How to Interpret the GI-Map Stool Test

• Diagnostic Solutions
• GI Map white paper
• GI-MAP Interpretative Guide
• Dr. Ruscio’s Additional Resources

Intro:

Welcome to Dr. Ruscio Radio discussing the cutting edge in health, nutrition, and functional medicine. To make sure you’re up to date on this and other important topics, visit drruscio.com and sign up to receive weekly updates. That’s DrRuscio.com. The following discussion is for educational purposes only and is not intended to diagnose or treat any disease. Please do not apply any of this information without first speaking with your doctor. Now let’s head to the show.

DrMichaelRuscio:

Hi everyone. Today I spoke with Dr. Tom Fabian about the GI MAP stool test and how to best use this. One of the things that you’ve likely heard me mention many times is that we have to be careful with not over interpreting these tests. At the same time, there is valuable data contained in these tests. The challenge is finding that optimum balance and knowing what markers are valid, or at least have some initial data to support a safe inference. Conversely, it is important to know when you may be over reading the test and therefore over-treating the patient. Tom did a pretty good job of supplying a few specific examples of organisms that may track with inflammation. Most curious and interesting to me are organisms that have been shown to track with H. pylori and potentially with insufficient hydrochloric acid secretion. There may actually be a stool test finding that can help support or at least inferentially support the use of hydrochloric acid. We also discussed some fungal markers, a few markers that we want to be bridled in not treating them directly because they may actually be downstream effects of dysbiosis further up the GI tract. We also discuss what the viral markers mean. Many very impactful practical takeaways from this podcast with Dr. Tom. I think you guys will really benefit from it. I also want to remind you in this podcast, one of the recurring themes is making sure you don’t fall into the hubris of treating just a lab marker. It is vital to make sure that you’re looking at a given lab value in the greater context of the individual and the gut ecosystem. This is something that is very well imbued in the narrative of Healthy Gut, Healthy You. Again, I just want to bring your attention to the fact that if you’re looking for a set of guidelines to improve your gut health in a holistic and broad-spectrum way, that will look at your gut as a complex ecosystem and not just one variable, then I welcome you to grab the book and go through the Healthy Gut, Healthy You protocol. Hopefully, it will be as helpful for you as it has for so many who have read it and benefited from the book. So with that, we will now go to the conversation with Dr. Tom and I hope you enjoy it.

DrMR:

Hi, everyone. Welcome back to another episode of Dr. Ruscio radio. This is Dr. Ruscio. Today I’m here with Tom Fabian and we’re going to be talking about and getting deep into the world of the GI MAP stool test. We’ve talked about this before on the podcast and discussed its merits and how we can best use this tool. So, Tom, thanks for being on the show today.

DrTomFabian:

Thanks so much, Michael. Great to be here.

Background – Tom Fabian, Ph.D., CNTP

DrMR:

It’s great to have you here. I should really introduce you as Dr. Tom to make sure people know that you do have a background as a Ph.D. and a CNTP. Why don’t we start there? Why don’t we start with your background. We were discussing offline, you’ve been fairly ensconced in everything microbiome for the past several years. So give us a little bit of your background, education and kind of how you found your way into the wonderful world of the microbiome.

DrTF:

Absolutely. So I’m currently serving as a clinical education and science consultant for Diagnostic Solutions Lab, and I’ve consulted with other GI and microbiome tests in recent years as well. So consulting is a big part of what I do now, currently for DSL. I also split my time a little bit between that and educating clinicians on the microbiome. I offer online courses on the microbiome. I also, although I don’t have a significant practice right now, I do, in my spare time, see a handful of clients regularly. So I keep my toe a little bit in that area. Primarily though, I’m mostly focused on consulting with clinical testing companies. As far as my background, I actually started out in biomedical research. So I got my doctorate, my Ph.D. in molecular and cell biology from the University of Colorado in Boulder, and then moved on to do my postdoctoral research at the University of Utah. After that, I spent several years as a research scientist in the biotech industry and then eventually transitioned, after a period of time, to wanting to apply this information in a variety of ways, but particularly in the realm of healthcare and specifically in functional medicine and functional nutrition. Since I didn’t have much of a clinical background up until that point, I decided to go back and just get a certification in nutrition at the Nutritional Therapy Institute, which is in Denver. It was really at that point when I decided how I wanted to apply my biomedical background to this field. It was really when the microbiome was kind of starting to become much more of a big thing so I really saw the impact there potentially on how that might help improve what we do as clinicians.

DrTF:

So I started specializing in the microbiome and in related fields cause you really have to understand, for example, mucosal immunology to understand the microbiome. So I started focusing on these other areas as well. Really got up to speed in that area and what I do is essentially kind of translational science. I apply that, as I mentioned, in three different ways: Working with clinical testing companies, educating clinicians on the microbiome and working, in a limited way, with individual clients. That’s essentially kind of my background.

DrMR:

There’s a lot here to unpack with a stool test. On its face, a stool test can make one conclude that when there’s stuff that shouldn’t be there, we should use antimicrobials. I think that’s the “using this like a hammer” application that is a bit of a remnant from older schools of thought on natural medicine. However, as we’ve become a bit more nuanced in our understanding, there are different approaches in terms of how we can try to push the gut into a healthier direction. Today I want to give people a better understanding of how we interpret what I oftentimes label as gray area findings. If you see an overt pathogen, that’s fairly straightforward. But before we go down that road, let me slow my personal clinical curiosity down a little bit and take a small step back for people. Can you just define the type of test this is? The PCR based test. Tell people what that means and how that compares to a more traditional stool test. Then we can work our way into some of the nuances.

What Makes the GI-MAP Test Different

DrTF:

Absolutely. Again I’m talking specifically about the GI-MAP test from Diagnostic Solutions Lab. So it’s in the general category of comprehensive stool testing, which means we have a number of markers that reflect the status and the presence of certain microbes that can be very informative as far as what’s going on in the gut. In addition, there are physiological markers. So we essentially see both sides of the coin. We see what’s going on with the microbial ecosystem and then we also see what’s going on to some extent with GI physiology. It’s really important to have both sides of the equation there so that you can really correlate what’s going on at a bigger level in terms of overall gut health. So on our tests, we categorize the organisms first by pathogens, then by essentially normal commensal bacteria, aka the normal residents of the gut, and then a variety of opportunists. That’s sort of a general categorization. As you mentioned, generally, pathogens are pretty straightforward. Although with PCR, one thing I want to mention since we can detect pretty low levels and especially with quantitative PCR, which is the methodology that we use, which allows us precise quantitation of these microbes. Again, we’re looking at DNA detection of the microbes, essentially we can see low levels. Low levels are kind of in that gray area, kind of an equivocal area where sometimes they may be clinically significant. That’s where clinicians really have to use their judgment, their assessment to determine whether symptoms, et cetera, are consistent with a potential impact. Also, based on a bunch of new research that’s come out recently, the presence of pathogens at moderate levels, even if there are no significant symptoms, tell us potentially that certain protective factors may be lacking. We are learning more and more about what those are. Oftentimes when we see, for example, the presence of C. diff, and we know from research that C. diff is more likely to be present when patients have low stomach acid, when they’re not digesting well, when there’s excess protein or amino acids in the colon from not digesting well, that could potentially lead to the growth of C. diff. So we get some insights potentially into these physiological areas. So that’s just a quick example of some of the additional information that we can get by this new type of assessment with quantitative PCR.

DrMR:

That’s really a quite serendipitous specific example to use. We recently published a case study where there was C. diff found on a GI MAP and it was detected, but not flagged. For the audience, what I mean by that is that the test will report if more than zero has been detected, but not necessarily enough to be over the threshold of what’s considered a true positive. In this case, the individual had a true positive, but it seemed that longterm herbal antimicrobial therapy actually worsened their entire situation, in terms of followup testing and their symptoms looking worse. It was actually a high dose of probiotics with removal of the antimicrobial therapy that reduced symptoms and finally cleared the C. diff.

More Treatment Isn’t Always Better Treatment

DrMR:

So this kind of ties into one of these themes that I’d like to discuss, which is not over treating someone. I think there has been this mistake in thinking that if there is anything bad we have to blast it with antibiotics, antifungals or some kind of anti-microbial herbal therapy. They absolutely have their time and place. However, my fear, and Tom, I’m definitely curious to get your thoughts on this too, is that when we have a lab test that can justify using antimicrobial therapy, sometimes it seems that clinicians get this overly confident thinking and jump to antimicrobial therapy without fully appreciating that the microbiota is truly this ecosystem, a garden-like terrain. We don’t always have to kill certain things to get rid of them and we can use more supportive interventions. This case study really reflected that. What are your thoughts there, Tom?

DrTF:

Absolutely. That’s definitely one of the areas where we tend to help clinicians understand how to connect these dots. Again, based on what we see on the test, combined with the volumes of new research that’s coming out, and of course, what they’re seeing clinically with their patients. So in the case of C. diff, most people assume that is a pathogen that you don’t want to have there. If they see it detected, not even at the level where it’s flagged as high, they’re often inclined to want to address that with an antimicrobial. That inclination will sometimes change after we walk them through an interpretation of the results and help them understand that if patients are not experiencing significant symptoms that could be attributed to C. diff. For example, if we do not see elevated calprotectin, so if we don’t see any evidence of inflammation that might be attributed to C. diff, that suggests that they may just be a carrier and that potentially that level of C. diff is not problematic for that given patient. That’s an important general concept. Even though the levels of organisms do generally tell us that the higher the number, the more likely they are to be pathogenic, that’s not necessarily the case for all people, depending on other factors that are going on. So, as I mentioned before, low stomach acid is well documented in the literature, particularly for patients that are on proton pump inhibitors as increasing the risk for C. diff growth and infection. But we also know other things, such as the presence of excess amino acids. That has been very well researched and shown specifically to come down to the presence of proline, which is a particular amino acid. They’ve actually done some small scale clinical studies looking at proline restricted diets, as well as generally protein restricted diets as one adjunct to helping to reduce the growth of C. diff.

DrTF:

Then the flip side of that is we also know from research that a lack of fiber intake. This results typically in lower levels of certain types of beneficial bacteria, such as the Clostridia that produce butyrate. When certain butyrate producers are low, that’s also been shown to promote the growth of C diff. So when you take all these things into account, we need to evaluate are we looking at actually just trying to improve digestion first and then trying to improve the balance in the microbiome. What are those factors and will that be sufficient to help to reduce or eliminate that particular low level of C diff.

DrMR:

Now to my knowledge, there’s no marker on the GI MAP profile that would give clues to one’s hydrochloric acid secretion capacity. Is there anything there that you know of that may drop any hints to the clinician?

DrTF:

Absolutely. Yeah. We do know, for example, that the majority of people that have H. pylori as a chronic infection tend to have hypochlorhydria. That’s documented in many studies. The effect of H. pylori on stomach acid can vary depending exactly on where in the stomach it’s infecting and other parameters. So a small subset might actually have increased stomach acid, however, in the research and also what we consistently see clinically, is that patients typically would have low stomach acid. Now we’re mostly gauging that by patterns of the microbiome that have been shown in research to be associated with low stomach acid. We don’t, of course, have any direct measure or direct way to measure stomach acid. So we’re going by indirect patterns that have been shown in research. Another common pattern would be in our opportunistic bacteria section, where it’s been shown, in many research studies, that higher levels of Streptococcus and higher levels of Enterococcus correlate with lower levels of stomach acid. So those are just a few examples. We know a lot about organisms and which ones tend to thrive at which types of pH, some are much more tolerant to acid. Some are not tolerant to acid. So there’s a lot of information that we can kind of bring to the table in interpreting the patterns with GI MAP. But that’s a particular example of some of the groups that are really well-documented to be associated with low stomach acid.

DrMR:

Just to clarify, were you saying this is an overgrowth, with the Streptococcus and Enterococcus that may indicate low HCL?

DrTF:

Exactly. I mean, it’s part of a general pattern that we tend to see of overgrowth. We often see this in the normal bacteria section, as well as the opportunistic bacteria section. Through several lines of evidence, both from research and what we’ve seen clinically correlate with evidence of reduced digestion. One of those factors can be low stomach acid, and that does tend to be more likely when patients have H. pylori overgrowth as well as Enterococcus and Streptococcus overgrowth.

DrMR:

Is that the main finding that H. pylori tends to co-present with Streptococcus and Enterococcus? Is that the main research finding?

DrTF:

Exactly.

DrMR:

Gotcha. That makes sense. Okay.

DrTF:

It’s probably best studied with proton pump inhibitors. There’s just a ton of research out there on the effect of various drugs, especially PPIs as well as antibiotics, et cetera, on the microbiome.

What the Research Shows

DrMR:

In these studies, are they doing duodenal and jejunal biopsies, or is this stool testing that they are looking at? For the skeptic, they may be asking, can a stool test, give me a good indication of what may be happening higher up in the GI, or is this research looking at mainly stool as a measure?

DrTF:

That’s a great question and actually kind of opens up a whole other topic I’d love to get into, but so the short answer is yes, most of those studies are looking at stool samples. Since then there have also been a lot of studies that are starting to characterize the small intestinal microbiome, the gastric microbiome, et cetera. So when you look at all this research together, it helps fill in the dots. Some of the most important studies have to do with looking at which microbes are active or thriving in which parts of the GI tract. So H. pylori is the classic example where we assumed, based on prior evidence and common knowledge that it’s mostly something that thrives in the stomach, but of course we can detect it in the stool sample with DNA testing.

DrTF:

So the question is, are we detecting active thriving H. pylori that’s somehow thriving in the colon or is it sort of coming from the stomach and it’s still potentially intact, but dormant or potentially just at that point degraded into DNA. So that latter question, there’s really not a lot of research telling us whether or not H. pylori may be dormant or dead by the time it reaches the stool. But these studies where they’re looking at RNA, which is a measure of gene expression – just to kind of back up, bacteria have to be active and thriving in order to express their genes – with RNA testing, they can tell whether or not what’s detected in a DNA test is still active. So these, what are called metatranscriptomic studies that are looking at RNA, have shown that H. pylori that’s detected in stool is no longer active. The same with a number of other organisms, such as Pseudomonas, which we do detect on our test. We can pick it up with DNA, but the evidence so far indicates that it’s not active plus other evidence indicates that it’s probably most active in the upper small intestine and then possibly also in the stomach. So there’s a lot of detailed research that’s been coming out, looking at what thrives in what part of the GI tract, when you combine that with what we know about these organisms, in many cases, that all that information kind of syncs up and really makes a lot of sense.

DrMR:

This is a great insight about the Streptococcus and Enterococcus. I’m going to start looking at that more closely. In my mind it is a very delicate balance of trying to read these opportunistic dysbiotic organisms for any useful patterns on the one hand, and then on the other, not let that overcome the patient symptom profile and response treatment right in front of you. That’s the other side of this coin, which is we get so much feedback from the patient’s symptoms and their response to therapeutics that I’m careful not to let a lab finding trump that ifwe’re getting to the clinical end point of a resolution of symptoms. However, this will be helpful in looking for this type of pattern in my patients to see what kind of, I don’t want to say predictive value, but I guess how well this correlates with those who respond to hydrochloric acid supplementation. That is one thing I’m sure many clinicians struggle with. Who needs to be on this, who doesn’t need to be on this. There are risk factors as we’ve discussed in the podcast, age (being 60, 65 or older), history of anemia, history or current autoimmune conditions, all of those increase the likelihood that someone will need hydrochloric acid. H. pylori, which I’m glad you brought up can kind of cut both ways, but certainly can lead to kind of this atrophic like gastritis. So this is one more pattern for clinicians to look at to see if it helps them guide the therapeutic trial on HCL.

Food Sensitivities

DrTF:

I think that there are a lot of insights that we can get once we start to take this information into account as part of how these results are interpreted. So another good example that’s related to that as I mentioned, is Pseudomonas. Pseudomonas, based on all the information we have from research so far suggests that it may be more likely to be thriving in the upper small intestine. There’s a major study that just came out last year, linking overgrowth of Pseudomonas and the production of a particular virulence factor, which is essentially is a kind of enzyme called a protease that helps break down proteins. That product can stimulate inflammation in the small intestine, which has been linked to an increased reactivity to gluten and to other foods. So it’s their conclusion in the study is that it’s likely a contributor to food sensitivities.

DrTF:

It is something that we often do see elevated in patients that have extensive food sensitivity. So it’s one of those cases where, once we saw the research and then we start to look at it to what’s happening with patients, we do see that link pretty frequently. It really makes a lot of sense because oftentimes we’ll see it in conjunction with H. pylori. If you kind of look at what we know about those organisms, for example, Pseudomonas tends to thrive on partially digested proteins. That’s actually how they grow it in the lab. So it can thrive, for example, on casein, which is a protein from milk. It can also thrive on gluten. In fact, giving lab animals gluten with Pseudomonas can cause Pseudomonas to grow to a higher level, but when you have low stomach acid that can particularly have a negative impact on protein digestion. So that may be an explanation for why we tend to see Pseudomonas more frequently when H. pylori is present. Then based on what we know from that research that suggests that Pseudomonas might be further interfering with digestion. If it’s causing inflammation in the small intestine, in some patients, and that inflammation might have a negative impact on brush border enzymes and transporters. So we often see evidence that would be consistent with that for patients.

DrMR:

Gotcha. So you’re looking at all three of those as potential indicators of insufficient hydrochloric acid production.

DrTF:

That is one potential contributor. The low stomach acid.

DrMR:

Is the Streptococcus and Enterococcus more tightly tied with that and the Pseudomonas more multi-causal?

DrTF:

So in research the presence of Pseudomonas, I haven’t seen research so far, that has linked it to low stomach acid. That’s mostly inference based on the fact that it tends to thrive on undigested protein. If you have low stomach acid, then you’re going to end up with more undigested protein in the small intestine.

SponsoredResources:

Let’s talk about one of my favorite tests for digestive health, the GI-MAP from Diagnostic Solutions, who has helped to make this podcast possible. Now if you’ve been reading any of the case studies that I’ve published in the Future of Functional Medicine Review clinical newsletter, you’ve likely seen that this test, the GI-MAP, is a test I frequently use in my practice. Why? Well, one of my favorite things about this test is it has excellent insurance coverage. So this is a few hundred dollars that I save patients. This lab is also CLIA certified, which is essentially the quality assurance bureau for labs. So it’s important that these labs are being monitored, not cutting any corners. That’s where you get your CLIA certification. Now, this test uses quantitative PCR technology. So it’s a DNA test. And you’ll get a good read on dysbiosis with this test because they will assess and report out various types of bacteria, yeast, and parasites including protozoa, worms, and amoeba. They also have some valuable and helpful clinical markers like calprotectin which can help rule in or out inflammatory bowel disease, and zonulin, a marker of leaky gut. So head over to DiagnosticSolutionsLab.com to learn more and to order your test.

Resolution of H. Pylori with Probiotics

DrMR:

So this, this is such a great example because I was pondering doing a quick video on a patient that we hadn’t seen in a year. We had done a baseline GI MAP with them. He scheduled a follow up about a year later and had a followup GI MAP right before our visit. What was interesting is that his original GI MAP from about a year ago, from January of 2020, he did have H. pylori positive with a virulence factor positive. He also had elevations of Streptococcus. We had recommended at his visit a year ago to use some probiotics. He did and that led to a fairly marked improvement in his symptoms. When he performed a followup test, the H. pylori was completely clear. The Streptococcus still remained elevated, but the H. pylori was cleared and his symptoms were almost fully eradicated. He has some low level lingering symptoms that we’re following up on. I just want to pose as an example for the audience. At least in my thinking, and this seems to follow the research on H. pylori, unless there’s been a major revision in the past few months that I’ve missed, looking at it more as a commensal or pseudocommensal not something that maybe necessarily needs to be strictly eradicated. That’s where, in my mind anyway, the probiotics may just help reestablish the right colonization ratio. So in this case, one could argue, “Oh my God, H. pylori, we’ve got to go after that with the big guns”. However, in this case, that doesn’t seem to be the situation. His symptoms are markedly improved and his H. pylori, which did have virulence factors positive, are now clear. Would you agree with that Tom? Would you modify anything?

DrTF:

That’s a really interesting case. I would definitely say there’s an ongoing debate in the scientific community as to sort of how commensal H. pylori might be. There’s evidence that it’s certainly widespread overall. I think worldwide, the incidence is at least 50%, if not higher. It is certainly higher in developing countries. It’s thought to be something that may have been with us for thousands of years, if not more and that actually reduction in H. pylori incidents might be due to modern antibiotics, at least in part. So the short answer is yes, there’s evidence that could be used to argue that it’s likely a commensal to some extent, or sort of an opportunist that only causes problems when it’s overgrown or acquired certain virulence factors, for example. It is also as possible that the use of antibiotics may have promoted the growth of more virulent type forms over time.

DrTF:

So that’s all kind of open for debate. There is definitely good evidence in the research. In general, in terms of dysbiosis in any part of the GI tract, once the normal commensal microbes, the beneficial microbes tend to be out of range (generally too low, or just out of balance) that allows opportunists to take over. So that could be what’s happening with modern lifestyles, modern diets, medications, et cetera, with H. pylori. Trying to restore that balance could be very important. There are studies that help support that, particularly with lactobacillus species.

DrMR:

Fully agreed. Also, and the evidence here is a bit more sparse and inferential, but I think fairly justifiable. We know sleep impacts microbiota. We know diversity scores improve when people go from sedentary to exercising. We know stress causes a weaning of certain lactobacillus and bifidobacterium populations in the gut. So while these things seem trite perhaps, and not very exciting, as I discuss and really trying to harp on in Healthy Gut, Healthy You those are all inputs encouraging your gut commensals to move in a healthier direction. This is maybe why some of the research centers, as one example, may report a high relapse rate in IBS and/or SIBO. I’m assuming in many of these kinds of primary clinic settings, or even tertiary care where they’re seeing progressed IBS and IBD, if it’s just kind of standard conventional medicine, there may be a fair facet of people in that population who are still smoking and eating fast food and just really living kind of the standard American lifestyle and eating the standard American diet. It seems like it’s a reasonable conclusion to draw that it would be much more difficult for the microbiota to remain balanced after an antibiotic course or herbal antimicrobial course because none of those healthy inputs are there.

DrTF:

Yeah. I would definitely agree with that. I mean, that’s definitely one of the challenges when we’re doing consultations at Diagnostic Solutions Labs. Clinicians call in when they would like assistance with interpreting a test. We have typically a 30-minute window to quickly gather the patient’s information and then walk them through the test and help them understand what the markers mean, what patterns mean, et cetera. So, as I mentioned, that digestive dysfunction type pattern, we kind of intentionally referred to that sort of generically, because we know there can be many factors that come into play there with low stomach acid being potentially just one. For many clinicians, you know, sometimes we have to gently remind them that we don’t always see the cause on the test itself because oftentimes they’re specifically trying to determine if H. pylori that is causing this or is it potentially something else on the test? Those things certainly may be contributing. They might be a primary cause if they’re there, but as you mentioned, gut-brain axis issues are huge, immune system issues, autoimmunity, diet issues, the list just goes on and on. So that’s really the tough part, kind of going upstream and looking at the root causes of some of these things. Where we can kind of come into the picture is helping connect those dots within the picture of what we can see with GI MAP. Again, that’s largely looking at overall digestive function, largely the microbiome in the colon, the large intestine, and to some extent, some insights into what’s going on in the upper GI tract.

Commensals & Opportunists

DrMR:

So while we’re in this area of looking at patterns in commensals and opportunists, I know there are a lot of theories out there. Are there any theories that you feel are a bit more well-developed or have good clinical anecdotal corollaries supporting them?

DrTF:

Absolutely. So when we’re looking at patterns, for example, if you’re looking at the beneficial bacteria section, we recently added two Keystone species: Akkermansia and Faecalibacterium prausnitzii. So that second one, Faecalibacterium prausnitzii, is a major butyrate producing bacteria. So that’s a short-chain fatty acid that has many well-documented beneficial effects in the gut. So we know from research that a pretty wide range of chronic diseases, autoimmune diseases, et cetera, tend to be accompanied by low levels of Faecalibacterium. So that’s just an association, but suggests that it’s possibly a very important organism. When you look at the detailed information that’s available on Faecalibacterium, we know that it appears to be particularly sensitive to inflammation. So when we see low levels of Faecalibacterium, and especially if that’s in conjunction with low Akkermansia, based on everything we know about those organisms that suggests that the intestinal lining and the microbiome in the lower gut, in the colon, is probably not very healthy. One of the things to potentially check for is elevated inflammation. So that is one of the common patterns that we see. Well, we will often see calprotectin, which is our marker for inflammation, is elevated when those two markers are low, but that’s not always the case. That begs the question of why is it consistent with high calprotectin in some cases and not others. One of the other major things that we have found from research, again, this is something that’s been replicated many, many times, is excess amounts of what’s called protein fermentation in the colon. Essentially the two major types of fermentation that bacteria carry out in the colon would be what we were all familiar with. Number one would be fiber fermentation, which is in the general category of carbohydrate fermentation. That’s generally synonymous with a healthy microbiome and with production of butyrate.

DrTF:

Whereas if you have a predominance of protein fermentation, which can be due to things like lack of fiber, excessive protein intake, poor protein digestion, that can be another factor that’s been shown to promote dysbiotic pro-inflammatory type bacteria. This is often another scenario where we’ll see low Faecalibacterium. Now we’re connecting dots again. So if you see evidence of reduced digestion, the most direct marker on our test would be elastase, for example. So if you see direct evidence based on low elastase or indirect evidence, based on the microbial patterns that suggest that poor digestion may be part of the picture, that could be another reason why there is elevated calprotectin and/or low levels of these beneficial bacteria. So that’s all really well-documented in research. And it’s certainly something that we see evidence of clinically as well.

Calprotectin Testing

DrMR:

I’m glad you mentioned calprotectin, cause this is one of the things I wanted to ask you. I am fairly confident and I’d love to be talked out of this conclusion or “soft hypothesis” that the GI MAP suffers from false positives on calprotectin. This is after seeing a several patients who they didn’t fit the picture of where I would expect to see an elevated calprotectin. I cross-referenced that with either LabCorp or Quest, and this was either Ilana Gurevich and/or one of the other doctors in our clinic who followed up and looked into methodologies. I believe LabCorp and Quest are doing a refrigeration of the calprotectin sampling before running the analysis and I don’t believe GI MAP is doing that. So there may be a methodological difference that’s leading to this. That’s the conclusion that I’m currently at. But I’d love to be talked out of that and/or understand better why I’m seeing what seems to be a clinically non-representative elevated calprotectin.

DrTF:

That’s a good question. The test that we use is an FDA cleared test and as a CLIA lab there are certain requirements that we must satisfy for each test, to show validation, et cetera. So based on that there’s a pretty solid basis for our test. The test that we have currently does have a wider dynamic range so we do tend to see a little bit more on the positive end of things. I guess the question is, if you compare two tests, so you do a Quest test versus our test and ours is positive and the Quest test is negative, there’s no way to determine directly whether the high calprotectin is a false positive or the negative result on the other test is a false negative. So there are some differences in methodology. We’re using a newer kit. Again, it’s an FDA cleared kit that has a wider dynamic range. So that could be one difference between results from different tests.

DrMR:

Now to clarify the meaning behind wider dynamic range. Is it fair to say that the cutoff value established by LabCorp and Quest, which I believe is maybe 150 or 200, it may be tiered differently at different labs. Whatever their cutoff is, and that’s just easily able to be verified by going to either website and looking it up, correlates with an appreciable jump in inflammatory bowel disease activity. Because in conventional medicine, that’s really the primary use of this information. So is that kind of what you’re saying, where if the LabCorp and Quest ranges are over the positive threshold that correlates with disease activity and changes that are significant in IBD, whereas yours, isn’t looking through that same lens and that’s where the difference comes from.

DrTF:

That’s a good question. I think that the cutoff levels are determined in similar ways, but any sort of cutoff, to some extent, is going to be arbitrary. So just because a level is above that cutoff doesn’t mean that the patient has IBD. It’s just sort of a likelihood scenario. So that diagnosis is more likely above a certain level. The cutoff levels really have to do with the lab specific ranges. So that really is, I think a significant difference is even if the cutoff levels established by different labs appear to be similar, how those are determined can be somewhat different between labs.

DrMR:

Gotcha. Just for our audience, I just looked up the LabCorp cutoff which is 120, although that, again, may change regionally, but just to give people a general idea. Okay. So any other thoughts then on calprotectin? I guess one of the main things I’m after is trying to bridle the clinician who looks at that too overzealously and maybe not looking at that, of course depending on the level of inflammation, but as something that requires strong anti-inflammatory therapy or scaring the bejesus out of someone. I mean, maybe it does. Maybe I’m being a little bit too circumspect, but how would you advise people on looking at this from a more nuanced perspective if that’s advisable?

DrTF:

Sure. I mean, part of it is looking at the overall results of the test itself. Again, within the context of what we can determine within the test, are there any pathogens present that might be explaining or correlating with that higher level of calprotectin? Do we see any evidence of inflammatory dysbiosis? Um, those are really kind of the main ones that we tend to see. Plus, is there a lack of beneficial bacteria? So we do know that a lack of beneficial bacteria in and of itself may not cause inflammation, but they act as a restraint on inflammation by producing anti-inflammatory products. So we often will see calprotectin at least high normal, if not officially high sometimes when beneficial bacteria are low. There can be many potential triggers or causes of inflammation, such as NSAIDs, for example. We don’t have any evidence of seeing on our tests other than they may lead to evidence of inflammation, possibly some dysbiosis.

DrTF:

So really you have to take into account what can we tell from our test based on a disturbed microbiome or presence of a pathogen. One other area where there is not really a lot of research yet to say anything too conclusively, but there have been some intriguing studies about proteases. So I mentioned the protease produced by Pseudomonas, but of course we produce proteases ourselves from the pancreas. A couple of studies have shown that pancreatic enzymes, at least the protease part of it, maybe one contributor to inflammation in the colon for some patients and that may be a contributor, for example, to IBD.

DrMR:

Is that a depression of pancreatic enzyme?

DrTF:

No. A high level. So it turns out that because high levels of certain proteolytic enzymes, proteases, can activate certain receptors called PARs, that can cause inflammation. That study essentially looked at that. I think there’s a couple of studies out there now, but we have seen that in a couple of cases cause we get asked, is there an upper limit to elastase? We do see occasionally that values are up towards 1000 or so. There’s really no well-established upper limit to elastase. So officially, anything above roughly 500 or so we consider optimal and above 200 may be okay. Although as you get closer to that 200 level, some patients may benefit from digestive support. But in a few cases, we have seen that when patients have very high levels of elastase, that can be the only correlate with elevated calprotectin. Again, there is some evidence from research suggesting that that may be the case and also new evidence from research indicates that beneficial bacteria produce protease inhibitors. So in those same cases, we saw evidence of low beneficial bacteria.

Literal Interpretation vs. Clinical Correlation

DrMR:

I’m going to ask you if maybe those people are eating too high of a protein intake, but it seems much more intuitive to me that it could be just this dysbiosis that’s leading to these downstream effects.

DrTF:

Exactly. Yeah. So that’s something that we may mention to clinicians in interpretations. Of course we’re very careful to say this is just based on some studies and needs to be further validated, but it may provide an explanation to what we’re seeing here.

DrMR:

I think that the way you’re phrasing that is incredibly important, clinicians and patients seem to easily fall into this very literal interpretation of these lab tests. I think it’s vitally important just like you alluded for clinicians to understand that these are just probabilities or suggestions and then we correlate that with response to treatment. Then we modify our conclusion based upon that response. It just really kills me when I see a patient who just keeps getting pigeonholed into something based upon a lab value, even though clearly the therapeutic interventions for said lab value are leading to no improvement and sometimes flaring. I hope clinicians are all becoming more privy to the fact that we look at the lab data, as perhaps one fourth of the data, and combine that with the history of their symptoms and response to treatment and then their labs and all that’s used collectively to determine what the next step should be.

DrTF:

Yeah, exactly. I couldn’t agree more. As a clinical lab in these consultations, we’re prohibited from giving any sort of medical advice. We can give the general information on the microbes. We can talk about studies that support certain potential interpretations, et cetera. Even after we sort of let them know that we can’t give medical advice, sometimes we’ll still get asked “should I treat this organism?” So we have to kind of turn that back around to them and say, “well, based on the information I’ve given you, plus your assessment of the patient, plus anything else you think is relevant is really what’s going to determine whether or not you decide to treat that”. So we do see that quite. Clinicians do have a tendency to want to treat to the test as opposed to the patient. So we do have to kind of bring them back to that perspective that this is telling you that this is there at this level. It’s really a matter of your decision and your judgment with the help of some of this information we’re giving you to decide, is that something you want to act on, and then how do you want to act on?

DrMR:

Yeah. Again for clinicians, and I consider myself as part of this evolutionary process where we’re all trying to constantly be better than we currently are. Something that I think is an unintended side effect of the plethora of lab testing we now have is a handicapping of clinical decision making. Of that process of looking at the patient, looking at their response and trusting your own ability to look at someone’s response to treatment, their history, all of these things that we just outlined, and make a decision, not exclusively based upon the labs. It is easier, and we can sometimes feel safer saying, “well, I’m just I’m treating the lab and I’m justified in my decision”. However, I feel that this is reflective of an overreliance. Hopefully some of this is landing for people and will help to calibrate us back to a more reasonable incorporation of these lab values into the clinical decision making process.

DrTF:

Absolutely. We definitely see that sometimes where something just doesn’t really make sense. We don’t really know why. We’ll see high calprotectin when there is no evidence of inflammation, et cetera, based on the microbiome. So it’s really up to the clinician to decide, is there some other thing that they know from that patient’s history from their assessment that might be related to that. If they’re not having any significant symptoms, maybe that’s something in that particular case that just doesn’t need to be treated.

DrMR:

Yeah. You know what you said, I think is so profound, it’s really worth reiterating. Not every marker requires treatment. It sounds crazy maybe, depending on what circles you run in, but not every market requires treatment. Sometimes you can wait and see and, or retest, especially if it’s something that really strikes you as odd. I have found that most labs are pretty good about, in some cases just running a retest for free or giving a discount if you suspect there was a lab error. So don’t be afraid to ask labs to help you out. I understand that asking for another $300 or whatever is a big ask in some cases. I have actually been very pleased at how accommodating labs have been in helping to get through that and do a targeted retest.

Fungal Markers

DrMR:

I want to shift gears for a second to fungal markers. This is an area that I suspect there is much less research and more inference. I’m happy to be proven wrong there or just kind of be a bit more caught up to speed. What kind of evidence do we have for these stool, yeast and fungus markers correlating with various sequella and maybe even better yet predicting response to any kind of antifungal treatment.

DrTF:

Far and away the number one marker in that fungal section that is clinically relevant would be candida. That’s the only one that really tends to be kind of a true resident of the gut. So it’s kind of a true opportunist. That’s typically not causing issues unless it’s overgrown due to disturbance in the ecosystem. A lot of new research that’s come out recently indicates that most of the fungi detected in the gut are essentially just passing through. Their sources are from things like diet, et cetera, with diet being probably number one. So they’re passing through. If there’s a bit of a niche then they can temporarily grow. They’re not necessarily, by and large, problematic. Although for some people, particularly immunocompromised patients, they can be problematic. So again, that’s really coming back to the interpretation based on what you know about the patient, if they’re otherwise fairly healthy, not immunocompromised, it could just be related to something that they ate recently.

DrTF:

We do tend to see them present a little bit more often when there’s other evidence of dysbiosis, particularly what we would call that digestive dysbiosis type pattern. This suggests that they’re more likely to grow a little bit in the gut, maybe not enough to really result in symptoms when there’s other imbalances. So a lot of what we see in terms of dysbiosis may not, in and of itself, be a problem, but maybe reflecting that there’s just overall disturbances in some aspect of physiology or just microbiome balance. If there are symptoms for some of them, they’re fairly clearly defined depending on the pathogen, some can cause loose stools, diarrhea, et cetera. So if patients do have that and there’s no other obvious explanation that may be a candidate to suspect that in that patient might be causing a problem.

Methanobrevibacter and Methane Positive SIBO

DrMR:

Hmm. Then shifting to another category altogether, the Archaea or the Methanobrevibacter. Obviously, this begs a question for our SIBO savvy facet of the audience. Does stool PCR elevation of Methanobrevibacter correlate to methane positive SIBO? Have any of those studies shown correlation?

DrTF:

I’m not aware of studies looking at that, but I would say anecdotally, based on what we’ve seen with our tests, that only at the very high end of that spectrum, do we tend to see this. This is only in cases where clinicians have already run a breath test and know the results. If it is significantly elevated, then that could be indicating that patients may have a problem with methane dominant SIBO rather than just methane related constipation. It doesn’t, of course, always have to be related to SIBO. We do know from how the ecosystem functions that methanogens depend pretty much exclusively on carbohydrate fermentation and the hydrogen that’s produced from that in order to produce the methane that they produce. So it’s a really good gauge for overall fermentation activity. We tend to see it at least in the high normal range when there’s other evidence of patients not digesting well. It’s a fairly good indicator based on everything we know about how that’s been characterized in research and also what we see clinically. It does seem to be a very good indicator for overall levels of fermentation, which can give us some insights again and further support whether patients may or may not be digesting well.

DrMR:

Something else we talked with Thomas Guilliams. There is this kind of chicken or the egg debate, or I shouldn’t say debate, it’s really probably a bi-directional relationship between motility and methane and methane and motility. Some evidence has shown that if you facilitate motility, methane levels go down. Also if you treat methanogens, you facilitate motility. So it’s something else for clinicians to consider. I don’t know if this has been specifically demonstrated, this is an inference, but if someone has elevations on the stool test of methanogens, then it could be possible that the solution there is just working on their motility rather than having to go in there with harsh antimicrobial agents or even antibiotic therapy.

DrTF:

Absolutely. That’s definitely what I’ve seen mostly in the research. There is research to support that overall scenario, that methanogens are more likely to overgrow when motility is slower.

RuscioResources:

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Biliary Stasis/Insufficiency

DrMR:

What about an elevation of steatocrit or fat in the stool? Recently I was poking around in Up-To-Date to find medical consensus on diagnosing bile insufficiency or bile acid malabsorption. It looks like most of the testing that is recommended is fairly invasive and/or expensive. I’m kind of asking two different questions here, combined into one.There’s bile acid malabsorption, which can cause diarrhea, but there’s also fat in the stool which may be caused by biliary stasis or biliary insufficiency. I’m unclear, on the latter of those, with the elevated steatocrit, is that fairly diagnostic of someone having biliary stasis or biliary insufficiency? And if so, how good is the evidence there?

DrTF:

The short answer is no, because that’s only one of several possibilities for high amounts of fat in the stool. So if you see a high steatorrhea or steatocrit, that certainly could be one contributing factor, but other possible contributing factors would be poor pancreatic function. So lack of lipase to help digest fat and then also issues in the small intestine, which is the main site of fat absorption. Whenever we see certain patterns, probably the most consistent that we see with that, other than certain parasites like Giardia which are often seen with elevated steatocrit, would be that scenario that I mentioned where you have all the troublemakers present that are likely having an effect more in the upper GI and particularly the small intestine. There’s H. pylori starting in the stomach, Pseudomonas, presumably mostly thriving in the small intestine and then candida, which is often in the small intestine as well. Sometimes we’ll see all three of those together. That implies that there may be more of an issue in the small intestine. There’s no way for us to directly measure that, but we know that candida can be inflammatory. Pseudomonas can be inflammatory and they’re more likely to be in the small intestine than the large intestine. So when we see that type of pattern, that’s a scenario where we often will see higher levels of steatocrit.

DrMR:

Some of this, I’m assuming ties back to the fact that we know that SIBO, as just one example, and not to make it all about SIBO for our audience, this is just where there’s some research to cite where SIBO can deconjugate bile and kind of thwart the appropriate function of bile. If bile digests fat, as you’re saying, this down the line problem of fat malabsorption may not be due to a true fat malabsorption problem, but may be more of a dysbiotic or an overgrowth.

DrTF:

Exactly.

DrMR:

So again, this is important for the clinicians to keep that kind of algorithm in mind as another example of where a lab marker, interpreted too literally, may move you away from what the patient actually needs. An example there may be, if you see elevated fat in the stool, steatocrit, you may say, well, let’s give bile, but they may be a patient who also has SIBO and that SIBO is causing deconjugation and potentially malabsorption of the bile leading to diarrhea. You may really exacerbate that patient, and in fact, we’ve published a few case studies of patients who are taking too much bile and that was the cause of their chronic diarrhea. It is important to always have that kind of clinical algorithm to make sure you’re covering the deepest foundational causative factors first, in this case, dysbiosis. I would put that before trying to refine any kind of enzymes or bile or what have you.

DrTF:

That’s definitely a consistent with what we see as well. The whole topic of SIBO I think is really interesting because I would say one of the most common scenarios that we tend to see in these clinical consults are clinicians that had suspected SIBO, obtained a breath test, and then say they confirmed SIBO and then treated but the patient wasn’t really very responsive. They still were very symptomatic or potentially relapsed. So then they want to get a deeper insight into what might be going on in the gut by looking at the GI MAP. Among the most common scenarios that we tend to see, after SIBO treatments that were not successful would be that scenario where you see H. pylori or Pseudomonas or candida. Those are probably the three most clinically relevant organisms, at least that we see with our tests in patients that were not responsive to SIBO treatment or in cases where patients had SIBO type symptoms and were tested for SIBO based on breath testing and that was negative. Again, we often see this type of pattern on GI MAP.

DrMR:

Those three again, one more time?

DrTF:

So the most common sort of clinically relevant organisms that we see in relation to SIBO like symptoms that may or may not be SIBO, would be H. pylori, Pseudomonas, and candida.

Virology in the GI MAP

DrMR:

That makes sense. So far, this has been fantastic. One of my final questions is how you’re looking at the, the viral aspect of the panel. We’ve discussed on the podcast, maybe as far back as four years, how in some very recalcitrant inflammatory bowel disease cases, cytomegalovirus may be the culprit there. This is something I was always excited about initially and as I dug more into it, I found it was extremely rare when you’d see a case of this. In fact, I believe it was Neil Stollman who was on the podcast who, either on the podcast or in our post recording chat, said that you see those cases, but they’re quite rare. This is someone who, you know, worked several years in a hospital where I’m expecting, you would see quite a high volume of these cases. So there’s something there, but that seemed to be not super fruitful because it was just so rare, but yeah. Just wondering what your general thoughts in the virology.

DrTF:

Sure. So specifically for CMV, that is one of the markers that we hardly ever see positive. What we know from research and what I have seen in the few cases where it was detected at a high level is it is linked to a particular type of IBD, ulcerative colitis. It’s sort of open for debate as to whether that’s some sort of causal factor, whether it’s just sort of exacerbating symptoms. I think the research is leaning more towards the latter where if it’s present, it might just be exacerbating symptoms for some patients. We know that since CMV mostly is latent in most people. In certain immune cells, including what are called monocytes, there are actually studies showing that when there’s increased inflammation and/or immunosuppression, a lot of IBD patients are on immunosuppressive therapy, that can cause the virus to be reactivated and one of its target tissues tends to be in the colon or colon mucosa.

DrTF:

The colon mucosa is where it basically influences how those particular immune cells develop and they become more inflammatory macrophages. That’s probably how we’re detecting. When it relocates under certain conditions to the colon. The few cases where I’ve seen it elevated, I remember at least one case where the patient had already previously been diagnosed with ulcerative colitis. So that does seem to be consistent with the research. As far as EBV, that’s another one we don’t see very often, it’s a little less clear as to the potential clinical connection. Although some research suggests that it can actually be activated in the gut epithelium in some patients. So some patients may harbor it in the gut epithelium and it may be reactivated at some point where it’s thought to contribute to general inflammation, possibly increase intestinal permeability. Clinically it’s just not something we see very often at all.

DrMR:

Gotcha. And then, with the viral pathogens. Those, as far as I understand, unless I’ve missed something, tend to generally be self-limiting. Is there anything regarding any of the virology that you, you want to share with clinicians,

DrTF:

Particularly with norovirus. So again, newer research that’s come out in the last few years indicates that in some patients, they can harbor norovirus longterm. It’s at least been associated with issues like ongoing low grade inflammation in the upper small intestine, as well as increased permeability. So it could be if it’s present in people longterm, that could be an issue. Typically when we see it, it could be just a subclinical acute type infection because a lot of times the patients don’t report any recent gastroenteritis when we see it. Again, we don’t see it very often and it is somewhat seasonal, et cetera. So it kind of varies as far as how often we see it over time. Generally when we see it in the gut, if it’s not obviously related to a gastroenteritis episode, at least recently it’s possible that in that patient, they may be harboring it long term and some studies have linked that to dysbiosis.

DrMR:

Is there a sanctioned treatment for this or something that at least is suggested? I mean, I’m assuming there’s some specific targeted prescription antiviral. Is there anything outside of that that maybe the more naturally minded provider should consider?

DrTF:

Not really. I mean, it’s not a well developed type scenario, like say for example, candida or H. pylori, which have very well developed protocols available. There is research indicating that certain natural agents do have anti-norovirus activity. That encompassed as many of the common anti-microbial botanicals, think oregano for example, or berberine and even probiotics have been shown to help reduce it. But again, it’s not something that’s really been looked at very consistently or comprehensively from a natural medicine type approach.

DrMR:

Gotcha. I love the fact that there’s at least some activity with the tools that we’re often using in our kit probiotics, antimicrobials, what have you.

DrTF:

Exactly. Yeah. It could be that it’s related to kind of the typical inflammatory dysbiosis that we are familiar with. Protocols for that type of dysbiosis are better worked out since that’s an association with the virus. It’s possible that addressing the dysbiosis, this might have a positive effect.

Episode Wrap-Up

DrMR:

Sure. Yeah. Makes sense to me. This has been a really insightful call. Is there anything else that you want to leave people with and then would you please tell people again about the lab and you know, anything else there that you want to point them to. Website, etc.

DrTF:

Yeah. I think one of the key things with GI MAP is really kind of understanding that a unique thing about GI MAP has to do with the combination of markers plus especially the qPCR methodology, which allows us to look at things from a more quantitative standpoint. This is very helpful, both for interpreting clinical value versus just say a positive/negative, but also looking at the effects of treatment to see if the target pattern or target organisms are increasing or decreasing. So those are really some of the key aspects. Then of course all the educational and interpretive information that we offer to help clinicians. The other thing is really just realizing that we’re kind of moving away from that paradigm of just looking at a particular marker and trying to match that with a treatment. Now that certainly is more appropriate in the case of serious pathogens, but in the case of overall dysbiosis, there’s really not one type of dysbiosis.

DrTF:

That’s one things we didn’t really have a chance to get into. We generally recognize three types of dysbiosis that are more general with GI MAP. Of course there are individual differences as well. Understanding those patterns and how they relate to physiology, what may be going on in the gut is really important. And to your point, Michael, that it helps clinicians understand that there are multiple ways to approach things other than just always resorting to an antimicrobial to correct dysbiosis. Maybe again, it’s looking at digestion, et cetera. So those are some of the key things I think that would be take homes regarding GI MAP and how to work with it. As far as further information, I would direct your listeners to diagnosticsolutionslab.com. We have quite a bit of information on our various tests and then of course, specifics on how to order them. I believe if you go to our, just our homepage there’s information directly there with a couple of buttons to learn more about GI MAP and also how to order.

DrMR:

Awesome. Well, Tom, again, I really do appreciate some of these insights. There’s a few patterns here that you’ve made me aware of. I’m going to be looking for in our day to day lab ordering and interpretation. I’m excited to see if they help hone my precision a bit more. Again, overall, just really appreciative of the call and thank you for all the work that you’re doing.

Outro:

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