Is Roundup—a popular herbicide that contains glyphosate—safe to have in your food? Probably not. In this episode, we go in depth on what the evidence shows, with returning guest and research microbiologist Kiran Krishnan. The good news is, there are simple steps you can take to build resilience in your health, even if you can’t avoid consuming it completely.
Dr. Michael Ruscio, DC: Hi, everyone. Welcome back to another episode of Dr. Ruscio Radio. This is Dr. Ruscio. Today I’m here with Kiran Krishnan who is a second-time guest. The last time he was on, we geeked out on probiotics and all things gut health, and I really appreciate the research effort that Kiran is putting in with everything that he’s doing. He seems like a really grounded, reasonable chap. So I’m glad to have you back on the show today, Kiran, to go over all things gut. We’ll go into the 102 episode!
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Kiran Krishnan: Yeah, absolutely. First of all, thank you so much for having me back. It’s an honor and a pleasure. I really enjoyed our initial conversation, and super excited to geek out some more, Dr. Ruscio. So yeah, ready to do it.
DrMR: Same here. Now, in case people haven’t heard your name before, give us a quick synopsis of your background.
KK: Yeah, so I’m a research microbiologist. Over the last couple of decades, I’ve focused heavily on the microbiome itself, developing probiotics, prebiotics, and other therapeutic tools mostly for the functional medicine marketplace. We are branching into allopathic space as well now, because there are certain areas within the hospital and within acute care where probiotics and microbiome tools can be really useful, and docs are opening up about the use of them. So we’re conducting a lot of clinical research. We’re making lots of discoveries, and I’m doing a lot of lecturing at about 45 conferences a year on the topic of microbiome.
DrMR: That’s great. Let’s talk a little bit about research. I know there have been some changes on your end since the last time we spoke. Even though wheels in research tend to turn slowly, it’s been at least a year since we spoke and I know that you have some new projects that you’re currently working on. So get us up to speed in terms of what your research projects are looking like and anything new that you’ve published or found.
KK: Yeah. Actually since the last time we spoke, we’ve completed a number of trials. A couple of them have been published. Some of them are still going through the peer-review process (when you submit for publication). Some exciting stuff. And then I’ll talk about a scary trial with Roundup and glyphosate. But a couple of really exciting areas.
We finished a trial on the gut-skin axis and seeing if modulation in the gut can actually result in changes in the skin and, in particular, acne. We were able to show about a 45% reduction in acne lesion count in 30 days by utilizing a spore-based probiotic to modulate the gut. What’s interesting about that is when you start looking at the mechanism of what changes in the gut resulted in the skin changes, you start to see that certain microbes, when you increase their count, seem to have a protective role in the skin. So Ruminococcus is what we call a keystone strain, a very important, protective microbe. If you can increase Ruminococcus, whether through a probiotic or prebiotic, you can actually significantly alleviate issues on the skin.
We also finished a triglyceride study, where we showed we can reduce triglycerides by modulating the microbiome.
We completed a study on hepatoprotection. And this is done in animal models where you can induce hepatotoxicity—so, liver toxicity—by giving overdoses of acetaminophen. Then you can compare different tools to protect the liver. We used probiotics to do that. We saw that probiotics in the microbiome can have a significant protective factor on the liver.
Then we finished a probiotic/prebiotic trial where we showed a significant ability to modulate what the microbiome population looks like in terms of diversity, short-chain fatty acid production and so on, and all of those things are associated with a significantly increased health outcome.
The other study that we completed is a study on Roundup and glyphosate, looking at what the impact of glyphosate and Roundup is on a pediatric microbiome. And I can tell you, the data is kind of scary!
Health Effects of Glyphosate, Roundup
DrMR: Well, let’s go into a bit more detail about Roundup and glyphosate. For people who maybe haven’t heard of this before, let’s give them the short synopsis on what it is, where it’s found, and what it might do that’s deleterious to one’s system.
KK: Yeah. So the very infamous company, Monsanto, developed several herbicides and pesticides. The most famous herbicide is one called Roundup. The active ingredient in Roundup is a compound called glyphosate. What’s interesting is when they first developed glyphosate—this was way back in the late ’60s, early ’70s—they discovered it to be an antimicrobial. A patent that was filed in the 1970s by Monsanto showed it to be a very strong antimicrobial, so basically an antibiotic.
But then they also found that lower order plants, things like weeds, used a biochemical mechanism called a shikimate pathway to produce something that’s really important for health and wellness, and for biological function, something called aromatic amino acids. This shikimate pathway is what they use to produce aromatic amino acids, and this glyphosate compound basically inhibits the shikimate pathway.
Now, the reason that’s important is because the premise of the safety of glyphosate, or the reasoning they had why spraying this synthetic chemical compound is fine and exposure to humans is fine is because in the human cell, we don’t use the shikimate pathway to produce our aromatic amino acids. So their reasoning is, certain microbes and bugs and weeds use it. It can kill all those things, but humans don’t use it, so it’s not going to be toxic to humans. That was a premise that allowed it to come to market, and then it became the most widely used herbicide, pesticide in the world, and it’s been used for three decades now.
The other problem with it is it’s got a very long half-life. So even if a farm used it 10 years ago, you’ll still find Roundup residue in the soil, leaking into the water system for years after that.
As it turns out, this antibacterial glyphosate compound does affect bacteria, as one would imagine, but it does so in a very sinister way. It seems to selectively kill off beneficial bacteria in the gut. There are numerous pathogens in the gut that are actually resistant to the effects of glyphosate, pathogens like Klebsiella or Enterococcus, Pseudomonas, certain types of Streptococcus, E. coli, these pathogens that are regularly present in the gut but at very low levels because your good bacteria keeps them in check. Those particular pathogens are resistant to the function of glyphosate, where your commensal (your good) bacteria, tend to be extremely susceptible to it.
So long-term, small exposure to this stuff from our food, from our water source, from our soil, in the air, all of these areas where it’s so pervasive, creates a selection pressure in our digestive tracts, where we see a significant increase in these pathogens and a significant decrease in beneficial bacteria.
We always talk about the dangers of antibiotics. This is even worse because it’s a selective antibiotic that selectively kills good stuff and allows bad stuff to proliferate. And it’s everywhere. It’s ubiquitous. Everyone’s getting exposure to it all the time. That’s where the danger of it comes from.
Evidence of Harm from Glyphosate, Roundup
DrMR: Now, I doubt that many people in our audience would be a hard sell on this concept, and they’re likely leaning in the direction toward organic food anyway. But for those that might be a bit more skeptical of this, where is the evidence? I know that there’s debate on this issue and I think that might be because the evidence may be preliminary, substantiating this. I’m not sure where the evidence has gone in the past year or so. It’s been probably about a year to a year-and-a-half since I’ve reviewed it. I’m wondering, do we have anything that we can point to for the skeptics?
What would be great is if there was a prospective followup, where some people ate organic food and other people did not, and the people not eating organic were exposed to glyphosate. And in the non-organic glyphosate-exposed group, there was a significantly higher reported case of any gastrointestinal adverse events. You can maybe make an argument for neurological. But to keep things simple, a study like that—just looking at gastrointestinal adverse events that were higher in the group consuming this—could be a really powerful study to point to for the skeptics.
That might be a little bit too hopeful of a wish, but where is the science right now, for those who are saying, “Eh, the dose isn’t high enough and the studies haven’t shown a measurable impact.” Where are we with combating some of that thinking?
KK: Yeah, and that’s a really important question. In fact, there are a couple of areas of study that have really come to light in the last year-and-a-half or two that support the notion this really is a toxin that is either correlated with (at the minimum) or in many cases causative of numerous health conditions.
The first one is, the World Health Organization did a massive review on the effects of glyphosate. They looked at things like animal studies and some human studies, and laboratory tests and so on. They’ve concluded that glyphosate is a probable carcinogen. And that’s actually on the World Health Organization recommendation list.
They are the global, objective, scientific community, and they’ve looked at the global data and have labeled it officially as a probable carcinogen. So that in itself is like, “Wow, okay. We’re spraying probable carcinogens all over our food supply.”
DrMR: And just for the audience to clarify some of this language, because sometimes the scientific community will use very conservative language and subtleties. And correct me if I’m wrong here, but one degree up from “probable” is “proven,” and then this would be banned pretty much globally.
DrMR: So we’re pretty much skirting on that, where the evidence is showing this probably causes cancer. We can’t say definitively yet, but once the definitive evidence is in… if it does come in that way through further analysis, this would be banned worldwide. So we’re maybe one domino falling away from that. Is that a fair reiteration for the lay audience?
KK: Absolutely. And that’s a really important point that you bring up, because the World Health Organization’s also careful not to get into political issues, so they want to present the data objectively. What they don’t want is a whole bunch of associations using their determination that it is a carcinogen as support for massive lawsuits all over the world.
But also it’s very hard to determine these types of compounds as being an absolute carcinogen the way you would normally test it, because the only way to do that is to actually deliberately give people different doses of this compound and then watch what happens to them over time versus those that don’t have any exposure to it.
DrMR: We’re limited really by observational data. And the challenge with observational data is that there are other things that aren’t going to be controlled, oftentimes, in an observational study. You can control for these in regression analyses, so you can say, “Well, this group of people were smoking, so the smoking may skew things,” and you can try to control for that. But essentially, we’re limited to observational studies which are inherently imperfect.
KK: Totally, yeah. And if you show that there’s a correlation between the exposure and consumption of glyphosate and Roundup to certain types of cancer, what makes that more legitimate is if you can find a mechanism of action. And that’s where leaps and bounds have been made over the last year and a half.
There have been numerous studies—many of them done on animals, because you can’t do this kind of study on humans—that have shown or elucidated mechanism of action by the type of antimicrobial effect that glyphosate has and also the type of toxicity that glyphosate has and the pathophysiology to cancers. There are studies that have been published in 2017, 2018, and even this year, 2019, that definitively show mechanisms of change within the microbiome that are associated with increased risk of cancers. In fact, one of our studies which we haven’t published yet also shows that.
One example of that is we took pristine microbiomes… we used a system called a SHIME system, which is a full, simulated human gastrointestinal tract starting from the stomach all the way down to the distal colon. It’s inoculated with an entire human microbiome, with a mucosal layer, everything. So it’s the best imitation of a human GI tract, and then you also feed it food over a few week period to stabilize it. The food moves in the stomach, small intestine, large intestine and so on, just like in a normal GI tract, and then you can start adding substrates into the system to see how these various substrates affect the microbiome in different areas. And we started introducing glyphosate, the active ingredient in Roundup, on its own. Then we introduced it as the commercial product Roundup.
What was interesting was that we found that the glyphosate by itself did not have any real significant impact on the microbiome in a three-week period. The system is limited in that you can really only study what happens within three weeks, then the microbiome becomes kind of destabilized. So in that three-week period, we didn’t see a lot of change with the active ingredient glyphosate. But then when you compare that to Roundup, the commercial version of it is significantly disruptive to the microbiome.
In particular, one of the features that it shifted in the microbiome very dramatically within the first week is it significantly increased ammonia production and proteolytic fermentation. Which means that the microbiome is now making less short-chain fatty acids, things like butyrate, propionate, and acetate, and making more things like ammonia and p-Cresol and all these toxigenic compounds that are associated with Crohn’s, IBS, IBD, and certain cancers.
We also saw a decrease in short-chain fatty acids and a significant increase in branched-chain fatty acids. And high levels of branched-chain fatty acids and high levels of ammonia are the picture of a colorectal cancer gut. So there now seems to be a better understanding of the mechanisms by which a compound like this could, in fact, add to your risk factor of developing these conditions.
One more thing to point out: the USDA has actually published a number of charts over the last couple of years that look at the prevalence rate of several conditions, plotted against the increase in prevalence of use of Roundup and Roundup-ready crops. They’ve looked at things like intestinal infections, celiac disease. They’ve looked at diabetes. They’ve looked at dementia, obesity, liver dysfunction, bile duct dysfunction, senile, dementia, as I mentioned, thyroid cancers. And when they plot this against the graph of increased use of Roundup and glyphosate, you see almost parallel lines. It’s quite uncanny. So there’s a lot of supportive evidence that shows that this toxin really does have a significant impact on our overall health.
Is There a Safe Level of Roundup Exposure?
DrMR: So this begs the question, which is, is there a certain threshold of exposure that seems to be okay? And I ask this question knowing that people, as an example, with IBS are more prone to anxiety. That people can very easily become afraid of food. I’m wondering, is there a little bit of leeway? Will occasional exposure pose a problem, or does someone need to be really diligent with avoidance?
And probably hard to answer also. I understand that this is not an easy question to answer, but to the best of your ability.
KK: Yeah. I think it’s a really, really great question because the last thing we want to do is create this massive amount of fear of even just going outside and putting anything in your mouth.
What the data do show is that number one, the impact of glyphosate on your health and microbiome occurs over long periods of time. So that’s one important factor, which means that it’s frequent, chronic exposure on a regular basis. And there is a dose dependency to some degree. There are studies that look at 0.1 parts per billion all the way up to 5,000 parts per million. Those are very, very different doses. Both doses seem to have an impact, a little bit more on the higher dose. So there does seem to be a dose dependency effect to it.
For a certain small group of the population—because there are some people with a SNP, or a single nucleotide polymorphism called a PON1 SNP, who tend to preferentially accumulate toxins like glyphosate in certain fatty tissue—they have a problem of detoxing. But that’s a smaller percent of the population.
For most people, the impact of this is going to be on your microbial community. That’s going to be where the most profound change occurs. But the beauty of it is… part of our study was that you can do things to undo the damage from glyphosate. Again, it’s an ecological change in the microbiota. And any time there’s an ecological change in the microbiota, you can reverse the change by the right probiotics, prebiotics, dietary changes, and so on.
So, absolutely, we can have resilience to this. We can have resilience to the changes that it causes, if we make a few smart choices in terms of things that can help reverse the negative effects on the microbiome.
DrMR: Great. And I definitely want to expand on what can be done about this. But one brief question before we do. I’m trying to ask this type of question more often because I think it’s helpful for people who either listen to this or read this post, and then a week later, they’re confronted with a counter argument stating that glyphosate concerns are kind of hyperbolic. What is the most common counterargument that suggests that glyphosate exposure is okay, or Roundup exposure is okay? And what would you say in response to that?
KK: The biggest counter argument would be from the perspective that we talked about, where there isn’t a study that definitively shows a causative function of glyphosate in cancer, IBD, Crohn’s, or IBS. And part of the reason is because, number one, the dangers of glyphosate have only been realized for the last half a decade or so with a high amount of publicity. So the work on understanding the damages of glyphosate is recent. We don’t have a lot of historical data to look back at to evaluate the information.
That follows the exact pattern that we saw in the smoking issue. For the longest time, there were these scientists that were saying that smoking causes cancer, and industry-related scientists would say, “There’s no definitive study that shows smoking causes cancer. That’s correlative data that they’re relying on, and that’s not causative,” and so on.
But then as you start getting into the mechanism to figure out how can it actually cause cancer, that’s where it becomes more clear and more definitive. The response to the argument that there isn’t a definitive study that shows that glyphosate causes cancer or glyphosate causes any particular condition is, number one, you can’t do those studies in humans. So it may never exist. And number two, there are mechanistic studies and population longitudinal studies that show significant correlation and clear mechanism. When you put those two together, you’ve got enough evidence to say,
“You know what? Maybe we shouldn’t be consuming this at the levels we are.”
DrMR: And this is a good reminder for our audience when we can use lower quality data to help guide decision-making.
Just to clarify—for our audience, in case you haven’t heard this before—I have oftentimes criticized that one of the main follies of functional and integrative medicine is that they draw way too many inferences. They take one rat study, and then they’re shouting from the rooftops, proclaiming, “This is the next best treatment,” often ignoring the clinical outcome data that can better guide the clinical decision-making process. So when we have clinical outcome data and we have that more gold standard definitive data, we want to use that.
But there are instances where we don’t have that, so we have to resort to observational data, mechanistic data, and then draw the most reasonable inference we can from there. And this is, I think, a shining example of that. This is where I have concerns about people who are solely evidence-based, because it limits the ability to think inferentially one step ahead of where we currently are.
We want to be careful with the inferences that we draw. But if there’s suggestion via the mechanism, if there’s suggestion via the observation, then the way I like to proceed here is, for non-natural interventions, they are guilty until proven innocent. If I’m trying to convince someone that carrots don’t cause cancer, I don’t really need high-quality data for that. But if this is a new chemical and we’re trying to prove it does not cause cancer, in my mind, until we have more definitive data, I assume guilty until proven innocent.
KK: Absolutely. I’m so glad you brought that up because it’s absolutely true as a major folly in the functional medicine world. And I find myself probably too often online arguing against one simple mouse study on an IBD model and the massive conclusions people are drawing from that.
But yeah, in this case, you will never have a gold standard study on glyphosate versus no glyphosate in a human system. We have to go with the collective supportive data. At the end of the day, I love that you mention that these chemicals, synthetic entities, are guilty until proven innocent. In this case, it’s very hard to prove that it’s innocent with data, but there are a lot of data showing that it’s probably guilty.
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So a trial of prebiotics should be included in your gut health plan. This is why I include prebiotics in the Healthy Gut, Healthy You program. If you visit thriveprobiotic.com, you can use the code RUSCIO15, for a 15% off discount, which can be applied to all Just Thrive products. They are also available on Amazon. Check them out.
How to Build Resilience to Glyphosate, Roundup
DrMR: Exactly. So what can we do about it?
KK: That’s a really important question. We are the first ones to do a glyphosate study on a human microbiome. So all of the studies that have been done on glyphosate—the toxicological, the microbiome studies—are done in animal microbiome. You’re using mice or rats, and you’re looking at the changes in the animal microbiome to see, and then extrapolating what that might mean in a human system.
The problem there is we know in microbiome research in general that, more often than not, the changes that we see in the rat microbiome don’t necessarily translate to human microbiome. So we utilize this system that I talk about, the SHIME system, which is very well-published, shown to be very good in terms of mirroring what an actual human’s microbiome would do. We wanted to look in there and see what the impacts are.
The general impact that we’re seeing in a short period of time is low diversity, reduction of diversity, reduction in certain keystone strains, in particular Akkermansia and Faecalibacterium. Those two are extremely protective over inflammatory conditions and metabolic dysfunctions in the bowel. We see significant reduction in short-chain fatty acid production, so butyrate, propionate, and acetate. And then we see this significant increase in ammonia and other toxicological gases. Those things can all be shifted.
And part of our study is, can we start shifting them back as we still continue the exposure to glyphosate with prebiotics and probiotics? I think that becomes extremely important in terms of the idea of shifting the microbiome back towards health, despite the exposure of glyphosate.
In this case, we added in some oligosaccharides. We added in two fructooligosaccharides and a xylooligosaccharide, and then we used our spore probiotics, which is what we work with. We started to see the glyphosate-only exposure period caused this measurable, significant perturbation. Then we continued the glyphosate exposure but threw in prebiotics and probiotics. And over the next couple of weeks, we started to see a reversion of some of those dysfunctions, despite the fact that glyphosate was still in the picture.
So we can influence our microbiome back into health by the substrates we put into it, which means food is going to have a huge impact on it. Of course, you can choose foods that reduce your glyphosate exposure, and then choose foods that support a diverse, healthy microbiome. And then supplementation seems to be able to help as well so far. Prebiotics and probiotics may play a really important role in doing so.
DrMR: What’s great about this is this is a simple intervention. Oftentimes, at least in my experience, people are looking for very exotic, “Well, if the one thing to be concerned with is glyphosate, what’s the one natural compound that can counteract that?” I guess that’s attractive. We’re always looking for the one fix for the one symptom or the one pathway.
But in this case, there are multiple benefits from utilization of probiotics and prebiotics. Especially with the burgeoning field of probiotic literature, we can point to evidence showing that probiotics can improve brain fog, fatigue, IBS, IBD, some studies showing probiotics can improve sleep.
I’ve shared this quote before… I don’t know who said it, but the saying is, “The closer you get to truth philosophically, the more commonalities you find.” What’s nice here is we see the commonality of probiotics and prebiotics being able to help with a multitude of different ailments, including, in this case, counteracting the negative changes induced in the microbiota from glyphosate.
KK: Absolutely. That’s a really important way to put it, because we have the choice of selecting foods that have not had glyphosate exposure. So we can go organic. We can grow stuff in our own garden and reduce some of our consumption of produce from the outside world. We could certainly reduce our consumption of processed foods that use grains and things that use glyphosate in a very heavy way during the production.
So we can lower our exposure. And then as we’re lowering our exposure by going organic, and growing some of our own things, we can also start to increase our intake of more diverse foods. The more diversity we have in our diet, the further it’ll enhance diversity of the microbiome, which is one of the negative impacts of glyphosate in Roundup: it shrinks diversity. Then with the probiotic and prebiotic element, we can think of it as our daily protection against a toxigenic world that tends to impact our gut microbiota in a very significant way. And like you said, there’s this host of other benefits that come about from utilizing your probiotics and prebiotics. So it becomes basic.
DrMR: Exactly. Now, I’m curious about your thoughts on this compound circulating called Restore. It claims to really counteract the impacts of glyphosate. I’ll just give my position on this—for the audience, in case you haven’t caught my take on this prior—which is, I remain open, but I am a bit wary given that this company hasn’t produced one outcome-based study or even an intestinal model study.
I could be wrong here, and I will be the first to update my opinion should the appropriate evidence be produced, but I get very wary when you have a company making one product, heavily marketing that product, obviously they have funding behind them, and they haven’t been able to spackle together at least a retrospective chart review, which wouldn’t cost any money.
The quick scapegoat that will be used is, “Well, we don’t have the funding needed.” You can find a clinician who treats IBS patients, like myself, and say, “Hey, we’ll send you 20 bottles of this compound, and we’d like you to use it for awhile, track the results, and then we compare all that to patients who aren’t getting this.” You can do a pre/post IBS symptom inventory survey. It doesn’t cost anything.
And we can at least put a retrospective chart review pilot study out there for little to no cost. Substantiate that this compound you’re making these claims regarding actually holds water, and that the mechanism you’re showcasing actually will produce a beneficial result.
KK: Yeah, there’s a lot there in what you said. In fact, I’m with you on that. I see the company at various conferences and things that I go to, and I’ve talked often to people involved in the company. And that’s been my point of contention as well. Maybe this can be a really effective solution to intestinal permeability or damage from glyphosate. And if it is, then fantastic. It’s a tool that functional medicine doctors and consumers can use. But it has to be proven, and there is no excuse for not doing science.
As you just illustrated, there are many very affordable ways of doing it. In fact, we’ve done numerous studies that way where we pair up with a clinician, we use an IRB. With a central or local IRB, it costs 2,000 bucks to put a protocol through IRB, and many clinicians will do it at no charge for their time because they are scientifically curious and want solutions themselves. So we’ve done numerous studies. In fact, we’ve published and submitted studies for publication that have been done in that manner.
So they have zero evidence. And, in fact, when the company started, they were promoting it as a solution for leaky gut, based on a Petri dish study essentially, on intestinal cells. When you sprinkle LPS on intestinal cells, it makes the tight junctions dysfunctional. Then they added this lignin-based mineral mix, and it seemed to reduce the intestinal permeability. And then they went out to the market saying, “This is a cure for leaky gut.” That’s a massive leap from a Petri dish, right?
DrMR: A big leap, haha. Yeah.
KK: To an actual human with the microbiome, mucosal system, immune system, and all this stuff that’s going on! For the first couple years, they went hard on the leaky gut. Then somehow they pivoted to it being a rescue for glyphosate damage.
And like you, I have asked and looked for and not seen any evidence at all. So I would caution people, because the compounds in the product are not regular compounds that you would be naturally exposed to in many parts of the world. These lignites are from very special type of minerals. And there are cases of it being a stress on the kidneys to clear it from the system and so on. So I’ve always encouraged them, “Do a study. Let’s see. Maybe it is, but until you do a study to prove it, you have no idea what it’s doing.”
DrMR: Yep. And I try to be open-minded. If there is an area where we have no treatments, and this is at least something, fine.
But in this case, we have a lot of good leaky gut treatments that have been well-studied. So it’s unfortunate when excitement takes hold of all the decision-making, and clinicians just jump on the bandwagon. But we’ll keep watching the evidence, and I think we’re in agreement. I would be cautious. I personally wouldn’t use it until there’s at least some documentation showing a favorable outcome in humans.
KK: Yeah, I’m with you. I’ve never used it myself, and people ask me about it all the time. I work with lots and lots of functional medicine docs, and that’s always my recommendation, that it’s wait and see. It’s not something I would use right now.
DrMR: And not to totally beat this dead horse, but—as I’ve said to clinicians—what I’ve noticed is oftentimes the difference between success and failure clinically is just mastering the available treatments and being able to apply and personalize those to the individual effectively. Oftentimes, the difference between success and failure is merely that, not some miracle compound. The miracle compounds are pretty much nonexistent. Rather it’s having a mastery of the tools, and being able to use them with a given individual in the most effective manner.
KK: Absolutely. And then, of course, being convincing enough to your patient to get him to make those lifestyle changes that are so important.
DrMR: Yep. Now, when we talk about prebiotics, there’s contention regarding prebiotics in SIBO. Just a quick preface for our audience: I think most of the SIBO community is very wary about prebiotics and SIBO. I share some of that trepidation. But we’ve also discussed on the podcast before what I’ve termed (and Allison Siebecker and I have discussed… again, this is a loose term of our own coining) prebiotic responders in SIBO.
And if you look at the IBS literature, it essentially overlaps with the larger body of research. In IBS—as compared to SIBO, which shows that there is clearly a body of people who do respond favorably to prebiotics—I think the more severe the gut ailment becomes, the higher the probability of a negative reaction to prebiotics. So a little bit of caution is warranted. But it is something that does have a time and a place. It’s why I’ve written it into the algorithm in Healthy Gut, Healthy You.
I know that’s one of the first questions that will come up in our audience when we mention prebiotics: “What about SIBO?” They have a time and a place. But what would you offer someone struggling with that question?
KK: If at all possible for someone with SIBO to get some sort of prebiotic into their system, it becomes absolutely critical. And the reason for it is, SIBO is a condition within the small bowel. But the unintended consequence of the diet choices and the minimization of prebiotics and all that is that the large bowel bacteria start to suffer.
We go to a diet that is very low in fermentable carbohydrates in general, resistant starches and so on. So the vast majority of your microbiome which is in the large bowel aren’t getting the substrates that they need to produce the really important compounds, like urolithins and short-chain fatty acids and all of these things that we require to function properly.
So we’ve worked on what we consider to be precision prebiotics. And what we’ve been looking for are oligosaccharides, in particular, that have very high degrees of polymerization. The higher the degree of polymerization in general, the further down the digestive tract it goes, because the complexity of that carbohydrate structure requires very specific enzymes. It has become part of the natural evolution of the human microbiome that the more complex carbohydrate, the further down it goes, because the microbes towards the distal end of the colon have these specialized enzymes to break them down.
We’ve actually been working with clinicians (that we tend to work closely with) with precision prebiotics on oligosaccharides that have really high degrees of polymerization, with people who have SIBO and tend to be intolerant of prebiotics, to see if they can tolerate even small amounts of these types of oligosaccharides.
So far we’re having some pretty good success. These oligosaccharides are making it past the overgrown bacteria. They don’t necessarily have the enzymatic capability to break them down because rarely do we find in the small bowel overgrowth of distal bowel bacteria. It’s typically bacteria from the cecum and/or bacteria that came in as colonizing pathogens. And so they seem to be making it past that area of aberrant fermentation and then making it to the distal bowel, where it is feeding some of the beneficial bacteria.
There’s a secondary benefit to that. One of the things I talk about when I do talks on SIBO is leaky gut is a big driver of SIBO, because leaky gut is a major driver of stasis in the bowel. And many docs that study and work with SIBO understand that stasis in the bowel is a major factor.
There’s evidence that shows that LPS—when it leaks through the intestinal lining and enters the enteric nervous system—can actually enter into the vagal afferent nerve and block the peristaltic signals that are coming from the central nervous system to the bowel, actually stop bowel motion, and significantly affect the migrating motor complex. These are all the natural protections against microbes hanging out in the small bowel and putrefying and causing problems. And butyrate is a major fixer of intestinal permeability. So if we can get some oligosaccharides into the large bowel and get some of that short-chain fatty acid production going, it will help a whole host of things. But it can also be a help for SIBO.
DrMR: There’s an interesting hypothesis being put forth by Richard McCallum. He’s a gastroenterologist we have had on the podcast recently. His recent paper is putting forward the hypothesis that SIBO might more so be dysbiosis—meaning imbalanced ratios or incorrect bacteria rather than overt overgrowth—and some of this may actually be coming from the oral cavity.
So, it’s just interesting to ponder if, again, using prebiotics in a cautious way and not going to the extreme of whoppingly high doses of resistant starch (as was in vogue three to five years ago), using prebiotics in a controlled and monitored fashion, could they feed some of the healthy bacteria in part of the small intestine that could help combat some of this dysbiosis, that maybe trickled down from the oral cavity into the SI?
KK: Yeah, absolutely. I’m actually putting together a talk on SIBO and looking at the true root cause of SIBO. And I’m finding a lot of information on bile function and small intestinal bacterial overgrowth. Of course, on the use of antacids and the use of PPIs and the disruption of stomach acid. And of course, conjugated bile salts as well. So all of those things seem to play a role in allowing an overgrowth of microbes in the small bowel, and the oral cavity in particular becomes a source of gram-negative bacteria in the small bowel.
Here’s an interesting connection. The gram-negative bacteria in the small bowel tend to increase the production of something called secondary bile salts by metabolizing bile. Those secondary bile salts actually act as pro-inflammatory compounds in disrupting the lining of the small bowel, and then also leaking into the large bowel and causing diarrhea. So in the IBS with chronic diarrhea, that seems to be a mechanism that’s being elucidated right now. And that speaks to more of a dysbiosis rather than some pure infection. Modulating that dysbiosis can come from improving saccharolytic bacteria or gram-positive bacteria in short-chain fatty acid production over these types of gram-negative bacteria.
So it’s a really interesting area. I think, in general, the overt use of PPIs, antacids, aspirin and other NSAIDs that also reduce stomach acid production—all of those important natural antimicrobial compounds that keep bacterial growth in the small intestine low, all of those things adding to it—creates this picture where we’ve allowed a haven of the wrong bacteria to take hold and overgrow in SIBO.
Liver Function, Thyroid, & SIBO
DrMR: It’s interesting to ponder if there might be any liver to bile causality to SIBO.
DrMR: For our audience (just as a refresher), we’ve discussed numerous studies and in fact, even meta-analyses, showing that probiotics can help with non-alcoholic fatty liver disease. This is pure speculation, but if liver function is not optimal and that’s causing a non-optimal production of bile (because the liver produces bile), could that be one of the factors that is leading to the stage for SIBO to be able to grow? And might this be why probiotics have also been shown to be quite effective for small intestinal bacterial overgrowth?
KK: Yeah, in fact, there are some studies that work to that conclusion. There are studies now on cirrhosis—people with end-stage cirrhosis and small intestinal overgrowth—that find that as cirrhosis progresses, bile production reduces dramatically, and small intestinal bacterial overgrowth increases dramatically.
They’ve also done studies on people with bile duct ligation, for whatever reason, whether it’s obstruction due to stones or so on. And when they ligate and disrupt or remove the bile ducts or the gallbladder in general, they see a 10-fold increase in both aerobic and anaerobic bacteria in the small intestine, and a higher translocation of bacteria to inside the mucosal layer and into the mesenteric lymph nodes as well. So there’s a very direct tie between dysfunction in the liver and subsequently the secretion of bile to huge amounts of overgrowth in the small intestine.
DrMR: And I wonder (again, this is just my speculation, it’s an inference based upon reading the data and watching the data evolve) if we’ve been perhaps a bit misled regarding the importance of motility in SIBO.
When you look at motility, one of the leading hypotheses advanced by Pimentel, the story essentially goes as such: lack of motility leads to a slowing down of transit in the small intestine, which can allow bacteria from the colon to retrograde or slip back upward from the colon into the small intestine. That is a mechanism, and I think Pimentel has borne that out, and I think he’s done a fantastic job going to the difficult lengths of documenting that scientifically.
However, the larger question is, does that affect 20% of SIBO cases? Does it affect 80% of SIBO cases? I think it’s been represented as representing 80% of SIBO cases where, in actuality, it might be the minority of SIBO cases. And what may be underappreciated is this more loosely termed “top-down” impact on SIBO, lack of hydrochloric acid, lack of liver and biliary function.
And this connects in with another dot, which ties in the thyroid to this conversation. We’ve discussed one analysis, in particular, looking at 1,800 patients and looking for what factors were the most associated with SIBO. They looked at people who were on immunosuppressive drugs, people who had had prior intestinal surgery. Out of all these factors, the most associated was actually being hypothyroid or being on levothyroxine.
I think why that could be is because we know that, depending on the study you read, up to 30 percent of patients with hypothyroidism (maybe even a bit more) also have decreased production of stomach acid, what’s known as atrophic gastritis and anti-parietal cell antibodies. So perhaps the association between thyroid and SIBO is because hypothyroidism and low stomach acid has an overlap, and that might be where this top-down SIBO hypothesis is coming from.
KK: Absolutely. I’m glad you brought that up because I found that in my research as well, as I’m putting together this SIBO talk. The motility aspect is a component of it, but if that was the biggest driver, then you would be able to resolve 80% of SIBOs by just using a prokinetic. And we know that doesn’t happen. We know that you can do an antibiotic and a prokinetic together, and you can bring down the load in the small intestine and kick up the motility function of the gut, and it still doesn’t go away. It comes right back.
So, like with anything in the gut, it’s never going to be just one reason. The gut is such a complex ecosystem and multifactorial organ that it’s always going to be a number of factors. I think gastric secretions, I think bile, I think dysbiosis in the gut, where we’re looking at proteolytic gram-negative bacteria with saccharolytic fermentation. And then the volume and accumulation of the bile acid pool, the presence of microbes that produce an enzyme called bile salt hydrolase (BSH), which takes bile and instead converts it into secondary bile salts and all of the problems that those cause. So there are numerous things, but it starts from the top down.
And I believe the overt use of these PPIs and antacids and all that starts some of this process.
DrMR: I just read a study, a very large review on a group of veterans. They found, in this very large cohort study, that PPI use was correlated with all-cause mortality, so essentially death from any cause, even in people who didn’t need the PPI. There were some people who didn’t have reflux or some type of hyperacidity that required a PPI, and were on them for reasons I’m not sure. But they found even if you didn’t need the PPI and you were on it, there was something about the PPI in and of itself that led to a higher chance of death from any cause.
So not to scare people if you’re on a PPI. I wouldn’t just take yourself off it without checking with your doctor or preferably working with someone who understands how we can use things like an elimination diet, a low-FODMAP diet, probiotics, gut-soothing agents, and then you have a very high probability of being able to overcome reflux.
But it shows us this emergent picture, the importance of stomach acid not only for SIBO prevention, but also for overall health and prevention of mortality from any cause.
KK: Absolutely. And it speaks to some of the arrogance and almost crazy thinking of straight allopathic medicine. Clearly, our stomachs produce stomach acid for a very specific purpose, and it has probably since the evolution of man. And then just going ahead and stopping that can have huge consequences. So there are other ways around it.
DrMR: Well, Kiran, it’s been a great discussion, as I knew that it would be. Is there anything else you want to leave people with? And then please tell people about your website, your product line, because I think you’re doing—as is probably obvious at this point—a great job of pursuing research. You’re making products, but also researching and producing the evidence to substantiate the efficacy of those products, which I applaud you for. We really do need more of that, so I want to thank you for doing that.
Let people know any closing thoughts you want to share with them, and also where they can learn more about you and the good work that you’re doing.
KK: Thank you so much, Dr. Ruscio, for having me again. It’s always a pleasure. A really important message is… I think a lot of people in your audience are dealing with chronic issues that are everywhere, from a basic annoyance all the way to debilitating. We’ve got things like basic food intolerances, which has an impact on your quality of life because it restricts you from what you can eat and how easily you can enjoy social outings with your friends and so on, all the way to debilitating depression, anxiety, autoimmune conditions, and so on. The further we get into this space of microbiome science, the more we understand the impact of the gut microbiome on all of these conditions. What’s good about that is it’s giving us a peek into where many of these conditions come from and/or are perpetuated by.
So a lot of the conditions that people are dealing with used to be thought of as congenital defect: “They must have some gene that is defective, so there’s no way around it.” Now, we come to know it can all boil down to an ecological problem within your microbiota. That’s so exciting and so promising. If it’s an ecological problem, there’s a way of fixing it. So many of these conditions that people are suffering from, that maybe at points they have felt they will never get better from… hang in there. There are a lot of solutions coming out, and we’re understanding these problems better and better each day that goes by. Many of them can be fixed and/or improved significantly because it’s driven by ecology in the body.
We’re doing a lot of work. I think we have a total of about 18 trials that are either completed or ongoing and about 4 trials published. You can come to thriveprobiotic.com to check out some of the work. And if you put my name, Kiran Krishnan, in YouTube, you’ll find a lot of webinars and interviews and all that as well. And again, appreciate the opportunity. Thank you so much for having me back on.
I care about answering your questions and sharing my knowledge with you. Leave a comment or connect with me on social media asking any health question you may have and I just might incorporate it into our next listener questions podcast episode just for you!
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