Andrew: Well, I’ve gotta say the honor is mine, mate, because I remember you and I sitting down at the centenary of the NHAA conference in Melbourne, and I didn’t know you then, but, wow, you’ve exploded onto the scene. And you’ve really helped to clarify a lot of muddy waters, and things that we get dragged into because they sound nice. You’ve cleared up a lot of this stuff, and it’s wonderful to see your work now being finalized as your PhD. It’s great to see, mate.

Brad: It is really nice to almost be that one to say, “Hey, let’s clear up the murky water, and provide a bit more evidence and backing and understanding to what we call our profession.”

Andrew: Now, I need you to take us through a little bit of your career, and sort of, you know, what led you to focus on leaky gut, this syndrome we were taught it was called, as a research subject? And also, can you take us through your supervisors at Southern Cross Uni as well, please?

Brad: Yeah. So, my PhD was at UTS, ARCCIM, with Dr. Amie Steel, Professor David Sibbritt, and Dr. Erica McIntyre, who are, by far, and I say this without any bias, the best supervisors anyone could ask for. You have the stats of David, you have the caring and larger picture of Amie Steel, and then Erica, she’s just absolutely wonderful when it comes around to trying to conceptualize what we’re trying to do with my PhD.

So, to take you a step backwards, my career started back in 2008 now, it’s a while now, when I undertook a advanced diploma in Ayurvedic medicine. Now, what’s quite interesting here is, Ayurvedic medicine, there’s a lot of focus on gut health, and I even recall being an Ayurvedic practitioner, telling a patient, “Mm, leaky gut syndrome, or leaky gut, it doesn’t exist.” Well, you know, I shake my head now, looking back at what I used to say to what I say now. Fast-forward a few years, and completed my bachelor’s, and then it was my Honours where this interest in intestinal permeability really started. You see, I became quite fascinated with autoimmune conditions, and I wanted to do my Honours, and so I contacted Dr. Janet Schloss, and I was like, “I want to save the world. I wanna find the cure for all autoimmune conditions.” She sits me down, she goes, “Brad, first of all, we need Amie Steel.” So, we bring Amie Steel into the room, and they say, “We love your ambition, but you need to take a step back. You can’t find the cure for all autoimmune diseases in an Honours, or even a PhD, or a lifetime. You need to pick one small, tiny element of that topic, and focus on that.”

Now, at that time, I was fascinated by a researcher, the pioneer of intestinal permeability, Professor Fasano. I had the honors of meeting him a number of years ago. And I’ve even got a mug, with a photo of him and I on it, that says “Dr. Brad Leech,” that I got made probably about four years ago. Almost that encouragement, to say, you know what, you can do this. Anyway, we digress. In the meeting, we looked at, okay, well, what’s a driving factor for autoimmune conditions? And we fell onto intestinal permeability. And so that’s really where the focus of this permeability started. Now, at the end of the day, my number one goal in all of my research is to improve how clinicians treat and manage disease in their patients. So, with that goal in mind, I undertook a number of different research topics to support clinicians in their treatment and assessment for intestinal permeability. So, really, in a very short way, that’s how it kind of came about, this concept of what’s now referred to as the IP guideline, and my joy and fascination by intestinal permeability.

Andrew: Well, I can see your joy always, but I have to first ask before we move on, have you met Alessio yet? Alessio Fasano?

Brad: Yes, yes. I met him in 2018, over in America. And we were wearing almost matching…he was wearing a tie, and I was wearing a bow tie, and they were knitted,  and it is a photo I will treasure for the rest of my life.

Andrew: I love your idiosyncrasies. You wear a bow tie, but you’re extremely artistic. I won’t get off topic, but I love your personality, Brad. It’s got so many compartments to delve into. So, let’s move on with the IP guideline, which you’ve mentioned. So, from conceptualizing, first, intestinal hyperpermeability, can we talk first about this syndrome bit? Where did it come from? What’s the history of that wording, that phrase? And why did it take hold? Because I can still remember, back in the late ’90s, hearing about it, and never fully understanding, or sort of understanding the relevance of it, if you like, the practicality of it, because it was something that was there, but how do you treat it? Like, if you’ve got sinus, if you’ve got tiredness, if you’ve got this, that, and the other, you’ve got so many causes, and they’re saying it’s this? And it’s like, “Come on. Like, where do we sit here?” I always had problems with that concept that it was.

Brad: And that’s a great question. You see, the concept of leaky gut syndrome, we have debunked that, and I will say to my critics, I’ll say to the people who have tagged me on many social media posts, to say, “Intestinal hyperpermeability doesn’t exist. Here’s this article from Stanford University.” The number of times I’ve been tagged in this article, where they basically say leaky gut syndrome doesn’t exist. Now, I support that. There is no such thing as leaky gut syndrome, because the concept of syndrome means that there’s a group of common signs and symptoms that someone can be classified as having, like IBS. But with intestinal permeability, there’s no group of symptoms that everybody presents with, so we can’t classify it as a syndrome.

Now, in this Harvard article…or was it from Stanford? Either/or, they go on to say, “Yes, intestinal permeability does exist.” I 100% support that. Whereby, this reaction within the gut, not a condition, not a disease, but this reaction in the gut, called increased intestinal permeability, it’s been linked with multiple different conditions, gastrointestinal conditions, metabolic conditions, autoimmune conditions, and what the research has shown, time and time again, is that those with intestinal permeability have got increased disease activity and severity, and when you go about treating intestinal permeability, with some of the interventions that we might speak about today, their disease activity and severity reduces. So, very interesting there, that we have evidence to say that managing intestinal permeability in clinical practice has a profound impact on how our patients are feeling and presenting.

Andrew: Can I ask something, just to clear something up in my mind? My understanding is that intestinal permeability is a normal part of life. We send out dendritic cells from the gut into the lumen, to sample things normally, but it’s intestinal hyperpermeability that’s the issue. Am I correct or not?

Brad: Yes, that’s correct.

Andrew: Great.

Brad: So, we can have intestinal permeability. Everyone has that, you know. It fluctuates with age, it fluctuates with different times of the day, but it’s when there’s ongoing, low-grade, chronic increased intestinal permeability, that’s when it becomes a problem.

Andrew: Right. So, do we know a level? Do we have that sort of data yet, to say “this is an acceptable range?” I know we’ve gotta go into measurement and assessment then, but do we have that parameter yet?

Brad: Andrew, you are opening up a can of worms, and when I was in the early stages of the PhD, I looked at this can of worms, and I said, “No. This is way too big, way too difficult. I’m not going there.” But very briefly, what I can mention here is, every lab, every method of assessment, is different, and that that individual method of assessment needs to be validated. So, we know, for example, stool zonulin can be, or is an accurate marker for intestinal permeability, when it’s actively being stimulated. Now, that result, or that level pathology marker, within the stool, that’s been validated in a number of different settings and a number of different pathologies, and then you’ve also got the lactulose:mannitol test. Now, every research article will have a different cutoff threshold when looking at the ratio between lactulose and mannitol, so you can’t collectively form a consensus, because each process, the amount of water patients drink, the amount of lactulose and mannitol they take, how long they collect urine for, is all different, so it needs to be internally validated. Once we have that internal validation, then it can be a indication of intestinal permeability.

Andrew: Do we have any surrogate markers which we might use, not the actual things that we ingest, but other things that might be indicative of some issue with the gut, like, for instance, a raised ESR, or a C-reactive protein, or a high-sensitivity CRP?

Brad: You know, it’s interesting. One of our studies found that there was quite a strong correlation between intestinal permeability, the marker zonulin, and inflammatory markers, such as CRP, ESR and calprotectin, but, the chicken or the egg, what comes first, is it the inflammation driving the permeability, or is it the permeability driving the inflammation? So, it’s quite difficult to determine exactly which one came first. Other markers, there are markers out there. Let’s take lipopolysaccharides. That’s quite a utilized marker in research, to evaluate the end result of intestinal permeability. So, we know if there’s intestinal permeability, then there can be an uptake of lipopolysaccharides, LPS, into the bloodstream. We don’t have a blood pathology marker available in clinical practice just yet, but there’s a number of bacteria that we know that produce LPS, and measuring that in the stool can provide us with a bit more indications as to, could there be a intestinal permeability in those patients? Does that make sense?

Andrew: Yeah. Yeah, it does, but I’m glad you say number of bacteria. I was always very uncomfortable when they said, yeah, it’s a fragment, basically, of the cell wall of E. coli, and I thought, “What, only E. coli?” I have a problem with these switch mentalities.

Brad: There’s multiple other bacteria. Now, I can’t recite all of them off by heart, but there’s multiple, I wanna say about 30 or 40 different bacteria that can produce LPS. And so, it’s another way that we can collectively look at permeability. Although it’s not a validated marker, it can give us an indication whether or not our patient may have intestinal permeability.

Andrew: Now, we’ve said that you’ve written a guideline. I’ve actually got it up on the other screen here, and I’ve gotta say, it’s so enlightening, but it really, seriously, is enlightening, because…and challenging, I gotta say, for me, because things that I thought, “Yep that’s got merit,” it seems like the evidence isn’t there for these things. So we really have to pull our heads in and say, “Okay, how do we manage this, and indeed, are we treating the leaky gut, or are we treating the condition which the patient presents in front of us with, and the leaky gut just happens to get better as we’re moving along?” So, I guess, to start, treatment guideline, or a practice guideline? What is a practice guideline? What’s the term for it?

Brad: It’s, so, a clinical practice guideline, it’s a systematically-developed statement, that includes recommendations, with the intention to optimize patient care, by assisting practitioners like you and I, naturopaths, nutritionists, doctors, pharmacists, in their decision-making. So, a clinical practice guideline is required to be based on published evidence, so, research, rather than my opinion alone, or anyone else’s opinion. These guidelines are designed to support clinicians in their decision-making for the diagnosis, and even the management of any particular area, from cancers to cardiovascular disease to intestinal permeability. They are actually considered one of the best ways that we can present evidence-based recommendations to the clinicians, while actually reducing any inappropriate care.

Something to note here is the recommendations are not intended to supersede clinical judgement. Clinicians are always advised to consider the patient who’s in front of them, first and foremost, before actually following the recommendations in any guidelines. Recommendations in the guidelines are there to support and guide clinicians, not to do the job of a clinician. Something to note here is, you can have clinical practice guidelines which are published, and published in peer-reviewed articles, and disseminated to healthcare practitioners, but sometimes, a very small percentage of the time, these days, some of the older guidelines, they actually lack structure. And so it’s really important, when developing a guideline, that there is a clear structure to follow. Now, we are so lucky here in Australia, because we have the NHMRC. Now, the NHMRC, in 2009, and then updated in 2017 and 2021, they produced the NHMRC guidelines, a set of guidelines that guideline developers, like myself, and other researchers, can actually follow, to ensure that they create non-biased, accurate, clinically-relevant recommendations for clinicians.

Something I’ll note here is, a few listeners will be like, “Ooh. I don’t know what a clinical practice guideline is.” Or, “I’ve never used a clinical practice guideline.” Now, Andrew, I know your background is in nursing, so you’ll be like, “Well, this is very common in a hospital-based setting.” So, GPs, nurses, integrative medicine practitioners, they rely on clinical practice guidelines, but naturopaths and nutritionists, they don’t necessarily rely on these guidelines.

Now, there could be a number of factors why clinicians are not utilizing guidelines. I believe it’s because clinicians, naturopaths, nutritionists, herbalists, they’re not actually involved in guideline development, and thereby, their views and values and perspectives, and even how they treat conditions, aren’t considered, because, let’s face it, guidelines, on average, will take a million dollars to produce, and five years of somebody full-time, with a team, to develop them. I developed my guideline for a lot less than a million dollars, but that was because it was my entire focus, and I, let’s face it, I didn’t have a life outside of this guideline. I get off track.

So, really, when it comes around to guideline development, we actually want naturopaths, nutritionists, members of associations, to actually partake in guideline development, and actually, they are our stakeholders. And so, let’s take the IP guideline for an example. We ensured that we had patients, and educators, clinicians, major associations that we have, pathology companies, supplement companies, all involved in the guideline, to ensure that what I was producing, what my team was producing, was relevant to not just the patient and clinician, but also to our whole profession. So that basically summarizes what a clinical practice guideline is.

Andrew: Can you take us through, then, just some of the key points of the guidelines? Because one of the ones that’s important to me, I consult in a pharmacy situation part-time, and that is the use of probiotics with long-term NSAID use. And now, previously, many years ago, we actually favored this with the use of certain probiotics. But looking at the evidence here, it seems like it’s very shaky ground to use a probiotic alone. Can you take us through the importance of cherry-picking certain things, and how, as naturopaths, it actually falls into naturopathic practice, in a much easier way?

Brad: Yeah. So, to answer that question, I think we actually need to take a step back, and actually understand how I developed the intestinal permeability guideline. Because I know a lot of clinicians out there will be like, “Brad, don’t go talking about the methods on how you developed this guideline. Just tell me what are the recommendations, and how should I follow them?” But it’s so important to actually understand how recommendations are developed, because I’ve told multiple patients, “Hey, this is the recommendation.” Just like the recommendation that you’ve said about probiotics and NSAIDs. And their response is, “Well, hold on. What about this intervention?” Or, “Why did you write it like that?” So, to use recommendations, and any guideline, and especially, let’s take the IP guideline, it’s actually important to consider, well, what went into actually developing the intestinal permeability guideline?

So, do you mind if I just mention, very briefly, those steps that I undertook to ensure that our listeners can understand?

Andrew: Yep.

Brad: And, fantastic. Because I know that you’ve already opened up the guideline, you’ve looked at it. I’ve got the guideline. For those watching, I have the guideline in my hand. For those listening, just imagine I’m holding the Bible for intestinal permeability. So, it’s very precious. All right. So, quite broadly speaking, there were five major phases that we actually undertook to develop the IP guideline. We assessed the patients. So, we did a consumer survey. We looked at the literature quite extensively. We drafted the recommendations. So, in total, there were 38 recommendations. We also got feedback from stakeholders. And then after that, we were left with these final recommendations that you as the clinicians can actually read up on, and get a better understanding of how to treat intestinal permeability.

So, quite briefly, the consumer survey, we wanted to ensure that the recommendations that we were developing were going to be appropriate for the patient, rather than just focusing on the evidence. There’s no point developing a recommendation that clinicians or patients don’t wanna follow. So, we know this with pharmaceuticals. We asked 589 patients, “What are the types of interventions you wanna use to treat intestinal permeability?” Now, only 11% said pharmaceuticals, where 90% said, “I want natural supplements, probiotics, prebiotics, vitamins, minerals,” and that was even the same for healthcare practitioners. So, with that in mind, we undertook, let’s say, the most comprehensive review of the literature that has ever taken place, when it comes around to possible treatments for intestinal permeability. Now, when I say comprehensive, I’m talking over 10,000 articles I independently read and looked at. That was a very sad time in my life. It was a very focused time in my life. I was doing 60, 70 hours a week, in a little box at UTS, just reading articles.

Anyway, with these articles, there’s a lot of studies that we actually excluded, for very good reason. We know that intestinal permeability evolves over a lifetime, and that the results of the IP guideline, we want them to be focused on adults. So we actually excluded children-based studies. The other one to consider is we excluded studies that looked at critically ill patients. Believe it or not, I wanna say about 30%, maybe even 40% of the recommendations or the treatments that have been investigated for intestinal permeability have been on critically ill patients.

Andrew: Sepsis?

Brad: Sepsis. Exactly. When I say critically ill, I’m talking end of life. Burn injuries, kidney disease. What we know is that is a very different type of intestinal permeability than what you and I will see in clinical practice. So we need to exclude it. Does that make sense?

Andrew: Absolutely.

Brad: So, after we looked at all the research, we developed these recommendations. So, we wanted to ensure that the developed recommendations were applicable to healthcare practitioners, and also our patients. So, based on all of the previous research we looked at, we followed down all the articles, and said, “Let’s focus on the main areas that clinicians are going to use.” They were the pre and probiotics, amino acids, minerals, herbal medicine, omega 3, vitamins, and colostrum. Because they’re the main supplemental, and I’ll also add, dietary recommendations, of course, that us as clinicians will actually use to treat intestinal permeability.

So, we gathered all these articles, we pulled out all of the relevant information. Now, this is the point of difference. We undertook something called a risk-of-bias assessment. Now, before your eyes glaze over, Andrew, sit back, relax. I wanna tell you the importance of a risk-of-bias assessment.

Andrew: It’s huge.

Brad: So, basically, it’s a huge process, where you look at every tiny little detail of the article. You read the article three, four, five times, to ensure that you understand what the article was about. You contact the researcher for any additional information that may be missing. Now, let me give you an example here. Sometimes, not all the time, but sometimes, you have studies that call themself a RCT, a randomized control trial. Now, when you go through the methods, you go, “Hold on. This is a clinical trial. This is not a randomized trial. There was no randomization behind it.” Because there was no randomization, there’s an increased risk of bias that the results may not actually be what they are.

Another classic example that could actually impact risk of bias, when it comes around to these studies, is, now, the researchers who are listening will totally understand, the clinicians may go, “Ooh, I’ve heard of this before,” is the methods of analysis. So, we’ve got a number of methods of analysis, intention to treat, per protocol. What we know is when an article will do a per protocol, then the results are gonna be more favorable. But when the researchers analyze the data, intention to treat, that is, including everyone that dropped out, or who had side effects, or who didn’t take the intervention, in their analysis, the results are less statistically significant. So, that’s another element at play.

So, as you can see, a lot’s going into developing these recommendations. It’s not just, “Oh, I have a clinical trial on the effectiveness on zinc on intestinal permeability. We’ll make that a recommendation.” There is so much more that goes into grading the evidence. What I find, or what we actually utilized, was something called the NHMRC grading matrix. So, this is a matrix, consisting of five different domains, to categorize all the research. So, these domains, let me see if I can recall them, they are evidence-based, consistency, clinical impact, generalizability, and applicability. So, what I mean by these is evidence-based. This level, now, these are graded from A to D. So, if you’ve got a A grade for evidence-based, it’s going to be a systematic review of randomized controlled trials, with low risk of bias. And then it progressively gets worse, where it’s observational studies with high risk of bias, all the way down the end. What is quite cool about utilizing this matrix, this NHMRC grading matrix, is it takes into consideration a number of factors.

Clinical impact. So, we know that results can be statistically significant, but they’re not gonna be clinically relevant. So, if I told you to follow this extreme diet for six months, it will statistically significantly reduce weight, but at the end of the six months, it’s only 500 grams, yes, that’s statistically significant, but is it clinically relevant? No. So, we can determine how much of the permeability was actually changed, and whether or not that was a…

Andrew: Whether that made a difference.

Brad: …huge improvement. Exactly. And the component…

Andrew: Sorry. You’ve seen this used in a negative way. For instance, I remember the common conception, the common knowledge out there, is from doctors, surgeons, anesthetists, is, stop fish oil two weeks prior to surgery, because it will increase bleeding. Well, it does, but they looked at this at the Alfred, and it was 200 mill. So, it was statistically significant, but it was by no means clinically significant. Indeed, the Alfred Hospital had them on this high-dose fish oil up until the day before surgery. So, you know, it’s a perfect example of a misnomer that’s still to this day, that myth is carried through.

Brad: And we’ve applied this to the results, where sometimes, the diet interventions were just so extreme. I’m not gonna be putting that in a recommendation for clinicians to suggest, because adherence is going to be very poor. The other one that I’ll mention here is generalizability. So, a lot of studies aren’t actually conducted in the Australian population. You’ve got studies that are conducted in rural Sahara Africa, or rural China. Now, those studies, and I recall a few of them that we actually excluded, they utilized whey and glutamine to reduce intestinal permeability, in young children who were extremely protein-deficient. Yes, of course, that’s going to be beneficial, but can we actually apply those results to the Australian population? I’m gonna say no. So, this matrix, I know it might sound a little confusing, but I want the listeners to understand that we have considered every possible element, but the beauty is, you don’t need to understand or memorize anything that I’ve just mentioned. You just need to be aware of it, because, at the end of the day, we produce these recommendations, and we classify them as a strong recommendation, a recommendation, or a consensus-based recommendation. So, there’s three main levels that will determine, well, how strong do we believe that you should follow this recommendation? And that’s embedded into the intestinal permeability guidelines, and even how we write the recommendations.

So, when we dive into some of the recommendations, you’ll see that I use terms such as “offer,” or “advise,” when it’s a strong recommendation. So, when there’s systematic reviews backing up the evidence. But when there’s lower level of evidence, I’m gonna use terms like “may consider,” and a little bit more free-flowing. From there, we actually developed these recommendations, and we sent them to major stakeholders. Now, when I say “major stakeholders,” I’m talking about some of the biggest and brightest professionals in our profession. I’m talking Dr. Jason Hawrelak, I’m talking Dr. Nirala Jacobi, Dr. Ronald, Dr. Michael Osiecki, Dr. Amie Steel, Benedict the list goes on. What I’m trying to say here is these amazing, amazing stakeholders, they reviewed these recommendations, and they provided suggestions, a lot of suggestions, where we tweaked the recommendations, to ensure that when we release it to the public, this moment right now, that clinicians will be like, “Yes. I agree with this recommendation.”

Just before we dive into the recommendations, Andrew, I just wanna take a step back, and almost say how important graded recommendations are. Now, something to bear in mind is we’re in the era of almost too much research. Now, I know that’s crazy to think, but there are multiple studies in one particular area, but the studies will show different things. I often see presenters, even myself, and companies, they will make a claim based off a single study. And a lot of the times, there could be fundamental problems with that study. So, I want to actually put a call to action out there. I wanna see more companies, more healthcare professionals, more presenters, actually using graded recommendations. Now, if that’s too difficult, I want people to be utilizing a risk-of-bias assessment, to actually not just use, “Here’s a randomized control trial,” but to systematically look at the study, and go, “Could there be any confounding factors that impact the results?” Is that too much to ask for, Andrew?

Andrew: It’s a big ask, because when you consider that something like 80% of orthodox medicine is without guidelines, without proper guidelines, without proper evidence, this is a big ask, this stuff. What you’ve done is a mammoth task.

Brad: I’m not saying that we need a clinical practice guideline for everything. I’m more saying, rather than just stating, “Oh, here’s a research article that promotes this,” or is associated with that disease, to take a step back and to actually make sure that we read the article, to go, “Are these results accurate? Can we trust them?”

Andrew: Yeah. Oh, yeah. Yeah. And I’ve seen that some, like, both ways. For instance, one article on one research paper on a probiotic was glowing in its results. It had zero dropouts, and I went, “Meh. I smell a rat.” You know? Sorry. Zero dropouts, 100% effective? And then you’ve seen the research on this particular probiotic strain vacillate, between good and, you know, merit and no merit, in this condition. So I start to go, “Yeah, what are we seeing?” What I referred to earlier, and this came down to the wording that you used, is clinicians…what is it? Clinicians may…

Brad: Consider?

Andrew: May consider not to recommend.

Brad: Yes.

Andrew: So, it was really interesting, with regards to a probiotic in NSAID use, and a prebiotic in NSAID use, but wasn’t there, did I read this properly, that when you combine them as a symbiotic, then you may consider its use? And this sort of falls into the more naturopathic treatment paradigm, of not one magic bullet, but a whole treatment management plan. Am I correct?

Brad: And… You’re absolutely correct. So, you’ve got the intestinal permeability guideline. Now, I’ll direct your attention to table three. So, this is where we have listed…

Andrew: Here we go.

Brad: …all of the recommendations. So, Andrew, you’ve just mentioned recommendation 2.16. There are 38 different recommendations. So, maybe we can discuss some of these. Now, I won’t mention all of them, because that will take way too long to pull apart.

Andrew: Way too long. [crosstalk 00:38:15] This is a read, by the way. This is… What are we talking about? We’re talking about…how many pages? Thirty-eight pages.

Brad: That’s only one document, Andrew. There are two other documents. One of those documents is 80 pages. The other one is 45 pages. Okay. So, let’s dive into this a bit more. NSAIDs and intestinal permeability. What we know is NSAIDs are used, in the research, to induce intestinal permeability. Okay? It’s a very common method. Multiple studies have looked at whether or not a particular intervention is useful at mitigating intestinal permeability, in those patients who have taken NSAIDs, so, to induce their intestinal permeability. Now, you’ve pointed out here, I’ve got a section between 2.16 and 2.18, where we looked at whether or not taking probiotics, prebiotics, or symbiotics had any protective effect when it came around to preventing NSAID-induced intestinal permeability. What is quite interesting was we didn’t set out to develop this recommendation. This was more so that there was quite a lot of research here. So, these are evidence-based recommendations. And if we’re looking at the code, there’s three stars, so this is, it’s not the strongest recommendation, but it’s an opinion.

What I wanna emphasize here is, when it comes around to guideline development, we do need to consider what the research says. Although, if I had a patient in front of me, and I had the potential of prescribing a pre, pro, or symbiotic, would I give it to a patient who’s got NSAID-induced intestinal permeability? You know what? It’s not going to help. Sorry. It’s not going to hurt. It could be beneficial, but the research on those particular strains has shown that it hasn’t. So, I am sure that there are some strains out there that are very effective at preventing NSAID-induced intestinal permeability, but unfortunately, they weren’t researched, and they haven’t been researched in this cohort, thereby we couldn’t include them. But, but, I know people are interested in NSAIDs, so I’ll give you a bit of a caveat here. And that is recommendation 3.3. And I’ll read this one to you. And it says, “Clinicians should consider the use of short-term lactoferrin supplementation for the treatment of people with non-steroid anti-inflammatory drug-induced intestinal permeability.” So we do have something, with evidence, that we can recommend to our patients, that has been shown to be effective at preventing NSAID-induced permeability.

Andrew: But not colostrum? There was no evidence with colostrum? Nobody’s looked at that on its own?

Brad: That’s an interesting one. Unfortunately, all the research on colostrum had to be excluded, so we couldn’t produce any recommendations for colostrum, because we had to exclude it. The vast majority, if not all, were in patients with exercise-induced permeability. So that was one of our exclusion criterias, because if we looked at exercise-induced permeability, that opens up a whole ‘nother can of worms.

Andrew: Yeah. Heat shock proteins and everything.

Brad: Exactly. So, if anyone would like to do a clinical practice guideline for exercise-induced permeability, I would be happy to provide some recommendations. But yes, that is the reason

Andrew: If they’re willing to become an absolute nerd, and lock themselves in a way in a dark room for four years, having no life.

Brad: Shall I give you a few more examples, Andrew, of recommendations that we

Andrew: Please.

Brad: Please. All right. So, we have recommendations for alcohol use, dietary fiber, macronutrient ratios, energy intake, so that’s kilojoules, gluten-free recommendations, a number of pre-probiotics, recommendations for glutamine, omega 3, and zinc. Something I’ll note here is alcohol. So, I will be the first to say that alcohol induces intestinal permeability. I’m not afraid to say that. But, when you look at the research, all the research on alcohol, the effect of alcohol on intestinal permeability is short-term. I’m talking, participants would take one, two shots of alcohol in a setting, and then measured intestinal permeability. So, we couldn’t actually create a long-term recommendation for alcohol consumption. So we actually had to fall back on the Australian dietary guidelines, and basically say, don’t drink more than what the guidelines recommend, because we didn’t have the evidence to say “stop drinking.” In saying that, we produced what’s called a consensus-based recommendation. That’s where the brainiacs of the group sat down and go, “Okay, well, we know that alcohol can impact permeability. There is research to say it does, but no long-term. What can we do?” So, we have a recommendation that people with intestinal permeability should limit or avoid alcohol consumption when they’re actually treating intestinal permeability. Does that make sense?

Andrew: Yeah. Absolutely. And forgive me, I actually said the wrong thing. I reread the guidelines, and it says, “You may consider not using a symbiotic.” So, it’s prebiotics, probiotics, and symbiotics aren’t really recommended for NSAID-induced intestinal hyperpermeability. Wow.

Brad: With the caveat that those strains, the strains that were researched, were found not to be protective. That is not to say that there’s other strains out there with lower levels of evidence that weren’t included, that are effective. And I love my prebiotics, I love my probiotics, and I want there to be an effective one, but unfortunately, we didn’t include any research to support that. That’s not to say that from the thousand other strains out there that there isn’t an effective strain.

Andrew: Yeah. I mean, look, how many species are we allowed to have in Australia? Fourteen? Something like that. Most of them based on milk, not all, but most of them. We don’t, certainly don’t have the joy of being able to access things like Akkermansia, eosinophilia, or Faecalibacterium prausnitzii, or any of those ones, which, I’m gonna do a shout out here to Clara Belzer, who enlightened me to the merits of these microbes. But, you know, unfortunately, at this stage, we don’t have the facility to use those in a therapeutic environment. But one point that I make is you actually wrote this with the intention that future research will change these recommendations.

Brad: Of course. That is the underlying principle of a clinical practice guideline. It’s developed every five years, because research is coming out every single day. I recall finalizing a recommendation, and then you’d do one final sweep of the literature, and realize, “Oh, wait. This groundbreaking research has just been published.” And I actually had to get to a point where I said, “That’s it. This is the cut-off line. I can’t look at any more research,” because I’d still be validating the research till this date. So, these recommendations are valid as of 2023. I would like to say that the overall trend of these recommendations will stay very accurate for a number of years to come. But, as clinicians, we should always take these recommendations in consideration to any new research that has been done after 2023.

Andrew: Yeah. Like, I notice, galacto-oligosaccharides isn’t included in the… I mean, I get it. You can’t…

Brad: Yeah. It’s an interesting one, where we know that GOS is very therapeutic at reducing LPS-producing bacteria, which is linked with permeability. But that level of evidence, to get into a clinical practice guideline, it didn’t meet that threshold.

Andrew: Indirect. Indirect evidence, rather than direct.

Brad: Yeah.

Andrew: Brad, there’s so much to learn, but, like, really. People really need to look at these guidelines. Where can they download them?

Brad: Yeah. So, they are free to access. I’d like you to, if you can, include them in the show notes, so then they’re easy for people to download.

Andrew: Definitely.

Brad: If not, you can download them on my website, drbradleech.com, and you can just download them there. There are three documents here. You’ve got what’s referred to as the IP guideline. That is basically the summary of all the recommendations. For the gut nerds who are wanting a little more information, you can download the technical report, and the guideline development process document, two documents that have a lot more information, for someone who’s more wanting to look at this from a research perspective, rather than a Bible that clinicians should be keeping up in their clinic room, to quickly refer to, “Oh, yes. I can utilize this treatment recommendation.”

Andrew: And forgive me, Brad. I know we’ve covered the major areas, but just quickly, things like zinc, things like herbs, the…not the, well, the you could include, but also the antimicrobial herbs, like Coptis or goldenseal, which, you know, people are using. Can you give us just a quick synopsis of whether they’re indicated, or whether there’s issues with them?

Brad: Yes. So, with zinc, there was a number of studies, and it is a recommendation. I’m just trying to find it here in the guidelines. Here we go. Recommendation 6.1, clinicians may consider using zinc supplementation in the treatment of patients with intestinal permeability. As for herbal medicine, now, unfortunately, we couldn’t actually produce any recommendations for herbal medicine. Believe it or not, there isn’t a lot…there isn’t any studies that use a validated method for the assessment of intestinal permeability in patients who are not critically ill, over the age of 18, with appropriate statistical analyses. I recall, there’s some curcumin, and there are a number of herbs, but the study did not utilize a validated method to assess intestinal permeability. Thereby, we didn’t want to include any of those articles, because we wanted to ensure that the recommendations that we produced were of the utmost highest level of evidence.

Andrew: Now, I’m going to be attending a talk that you’ll be doing soon. In that talk, are you going to be talking about or discussing the major conditions which people present with, where intestinal hyperpermeability is a major factor, where we really should be addressing this, to bring the symptomatology and efficient management, or effective management, of these conditions down? That’s incorrect syntax, but to create effective management?

Brad: I believe you’re referring to a presentation I’m giving on how to treat the microbiome and gut-related conditions. And in that presentation, it’s going to be talking about what can we do to support the microbiome, to support gut-related conditions. But I’ll also be presenting at the NHAA conference this year, down in Melbourne, which I’m very excited about, on a topic very dear to my heart, on the impact of antimicrobial herbs on the microbiome, and whether or not some antimicrobial herbs may actually have a potentially detrimental impact on our gut microbiome. So, I won’t give too much away, but yes, I’ve got a number of upcoming events that I’ll be talking and presenting at over the next six to nine months.

Andrew: But you’re also doing, this is a public talk you’re doing. It’s on the 23rd of February, and it’s one that…

Brad: Yes.

Andrew: …patients can access. It’s a patient guide to wellness.

Brad: That’s correct. It’s focused on what patients can do to improve their gut health.

Andrew: Yeah. Wonderful stuff. Brad, you and I, seriously, I could learn so much off you, just talking for a couple of hours and chatting, preferably over a Pinot Noir?

Brad: That sounds lovely, Andrew.

Andrew: But it might transiently affect our intestinal hyperpermeability. But there’s so much to learn here, and so much to put into little boxes. But I love the way that you’ve done it, with scientific rigor, but from the point of care, from the point of actually caring for patients, to make a positive impact in their lives, rather than just selling them supplements, going, “The company said it worked.” I love this rigor. It’s fantastic, and it sees not just you, but it sees natural medicine practitioners in a higher light. You’re improving the professionalism of our professions. It’s [inaudible 00:52:54] you’re improving the standing of our professions. So, it’s wonderful work that you’ve done. There’s so much more for us to learn here, and so much more work that you have to do to make this a 90-page document.

Brad: Thank you, Andrew. And I’m only one piece in the puzzle. There are amazing researchers out there, who are just doing incredible things for our profession. I know a good friend and colleague of mine, I did my Honours and PhD with her, Dr Jessica Bayes. She’s now a postdoctoral research fellow at Southern Cross University, and she is producing incredible work when it comes around to mental health and the diet. So, we’re very fortunate here in Australia that we are producing so many more PhD-qualified healthcare practitioners, who are producing quality research to advance our profession. We’ve got amazing mentors. You know, Dr. Amie Steel, she has got so many PhD students. So I’m only one piece of the puzzle. So it’s great to have the support, and have so many peers who are doing so much to support our profession.

Andrew: Thank you so much, Dr. Brad Leech, for joining us today, and sharing your wealth of knowledge, but also your care for not just the profession, but also your patients. I really admire you. Thanks so much for joining us on “Wellness by Designs” today.

Brad: It’s my pleasure, Andrew. Thank you.

Andrew: And thank you, everyone, for joining us. Remember, you can catch up on all, and I mean all, of the show notes that we’ll have for you today. There’ll be a lot. And of course, the other podcasts on the Designs for Health website. I’m Andrew Whitfield-Cook. This is “Wellness by Designs.”