Have We Been Wrong about SIBO? with Dr. Purna Kashyap | RHR

RHR: Have We Been Wrong about SIBO? with Dr. Purna Kashyap

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Is SIBO the result of bacterial overgrowth, or decreased bacterial diversity? In this episode of Revolution Health Radio, I talk with Dr. Purna Kashyap—an expert in the microbiome and G.I. issues—about his recent study on SIBO and the implications it has for treatment.

Revolution Health Radio podcast, Chris Kresser

In this episode, we discuss:

  • How our understanding of gut issues has changed
  • Kashyap’s recent findings on SIBO
  • How diet impacts SIBO symptoms
  • Why individualized treatment for SIBO is better than one-size-fits-all
  • Diet, lifestyle, and a healthy gut microbiome
  • Resolving SIBO symptoms
  • Better treatment and testing methods for SIBO

Show notes:

Hey, everybody, it’s Chris Kresser. Welcome to another episode of Revolution Health Radio. This week I’m really excited to welcome Dr. Purna Kashyap as a guest on the show to discuss his recent Nature paper on small intestinal dysbiosis.

If you’ve been listening to this show for any length of time, especially recently, you’ll know that I have some significant concerns about the current understanding of SIBO, or small intestinal bacterial overgrowth—everything from the way we test for it to the way we treat for it. And I recently had Dr. Mark Pimentel on the show as a guest who represents perhaps the current paradigm of understanding SIBO, although that is evolving, as you know, if you listened to that show. He now understands it as an autoimmune condition that affects the nerves of the small intestine that tends to occur after an episode of food poisoning. So even that is different than what we used to understand about SIBO. But Dr. Kashyap published a paper which raises even more questions about the definition and the diagnosis of SIBO and perhaps even how to treat it.

So Dr. Purna Kashyap is an associate professor of medicine, physiology, and biomedical engineering and the co-program director of the microbiome program in the Center for Individualized Medicine at Mayo Clinic in Rochester, Minnesota. He’s a fellow of the American Gastroenterological Association and member of their Center for Gut Microbiome Research and Education and serves on the council of the American Neurogastroenterology and Motility Society. He’s the associate editor of the journal Gut Microbes and serves on the editorial board of Neurogastroenterology & Motility and The FASEB Journal.

Dr. Kashyap’s gut microbiome laboratory is interested in understanding the complex interactions between diet, gut microbes, and gastrointestinal function. Deleterious alterations in gut microbiota have been associated with a number of disease states, such as Clostridium difficile colitis, functional bowel disorders such as irritable bowel syndrome, and metabolic diseases such as obesity. However, the functional role of gut microbes in the development of these diseases remains largely unknown, and that’s what Dr. Kashyap’s laboratory focuses on.

So, as with the interview with Dr. Pimentel, this one might get pretty technical. So apologies for that in advance. Those of you who are healthcare practitioners may enjoy that, while it might go over the head of some of my lay listeners. But it’s a really important topic, one that causes a lot of confusion and misunderstanding in medicine. And because SIBO is getting so much attention now in the medical world, I think it’s really important to develop a more clear understanding of what causes it and how to treat it. So let’s dive in.

Chris Kresser:  Dr. Kashyap, thank you so much for joining us. I’ve been really looking forward to this.

Purna Kashyap:  Thanks, Chris. Thanks for having me.

Chris Kresser:  So let’s start with how you got interested in researching the microbiome and SIBO in the first place.

How Our Understanding of Gut Issues Has Changed

Purna Kashyap:  So, looking back, my training was in gastrointestinal physiology. I was interested in how the G.I. tract functions and the basic function of the G.I. tract. And the role of the microbiome was fairly ill-defined in this space. There were early studies back from the ’50s and ’60s, but it seemed like it fell off the radar. But it wasn’t surprising because over the years our biggest problem was that we didn’t have a way of studying the microbes other than culturing them.

Chris Kresser:  Right.

Purna Kashyap:  So until the next-gen sequencing came back, we were really restricted. While we knew they were important, we really didn’t have the tools that we needed. And so as the field started coming back with next-gen sequencing, I got more interested in being able to study the effect of microbes on gastrointestinal physiology per se. But when it comes to small intestine bacterial overgrowth, it’s more from my clinical practice. Because practice is primarily patients who have functional G.I. diseases.

So they have symptoms ranging from diarrhea to constipation to chronic pain to bloating. And there has been this growing sort of, seems like every year, the number of patients who come complaining of small intestine bacterial overgrowth kept increasing. And this was being blamed for a lot of patients’ symptoms without really as good of an evidence as I would’ve liked. And having just trained in the microbiome and knowing the ill effects of antibiotics on the microbiome, I was more and more wary of looking at patients and how they were being treated with antibiotics. So that really took me, that led me to have a pause and try to figure out what we are doing here.

And really, when you stop and think for a moment, it’s really remarkable, right? It’s probably the only disease where we just quantify the amount of bacteria and then we treat them with antibiotics to decrease the number of bacteria. So we really don’t know what’s there and we really don’t know what we’re treating.

Chris Kresser:  Right.

Purna Kashyap:  And this was okay back in the ’50s to ’70s when it was first described because it was described in a very specific subset of patients either who had anatomic abnormalities in the gut because of which a part of the gut was not as motile as it should be, or because of diseases such as infiltrative diseases where the gut motility was slowed and they saw an increase in bacteria in the small intestine.

But this was accompanied by malabsorption and diarrhea and weight loss. And so they had to find a way of treating these patients because you couldn’t really correct anatomic abnormality or you couldn’t correct underlying gut dysfunction. So they found a way.

But back then they didn’t have next-gen sequencing, they didn’t have the tools that we have right now.

Chris Kresser:  Right.

Purna Kashyap:  But somehow over the years, the diagnosis of SIBO started expanding to multiple G.I. conditions and multiple G.I. symptoms, and it was largely based on position statements, consensus among individuals, and practices started diversifying the original description of SIBO of greater than 10 to the five colonies forming units of total bacteria in the small intestine has then morphed into different thresholds of 10 to the three or 10 to the five, depending on the lab.

The type of culture media used has been changed, but overall, we still are just counting the bacteria in the small intestine. So bacteria present in the small intestine, all we’re saying is as an increase or decrease. But the biggest dichotomy is for the same group of patients that we treat with antibiotics, we also give those same patients probiotics because we feel like we need to treat them with healthy bacteria. But guess what? When we’re looking at SIBO or we’re looking at bacterial culture, the culture doesn’t define which is a good or bad bacteria.

So on one hand, we think giving good bacteria is helpful. On the other hand, we think reducing bacterial numbers is good. And so this dichotomy was really something which bothered me for the longest time, and I think what I really wanted to do was try to move the needle forward at least a little bit to try to get us away from simply relying on culture alone to moving into the technology which has emerged over the last decade, which we are utilizing for everything else. But we haven’t as well for the small intestine.

Chris Kresser:  Right. And cultures, of course, only one of the methods used for testing for SIBO in a clinical setting, breath testing being the other one and perhaps even more problematic. But let’s—

Purna Kashyap:  So the problem here of course, like you just said, the cultures were how SIBO was defined. So all the tests which came beyond that in some ways were trying to compare themselves to the culture to find the correlation, and that’s how the breath test slowly emerged, and then they sort of took a life of their own. Because the idea was if you can have a noninvasive way of detecting this, it would be even better. But it didn’t change the specificity of the diagnosis. It was still relying on bacterial fermentation of the total amount of bacteria present.

SIBO: is bacterial overgrowth always the cause? In this episode of RHR, we discuss how a lack of bacterial diversity in the small intestine—not bacterial overgrowth—could be the cause of SIBO symptoms for some people. #functionalmedicine #chriskresser

Dr. Kashyap’s Recent Findings on SIBO

Chris Kresser:  Right. So let’s … you and your colleagues recently published a paper in Nature, which I was really intrigued to read, that had several results that seemed to contradict some of the current dogma. You alluded to some of them just now about SIBO, but can you briefly summarize the findings of this paper in Nature Communications?

Purna Kashyap:  Sure, and I wouldn’t say we were trying to contradict the current dogma. We reported the findings primarily by doing both culture in our patients and doing microbial composition analyses using 16S rRNA, which is one way by which you can define the community composition.

Chris Kresser:  Right.

Purna Kashyap:  And the goal was to try to not only see how many bacteria are present, but also to see what kind of bacteria are present. And so in the initial part of the study, we basically took patients who were clinically symptomatic. So they had symptoms which were ill-defined, which means we didn’t know what was causing the symptoms. And oftentimes these patients get tested for small intestine bacterial growth by obtaining a culture from the small intestine because they often have upper endoscopies done as a part of their work-up.

And so we decided to take a consecutive group of these patients who were being tested for small intestine bacterial growth, and while a part of their sample went to the lab just for clinical testing as it normally would go, we took the remainder of the sample to do microbial community analysis on the same subset of, the same sample type. And our goal was to try to see when we talk about bacterial overgrowth, are we talking about overgrowth of normal bacteria? Are we talking about overgrowth of abnormal, different bacteria? So we didn’t really know how the microbial composition correlates with the bacterial overgrowth test that we do in the lab.

And so what we found was when you just look at presence or absence of small intestine bacterial growth, which is microbiological diagnosis, because it’s based on culture, and you compare that to the microbial composition, there’s very little difference in the microbial composition of patients who had this one test of bacterial overgrowth or who did not have small intestinal bacterial overgrowth.

Now, if you take a group of healthy individuals who don’t have any symptoms and this was done as part of other recent studies, and then you look at their microbial composition and you try to compare the composition of all the symptomatic patients combined, then you actually see the microbial composition. If you try to compare that, that’s actually quite different from healthy individuals. So patient with symptoms had a change in the microbial composition, but the increase or decrease in the total number of bacteria did not necessarily correlate with symptoms. So what happens when you take a group together is statistically you can see a difference.

But how meaningful is that? So we took a look at the symptomatic patients and said, are these truly different from the healthy individuals? And what we found was that a subset of these symptomatic patients in fact had microbial composition which are very similar to healthy people. So they didn’t differ as much from the healthy people. Whereas there was a group of patients who had microbial composition which was quite distinct from healthy people. So what we were trying to highlight is, one, we don’t know what causes symptoms in these patients. So we kind of assume that the small intestinal bacteria is responsible for symptoms in all of these patients. But once we start looking at the microbiome, now we can start sub-categorizing these patients based on their microbial composition, which allows us to, in the future, answer the question, is the disruption in the microbial community structure responsible for symptoms in patients?

So it’s basically moving from an imprecise way of assessing the small intestinal microbiome to slowly trying to define the microbial composition better and trying to find where there is an abnormal microbiome or an altered microbiome and where it’s a healthy-appearing microbiome.

Chris Kresser:  So you found, I believe, that those who tested positive using the culture method for bacterial overgrowth in the small intestine had an overgrowth of mostly anaerobic bacteria rather than aerobic. What is the significance of that?

Purna Kashyap:  So again, it’s not surprising, right? So when small intestinal bacterial overgrowth was first described, we know that anaerobics were unusual in the small intestine. They were primarily in the colon, and you could still see some aerobic bacteria in the small intestine. When it was, so that’s technically, it was the overgrowth of anaerobic bacteria that most people used to see—

Chris Kresser:  Sure, it drives the condition. Yeah.

Purna Kashyap:  But it’s always being defined as a total amount of bacteria, including both aerobic and anaerobic. So we were not surprised because that’s what our test was checking.

How Diet Impacts SIBO Symptoms

Chris Kresser:  So with the, I think you also found in the paper that a subset of healthy individuals who were eating a high-fiber diet had bacterial overgrowth, or what is characterized as overgrowth. Are you thinking now at this point that in some patients what is called SIBO is a nonpathological condition, and for some reason they can have bacteria in their small intestine and not have symptoms? And it’s more of an indicator in those cases of their diet than anything else?

Purna Kashyap:  Great question, right? I mean, so, that’s what, what we really need to do is sit back and think of what small intestinal bacterial overgrowth was. It was always an epiphenomenon. It wasn’t the primary disease. So patients had some dysmotility, which led to an overgrowth of the bacteria. So it was an epiphenomenon. Which means there was some alteration which then provided an environment which allowed the bacteria to overgrow.

Chris Kresser:  Right.

Purna Kashyap:  So, in our healthy individuals, diet could’ve been playing a role where it provided the appropriate niches for intestinal bacteria to grow in the small intestine, and it’s an epiphenomenon of a condition where it’s not causing symptoms. So I don’t think just, like, you already know that small intestinal bacterial overgrowth does not correlate with individual symptoms in patients. And we don’t have good data to say that it is in fact, the driver of symptoms. We don’t have a mechanism by which we can explain this.

So, we have a mechanism by which we know small intestinal bacterial overgrowth can cause malabsorption and diarrhea. But we can’t explain the symptoms that patients have in terms of abdominal bloating and pain and discomfort in terms of what’s the mechanism for that. So I think patients can have small intestinal bacterial overgrowth without having symptoms. We do know that healthy people can carry, can have more bacteria in the small intestine without symptoms.

But in this study, what was interesting to us is these patients were on a high-fiber diet, and maybe that provided an environment which is conducive for these bacteria to grow and flourish in the small intestine without actually causing any problems. So it was an indication to us that just the presence of SIBO may just be a red herring and we should be careful when we interpret these results where it may or may not be responsible for symptoms.

Chris Kresser:  And then the flipside of that, you found that people who were eating a lower-fiber, more processed diet were more likely to have not SIBO, but I think a disrupted small intestinal microbiome or lower microbial diversity and thus be symptomatic.

Purna Kashyap:  So what we found was, so it’s interesting how we got to this point. So, when we looked at our symptomatic patients in our first study, we found that they had, what was remarkable to us was that there was a decrease in Prevotella, which is one of the bacteria present in the small intestine and the colon. But it correlates with carbohydrate digestion. So the healthy individuals had higher levels of Prevotella, the symptomatic patients had lower levels of Prevotella. And since Prevotella correlates well with diet, especially with high-fiber diet, we were curious to see what effect a high-fiber diet has on the microbiome.

And it’s the same group of patients that we actually switched them from what their baseline diet was to a low-fiber diet. And we wanted to see when we switched them, is there an effect on their microbiome and on their symptoms? And so it was interesting that when we switched them from a high-fiber to a low-fiber diet, all of them developed symptoms. All of them had G.I. symptoms, but remarkably, some of them had symptoms outside of the G.I. tract, like fatigue and feeling of inability to concentrate, things which we often hear from patients, but we don’t know what’s obviously the driver of these.

So it was quite interesting to us that even though it’s a small study, it’s a pilot study, we can’t really make big conclusions from this, it was more an indicator that this needs to be looked at more carefully. Because just seven days of intervention of switching the diet from the baseline high-fiber diet to a high-simple-sugar diet led to symptoms, led to decrease in microbial diversity which correlated of the increase in intestinal permeability and presence of G.I. as well as non-G.I. symptoms. Which is quite interesting because these patients, when they’re on a high-fiber diet, actually had higher fermentation, higher production of short-chain fatty acids when compared to when they were switched off to a low-fiber diet, when the short-chain fatty acid concentration decreased in the small intestine. And we always blame fermentation for patient symptoms.

Chris Kresser:  That’s right.

Purna Kashyap:  There’s increased fermentation, so you get symptoms, and here we’ve seen the converse. And that tells us that we shouldn’t always be jumping on this idea of restricting patients’ diets to decrease bacterial fermentation because we think that that’s what’s driving the symptoms. That may not be the case.

Chris Kresser:  So what do you make of, I don’t know if you’ve had patients in your practice who’ve been on low-FODMAP diets or other low-fermentation diets and have experienced relief. What do you think might be happening in those cases?

Purna Kashyap:  So one low-FODMAP diet is a restriction of many specific carbohydrates. So if you think of it, it’s fermentable monosaccharides, disaccharides, and oligosaccharides and polyols, right?

Chris Kresser:  Yeah.

Purna Kashyap:  Monosaccharides and the disaccharides are actually simple sugars.

Chris Kresser:  Yeah.

Purna Kashyap:  So a high level of simple sugars, restricting them is not going to have as much of an effect in the microbiome.

Chris Kresser:  Right.

Purna Kashyap:  Now when you talk about oligosaccharides, that’s where it gets tricky because fruits and vegetables and food components don’t all have just one kind of sugar. They can have complex carbohydrates, they can have simple sugars, they can have oligosaccharides. So they are always a mix.

And so if it’s well-administered, it’s possible that you’re just restricting certain simple sugars, whereas you’re still keeping the complex carbohydrates, depending on how well the dietician is able to balance the diet. And that’s why this is best done under the direction of a nutritionist and not done by patients themselves looking on the web. So yeah, why do these patients improve in symptoms? It may be related to actually the restriction of simple sugars as opposed to restriction of complex carbohydrates.

Chris Kresser:  Right.

Purna Kashyap:  And the problem is you would not know unless you break it down into restricting just fermentable mono and disaccharides as opposed to restricting the entire group, right?

Chris Kresser:  Right.

Purna Kashyap:  So when we say FODMAP, it’s a group of components, and we don’t know which individual component of this is actually providing the actual relief in symptoms. The other problem with FODMAPs is the long-term follow-up. So in patients, we often see immediate relief of symptoms with a lot of different interventions. But the question is durability of response and how long can the patients be asymptomatic.

Unfortunately, all the patients who come to us, because it’s a tertiary referral center, have obviously failed these restrictive diets. And I’m more a proponent of increasing complex carbohydrates in the diet. So I make them do the reverse. But I usually don’t put patients on restrictive diets. But I will restrict simple sugars in these patients.

Chris Kresser:  Yeah, and there’s the papers that have been published over the last few years looking at the colonic microbiome in people who’ve been following a low-FODMAP diet for an extended period and seeing some decrease in microbial diversity, I think. And some possibly concerning effects on the colonic microbiome with those diets.

Purna Kashyap:  Yeah, and remember there’s always collateral damage. When you give antibiotics to treat small intestinal bacterial overgrowth, they’re not selectively going and killing bacteria in the small intestine. When you change somebody’s diet, you’re not selectively changing fermentation in the small intestine. It’s going to have an effect across the bowels. So you’re going to see collateral damage in different parts of the gut, and that’s why we need to be careful when we are trying to intentionally disrupt the microbiome that there are going to be unintended consequences of that.

Why Individualized Treatment for SIBO Is Better than One-Size-Fits-All

Chris Kresser:  What do you think about, along similar lines, if it’s not overgrowth that’s causing the symptoms and it’s instead decreased diversity, then for the subset of patients who do take rifaximin and improve, which is, for the listeners, the most common medication used to treat SIBO, what do you think is happening there?

Purna Kashyap:  So, rifaximin acts well in the presence of bile. So, it works better in the small intestine, so that’s one advantage. And it does target specific groups of bacteria. So it’s not 100 percent effective in everybody, which means it is effective in a subset of patients who have small intestinal bacterial overgrowth. But if you look at our entire cohort, there are patients who have small intestinal bacterial overgrowth and a disrupted microbiome, and you have patients with small intestinal bacterial overgrowth who have a normal-appearing microbiome.

So you can definitely have patients who have a disrupted microbiome and there’s overgrowth of those bacteria which could respond to specific antibiotic treatments. But the question is, we should be more selective. We should be targeting individuals who have a disruption, who we think would respond to these interventions rather than trying to treat the whole group as one big group.

Chris Kresser:  And of course, we know that the recurrence rates for people who are treated with rifaximin are pretty high, both in terms of SIBO as measured by the breath test—which, as we’re talking about, may not actually be that irrelevant—but in terms of symptoms, certainly as a clinician, in our clinic we see a lot of people who have taken that medication and then the symptoms come back.

Purna Kashyap:  Absolutely.

Chris Kresser:  Sometimes they don’t go away or sometimes they come back in a week, sometimes it’s three months. But it’s higher than 45 percent, which is what I’ve seen in the literature in our experience.

Purna Kashyap:  And again, that’s exactly my point. Because I started this conversation by saying that we are in the next-gen sequencing era, and we still have this disease, which is reliant on we don’t know what’s growing, we don’t know what we’re treating. It’s a very empiric way of treating. And if an infectious disease doctor was going to look at this and do this, they’d be horrified. You have no idea what you’re treating, and we’re giving these patients antibiotics.

And so, I think we have to be careful in how we assess these patients and approach it. There’s definitely going to be a subset of patients which has been previously described by small intestinal bacterial overgrowth likely plays a role. It was well-described back in the literature. Those patients still exist. I mean, you know patients with anatomic abnormalities in their G.I. tract, where we don’t have other options. But they have truly malabsorption with diarrhea and weight loss, and we can attribute it to the original description. But the debate has expanded in terms of its application. That’s what’s a bit scary at this point.

Chris Kresser:  Right. Dr. Pimentel has proposed, and this isn’t necessarily directly related to this conversation about SIBO we’ve been having, although it certainly is related, that in some cases, a subset of patients with IBS-D and IBS-mixed who also test positive on a breath test for SIBO have antibodies to vinculin proteins, the vinculin and CdtB, in that their condition may be a result of a food poisoning episode that they had in the past and almost kind of like an autoimmune-like reaction that’s affecting the small intestine in a kind of post-infectious IBS presentation. I’m just curious if you, what your thoughts are about this. It’s relatively new.

Purna Kashyap:  I mean, I think we all encourage investigation in this area because we all would like to know what the mechanism is. And like you just started with the conversation, the start of the sentence by saying a “subset of patients.” It’s basically trying to identify different subsets of patients where we understand what the mechanism is so we can actually treat these patients more precisely, rather than using this one-size-fits-all.

So Mark has been doing good work in this area in trying to identify what might be the initial instigator and driver of symptoms, and we all support trying to understand the mechanism behind these. And maybe this will allow us to subclass or subcategorize patients who may benefit from a specific treatment. And the idea is that, right? So, we want to be able to categorize these patients where we understand what might be causing the symptoms and specifically target those symptoms, or those mechanisms.

So, like I said, I’m not doing work in that area, but I’m completely supportive of research which allows us to understand the mechanisms of pathogenesis of symptoms in these patients.

Diet, Lifestyle, and a Healthy Gut Microbiome

Chris Kresser:  Do you have any speculation yourself about what causes the reduction in diversity in the small intestinal microbiome that is potentially causing symptoms in these patients? There’s a diet that’s low in fiber, which may be contributing. Do you have any other suspicions or thoughts about what might be the cause of that?

Purna Kashyap:  I think when we think about a diet which is high in simple sugars, we also know we have a highly absorptive small intestine which is going to be very efficient in absorbing these. Because we don’t need to work to get these nutrients.

Chris Kresser:  Right.

Purna Kashyap:  You don’t have to do anything. So there is definitely going to be decreased nutrient load, and you have to remember, the small intestine is already an adverse environment for the bacteria. The reason you see a steady increase in the bacteria from the small intestine towards the colon is because of the flow of fluid. You have the bile acid, you have lower availability of nutrients.

So diet can play a role in determining what grows and what does not grow. So if you have a balanced diet and there are nutrients available for specific bacteria which survive better in the presence of bile, which can utilize nutrients, they will do better in the small intestine. Because they have less competition here than down in the colon. Whereas those who don’t survive in the presence of bile will likely migrate down further. So there are these geographic factors which drive the population dynamics within the small intestine to the large intestine. And these are going to vary in different individuals.

These are going to be adapted to an individual’s diet or what their normal dietary habits are. And always these things come in the picture when you change something. When a person, there’s no … We’ve always struggled with defining what a healthy microbiome is. Because each individual has unique circumstance in terms of their diet, their geography, the environment. And the microbiome is well-adapted to their habits and the person who is symptomatic. We can’t call one microbiome healthier than the other microbiome.

Chris Kresser:  Right.

Purna Kashyap:  So we’ve struggled with this idea that “what is a healthy microbiome?” To me, a microbiome which is well-adapted with an individual and their lifestyle and their diet is a healthy microbiome. So in some people that’s why people who have, even though they have a higher number of bacteria or they have bacterial overgrowth, they have a healthy lifestyle, they have a healthy diet, they’re asymptomatic, I can’t say that’s abnormal.

Chris Kresser:  What do you think? Do you think stress and lack of sleep could be playing a role here since the gut is a nervous system and the enteric nervous system? And certainly we see anecdotally that stress affects the gut powerfully. We have a lot of sayings even in our language about “I’ve got butterflies in my stomach,” for example, or someone who’s going to be speaking publicly who has to run to the bathroom. Just, I haven’t seen a lot of specific research here about this particular condition and stress. But I’m just curious if you’ve speculated on that.

Purna Kashyap:  So, the gut is autonomous in some ways, that it can function on its own. But it also gets modulated by the autonomic nervous system. You just mentioned butterflies in the stomach or feeling acute stress that’s typically the fight-or-flight response. People get diarrhea, right?

So the autonomic nervous system does have an impact on G.I. physiology and G.I. function and can drive some of these changes that you see. When you talk about chronic stress in patients who have stress as a part of their life and it’s affecting … We know that they can have changes in the architecture of the small intestine, of the large intestine, comes up low-grade inflammation, or loss of mucus. And so, yeah, stress can predispose individuals to certain conditions. But when we’re starting to consider this whole mind-body connection as one entity, right? All of these go hand-in-hand.

We don’t think that one thing leads to the next, leads to the next. This idea of having sequential changes, it does not always hold true. And I think of our bodies as one unit and when you see changes in one, you see concurrent changes in another. And you have to address both. You don’t, I don’t think we can sit back and say, “Oh, let me take care of that stress and everything else is just going to go away.”

Resolving SIBO Symptoms

Chris Kresser:  Sure, sure. And so, from a clinical standpoint, like, someone comes to see you as a patient and they’re having symptoms of gas and bloating and maybe changes in stool frequency, and you ruled out other structural problems like inflammatory bowel disease, how do you think about and how would somebody who’s dealing with these symptoms think about it? Is it important to know whether the issue is in the large intestine or the small intestine? Is it even possible to know that for most people at this point, given where we are right now? Or is it just more a question of figuring out from your perspective the right combination of diet and other therapies to provide relief?

Purna Kashyap:  So, to me, the most important part where patients come in with bloating and discomfort is to try to address their bowel pattern. Because oftentimes patients with constipation will have these symptoms. And if we can treat the constipation effectively, it could get rid of some of these symptoms … I mean, the whole idea of small intestinal bacterial overgrowth, as I mentioned, started with this idea of dysmotility. But over there, we couldn’t do anything.

But patients who have constipation, we can treat them effectively. Patients don’t, the problem is, they will not tell you that they have constipation because most patients, if they have a bowel movement, they feel like that’s, they are having bowel movements. But what bothers them more is the bloating and the abdominal pain and the discomfort. So they will only express what bothers them most. It’s really our job to figure out what the underlying abnormality is. So I think we need to investigate these patients to make sure that they don’t have constipation, which they don’t recognize as well.

And so that’s why you need to delve deeper, a little deeper into their symptoms, and try to ask them what they describe as a bowel movement. Do they have a sensation that they’ve completely emptied? Do they need to go multiple times to have a bowel movement? We could get a simple X-ray of their abdomen to see what the stool burden is in their colon. If they have stool packed throughout the colon, that’s an indication that they’re clearly not emptying out the colon as effectively. So I think it’s important to be able to differentiate that.

If they tell you that they’re just having loose stools, it’s important to know what volume of loose stools are they having. Patients have a very different perception of bowel pattern, right? If they have a loose stool, they feel they’re having diarrhea, which may not always be true.

Chris Kresser:  Right.

Purna Kashyap:  And they might just be passing a small amount of liquid stool, which could be overflow diarrhea, but they still have constipation. So I think it’s our job to try to understand what the underlying problem is and not just put the burden on the patient to try to tell us what the problem is. So I think a lot of patients we can treat effectively if we treat the underlying bowel pattern. I’m not saying that’s going to treat everybody with abdominal discomfort and bloating, but there’s going to be a subset of patients who have. And we know that there are two different components.

One is how the intestines sense the presence of normal or abnormal gas, and the other is truly increased or decreased production of gas. And majority of the patients, it tends to be an abnormal sensation of normal amount of gas. So when we think about patients with bloating, we have to be careful in that if you don’t see either imaging-based changes where you do see truly gaseous distention, we should consider whether there is a sensory issue where they have an abnormally elevated sensation of normal products.

Better Treatment and Testing Methods for SIBO

Chris Kresser:  So when you, as you think about what’s next in your research, where are your investigations headed? And what do you think, do you have thoughts on where this might go in terms of therapies? I know you have concerns about using antibiotics for all of the obvious reasons. What are you thinking about might be possible in terms of therapies once we better understand this condition?

Purna Kashyap:  So I think we just started the investigation of the small intestinal microbiome, right? And I’m more interested in trying to understand what these altered microbes are and what their function is and what they might be doing in the small intestine. We previously thought that when you have small intestinal bacterial overgrowth, we could be deconjugating the bile acids and that’s why it leads to fat malabsorption and these patients get diarrhea.

We know what bacteria carry bile salt hydrolases. In fact, Lactobacillus and Bifidobacterium carry bile salt hydrolases. So, and we saw that increased in our patients who had an altered microbiome. So are these bacteria leading to increased deconjugation of bile acids, or could they be causing diarrhea by the mechanism which we’ve always known? So, identifying subsets of bacteria in the small intestine in this population and trying to understand how they might be influencing symptoms which tend to vary all the way from bloating to diarrhea to abdominal pain could be the first step of trying to classify these patients based on the underlying mechanism.

And then you ask what question is obviously valid in terms of what do we do. I think we’re trying to get to the part where we can get more precise targeting of the microbial members of the gut, right? We know that antibiotics tend to be too broad. So if we can identify specific microbes that we want to target, then we can develop strategies which are less harmful to the remaining microbiome, but more precisely directed against those specific microbes. And that’s where a lot of the field has been focused on. Whether it’s phage therapy or bacterial sims or specific molecules which can target individual groups of bacteria and individual bacteria, I think we can get to that point where we can be more selective in targeting. Where before we need to identify with specific bacteria.

Chris Kresser:  What you’re targeting.

Purna Kashyap:  Yeah exactly.

Chris Kresser:  Yeah.

Purna Kashyap:  So part of the goal is to be able to identify what needs to be targeted and the other part is to develop selective therapies. And I’m confident now that the field has gotten interested in the small intestinal microbiome, that we will get there. I think our goal really was to push everyone to start thinking about characterizing the microbiome and the small intestine rather than just relying on … We’re not saying the SIBO test is not valid, it’s not relevant. I think there is a role for it. But what we’re saying is let’s move beyond that and expand what we can do and be more precise. Because now we have the tools, unlike before when we didn’t.

Chris Kresser:  Right. So there is now, we have the tools in the research setting that are not readily available for clinicians yet or patients who are outside of a research study. What do you, do you have any idea or thoughts on when somebody might be able to get their small intestine sequence or how that will even work?

Purna Kashyap:  I don’t think we’re that far off. I mean, if you look at microbiology where we’re trying to identify infectious agents, we’ve made big headways in terms of using next-gen sequencing in being able to identify pathogens which we couldn’t culture. So it’s already entered the clinical laboratory area where next-generation sequencing is being used to identify pathogens.

Now it’s a matter of being able to apply it to larger microbial communities, and the advantage you have with the small intestine is it’s a lower microbial diversity. So it’s not as dense as the colon. So I do think that we’ll be moving towards characterizing the small intestinal microbial community fairly soon. What we do with it is a different question. But I think we’ll move in the direction of being able to characterize these communities fairly soon. Now, I say “fairly soon.” You have to look at the timescale of five years, which is what we consider fairly soon.

Chris Kresser:  Yeah.

Purna Kashyap:  But I think it’s coming. I think the tools are being developed, they are already entering the clinical laboratory area. It’s just a matter of adapting them to do more than just identifying pathogens to start using them to characterize whole microbial communities. This tends to be easier in areas where there’s lower microbial diversity, like the vaginal microbiome, like the small intestinal microbiome. I think these are going to be relatively easier than more complex microbial communities.

Chris Kresser:  And how do you imagine that test working in an outpatient setting?

Purna Kashyap:  So, it’s likely not going to be in the initial stages as non-invasive as a breath test.

Chris Kresser:  Yeah.

Purna Kashyap:  But when we do an endoscopy to collect an aspirate for culture, that’s the exact same thing that we would do for looking at the microbial community composition.

Chris Kresser:  Right.

Purna Kashyap:  So it’s not any different than what we’re doing currently.

Chris Kresser:  Yeah.

Purna Kashyap:  We are collecting aspirates. But we do think there are people who are working on capsules that can be swallowed, which would not only measure the gut environment, but it also allows to sample through different parts of the gut. And those capsules may be a non-invasive way where we’ll be able to capture the small and large intestinal microbial communities by swallowing a capsule.

Chris Kresser:  Great, yeah. I’ve heard a little bit about that. That sounds like a potentially interesting avenue. So, anything you’re working on now that you can tell us about in terms of research direction?

Purna Kashyap:  So, of course, we still have a lot to finish up from this current study because we have the microbial communities. Our lab is a clinical translation lab, so we typically, once we have findings in patients or in humans, we then take them down to our mouse model. So we use a germ-free mouse model, so we’re trying to use that model to study the effect of these microbial communities on the intestine.

And so that’s where we are starting to see how these communities can affect either gene expression of the host, how it affects function in the small intestine. But beyond that, we will extend this to human subjects where down the road, well, not down the road, but moving forward, we’ll try to identify patients who might have a disrupted microbiome and try to follow them prospectively to see if that subgroup responds to treatment better than taking the entire group of patients.

Chris Kresser:  Great. Well, thank you so much for all of the amazing work that you have been doing, Dr. Kashyap. I’m excited to know that the field is moving forward and that we’re continuing to learn more about this. Because there’s truly so many people, as you know, who are impacted by these kinds of G.I. conditions. And they’re looking forward to a time when we understand them better and have more to offer as treatment.

Purna Kashyap:  Absolutely. The only thing I tell patients is don’t try to be your own doctor and don’t look on the internet and diagnose yourself. I think it’s important to have conversation with your physician about your condition. Let them do a job. It’s important to be informed, to be able to ask intelligent questions, but there’s a lot of information and misinformation on the internet. And our brain tends to focus on the misinformation, which fits what we are thinking oftentimes, and not be objective. And that’s why we always say don’t treat yourself.

For physicians too, because we can’t be objective. And the same thing we tell patients is don’t try to come up with your own diagnosis and treat yourself. Be collaborative, sure. You should ask questions and question what the physicians are doing. But at the same time, have the conversation with them and that will allow you to develop a plan together. Rather than doing what you think is right for yourself.

Chris Kresser:  There’s that old saying, “The doctor who treats himself has a fool for a patient.”

Purna Kashyap:  Exactly. And it applies to everybody, not just doctors.

Chris Kresser:  Yeah. Well, thank you again, Dr. Kashyap, for coming on the show, and best wishes with your work. We’ll be following it with interest.

Purna Kashyap:  Thanks, Chris. Thanks for having me.

Chris Kresser:  Right. Take care. Bye-bye.

Purna Kashyap:  Bye.

Now, I’d like to hear from you. How have you encountered SIBO—as a patient, or a practitioner? What are your thoughts on Dr. Kashyap’s research? Comment below and let me know.

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