaxmin and Neomycin for methane SIBO and he’s not sure what to do for hydrogen sulfide. He is hopeful to have a new breath test out that will enable us to diagnose hydrogen sulfide SIBO.  He is hopeful that the data on Lovastatin will pan out and they can use that for methane SIBO.  If they don’t respond, they may use natural products like peppermint and berberine and allicin.  If they are positive on IBS Smart test for vinculin antibodies, then he will give a prokinetic.  Once they get rid of the SIBO, they place patients on a specialized diet like low FODMAP, but he prefers the low fermentation diet, because you will have a better quality of life.  He’s not sure if a low sulfur diet might be helpful for hydrogen sulfide SIBO.  He prefers not to use a low fiber diet until after the antibiotics treatment, since if you starve the bacteria, the antibiotics may not work as well.

48:30  Dr. Allison Siebecker and Dr. Steven Sanford-Lewis, two of the top integrative doctors who are experts on SIBO, both treat SIBO successfully by using Rifaxmin or natural antimicrobials and a low FODMAP diet simultaneously and they find that using both simultaneously is more effective. Dr. Pimentel will typicall treat with antiboitics first and then add in the low fermentation diet and often a prokinetic, and Prucalopride or Motegrity is his favorite one to use, though he may use low dose erythromycin because of the lower cost.

56:36  Lovastatin that’s on the market now is designed to be absorbed into your blood to reduce cholesterol. In order for Lovastatin to have the desired effect in the gut for methane SIBO, it will have to be non-absorbed into the bloodstream and slowly released in the gut, so Dr. Pimentel is developing a novel form of the drug, which is not yet available on the market.

59:07  Some patients with SIBO get brain fog and neurological symptoms. This could be caused by D-lactic acidosis, which Dr. Satish Rao has published on. Methane is a gas similar to halothane and isoflurane, which are gases used in the operating room to induce sleep. Methane is also associated with higher blood sugar and higher cholesterol, so methane is clearly a bad actor.

1:00:20  Dr. Felice Gersh, a gynecologist and women health expert in Irvine, California asked since a lot of cases of IBS and SIBO occur in women, how estrogen affects their enteric nervous system and their microbiome?  If you are a woman and you get food poisoning, you are almost twice as likely to get IBS as men. Women have more autoimmune disease. Dr. Pimentel explained that estrogens are growth factors for some bacteria but he does not have the answer yet as to how estrogen impacts the microbiome.

1:04:30  There is a study that shows that spore based probiotics containing bacillis strains performed better than either Rifaximin followed by conventional probiotics or Rifaximin followed by a low FODMAP diet. (Catinean A, Neag AM, Nita A, Buzea M, Buzoianu AD. Bacillus spp. Spores-A Promising Treatment Option for Patients with Irritable Bowel Syndrome. Nutrients. 2019;11(9):1968.)  Dr. Pimentel is excited about the potential for probiotics to be helpful, but most of the probiotic studies are small and we really need a large, well designed trial, like with 500 patients, to really answer this question.

1:06:18  If you have a patient with both SIBO and H. pylori infection, Dr. Pimentel would treat the H. pylori first, since it requires a larger trial of antibiotics and you might wipe out both infections, so you should repeat the breath test after the treatment for H. pylori to see if the SIBO is also gone. Dr. Pimentel is also exploring whether there could be parasites that are stimulating this autoimmune response in the small bowel that leads to SIBO and he pointed out that Giardia has vinculin in it and he is exploring whether that could that trigger vinculin antibodies.

1:10:48  SIBO could affect B vitamin status. You can get an elevation of folate with SIBO, since folate is produced by gut bacteria. You do sometimes see a vitamin B12 deficiency in SIBO.

 

 


 

Here are links to some recent important papers by Dr. Pimentel:

1.Pimentel M, Saad RJ, Long MD, Rao SSC.  ACG Clinical Guideline: Small Intestinal Bacterial Overgrowth. Am J Gastroenterol. 2020; 115(2):165-178.  (This is the paper where methane SIBO is recategorized as IMO.)

2. Leite GGS, Weitsman S, Parodi G, et al. Mapping the Segmental Microbiomes in the Human Small Bowel in Comparison With Stool: A REIMAGINE Study. Digestive Diseases and Sciences (2020) 

3. Pimentel M, Lembo A.  Microbiome and Its Role in Irritable Bowel Syndrome. Dig Dis Sci. 2020;65:829-839.

4. Morales W, Rezaie A, Barlow G, Pimentel. Second-Generation Biomarker Testing for Irritable Bowel Syndrome Using Plasma Anti-CdtB and Anti-Vinculin Levels. Dig Dis Sci. 2019;64(11):3115-3121.

 

 



Dr. Mark Pimentel is a Gastroenterologist who is head of the Pimentel Laboratory and Executive Director of the Medically Associated Science and Technology (MAST) program at Cedars-Sinai, which is focused on the development of drugs, diagnostic tests, and devices related to condition of the microbiome, with a focus on IBS. Dr. Pimentel has published over 100 scientific papers and he speaks around the world at conferences, esp. about SIBO and IBS. Here is a list of some of Dr. Pimentel’s key publications: https://www.cedars-sinai.edu/Research/Research-Labs/Pimentel-Lab/Publications.aspx

Dr. Ben Weitz is available for nutrition consultations, including remote consults via video or phone, specializing in Functional Gastrointestinal Disorders like IBS/SIBO and Reflux and also specializing in Cardiometabolic Risk Factors like elevated lipids, high blood sugar, and high blood pressure and also weight loss, as well as sports chiropractic work by calling his Santa Monica office 310-395-3111 or go to www.drweitz.com. Phone or video consulting with Dr. Weitz is available.



 

Podcast Transcript

Dr. Weitz:                            Hey, this is Dr. Ben Weitz, host of The Rational Wellness Podcast. I talk to the leading health and nutrition experts and researchers in the field to bring you the latest and cutting edge health information. Subscribe to The Rational Wellness Podcast for weekly updates. To learn more, check out my website, drweitz.com. Thanks for joining me and let’s jump into the podcast.

Okay. Welcome everybody. Our topic for tonight is small intestinal bacterial overgrowth and irritable bowel syndrome. Our special guest at our Functional Medicine Discussion Group meeting tonight is Dr. Mark Pimentel. I’m Dr. Ben Weitz and I’ll start by making some introductory remarks. Due to such a large crowd, I’ll ask everybody to type in your questions and then I’ll try to call on you or I’ll ask Dr. Pimentel the question when it’s appropriate for the discussion. Let’s see. Unfortunately, I guess I have to keep manually admitting everybody as we go. If you’re not aware, we have a closed Facebook Page, the Functional Medicine Discussion Group of Santa Monica.  If you’re not on there, you should join so we can continue the conversation when this evening’s over. I’ll be recording this event and I’ll post it on my YouTube page and I’ll include it in my weekly Rational Wellness Podcast. If you haven’t listened, please check out my Rational Wellness Podcast and subscribe to it. It’s on Apple Podcasts and all the places you can get podcasts, Spotify, et cetera. If you do like listening to it, I’d appreciate if you give me a ratings and review on Apple Podcasts. We have many excellent interviews with many of the top doctors in the Functional Medicine world. We just posted a discussion of testing for COVID-19 with Dr. David Brady.

Tonight, Metagenics will be our sponsor. I’d like to tell you about a few products that they have that are awesome for gut health. CandiBactin-AR, which contains oregano and thyme oils along with sage leaf extract and lemon balm, and CandiBactin-BR, which contains a number of herbal sources of berberine, along with some Chinese herbs. This combo is really awesome for SIBO and many other forms of gut dysbiosis.  It’s been used in a study at Johns Hopkins by Gerald Mullins to be equally as effective as rifaximin, which is the gold standard antibiotic treatment for SIBO. Also, I wanted to tell you about one of Metagenics line of quality probiotics, UltraFlora Integrity. This contains Lactobacillus salivarius UCC118, which has been shown to support tight junctions and reduce intestinal permeability. In other words, it reduces leaky gut. In addition, a study was conducted at Cleveland Clinic that found that this particular strain of probiotic used daily for 90 days was effective in reducing symptoms of SIBO. Anyone who would like additional information or would like to set up an account with Metagenics please call or text our local representative Kaylee Ogaard at (310) 321-8785.

                                                Dr. Mark Pimentel is the head the Pimentel Lab and Executive Director of the Medically Associated Science and Technology program at Cedars-Sinai. He’s a very prolific researcher having published over 120 scientific papers. The Pimentel Lab research is irritable bowel syndrome, the microbiome, and many other gastrointestinal conditions. Irritable bowel syndrome affects 10 to 15% of people in the United States. For many years, prior to Dr. Pimentel’s research, IBS was thought to be a diagnosis of exclusion. Once inflammatory bowel disorders, celiac disease, parasites, and all the other causes of gastrointestinal disorders were ruled out, you were sometimes left with a diagnosis of IBS. Generally, there was not an organic reason for this condition. Dr. Pimentel has many accomplishments. He’s the first researcher to demonstrate that small intestinal bacterial overgrowth is the cause of IBS in a majority of cases and that SIBO could be diagnosed with a lactulose breath test. Dr. Pimentel also pioneered the use of rifaximin, a nonabsorbed antibiotic as a treatment for IBS, especially for IBS with diarrhea.   He’s developed an autoimmune model of IBS being caused by an episode of acute gastroenteritis, which most of us called food poisoning. He’s developed a blood test looking at antibodies to vinculin and cytolethal distending toxin to diagnosis this autoimmune cause of IBS. Dr. Pimentel has discovered that the methane producing organism Methanobrevibacter smithii causes constipation and that lovastatin can inhibit this methane production. Dr. Pimentel and his colleagues have recently renamed the methane version of SIBO as IMO, which stands for Intestinal Methanogen Overgrowth. Most recently with his Reimagine Study, Dr. Pimentel for the first time ever has mapped out the microbiome of the small intestine, a monumental achievement. Dr. Pimentel has really spurred the development of an entire SIBO community complete with SIBO testing, SIBO drugs, SIBO supplements, SIBO podcasts, and SIBO conferences. I hope one day we’ll be able to go to conferences again. But until then, we’ll have to do Zoom conferences like we’re doing now. Most importantly, Dr. Pimentel has given hope to millions of patients with IBS that they might finally be able to feel better and stay better. Thank you, Dr. Pimentel for joining us tonight.

Dr. Pimentel:                     Well, thank you, Ben. It’s a pleasure to be here and thanks for such a broad introduction. I really appreciate it.

Dr. Weitz:                          Before we get started with the discussion of SIBO and IBS, Allison Siebecker called me and asked me to ask you a question, which I’ll ask you in a little bit. I told her I was happy to finally be discussing something other than COVID-19 because I’ve been doing all these podcasts about COVID-19. She told me about your project to use UV light inside the body to kill the virus. I said, “I can’t believe that. I just saw president Trump talking about light inside the body to kill the virus.” You have to tell us about this project. Are you looking to replace Dr. Fauci? I’m just kidding.

Dr. Pimentel:                     Replace Dr. Fauci although he’s disappeared.  We had been working for about three or four years. Dr. Rezaie sort of came up with this notion of using light, Ultraviolet A light, to treat infections. We did a broad array of experiments. Some of this is public information because we presented at the European meeting of gastroenterology that a particular wavelength of light for 20 minutes to 40 minutes will kill most pathogens. Because our research was paused by COVID, one of the applications was to put it in the endotracheal tube to prevent a pneumonia from endotracheal tubes. Then we began to test it on coronavirus. That’s all I can tell you right now, but yes, we’re very interested in what we could do to maybe help save lives. Again, that’s all I can say for the moment, but stay tuned because we’re publishing the work that expresses or goes beyond that abstract at the European meeting. Yeah, just trying something different for the moment because we’re closed otherwise.

Dr. Weitz:                          Yeah. My understanding is, is that this is potentially something that might in the future be able to help with SIBO as well.

Dr. Pimentel:                     It could. We’re looking at ways to apply it internally. One of the bugs that we tested and was presented at the European meeting was C. diff is very susceptible to this light. Stay tuned, we’ve got a lot of things coming from that technology. Very exciting.

Dr. Weitz:                          Yeah, that’s very exciting because C. diff is a very difficult bug to kill. Before we get into some of your latest research, perhaps we can define some terms so everybody is on the same page. Can you explain what is IBS, what is SIBO and how should we rethink of these two conditions?

Dr. Pimentel:                     I’m explaining it just a little different these days. Maybe you’ve heard it from other podcasts, but I think it helps to understand because people are confused. Patients are confused as well because they say, “Well, is it SIBO or is it IBS?” The answer is, yes, because it’s both. The way I explain it now is, if you go back into the 1980s and look at peptic ulcer disease. Peptic ulcer was a ulcer in your stomach and you had pain and so forth and so on. Then they discovered that H. pylori was the cause of that ulcer, but it only caused about 60 or 70% of ulcers. We didn’t change the name to H. pylori disease. It’s still peptic ulcer disease, but H. pylori is the cause of 60 or 70%. Sort of a similar story here. It’s irritable bowel syndrome, and about 60 or 70% of IBS is caused by SIBO, I think. That’s basically how we frame it now. But like H. pylori, there’s a bunch of people with H. pylori that don’t have ulcers and there’s a bunch of people with SIBO that it isn’t IBS. There’s another cause.  There could be narcotics as a cause or adhesions as a cause or something else. Not just IBS and not just this post-infectious autoimmune thing. It’s just how the terminology is used.

Dr. Weitz:                            Okay. Can you explain your autoimmune concept of SIBO?

Dr. Pimentel:                     Yeah. I mean, to me, this is the most exciting stuff, because it may suggest we could be close to a cure if we can cross the next couple of hurdles. But essentially, food poisoning starts the process, it’s like a trigger. People don’t remember. I mean, they don’t remember two days of diarrhea two years ago and they now still have diarrhea. But sometimes you do remember. Sometimes it ruined your vacation or whatever, and ever since then, your bowels have never returned to normal. But that trigger is what trips you into a problem. We now identified that food poisoning, it could be E. Coli, it could be salmonella, shigella or campylobacter, they all share one toxin in common. This is what we sort of latched onto in the 2000s and said, “Well, could this toxin be a culprit?” Because they didn’t have anything else in common, but they had this toxin. We actually created a campylobacter without this toxin and infected rats, and they didn’t get IBS. But the rats infected with campylobacter got IBS. We’ve continued even to this day with that animal model.   Just at this past DDW, we had a huge abstract and presentation, but DDW didn’t happen. But the bottom line is that, toxin, CdtB creates antibodies in your blood that we can detect. Exposure to that toxin creates an autoimmunity to a protein in your gut called vinculin. Vinculin is important for the nerves to kind of connect. With attacking vinculin, those nerves are not connecting properly, the gut doesn’t flow correctly and bacteria build up. That’s how it works. We were supposed to present even more data that substantiates that story to a greater extent about two or three weeks ago.

Dr. Weitz:                            If somebody gets a bout of food poisoning, this is a question that Allison Siebecker asked me to ask you, is there a way to prevent them from this turning into SIBO? Is there some strategy they could use?

Dr. Pimentel:                     Well, let’s say you get food poisoning today. Well, one strategy that we tested in the animal studies was, let’s say you were going on a weekend trip to an underserviced area in an underserviced country to maybe build homes or something as a mission work or other things. And you were there for a short period of time in an underserviced area. If you took antibiotics with every meal, I know that sounds strong, you will prevent food poisoning and you will not get IBS. Our rat studies showed that. We do that in humans for some people who travel to very difficult areas. But I’ll explain another way we use that also. You can prevent. If you have food poisoning today, we used to say, let it go because it’s self-limited, it’s going to go away after a few days. But we now know based on all the meta-analysis and in fact Mayo Clinic did a beautiful 45 minute presentation that proves food poisoning causes IBS. What they found, was the longer the food poisoning, the more likely you were to get IBS and SIBO and all that stuff. [inaudible 00:14:07], then maybe you’re going to help you.   [inaudible 00:14:13] is [inaudible 00:14:20]. For example, now you had food poisoning, it’s gone and you want to [inaudible 00:14:24] to be able to [inaudible 00:14:25]. But the study was only 30 patients, so it wasn’t strong enough or powerful enough to show that it prevented. That jury is out on that, but to be honest….

Dr. Weitz:                          Hang on one second, Mark. I’m going to mute everybody and then unmute you again because I can’t find where she is. Okay. There we go.

Dr. Pimentel:                     Okay. Perfect.

Dr. Weitz:                          Okay. Good. Thanks.

Dr. Pimentel:                     The third thing is the steroid jury’s out, but I wouldn’t recommend steroids because of the side effects.

Dr. Weitz:                          Right. Okay. Then can you talk about the serum test that you developed and now you’re on the second version of it that helps us measure this autoimmune form of SIBO?

Dr. Pimentel:                     Yeah. We developed the first version, but it’s specificity and sensitivity needed some tweaking. The proteins, vinculin and CdtB are quirky, and so they need to be stabilized. We figured out a way to stabilize it, we call it epitope optimization. Now the new generation test is very specific, over 90% specific with either marker, and it’s called ibs-smart. Now ibs-smart helps me a lot in my clinic for anybody with diarrhea. Because, I’ll give you an example, I had a patient in my clinic. She was 19 or 20 years old. Her mother said she wanted her to have a colonoscopy and I would say, “This is 19 years old. You have no blood in the stool.” I did the test, it was negative. Then I said, “Okay, I will scope this one.” It was microscopic colitis. I wasn’t expecting that in a young person. In another case, it was a young man who was 23 years old. His mother has vinculin antibodies over three. So she’s super autoimmune. She said her son is having the same symptoms. I measured the antibodies and the vinculin was high, but not really high enough to be IBS.  Then he said, “Well, I’m going to Southeast Asia in about six months. What should I do?” I said, “Well, you can’t let those antibodies get higher because you’ll be harder to treat.” This is what we see in our clinic, the higher the anti-vinculin, the harder they are to treat. But the amazing thing with this young man was, he was in his early 20s. He’d had a colonoscopy already. He had a CT scan of the abdomen, the ultrasound, stool study. I mean he had a $4,000 workup. That’s his copay. That’s not how much the workup costs. Where he could have had the test and the test would have saved them all that copay because it was positive. We’re using the test not just to make patients feel comfortable that the diagnosis is correct because the test is very accurate, but also to guide prognosis and to save money for patients and for healthcare.

Dr. Weitz:                            It’s kind of exciting for us in the Functional Medicine world, because we see a lot of patients who have these autoimmune conditions and we find that food sensitivities and reactions to toxins and heavy metals and things like that seem to be factors. We’re always talking about this cross-reactivity model and here we have a very concrete cross-reactivity model that’s been thoroughly proven in this particular arena. It kind of gives more credence to that cross-reactivity model that we often utilize to explain how sensitivity to gluten or dairy can lead to autoimmune thyroid disease and things like that.

Dr. Pimentel:                     Well, two things to say on that. First of all, we think that these two markers, anti-CdtB and anti-vinculin, are not markers of the disease, they’re actually causing the disease. That’s the part that I’m really excited about because, particularly in anti-vinculin’s case, if we can get that out of your bloodstream, it’s possible we can cure IBS and SIBO. That part makes me very excited, but it’s also a little challenging to do that. The second part of what you said is, for me to swallow my tongue and say something I didn’t expect to say. Which is that I’ve sort of been on the fence about gluten. I’ve always said, “Well, I’m not sure …” Celiac disease is clear. Gluten sensitivity was always unclear to me. This Reimagine Study that we’re doing, we were supposed to present … It’s public domain now because the abstracts are published, but it was at the meeting, the DDW meeting. People who were gluten free and not celiac, their cytokines in their blood were much lower. They were less inflammatory. I was expecting to see nothing.

Dr. Weitz:                          Interesting, fascinating.

Dr. Pimentel:                     Well, now I have data. It’s not that I need to see my own data to be correct, but it’s more that I have a way of thinking through problems. As we thought through this problem, it’s clear there’s something there that needs further exploration and more objective evidence. But I’m convinced there’s something there in some people. I’m glad you brought that up because I needed to clear the air on my own conscious and say…

Dr. Weitz:                          That’s right.

Dr. Pimentel:                     … something to gluten.

Dr. Weitz:                          Interesting, yeah. Alessio Fasano and other researchers have found that 100% of patients who consume gluten on a regular basis have some evidence of leaky gut and other issues. So that’s interesting. One of your recent papers is the ACG Clinical Guidelines for SIBO. In those guidelines, you list six factors that are important for helping to maintain small bowel ecology. You talk about hydrochloric acid and digestive enzymes and bile and motility and the ileocecal valve and the gut immune system. I thought maybe we could talk about some of those and which ones do you think are most important in the etiology of SIBO?

Dr. Pimentel:                     All of those are what I call classic or traditional notions of what can prevent bacteria from getting in your gut. Yes, acid prevents bacteria from getting in the gut. Well, the irony of that is, we did present it at DDW and this paper is coming out just shortly, that people on PPI did not have too much of a different microbiome in the small bowel. That shocked me also because I was expecting PPI to radically change the microbiome, and it didn’t. There were a couple of small changes, but nothing as remarkable as I expected and definitely PPI was not associated with SIBO. This was a very large group of patients. Acid is funny because acid kills bacteria, but you don’t need much time with acid for it to kill. In five minutes with a pH of one, bacteria are pretty much destroyed.

Dr. Weitz:                          It seems like maybe your group has gone back and forth on the PPI because it actually states in the paper that PPI use is associated with higher risk of SIBO.

Dr. Pimentel:                     Yeah. Okay. Traditional studies had said that, and our paper hasn’t been published yet. Now in the Reimagine Study, we didn’t find SIBO. That hasn’t been published, so we couldn’t put it in there yet. It was only an abstract and they don’t like abstracts for guidelines because it’s not peer-reviewed as thoroughly as a paper. But we didn’t find it. But there’s two things that were happening that’s in the literature. Number one, if you’re IBS and you’re on a PPI, we didn’t see more SIBO even in published literature. But if you a healthy individual with no GI symptoms, just GERD and you’re taking a PPI, there was more SIBO. It’s a little confusing. The third sort of confusing leg of this three-legged stool of acid and bacteria is, methane organisms love acid. They can use hydrogen or acid hydrogen to make methane. People on a PPI had less methane overgrowth because they had less acid. Sometimes no acid is good depending upon if you’re methane, sometimes no acid is bad if you’re … Yes, the thing is confusing.

Dr. Weitz:                            Yeah. Interesting. Then digestive enzymes, I know that one of the things that you think is super important is this migrating motor complex and motility. Allison Siebecker was talking about it and she was explaining how the digestive enzymes and the bile are kind of like the soap as part of this process by which the MMC helps keep the intestines clear. For those, you who are not aware, the MMC is gastric contractions that occur in between eating. When you haven’t eaten for a while, you get these peristaltic activity that helps to keep the small intestine clear of bacteria.

Dr. Pimentel:                     Yeah. It’s like a dishwasher. It washes your small bowel in preparation for the next meal. To me, that’s the most important. Of all the factors for SIBO, not having that wave means SIBO or having a reduction in the frequency. That happens every 90 minutes when you’re not eating. Morphine causes SIBO and morphine’s a potent inhibitor of that wave. Anything that blocks that wave from occurring will cause a lot of SIBO. We think that’s what vinculin antibodies are doing, is that they’re impairing that cleaning wave. That’s based on the research in the animals.

Dr. Weitz:                            What other drugs inhibit that wave?

Dr. Pimentel:                     It’s mostly opiates that do that. Then there are drugs that stimulate that wave, like motility drugs, Prucalopride, Tegaserod or Zelnorm, and even erythromycin low dose can do it.

Dr. Weitz:                            Okay. Last time we talked, we were talking about motility and you explained something that was really fascinating and I think most people are not aware of. Which is that, without normal intestinal motility we’ll actually have diarrhea, not constipation. Can you explain that?

Dr. Pimentel:                     Yeah. It’s a little confusing because even when I train the fellows about motility, people think you don’t have stuff coming out because the gut isn’t moving. But the way that that actually works is, if your gut can actually squeeze and hold things in, that’s active slowing. But for example in scleroderma, if the bowel becomes thicker and can’t move because it’s so thick, it actually just pours through like going through plumbing because there’s nothing holding it back. You can actually have diarrhea if the peristalsis is thick and unable to perform its retaining function. Motility is kind of fascinating because there’s so many ways you can have symptoms based on the lack or presence of motility.

Dr. Weitz:                            Now, is the migrating motor complex, is that exactly the same thing as the peristaltic activity that happens when you eat food or are those separate things with separate neural control?

Dr. Pimentel:                     Yeah, they’re totally separate. It’s almost like you have a switch with two modes. You have the cleaning mode and then you have the eating mode. The eating mode is, grind three times, four times, then stop and wait, let the food kind of absorb and then grind a little more and then let the food absorb. Then keep doing that over and over again. The small bowel moves the food forward and back and forward and back and forward and back getting it all mixed with … Like it’s mixing it up. Whereas the cleaning wave, it starts at the top and goes choo,choo,choo, like marching down, squeezing things through in a very systematic, straight top to bottom kind of way to strip everything out. All the lettuce and things you can’t eat or can’t digest. They’re different mechanisms. Going back to acid, this is a funny part, people on a PPI, the bowel thinks you don’t have as much food in the stomach and it goes to cleaning waves prematurely or sooner than you should.  Because when you eat, you’ve got a lot of acid and all that acid prevents the switch from switching from eating mode to cleaning mode. But when you’re on a PPI, you don’t have that signal. You switch to cleaning mode earlier and you actually get more MMCs or cleaning waves. Again, another reason why SIBO may or may not be associated with acid reduction medication. Was that kind of confusing or …

Dr. Weitz:                          Yeah. Well, what’s the implication of that MMC happening earlier?

Dr. Pimentel:                     Well, in some ways it’s good. But there are patients for example, and this is not that common, who have what are called neuropathies. Where the nerves are irritated and the switch is not in the right position. The last thing you want is a cleaning wave when your stomach’s full of food, because then everything’s just going to go whoosh right to your colon and out. That doesn’t happen very often at all. People think it happens because they get what’s called a gastrocolic reflex where they eat and then they’re running into the bathroom. But that’s not that meal. This event that I’m talking about is very rare. But there are also people who never switch to cleaning mode and then that’s a problem because they never clean. There’s various forms of neuropathy that are out there.

Dr. Weitz:                          We have a slightly different neural control of motility in different parts of the track? Stomach is different than small bowel than large bowel?

Dr. Pimentel:                     Yeah. The only time they all come together is that cleaning wave. The stomach starts, then the small bowel, and then it gets to the colon and the colon sort of holds everything right after that to get everything dehydrated to make stool. Everything kind of activates during that cleaning wave to keep things moving along. It’s integrated only when you’re not eating. But when you’re eating, every part is moving separately and doing things in a different way.

Dr. Weitz:                          A lot of people talk about the vagal nerve, the gut brain connection and the vagal nerve is sending a lot of signals to control motility. What do we know about the importance of the vagus nerve? Is there a way to stimulate it to help with SIBO or motility problems?

Dr. Pimentel:                     Yeah. Stimulating the vagus nerve is a little challenging. There are neurostimulators and other things that could be used, but not well studied in SIBO particularly. Now the problem with SIBO is, the nerves are … It’s sort of like that … What I tell my patients is, “You have electricity come into the house. That’s your vagus nerve. Okay. The wires from the pole are coming to your house, but not all the wires are touching the light bulb sockets.” You’ve got half the lights. You turn on all the lights in the house, but only half are turning on. That’s the problem with SIBO. You could make the wires from the house push more electricity, but it’s not really working terrific. Now, again, that’s what the prokinetic does, is it turns the energy up so that all the light bulbs that do work are brighter and you get a bit of light. That’s why we use a prokinetic to kind of, whatever’s working, make it work better. But you can’t repair the phase until you get rid of the antibody. That’s the way I see it.

Dr. Weitz:                          Okay. Let’s talk about your research mapping the microbiome of the small intestine. This is the first time this has ever been done. What are some of the implications that we’re getting out of this data to help us understanding and treating SIBO?

Dr. Pimentel:                     Yeah. This is super cool because there’s a lot of things we’re learning that would be very important for you to understand today. But about 10 years ago, maybe 13 years ago, the Human Microbiome Project was published in the journal Nature. This was a huge thing because the microbiome was mapped for the first time. What they said was, “We mapped the gut microbiome.” The answer is, no, you didn’t. Because you mapped the stool and you said because you mapped the stool, you mapped the whole gut. What we learned is that, the small bowel in the study that you’re referring to that was just published, is completely different from colon. It’s literally like the sun and the moon. It’s completely different organisms, the different structure of the types of bacteria and so forth and so on. Now, the other thing that is a bit of a fallacy, and this will be easier to understand is, they think because the stool has a size and that it contains a ton of bacteria, oh, that’s really important.   The problem is, the stool is like this and the bacteria is sitting in the center, it’s not doing anything to you. It can’t reach you because it’s got all these other characters in the way. Even though there’s a lot of bugs in there, it’s not a lot of bugs compared … Now think about the small intestine. The small intestine has the surface area of a tennis court. Imagine if you smeared a thin layer of peanut butter across our whole tennis court, how much peanut butter you’d need. We think the small bowel might actually have more microbes than the colon if you consider surface area.

Dr. Weitz:                          Oh wow.

Dr. Pimentel:                     Okay. Then when you add to that, that the small bowel absorbs but the colon doesn’t, it just absorbs water, imagine the chemicals, the bugs in that surface area of a tennis court are giving to you on a daily basis helping, hurting or neutral. We don’t know. And what impact that could have. The Reimagine Study is trying to figure out what bugs and what disease.  Because look, the 13 years since the Human Microbiome Project, zero.  One bug, one disease. Look at C. diff. C. diff was discovered in the 1980s using old school microbiology. But 13 years of microbiome research hasn’t found one bug, one disease. We’re already finding one bug, one association in the small bowel. I can’t talk about that yet because we haven’t published it yet. But it’s fantastic what’s going on in the small bowel in terms of maybe helping diseases.

Dr. Weitz:                          Now we’ve had controversy over where the bugs that cause SIBO come from. Are they overgrowing up from the large intestine or are they in the small intestine and just overgrowing? Has your study helped to answer that question?

Dr. Pimentel:                     My thinking used to be, colon coming up.  My thinking has changed now. It’s, they’re there. You probably all live in LA or I imagine most of you live in LA somewhere-

Dr. Weitz:                          I think most of us, yeah.

Dr. Pimentel:                     We had the drought last year and just before the rains came about two years ago, actually. Burton Boulevard has this beautiful central boulevard of grass, and the grass is Beverly Hills pristine. Then they stopped mowing the lawn just because they wanted to save water. There wasn’t a lick of grass. There was tall weeds, about three feet deep. Not mowing the lawn, the grass couldn’t compete, the weeds worked. Without the cleaning wave, the weeds grow. The weeds are there, they’re just … It’s E. Coli and Klebsiella. That’s what’s causing bacterial overgrowth. Once they get a foothold, it’s hard to flip them out and get the weeds gone. That’s what we think is overgrowth based on the Reimagine Study. It’s E. Coli and Klebsiella, those two characters and a little bit of Aeromonas.

Dr. Weitz:                          Is there such thing as region specific SIBO? Is there duodenal SIBO versus jejunal SIBO?

Dr. Pimentel:                     Yeah. In this study, we mapped the whole small bowel and ironically, it was remarkable that there wasn’t as much of an increase as you get closer to the colon as we had expected based on people just talking. I mean, people talk and they say, “Oh, it must get higher and higher as you get to the colon.” That wasn’t what we found. It wasn’t dramatic like that. As we now get truth, the truth is telling us what the answers are and it’s not quite like that. I don’t think that there’s actually as much regional SIBO as we used to think, but we’re continuing to collect data and I may correct myself in a year if our data suggests otherwise.

Dr. Weitz:                          In your study, I didn’t see methanogens on the list of organisms you found. My question is, did you find methanogens in the small intestine and what about fungus and parasites like protozoa that are normal to the colon?

Dr. Pimentel:                     Yeah. The sequencing we did was for bacteria initially, not for archaea and not for fungus or parasites. But we have all the DNA of all of that and we’re looking through that. In fact, right now my lab had just come back finally, and they’ve been marching through the methanogens in the small bowel, the colon and everywhere, because that’s really important. We’ll have data to share on that hopefully in the next few months.

Dr. Weitz:                          What’s the significance of this reclassification of methane SIBO?

Dr. Pimentel:                     Yeah. The term is SIBO, small intestinal bacterial overgrowth. First of all, it’s small intestine. It has to be in the small intestine, which we agree SIBO is. And then it’s bacterial overgrowth. Methanogens are not bacteria they’re archaea, so you can’t call them bacterial overgrowth. We used to call it methane SIBO, but that’s a wrong terminology. The second part is that methanogens grow in the colon too much as well in these patients, not just the small bowel. We couldn’t say small bowel because it’s both the colon and the small bowel in the case of methanogens. We had to reclassify the term. It’s an overgrowth if it’s a bloom and it’s excessive number of methanogens, but not just in the small intestine.

Dr. Weitz:                          Conceivably, methane SIBO could be primarily in the colon?

Dr. Pimentel:                     It could be. We’re mapping the bowel now and then comparing that to … Again, I’ll be able to tell you more with more granularity that in a few months, but-

Dr. Weitz:                          But of course, if it comes up positive on the SIBO breath test, then that means especially if it occurs in the first 90 minutes, then we know that that’s got to be the small intestine?

Dr. Pimentel:                     Well, methane is different because methane is either there or not. On the breath test, often a methane producer normally hydrogen starts at five and then works its way up over 20, and that’s positive. In methane, it starts at 30 and stays 30. You’re either methane presence or not. It doesn’t really go up that much with lactulose. It’s a different characteristic of the breath test.

Dr. Weitz:                          What should be the cutoff for the breath test for methane? Should it be 10? I’ve heard you mention that perhaps it should be lower.

Dr. Pimentel:                     Yeah. The North American Consensus and the recent SIBO guidelines from the American College of Gastroenterology are saying, for methane, any number over 10 within the first 90 minutes. Then for hydrogen, it’s a rise of 20 within 90 minutes. If you start at five, it’s got to go to 25, and then that’s considered positive.

Dr. Weitz:                          I’ve heard you say perhaps maybe methane at three should be significant.

Dr. Pimentel:                     Okay. This is the problem with consensus. Is that I have my opinion and there’s 20 other people in the room and we have to go along with consensus. The group felt that 10 was a better marker. But let me explain why 10 might be a better marker. When you do research on methane, Dr. Rezaie and I looked at all the breath tests, 12,000, 15,000 breath tests at Cedars over a decade. We looked at, if somebody had three, 90% of the time they went over 10 at some point during the test. Even if we used three, almost all those patients would be over 10 anyway at some point and meet that criteria. It wasn’t so big a deal. But the second part is, if you’re going to give a drug to lower methane, it’s better that it’s 10 so you can see it go down than three, where there’s nowhere to go. We sort of like the 10 now because if we’re going to develop drugs as we’re doing now to reduce methane, at least you have somewhere to go from 10. You don’t have more to go from three. That makes sense?

Dr. Weitz:                          Sure, yeah. Why do you think methane is so difficult to treat?

Dr. Pimentel:                     Yeah. There’s a couple of things about methanogens. Number one, they tend to be closer to the surface of the mucosa or the surface of the human cells. There’s a thick mucus layer where rifaximin and a lot of drugs can’t penetrate, not as well anyways. That’s part of it. The other thing is, they’re not bacteria. We developed antibiotics for bacteria and not archaea. It’s sort of like trying to use antibiotics for yeast and it’s not developed that way, they’re different. That’s why we’re trying to take different approaches. We’re using, as you mentioned in your introduction, sort of a variety or a version of lovastatin which goes into the bug and stops methane production. Then the energy of the bug can’t be produced and the methane is not produced so the constipation gets better. We’re just in the middle of the trial of that drug. We’re super excited to get that done soon.

Dr. Weitz:                            I was just talking to Dr. Rahbar a couple of days ago. He was saying that he sees in cases of methane, he often sees a fungal overgrowth. He said that lovastatin actually has antifungal properties and that could perhaps be one of the reasons why it helps.

Dr. Pimentel:                     Remember, lovastatin comes from Aspergillus, which is a fungus. Aspergillus, didn’t make the lovastatin for human cholesterol. It’s making it to affect things around it. It could be to prevent other fungus from growing there and getting in its way. Certainly in swamps and other places where Aspergillus is prominent, there’s a lot of methane and methanogens which may be intoxicating to the Aspergillus and it wants to block that. Obviously lovastatin has a chemical property that does something to the microbiome which we think is beneficial, but we’ll see. We’ll get some results later this year.

Dr. Weitz:                            Since the methanogens are found in the mucus and it’s one of the reasons why they’re hard to get at, I wonder, would it makes sense to use agents? We have certain nutritional agents that are known to break up biofilms like bismuth, we use certain enzymes, NAC is a mucolytic agent. I wonder if something like that would make sense to break up some of that mucus layer to get at the methanogens.

Dr. Pimentel:                     Yeah. I mean, but the challenge with these things are half-life of the products and how much surface area you have to cover. Because again, we’re talking about a tennis court size area. Yes, we’re looking at all of that actually, but we have to work it in a way that actually is effective in such a large surface area. Stay tuned, I’ll have more things to report in that context. This is all again, coming from the Reimagine Study. Because the Reimagine Study, and I can’t talk about all of this data, but we’re looking at the bugs in the center of the bowel, the bugs in the mucus and the bugs right at the surface. They’re different. As we study the layers, even in the small bowel, it’s pretty remarkable the different bugs. I’ll tell you where the SIBO is, is in the mucus. That’s why it’s hard to get rid of it because it’s in the mucus and that’s where E. Coli and Klebsiella love to live. That may be why we need to get better treatments and they’re coming, we’re working on something right now. It’ll be interesting to see how that evolves.

Dr. Weitz:                          What does your Reimagine Study tell us about hydrogen sulfide SIBO? Right now, our only way to try to diagnose is if we see a flat line of hydrogen all the way through the third hour. Do you think we’re picking up a substantial percentage of patients with hydrogen sulfide SIBO?

Dr. Pimentel:                     Yeah. Well, a new breath test is emerging soon that will be able to test hydrogen sulfide. But we think hydrogen sulfide is causing diarrhea. Methane causing constipation, hydrogen sulfide, diarrhea, and hydrogen is just the fuel source for either direction. Of course the methane bugs don’t like the hydrogen sulfide bugs because they’re eating the same rabbits, which is hydrogen. You either have foxes or you have wolves in the neighborhood because the rabbits are the hydrogen.

Dr. Weitz:                          Right now, what are your current treatment protocols for hydrogen SIBO, methane SIBO and hydrogen sulfide SIBO?

Dr. Pimentel:                     Well, the effective therapies that we use are usually antibiotic therapies. But again, what we’re trying to do is to use as little antibiotics as possible. Because that’s why when we treat … Okay. Let me go through it. For hydrogen, we use rifaximin as first line. There are other things we do if you want to get into it if they don’t respond including peppermint and other natural products that you’ve covered partly in your introduction as well. Then with methane, we use rifaximin and neomycin because there was a double blind study that shows that. Although we can’t wait for the lovastatin data. We’re hopeful that that will show something good. It may not work. If it doesn’t, then we regroup. Hydrogen sulfide, we don’t know what to do with that yet because we don’t have the breath test widely available. Once we get that, we’ll know within months what’s going to be effective there. I’m very sort of excited about that. But once you get control … This is why we do the ibs-smart test.  Because if they are vinculin positive, they got to go on a prokinetic more likely because they really have a motility issue. We’re more likely to give a prokinetic, at least in my practice. Then we try to use diet to try to ward off the overgrowth and prevented it from coming back. That’s also really important. There’re a variety of diets. Low FODMAP, we tend to use low fermentation because it’s better quality of life.

Dr. Weitz:                          When do you kick in a low fermentation diet? Do you do it while treating or do you do when you’re done with treating?

Dr. Pimentel:                     Well, I basically … The reason, and people know this of me, that I don’t do it while treating because of the old mantra of antibiotics back in the ’70s. Which is, starving bacteria, hibernate or form spores, or try to protect themselves by walling off because they’re stressed. Stressed bacteria are not susceptible to antibiotics. I don’t like using the starvation of low fermentation or low FODMAP because it might make it harder to treat. Other people have taken my words and said, “Well, let’s give guar gum, really juice up the bacteria, and then give antibiotics.” I don’t do that, but people have suggested that I said that and I haven’t. But I understand the rationale and maybe it’s helpful, but I haven’t tested it personally. But the bacteria that are fed are going to be more susceptible to the rifaximin or the rifaximin and neomycin. Better not starve before you do the antibiotics.

Dr. Weitz:                          It’s interesting you mentioned guar gum. Because my understanding is, hydrolyzed guar gum is the one fiber that does not really irritate SIBO.

Dr. Pimentel:                     Yeah, I understand that. I don’t know where that came from, but it’s out there and somebody said, I’ve said it, but it wasn’t me.

Dr. Weitz:                          Yeah. I know Allison Siebecker said that she and Dr. Sanford-Lewis normally treat with rifaximin or natural antimicrobials and a low FODMAP type of diet at the same time and find that they get quicker symptom resolution by including the diet at the same time. The concept is, is you’re trying to kill the bacteria and you’re starving them at the same time. You’ve got two different strategies at the same time.

Dr. Pimentel:                     Yeah, that’s true. I do use some other naturals, berberine does help in some patients.  Allicin is quite good for methane sometimes. Again, everything works sometimes and you just got to find the right thing for the right patient.

Dr. Weitz:                          Have you used a different diet when it’s hydrogen sulfide?

Dr. Pimentel:                     Yeah. The opportunity for diets is going to be interesting because a low sulfide diet will actually reduce hydrogen sulfide. But because I don’t have hydrogen sulfide to measure yet, I don’t know how well it works. Once we have this breath test up and running, I think we’re going to get some interesting results as to whether certain diets with low sulfate, for example, could be helpful in that instance. I think it might be, so we may have some tailored diets depending upon the gas profile.

Dr. Weitz:                          When do you think that new breath test will be available?

Dr. Pimentel:                     To be honest, a lot of breath tests are shut down because of COVID. Everything has gotten a bit delayed. I don’t have a timeline for you, but hopefully very shortly.

Dr. Weitz:                          Right. Promotility agents, prokinetics, should these be employed at the same time that we’re treating the SIBO or afterwards?

Dr. Pimentel:                     My routine is after, because that’s sort of how I’ve done it for years. I don’t object to the concept of giving it with the treatment, but here’s the rationale of why I don’t. Is because, back in the early days people were saying, “Mark, are you really giving a prokinetic to a diarrhea patient?” I said, “No, I treat them first. Now they don’t have diarrhea. Then I give the prokinetic.” The patient could suffer with diarrhea if they already have diarrhea and you’re giving them a prokinetic before the overgrowth has gone with the antibiotic. That’s my rationale there. For the constipators with methane, you could argue, you could give them a prokinetic at the same time. Although I sort of do it one after the other, it saves a little money too.

Dr. Weitz:                          What’s your favorite prokinetic these days?

Dr. Pimentel:                     I’ve got to say I love Prucalopride, Rezole or Motegrity it’s called in the US. It’s the most powerful prokinetic I’ve seen on the planet. Now, powerful doesn’t mean isn’t always good. But what I mean is, I start at usually a very low dose, like half a milligram at bedtime to get those cleaning waves going and people don’t have problems with that. It’s not powerful at that dose. You don’t want to start right at the two milligram dose in these patients, because if it’s too strong, they won’t like you for it. Start low and move up as you need to. That’s how I do it.

Dr. Weitz:                          Have you tested LDN or any of the natural prokinetics?

Dr. Pimentel:                     Yeah. I mean, occasionally LDN, and Dr. Rezaie uses LDN a little more than I do. There are prokinetic actions of LDN and anti-inflammatory also properties of that. I think there’s merit in that. You just got to choose what the patient’s going to respond to. I go for the big gun now, the Motegrity, because I think it’s just so superior to everything else. But if I can get away with LDN or low dose erythromycin, it’s cheaper especially for low dose erythromycin.

Dr. Weitz:                          Okay. Why is rifaximin so expensive in the US and are generic versions as high a quality?

Dr. Pimentel:                     Yeah. Well, it’s a complicated answer. Rifaximin is a weird molecule where there’s an alpha beta, gamma and delta form. There’s sort of four … If you make the chemical in your basement, you’re going to get a mixture of four different sort of shaped molecules that are the same molecule, but they bend in a different way. You have to use rifaximin-alpha. The rifaximin from brand name is alpha. The problem with some of the generics, they don’t describe how much alpha versus gamma, beta, delta, and that’s confusing. You might be paying a quarter the price, but you might be getting a quarter of the drug. I don’t know. I think the ones that are branded generic and are available here in the US might have the FDA breathing down their neck if it’s not alpha. But some of the ones from overseas or from other sources may not contain exactly … I mean it’s not toxic, but it may not contain things that you hope and be less effective as a result.

Dr. Weitz:                            What percentage of patients with SIBO do you think end up having recurrences and what’s the best strategy for trying to help when they’re coming back for the second round or the third round?

Dr. Pimentel:                     Yeah. When we did the TARGET 3 Study, which was the rifaximin three treatment trial, about a third of people who got treated and it worked with rifaximin never needed treatment again. That’s amazing. We’re studying that because there’s a term that one of our collaborators from Caltech uses and he publishes on, it’s called hysteresis. Where it’s like a teeter-totter. You’ve got the overgrowth here that’s weighing down, sort of the weeds, but if you get enough of the weeds gone, the totter flips and it’s hard to go back. You see what I’m saying? If the grass is able to grow hardy enough and you’ve got the weeds down far enough, the grass won’t let the weeds come back up. I think that’s true for a third of cases, we can get them to flip and they stay flipped. For some others, the weeds go down and then come up and down and up and we’ve got to keep treating about every three to six months. That’s sometimes frustrating for patients. That’s why we’re trying to look for even better therapies now to try and keep the teeter-totter flipped and growing grass, not weeds.

Dr. Weitz:                            Now, one way we think of it especially in a functional medicine community is, if we want that grass to grow, we give it more grass seed i.e probiotics.

Dr. Pimentel:                     Right. Well, yes. I guess what I’m getting … I don’t disagree with probiotics and I don’t dislike probiotics. I think now that we have Reimagine data and now we understand the small bowel data better and we understand who are the weeds and who are not the weeds … Because we didn’t. We were just giving probiotics. But as you pointed out, this is the first mapping of the small bowel. We were kind of shooting in the dark. Now maybe, there may be an opportunity now knowing what the grass is to give more grass. You’re right, I think that’s the evolution of this over time and maybe there will be something. I’m very optimistic, but we’re learning more every day.

Dr. Weitz:                          Right. Great. I think those are the questions I had. Did anybody have questions? I haven’t seen any typed out. I’m not sure if my screen is even showing them or not, but I don’t even know where they would be.

Dr. Pimentel:                     If you look at the chat bubble at the bottom, I think they’d come up.

Dr. Weitz:                          Okay, there we go. Let me look at some of these questions. Yeah, there’s a bunch of them. Sorry, everybody.

Dr. Pimentel:                     I’ve been doing a lot of Zoom in the last few weeks, I’ve become a Zoom super user.

Dr. Weitz:                          Somebody wanted to talk more about lovastatin for SIBO. Is it currently considered an acceptable treatment or not?

Dr. Pimentel:                     The problem with lovastatin that you would get right now, whose one of the brand names is Mevacor, is that it’s designed to be absorbed into your blood to reduce cholesterol. I want it the other way. I want it not absorbed. I don’t really care about cholesterol. I want it to be sort of slowly moving or released in a different pattern through the gut. The product that we’re testing now is sort of a dual release lovastatin that will release in the gut and won’t get absorbed. That’s what we’re testing because it will have a better effect. The other thing is, what we see in our practice, is to get methane down, we almost have to go to really high doses of lovastatin. Which start to give you body aches and side effects that are typical of that drug. It’s tricky. We do it sometimes and we do get some benefits, but it has to be done in a very particular way. It’s just not like what we’re testing in the big clinical trial right now.

Dr. Weitz:                            I see. One of the questions is, is certain bacterial strains produce methane, some produce sulfate and ammonia. Wouldn’t it be important to keep these bacterial strains in balance?

Dr. Pimentel:                     Yeah. There’s things we know about methane and we’re learning more and more about. Okay. When methane is here, I don’t want to get rid of methanogens because I think there should be a balance. But if your methane is here and normal is here, we just want to get it to here and to keep things in harmony. We’re going to have some data coming out that says, if we can get it here, the microbes start to make the balance come back and it stays here. It’s like that teeter-totter thing again I talked about. Yeah, the goal is not to … That’s why the lovastatin thing is so awesome. Because if it works, we’re basically getting into one organism, taming it a little so that everything grows normally again, instead of this bashing everything with a sledgehammer like in an antibiotic approach. Which is a little more coarse and not fine-tuned. I like where we’re going with more of a finesse touch rather than this sledgehammer approach.

Dr. Weitz:                            Some patients with SIBO get a brain fog and neural symptoms. What do you think is causing that?

Dr. Pimentel:                     There’s a couple of things. You could have what’s called D-lactic acidosis. It’s very uncommon. Satish Rao has published that a few … We’ve checked it a number of times and we find it very rarely. But that’s an extraordinary and sort of encephalopathy or sort of a confusion state that people can get from that. But more commonly, methane, for example, think of methane like halothane and fluorane, isoflurane. Those are gases that they use in the operating room to put you to sleep. Methane is a hydrocarbon like them. We see when the methane is super high in patients, people are more brain fog, more fatigue, more of that. Methane really, I think has an important role. Methane can do all sorts of things. Methane bugs are associated with obesity, they’re associated with higher blood sugar, they’re associated with higher cholesterol. Methane is a weird character. We don’t want it here. We want it nice and normal, and that’s what we’re shooting for.

Dr. Weitz:                            Here’s a question from Dr. Felice Gersh. Felice. I unmuted you, would you like to ask your question?

Dr. Gersh:                            Sure. Where am I? Hang on.

Dr. Weitz:                            I just-

Dr. Gersh:                            Can you hear me?

Dr. Weitz:                            I guess you’re not visual, huh?

Dr. Gersh:                            I can be. Do I need to be for me to …

Dr. Weitz:                            Felice is an expert on female hormones. There she is.

Dr. Gersh:                            Hello. Hi there. Hi there, everybody.

Dr. Weitz:                            Hi there. Go ahead with your question.

Dr. Gersh:             Well, yeah, I’m always bringing in what’s going on with the females and their hormones, because that’s a huge component that’s often left out. As you know, females make up a very high percentage of patients who are diagnosed with IBS. Women are very different in terms of how their estrogen affects their enteric nervous system, the gut microbiome. But the question I have is, about 90% of females these days spend a good bulk of their reproductive lives on either oral contraceptives or what I call similars, progestin agents. What is that doing to their gut microbiome? What’s it doing to their enteric nervous system? How is that impacting all of this? Because there is data published that shows that the microbiome is quite different in women who are on these products. Then of course, the universal event of menopause has many impacts on the gut. I just wanted your comments on the female side.

Dr. Pimentel:                     Thank you. I mean, that’s amazing. Ben mentioned in the beginning this hysterical woman comment, but I think he took it [crosstalk 01:01:55]-

Dr. Weitz:                            I was just kidding.

Dr. Pimentel:                     No, but you took it from one of my … You weren’t kidding because what I’ll tell you is, and this came out in one of my tweets. One of our fellows went to a conference where they were learning how to write the exam, the board exams. One of the senior gastroenterologists said, in 2017, “IBS is a disease of hysterical women.” [inaudible 01:02:18] in the 1980s and ’90s, this is the stupid way this disease was thought of. When Ben said, “Yeah, that’s how it used to be thought of.” It’s literally verbatim of what happened. It’s so wrong because you can’t blame a disease on women. Secondly, it’s not a female disease because men get it also. Those two things, it’s like saying pregnancy is a disease. It’s not a disease, it’s a natural phenomenon. Or these are the crazy things that went on. But let me get to your question. That is, the biomarker, the ibs-smart test measuring vinculin and CdtB.  If you’re a woman and you get food poisoning, you are almost twice as likely to get IBS as men. Women have a tendency to get more autoimmune disease.

                                                There’s more rheumatoid arthritis, lupus, other autoimmune diseases in women. That may be why there’s more IBS in women. It’s super important we figure that out, why is that happening. But it’s very interesting at the same time. But it’s not because of some psychological alteration that women have that they get this. That one I just want to settle that because that’s very frustrating to me that I’ve had to hear that as recently as 2017. The second part of your question is all these hormones. We know estrogens are growth factors for some bacteria. Yeah, I mean, it’s possible that you change the microbiome in the small bowel. Certainly there are studies in the colon, stool, but we’re really interested in seeing what’s going on in the small bowel with estrogen. You’re right, I don’t have the answer yet, but we’re looking at it. We have all the medications of all these patients that are undergoing scope. The only problem with our study, the Reimagine Study, is, they have to have be coming in for a scope for a reason.

                                                More often than not, it’s older folks that come in for scopes rather than younger people who might be on birth control or estrogen replacement. But yeah, and menopausal women, they’re on estrogen replacement. We’re going to address that and I think that’s a very, very, very important question. I have some answers, but not all the answers to your question.

Dr. Weitz:                            Somebody asked a question about bacillus probiotic spores. There’s a study on patients with IBS and apparently this study found that spore based probiotics perform better than rifaximin and a low FODMAP diet.

Dr. Pimentel:                     Yeah. I’m very excited about some of the probiotic studies that are coming out, and this is sort of another example. I’m not cuckooing probiotics studies and I’m not cuckooing this one, I’m excited about it. What I’m saying is that … I’ll give you an example with peppermint. The peppermint studies show peppermint is effective. There’s a double blind study of about 80 patients. But the weird thing about peppermint, when they did a 20 patient study or a smaller study, the p-value was amazing. It was like it was really working. Then they did a bigger study and the p-value is smaller, and a bigger study and the p-value is even smaller. If they did a 500 patient study, would it be statistically significant? This is the challenges that small studies that are positive get published. I’d love to see a probiotic company just step on the gas, put some money down and do a 800 patient study. If it works, wow, they will be … Well, first of all, they all make a lot of money. Which is good for them, I suppose, and that’s the whole incentive for them.  But it’ll help a lot of people if we can get some clarity around this. I love all of it. I want to see it happen and I’m happy to participate in these kinds of trials because I think there’s something there. We just need to do the big trial, the good trial and get a good answer.

Dr. Weitz:                            Somebody asked about, if you have a patient with SIBO and they also have H. pylori how would you treat it? Would you treat the H. pylori first? Would you treat the SIBO first? I’d also like to add in there, to what extent can SIBO be a cause of reflux?

Dr. Pimentel:                     Yeah. SIBO as a cause of reflux is possible. Especially we see that in methane because there’s sort of a double hit with methane. They get gas build up and the colon is slower and the bowel is slower. Everything is sort of building up and then you’re getting more pressure, which means more reflux. Reflux is a combination of two things. It’s this valve at the top holding the acid down, and how much pressure is below your chest and your abdomen that’s pushing acid up. When you have SIBO, that definitely … Now, I forgot the first part of your question.

Dr. Weitz:                          Yeah. If you had a patient who has H. pylori and SIBO.

Dr. Pimentel:                     Yeah, H. Pylori. I would treat the H. pylori first because it’s a larger cocktail of antibiotics and there’s a pretty good chance you could hit two birds with one stone. You might want, in that case, do a breath test after just to see that you kind of got them both.

Dr. Weitz:                          Okay. Interesting. Could there be other gut pathogens that stimulate the autoimmune response besides I guess cytolethal? I guess, could there be things other than bacteria that could be stimulating this autoimmune SIBO response?

Dr. Pimentel:                     Yeah. We’re exploring a lot of different things because there is a Helicobacter, it’s not pylori, that has CdtB. I think its Helicobacter hepaticus. I haven’t looked at this in a while. But Giardia has vinculin in it. If you kill Giardia and it releases all this vinculin, could you form vinculin antibodies? We don’t know. There’s stuff like that that is really ripe for exploration. But your question is right on, we need to look at these other organisms. We have already found some patients and I’m not going to get into the details … Again, it hasn’t been published yet. That do harbor bacteria that makes CdtB. That’s weird, they shouldn’t be there. We’re looking at that and what role that has and how bad their disease is. Or maybe they’re spreaders or they have a tendency to keep these bad bacteria in their gut in a different way.

Dr. Weitz:                          There was a question about anatomical differences. Certainly we know that if there’s obstructions or adhesions that could play a role in SIBO, right?

Dr. Pimentel:                     Yeah.

Dr. Weitz:                          Let’s see. What about your thoughts on a continuous low dose of Xifaxan or natural antimicrobial to prevent relapses? I’d just like to give my input real quick for a second. Is, we sometimes have patients who recover, we do several rounds. Sometimes I have found that a lower dose of one of the antimicrobials that resonates with them, like just a little bit of berberine or oregano that they just take every day, it seems to help manage the symptoms. What about your experience with that?

Dr. Pimentel:                     Yeah, for sure, I have patients who do that or I’ve prescribed that to. The only caution I have, and I’m sure you do this as well, Ben, is that, if they don’t respond like they are magically better and they at least stay better for a few weeks, or if they require this chronicity, I just want to make sure that it’s not an obstruction in the bowel or it’s not something else. Sometimes it’s a cancer or something that’s causing a blockage. I’m a little more aggressive with workup and maybe CT scans and other things just to see that I’m not missing anything. As long as I’m comfortable I’m not missing anything, then I proceed down that road. I think that’s just a point of caution.

Dr. Weitz:                            Yeah, good medicine. It’s always good to be cautious. Why the low fermentation diet? I think we know that. Probiotics, if you’re on birth control and you can’t absorb vitamin B, is vitamin B deficiency common in SIBO? Okay. I’m not sure. Are there vitamin … I guess that’s the question. Do we see vitamin deficiencies in SIBO?  We know the small intestine is how you’re absorbing nutrients from your food. If there’s too many bacteria lining the small intestine, it could potentially interfere with absorption of nutrients.

Dr. Pimentel:                     Yeah. A couple of things there. First of all, let’s start with folate because that’s an interesting one. The folate you get from you comes from bacteria. For example, in dogs, in veterinary world, they can diagnose SIBO by measuring folate. If folate is high in the blood, they think the dog has overgrowth and they treat the dog with antibiotics because he can’t do a breath test on a dog. But in humans, we see a high folate in SIBO quite often. That’s very common. It used to be thought that B12 deficiency could happen in SIBO. I still think we see that, but it’s not as common. That would be one of the B vitamins you’re talking about. What’s interesting is vitamin D, because we actually did a study, this was years ago … We never published it because it was just so profoundly negative. We didn’t see a deficiency in vitamin D and we also did bone scans. We didn’t see any osteoporosis in overgrowth patients, which I was a little surprised with. But this was about a 300 patient study, so quite large.

Dr. Weitz:                          What about if there’s fungal overgrowth at the same time as SIBO? What would you treat first?

Dr. Pimentel:                     Yeah. Generally, I mean, I’ve treated a lot of SIBO with antibiotics and I almost never have patients get worse with rifaximin. I’m not saying it doesn’t happen, I’m just saying it almost never happens. I generally give the rifaximin first. Then if I really think it’s fungal, then I will give the Fluconazole or something of that type for the patient as a backup. But yes, Dr. Rao actually cultures these patients more often but we haven’t been happy or confident with how we would culture yeast at our center yet. As I said, we have the Reimagine data and we’re looking at yeast in the coming months. We’ll be able to have a really clear picture of how many people who have yeast at a microscopic, a molecular level, not culturing. Which is more accurate.

Dr. Weitz:                          I mean, if we see fungal overgrowth on a stool sample, let’s say we have a patient, difficult to treat SIBO patient, not responding, and we see elevated fungal overgrowth on a stool sample. Is that a reason to think, Hey, this might be a case of SIFO?

Dr. Pimentel:                     Yeah, it could be. I mean, it could well be. If they respond to the antifungal, then I think you have your answer. It’s a little indirect because you’re measuring stool and not small bowel, but it may be an indirect way. Then again, as I said, if the patient responds dramatically, which I’ve had cases that respond dramatically, then I think you’ve got your answer. That’s a good thing for the patient.

Dr. Weitz:                          What about the use of elemental diet for patients who don’t do as well with the initial treatment?

Dr. Pimentel:                     Yeah. I used to do a lot more elemental diet when we didn’t have rifaximin and we didn’t have all the more modern approaches which are more effective. Because we’ve done about 3000 patients with elemental diet over the years. I use it a lot less these days, but it’s very effective for hydrogen. For methane, it’s about 50-50. People going into this, I sort of tell them that, “You will hate me the first three days. You will be fine for about seven or eight days. The last three days you’ll hate me more because you wish you were done.” Because it’s hard to do liquid only for 14 full days. But it’s about 80% effective in hydrogen. So very effective.

Dr. Weitz:                          Have you used metronidazole?

Dr. Pimentel:                     Metronidazole, I used … For methane, I use rifaximin and neomycin and sometimes I swap out with metronidazole. I see a question there with nitazoxanide, and that could also be a sub in for neomycin for methane. There are some people who are just using a linear or nitazoxanide. By itself, I don’t do that that often. Sort of because I think rifaximin adds something to that, we give both for methane.

Dr. Weitz:                          We have a question about glyphosate and I guess pesticides as a factor.

Dr. Pimentel:                     Yeah. I mean, all of that stuff is really … The big challenge we have is to understand our food system and our processes that go into producing food in the United States. I can’t tell you how many times I’ve had in my practice people who can’t eat pasta, they go to Italy, and they feel absolutely nothing. They feel perfect and they’re eating pasta every day. If there’s something we’re doing wrong, these are some of the things we’re doing wrong, polysorbate 80 or other agents that are food preservatives, sodium benzoate. I don’t know what we’re doing with all this stuff. There’s something different about the natural food you get in Italy and Europe as compared to here. It’s a quagmire, but I think there’s something wrong.

Dr. Weitz:                          Yeah. Our food system leaves a lot to be desired. We sometimes run some of these food sensitivity panels. One of the things they test is meat glue. Because apparently they glue the meat together. I mean, we really process our foods in all kinds of disgusting ways. Somebody asked about treatment for adhesions.

Dr. Pimentel:                     Yeah. I mean, there’s multiple ways to treat adhesions. I know there’s Clear Passages and other places that do manipulation of the bowel for adhesions, and I’ve sent patients there for that as well. Especially if it’s a single very pinpoint adhesion, that really is quite effective. The problem with surgery is, and for the complex adhesions, it often comes back. Will give it one try, a second try maybe, but after that, it’s futile and they just keep coming back. I hate adhesions and I think it’s one of the worst things I see in my patients.

Dr. Weitz:                          What do you do with it?

Dr. Pimentel:                     Well, again, Clear Passages is one option, so I will refer them there. But in the meantime, if they’re really bad and they’re almost obstructed, they have to go to surgery. I’ve had a couple of patients just in the last two months that struggled with that.

Dr. Weitz:                          Yeah. Okay. Thank you everybody for their questions and joining us. Thank you so much for being generous with your time Dr. Pimentel, we really learned a lot.

Dr. Pimentel:                     Well, I can tell your audience knows a lot because they’re asking some of the amazing questions and some of the tougher questions that I get. Thank you all for knowing so much and asking the right questions tonight because they were very good. Thank you.

Dr. Weitz:                            Great. Thank you. Talk to you soon.

 

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