Drs Brian Lacy and Mark Pimentel Discuss SIBO

In this podcast, Drs Brian Lacy and Mark Pimentel discuss the definition of Small Intestinal Bacterial Overgrowth, varying symptoms, new research, and future studies clinicians can expect.

Brian Lacy, MD, is a professor of medicine and gastroenterologist at Mayo Clinic Jacksonville, and Section Editor for Stomach and Small Bowel Disorders for the Gastroenterology Learning Network. 

Mark Pimentel, MD, is a professor of medicine and director of the Medically Associated Science and Technology (MAST) program at Cedars-Sinai Medical Center in Los Angeles, California.

TRANSCRIPT:

Dr. Brian Lacy:  Welcome to this "Gastroenterology Learning Network" podcast. My name is Brian Lacy. I'm a professor of medicine at the Mayo Clinic in Jacksonville, Florida.

I am absolutely delighted to be speaking today with Dr. Mark Pimentel who's Professor of Medicine and director of the MAST program, Medically Associated Science and Technology program at Cedars-Sinai Medical Center in Los Angeles, California.

It's hard to open up a GI journal these days without St. Mark's name. He has dramatically changed the field of functional bowel disorders, and especially disorders where we think patients may have bacterial overgrowth.

Our topic today is one that routinely comes up for every practicing gastroenterology, does the symptoms to patients reporting represent small intestinal bacterial overgrowth? Mark, thank you again for being on this podcast today.

Let's start with the basics. How do you define Small Intestinal Bacterial Overgrowth, or as we may refer to it during this discussion SIBO because the definition of SIBO really matters?

Dr. Mark Pimentel:  Thanks, Brian, for having me on the podcast. It's great to talk about SIBO, something near and dear to my heart in terms of just doing research on it.

Brian, not to date either of us, but we both know that breath testing started back in the '80s, in terms of trying to define what SIBO was, and equating a positive breath test. We can get into that later with Small Intestinal Bacterial Overgrowth.

The question is, what is SIBO? How do you define SIBO? If you go back to the 1960s, where a lot of people carry back to try and make that definition, SIBO was identified in patients with Roux-en-Y, blind-loop syndromes, and tracheostomized patients.

Back then we took the stomach out when there was a big ulcer that wasn't healing. We didn't have PPIs or other therapeutics. In those instances, there's so much status in the gut and malabsorption. They identify that there was a lot of bacteria in there. That's where SIBO came from.

That's where also the definition of greater than 10 to the 5 came from. We've soon learned in the last 20 years that those old definitions were the definitions of a blind loop, or a non-tracheostomized patients with so much spaces. That the real definition of what is going on in the small bowel of somebody who has a normal anatomy.

What's normal and what's not normal are very different now because we never find greater than 10 to the 3 in a normal person. Yet, we have to define abnormal by normal.

Back to your question. Small Intestinal Bacterial Overgrowth should be defined if you're going to do culture is greater than 10 to the 3 now based on the North American consensus, reviewing what is normal, and then breath testing.

I know we're going to have a lot of questions about the relevance of accuracy of breath testing. I may save that for later. We're learning more and more that breath testing may be more accurate than we think.

Dr. Lacy:  Mark, that's great. Thank you. As we frame this discussion, and I appreciate it, let's put the question about breath testing off just a little bit. Many of our patients have symptoms that they believe are consistent with SIBO.

They go online and they think that their symptoms represent SIBO. When we look at the data objectively, how common is SIBO? What is the real prevalence?

Dr. Pimentel:  What we don't want is for SIBO to be a fad. It's not a fad. It's the medical condition. When you're looking at the data objectively, SIBO is quite common, but it just depends.

For example, I don't like to think of SIBO as a diagnosis, to be frank. I don't think of IBS necessarily as a diagnosis. I know that may sound radical. Remember, if we don't understand the root cause of an illness, it's really the root cause that is the diagnosis because IBS is a constellation of symptoms, but what's causing it?

Once we get to the root cause, the nomenclature is likely to change. SIBO is always caused by something. For SIBO, it's almost always something causing spaces.

If a patient is experiencing symptoms, but they have a reason for stasis, let's say it's diabetic neuropathy of the gut or it's narcotics that caused stasis, or in the case of irritable bowel syndrome, one of the most common associations with SIBO there's maybe a lack of migrating motor complex or other motor dysfunction of the small bowel that's leading to this SIBO phenomenon.

The prevalence depends on what you look at: whether you look at breath testing or culture. If you use 10^3 as your cut off based on a study from Pasero and Magnus Simren's group, way back in 2006, 165 IBS patients cultured, 10^3 it's upwards of 43%. Had greater than 10^3 and qualified a SIBO, who were IBS, for example.

Now, we don't have those hard numbers for diabetic neuropathy or narcotics as much. In the IBS population, it's between 43 and 60%, based on culture using that Pasero study and a subsequent study by Polaris. It's quite a quite prevalent.

Dr. Lacy:  Mark, I like that answer for right reasons, so many layers to it. For our listeners who like GI physiology, don't forget the role of the migrating motor complex to sweep material through.

That comes to your point that when you think about SIBO and causes of SIBO, think about why? What are the underlying physiologic reasons that might predispose to somebody?

You mentioned a few medications such as opioids. You mentioned diabetes, you mentioned stasis for other reasons. Can you give us a few more, maybe your top five or six things that you think about that might cause SIBO?

Dr. Pimentel:  I'm going to get into my pet peeves a little bit here with SIBO because there are doctors, for example, who will treat their own patient and the patient responds transiently to antibiotics. They have SIBO and that's fine, but why?

We've actually sorted out a lot of these patients because they get referred in, and they have an adhesion, or they have a cancer on the bowel somewhere that is obstructing, or something extra luminal that's causing the bowel not to flow correctly.

Now those are rare, of course, but it's important not to just narrow it down to, "It's IBS and it's going to be SIBO, and they respond to antibiotics and we're done." You have to keep your mind open, but yeah, adhesions is another one.

Scleroderma is a very common cause of SIBO, and still the old school gastric bypasses. The blind loops are still part of our patient pool. We have to be mindful of those patients getting SIBO as well.

Dr. Lacy:  Perfect. Nice laundry list for people to consider when they're considering this diagnosis. Mark, we've danced around the issue a little bit, but when we think about symptoms, that's how the patient interview begins, what are your symptoms?

What are the classic symptoms of SIBO, and how accurate are these symptoms at predicting true underlying bacterial overgrowth?

Dr. Pimentel:  Again, we're speaking about whether the symptoms have been accurately validated, and we can talk about that in the context of methane and the context of hydrogen, and the different gases.

In general, when we're talking about an accumulation of bacteria to high numbers, when they're in the small intestine and they're at high numbers, they're basically getting fresh food. They're not getting residue. They're not getting the trash that goes into the colon after you've taken every ounce of what you can take out of a meal.

The residue in the colon is hard to ferment, hard to digest. It's fiber. It's this. It's that. It's not easy. It's a slower fermentation process and more work for bacteria, but not in the small bowel, they're getting simple carbohydrates.

Gas, bloating, distension, I would say those are the top symptoms, but then because bacteria levels shift, depending upon what you eat, it's often that these patients get a very irregular bowel pattern as well, sometimes diarrhea, sometimes no bowel movement one day.

In the case of methane, which we could get into, methane is constipating. Some of these patients are constipated, but the term SIBO doesn't work for them, for the methane group. That's a whole interesting conversation as well.

Dr. Lacy:  You're right. We may have to discuss things with you some other time. Mark, many of us were taught years ago that a simple way to identify true Small Intestinal Bacterial Overgrowth would be to do a blood test and look for vitamin deficiencies, maybe fat-soluble ones, or to look for changes in folate levels and vitamin B12 levels. B as in boy.

Is this true? Has this ever really been studied?

Dr. Pimentel:  Again, going back to the 1960s when SIBO was first discovered with those blind loops, they have malabsorption syndromes because of the iatrogenic anatomy from their surgical procedures, as much as the SIBO was contributing.

When they were finding B12 deficiency, we don't know that that was due to the SIBO or not. In fact, in the last 25 years, I rarely see true B12 deficiencies simply from SIBO. You remember the old shillings tests, where you used to give an antibiotic to see if that will make the B12 go up.

Maybe that's before both of our times, but that's the old textbooks on how to treat B12 deficiency, but folate is interesting because bacteria produce folate. I see folates in my bacterial overgrowth patients high a lot of the time.

In fact, in the veterinary world, they recognize SIBO as a cause of altered bowel patterns in dogs, for example, and they do a folate level. If it's high, that gives them the suspicion of SIBO. Is this based on large scale evidence-based medicine types of studies? Not as yet.

Dr. Lacy:  OK. That's great teaching point. For our listeners again, maybe looking at that folate level may provide a little bit of insight, but we haven't really validated that. Mark, we started the conversation with that about, not just what's the definition, but how to identify bacterial overgrowth.

This is a controversial area and I'm sure our listeners all have different opinions. What is the best way in your opinion? You're the expert here, to identify bacterial overgrowth, is it a duodenal aspirate? Is it a glucose breath test? Is it a lactulose breath test?

Dr. Pimentel:  This is my favorite question because...

[laughter]

Dr. Lacy:  ...there's so many dimensions to this question that can be not so difficult to explain. It's pretty straight forward. Here's the problem with the duodenal aspirate. We've published a series of papers over the last two years that digs into this and explains this.

If you take a duodenal aspirate, it's a lot of mucus in there and bacteria. If you try to culture that, you will culture stuff and you will get a certain number, but the mucus won't culture.

We understand now based on a validation of how to do a proper duodenal aspirate and culture, you have to add a mucolytic first, liberate the bacteria from the mucus because otherwise they get stuck in there and they don't culture out. That's one part of it.

If you're not doing the aspirate correctly, if you're just sending it to the microbiology lab and they're just throwing it on a plate because that's what they do, you're not going to get a good result. There are a lot of inaccuracies that occur there.

The second is where do you take your sample from? Is it duodenum, jejunum? All of those issues that make duodenal aspirate "the gold standard" because it's culture, but it may not be a perfect gold standard.

Then the issue of glucose and lactulose. We finally, this past year, published a paper where we compared duodenal aspirate culture using correct techniques using a double-lumen catheter that's sterile, so you avoid oral flora, and compared it to lactulose and compared it to deep sequencing.

We were able to see that lactulose, interestingly, the North American consensus said by 90 minutes if it rises by 20, that's suggestive of overgrowth. We were able to prove that 20 was the best cutoff. It predicted the culture and it predicted abnormalities on sequencing.

This is the most important part, it predicted that the metabolic pathways in the small intestine aspirate were augmented for hydrogen production. Brian, this is important because people say, "Well, the hydrogen is coming from the colon."

This paper that I'm quoting shows that, no, the upregulated pathways for hydrogen are in the small intestine in the patients where the culture is positive and the breath test is positive. The hydrogen is actually coming from the small intestine, those pathways are upregulated.

Then your second part of your question is glucose versus lactulose. Glucose gets absorbed very quickly. If you have a more mid-small-bowel overgrowth, maybe you don't pick it up with the glucose. It has a good specificity or higher specificity but a lower sensitivity.

I look at it this way. If you look at the Rifaximin trials, in general about 44% of people respond. We showed that using lactulose breath test, up to 76% of people responded to the breath test is abnormal and becomes normal.

If you used glucose, you would only pick up 25% of patients who might benefit from antibiotics. Even if you just use 44%, you'd miss 19% of people who might benefit. Now, if we were talking about a chemotherapy with a lot of side effects, then I would say, "OK, well, let's try and be conservative."

I don't like the idea of almost 20% of people missing out on a treatment that could be beneficial because you're using a higher specificity, lower sensitivity test. I hope that makes sense. I think lactulose, maybe it overcalls overgrowth, but at least you get everybody and everybody who could benefit.

Dr. Lacy:  Great teaching points, Mark. Maybe now this will be less controversial for many gastroenterologists . Mark, you've probably seen many of the same patients I do. They come in clutching a sheaf of papers, which includes a home breath test. Have these ever been validated? Do you think they're reliable?

Dr. Pimentel:  Well, I have a conflict of interest with one of these companies, which uses bags. The reason they use bags is because I'm counseling them not to do other techniques.

The challenge with breath testing, for those of you who do it, maybe those of you who don't, is we measure hydrogen, methane, CO2, and now more recently hydrogen sulfide.

I want to focus on the carbon dioxide. The carbon dioxide is measured not because we're trying to correlate it with bacteria, but the carbon dioxide is measured because we need to correct the breath to alveolar gas levels. Let's say, the alveolar gas level is 5.5% carbon dioxide.

If your breath sample comes back and it's 5.0, then you just got to correct up by a little bit all the gases, hydrogen, methane, and H2S. If the breath gas comes back at 1% CO2, that's a terrible sample. You can still correct at the 5.5.

Imagine you had a two-part per million or a four-part per million hydrogen on that sample, now you got a 5 times corrected to get to 5.5. You're infusing a lot of error. The closer you get to 5.5 on your breath sample, the better quality the sample is, and the less correction you have to do and less error.

In some of these open systems where you're, for example, the straw and you're blowing in, it's open to the air. There's higher risk if the patient is not doing it correctly to have CO2 diluted by room air. All of those things weigh into how the breath tests are working.

What I will say is that most of these places are CLIA-certified laboratories. They have had to validate the transfer technique. Even if they haven't published it, they should have on record how they validated that the technique was in fact doing it as intended.

Dr. Lacy:  Mark, great, thank you. That's incredibly helpful. Many providers report that elevated methane levels are diagnostic of bacterial overgrowth. You alluded to this earlier. Is that true or should we place this in another category?

Dr. Pimentel:  We were very fortunate to be able to participate in a SIBO guideline for the American College of Gastroenterology. The board commissioned one, and I'm grateful for that.

We recognize in that guideline that we still have a long way to go for SIBO in terms of trying to get hardcore-controlled trials for treatment, for example.

What we were able to do with methane is clarify that methanogens are in the colon, mostly. Maybe a little in the small bowel. It's not really, B bacteria, methanogens or archaea. The term SIBO or bacterial overgrowth doesn't work for methane.

We coined a new term called IMO. Intestinal, meaning it could be colon or small bowel. Methanogen because it's a methanogens. It's archaea overgrowth, so it's IMO. That's a new category that we've made.

For example, Nick Talley's group, first author is Shaw, have published a beautiful paper of meta-analysis, summarizing that methane is associated with constipation, and the hydrogen side appears to be very commonly positive in IBS.

That was a very nice meta-analysis that summarizes 20 years of data around this, and that there are two conditions, the methane positive and the other.

Dr. Lacy:  Perfect. Mark, regarding breath tests, and you've given our listeners so much great information, could you just give them maybe one or two reasons why you might get a false positive breath test or maybe a false negative breath test?

Dr. Pimentel:  There's a number of reasons you could have a false positive breath test. For example, patients who've had, let's say a pyloric sphincterotomy and they have dumping syndrome or rapid transit, you might expect even glucose or lactulose to reach the colon prematurely, and then you could get an early peek.

Anatomy is important in terms of patients. There are patients also with rapid transit, although that's less common. I think rapid transit has the potential for giving a false positive test.

The biggest challenge is the false negative test because patients on heavy narcotics or opiates, their stomach may not empty for two hours the lactulose or the glucose. It may be just negative.

Patients with gastroparesis, the carbohydrate will sit in the stomach for an indefinite period of time, and then you've done two hours and the hydrogen hasn't gone up. There's a number of things that could definitely impact that.

Ondansetron is a 5-HT3 antagonist. That can also result in slowing of gastric transit, leading to a false negative. There's a number of things you have to consider.

Dr. Lacy:  Perfect. I want to come back to that methane topic a little bit because it's such an area of interest. Many questions come up from both providers and patients. You've done some interesting research over the years showing that methane can change colon function and colon transit.

Do most patients with chronic idiopathic constipation, or IBS with constipation have elevated methane levels? Can you tell us a little bit more about the mechanism of action? What's methane really doing?

Dr. Pimentel:  When we look for methane methanogen, many people have them at very low levels. We've defined a cut-off for PCR up to 10 to the 3 in the stool is considered normal Methanobrevibacter smithii, which is the key culprit in methane.

When it overpopulates as an EMO, then you get this methane on the breath. This is what's interesting about methane, the higher the methane, the more constipated you are.

Back in the last decade, we did some physiology experiments where we put methane into organ baths of ileum and other colonic segments. Methane doesn't paralyze the gut. It causes the gut to become non-peristaltic and move to segmental contractions.

It causes an active slowing of transit in our animal model and in various other models that we've done since. Methane is, we call it gas or transmitter, you could say. We have a very nice study coming out with multiple facets that addresses this and in different ways.

We don't know why methane overpopulates the gut or these methanogens grow up to such a high level. Methane is very important. Interestingly, we actually did a study to see what the accuracy of methane is.

The doctor was blinded to the gas. The patient was blinded to their breath test. Then the doctor and the patient, independently determined whether that patient was constipated or not. We got upwards of 90% sensitivity and specificity.

I can't remember the exact numbers in terms of methane being able to diagnose constipation, just by a simple measurement of the gas. We see it in about 80% of people who are constipated, which is interesting, because that's a pretty strong relationship.

Also, one last thing, in the one double-blind study we did do, when we got rid of methane, the constipation was most improved in those patients. There may be a cause-and-effect relationship that we're starting to unpackage.

Dr. Lacy:  Very nice, good physiology, good biologic plausibility, and good effect with treatment. Speaking of treatment, Mark, this too is a controversial area. You've embedded yourself in a controversial topic. We know we don't have a large head-to-head comparison studies, demonstrating that antibiotic A is better than antibiotic B.

Given your expertise in this area in over the last 20 years, do you have an algorithm you could share with our listeners for patients with symptoms suggestive of SIBO and a documented abnormal breath test?

Dr. Pimentel:  In our work with SIBO and now, we're doing summaries of 12,000 plus breath-tests that we've done over a period of time at Cedars as part of a number of projects.

Here's a few things, if you go back to the textbooks and you look at the list of treatments for SIBO, Metronidazole always is the common one that people start with. That doesn't work at all almost.

In our SIBO population, the ability to make a breath test normal with Flagyl or Metronidazole, I should say, is less than 20%. Our common dogma that we teach or that we read in the textbooks, they don't pan out in real life.

The best antibiotics that even in some small controlled studies are, for example, Ampicillin-Clavulanate has been quite good. Ciprofloxacin with Metronidazole combined has been quite good. Azithromycin also, and of course, Rifaximin has been shown to be quite effective.

You're right, head-to-head, double-blind, large-scale trials, or any FDA-registered trials are coming, but they're not available yet.

On the methane side, there's one double-blind study, I mentioned methane. This is based on work in-vitro that methanogens are not bacteria. Antibiotics were devised for bacteria. They have some cross benefit, but Rifaximin isn't as good, and Neomycin isn't as good for methane.

When you combine them for some reason in the test tube, and then in the human study, a small double-blind study of about 35 patients, that combination did the trick for a lot of patients. We're thinking combinations are going to be more important for the intestinal methanogen overgrowth side of the equation.

Dr. Lacy:  Thank you, Mark. That's a great teaching point about Metronidazole, but not very effective. This has been an amazing discussion, but no surprise to me, and no surprise to our listeners who know your work so well. Any last comments for our listeners?

Dr. Pimentel:  The listeners just need to stay tuned. There's a tremendous amount of data coming out in the next 12 months and beyond. Now that we have the molecular signatures and sequencing for SIBO, we can really move things forward.

One of the things that's emerging is we're publishing all of this data. It is public information. E. coli and Klebsiella, those are the two characters that they're like weeds in the garden.

If you don't mow your lawn and don't have a migrating motor complex, E. coli and Klebsiella take the opportunity and take over, and destroy other organisms and the balance in the small intestine.

It's not just SIBO, we're starting to understand the depth of what it all means. It's going to be all about E. coli and Klebsiella on the regular SIBO side, and that Methanobrevibacter smithii on methanogen side. Stay tuned, lots to come.

Dr. Lacy:  That's great. I like that kind of upcoming news. That's great for all of our listeners and our other patients and providers as well. Mark, once again, thank you so much for educating me and our listeners. Looking forward to lots of great new experiments coming from your lab and lots of great new data. Thank you so much.

Dr. Pimentel:  Thanks, Brian.