Welcome to another episode of the SIBO Doctor podcast. I'm your host, Dr. Nirala Jacobi, and today's topic is all about intestinal permeability. And this is going to be a great one for you practitioners because we get really into how to properly diagnose it and what the different causes of intestinal permeability or leaky gut are.

And if you are somebody who's not a practitioner and you just want to know about your own health, I think is still going to be very interesting and bearing in mind that SIBO causes a lot of leaky gut. I think it's a very important topic for us to discuss in more detail.

And my guest today is Dr. Brad Leech, who is an internationally recognized clinical nutritionist and Ayurvedic herbalist, and he's just completing his, has completed his PhD at the Australian Research Center in Complimentary and Integrative Medicine, University of Technology Sydney.

His research involved developing the intestinal permeability guideline and evidence based clinical practice guideline for the management of increased intestinal permeability. And he also runs a busy online clinic specializing in autoimmune conditions and chronic gastrointestinal disorders. And he's been around a bit, he's mentored a lot and taught at different naturopathic colleges.

And he also works for Microba, which is a lab here in Australia, where he is a clinical science lead in integrated and functional medicine. So he has a lot of expertise and I'm really, really looking forward to this topic.

Welcome, Dr. Leech, to the program. It's so great to have you on

Brad Leech:

Nirala, it's wonderful to be here.

Nirala Jacobi:

In your intro you've just completed your PhD. Can you talk us through a little bit as to what your subject is or what your area of focus is of your PhD?

Brad Leech:

Yes, it is absolutely wonderful to finally have the PhD finished and completed after four and a half years. So basically my research focus was on intestinal permeability and my end goal was to improve clinicians' management of intestinal permeability. And so in the early days we sat down, we're like, "Okay, how can we actually improve clinicians management of this reaction that's happening in the small intestines?"

And we came up with the idea of creating a clinical practice guideline for the management of intestinal permeability. So this was a multifactorial part. We had multiple avenues that went into this guideline development, but basically, long story short, we created, and you know this better than anyone, you were one of our fantastic stakeholders in this guideline. We created this fantastic guideline that provided healthcare practitioners here in Australia and around the world with 38 different recommendations that they can follow based on, not only the evidence, but also the views and preferences of key stakeholders like yourself and other experts in the area in combination with what our patients actually want.

And so these recommendations are very elegant in the way that they're presented to ensure that the clinicians would be happy to follow them, that they're evidence based, and that the patients themselves would actually like to incorporate them within their health journey. So that's a very short version of what was a four and a half year endeavor.

Nirala Jacobi:

Wow. Yeah, no, I was really happy to participate because, as a practitioner, we all have patients that have been told they have leaky gut just based on a whim or on a few symptoms. And let's talk about some of the testing availability. There's the gold, what we always thought was sort of the gold standard, which is the Lactulose/Mannitol test. And now the new ones that are more blood testing that looks at zonulin and all of that. So can you kind of talk about the different assessment methods that are available to identify intestinal permeability?

Brad Leech:

I sure can. And it's something that you just said that really resonates with me and it's that the vast majority of clinicians, and we've done a research project on this actual topic, the vast majority of clinicians will actually use patients clinical signs and symptoms to determine whether or not they have intestinal permeability rather than relying on functional tests or measuring something that has been validated.

Now that in itself is quite interesting. A lot of clinicians would agree to this. I'd take it the step further. And in one of our studies, it had 600 participants of Australian adults with intestinal permeability, we actually asked them, "Well, do you want to be measured for intestinal permeability?" Recalling now, I think it was about 85% said, "Yeah, they want to be measured floor intestinal permeability using a validated method before receiving treatment."

So it really resonates with me that us, as clinicians, we need to communicate with our patients to see exactly what they want and utilize some of these functional tests to accurately identify the patients who have intestinal permeability.

So as you alluded to just before there is what we consider the gold standard test, that is the Lactulose/Mannitol test. And for those of you who may not be familiar with this test, it basically is a test where patients, they would consume two sugars, the Lactulose/Mannitol, after a overnight fast and then they'd collect urine for anywhere between two to six hours. And then you'd collect the urine on and then send it off to the lab. And it would measure the amount of Mannitol, being a monosaccharide and Lactulose, being a disaccharide. And it would determine the ratio, which is in the urine.

Now, if the lactulose is elevated, then that would be an indicator of intestinal permeability. You have other tests that are becoming more widely available. And it's interesting, you said blood markers here. And so probably when was it? It was 2000 that Professor Fasano actually discovered [inaudible 00:08:16] in his team.

And when I was over in America, before COVID, I had a chance to meet up Fasano and we had a little chat and I asked him just one question. I was like, "Fasano, what is the most accurate method to assess intestinal permeability?" And even him being the leader in this area of research said, "Oh, this is a very difficult question. I put this down to it depends on the individual. It depends on the subgroup of intestinal permeability that you're trying to identify because in some cases you'll do multiple different functional tests to measure intestinal permeability, and some will be elevated and some will be low."

And it just gives that example that really identifying what I've been referring to as subgroups of intestinal permeability really directs which method is best to use. So we have a protein called zonulin. Zonulin is the only physiological mediator discovered to date that is known to regulate intestinal permeability. Zonulin release leads to the cascade of events that consequently opens up the type junctions, AKA intestinal permeability.

One thing to consider here is zonulin being a protein, it is actually released from a number of different cells throughout the body. You've got liver cells, enterocytes, adipose tissues, heart, brain immune, and so on. So when it comes around to measuring zonulin, the most accurate interpretation of zonulin is actually in the stool.

So serum zonulin, because zonulin is released through adipose tissue. So your fat tissue, if somebody is overweight, this can actually result in a false, positive elevation in zonulin when it's not actually intestinal permeability, but rather just a marker of obesity. So stool zonulin in itself, I consider, is hallmark feature for intestinal permeability, but there's a little catch here.

Zonulin is an acute phase protein, meaning it has a relatively short half life. Zonulin, in the stool, is most accurate when intestinal dependability is actively being stimulated or it's in the early onset of disease. So if you have somebody who has cut out gluten, who's eating a healthy diet, taking glutamine and [inaudible 00:11:11], and they have a condition that's associated with intestinal permeability later on in life, if they do a stool zonulin test the odds are it probably won't be elevated because it's the zonulin protein in itself, isn't being stimulated.

So that's my take and my story when it comes around to zonulin and the Lactulose/Mannitol test.

Nirala Jacobi:

Before you go on, I just wanted to kind of clarify to the listener because not everybody that's listening is a practitioner. There's a lot of lay people that have got issues. And I just want to clarify that we're talking about leaky gut. So intestinal permeability is the sort of clinical term that we use for leaky gut, which is a condition where you have gaps between the cells that are lining your digestive tract. And specifically in the small intestine where sometimes undigested foods or organisms or bacteria can actually come in contact with the immune system through these gaps.

So would you say there is another way to describe leaky gut? But that's usually how I explain it to my patients and it can induce a lot of different clinical symptoms and also systemic symptoms. So we are talking about food allergies, rashes, fatigue, headaches, all kinds of inflammatory states. So just wanted to clarify that for the listener.

Brad Leech:

Fantastic. Sometimes I forget when your mind is so delved into the science, you basically figure the basic components. The other thing to consider here is the problem, or let's say the consequence, of having this leaky gut or intestinal permeability is that it actually exacerbates particular diseases.

So especially autoimmune diseases, gastrointestinal conditions, metabolic conditions. And in some cases it's actually seen to proceed the onset of clinical symptoms. So intestinal permeability, or leaky gut, is actually present there before we're actually able to diagnose a particular condition.

So it's a very interesting... I refer to it as a reaction within the small intestine because it's quite difficult to categorize it as a syndrome because a syndrome, generally speaking, is a cluster of symptoms that can't be explained when we know that the symptoms associated with intestinal permeability are so varied. So no excellent segue there.

Nirala Jacobi:

Did you have another... So besides the Lactulose/Mannitol and the zonulin, which you recommend would be better done through stool testing, what are some of the newer, or are there any tests on horizon that may be more accurate or are we still looking at these two? Because I've heard of different reports that zonulin is, like you mentioned, has a little bit of an issue around accuracy and I certainly will reconsider doing it through blood and maybe just add them onto stool tests. Some labs allow for that, but is there anything else coming?

Brad Leech:

My recommendation there is, when it comes around to serums on your line in the research, if they're able to confound for particular variables, age, sex, BMI, then it can actually produce quite an accurate understanding of intestinal permeability, but in clinical practice itself, it's very unreliable, serum zonulin, in itself.

In saying that there is some early research to suggest that serum zonulin may actually be utilized, and this is in five years time, I'm predicting, as a indicator for gestational diabetes as a risk factor. Now I know some people would be jumping up in their seats thinking, "Oh, fantastic, a blood test," rather than doing the long winded glucose tolerance test that a number of high risk women would actually need to do during pregnancy. So that's my take on that.

And yeah, generally to add it on to a stool test would be that the better option. There are some, what I refer to as non-validated methods, that can almost indicate intestinal permeability. The first of which is Secretory IgA. And when you actually dive into the research on Secretory IgA, it's really fascinating where it almost looks like Secretory IgA is a protective factor when it comes around to prevention of inducing intestinal permeability.

The other one I'll mention here, and this is a little caveat, and this is in relation to calprotectin. So calprotectin being a marker of acute intestinal inflammation. I hear a lot of my students and practitioners I mentor talking about, "Oh, if they've got intestinal inflammation, then they'll have intestinal permeability."

When if you actually look at the research, there isn't any direct correlation, and this is coming from three or four studies that I've identified. There's no direct correlation between stool zonulin and calprotectin. So although it would logically make sense, and on some level it is true that inflammation and intestinal permeability are linked, the evidence isn't actually there yet. So that's just one thing to consider.

Nirala Jacobi:

That doesn't really surprise me because when we talk about calprotectin, in my opinion, or in my experience, in my clinical experience, that being much more related as a marker for IBD or Inflammatory Bowel Disease.

I have oftentimes when I talk to somebody with Crohn's or see somebody with Crohn's disease with, which is obviously an inflammatory bowel disease state and their calprotectin will be up, but I don't see Crohn's disease very often associated with food allergies. And I don't, of course, we use anti-inflammatories like boswellia, et cetera, but not necessarily more. Some people that I see that have very clearly intestinal permeability, like SIBO patients, and this is a good segue to kind of go into what causes leaky gut or intestinal permeability.

So that's wouldn't be a surprise to me that it's not necessarily as linked, perhaps as Secretory IgA, which I find really fascinating, because it often is elevated in patients with intestinal permeability.

Brad Leech:

No, that's absolutely correct. And what I'm actually seeing in my own clinical practice.

Nirala Jacobi:

And it's a squirrely little marker, that Secretory IgA. It's not always as reliable. And that's why I really wanted you to have on the podcast because there is a lot of confusion around leaky gut in general. And I think practitioners take a lot of license to just diagnose somebody with leaky gut when that may not be the case. And sometimes it doesn't really matter because the treatment that wouldn't necessarily change. But I think the better clinical assessment we have the better. It's my opinion.

Brad Leech:

And accurately identifying if somebody has intestinal permeability is important, not just to direct treatment, but if they don't have intestinal permeability, why are they presenting how they do? We need to do further investigation to ensure that we're not missing something more critical.

Nirala Jacobi:

Yeah, that's a really good point. So let's talk about the causes of leaky gut and this the SIBO Doctor podcast. So SIBO is a huge contributor to intestinal permeability and research has been done around SIBO and leaky gut and how quickly it can resolve once SIBO is resolved. So that's the good news, but can you talk about some other causes of intestinal permeability?

Brad Leech:

It's a fascinating one when you look at the cause and risk factors, when it comes around to intestinal permeability. When it comes around to looking at the literature what's quoted time and time again is the two factors known to stimulate zonulin, which results in the dissembling of tight junctions and AKA intestinal permeability. The two components is gliadin, so gluten and dysbiotic bacteria.

Now you're thinking to yourself, "Well, hold on, we've got SIBO, especially in the small intestines. That is where intestinal permeability is occurring. We've got pathogenic and overgrowth of bacteria, stimulating intestinal permeability." But there is other factors that can contribute to intestinal permeability. And there are things like intense exercise.

So there's been actually quite a lot of research to the point where there's about two or three systematic reviews and meta analysis looking at how exercise can consequently result in intestinal permeability. When I say exercise, this is, the general consensus, is two hours of running at 60% of your best results in intestinal permeability. So this is quite intense exercise.

Other components are your medications. So in research studies we'll actually use NSAID. So they're your non-steroid anti-inflammatory drugs to actually induce intestinal permeability to trial whether or not a therapeutic intervention actually works. So there's a lot of evidence behind that. Other ones are acoustic stress and so loud noises can contribute to permeability, acute physiological stress.

So there was a study, it was probably about five years ago, where they got participants to give a speech in front of 30 or 40 different people. And they measured their intestinal permeability before and after giving the speech and a 20 minute speech resulted in intestinal permeability. So let's not underestimate the impact that stress can have on the gut.

Something I like to tell a joke when it comes around to a pre-exam poo. Those students who, they get loose stools before sitting an exam, I go, "That there is intestinal permeability." So there's way we can actually prevent that from happening the correct diet, avoiding the gluten, managing the bacteria in the gut, and so on.

But other factors that can contribute to permeability, you've got polyphosphate, polyphosphate exposure, and then also family members with an autoimmune disease or autism syndrome. So if you've got a family member then that increases that risk there as well.

Nirala Jacobi:

So if we can summarize, because I usually tell my patients, "Yep, the marathon running is actually how they induce intestinal permeability for research." So intense exercise, certain medications in the nonsteroidal anti-inflammatory group, and we've got microbiome induced, which we'll talk about in a moment, we've got dysbiosis induced like SIBO, that also includes probably SIFO, because we know that the hyphae of candida or fungal overgrowth can perforate the intestinal lining. That's my understanding of the research that I read many years ago. I don't know if anything has changed in that regard.

And then we have also chemicals like glyphosate, which is a chemical that's sprayed on non-organic vegetables and on grains to ripen them so that they kill the grain and harvest the grain with the glyphosate on it. And I didn't know that it actually has now been linked to intestinal permeability. I know that it has been linked to microbiome changes. And then also we have obviously infections like food poisoning and/or food, if you get a case of gastroenteritis that often induces intestinal permeability to flush out the toxin.

So the diarrhea you get is often from this event where water is just kind of being introduced through these open gates so that you're flushing out the pathogen.

So let's talk about this microbiome induced intestinal permeability, because that's sort of like your area of expertise and research. So I'm really curious to see what you've found when it comes to that?

Brad Leech:

So you are absolutely spot on. About probably three or four years ago now in early stages of my research in intestinal permeability, I was struggling with this concept that, "Well, hold on, why are some interventions' working and others are not?" And we actually proposed in the literature that intestinal permeability can actually be broken down into different subgroups.

So a number of them you were spot on, you mentioned just before you've got medication induced, alcohol induced, exercise induced, diet induced, and you've also got the microbiome induced intestinal permeability. And that is when the causative factor behind the intestinal permeability can be contributed to the microbiome.

Now this is where there's almost a aha moment for clinicians and even patients listening depending on the subgroup of intestinal permeability will actually determine what tests will be most accurate to identify intestinal permeability. And then what treatment methods should be actually employed to manage intestinal permeability.

So microbiome induced intestinal permeability, it is one of these ones where it's growing in the literature where we're actually able to look at particular markers within our microbiome to indicate and suggest, "Oh, this person may actually have intestinal permeability based on," let's take the example of LPS. So we know that LPS or Lipopolysaccharides is a contributing factor that's commonly found in overgrowth and dysbiotic intestines that can go on to contribute to microbiome induced intestinal permeability.

When it comes around to, let's say, identifying the microbiome induced intestinal permeability, we are restricted on how we can go about it because not all tests are actually made equal. And so some tests can quite accurately identify microbiome induced intestinal permeability, where others would be more suggestive. And that just comes down to the tech technology used in some of these microbiome tests.