In this episode:
04:48 The basics of intestinal permeability
06:52 Is it a good idea to test for leaky gut?
09:34 Testing options for intestinal permeability
11: 50 The lactulose/mannitol test
15:59 The antigenic permeability screen
Chris Kresser: Hey everybody, it’s Chris Kresser here, welcome to another episode of Revolution Health Radio. And we are going to switch things up a little bit. If you’ve been listening to this show for a while, you’ll know that I have cycled through a few different formats over the years. Initially I did single-topic episodes where we dive deep on a particular topic, then I did some Q&A shows where I would answer multiple questions from listeners. I’ve always done some interviews, and that’s of course what I’ve focused on over the past several months. It’s been almost exclusively an interview show. And I am going to now do some Q&As again.
In this case, we’ll just be answering one question per show. We’re going to continue with the interviews because I think those are really informative and I get a lot of great feedback about them, and I enjoy doing them myself. But we’re going to intersperse some Q&A episodes as well, at least for the next few months. And who knows what comes after that.
But let’s start with a question from Kent and let’s give a listen and I’ll come back and answer it.
Kent Langley: Hello, this is Kent Langley and I’m calling on behalf of some friends and family. I’ve read a lot of your articles over the years and listen to most of your podcasts. Thank you for the fine work. The question I have is really relatively simple, but I suspect that it doesn’t have a simple answer. Is there a direct and high-accuracy methodology for testing if you have a leaky gut? My online research hasn’t turned up much, and I thought I would ask. If the answer is no, could you please explain why? Thank you.
Chris Kresser: Okay, thanks again, Kent. That’s a really good question. It’s one that we get in various forms quite often and it’s something I’ve been talking about a lot lately in my clinician training program. I’d love to cover some of the highlights at least briefly in the show.
The Basics of Intestinal Permeability
So before we dive into the nitty-gritty about testing for intestinal permeability, I just want to cover a few basics of what intestinal permeability is for those that aren’t as familiar with it, and then some general aspects about testing for this condition.
The intestinal barrier covers a surface area of about 400 m² and requires about 40 percent of the body’s energy expenditure, and that’s pretty remarkable when you consider that only 20 percent of the body’s energy expenditure is required by the brain. So this tells us that the gut barrier is really crucial. It plays an important role in human health and disease. It prevents against loss of water and electrolytes and the entry of antigens and microorganisms, so allergens, things that could provoke an immune response, as well as bacteria, fungi, parasites, things like that, it allows absorption of nutrients in the exchange of molecules between anything that we eat or put into our mouth and then the inside of our body.
Do you have leaky gut? Two tests to consider.
I think I’ve said this before, but if you really think about the gut, it’s essentially just a hollow tube that connects the mouth to the anus. And everything that is inside of the gut is technically outside of the body. It’s kind of hard to get your head around that, but it’s really the inside of the gut is not technically inside of the body. And in order for it to move in the body, anything that’s in the gut to move into the body has to cross that barrier. And that’s really what the barrier is there for, it’s, at a simple level, supposed to let in things that should get in and keep out things that shouldn’t, that should stay out. And when it’s working well, it does a good job of that. But when certain conditions are present, the barrier’s capability of doing that regulatory task breaks down, and then this is when all kinds of problems can happen.
So there are a lot of different things that can interfere with the gut, the function of the gut barrier. Diet is an obvious factor. Western inflammatory diet, lack of fermentable carbohydrates, and lack of fermented foods, infections and toxins, so bacterial, viral, parasitic infections, fungal overgrowth, heavy metals, mold, etc. Certain medications like proton pump inhibitors, antibiotics, or NSAIDs; lifestyle factors like chronic stress or sleep deprivation or inappropriate physical activity, like too little or too much; inadequate immune stimulation during our developmental period. This is known as the hygiene hypothesis. So hygiene and really clean environments have done a lot to reduce acute infections and saved a lot of lives in that process, but there’s a theory that these overly or these particularly sterilized environments have actually contributed to immune dysregulation because our immune systems aren’t properly stimulated when we grow up in those kinds of environments. Which explains why autoimmune diseases are really quite rare in the developing world when compared to the incidents in the developed world.
Then there are other factors which we call endogenous factors, which means they’re just things that are going on inside of the body that can contribute to leaky gut like chronic inflammation, or SIBO, or gut-brain axis problems, where low levels of certain hormones like melanocyte-stimulating hormone, or MSH, which regulates gut permeability, and then there’s actually probably some genetic susceptibility to leaky gut. For example, one study showed that 70 percent of asymptomatic relatives of patients with celiac disease were positive for intestinal permeability when they were screened. So there does seem to be a genetic component.
Is It a Good Idea to Test for Leaky Gut?
So before we talk about the different types of testing that are available for intestinal permeability, we should actually take a step back and talk about whether it’s even a good idea to test for intestinal permeability and when we should test for it. So my opinion is that intestinal permeability is almost always caused by something else that’s further upstream, meaning that it comes before intestinal permeability and it’s the underlying cause of intestinal permeability. So it could be talking about any of the things that I mentioned just now: poor diet, gut infections, chronic stress, etc. And one of the key principles of functional medicine is that we want to get to the bottom of what is causing symptoms or even manifestations like intestinal permeability, and we want to remove or address those causes or triggers before we try to do anything about the symptom or the manifestation. And the more we can get to the root of the problem, the more effective the intervention will be and the longer term the result will be.
So if we’re just suppressing symptoms or dealing with manifestations of problems, it’s not only going to be less effective, this whatever we’re doing isn’t going to last for as long because we haven’t actually addressed the underlying cause. So with intestinal permeability, if you remove the triggers what’s causing leaky gut the first place—like you fix the diet, you treat the gut infections, the patient starts managing their stress—in many cases you won’t need to even address intestinal permeability because it will take care of itself. One of the amazing things about the cells in the gut is they regenerate every two to three days. And so if you remove the triggers that are causing the problem, then the cells can regenerate and the tight junctions can restore themselves and the intestinal permeability will go away.
So typically in our clinic, we’ll test and treat for SIBO, gut infections, other gut issues, we’ll correct the diet, we’ll address HPA axis dysregulation and screen for heavy metals and mold and other problems like that. And if the patient is still having problems that could be associated with leaky gut, at that point is when we’ll proceed to testing for intestinal permeability.
Testing Options for Intestinal Permeability
So if you look at the research, there are a number of different tests that have been used to define or identify intestinal permeability. And some of these are more common than others, but I’m just going to mention a few different ones and then I’ll tell you what we use in our practice and what I recommend.
So the first is the lactulose/mannitol permeability assay, and this uses molecules, sugars, long-chain sugars called oligosaccharides, and I’ll explain a little bit more about it in a moment.
The second is an antigenic permeability screen, and this looks at antibodies to particular antigens like lipopolysaccharides and then also antibodies to endogenous molecules like actomyosin and occludin and zonulin. So these are proteins that the body produces in the gut that help to regulate tight junction permeability and the structure of the gut and determine whether the gut is permeable or not.
The next marker that’s sometimes used in studies is called D-lactate or D-lactic acid. This is different than lactic acid that you may have heard about that can be high after exercise. This is a product of bacterial metabolism. So it’s produced in the gut. And when D-lactate levels are high, that in some studies has correlated pretty well with intestinal permeability. Butyrate, which is a short-chain fatty acid, has been investigated as a potential marker for intestinal permeability. When butyrate is low, that would be a sign of leaky gut. And then zonulin, as I just mentioned, is a protein that regulates the tight junctions in the gut. That’s being investigated as a marker for intestinal permeability.
But in terms of clinical practice and what’s readily available and what’s been most validated by the scientific research, the lactulose/mannitol test and the antigenic permeability screen, I think, are the two most useful tests.
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The Lactulose/Mannitol Test
With the lactulose/mannitol test, I’m not going to go into a lot of detail because it gets pretty geeky, but it essentially involves measuring levels of two sugars in the urine after the patient consumes those sugars orally. And these sugars have different molecular weights, and then you can look at the results and look at the ratio of those two sugars in the urine and that ratio can tell you whether the gut is permeable and allowing the larger sugar molecules that shouldn’t pass through the gut into the bloodstream or whether it’s doing its job and keeping those molecules out. And so that lactulose/mannitol test is available through labs like Genova Diagnostics, which is a pretty popular functional lab that offers this kind of testing. But there are some definite shortcomings of lactulose/mannitol testing. One of them is that the transport of lactulose or mannitol through the gut barrier is not actually or not necessarily an indicator of malfunction of the intestinal tight junctions. So in other words, a positive result doesn’t necessarily mean that there is intestinal permeability present.
There are a lot of factors that can influence the uptake of those sugars, like GI motility, use of medication like NSAIDs, the surface area of the intestine, gastric emptying, mucosal blood flow, etc., and so these variations can affect the result. But they don’t necessarily mean that the gut is permeable. The other thing is that some studies have shown that only really large molecules, larger than 5,000 daltons, can change the permeability of intestinal epithelial cells and then result in an inflammatory response in the body, which is really what we’re concerned with. And lactulose and mannitol are below 500 daltons, which means they’re much smaller than that, and that suggests that they may not be appropriate as challenge molecules for an intestinal permeability test. So that may have been a little more geeky than I intended it to be, but the takeaway is that the lactulose/mannitol test can give us some information about permeability. But it does have some limitations and it probably shouldn’t be used exclusively. It should maybe just be part of an overall workup that also uses the antigenic permeability test.
There are some ways to increase lactulose/mannitol testing accuracy. One of those is to avoid anything containing lactulose. One of the test molecules that’s used in the diet—and lactulose is not really in a lot of foods, but it’s found in heat-processed dairy and nondairy beverages like soy milk, for example, or some yogurts. You want to avoid mannitol for 24 hours prior to the test, and that’s found in brown seaweed, celery, carrot, coconut, cauliflower, cabbage, pineapple, lettuce, watermelon, pumpkin, squash, cassava, pea, asparagus, coffee, olives and berries, and chewing gum. So you’ll probably have to refer to the transcript for a list of those. You want to generally avoid dairy products for 24 hours before the test, and on the day of the test you want to just avoid drinking too much water, period. And those things can help increase the accuracy of the test. But as I said, it’s still potentially, there are some other issues with it that are more difficult to overcome. I think it’s useful, but it shouldn’t be used in isolation.
The Antigenic Permeability Screen
So the second test for leaky gut is called the antigenic permeability screen, and this was developed by Doctor Aristo Vojdani in Cyrex Labs. In large part, they developed the test because of the shortcomings of the lactulose/mannitol test that we just talked about. Since the lactulose and mannitol are small molecules that don’t necessarily initiate an immune response, Doctor Vojdani wanted to create a test that would better reflect pathological permeability of the gut, which again is really what we’re concerned with. So instead of using larger sugars, he decided to screen for antibodies to proteins and bacterial endotoxins, since those are the major concern when it comes to immunoreactivity. And we know that uptake of these kinds of antigens, proteins and bacterial endotoxins, plays a significant role in the pathogenesis of gastrointestinal and autoimmune disease. In other words, there are a lot of studies showing that inappropriate transfer of these proteins and endotoxins from the gut into the bloodstream initiates an inflammatory response that can contribute to autoimmune disease. And this explains the connection between leaky gut and autoimmune disease. Less than 10 percent of subjects with a genetic susceptibility to autoimmune disease actually progressed to having clinical autoimmune disease in their lifetime, and this suggests that environmental triggers like toxic chemicals and infections and dietary proteins are probably involved in the development of autoimmune disease.
So I’m not going to go into a lot of detail about exactly how this test works because it’s pretty complex, but it’s a blood test. The lactulose/mannitol test that we were talking about earlier is a urine test. This test is only offered by one lab that I know of right now, which is Cyrex Labs. It’s called Cyrex Array 2, and you can check it out at CyrexLabs.com. It needs to be ordered by a clinician. So unfortunately you can’t just order this on your own as a patient, and it is a blood test. And so they draw a blood sample and then they test for antibodies to lipopolysaccharide, they test IgM, IgG and IgA antibodies, which if positive is an indicator of gut permeability and dysbiosis, because lipopolysaccharide is produced by gram-negative bacteria. Those tend to be more pathogenic types of bacteria. Then they test for IgA antibodies to actomyosin, and if those are positive, that indicates epithelial cell damage and that would be an indicator of gut permeability. And then they screen for IgG, IgM, and IgA antibodies to occludin and zonulin. And those are proteins that regulate tight junction. And so if you get a positive result there, that’s an indicator that the tight junctions have been damaged.
And so there are different types of intestinal permeability, and that’s what these different markers give us information about. So those are the two main types of testing that I use in the clinic for intestinal permeability. I’ll say that I don’t actually find myself testing for intestinal permeability very often for the reasons that I mentioned. Typically we tend to look at the underlying cause of intestinal permeability and address that. And if we do a good job with that, in most cases, the intestinal permeability will resolve on its own. When we do test for permeability, we use these two different tests, and I also pay attention to D-lactate. D-lactate can be obtained by running a urine organic acids panel from a lab like Great Plains Labs or also Genova Diagnostics. And if D-lactate is very high then, and especially if Cyrex Array 2 or the lactulose/mannitol permeability tests are positive, I would think it very likely that intestinal permeability is present. So you kind of put together these various tests and along with looking at the history of symptoms and the more indicators you have pointing towards gut permeability, the more likely it is that it’s present. And that’s really the best that we can do from a testing perspective at this point.
Okay, so thanks again, Kent, for your question. Thanks everybody for listening, and I will talk to you soon. We did take a little bit of time off this summer and may have some time off coming up as well. So thanks for being patient in between episodes and hopefully we’ll be back with another episode soon. Thanks for listening.
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