Mast Cell Activation, Dysbiosis, and IBS with Dr. Tom Fabian: Rational Wellness Podcast 324

Dr. Tom Fabian discusses Mast Cell Activation, Dysbiosis, and IBS at the Functional Medicine Discussion Group meeting on August 24, 2023 with moderator Dr. Ben Weitz.  

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Podcast Highlights

6:18  IBS is a condition that is diagnosed mainly by symptoms and these are part of the Rome IV Criteria.  [These are found at TheRomeFoundation.org]  There are four recognized subtypes of IBS: IBS-C (constipation), IBS-D (diarrhea), IBS-M (mixed), and IBS-U (undefined).  Bloating and distension are common symptoms associated with IBS, but they are not officially included in the Rome IV criteria.  There is no currently accepted test for the diagnosis of IBS.  This is a good review article on what we currently know about IBS: Camilleri M, Boeckxstaens G.  Irritable bowel syndrome: treatment based on pathophysiology and biomarkers.  Gut. 2023 Mar;72(3):590-599.   

11:38  There are a number of conditions that result in similar symptoms to IBS, including Bile-acid malabsorption, exocrine pancreatic insufficiency, carbohydrate intolerance, SIBO, SIFO, Dyssynergic defecation, Ehlers-Danlos syndrome, mast cell activation syndrome, eosinophilic gastroenteritis, intra-abdominal adhesions, celiac disease, and giardiasis. Dr. Fabian noted that we are learning that a significant number of patients with IBS symptoms, esp. on the diarrhea side, have a sucrase-isomaltase deficiency, which is one of the brush border enzymes in the small intestine.  This leads to a malabsorption of sucrose and certain starches.

16:15  IBS Mechanisms.  Diet is an important factor since 85% of IBS patients report their symptoms are triggered by eating, often 60 min or so after eating.  Leaky gut is a factor in most GI conditions. We see immunoactivation/inflammation, though a more subtle form of inflammation than what we see with inflammatory bowel disease like Crohn’s disease. This is where mast cells come into play. There is also the gut-brain axis.

18:12  Disorders of Gut-Brain Interaction.  The new name for functional GI disorders being adopted in research is Disorders of Gut-Brain Interaction.  This is a good review article on this:  Vanuytsel TBercik PBoeckxstaens G.  Understanding neuroimmune interactions in disorders of gut–brain interaction: from functional to immune-mediated disorders     We see as part of the pathophysiology in IBS a subtle mucosal infiltration of immune cells, especially mast cells and eosinophils, along with the increased release of  nociceptive mediators, which lead to visceral hypersensitivity, which plays a role in abdominal pain.

22:20  The pathogenesis of IBS is explained well in the following article: Carco C, Young W, Gearry RB, Talley NJ, McNabb WC, Roy NC. Increasing Evidence That Irritable Bowel Syndrome and Functional Gastrointestinal Disorders Have a Microbial Pathogenesis. Front Cell Infect Microbiol. 2020 Sep 9;10:468.  Dysfunctional microbiota leads to increased intestinal permeability that leads to immune activation that results in mast cell activation and visceral hypersensitivity that leads to abdominal pain, bloating, and altered motility. 



Dr. Tom Fabian is a leading expert on the role of the microbiome in health, immune function, chronic disease and aging. He received his PhD in molecular biology from the University of Colorado Boulder, and he’s worked as a biomedical researcher in the biotechnology industry and more recently as a consultant in the microbiome testing field.  Currently, Dr. Fabian serves as a consultant and science advisor with Diagnostic Solutions Lab. Tom’s website is Microbiome Mastery.com. 

Dr. Ben Weitz is available for Functional Nutrition consultations specializing in Functional Gastrointestinal Disorders like IBS/SIBO and Reflux and also Cardiometabolic Risk Factors like elevated lipids, high blood sugar, and high blood pressure.  Dr. Weitz has also successfully helped many patients with managing their weight and improving their athletic performance, as well as sports chiropractic work by calling his Santa Monica office 310-395-3111. Dr. Weitz is also available for video or phone consultations.



Podcast Transcript

Dr. Weitz:                            Hey, this is Dr. Ben Weitz, host of the Rational Wellness Podcast. I talk to the leading health and nutrition experts and researchers in the field to bring you the latest in cutting-edge health information. Subscribe to the Rational Wellness Podcast for weekly updates. And to learn more, check out my website, drweitz.com. Thanks for joining me and let’s jump into the podcast.

                                                All right. Hello, everybody. I’m Dr. Ben Weitz, and welcome to the Functional Medicine Discussion Group meeting tonight with Dr. Tom Fabian on the connection between diet, gut dysbiosis and mast cell activation in IBS, quite a title. I want this meeting to be interactive, so please participate by typing your questions into the chat box and then I’ll either call on you, or ask Dr. Fabian your question when it’s appropriate. Thank you for joining our monthly meeting and I hope you consider attending some of our future events.            September 28th, we have an integrative approach to depression and anxiety with Dr. Peter Bongiorno. October 26th, we are going to go back to our in-person meetings at the Santa Monica Library, and that will be an integrative approach to cardiology with Dr. Howard Elkin. I don’t know if I’ll be able to make it available remotely live, but I’ll certainly record it. I’ve got to figure out how to possibly do that. November, I’m not sure what the date is, but we’ll probably do it on the third Thursday instead of the fourth Thursday since third Thursday is Thanksgiving. December, we won’t have a meeting, and then we’ll start up again in January.   If you’re not aware, we have a closed Facebook page for practitioners only, the Functional Medicine Discussion Group of Santa Monica, that you should consider joining so that we can continue this conversation when this evening is over. I’m recording this event. It’ll be included in my weekly Rational Wellness Podcast which you can subscribe to on Apple Podcasts, Spotify, or YouTube. If you enjoy listening to the Rational Wellness Podcast, please go to Apple Podcasts or Spotify and give me a five-star ratings and review.



Our sponsor for this evening is Integrative Therapeutics and Steve Snyder is here with us this evening. And so Steve, why don’t you tell us about a couple of the integrative products?

Steve Snyder:              Well, hi, Ben. Thank you. The conversation earlier about the gluten, we learned this kind of the hard way. There is actually a lower limit of gluten you can have in products, which you can call them gluten-free even though they’re not gluten-free. You were talking about where are people getting exposed to gluten when they’re really sensitive, all over the place. We had a product called AllQlear that had a vanilla flavor in it. It had a little bit of gluten in it. It was below that lower limit, but we kind of pride ourselves on truth and labeling, so we said, “This product contains gluten,” and everybody freaked out and wouldn’t use it. It turns out it had less gluten than half the things in Whole Foods Market that say gluten-free, so that’s just a little nugget there.

                                                I know that we’re going to talk about SIBO again, and you guys have heard this all before. But we have reformulated the Elemental Diet, it’s quite a bit less sweet, quite a bit fewer calories from carbohydrates, so it’s much better tolerated. It’s a super powerful treatment option for SIBO. We do really great with it. Something around the neighborhood of 85% at three weeks have a negative breath test. So we have lots of support materials for it, lots of suggested protocols. We have samples. So if anybody’s interested in at least learning about it, you can reach out to me. We have several other products that go with that that we can talk about as well, some good prokinetic formulas, things like that. Yeah, we can talk about it any time you want. That’s it for today.

Dr. Weitz:                            Yeah, I use the Motility Activator, and that’s my favorite go-to natural prokinetic.

Steve Snyder:                      And we appreciate that.



Dr. Weitz:                            Okay. So thank you, Steve. Our speaker for this evening is Dr. Tom Fabian, who’s a leading expert on the role of the microbiome in health, immune function, chronic disease and aging. He received his PhD in molecular biology from the University of Colorado Boulder, and he’s worked as a biomedical researcher in the biotechnology industry and more recently as a consultant in the microbiome testing field. Currently, Dr. Fabian serves as a consultant and science advisor with Diagnostic Solutions Lab.  Tom, you have the floor.

Dr. Fabian:                          All right. Well, thanks so much, Dr. Ben, for inviting me here. And it’s great to be here this evening. Good to see everyone. I know it’s probably a little late in the day. I know it is here. I’m in Denver, Colorado and it’s not too far away from my usual bedtime. So bear with me, because my brain is slightly slower in the evening. So you can see here the title again is really all about the connection that we’re learning from just kind of an inundation of research the last few years on the links between diet, the microbiome, and particularly mast cell activation, IBS.

Dr. Fabian:                          So I’m going to go ahead and start here. I do have a fair amount of content to cover, but again, feel free to interrupt whenever you have any questions or anything you want me to clarify. I’ll be happy to stop and just answer any questions or discuss any of these topics. So just kind of a quick refresher here. I think everybody knows most of this stuff already. But in terms of diagnosis, we know IBS currently is still based primarily on symptoms and especially the Rome IV criteria.   So, of course, that really includes just a couple of things, altered bowel habits that are a main part of the differentiation between the subtypes, IBS-C, IBS-D, et cetera. And also abdominal pain. That really cuts across all types of IBS, so that’s a common feature. We’re going to talk about some of this pathophysiology research that’s coming out, and that really relates to both of these mechanisms and especially to abdominal pain, and that’s really where the mast cells come into play.

                                                We all know that bloating and distension are also common in this condition, but actually not officially included in the Rome IV criteria. The stats are a little bit different between IBS-C and IBS-D, so there’s tends to be a higher rate of bloating in constipation dominant IBS. There’s currently no widely accepted tests for diagnosis of IBS, although there’s lots of activity in this space, some tests that are available out there that I think over time some of these as they gain traction will become widely accepted. But currently there isn’t a given test that’s widely accepted across the [inaudible 00:07:58].

Dr. Weitz:                            By the way, Tom?

Dr. Fabian:                          Yes.

Dr. Weitz:                            IBS, you have IBS-C and D, which are constipation and diarrhea, IBS-M is mixed, and then IBS… What is IBS-U?

Dr. Fabian:                          So that’s a definition that I see sometimes and it, excuse me, refers to the mixed version. I mean, I’m sorry, the undefined version. So I guess that’s kind of a catchall for suspected IBS based on symptoms that doesn’t fulfill the other criteria.

Dr. Weitz:                            So that person doesn’t know if they’re coming or going?

Dr. Fabian:                          Exactly. Yeah, I’m really not that familiar with that definition other than it’s kind of the catchall bin for patients that don’t fit the other categories. So this is a really great recent review article, kind of on this trend now that we have so much research into these underlying possible connections with what’s going on in IBS that we’re possibly able to just start down this path of looking at what are some of these mechanisms, what sorts of tests can reflect these mechanisms, and some of these that are probably going to end up being emerging biomarkers. So this is, again, great review article by two of the leading experts in the field. That’s Dr. Camilleri, who’s been around for a long time. He is a big name in the IBS field. And also Dr. Boeckxstaens, who’s done some really great research recently on some of the aspects of this mast cell connection.  So they cover some of this in this review article. But I just want to cut to their summary here, where they sort of talk about this trend that we’re moving towards as we have more availability of these non-invasive clinical tests that can appraise the symptoms responsible for symptom generation that provides the opportunity to advance the practice from just treatment based on symptoms to individualization of treatment that’s guided by this pathophysiology, then, of course, based on the identified micro biomarkers as well. So I think this is a very exciting area of research. That’s definitely why… my motivation behind presenting this information, because there’s just so much of this research out there, thousands and thousands of papers, and I think it’s hard to keep up on all this information. So I think this is really especially useful for those of you who do a lot of gut microbiome stool testing, because some of what’s coming out really pertains to markers on these tests including GI-MAP.

                                                In terms of IBS pathophysiology and symptoms, when we’re looking at these underlying factors, obviously they have to account for these main symptoms. They have to help explain the altered bowel habits, particularly abdominal pain since that cuts across all types of IBS. But also the related symptoms, particularly bloating, distension and even the comorbidities. We know that stress, mood disorders, anxiety, depression are much more common in patients with these types of conditions like IBS. Even allergies are noted to be more common in patients with IBS. And then also clarify the relationship with these related conditions, we’ll see a list in a moment, that feature similar symptoms. And in many cases, the symptoms are almost identical so it’s hard to differentiate between IBS and some of these other conditions without specific testing, and sometimes unfortunately invasive testing.

                                                So, this is an example of one of those lists. This is by no means exhaustive, but these are some of the common conditions. You can see the title of this table here from a recent review article that references at the bottom. So they’re basically looking at all these different conditions that have symptoms similar in this case to inflammatory bowel disease, which certainly, especially in terms of IBS-D, diarrhea dominant IBS, tends to overlap with IBD. But just to give you a sense here, here’s IBS, and of course these are the common symptoms. If you look through that symptom column, you can see that there’s quite a few things there that have virtually identical or at least overlapping symptoms.  So, at the top we can see… Actually, let me go back to that. You can see bile acid malabsorption, pancreatic insufficiency, carbohydrate intolerance. So those are related to different aspects of digestion absorption. We certainly see evidence of that with our experience with GI-MAP. And there’s a fair amount of research, especially on bile acid malabsorption pertaining to IBS-D. It’s thought that 25, 30% of IBS-D patients actually have bile acid malabsorption. Pancreatic insufficiency is fairly common as well, not necessarily the full outright pancreatic insufficiency.  We also see patients with decreased pancreatic function based on the elastase marker. That doesn’t necessarily constitute full-blown insufficiency and yet we still see patients frequently will have bloating and IBS-like symptoms without sufficient pancreatic enzymes. [inaudible 00:13:23]-

Dr. Weitz:                            And Tom, the bile acid malabsorption, is that seen with the fat in the stool?

Dr. Fabian:                          So sometimes yes. You can imagine if basically foods are moving through too fast, there’s not sufficient time to absorb the fats, that can be part of the picture. We do see that sometimes. We don’t actually see high steatocrit all that often though. It’s usually in pretty extreme cases, and a lot of that actually has to do with a pancreatic insufficiency. So patients have really a poor pancreatic function, then they’re much more likely to have steatorrhea, i.e., fat in the stool.   The carbohydrate intolerance aspect is important. Of course we’re all familiar with FODMAPs and that FODMAPs can cause symptoms in IBS patients. But there’s greater recognition now that other types of carbohydrates… depending on the details for the patient. So there’s growing recognition, for example, of this sucrase-isomaltase deficiency, so that’s one of the brush border enzymes in the small intestine. Patients may be actually having IBS symptoms, especially on the diarrhea side, due to a malabsorption of sucrose and also certain starches. It’s thought that if a low FODMAP diet isn’t really helping patients and they seem to still have some sort of carbohydrate tolerance, it may be the starches and sucrose.  And again, some studies suggest that that may be as high as one third of IBS-D patients may have this sucrase-isomaltase type deficiency. So a lot of active research there. We’re going to to go into a little bit of the connection there between that and the microbiome, especially Klebsiella, small intestinal bacterial overgrowth, I know your audience was very familiar with that as well through Dr. Pimentel’s work, small intestinal fungal overgrowth. And then there’s of course a number of other things here. Mast cell activation syndrome itself has overlapping symptoms, and of course now we think that mast cell activation, not necessarily the MCAS syndrome, the classic syndrome, but a form of mast cell activation seems to be part of the picture in IBS, at least a subset of IBS patients.  Then there are a few other things here. You can see celiac disease near the bottom, even giardia infection can mimic IBS symptoms. So important to kind of consider this whole picture, and not necessarily just to any one particular conclusion off the bat. You do want to consider what else may be going on for patients.

                                            All right, so quickly, this emerging paradigm, I’m just going to summarize it here and then show a fair amount of the supporting evidence that we can talk about as time permits. But certainly, again, there’s this focus on switch from the assessment, diagnosis and treatment going towards the evidence-based pathophysiological mechanisms. And these leading mechanisms mostly currently implicate diet. So there’s a major role for diet. About 85% of IBS patients report that their symptoms seem to be diet triggered. And some of these studies that look at the occurrence of symptoms and the timing of symptoms, symptoms tend to occur in most patients, the majority of patients, within about an hour after eating, and then it sort of trails off after that.  So it is going to be variable, but the data does show that that’s pretty common for symptoms to be pretty soon within that 60 minute or so after eating.  First microbiome, we’re going to talk a lot about that today. Intestinal barrier dysfunction is well noted, not just in IBS but a long list of conditions. Immunoactivation, it’s not the type of inflammation we see in IBD, inflammatory bowel disease, it’s a more subtle type of inflammation. It’s more akin to a allergic type inflammation. So that’s really where mast cells come into play, because they do play a known role in allergies. And actually now it’s thought that dissimilar mechanism may be at play in IBS patients.  Then, of course, there’s the enteric nervous system, and then the connections with the gut-brain axis. All of these areas are actively being researched. And again, it is challenging to stay up to speed on all of this. But that’s where these review articles, I think, can be very helpful.

                                               This is another great review article that just came out earlier this year, Understanding Neuro-immune Interactions. And so this refers to the new name that’s being adopted in research for functional GI disorders. The primary ones are IBS and functional dyspepsia. And again, that new name is disorders of gut-brain interaction, to recognize this connection on the nervous system component.  So again, this article includes a couple of the researchers whose research we’re going to be talking about today, who’ve done a lot of work in this mast cell connection to IBS. Actually, I probably am going to go through most of this abstract just because I think it’s such a nice summary of the current state of research in this area of IBS. So at the top, they just sort of refer to that these functional GI disorders are now renamed into disorders of gut-brain interaction. Then they go on to say in the middle highlighted area, “Our understanding of the pathophysiology has evolved significantly over the last two decades, especially the last few years. Initial observations of subtle mucosal infiltration with immune cells, especially mast cells and eosinophils, those two are often related, are since recently being backed up by mechanistic evidence demonstrating increased release of what’s called nociceptive mediators,” those are pain mediators, “by immune cells in the intestinal epithelium. These mediators activate sensitized neurons leading to visceral hypersensitivity,” which is what they think primarily leads to abdominal pain.   So IBS patients tend to be more sensitive to even normal stimuli, such as even… Well, we think of gas production as being part of IBS. Studies indicate that IBS patients don’t necessarily always have more gas production, but they’re more sensitive to that based on this hypersensitivity. And then the last part they say, “This interaction between immune activation and impaired barrier function of the gut is most likely bidirectional with alterations in the microbiome, stress and food components as upstream players.” So that tells us a lot about how we can potentially intervene in terms of diet, modifying the microbiome, and of course, behavioral approaches as well.  This is from that same article, just kind of represented visually. So you can see here there’s the brain part of the gut-brain connection. Stress is a major factor. Stress certainly is known to activate mast cells. I will look at one of those example studies in a little bit. Food composition has a big effect on IBS. We know that that can be partly through altering the microbiota and its metabolites that it produces. The list of metabolites now that are implicated in IBS just keeps growing. There’s a lot of different vernaculars that they can produce.  And then we have those effects then of these different components on the intestinal barrier immune activation, and that can lead to neuronal hyperexcitability, which then leads to this… Just let me go back here. … disturbed gut-brain interaction and then the visceral hypersensitivity and motility. So we talked about the pathophysiology has to explain those two features of IBS, abdominal pain and motility differences. So this is representation at a high level of all these factors that we currently know can come into play. Is there any questions on anything so far, before we can dive into some of the details here?

                                                All right, so this is a… We’re not going to zoom in or look at this figure here. I’m going to zoom in on it just a bit. But another great review article. It goes through the evidence currently on the role of the microbiome and linking all the dots here. So this is a really busy figure, but I just want to break it down here real quick. We have the dysfunctional microbiome, also increased intestinal permeability, so things like LPS, some of these other factors they can produce histamine, et cetera, can get through and then affect the immune system and that can activate the immune system. That can then lead to this hypersensitivity that then explains these phenomena in IBS.  I just note off to the side here, they depicted mast cell activation degranulation that then can have an effect on the sensory nerves in the gut. And that’s thought to be one of the main ways in which mast cells can cause abdominal pain and also may have effects on motility as well. So it’s kind of a nice visual summary, once you break it down, on some of these key mechanisms. So a little bit of history on mast cells. It’s kind of a long history. It goes back as far as the late ’90s. This is an article from 2007 where they already were aware of some of these mast cell numbers increasing in IBS patients, mast cells being more active in IBS patients. So they knew some of these details as much as 15, 20 years ago. You can see there it’s 2007.

                                                Now, this is from a review in 2016, in terms of what they knew at that point. And this is kind of a nice summary of the different mediators that are released by mast cells. I’m just going to touch on some of the top ones here. Again, this is from a few years ago. Histamine is probably the best known. That’s thought to be involved based on various animal studies and a few human studies in IBS-C and IBS-D. Tryptase is what’s called a protease enzyme. Proteases are also implicated in IBS. You can see here both types, IBS-C, IBS-D. Serotonin actually is another one released by mast cells. We certainly know that has major effects in the nervous system, also thought to be involved in IBS-C and D. So this is kind of a summary of what’s been known.

                                                And this is, I think, overall just kind of a nice summary visual. You can see the reference at the bottom for all these different ways in which mast cell activation is thought to play a role in the different aspects of IBS. At the top here are different things that can actually activate mast cells. This highlights stress, food and bacterial products. We’re going to talk about some of those here. And then that can cause mast cells to be activated, then it releases these mediators that we just talked about like serotonin, histamine and proteases. Then that can lead to further immune system activation, possibly chronic inflammation. It can also lead to altered permeability, i.e., leaky gut, smooth muscle cell effects that can change motility. And then again, affects on the enteric nerves that may increase visceral hypersensitivity.

                                                So essentially, even though mast cells are not necessarily thought to be the only mechanism of course, they certainly seem to play a significant role in all of the major aspects of IBS. This is a quick just example here that we know that stress… This is a study from a few years ago. You can just tell from the title, Psychological Stress. And then corticotropin releasing hormone, that’s one of the sort of high level hormones in the brain that’s released as part of that HPA axis stress response, that basically stress causes that to be released. And then that can affect an increase intestinal permeability in the gut through a mast cell dependent mechanism. So that’s been established for quite a while. We know that that’s one of the ways in which stress can affect the gut and leaky gut.

                                                All right, we’ve talked about the various connections here where stress, again, can disturb the gut-brain axis, impair the barrier, cause immune activation, neuronal hyperexcitability, et cetera. But now I want to talk about the microbiome a bit more and some of the metabolites. So the connection between the microbiome and mast cells seems to be through many different ways. But we know some of these microbes that are associated with mast cell activation, and in some cases we know the mechanisms for how they can activate mast cells in the gut. So this is a review article that summarizes some of what’s known about these various microbes. So in terms of the ones that are mentioned in this article, the key ones would be Staph aureus. That’s probably one of the key microbes overall, especially in studies on allergies, that are known to activate mast cells. Streptococcus species, Pseudomonas aeruginosa, Enterococcus faecalis, Candida, H. Pylori, and then these LPS-producing microbes like Klebsiella, E. coli, and others that also can produce histamine in many cases.

                                                So a lot of different types of opportunists. We have all of these on GI-MAP so they can be assessed in terms of whether they’re elevated compared to normal. But again, there’s links to activating mast cells in the gut from these various microbes. A number of them have also been implicated directly in IBS. We’re just going to focus on a few examples here. But just on a side note, at some point a little bit later when we have more of the Q&A, I do have a link that I could provide to this reference here if you’d like to have access to some of the list of functional groups that we have on GI-MAP, such as these mast cell activating microbes.

                                                So this is an example of recent study where they did this high-tech multiomics approach, looking at the microbiome, looking at their metabolites and other measures. But basically one of their observations summarized here… And you can see off the right here, whenever there’s a article that’s available that’s open access, that you can just go and download and read the whole article, I’ve noted that. So this is definitely one that doesn’t have a paywall, you can actually access it for free. So they say, “When using average data, but not the single time point data,” so this is basically looking at patients longitudinally, “we found a significantly higher abundance of multiple Strep both in IBS-C and IBS-D as well as in the composite IBS group compared to healthy controls.”

                                                There’s also an older study here also linking Streptococcus to IBS through an immune activation mechanism by promoting this inflammatory cytokine, IL-6. This is just an example of a study from about 10, 12 years ago linking Staph aureus also to IBS. So here they noted that about 17% of their population tested positive for Staph aureus versus none of the healthy controls. So again, another research association there. But this is thought to be one of the ways in which Staph… Again, this is probably one of the best linked to mast cells. But you can see here that it releases a number of these toxins that can induce allergic skin reactions in this case. But those have also been noted to be released in other areas where Staph can overgrow, such as the gut. So they noted this one is a potent inducer of mast cell degranulation.

                                                One more study here on Staph and Strep. Yet another pretty sophisticated study where they’re looking at gene interactions in a variety of different common GI conditions. So they specifically looked at colorectal cancer, IDB and IBS and looked at what are these interactions with various microbes, particularly with a genetic component of susceptibility. And you can see here on the left, they basically found that there were three microbes that were common to all three conditions, and that includes, and they show those on the other side here, Staph and Strep. So we see these commonly elevated on GI-MAP. Probably among all the opportunists, these are the most commonly elevated. It may be that they’re linked to so many different conditions. We also know that upstream, poor digestion also has been shown to increase their levels, especially low stomach acid. And we all know, I think, that issues with digestion tend to be pretty common as well, whether it’s low stomach acid, pancreatic function, et cetera. So not too much of a surprise there.

                                                There’s just this growing amount of evidence that these two certainly are associated with IBS and likely play a role partly through mast cell activation. This is just one of those examples of a meta-analysis where they looked at 19 eligible… So these are high quality studies looking at the effects of PPIs on the microbiome and they found consistently across these studies that PPIs, they inhibit stomach acid, lead to increased Strep and Enterococcus, Staph and Bacillus among others. So certainly that’s one of the common things we do see clinically as well.

                                                Just a couple more notes on some of these other microbes that are associated. Definitely some studies linking Pseudomonas to IBS going back about 12 years or so, and several other studies since then have also found the same association. Pseudomonas’s interesting, it’s a little bit different from some of the other LPS producers like E. coli and Klebsiella that can be in the small intestine and large intestine. This one is primarily in the small intestine. It’s not thought to be active in the large intestine. A little bit about Candida and fungal dysbiosis, that’s also been associated with IBS type symptoms and also specifically visceral hypersensitivity. So, of course, I’m not going to go through all these, but this is just showing you that there’s a fair amount of research linking Candida also with mast cell activation through specific mechanisms. So we know Candida is another one of these microbes that can activate mast cells.




Dr. Weitz:                            So we’re having a great meeting, but I’d like to pause for a second to thank our other sponsor for this evening, which is Diagnostics Solutions Lab. Diagnostics Solutions Lab offers the GI-MAP stool test, which is the stool test that we use most frequently in our office, and I rely on it very heavily because the results are very helpful and very accurate. It’s been just a godsend for our functional medicine practice. So the GI-MAP from Diagnostic Solutions Lab is a comprehensive gastrointestinal assessment that uses quantitative PCR technology to detect parasites, bacteria, fungi and viruses. Results from the GI-MAP help reveal the root cause of diagnostic complaints, immune dysfunction, skin conditions, and more. For unparalleled results that optimize patient outcomes, leading practitioners rely on GI-MAPs, so go to Diagnostic Solutions, get an account and start utilizing the GI-MAP stool test. I think for sure you’re going to find it very comprehensive, very accurate, very helpful and the technical support is also great. So now, let’s get back to our discussion.



Dr. Weitz:                          Hey, Tom, with respect to Candida being picked up on a stool test like GI-MAP, it doesn’t seem to come up that often. There’s a thought in the functional medicine world, and I’m not sure about the research on it, that stool testing is not that sensitive to Candida. A number of practitioners will use organic acids testing because they see that as a more sensitive way to pick up Candida. What do you think about that?

Dr. Fabian:                          Yeah, I mean I think we do know that PCR is pretty sensitive, so if it’s there in appreciable numbers, we will pick it up. Candida actually is a little bit more challenging from the standpoint that when you kind of do that whole processing of the stool sample, basically you’re having to open the cells to release the DNA so that you can purify the DNA and then run the PCR. Candida cells are harder to break down. Our lab does use the methodology that’s recommended for Candida to break those down, so they’re pretty confident that if it’s there we are likely to see it. But there’s always the chance, because it is harder to break those cells down, that we may be not seeing as much as what’s actually there. I think our overall [inaudible 00:36:52] is… Sorry.

Dr. Weitz:                            I’m sorry, go ahead.

Dr. Fabian:                          [inaudible 00:36:56]

Dr. Weitz:                            I was going to say another issue might be that Candida could be found in other parts of the GI tract besides the colon.

Dr. Fabian:                          Yeah, yeah. I mean we can detect organisms coming from higher up. I mean H. pylori is kind of the case in point, coming from the stomach but it is easily picked up in stool. And we even know from lots of studies that oral microbes, depending on the microbe, can be detected in stool. So it is going to depend on the microbes. Some survive the transit, they’re more hardy. Some don’t really survive the transit, so it’s a little spotty. If you want to know the composition of the oral microbiome, you have to do a saliva sample, for example. But we can pick up some of these. So long story short is it’s certainly possible that the higher up you go in the GI tract, the less likely we are to detect low level Candida. But if it’s a high level, we’re highly likely to detect it. So it’s hard to say because there haven’t really been studies comparing those two tests with a gold standard. That would really be what’s needed is looking at organic acids versus stool PCR versus some other ways to confirm the actual presence of Candida.

Dr. Weitz:                            Okay, thanks.

Dr. Fabian:                          But I see them as kind of a little bit at both ends of the spectrum because it does seem to be commonly assumed that organic acid testing may pick it up more frequently and we don’t have, again, any studies we can point to saying that that’s not the case.  

                                                All right. I’m just coming back to this list here of these organisms that are known to stimulate mast cells. We talked about Staph, Strep, Pseudomonas, Candida. Now I want to focus on these histamine and LPS-producing microbes a bit. And then once we get done with that, I’m going to go into a quick case example, unless there’s any questions before we dive into that. So this is a major study that just came out last year in one of the top journals, Science Translational Medicine. It’s kind of after all these years of research into the mast cell connection with IBS and knowing that there’s probably some general association with microbes in mast cells, this one really, I think, drove that point home in demonstrating in many different ways.  This is a very involved study. They looked at microbes in human, some of the products they produce and also looked at animal models to look at specific mechanisms. So it’s a very thorough study. But they were able to show… Actually, I’ll bring it up here in the next thing here that, “We observe that the fecal microbiota from patients with IBS with high, but not low, urinary histamine produced large amounts of histamine in vitro. We identified Klebsiella aerogenes carrying a histidine decarboxylase gene,” that’s the gene that converts histidine to histamine, “as a major producer of this histamine. Also, this bacterial strain was highly abundant in the fecal microbiota of three independent cohorts of patients with IBS compared to healthy individuals.”  They kind of went on to show that this histamine actually not only activate mast cells, but acted as essentially a chemokine, which is an immune molecule which attracts immune cells. So they found that histamine increased the number of mast cells in the gut, and then also activated the mast cells. This was thought to be produced in this case primarily by this Klebsiella species. From previous research, we know that there are other organisms, also that we have on GI-MAP, that are known to produce potentially high amounts of histamine. Morganella and Klebsiella pneumoniae are two additional ones. We often see these elevated in patients with IBS type symptoms as well.

                                                We do have these listed on our resource sheet in the histamine producing section. Now I’m going to just talk a little bit more about some of these patterns and additional microbes that are often seen in IBS. This is a review of what was known at the time a couple of years ago, 2019. And they’re summarizing the major findings visually here. So you can see, in general, this is particularly true in IBS-D, that there’s often a decrease in Bifidobacterium, and Faecalibacterium prausnitzii, that’s one of the major butyrate producers. We do see that frequently decreased in patients with different diarrhea conditions, whether it’s IBS-D, inflammatory bowel disease and infections sometimes also, where patients have diarrhea.

                                                And then there’s often an increase in other groups. But the ones that we see most commonly… We don’t see the Lactobacillus one as often, but we do see high Bacteroidetes. And then I don’t know if many of you are familiar with this term Enterobacteriaceae, but it’s commonly used in research to refer to these LPS producers. So organisms like Klebsiella, E. coli, Proteus tend to be in that Enterobacteriaceae group. That’s the inflammatory LPS group, they tend to be elevated. We see that a lot, especially E. coli. That’s a pretty significant signature for IBS-D.

                                                Interestingly, this other study noted that especially E. coli, was found in biofilms that are prevalent in IBS, and also to some extent in ulcer colitis. That’s shown here. For the top… mostly in health individuals that lack biofilm. And they found that the biofilm was mostly in the ileum and the first part of the colon. So that’s where the biofilm was mostly concentrated in IBS patients. For ulcerative colitis, it tended to be more in the colon, especially the distal colon. But you can see for the healthy individuals, they generally had good levels of Faecalibacterium prausnitzii. But in the ones with biofilm, that was about 60% of IBS patients, more likely to be the IBS-D patients, again, Faecalibacterium was low. E. coli was one of the organisms that was increased and found in the biofilm. So we do see these patterns quite a bit on GI-MAP. These LPS producers are also noted in this review resource article. 

                                                Interestingly, a few years ago, they had already noted that patients with IBS-D had increased serum levels of lipopolysaccharide. So it’s likely that this increase in LPS producers is part of that picture. And this is where the diet component starts to come into play. So, of course, it’s always been thought that FODMAPs likely cause symptoms through fermentation and gas production, which certainly is part of the picture. But these FODMAPs actually can feed the LPS producers, and we’re going to see some of that evidence with Klebsiella. But they say here, I’ll just cut to the part that’s underlined, “That our findings indicate that a high FODMAP diet causes mast cell activation by promoting LPS, which in turn leads to colonic barrier loss, meaning leaky gut. And then a low FODMAP diet reverses these changes.” So this is thought to be a major mechanism now for how FODMAPs actually when they’re high can cause symptoms, and how the low FODMAP diet may be beneficial by reducing this LPS.

                                                So to summarized so far, these are some of the key microbes that have been implicated in IBS pathophysiology. Klebsiella, Staph, E. coli, Pseudomonas, et cetera. And then of course there’s products that they produced, and there’s more and more… This is just kind of a short list. These are some of the ones that are better studied, but probably the one at the top that has the best evidence is histamine. Lots and lots of research now is showing that excess histamine seems to play a role, at least in a subset of IBS patients. But there are others like serotonin, lipopolysaccharide. Obviously it would take a lot longer to cover all these different metabolites in the evidence behind them. But just be aware that there are quite a few. All right, so any questions on any… We covered quite a bit here. Any questions before we dive into a case example?

Dr. Weitz:                            In terms of mast cell activation, where do we think it most likely fits in? Is it resulting from dysbiosis, bacterial overgrowth? Is it occurring at the same time? Is it leading to dysbiosis?

Dr. Fabian:                          That’s a great question. So it’s thought that for many patients it is dysbiosis. So Klebsiella is, again, one of the best studied ones in terms of that link. But then there are these others like Staph and E. coli. When you go through all the upstream triggers of IBS, so we know that there’s postinfectious IBS, so we know gastroenteritis can cause that, there’s lots of evidence that all kinds of infections, bacterial, viral, parasitic infections. Once they’re gone in a subset of patients, those patients have persistent dysbiosis and persistent either outright inflammation, which could actually lead to things like inflammatory bowel disease, or more subtle inflammation.  So that probably depends on the patient’s genetics and other variables, but there’s often a trigger. So antibiotics are thought to be a key trigger. Lots of research now shows that antibiotics can lead to a bloom of these LPS producers and then they can potentially shift the balance long-term. Diet, lots of studies show that high-sugar diets promote these LPS producers. So it’s probably a combination of things. I’m sure diet is a major component, but maybe not sufficient all by itself. There has to be usually some sort of initial trigger or even just a genetic susceptibility.

                                            Are there any questions in chat that we want to take now?

Dr. Weitz:                            Yeah, I don’t know. Some of these questions have to do with treatment like use of diamine oxidase for treating mast cells, probiotics possibly making things worse or better. Berberine, does that affect a microbiome? Do you want to address those later?

Dr. Fabian:                          Actually, yeah, if we go through the case example, I do have a section on some of the treatments, and I know Berberine was actually in one of those resources. So short answer is yes, there’s actually… In terms of the approaches, certainly we know that there are diet triggers, FODMAPs being one of the best known, but there are others. I mentioned the sucrose and also the starches, so the whole carbohydrate intolerance piece is part of that. And then there’s some other things as well, but there are also things that can address the dysbiosis. There’s also treatments for mast cells and histamine, so there’s potentially different ways to approach it depending on-

Dr. Weitz:                            And do you have a sense of… Do you recommend doing multiple things at the same time? So if you’re going to try to use diet for SIBO, you’re talking about the low FODMAP diet, but then if you’re trying to address histamine, there’s a low histamine diet. Do you layer that on top? Do you treat the dysbiosis first and then if you still have a problem, then look at the histamine? In terms of the treatment protocol, where do you think you put the focus on the histamine?

Dr. Fabian:                          That’s a great question. So certainly depends on where that histamine is coming from, so if we do see histamine producing type microbes, and especially if symptoms are consistent with that. I don’t work directly with patients, but I work on these free consults that DSL offers for practitioners. So I review a lot of cases, and it’s pretty common for us to see pretty significant dysbiosis, like Klebsiella overgrowth, Morganella, in patients where they’re described as having histamine type symptoms or mast cell activation type symptoms.

                                                So definitely if it’s suspected based on symptoms and we see those organisms, then those would be likely a key target for practitioners for using antimicrobial herbs. But you have to look at the big picture. So a lot of practitioners kind of go top down. If they see something happening upstream, like H. pylori, or something that’s more small intestine like Candida overgrowth or evidence of poor digestion… So there’s lots of evidence now that poor digestion is a major cause of dysbiosis. If digestion is not optimal, certainly that needs to be addressed. And that could be one of the reasons why antimicrobials alone either don’t work sometimes, or they work temporarily and then patients relapse, which is pretty common. And that’s likely because some of these other upstream root causes are not being addressed, with digestion being one, certainly diet.   It’s really going to depend… My experience in working with so many practitioners is it’s going to depend a lot of the patient and the details of their assessment, and also what the test results show. They rarely just treat the test results by themselves. They’re certainly taking that into account with everything else that they know about.

Dr. Weitz:                            Yeah. You’ve mentioned H. pylori a couple of times. That seems to be a more and more controversial finding on a stool test. I recently did a podcast with Dr. Steven Sandberg-Lewis, and he’s a big believer that you should, in most cases, not treat H. pylori, even if you find it. In fact, he says don’t test for it, and he feels that it’s typically a commensal and helps protect against reflux.

Dr. Fabian:                          That’s a good question. So certainly if you look at the research, that is recognized that it’s not necessarily automatically pathogenic or that it always needs to be eliminated. But even in research and medical circles, there is disagreement over just how pathogenic it is, how aggressive the treatment should be. Overall though, just from reviewing all these studies, I would conclude that at low levels, likely it does not need to be treated. So on GI-MAP, we have about probably 80% of patients that have that E2 level that’s not flagged as high. Most of those patients don’t seem to have significant symptoms that could be attributed to H. pylori, so it doesn’t appear that it’s something that would need to be treated. The higher the level is-

Dr. Weitz:                            What you’re saying is if we see H. pylori, it’s above detectable levels, right? Because theoretically, all these potentially pathogenic or pathogenic bacteria should be below detectable levels. So it’s above detectable levels, but it’s not flagged as high.

Dr. Fabian:                          Correct. Yeah.

Dr. Weitz:                            Okay.

Dr. Fabian:                          Yeah. So E2 range generally is considered pretty low, detected but usually not an issue. Some patients do seem to have issues though, and that’s mostly based on practitioner feedback that they decided they wanted to treat because it made sense in the context of patient’s symptoms, and then they report that the patient improved after treatment. So that would be evidence suggesting that in some cases, based on your assessment, that you may still want to consider treating. But I think there’s two categories of treatment. There’s the classic view of H. pylori as being very inflammatory, causing ulcers, increasing risk for stomach cancer, et cetera, causing severe gastritis. Certainly in those cases, obviously would have to be aggressively treated, or patients that are high risk for stomach cancer and other conditions.

                                                But in patients that don’t necessarily have a high risk or any severe symptoms, we do know H. pylori, from a functional standpoint, can suppress stomach acid. So it is often one of the contributors to hypochlorhydria. So I think that’s where practitioners in the functional medicine space may be more likely to treat at levels that are maybe lower than what would be treated in conventional medicine.

Dr. Weitz:                            And what part does the… GI-MAP, for those who don’t know, also listed virulence factors for H. pylori. To what extent the appearance or non-appearance of those virulence factors, how does that change whether or not we should consider treating H. pylori?

Dr. Fabian:                          That’s a good question. So as always, it’s in the context of the patient, your assessment of the patient, their symptoms, but in general, they’re considered risk factors. So it’s a bit of a numbers game. The more virulence factors that are detected, the more likely the strain or strains that are present are more aggressive, more potentially pathogenic. And even there’s some differentiate among the virulence factors, with CagA and VacA being kind of the most widely recognized, more inflammatory type of virulence factors. So it does add some weight to treatment, but again, by itself it may not be sufficient unless the patient is obviously really symptomatic or high risk. But it’s really up to practitioner judgment as to… We try to educate them on these various considerations, but it’s every practitioner’s decision on whether they feel it should be treated or not.

Dr. Weitz:                            Okay. Great. Thanks, Tom.

Dr. Fabian:                          You’re welcome. So I’m just going to cover this quickly here. It is 8:30, at least my time, so we’re at the hour mark. Not your time. What time would you like me to completely wrap up by?

Dr. Weitz:                            I mean, we sometimes go till another 30 minutes, but it’s up to you.

Dr. Fabian:                          Okay. I do have the time to go through the… I do have another 30 minutes.

Dr. Weitz:                            Okay.

Dr. Fabian:                          So for those who want to stay, I’m happy to continue going through-

Dr. Weitz:                            Okay, great.

Dr. Fabian:                          So as far as this case example, it’s a pretty interesting one because it pertains to one of these sort of differential diagnoses and where there might even be an overlap. And kind of a side note is there’s a relatively new video I just saw. I’m not sure if anyone in this group is familiar with Dr. Lin Chang. She’s at UCLA, she’s one of the leading IBS researchers globally. At the DDW conference this past May, she gave a keynote lecture on the connection between stress and IBS. But she had kind of a short video with one of the other leading IBS researchers on this sort of differential diagnosis and overlap of IBS, especially IBS-D and inflammatory bowel disease. And that’s actually what this case here is about.

                                                So if you look that up. I think it was on… I’ll have to put that in the chat as well if I can find that link. But I think it was on something like Medical Xpress or one of those websites. But I’m sure if you google her… And then the other researcher is Magnus Simren, S-I-M-R-E-N. And they had a helpful video on this overlap scenario. The patient here, as you can see, is female, 74 years old, diagnosed with Crohn’s disease decades ago. The practitioners that we consult with don’t always have the full information, but they mentioned that part of the intestine was removed. They did not have the details of how much, which was certainly a key piece of information that does help with interpretation. But we certainly know that part of the intestine was removed.

                                                This patient always has some degree of diarrhea, depends a lot on Immodium. But recently, kind of inexplicably, their diarrhea worsened. So this patient has really been adamant about avoiding the standard medical approaches. For a while had been on steroids, for example, but eventually went off them with the help of a functional practitioner. You can see her had been taking a Chinese herbal colitis formula, also supplementary short-chain fatty acids, particularly butyrate and the typical probiotics, some polyphenols, definitely increasing the berry intake, more vegetables. And unfortunately multiple three-month rounds of antimicrobial herbs, and then three months on an elemental diet, basically none of these ultimately helped, and this patient’s diarrhea is still not so good.

                                                So the patient’s very discouraged because the natural approaches weren’t working and they really don’t want to have to go back on steroids. This patient, I think, from what I understand, hadn’t had a recent colonoscopy. Of course, that was discussed as well as to… Depending on how recent that was, that’s something that probably would need to be repeated. So this is their GI-MAP, no current pathogens detected. H. pylori was negative. Now, we’re looking at two time points here, so that’s why this looks a little bit different. They had done these about three months apart, with some of these antimicrobial herbal protocols in between. But again, really no significant improvement in symptoms.

                                                So this is the normal commensal section. You can see there’s a little bit of a shift here overall. Generally though not much… kind of some slight improvements, like you’ll see the Akkermansia was not detected, now it’s detected. So there were some minor improvements, but also some things that worsened. One thing I want to point out here, and I’m actually going to… I think this is highlighted. Yeah. So that classic signature of IBS, diarrhea dominant, is very similar to inflammatory bowel disease. Both of those conditions feature typically increased Escherichia, that’s E. coli. We did see that. It was high certainly on the second test. Faecalibacterium prausnitzii is typically seen as low or not detected with patients with inflammatory bowel disease and also diarrhea dominant IBS.

                                                So that signature was present. That’s a common signature. It’s known in literature, and we see this a lot in patients with diarrhea. Same with the high Bacteroidetes. We don’t always see the high… Or actually, no, this is low Formicidaes, but we do see a high Bacteroidetes. That’s thought to maybe play a role in this bile acid diarrhea scenario, which I won’t get into the details there, but there seems to be a link where Bacteroidetes may worsen the symptoms or contribute to bile acid diarrhea. So this is a classic signature. We definitely saw this for this patient. We do know that she was already diagnosed with inflammatory bowel disease, so not a surprise.

                                                And again, this is just reiterating that this is a common signature, well known in research for inflammatory bowel disease, and it over laps with IBS-D. So that’s, again, high Bacteroidetes, these Enterobacteriaceae, LPS producers tend to be high, Faecalibacterium tends to be low. You also note Roseburia, which we do have on GI-MAP, is also something that tends to be low in IBD. So this is their overgrowth opportunistic microbe section. Still looks pretty bad both times, despite all these treatments. You can see Bacillus was high, and Terracoccus, Morganella, that’s one of the key histamine and LPS producers. That was super high.

Dr. Weitz:                            Hey, Tom, in terms of Bacillus being high, Bacillus is a bacteria that’s included in spore-based… All spore-based probiotics, I think, are Bacillus based.

Dr. Fabian:                          Right.

Dr. Weitz:                            So should we think of Bacillus as potentially bad in some situations?

Dr. Fabian:                          It’s listed in this. You can see the title here, not the main title, but the subtitle is Dysbiotic and Overgrowth. So it’s really just an overgrowth bacteria. It tends to be elevated, especially in patients that are not digesting very well. Whether or not it actually contributes to symptoms is unknown, but not likely. Numerically, it’s not that prominent in the gut. And we get asked that question a bit, if it’s high, is it something where we would not recommend taking these spore-based probiotics? I don’t think it would be contraindicated. And there are plenty of practitioners that still supplement because they suspect SIBO or other conditions where these are commonly used and patients tend to improve. Part of that could be-

Dr. Weitz:                            If a patient were taking a spore-based probiotic, would we expect a Bacillus potentially to be high?

Dr. Fabian:                          It can, yeah. And that may be one of the reasons why we didn’t… In the early years of GI-MAP, we didn’t seem to see the Bacillus as high as often. And then these spore-based probiotics came out, became very popular, then we started seeing higher levels. We have no way of knowing whether that’s due to the probiotic, but it doesn’t seem to be a negative to supplement even though these numbers are high. And that could be because the specific species and strains in the probiotics are not the same as the ones that are in the patient’s microbiome, so they may still be getting the benefit of those probiotic strains.

Dr. Weitz:                            Are the Desulfovibrio and Methanobrevibacter broken out because those are often known to be associated with SIBO?

Dr. Fabian:                          No, they’re broken up because… So the commensal term just means that they’re present, they’re normal residents of the gut. They’re present in virtually everyone. And they’re thought to be beneficial at normal levels. And then they’re thought to be an issue when they’re overgrown. So again, that’s why they’re in this overgrowth section, because-

Dr. Weitz:                            I thought all the dysbiotic bacteria were potentially present in normal levels.

Dr. Fabian:                          It’s kind of a fine point of distinction, but it has to do with overall prevalence. So that’s frequency in the population. So these commensals are highly prevalent, so most people have them, whereas most of these dysbiotic microbes, with a few exceptions… So streptococcus arguably could be under the commensal, because it is a commensal in the mouth all the way through the small intestine.

Dr. Weitz:                            Okay.

Dr. Fabian:                          So it’s a little bit of a mixed picture, and there’s just kind of these nuances with the microbiome. But Desulfovibrio and Methanobacteriaceae, the methanogens, are present in virtually everyone, and usually not an issue unless they’re overgrown.

                                                So we definitely see an overgrowth pattern here. One of the most common contributors to this type of pattern, both from research and what we see clinically, is poor digestion. So it certainly doesn’t prove that patients have low stomach acid or pancreatic dysfunction. Luckily we do have a pancreatic marker on our test, so that can be checked, but it’s certainly something to suspect when you see these elevated. And many of these are more predominant in the small intestine. So that’s true in particular for Pseudomonas, which wasn’t initially in this case. Especially true for Staph and Strep. Those are much more common and much more abundant in the small intestine. In fact, Streptococcus is usually the number one most abundant species in the mouth, all the way down through the small intestine.

                                                So, again, Morganella tends to be one of these that is commonly associated with inflammatory bowel disease, and it does produce high amounts of histamine, so it may also be a contributor to IBS type symptoms. In this next section or two, we have the inflammatory microbes, particularly Klebsiella in this case. Now note that Klebsiella is not officially high. But there’s some nuances with these organisms and we do tend to see that patients often have symptoms when Klebsiella pneumoniae is present. And it’s thought that actually Klebsiella is a lot like Strep in its location. It’s actually thought to be a resident in the oral cavity and the respiratory tract. You can kind of guess by the name that it’s found in the lungs, Klebsiella pneumoniae. But they’re generally found pretty commonly a higher up and tend to populate the lower gut after there’s disruptions.

                                                It’s been linked to low stomach acid. Antibiotics can predispose to its colonization of the lower gut, et cetera, and it’s likely coming from higher up. And studies actually show that, that once you detect it in stool, that means it’s definitely colonized and likely overgrown higher up. In the commensal inflammatory section, this patient also had, at least on the second test, high Escherichia, that’s E. coli, high Fusobacterium, which has also been linked to inflammatory bowel disease. Several different studies out of different labs have linked Fusobacterium to some cases of IBS-D as well. And also Prevotella, which can be an inflammatory microbe in some cases. No fungi yeast, no viruses, no parasites at all. So those look good. And then we get to this last section, the intestinal health markers. So digestion actually looks like it’s, from the steatocrit standpoint, improved with the treatments. So a little bit of fat malabsorption before, now it’s fine. Pancreatic function looks to be pretty good. But look for that to be around 500 and above. It’s pretty close, not too bad.

                                                Again, we might suspect low stomach acid based on the overgrowth patten, but there’s no way to test for that directly with stool testing. GI markers, the first one looks good, Beta-Glucuronidase. Of course the occult blood, which is a common feature of IBS-D, this patient did have… I’m sorry, I should say inflammatory bowel disease, not IBS-D, especially ulcerative colitis. So this patient still had detectable occult blood. It was a little bit better. Secretory IgA went down, so that’s an improvement. Anti-gliadin actually went up. So this patient may have had some gluten exposure, which may have been related to some of these other patterns that worsened over the second time.

                                                This eosinophil activation protein, so that’s… I want to take a minute there just to talk a bit about that connection with mast cells. So mast cells and eosinophils tend to work together. They tend to activate one another. We don’t have a direct marker for mast cells, but eosinophil activation protein can be taken as a potential indirect marker. We also know from studies that this protein is linked to, and just general eosinophil activation is linked, most commonly to food sensitivities, but also to inflammatory bowel disease as well. So it’s again, another type of inflammatory cell. It’s telling us that there is an issue there as well.

                                                But calprotectin, which is a classic marker that we look at for especially inflammatory bowel disease, wasn’t too bad before. It was kind of in that yellow range, only 69. I didn’t include the cutoffs here, but it’s at 173, so it’s pretty far below 173. But the second time around with this patient not improving and some of the inflammatory microbes getting worse, calprotectin looks great. Right? So this patient’s been very concerned about having to go back on steroids. But so far, based on the calprotectin, that would suggest that this IBD scenario, that the patient may still be in remission. Only a colonoscopy would be able to confirm that. But this is suggestive then that this patient’s current symptoms may not actually be due to an IBD flare and it may be related to this IBS and IBD overlap. So this is one of the markers that is often used to differentiate between IBS and IBD. And again, at this point it appears like this patient may have actually IBS, diarrhea dominant.

Dr. Weitz:                            Would they still be having blood in their stool if they were not having an IBD flare?

Dr. Fabian:                          That’s a good question. Yeah. I mean that’s why likely this patient, if they haven’t had a colonoscopy recently, their gastroenterologist likely would want to, of course, revisit that, because occult blood is potentially concerning. But that would not be a common finding in IBS-D. So again, this speaks to this overlap where it’s kind of an in-between scenario, not fully consistent with IBD, but suggests possible overlap with IBS.

                                                And we’ve just talked about those markers, so I’m not going to focus on that. But that kind of takes me to… So that’s basically the patient scenario. I’d love to chat about… if you have questions about any of the potential ways to address those imbalances. But just a couple of things I want to talk about before we do. So we didn’t really talk about this food component here. I just want to touch on that a little bit, especially with regard to Klebsiella. So we tend to think of Klebsiella as a bad guy. It’s linked to all these different conditions. It’s also linked to a variety of autoimmune conditions, rheumatoid arthritis, ankylosing spondylitis, et cetera. So it’s found in a lot of different conditions, not just IBS-D. And I think we’ve known for a long time, especially those who are maybe more familiar with the ankylosing spondylitis scenario and the connection between Klebsiella and starches, this reinforces that. It’s just a brand new study. And also extends that observation that basically a full range of simple carbohydrates promotes Klebsiella growth. And that includes sugars, starches and even FODMAPs.

                                                That’s from various studies as well, not just from this study here. But they say, “We identify simple carbs as critical to the colonization of Klebsiella.” So that’s something to assess, of course, with patients’ diets, especially if the antimicrobial isn’t working so well. And they also find the opposite, that dietary fiber is necessary for colonization resistance against Klebsiella. So that gets in the conversation of if you’re eliminating FODMAPs then how do patients still get adequate fiber?

                                                Just another kind of interesting insight here. So they found that lactulose can be utilized as the sole carbon source, this is of course done in culture, minimal media for the tested strains of Klebsiella pneumoniae. “We confirmed that the addition of lactulose to cecum extract, so basically colon contents, increased the the growth of Klebsiella pneumoniae measured by optimal density, et cetera. Mice were provided lactulose in drinking water after colonization of Klebsiella. Compared to the water control, lactulose increase Klebsiella pneumoniae by tenfold.”

                                                So technically lactulose is considered a FODMAP, even though it’s not a natural compound. But interestingly, it kind of makes you think about the breath test prep and the breath test itself, because patients are recommended to avoid fiber, at least for a short period, maybe longer for constipation, and then they’re given a large dose of lactulose. So if they happen to have Klebsiella, technically this may actually make their Klebsiella worse. So I’m not sure how that might affect the breath test though.

                                                A couple of other things, so in terms of the fiber, we know that fiber definitely inhibits a range of these LPS producers, inflammatory microbes. And that’s likely through this mechanism, at least in part, that basically fiber leads to short-chain fatty acids, and then that can help to help to acidify the local environment. That’s just noted here. They say, “Here we demonstrate that an antibiotic, naive microbiota, suppresses growth…” So that’s basically commensals, “… suppresses growth of antibiotic resistant Klebsiella, E. coli and Proteus by acidifying the proximal colon and triggering short-chain fatty acid mediating intracellular acidification of those bacteria.” So that’s thought to be one of the key ways for how fiber helps to protect against these bad guys. So pretty essential in considering dietary approaches to keep these microbes from overgrowing.

                                                So I just want to mention real briefly some of the articles that point to some of these factors that may help with mast cells. There’s a lot of research on this. Certainly you know about certain things like quercetin that can inhibit mast cell activation. This figure shows a few others like lipoic acid, N-acetylcysteine or taurine, even biotin. So there’s growing research now that lack of biotin promotes these inflammatory microbes. And making sure there’s adequate biotin in the diet can suppress the inflammatory microbes.

                                                And that’s where berberine… I know we talked about that earlier, but berberine comes into play. Interestingly, this is a conversation for another day, but hydrogen sulfide I think these days has kind of a bad wrap over concerns about hydrogen sulfide SIBO and things like that. But normal physiological levels of hydrogen sulfide are thought to actually promote health in the gut. There’s a fair amount of research showing that normal production of hydrogen sulfide… Even certain beneficial bacteria can produce hydrogen sulfide and sulfur related compounds. So it’s thought that one of the ways in which berberine might be helpful, and/or hydrogen sulfide related compounds, is through these same mechanisms that can help to reduce mast cell activation. And I actually looked into that a bit, so that was an interesting connection. But hydrogen sulfide actually, there’s a lot of research now showing it can inhibit mast cell activation.

Dr. Weitz:                            Interesting. Hey, Tom, in terms of antimicrobials like berberine, have you seen, from looking at all these stool tests and talking to clinicians, et cetera, that the use of antimicrobials like berberine… do you see that they tend to damage the microbiome?

Dr. Fabian:                          That’s a good question. So it depends on, of course, the dosing and how long. So generally, no. A typical course of antimicrobials, afterwards the microbiome usually looks noticeably better. Frequently your key targets, which are those opportunists on page three, tend to be much improved in most cases. And that’s a major deal, because you need to get those opportunists down to help the good guys to recover. So for the most part, no, we don’t see that. But I have had a few unusual cases, for example, where for example a child, an autistic child, had been on Biocidin for a year or more and was really deficient. And for whatever reason, I don’t know why, but the clinician recommended that they just keep taking Biocidin indefinitely. So that’s an anecdote. We don’t have statistics, of course, to show for sure what’s happening. But from a clinical anecdote standpoint long-term… And it’s surprising how many clinicians will have patients on these antimicrobials for months and months or longer. So I’m not sure exactly why that’s the case. But I past a certain point, I would assume that if it’s not working, that suggests a different approach is needed.

Dr. Weitz:                            On the opposite end, in terms of probiotics improving the microbiome, we know that probiotics typically don’t become permanent residents. But now we’re starting to get a new breed of probiotics, in other words, Akkermansia is now available, and I think that Faecalibacterium prausnitzii may also be available. And there’s some speculation that those probiotics may actually colonize the gut. Have you seen anything in terms of that?

Dr. Fabian:                          Not so much yet in terms of published data. So probably the closest would be FMT, which is of course less defined than a probiotic. But FMT if fecal microbiota transplant, some of the microbes it depends on the individual, but often a large proportion of them seem to colonize. But some don’t, not sure why. And then some of these more defined commensal probiotics, I don’t think we have enough data on them yet to know for sure, but so far preliminary data suggests that probably they do colonize to some extent, certainly more than the typical probiotics.

Dr. Weitz:                            Okay.

Dr. Fabian:                          I think we’re just about at the end here. I think I had a couple more. One was about resveratrol, several studies showing that that also could inhibit mast cells, and probably many other polyphenols. Probably won’t get into this since we’re just at the end. I want to make sure we have some questions. But this is just getting into the idea that it’s not just FODMAPs and carbohydrates, that also some patients with IBS may have a food-allergy-like scenario where their mast cell activation and their IBS symptoms are due to a specific immune reaction that’s similar to a food allergy, but they have IBS symptoms instead of food allergy symptoms. So that would suggest some patients may have to get pretty specific about what foods that they’re avoiding because it may be very specific foods and antigens in those foods that are triggering symptoms. And that’s basically what this is speaking to, a major study from a couple of years ago. So I think I’m going to end here. Yeah, that was my last slide.

Dr. Weitz:                            Okay. So anybody who hasn’t been able to ask a question, do you have any questions you want to ask Tom about the microbiome or mast cell activation or IBS?

Dr. Fabian:                          I see Steve has his hand up.

Steve:                                   Right. Thank you, Ben. Thank you, Doctor. Quick thing I wrote in there, do you see any cross reactivity that people have had long-term Strep infections, especially some of our younger children now, and taking a probiotic that has Strep in that, do we see any cross reaction?

Dr. Fabian:                          I wish I had a good answer for you, but I’m not aware of any research on that and I haven’t come across that specific scenario clinically either. So theoretically, certainly I think that that could happen, but I don’t have any specifics that I can point to.

Steve:                                   Okay, thank you. Also, with the carnivore diet, do you see any pathologies in these patients that have gone carnivore?

Dr. Fabian:                          So that’s a really interesting topic and we don’t have enough samples, or at least I haven’t come across enough samples to say conclusively. I would say in total I’ve come across only a handful, maybe 10, over the last couple of years or so. And in most cases, but not all, and some cases there was a before and after, the microbiome often looks very dysbiotic. Whether that’s a long-term problem or not, we don’t really know. But from a standard assessment of the dysbiosis, we would say the dysbiosis tends to be pretty bad on the carnivore diet. That may be due to the fact that we know that amino acids, when there’s an excess that gets into the colon… So if you eat too much protein and you’re not digesting it optimally, and some of it gets into the colon, that can stimulate dysbiosis and protein fermentation. So I think a lot of it has to do with digestion as well.  If you digest protein really well, you may be doing much better on a carnivore diet than someone who does not digest well. But I do wonder about how these microbes with all these beneficial products fare without a good source of fiber because that’s really what they thrive on.

Dr. Weitz:                            Steve had also written a question about is there anything on the GI-MAP that has any relationship with polyps? And I would ask, and is there anything on the GI-MAP that might tell us anything about the potential risk of colon cancer?

Dr. Fabian:                          That’s a great question. So probably the number one marker that would at least raise suspicion of something off would be the occult blood. Fortunately, that’s pretty rare that a patient who hasn’t, for example, had a colonoscopy in a while but turns up with high occult blood. Usually it’s something temporary or it turns out to be something like an inflammatory bowel disease. But in rare cases, I’ve heard of a couple examples, where the patient went on to have a colonoscopy and they did find colon cancer. So the fecal occult test is one of the tests that can. It’s not exclusive to colon cancer, that’s the issue. So there is no marker that says, “Yes, of course.” We don’t have anything on the test that would be diagnostic for colon cancer. We have a few markers that would raise suspicion. A Fusobacterium would be another one. There’s definitely links between increased Fusobacterium in general and a higher risk for both IBD and colon cancer.

Dr. Weitz:                            Oh, interesting. I think Fusobacterium is one of the bacteria associated with hydrogen sulfite SIBO.

Dr. Fabian:                          Yeah, it is a significant hydrogen sulfide producer and it’s thought to mostly be present in the oral cavity. It’s known to produce a lot of hydrogen sulfide there. But when it gets down into the colon, it’s thought to stimulate inflammation in the colon. Not necessarily in everyone, but it’s something that can happen more frequently. It is an LPS producer, so that may be one of the ways in which it actually contributes to inflammation as well.

Dr. Weitz:                            Awesome. Thank you so much, Tom.



Dr. Weitz:                                                 Thank you for making it all the way through this episode of the Rational Wellness Podcast. For those of you who enjoy listening to the Rational Wellness Podcast, I would certainly appreciate it if you could go to Apple Podcasts or Spotify and give us a five-star ratings and review, that way more people will discover the Rational Wellness Podcast. And I wanted to let everybody know that I do have some openings for new patients, so I can see you for a functional medicine consultation for specific health issues like gut problems, autoimmune diseases, cardiometabolic conditions, or for an executive health screen and to help you promote longevity and take a deeper dive into some of those factors that can lead to chronic diseases along the way.  That usually means we’re going to do some more detailed lab work, stool testing, sometimes urine testing, and we’re going to look at a lot more details to get a better picture of your overall health from a preventative functional medicine perspective. So if you’re interested, please call my Santa Monica Weitz Sports Chiropractic and Nutrition office at 310-395-3111, and we can set you up for a new consultation for functional medicine. I’ll talk to everybody next week.


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