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Leaky Gut Syndrome: Fact or Fiction? with Brad Leech

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Leaky Gut Syndrome: Fact or Fiction? with Brad Leech

According to Brad Leech leaky gut syndrome is pseudoscience and doesn’t actually exist.

Brad Leech is a clinical nutritionist, ayurvedic herbalist, lecturer and researcher. His PhD research through ARCCIM is looking to develop clinical practice guidelines for Australian practitioners for the assessment and management of increased intestinal permeability in patients.

In today's episode, Brad takes us through the origins of intestinal permeability, how to assess it and why we need to be careful about calling it "leaky gut" as it doesn't reflect current scientific opinion. 

Covered in this episode

[00:48] Welcoming Brad Leech
[01:56] Defining intestinal permeability (IP)
[05:25] Viral contributors
[06:22] Prevalence of IP
[08:20] IP and autoimmune conditions
[10:17] Inflammation and IP
[12:59] Tests to measure IP: Lactulose-Mannitol, 
[17:24] Testing: Serum Zonulin
[20:45] Testing: Faecal Zonulin
[22:39] Using the rule of three
[23:34] Further discussing the various testing
[27:31] Repeatability in testing
[29:34] Why leaky gut syndrome doesn’t exist
[32:11] The subgroups  of small intestinal permeability
[34:14] Vitamin C and IP
[36:23] Alcohol and IP
[37:54] Signs, symptoms and risk factors of IP
[42:57] Treating IP
[47:11] Brad’s research
[50:01] Probiotics and prebiotics


Andrew: This is FX Medicine. I'm Andrew Whitfield-Cook. Joining us on the line today is Brad Leech. He is a clinical nutritionist, ayurvedic herbalist, lecturer, and research supervisor at Endeavour College of Natural Health. Brad is currently undertaking his PhD at the Australian Research Center in complementary and integrative medicine at the University of Technology, Sydney, where his research involves developing a clinical practice guideline for the assessment and management of increased intestinal permeability for Australian practitioners. He's an international presenter and published author writing both peer-reviewed manuscripts and book chapters, including the food allergy and intolerance chapter in the prestigious third edition of "Clinical Naturopathy" by Sarris and Wardle. In addition to teaching and researching, Brad works in clinical practice where he draws upon 10 years of experience within the complementary medicine profession to provide his clients with practical and evidence-based treatments for the management of autoimmune disease. Welcome to FX Medicine, Brad. How are you going?

Brad: I'm very well. It's great to be here, Andrew.

Andrew: We're discussing intestinal permeability and this ties in with leaky gut syndrome. We'll get to that a little bit later. But I guess first, what exactly is intestinal permeability and when was it first mentioned in the literature?

Brad: Interesting question. You see, the first concept of this so-called “leaky gut” was established in the literature during 1965 and was collectively referred to as the intestinal pore hypotheses. Now during the early 1970s research emerged surrounding the association between intestinal permeability and coeliac disease with preliminary data suggesting that the degree of intestinal permeability correlates with the severity of coeliac disease. But just think about that. We have known about the correlation between intestinal permeability and disease for over 15 years.

Now, it wasn't until another 20 years later that the action was actually discovered by Dr Vizzano and his team over in Italy. So intestinal permeability involves the loss of integrity within the small intestine. Now, more precisely, intestinal permeability occurs when the intracellular proteins holding the tight junctions together actually disassemble. This disassembling of the tight junction, is governed by one of my favourite proteins, a particular protein called zonulin. Now, in fact, zonulin is the only physiological mediator discovered today known to regulate intestinal permeability.

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Andrew: When we're talking about intestinal permeability, we always tend to refer to the small intestine. What about the large bowel?

Brad: That's completely different. You see that's large intestinal permeability, and a lot of the research is actually focused on small intestinal permeability. Yes, we can have permeability of the stomach lining and the large intestines or collectively the whole gastrointestinal tract. But when we're actually thinking of this leaky gut, this leaky gut syndrome, it's actually referring to the small intestine.

Andrew: Right.

Brad: Now, what's quite interesting is actually looking at the aetiology of this small intestinal permeability, which is quite different to, let's say, gastric or colonic permeability. So small intestine permeability in itself is actually thought to be contributed through environmental, genetic, and epigenetic factors. Now, when I talk about particular environmental factors contributing to this small intestinal permeability, it's important to remember that it does this via the release of zonulin, okay? Within like gastric permeability and colonic permeability, there's other mediators at play, but within the small intestine, the intestinal permeability may actually lead to the increased absorption of dietary antigens, also known as lipopolysaccharides, LPS, from gram-negative bacteria. Now, this exposure, as a lot of us already know, is that it can actually interfere with the host immune system, it can stimulate inflammation and actually go on to lead to dysbiosis.

Andrew: Okay, so you mentioned viral genetic and epigenetic factors. So, you know, when we're talking about genetic factors, I'd be thinking about coeliac disease. When we're talking about epigenetic factors, we'd be talking, I think we'll be discussing this a little bit later, about, you know, the food stressors that we put into our gut that we have to handle. What about the viral causes though?

Brad: Yeah see, there is a lot of research into a number of particular viruses, including the Epstein-Barr virus, you know, the model into the development and progression of this intestinal permeability. But at the end of the day, it's a lack of research which is preventing us to actually have a concluding evidence statement to say, "Yes, these particular viruses can actually contribute to this pathogenesis of intestinal permeability."

Andrew: Right.

Brad: And when we actually look at intestinal permeability from a prevalence perspective, it's actually quite difficult to calculate. You know, some initial research suggests that about 5% of healthy individuals will actually have intestinal permeability. Now, this is compared to the prevalence of people with, let's say, a condition with a known association. Someone with one of these conditions with a known association may have a prevalence anywhere between 10% to, you know, almost 80%. And it's actually been suggested that one in three individuals will experience intestinal permeability in one of these associated conditions.

Andrew: Okay. Again, when we're talking about intestinal permeability or IP, this is normal to a certain extent, correct?

Brad: Yes. Yeah, intestinal permeability is a natural homeostatic mechanism essential for life. We need it, and it was actually discovered this way, we actually need it to flush out bacteria when there's infection in our gut, okay? And some research is actually suggesting that it either supports or facilitates immune transfer between the mother and the foetus. So, before I get into, you know, the doom and gloom of intestinal permeability, we need to remember that it's normal, it's a natural part of life. 

But it’s when it's long term or when it's simulated constantly, that's when there's a number of consequences that can actually develop from it. Within the research community at the moment one of the biggest questions we are trying to answer is, does intestinal permeability cause the disease or does the disease cause intestinal permeability?

Andrew: Right. Right.

Brad: Now, what we know is intestinal permeability is suggested to be involved in the pathogenesis of autoimmune disease such as Crohn's disease, coeliac disease, inflammatory bowel disease, type one diabetes, and even IBS part D, that's diarrhoea. Now, many theories suggest that without intestinal permeability particular diseases wouldn't progress. Well with many studies showing IP, intestinal permeability, is involved in the development and exacerbation of autoimmune diseases. This involvement of intestinal permeability in diseases is also seen in Crohn's disease where it can actually serve as a valid predictor for any relapse within Crohn's disease.

Now, on the other hand, correcting intestinal permeability has been shown to reduce clinical signs and symptoms associated with a number of these diseases. Whereas on the other hand, if we actually induce intestinal permeability, this can actually increase disease severity. Intestinal permeability in itself, one of the prominent theories suggests that intestinal permeability is both a cause and consequence of this lipopolysaccharide absorption, right, lipopolysaccharides, LPS…

Andrew: Yep.

Brad: ….have been shown to trigger inflammation that may alter glucose metabolism resulting in poor glycemic control, insulin resistance. In addition to this is, dyslipidemia may contribute to the loss of intestinal integrity as the HDL is, in part, responsible for neutralising the LPS.

Andrew: Okay, so is LPS the only cause though of this intestinal permeability worsening?

Brad: No, not at all. You've also got inflammation. 

Andrew: Yep.

Brad: Inflammation can significantly exacerbate intestinal permeability in itself. But then intestinal permeability can then go on and can cause inflammation. A number of Dr Vizzano's research has actually shown that any consumption of gluten whether you're a healthy individual, whether you've got coeliac disease or non-coeliac gluten sensitivity, there will be a relief of inflammation when the cells come in contact with gluten molecules.

Andrew: Even in healthy individuals who aren't coeliac?

Brad: Yes, very minute, but still that release of I believe it's Interleukin 8, which can then contribute onto this intestinal permeability picture.

Andrew: Okay. But is that still along the spectrum of, you know, just the normal intestinal permeability, the controlled IP, you know, not necessarily pathogenic? You know, I have some people who are saying “gluten is bad. It's always bad. It's bad for everybody.”

Brad: What it is is this intestinal permeability, it's not the holy grail of, let's say, treatment. I, myself, you know, like, you know, someone who dedicate their entire life to intestinal permeability, it's interesting because intestinal permeability is just one part of it. I would actually say that dysbiosis would actually be more significant in a clinical picture than this intestinal permeability. Because, okay, yes, you've got intestinal permeability, but if you've got the good bacteria, if you've got a good diet, then that intestinal permeability in itself isn't going to be the end of the world. It's when it's combined with, let's say, this virus, this picture.

Andrew: You know, probiotics have not been the holy grail that we would like them to be with regards to immune-mediated inflammatory disorders like Crohn's. You know, they've gotten certain result in some studies, but it just hasn't been that switch that we would have liked, lending, I guess, to the theory that it there's other controllers rather than just dysbiosis. Having said that, certain antibiotic therapy can lessen inflammatory disorders of the gut in certain instances. So it's kinda like, wow, where do we go with this sort of thing?

Brad: Yeah, that's that's exactly right.

Andrew: If we're talking about measuring IP, and I guess I've jumped the gun here a little bit, but if we're talking about what do you measure, we don't have a one phenotype of what a healthy microbiome, microbiota is. We don't subscribe or it's not necessarily accepted, if you like, to measure IP. What do we measure?

Brad: Well, there you go. I mean, you basically answered your own question. What I can say is, there is no gold standard for measuring intestinal permeability. Now, this makes identifying intestinal permeability very difficult and controversial at the same time. And I actually believe not having 100% reliable tests to identify intestinal permeability is our biggest drawback when it comes to researching intestinal permeability. What we do have, we've got a number of tests on the market available to practitioners that they can use. But what I can say is these tests, they have their limitations.

Andrew: Yep.

Brad: So let's take the dual sugar test, the lactulose mannitol, probably the most common test that practitioners will be aware of or actually use within their clinical practice. This dual sugar test actually involves, you know, the consumption of two sugars after an overnight fast followed by the collection of urine for about six hours. Now, the fundamental principle behind this dual sugar test is the different molecule size of the mono and disaccharides when the integrity of the intestine is healthy. The monosaccharide, which is the mannitol, is easily absorbed whereas the disaccharide, the lactulose, is poorly absorbed and remains in the intestine.

During altered intestinal permeability, the disaccharide is actually readily absorbed, resulting in an increased ratio between the lactulose and the mannitol in the urine. Although many factors such as, you know, kidney function, water consumption, and other variables can actually be controlled for when we actually take two sugars, there is one issue with this test and it is collection time. All pathology labs in Australia will collect urine for six hours. However, the research is actually showing, time and time again, that this is too long. 

Andrew: Right.

Brad: The ideal time is somewhere between that three to four hours of urine collection.

Andrew: Right.

Brad: So this long collection time allows for potential inaccurate results. Sure, we could just change collection time but we would first need to recalculate the reference range, which would require about 150 participants and over $100,000. I mean, hey Andrew, if you've got that laying around, give it to me, I'd be more than happy to do that study. But unfortunately, that's not the case when it comes to research. 

A way around it is to actually measure the dual sugar within the blood. Okay, so I actually stumbled across this test only recently and it's from the CSIRO lab. Now, they actually do a test where you fast for 10 hours, you drink a very similar dual sugar solution, you wait 90 minutes, and then you do blood collection, okay? And then they measure the amounts of sugar within your blood rather than waiting for it to be present within the urine.

This test in itself, it's potential, there's research to support it, the one thing that I would change about it is when they actually take the sugar test. So, the test actually is only available within Adelaide, which is unfortunate. And participants actually have to go in to the clinic, take the sugar, and then wait 90 minutes. For me, if you're looking at time as a principle, you know, a lot of people don't want to be waiting around for 90 minutes for sugar to get into the blood. So, potentially, you know, there’s the blood test, which could have potential benefit, okay?

Andrew: Yeah.

Brad: Now, on the same line of the blood, we've also got something called zonulin. So, remember, the disassembling of the tight junctions is governed by this particular protein called zonulin. Now, in fact, zonulin, as I mentioned earlier, is the only physiological media that's discovered today known to regulate this intestinal permeability. A few interesting things about the zonulin is zonulin is an acute-phase protein, okay? Meaning it only has a short half-life, okay? So, you have two options when it comes around to testing zonulin within humans, okay? You've got serum zonulin and you've got stool zonulin, okay? Both very different, especially from a clinical perspective. You've got the serum zonulin. Now, the good news is the serum zonulin and the dual sugar test, that's the lactulose mannitol test, are both strongly correlated with each other, which is great news.

Andrew: Right.

Brad: However. However, serum zonulin is more likely to give a false-positive result. Which is, ugh, we don't need that. Why? Because zonulin is actually released from adipose tissues. So, someone who has a high BMI or has a metabolic-like condition may have high levels of zonulin not caused by the disassembling of the tight junctions. In fact, a study out of Monash University, actually it was published beginning of this year advises the medical community to exercise caution when interpreting these commercial zonulin tests, which is massive. 

Andrew: Yeah.

Brad: Now, this particular study shows the commercially available zonulin test here in Australia doesn't actually detect zonulin, okay? We still don't know which protein or proteins this so-called zonulin test is measuring. Although, it may turn out later on that it does reflect intestinal permeability, but we don't know yet.

So…and here's the next catch, serum zonulin is no longer available in Australia. In the beginning of this year, in January, it was available. However, it's been, let's say, stripped from the market. Why? Some may say it's because the cost of it, some may say potentially because of the study that I just mentioned. 

Andrew: Yeah.

Brad: The thing we need to remember when it comes around to zonulin, okay, at the moment where it stands, serum zonulin in clinical practice may not be the best test to utilise. However, research utilising serum zonulin is slightly different. You see, we can actually control for these potential confounders such as BMI and age, thereby, when we actually see a study where they use zonulin to actually assess and interpret intestinal permeability, I guess we should always take it with a grain of salt, but we should consider it to be more accurate than what we would see in clinical practice because hypothetically, these researchers would have controlled for a number of these factors which are affecting the results. 

Now, that’s serum zonulin. You've also got faecal zonulin or stool zonulin…

Andrew: Right.

Brad: …which is one of my favourites. Now, the stool zonulin is generally better to assess the early stages of, let's say, permeability, okay, or when there’s active intestinal permeability. The other use of the stool zonulin is in conditions where it's situated within the gastrointestinal system. So, IBS, IBD. Now, unlike the serum zonulin, stool zonulin is more likely to give a false-negative. 

Andrew: Oh.

Brad: So, you need bear that in mind. The good news is, it's relatively cheap. So, to actually test faecal zonulin, you're looking at about $40, okay? And you know, if you if you're doing, let's say, a stool test, you know, you can actually add on other tests, which would actually provide some great clinical evidence such as, let’s say, calprotectin, an inflammatory marker. So, those couple of tests, they would be the most used or, let's say, the most somewhat accurate tests.

There are other tests, let's say, suggestive tests that a lot of clinicians will use within clinical practice and we know that from previous research. And these suggested methods would be your food intolerance, your food sensitivity tests looking at IgG. Some naturopaths may utilise your ecology, or even haemaview, or even on the other hand, kinesiology. What I can say about these few methods is they're suggestive. There's very limited research to actually conclude that they work.

So, where do I actually stand when it comes to the most accurate method to test for intestinal permeability? We must use what we have available, okay? What we have available, okay, it’s not perfect, but it's what we have available. We can also utilise the rule of three, that is, if there's three factors that present in the patient themselves that indicates that they have intestinal permeability, then maybe they do. Maybe they have, you know, food sensitivities, maybe they have a positive lactulose mannitol test, and maybe they have other associated conditions. If they got the rule of three, then yes. Now, you must use your clinical skills. Take into account signs and symptoms. You must utilise signs and symptoms that actually correlate with intestinal permeability, not like this hypothetical correlated signs and symptoms.

Andrew: A couple of questions about the measurements. So, my big issue is repeatability. So when we're talking about, you know, you mentioned the time lag with regards to lactulose mannitol coming out in the urine. So, has that been tracked over a time, say, from 30 minutes to, you know, 1, 2, 3, 4 hours, and do you see, let's say, a normal curve or an area under the curve being developed? Is there any standard for that that's been developed yet? Or is this one of the whole problems that we just don't have that as yet?

Brad: So, a study came out, forgive me, I forgot the researcher's name but her entire PhD thesis was this topic in itself and you actually use non-serum anti-inflammatories to induce intestinal permeability to actually measure when they should be within the urine and so forth and she tracked it, I believe, every 30 minutes or maybe even every 15 minutes…

Andrew: Right.

Brad: …from the very start up until 8 and then going on to 24 hours. And this is why I mentioned this three-to-four-hour window. She actually concludes two-and-a-half to four hours is what represents small intestinal permeability, not colonic permeability, not other types of permeability, but small intestine.

Andrew: Gotcha.

Brad: The research is out there. The research is saying...now, this is still new, okay? This is still new research saying that this is the collection time, which is the biggest hindrance when it comes down to the lactulose mannitol test, and potentially all we need to do is to adjust the collection time. Now, I can tell you I've recommended this test a number of times. I know that my patients would be much happier collecting urine for a shorter time than hanging around at home waiting to collect urine for six hours. So, there's two benefits there.

Andrew: With the lactulose mannitol test, you've also got lactulose being basically a food, like a prebiotic food as well. So, it's kind of like a confounder that the test is also a treatment. You know, that's sort of if dysbiosis is a potential cause of the problem and your measurement is actually a treatment, isn't that one of the confounders?

Brad: A number of studies have actually, you know, looked at the safety profile and yes, the lactulose mannitol test is a very safe test and the research has shown that time and time again. So, it's not like if someone, let's say, presents with fever, it's not like it's a potential exacerbator of it although it's not advised in someone with diabetes because of the sugar content. It's what we have available.

Andrew: It's only one test. I guess the issue comes how often are you're going to repeat it. The question with zonulin measured via serum, you've then got an invasive test. So, that decreases right away the people who can conduct that test.

Brad: Yes.

Andrew: So, I was interested though when you're talking about fecal zonulin. What about breakdown products from zonulin? Like these claudins and, you know, although this would be fraught again with issues, the actin-myosin cytoskeleton proteins.

Brad: Listen, within the research, they're available and they're being utilised within the research.

Andrew: Ah.

Brad: A number of studies will utilise the byproduct. It's what's available to clinicians. 

Andrew: Oh, okay.

Brad: Now, because I'm a clinician at heart and because my entire focus is intestinal permeability within clinical practice, you know, let's just focus on what practitioners may actually potentially be able to use rather than dreaming of a particular test which is not accessible but highly accurate. You know, we've got to work with what's available.

Andrew: So, just going on from that lactulose mannitol test, Brad, with regards to repeatability, have we got data that shows that an increased intestinal permeability, i.e. pathological process, is repeatable? That once you get to a certain stage, it's a pathological process, not just a normal process that waxes and wanes throughout, you know, the daily activities of handling food and things.

Brad: Yes, I think so. There are a number of confounders when it comes around to the measurement of intestinal permeability. But research has shown that the lactulose mannitol test is repeatable, okay?

Andrew: Right.

Brad: Although the research is old, you know, probably looking at 20, maybe 25 years old, the particular research, you know, where they get, you know, people with coeliac disease, people who are healthy, and they repeat it time and time and time again to ensure that it's giving the same result. It is a repeatable test. So we know that, which almost support that hey, yes, it is a beneficial test in clinical practice, it will give the same results time and time again. But it just comes down to this collection part.

Andrew: Yeah, okay. So, that's the important thing. Are you working with various labs to, you know, show them this research to get it out there to...? I mean, this would change the landscape of the usefulness of that test.

Brad: Listen, how do I say this in the nicest way possible? Don't make any enemies. Listen, let’s say I have approached companies. However, it comes down to this test retails for about $110, okay? And I need a minimum of $100,000. It's just not feasible.

Andrew: Got you.

Brad: At the end of the day, if someone has a lazy $100,000 laying around, sure, I'll do the study for them. But yeah, it's difficult to actually get pathology companies to do this because it's going to cost them a lot of money.

Andrew: You know, we've spoken about IP as a normal and a pathological process, and I guess we get into here the leaky gut syndrome, which it's dogging us now. We have leaky gut but what's the difference with this leaky gut syndrome?

Brad: Alright. What I can tell you is I was the greatest sceptic when it came around to the so-called "leaky gut,” okay? Let's be serious, holes within our intestines? How is that physiologically possible, you know? It's not. The reason why I was so naive, it's simple, I was thinking about leaky gut syndrome. Leaky gut syndrome is considered both medically and from my own perspective as pseudoscience, okay? 

Andrew: Yep.

Brad: Whereas increased intestinal permeability isn't. Now, if we look at syndrome by definition is a collection of medical signs and symptoms that are correlated with each other that are not contributed to a single disease. Thereby, you know, there's no such thing as this leaky gut syndrome.

There's three lines of thinking when it comes around to this integrity of the lining. Number one, you've got a syndrome, aka leaky gut syndrome. Number two, you've got something, you've got a medical condition where it's a diagnosed medical condition. And number three, it's a reaction, i.e. it's a response to a stimulus, okay? 

Andrew: Yeah.

Brad: Intestinal permeability is not officially recognised as a medical condition anywhere in the world. Intestinal permeability is not a condition, but rather a reaction, which is a concept that we need to get our heads around. We as practitioners can call intestinal permeability leaky gut. I do not have a problem with that, especially when I am talking to clients.

Andrew: Yeah.

Brad: You don't want to bamboozle them with increased intestinal permeability. Sure, use leaky gut or altered intestinal permeability. But when it comes around to talking with a practitioner, writing a manuscript in a paper, let's refer to it as intestinal permeability, increased intestinal permeability, or altered intestinal permeability, or altered intestinal integrity. Let's try and avoid this use of leaky gut and then it doesn't actually get confused with this leaky gut syndrome.

Andrew: In the same way that you know, a specialist will speak to a patient and say, "It's a problem with your tummy." But when they're speaking to a colleague, they'll say, "It's the right upper epigastric quadrant," or something like that.

Brad: Exactly, exactly. And when we actually look at this small intestinal permeability, it can actually be classified further into two major subgroups. You've got what we call low-grade chronic small intestinal permeability. Bit of a mouthful, but that's what described it. Now, that there is what we know within clinical practice. That's your so-called leaky gut in clinical practice. You've also got something called acute intestinal permeability. Now, this is more common within a hospital setting where pathogenic bacteria will actually trigger a change in the intestinal integrity resulting in sepsis. And then this kind of acute intestinal permeability is seen in conditions like a burn injury, you know, serious medical conditions where there is a major and significant increase with your permeability in an acute setting, okay?

Within clinical practice, we have this low-grade chronic intestinal permeability, just like we had low-grade chronic inflammation, okay? You know, that CRPs are, you know, 200, 300, but if I've got a CRP of C reactive protein, of you know, 20, 30, us as clinicians, we're still going to see that as significant as, hey, you know, let's see what's triggering this inflammation. Just like within intestinal permeability, it's low-grade intestinal permeability, you know. And, in fact, this intestinal permeability within clinical practice can actually be broken down into further subgroups. Now, this is a particular theory that I'm working on at the moment, which I have actually proposed with my authors, co-authors, within the literature where we've got things called, let's say, alcohol-induced intestinal permeability. We have exercise-induced, we have genetic-induced, we have medication-induced, we have pregnancy-induced, we have disease-induced, we have diet-induced, we have metabolic-induced, and of course, dysbiosis-induced intestinal permeability.

Andrew: I've seen research with regards to the use of intravenous vitamin C, hydrocortisone, and thiamin, I think it was. Basically you know, they're not waiting for evidence now. They need something for sepsis, drugs just haven't worked. The proposed mechanism of action is the IV vitamin C is protecting endothelial linings. I'm wondering if that might be having some effect on acute increased intestinal permeability. What's your thoughts on that?

Brad: That's difficult to answer but what I can tell you...now, this will actually come as a surprise to a number of your listeners. Vitamin C at I think it would be about 400 milligrams can actually induce intestinal permeability.

Andrew: Right.

Brad: Okay, so, you know, you think of, let's say you go to a naturopath, you're on three or four different supplements, I guarantee you will have a couple hundred milligrams of vitamin C in that, okay? The research has shown that the vitamin C is actually inducing intestinal permeability. They've actually done studies where they dose up NSAIDs and vitamin C at the same time and there's not a synergistic effect, where they're actually saying that the mechanism of action for inducing intestinal permeability with the vitamin C and the NSAIDs are different. I mean, still in clinical practice, you know, I'll recommend vitamin C. I don't think we have enough evidence or justification to warrant caution when it comes around to intestinal permeability, when it comes around to vitamin C and intestinal permeability, but it is something that we may need to be aware of. Let's hypothetically say that, you know, someone is on 500 or 1000 milligrams of vitamin C and they are presenting with so-called symptoms of intestinal permeability, potentially we can maybe withdraw that see if that having any effect on the patient.

Andrew: So, I guess this goes back to the range of normal versus the range of pathological intestinal permeability, doesn't it? 

Brad: Yes.

Andrew: You know, we know that foods will increase intestinal permeability. That's part of the nutrient absorption process, isn't it?

Brad: Yes, yes. Now, this is quite interesting, and it's actually quite hard. Moderate alcohol intake equivalent to one standard drink a day has actually been shown to induce intestinal permeability in healthy individuals directly after consumption.

Andrew: Yep. But is that bad? You know, like, it can increase it, sure. But is that bad? Or is that just part of the normal waxing and waning of the homeostatic range of intestinal permeability?

Brad: I would say that it's bad only when someone has dysbiosis as a minimum, okay?

Andrew: Right, right.

Brad: Given the prevalence of dysbiosis within the community, okay, it's quite high. When you look at alcohol consumption in itself can contribute to dysbiosis. So, unless someone has a perfectly healthy gut, you know, they're not consuming any potential triggers within their diet and they've got healthy digestive system that's breaking down all these proteins, sure, this intestinal permeability isn't necessarily an issue. But it's when it's combined with inflammation, dysbiosis, and other conditions which can actually be exacerbated.

Andrew: We've spoken before about these signs and symptoms. Which signs and symptoms are more reliable and which ones are just so vague that we have to leave them alone?

Brad: Okay. I ask you and the listeners to think to yourselves, “what are the symptoms of intestinal permeability, okay?" Now, don't get confused by thinking about diagnosed diseases such as IBS, inflammatory bowel disease. Think about the symptoms, okay? You're probably thinking about things like bloating, reflux, gas, the so-called “brain fog,” fatigue, indigestion, mood swings, and so on. Okay, this does not appear to be the case. We recently published a paper looking at risk factors for intestinal permeability in adults. Now, we identified over 100 potential risk factors associated with intestinal permeability. Now, the strongest risk factors were inflammation, dyslipidemia, hyperglycemia, anthropometric measurements that resemble obesity, advanced disease severity, co-morbidities, and the consumption of a Western-style diet.

Now, an unexpected finding of our research was the small amount of digestive health symptoms reported to be associated with intestinal permeability. A long time, the magnitude of risk factors that actually resemble a metabolic-like condition. 

Andrew: Right.

Brad: Now, although digestive health symptoms such as bloating, abdominal cramps and pain, heartburn, reflux, nausea, I know you think gas, were actually measured in a number of these studies, none were reported to be significantly correlated with the risk of intestinal permeability. 

Andrew: Right.

Brad: It actually appears that digestive health symptoms lack the association with intestinal permeability. 

Andrew: Yeah.

Brad: However, this should not undermine the association between gastrointestinal conditions and intestinal permeability.

Andrew: Okay, so where do we go from there with regards to helping to identify that there's an issue with IP?

Brad: Well, look at the other risk factors, okay? So there's other risk factors, such as the number of family members you have that have an autoimmune disease, the number of full-time pregnancies, oestrogen imbalance, glyphosate exposure, dietary intake such as fructose, gluten, saturated fat, arachidonic acid, and so forth, nutrient deficiencies such as vitamin D, zinc, and glutamine, or whether the patient is taking things like antibiotics, methotrexate, NSAIDs, acute psychological stress, okay? And also, acoustic stress. Okay, acoustic stress, have you heard of this one, Andrew?

Andrew: Yeah, I have.

Brad: Yeah, acoustic stress can actually stimulate both inflammation and intestinal permeability, okay? So, I've actually got a business proposition for anyone who's listening, okay? If you think about where you're exposed to the greatest level and, let's say, annoying level of acoustic stress, you'd be looking at...well, here in Sydney you would be looking at Kings Cross, you know? You'd be looking at the venues where there's nightclubs and dance areas. So, the business proposition for you is actually stand in front of the nightclubs handing out earplugs saying it will reduce intestinal permeability or reduce the inflammation. There you go. There's another avenue you could go down.

Andrew: I'd like to see that sort of handed out at building sites even though there's adequate warnings about protecting your hearing, you see so many workpeople on building sites not taking care of their hearing, even in such a loud and monotonously loud environment.

Brad: Yeah. And the other interesting thing in looking at these risk factors is the synergistic effects that some may have with each other. Now, sure, there may be more that we know within clinical practice, but what the research is actually showing is when there's more than one of these potential risk factors, it can actually be exacerbated. So in particular, things like a high BMI, age, alcohol consumption, and inflammation, when they're combined with any of these risk factors, the likelihood of, let's say, intestinal permeability actually increases. We may also look at someone's diet. Now this one comes as a surprise, but a high energy, nutrient-dense diet with either inadequate protein intake or excessive animal-derived protein in combination with alcohol consumption are a potential risk factor for the intestinal permeability and something that we need to be aware of within clinical practice.

Andrew: So, with regards to treatment, when we've got no given gold standard test and the symptoms don't necessarily correlate with what we would think would be the obvious symptoms of intestinal permeability, should we just treat with things like a plant-based diet, good fats from mainly non-animal-derived or, say, more fish-derived fats and vegetable-derived fats? Where do we head with this with regards to treatment? What's your advice to practitioners?

Brad: Well, that comes down to what does the patient want? We got to remember we are here to help and serve the patient. What if the patient wants to be tested? What if the patient wants that confirmation, I do or I don't want intestinal permeability? That's something we need to bear in mind. But when it comes around to particular things regarding the treatment and the assessment of this intestinal permeability for practitioners, sure, I can give some recommendations.

The number one thing I would say, and this is quite interesting, is the effect that exercise has on intestinal permeability, okay? Now, we know from the research that prolonged exercise can actually increase core temperature…

Andrew: Yep.

Brad: …okay, so about 39 degrees. However, intestinal temperature can reach about 41 degrees, okay? Now this is because there's less blood flow within the intestines and the temperature increases because the blood's unable to leave and be able to cool down. Now, here's one for you, it only takes an increase of two degrees in the intestine for intestinal permeability to be increased by three-fold.

Andrew: Right.

Brad: That's something that the practitioner needs to be aware of. Now, a recent systematic review, or actually it's not that recent now, probably 2017, actually concluded that the amount and intensity of exercise, okay, found to be the threshold for inducing intestinal permeability is less than 2 hours of exercise at 60% of your best. So, I recommend practitioners during, let's say, this gut repair phase of your treatment protocol, you know, if you go, "All right, I'm on a treatment protocol for one month of this gut repair," okay, in that time, limit intense exercise, okay? However, if that's unavoidable, then utilise the things with the research to say, actually reverse the negative effects of alcohol-induced intestinal permeability. They are things like zinc, idatramine and, in particular, probiotics.

Another potential advice to practitioners would be to incorporate signs and symptoms and other biomarkers into your differential diagnosis, okay? Yes, if you've got a test, great, but also assess the patient as themselves. You know, you look to see whether there's inflammation whether there's that dyslipidemia and other contributing factors to this intestinal permeability picture. Now, just treating the tight junction of the small intestine is significantly insignificant for the treatment of intestinal permeability. We need to remember that if intestinal permeability is present, it's not the only and one part of that, it's the one part of the whole, we must treat the person holistically and treat the whole person rather than just that one part of that so-called intestinal permeability.

Andrew: Brad, there's so much more that we could delve into here. This is such a can of worms and I think it's indicative of a change in what vernacular we need to be using when we're describing, you know, normal versus pathological processes, and indeed, wanting to test and treat things. I'd love to get you back on the show at a later stage. 

But in the meantime, can you tell us a little bit more about your PhD and the research that you're doing?

Brad: Yes, sure, Andrew. You see, my PhD involves the development of a clinical practice guideline for the assessment and management of increased intestinal permeability for practitioners here in Australia. I can't emphasise enough just how important this guideline will be. We need consistency and integrity when it comes around to the assessment of intestinal permeability. For instance, our previous research has shown that there's confusion among clinicians as to the most appropriate method of identifying intestinal permeability and they generally rely on patient signs and symptoms as a method of assessment. It is the aim of our research to provide the clinician with direction as to which health condition should be expected for intestinal permeability, factors to be considered in the management of intestinal permeability, and the available treatment methods.

We want to answer the following two questions, how, when, and why should practitioners test for intestinal permeability? And secondly, what are the treatment options for intestinal permeability? Now, it's one thing to actually develop a clinical practise guideline and it's another thing to actually make it accessible. That's why our project isn't just about the development but we're also involved the dissemination and implementation of this guideline. We're actually going to just implement it within clinical practice and educational institutions.

Now, as part of the development of our clinical practise guidelines, it's important to incorporate the views and preferences of the consumer. You see, the involvement of consumers ensures that the guidelines are not only accurate but relevant. 

Andrew: Yes.

Brad: Therefore, we're actually undertaking a study to better understand the health-seeking behaviour of adults with suspected increasing intestinal permeability. And at the moment, we are recruiting, and we actually need about 400 participants to complete a 20-minute online survey. So, if you think you have intestinal permeability or you know you have intestinal permeability, over the age of 18 living in Australia, please, we want you to fill out this survey. And you can actually head over to www.leakygutsurvey.wordpress.com for a link to the survey.
And then before I finish up Andrew, I must give my sincere and absolute gratitude thanks to my wonderful supervisors, Professor David Sibbritt, Dr Amy Steele, Dr Eric McIntyre, and Dr Janet Schloss for all their support and encouragement for my PhD.

Andrew: You know, Brad, I've enjoyed speaking with you ever since I first met you at the NHAA. But there's one quick question I need to ask you before we go. And that is, do you think probiotics have the bang for buck given the variables with regards to species, strain, dose, mixture, timing, all of that sort of thing? Or do you think probiotics are the way to go, or do you think we should really be trying to work with the patient’s innate microbiota with regards to prebiotics and diet?

Brad: The combination of both prebiotics and probiotics are essential. The thing that I need to emphasise is it comes down to the exact strain. We need to ensure that that's the strain that the patient needs for the presenting complaint. None of us are just taking a probiotic for the sake of it. You need to take it because you need it.

Andrew: My knowledge is that the only strain that's shown that is Lactobacillus rhamnosus GG, is that correct or is there others?

Brad: There are others, Saccharomyces boulardii, you've got E. coli m 17, there are a number of strains. Limited research and limited availability in Australia but more and more research is coming out on the involvement of both pro and prebiotics for the management of intestinal permeability within the research.

Andrew: Brad Leech, thank you so much for dispelling some of the myths, but also, you know, letting us know what are the conundrums and hopefully, where we can find answers in the future with your research. Well done, and I look forward to welcoming you back to FX Medicine in the future.

Brad: Thank you, Andrew.

Andrew: This is FX Medicine. I'm Andrew Whitfield-Cook.


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