Cutting-Edge Metabolomic Testing for IBS, Longevity, and Metabolic Health

We’re witnessing an exciting shift in how we understand gut health and disease—and it’s all thanks to the powerful metabolites produced by the microbiome, like short-chain fatty acids (SCFAs) and secondary bile acids. In today’s episode, Dr. Tom Fabian shares groundbreaking insights into how these postbiotics influence intestinal barrier integrity, immune balance, and even muscle regeneration. These compounds are also connected to key processes like glucose metabolism and healthy aging. What’s truly fascinating is how this science is opening up new frontiers in treating IBS, metabolic conditions, and chronic gut issues. With the upcoming launch of Diagnostic Solution Laboratories’ StoolOMX test, an add-on to the GI-MAP, we now have a tool to measure these metabolites in clinical practice, making personalized and effective treatments more attainable. This is a pivotal moment in functional medicine that you don’t want to miss.

Be sure to download the Interpretive Guide and follow along as we dive deeper into how these discoveries can transform clinical practice! ~DrKF

In this episode of New Frontiers, Dr. Tom Fabian is back to lead us on a deep dive into how short-chain fatty acids (SCFAs) and secondary bile acids impact gut motility, immune function, and metabolic health. These metabolites are emerging as key regulators in conditions like IBS, cardiometabolic diseases, and healthy aging. Dr. Fabian explores how DSL’s StoolOMX test provides clinicians with detailed insights into these vital compounds, offering a new way to measure and optimize treatment for gut-related disorders. Tune in to learn how understanding these metabolites can lead to more targeted approaches in improving patient outcomes and enhancing overall wellness.

In this episode of New Frontiers, learn about:

Dr. Kara Fitzgerald: Hey practitioners, exciting news. Diagnostic Solutions Lab has updated their GI-MAP Interpretive Guide with a whole new section on StoolOMX, a stool metabolomics test and we’re going to be talking about this for our entire conversation today with the great Dr. Tom Fabian. You’re going to get detailed information on bile acids, short-chain fatty acids, and how to use these to better understand conditions like BAM (bile acid malabsorption), IBS, short-chain fatty acid imbalances, and more. In fact, just listen to this podcast and you’ll get why the release of the StoolOMX assay is just going to be an awesome addition to what is already a great test.

Dr. Kara Fitzgerald: Welcome to New Frontiers in Functional Medicine. We are always interviewing the best minds in functional medicine and of course today’s no exception. As I’ve already told you, I am here with Dr. Tom Fabian. If you’re with me on YouTube, you can see him sitting here next to me. Let me give you his background and we’ll jump right into this really cool discussion. Dr. Tom Fabian, PhD CNTP, is a leading expert in microbiome research and its clinical application in integrative and functional medicine. With a PhD in molecular biology from the University of Colorado Boulder, he has extensive experience as a biomedical researcher, consultant, and science advisor in the microbiome testing field. Dr. Fabian is currently a consultant and science advisor for Diagnostic Solutions Lab, and he’s a science advisory board member with Designs for Health. Tom, welcome back to New Frontiers.

Dr. Tom Fabian, PhD: Thanks so much, Kara. It’s great to be here yet again. I know we’ve had a couple discussions prior to this, so I’m looking forward to today’s session.

Dr. Kara Fitzgerald: Yeah, we have. When we prepare a podcast together, you more than any other person that I talk to, really send me an avalanche of studies. But it’s really a welcomed avalanche. I was quite in the rabbit hole in preparation for this. And by the way folks, the papers that Tom has sent to me, we’ll make sure we park on the show notes so that you can access them. In fact, we’ll include the Interpretive Guide there so you can just access this StoolOMX data over there as well. We’re talking about bringing GI metabolomics front and center in the GI-MAP test. Talk to me about the analytes you guys are thinking about and why the gut metabolome is important. Why do we, as clinicians, really need to be thinking about it?

Dr. Tom Fabian, PhD: Absolutely. Yeah, I think it’s certainly the core of what makes the microbiome exciting and important in terms of its impact on our health. There’s so much research now, going back 10 plus years, on all these different metabolites and we’re learning more about these products that the microbiome produces. There are different categories, and we’ll kind of zoom into a little bit about what is covered on the StoolOMX test and why that can give you so many great insights.

Dr. Tom Fabian, PhD: But the crux of it is that basically, the metabolites, and we’ll go through some of the categories here, are really the center of how the microbiome influences our health. And of course, when they’re imbalanced, that’s one of the things that can contribute to how the microbiome, when it’s imbalanced, may influence disease development as well. So being able to assess these and recognize them will really give you a lot of information that complements all of the detailed microbes that are on GI-MAP already. It’s another major piece of the puzzle to help practitioners put this together. It’s meant to be an add-on to GI-MAP, so it’s really going to be complementing what’s on GI-MAP. We’re looking at pathogens, opportunists, some of the key commensal microbes on GI-MAP, but also many of the markers that tell us about the physiology.

Dr. Tom Fabian, PhD: So you’re getting the whole microbial picture— good guys and bad guys. You’re getting this really important information on the immune system in the gut, digestion, leaky gut, etc. And then on top of that, we’re getting some really key information on the three major categories of metabolites. The ones that are on this stool metabolomics, and it includes over 30 microbiome metabolites, which I think is at this point probably the most of any test that’s being used currently in our field. That includes all of the short-chain fatty acids, several of the branched-chain fatty acids, and we’ll talk about their importance as well, and then up to 25 different bile acids.

Dr. Tom Fabian, PhD: That area has really just exploded in terms of a whole bunch of new bile acids have been identified in recent years. We’re already starting to see connections to conditions like heart disease, metabolic conditions like metabolic syndrome, diabetes and even now, some of these are linking to aging and longevity. So really a great picture there. The bottom line is this is going to really widen out the lens and provide that key piece of the puzzle in terms of what are they producing, basically who’s there and doing what based on the microbes and then what are they producing?

Dr. Kara Fitzgerald: That’s interesting. And you will be able to guide us. I’m sure we’re going to have a follow up conversation around this as to, okay we have these two pieces of information and now how do we really influence. Because as we dive into the research around these bile acids, we’re going to want to make sure we’ve got an abundance in certain players and we’re going to need to know how to influence that. But I want to say one thing before we start talking about these more specifically and ask you, because I don’t really know the answer. I think we’ve talked about this before. It’s not a hard and fast rule that it’s only a certain few that produce butyrate or produce these secondary metabolites.

Dr. Kara Fitzgerald: Many different organisms could be participating, could have the genetic apparatus to be able to produce them when they’re given the appropriate substrate. It just seems to me that probably the omics investigation is just going to grow so that we can see that they’re producing them and maybe supplant our need to look at the microbiome. What do you think? Do you think both will grow in tandem or what do you think?

Dr. Tom Fabian, PhD: In reality, and it’s pretty clear from the research, having a multiomic approach where you’re looking at the microbes, at who’s there and also what they’re producing, can give you a lot more information. And keep in mind, there’s sort of methodological considerations, but when it comes to the metabolites, we’re looking at what’s contained in the stool. So that’s sort of the end result of their journey through the GI tract and the different microbes acting on the food components and then producing these. But there’s also things that happen along the way, which we’ll get into.

Dr. Tom Fabian, PhD: When interpreting short-chain fatty acids in stool, you can’t get very far unless you also know the microbes. To keep it simple, there’s basically the production by the microbes, and some of that can happen very early on in the first part of the colon, and then many hours later, by the time they’re sort of at the end, your body has already absorbed a lot of those. And also they’re using some of those short-chain fatty acids and interconverting them into something else. So you can’t really get that many insights by just looking at one part of the picture, especially the metabolites. You really need to know more of what’s going on. Certainly you need to know about digestion and you need to know about the immune system as well. And that’s really what I was kind of getting at as far as, it’s a piece of the puzzle, a really important piece, but in many ways, I don’t think it’s going to completely take the place of looking at some of these other aspects.

Dr. Kara Fitzgerald: Okay, alright, well that’s cool. That’s good to know. It makes sense. It makes total sense. By the way, are you going to be quantifying these? They’re going to be quantified.

Dr. Tom Fabian, PhD: Absolutely.

Dr. Kara Fitzgerald: Yeah, so that’s an exciting change as well.

Dr. Tom Fabian, PhD: Yeah, the methodology is basically the latest in tandem mass spec, so that’s a very precise method. It’s been around for a while, but of course they’re always making improvements to it. Currently it’s able to very precisely identify these individual metabolites and it’s pretty sensitive as well. That’s why we can look at so many, for example, bile acid metabolites that may not be present at really high levels but already have documented effects, even at low levels, and then we can quantitate that precisely as well. They’re going to be reported in two different ways. Kind of a high level summary will also include percentages, because you want to know what that overall breakdown is, but ultimately, you want to know how much is there. And then that’ll help you correlate that to the level of microbes, which is also quantitated on GI-MAP.

Dr. Kara Fitzgerald: Awesome. So let’s start talking about them. Our audience largely knows butyrate. I would say 99% of the listeners are familiar with butyrate and know that it’s really essential. But there’s other short-chain fatty acids. Some of us are familiar with them. Let’s start with an intro to short-chain fatty acids and why they’re important. And then let’s move to the branched-chain fatty acids.

Dr. Tom Fabian, PhD: Absolutely. I think a lot of people are already pretty well aware that short-chain fatty acids are a major group of metabolic products produced by largely beneficial bacteria, particularly the ones that are best known like butyrate, for having beneficial effects. They’re produced from the metabolism of carbohydrates. So the residual carbohydrates that get into the colon, ideally in a healthy situation, of course, that’s primarily fiber and other types of fermentable carbohydrates. They convert those into the very short-chain fatty acids. That whole process, though, is influenced, of course, by the gut microbiome composition. And it goes two ways. Of course, if you’re feeding the certain microbes that thrive on a certain food component, they’re going to do better.

Dr. Tom Fabian, PhD: But it also reflects your capabilities. If you take an antibiotic, for example, or you have a lot of inflammation that’s knocking down your microbiome, you’re not going to be able to get the benefit of the fiber unless you’re building your microbiome back up. That’s one of the key things. We know that they’re products of what we consider to be largely a healthy diet. Polyphenols also kind of help that process. They also tend to promote an environment that’s going to promote these commensals, so it’s kind of synergistic with fiber as well. But we also want to know about the related metabolites that are produced from the breakdown of branched-chain amino acids. This is more carbohydrate metabolism or carbohydrate fermentation. The branched-chain fatty acids are produced from branched-chain amino acids. That’s a really different scenario.

Dr. Tom Fabian, PhD: In a healthy gut, what typically happens is the microbes, the ecosystem overall prefers the fermentable carbs, right? Because they are what they’re geared to thrive on. They’re relatively easy to break down in certain ways and the energy yield is good. So basically when they run out of those or those are depleted past a certain point, they’ll turn to amino acids as a source of energy and that leads to this concept of what’s called protein fermentation. Branched-chain fatty acids are produced, again, as a product from that, so it’s kind of a marker for protein fermentation. There’s a whole lot of research on the health links to that process. In a healthy gut, you’re going to definitely have a predominance of the fiber fermentation and short-chain fatty acids. You are going to have some of these protein fermentation products even in a healthy gut, but the idea is you’re going to have far fewer, right, because that’s a normal process. You just don’t want that to be predominant because that can mean you have not enough fiber.

Dr. Tom Fabian, PhD: Another key thing that we know from research is high levels can be a sign that your transit is slow because slow transit obviously leads to more time to deplete those carbohydrates and then you get a big increase in protein fermentation. When you get too much of the protein fermentation, that can produce a range of other toxic products, such as ammonia, some of these biogenic amines that may not always have beneficial effects, etc. So it’s really helpful for understanding what’s going on in the gut and then how that could be impacting a patient’s health. That’s also linked to a lot of different conditions, particularly IBS, which we can talk about.

Dr. Kara Fitzgerald: IBS. Okay, let me just ask you a couple of questions. I want to back up and just say a good short-chain fatty acid distribution is just a nice insight into a robust microbiome, but also feeding a good fiber-dense, polyphenol-dense diet. And fiber and polyphenols generally track together so you can see this particular gut is eating a good high quality plant-based diet. Are there any ratios we’re concerned about? I mean, do you remember when the mice studies came out demonstrating propionate sort of prompted neurodivergent sort of neurodevelopmental problems in this mouse model. They likened it to autism. Where are we at with that? Propionic acid got vilified for quite a while, but you’re suggesting that they’re all beneficial. Where’s the research with balance? Go ahead.

Dr. Tom Fabian, PhD: Yeah, it can be a little bit of a mixed picture. Like anything, it’s kind of context dependent, but in general, the research shows, and these are sort of rough figures, but on average in a healthy gut, about 60%, (plus or minus say 5 or 10%) of your total short-chain fatty acids is acetate and then it’s roughly evenly split between butyrate and propionate for the other 40%, so roughly 20% butyrate, 20% propionate. That is going to depend a lot though on a lot of factors. We do know, for example, that propionate is primarily produced by the bacteroidetes phylum. That’s one of their key products for many of those microbes. So if you have a predominance of those microbes it’s telling you, of course, that your microbiome is imbalanced and it may be imbalanced for a variety of reasons.

Dr. Tom Fabian, PhD: Depending on those details, that could be related to conditions like autism if you’re really imbalanced. The context really does play a big role. I think that the ratios are really important to pay attention to as well as the absolute amounts, because you can have a good ratio, but if your overall levels are really low that means you’re still not producing enough total to have these positive effects. We try to see both sides.

Dr. Kara Fitzgerald: Okay. It’s going to be interesting, just as you guys have more and more data come out, it will just afford us the opportunity to really explore these in a deeper way.

Dr. Tom Fabian, PhD: Yeah, I’m really excited about it.

Dr. Kara Fitzgerald: I want to talk about the branched-chain fatty acids that there’s some association in literature with IBS. We’re going to see this in people on keto. In our clinical rounds the other day we were talking about a long time patient of ours, and he had just really refractory SIBO and he’s arrested it for the last year on a hardcore, complete keto diet. He’s just shut his SIBO down and he’s been very clear to my colleague in the clinic, Dr. Ken Litwin, that he’s not changing it. He’s going to stay keto. And I can’t blame him because he struggled with SIBO for so long. So for him, it appears to be working. But you see fall out in plenty of folks. So, how do we think about these?

Dr. Tom Fabian, PhD: That’s a great question. Like anything, again, there’s multiple levels, and this is sort of my opinion. This is true also for the carnivore diet, because you hear a lot of people going on carnivore diet, and their symptoms seem to go away, at least certain symptoms. I suspect that a lot of those patients probably have some level of carbohydrate intolerance, so it’s a way to reduce those symptoms. Now, is that really the healthiest way to do it?

Dr. Tom Fabian, PhD: There’s study after study after study that fiber is really key towards getting healthy levels of short-chain fatty acids. If you’re primarily getting those from protein, for example, on a carnivore diet or on a keto diet, of course, it’s more fat, that also can produce some beneficial effects in the microbiome. But I think they’re starting to recognize now that there’s potentially, at least in some people, a downside, depending on how they’re able to handle that different spectrum of products that your microbiome is producing. So that is a key thing to keep in mind, is that when you’re dramatically changing your diet, especially dramatic differences in macronutrient ratios and the amount of fermentable carbs, you are going to dramatically affect, not just the microbes themselves, but what they’re producing.

Dr. Kara Fitzgerald: Okay. Yeah.

Dr. Tom Fabian, PhD: And that hasn’t always been well studied in all these different scenarios. Short-term benefit in terms of symptoms, I mean, you could certainly compare that to antibiotics. Antibiotics often get rid of infections and make people feel better, but can then, down the line, predispose you to all kinds of different imbalances and even various conditions, potentially. So the long-term effects are not that well known and I would be wary of just trading short-term improvement in symptoms for something that’s not established as being healthy yet.

Dr. Kara Fitzgerald: You know, I do agree with you. I mean, I am a fan of an appropriately prescribed keto diet and under some circumstances, one might be able to really achieve an adequate amount of fiber and polyphenols in that. But yeah, to your point, it’s also aggressive, almost fasting the microbiome. I know that’s simplistic, but it just so radically changes it. But I can’t stand in his way when he’s finally experiencing some [reduced] symptoms.There’s very few people I could count that have responded for that duration of time. Usually people transition out of these pretty aggressive and restrictive diets, but for him it’s done pretty well. And maybe as we study this and as you guys get more data points, it would be really interesting to kind of look at the cohort who’s thriving long-term on something like this and what their microbiome looks like. Because we know in traditional diets there’s some people who’ve eaten some really restricted sort of keto-leaning diets, like the native population in Alaska and diets of that nature. Anyway, it’ll create some interesting opportunities for us to look at.

Dr. Tom Fabian, PhD: (20:55) Yeah. I think that will certainly be important to see, you know, what are those effects. Maybe they’re getting some kind of compensatory thing that’s altering things in a way that in one way is not as healthy, but then it kicks something else up that actually is sort of compensating for that. But I always like to consider the root cause. Of course, in functional medicine, being able to come up with something that improves symptoms is certainly one of the goals, but it’s not always the ultimate goal. Right? Because we know that sometimes it’s a band-aid. There are times where you may want to look into is there a way to figure out upstream what might be causing those symptoms and figure out whether addressing those upstream causes then allows them to have a more diverse diet, for example.

Dr. Kara Fitzgerald: Yeah, I agree. I mean, you’re preaching to the choir. Diversity is something that we always try to achieve and we limit those interventions short-term and kind of controlled, and we pay careful attention. So I do agree with you broadly. Let’s see, let’s talk about the rest of them. We got through the short-chain fatty acids and the branched-chain fatty acids. Let’s talk a little bit about bile acids. Actually, before we go into that, because that’s going to be a big conversation, let’s talk about the fatty acids beyond the gastrointestinal tract.

Dr. Tom Fabian, PhD: Yeah, it’s becoming a really interesting story and I think even just a little bit into the aging field, based on some of the studies that have come out recently. I think one of the ways to conceptualize this is we know that now there’s all these gut-organ axes. There’s the gut-brain axis, there’s the gut-skin axis, the gut-liver axis, on and on and on, and that’s largely mediated by different metabolites. I think one interesting example, and I came across some of this research a couple of years ago, looking at research on the microbiome in eczema, that actually there are studies now showing that butyrate actually has positive effects on skin health, particularly the skin barrier, and may help to reduce the effects of Staphylococcus aureus, which is one of the main pathogenic microbes in that condition.

Dr. Tom Fabian, PhD: We certainly know that it has positive effects on brain health. One of the most interesting ones I saw recently, this is probably about a year ago or so— and this is probably local effects of butyrate in particular, to some extent propionate— that can basically promote the anti-inflammatory and immune tolerance aspects of the immune system, right? So those are largely mediated through what are known as regulatory T cells or T regs. Long story short is they were looking at muscle regeneration and they noticed that there’s this accumulation of different immune cells, T cells, that seemed to play a big role in promoting or influencing muscle regeneration, say after exercise or after injury.

Dr. Tom Fabian, PhD: And they found that the T reg cells that were present in muscle came from the gut and basically helped to balance the immune system. If you have too much of an inflammatory response it skews the repair process in a certain direction that’s not so optimal. Versus if you have this balancing effect based on the short-chain fatty acids promoting this in the gut, and then those immune cells travel to the muscle and they can promote proper regeneration at distant sites. And I think that’s also been shown recently for liver regeneration and then also to some extent for bone health and influencing that osteogenesis process with promoting the osteoblast and then the osteoclast balance as well.

Dr. Kara Fitzgerald: Wow, and this can be kicked into generation with a robust showing of short-chain fatty acids.

Dr. Tom Fabian, PhD: Yeah, and it’s probably best characterized in the gut itself. That short-chain fatty acids and other microbial products influence the regeneration process itself in the intestine. If you think about gut healing and leaky gut, we’re so focused on tight junctions and zonulin and that gap between the cells, but ultimately the main thing that happens on a regular basis to keep your gut healthy is those gut stem cells that divide to the point where they can regenerate the entire intestinal lining within about five days or so. And so they influence that process.

Dr. Kara Fitzgerald: That’s amazing. Just really, really, really interesting. Anything about systemic on the branched-chain fatty acids before we hop over to talking about bile acids?

Dr. Tom Fabian, PhD: Yeah, I mean, that scenario actually I haven’t looked into as much, but on the metabolic side, I know both excess– The microbiome can even produce branched-chain amino acids and certainly an excess of those has been linked to metabolic issues, particularly diabetes. But also the branched-chain fatty acids may influence that process as well. So even though we know short-chain fatty acids can promote metabolic health in many ways, including GLP-1, we can certainly talk about that, but also the branched-chains, kind of in keeping with this idea that if you have an excess of these protein-derived products, protein fermentation products, that can have negative effects if they’re in excess.

Dr. Kara Fitzgerald: You and I have talked about this before– Everybody is trying to hit at least a gram of protein per pound body weight and I just read a paper that came out recently, I feel like they were up to three grams. I’m not sure, it might have been kilograms though, you know, three grams per kilogram. It’s just getting higher and higher and higher. The quantity of protein people are trying to get in their bodies, it’s really pretty intense.

Dr. Tom Fabian, PhD: To me, that would be a whole topic in and of itself to discuss because again, there’s so many nuances and what we just talked about. A key part of keeping your skeletal muscle healthy is through regeneration, so when you’re weightlifting, of course, you want to have that to have a response. You want to be able to build muscle. In order to do that, we do know again, the microbiome influences that apparently mostly through the production of short-chain fatty acids, particularly butyrate. That process can be inhibited by too much protein, particularly if you’re not digesting and absorbing your protein. So that’s one of the big take homes is how much protein you take in and how much you actually can make use of is going to depend to some extent on how efficiently you can digest that and absorb it. In general, if you’re not absorbing and digesting so well, you get an excess of that into the colon. That can shift the balance towards the production of these amino acid products that can be potentially detrimental. I think you have to take the patient into account in how they’re digesting.

Dr. Kara Fitzgerald: That’s interesting. For sure, and it’s a good ah-ha. I think it’s a good reminder that we need the high-fiber, high-polyphenol diet to support muscle regeneration. Like it’s right there, you know, as important probably, would you say, as the protein itself?

Dr. Tom Fabian, PhD: Yeah. I think it’s early research, but presumably the regeneration process is a very central feature and these articles seem to be pretty clear so far in that that is a very significant factor, these cells coming from the gut. So if you’re connecting those dots, to your point, fiber and polyphenols, you don’t think of those as muscle building nutrients. We’re finding out that likely they are indirectly.

Dr. Kara Fitzgerald: So fascinating. Yeah, they’re traffic directors it sounds like. They’re not the substance of muscle, the ingredients of muscle, but they’re basically telling the construction workers what to do, if you will. Wow, that’s really interesting. That’s really interesting to me. When I was trying to put together my own program doing resistance training, it just made a lot of sense to me to have discrete high protein days, you know, maybe two or three depending on my lifting schedule, next to my usual super dense polyphenol/fiber diet. Kind of layer it in occasionally, but just go back to my usual dietary pattern in addition to that.

Dr. Tom Fabian, PhD: That to me makes a lot of sense because I think we’re getting more information from research that hints at looking at this from a more sophisticated standpoint that there are times where you want to be more in that anabolic mode, even when you think about the timing. So after you eat, if your digestion is good, you’ve got good protein in your diet so you’re basically breaking down and then absorbing amino acids in the small intestine. So that’s a relatively early process, but many hours later, once the fermentable carbs enter the colon, and in many cases that might even be at night while you’re sleeping and not eating, and not as much in sort of that anabolic mode, or in the repair side of things, that can be potentially when your short-chain fatty acids might be kicking in more. So the differential in timing, I think, is sort of interesting and part of that equation as well.

Dr. Kara Fitzgerald: Super interesting. If anybody’s interested, we have a protein blog that outlines what I’ve been doing that might be a nice ancillary to what Tom’s talking about. When we have access to the StoolOMX Test we can really start to look at what’s happening with the various dietary patterns. Okay, let’s talk about bile acids. This is really interesting. It’s crazy interesting.

Dr. Tom Fabian, PhD: It’s become interesting. Of course, bile acids traditionally may not have been that interesting because we think of it as just something that’s basically released from the gallbladder during digestion that’s stimulated by cholecystokinin. It’s basic digestive physiology when you have particularly, fat hitting the small intestine. You have those cells that are sensing what’s going on and then producing this cholecystokinin that triggers the release of bile. And the bile acids, the primary ones are cholic acid and then something called chenodeoxycholic acid. They’re easy to think of as just CA and CDCA. Those are the primary ones produced by the liver and then released by the gallbladder during digestion. We always thought of those as being important for helping to basically emulsify the fats. So, basically break them down in a way into these little vesicles that are just much easier for the digestive enzymes to work on so that we can absorb fat more efficiently.

Dr. Tom Fabian, PhD: And of course, fat soluble vitamins, right? So if you’re not producing enough bile, that certainly can be a problem for fat soluble vitamins. So that’s mostly what we’ve known for many decades in the early years but now with all the new information coming out about the microbiome, and this entire category of what are called secondary bile acids. So the ones produced by the liver are called primary and then the ones that are modified by the microbiome are called secondary. There’s a couple of different modification categories.We know that bile acids of course are “conjugated” to amino acids in the liver and the two main ones are glycine and taurine.

Dr. Tom Fabian, PhD: Microbes can make use of those as energy sources and also for just their growth so they produce enzymes, called bile salt hydrolases, that can break those down. They can also carry out a wide range of other modifications on bile acids to create these secondary bile acids that have a growing list of effects and I would say that those come down to a few categories. They have effects locally in the gut, particularly in terms of motility, intestinal barrier function, and immune function. And then maybe more systemically we’re looking at sort of this metabolic picture with glucose homeostasis, insulin, GLP-1, etc. So there are lots of roles that they can play, but it kind of comes down to this core process of the production and release of bile acids, and then how the microbes act on them. That’s going to, of course, depend on lots of factors, but particularly your microbiome composition.

Dr. Kara Fitzgerald: It’s going to be very interesting to explore this. So there’s a collection of primary bile acids, those are the ones that we think about and we think that they help us with digestion and then we really kind of stop there. But now there’s this whole universe of, you know, I’m thinking of them as postbiotic bile acids. Secondary bile acids, but they’re postbiotics, and that’s a term that we’re thinking about a lot these days, the wonderment of these postbiotic compounds, how powerful they are. They are serious signal molecules and associated with very interesting physiologic activities systemically, and so far in the papers that you sent me, they are really, profoundly beneficial.

Dr. Kara Fitzgerald: And again, I will make sure these are posted onto the show notes folks. So I guess the big thing is, you know, when people have a cholecystectomy or just thinking about an appendectomy as well, you know, just getting rid of this. There was a time when the gallbladder, well, the appendix definitely, you know, was thought to be vestigial. Let’s just get rid of it, you know, and the gallbladder is not really that far behind. I know people have some really profound problems with stones and so forth, but we readily remove it and I would imagine this whole journey here needs to be disrupted. Do you want to comment on that? And then we’ll talk about maybe some of the specific bile acids.

Dr. Tom Fabian, PhD: Anything that disrupts the flow of bile, or the timing, or the composition, again, because we know that there are these different physiological effects and it’s a very fine tuned process. There are actually specific receptors in the GI tract and even on various cell types for detecting the different types of bile acids and that’s actually one of the main reasons or main ways for how they can have these divergent effects on motility, on the immune system, on the intestinal barrier, and also on metabolic function as well.

Dr. Kara Fitzgerald: It’s extraordinary. So we’re going to be thinking about these guys. And which ones in particular, if you can pull some out with regard to intestinal permeability, for example? Who are some of the key players there?

Dr. Tom Fabian, PhD: Generally there’s an excess of bile, particularly in the colon. There’s this phenomenon called bile acid malabsorption (BAM) and if it’s really significant in terms of symptoms, that can lead to bile acid diarrhea. Then basically you’re not getting this full deconjugation process. You’re not getting the conversion to secondary bile acids as efficiently. Because bile acids are in the small intestine, their function, basically, is to digest and absorb fat. They have this detergent function, but obviously that could potentially be irritating if it’s excessive and especially if it’s in places like the colon where it’s not supposed to happen. So certainly too much of the bile acids getting into the colon. That’s often diagnosed in research and also medically through the increased production of primary bile acids.

Dr. Tom Fabian, PhD: So those are ones that are not converted to the secondary and that’s actually a measure that will be on this StoolOMX test so we’ll get some great insights into that. That condition, bile acid diarrhea, is known to be like 30% or so of IBS-D, diarrhea dominant IBS. That’s a condition that’s widely known to also have leaky gut or intestinal permeability as a common feature. But the flip side are these secondary bile acids. There are some differences in terms of the individuals. I don’t want to get too much in the weeds here, but we know, for example, that LCA, that’s lithocholic acid, that’s one of the major secondary bile acids. That and several other secondary bile acids can interact with receptors. One is called TGR5 which has been linked widely to metabolic health, but also to improving the intestinal barrier.

Dr. Tom Fabian, PhD: So they have really profound effects in helping to support the intestinal barrier. One of the really interesting ones I just came across was that, again, those stem cells that we talked about in the gut that help regenerate the whole intestinal lining every five days or so, part of the gut healing process, bile acids play an essential role in that process. So if you’re not producing enough bile or too much bile or your proportions are off, that can affect all those processes, which can be pretty significant obviously for a patient.

Dr. Kara Fitzgerald: Yeah, it seems to me that this could potentially really change our thinking around how to treat— Well, going back to the patient that I was just mentioning who’s been on the keto for the last year, maybe what predisposed him to this was just a profound imbalance in his bile acids. Or it could have contributed, you know, to changing motility, barrier disruption, immune imbalances and so forth. I would imagine this could really give us some insight, potentially, in some of those super refractory conditions that we see more and more, you know, just very challenging guts. Would you agree with that? That must have been underlying the reason why you guys decided to even launch this is that we’ve been hitting our head against the wall for a lot of these gut cases.

Dr. Tom Fabian, PhD: Absolutely, yeah. We’ve had pretty limited markers for so many years. Zonulin is a great marker, but we see a lot of patient cases where the practitioner, based on how the patient’s presenting, their conditions, they’re like, I know this patient has intestinal barrier issues, but their zonulin looks fine, right? They don’t seem to have leaky gut. What else is going on? And again, we know those short-chain fatty acids play a role if you don’t have enough of those. Butyrate, etc, can be part of the problem. So with the StoolOMX you’ll be able to see that side of the picture. But now that we also know about these different bile acids and way beyond just the— There are tests that have had a couple of them on the panels for a while, like the LCA and the DCA, those two major secondary bile acids. But that only gives you part of the picture because they’re really generated from there into many different secondary bile acids. And a lot of those play important roles in the intestinal barrier.

Dr. Tom Fabian, PhD: But in addition to that, of course we know the intestinal barrier is kind of a key for a lot of different conditions, particularly autoimmunity, also allergic conditions, and then certain chronic inflammatory conditions such as IBD, inflammatory bowel disease. But motility— It turns out that short-chain fatty acids and especially bile acids have a major influence on gut motility. So within the context of IBS, and we know, of course, the two extremes, there’s IBS constipation dominant, IBS diarrhea dominant. I just mentioned a little bit earlier that bile acid diarrhea, so too much bile acid, which promotes motility but in the excess, that can be one of the major causes of IBS symptoms, IBS-D. Lack of bile acids now is thought to be one of the contributors to IBS-C, constipation dominant.

Dr. Tom Fabian, PhD: So it gives us more to work with. There’s a lot of focus on SIBO and the gases and their potential role, but the research actually is much better established for some of these major categories like short-chain fatty acids and bile acids. We know one of the main ways they can influence motility is by influencing serotonin in the gut and serotonin, of course, being a neurotransmitter, has a big effect on the function of the enteric nervous system.

Dr. Kara Fitzgerald: Interesting. So they’re signal molecules, would you say? And they combine receptors? How are they influencing serotonin?

Dr. Tom Fabian, PhD: So there’s receptors, the general category, and I don’t want to get too much into technicalities. It’s a really interesting thing to know, but these receptors called G protein-coupled receptors, they’re everywhere. Probably the majority, if not all cells, have a whole set of them. One of their major roles is to detect environmental factors, so dietary constituents and also products produced by the microbiome and then produce responses or effects. One of the key cells in the intestinal lining, these are called enteroendocrine cells, their role is to sense what’s going on in the gut from primarily nutrients and also gut microbial metabolites. So they have receptors on them, these G protein-coupled receptors and there are ones that are specific for short-chain fatty acids.

Dr. Tom Fabian, PhD: Butyrate can bind, I think, to two or three different types and then that binding process leads to the release of serotonin into the mucosa, which can affect the enteric nervous system. Bile acids also have receptors as well. The two main ones, again this is probably not something we want to try to focus on too much, but there’s one called TGR5, which is thought to be one of the major ones, and FXR. The point is that there’s specific receptors that they can interact with. But another way in which they can influence cell function is through epigenetics, and I know, of course, that’s a topic that you’ve spoken a lot about. I think it’s not as well known or well appreciated in our field is that short-chain fatty acids also can influence our epigenetics and therefore the gene expression, so the function of cells.

Dr. Kara Fitzgerald: Yeah, that’s right. That’s extraordinary. I look at the products, the postbiotic compounds, as definitely being epinutrients. That’s how I think of polyphenols and bacterial action making these really potent postbiotics. It would be interesting to kind of dive in and explore some of these secondary bile acids, this whole other universe of postbiotic compounds. I’m sure that we’ve got much to uncover. It’s pretty exciting in health and disease. Let’s talk about beyond the gut, anything else you want to add and some of the really fun papers that you sent to me, just knowing me and knowing what I’m going to love, is just looking at some of these secondary bile acids and longevity in healthy centenarians. Perhaps the benefit of caloric restriction and so forth. I mean, it’s kind of cool. We definitely want to have some of these players around. So talk about those things.

Dr. Tom Fabian, PhD: Absolutely. Yeah. And I think that was a really interesting set of research that I came across recently. I had no idea that they were even basically known to be linked to longevity and aging. Basically, through these different research studies, they found that certain secondary bile acids, for example, it’s a derivative of the major one called LCA, lithocholic acid, and this one is called isoalloLCA. They kind of have these long confusing names, but that part’s really not as important as the fact that they were able to find, in really two different studies, that is isoalloLCA, in one set of studies, seemed to be increased in centenarians. So their microbiome had microbes and then their related pathways enriched that could create this specialized secondary bile acid. And that one actually is on StoolOMX.

Dr. Tom Fabian, PhD: So if you’re interested in your isoalloLCA levels, especially if you have any centenarians in your family, that could be interesting to know if you see that upregulated as well. So that’s certainly one way in which they can influence the process. Specifically, they kind of dove in and looked at what are these longevity pathways that might be involved. We know about the sirtuins, that’s through David Sinclair’s work and other researchers in that field, elucidating the role of these various sirtuins in kind of the stress response related to, for example, caloric restriction. For a long time, they’ve been looking for compounds that actually kind of mimic caloric restriction. They basically have these pro-longevity effects, pro-healthy aging effects.

Dr. Tom Fabian, PhD: It turns out that in one of the studies, LCA, lithocholic acid, and some of these derivatives may actually be one of those, they call them calorie restriction mimetics. These are things that sort of mimic the functions but you don’t have to go through the pain of restricting your diet so severely over a long period of time. That pathway seems to be one of the key ones affected. Probably also these effects on the T regulatory cells, we know that those help keep inflammation in check. We know inflammation is one of the hallmarks of aging. We also have seen, from what we talked about, that there’s influence on stem cells and regeneration and reduction in regeneration, stem cell exhaustion, is also another one of those hallmarks of aging. So I think we’re seeing a lot of more connectivity between the microbiome and these different hallmarks of aging now.

Dr. Kara Fitzgerald: How do you guide us to optimize these? We have to have a sufficient amount of the primary bile acids available and then we have to have healthy microbiome to do the conversion, but what are your thoughts on how we’re going to address these clinically?

Dr. Tom Fabian, PhD: For the bile acids, short-chains or kind of the whole picture?

Dr. Kara Fitzgerald: Well, we talked about the secondary bile acids. Like, the bile acids and the derivatives, how will we optimize it? We’re going to be seeing lots of imbalances. I’m just curious.

Dr. Tom Fabian, PhD: There’s kind of two ways to look at it. So one is, as you pointed out, the starting material. Essentially, you want to make sure that the liver is healthy. Basically, bile acids are synthesized from cholesterol and for anyone that has cholesterol synthesis issues, maybe… I haven’t really looked at the research on this, but it’s possible that maybe statins might affect that process, for example. Not really sure.

Dr. Kara Fitzgerald: If we’re dropping our cholesterol levels down like sub 90. Interesting.

Dr. Tom Fabian, PhD: Too low. That’s a possibility. So there’s kind of looking upstream at how do you optimize liver function within the healthy range. You don’t want to have too much cholesterol, of course, but… And then the digestion process. You can have the bile there, but if you’re not really stimulating the full release due to all the things we talk about for optimizing digestion, make sure you’re not stressed, just all the different things that we would typically do there. But downstream, to get these secondary bile acids, you have to have a healthy and diverse microbiome.

Dr. Tom Fabian, PhD: And that’s one of the benefits of having these 25 different bile acids listed versus just a couple, is once you get into those details, some of those are only produced by a small subset of microbes. If you don’t have those microbes, then you’re not going to get the benefit of their products. So that’s, I think, a really concrete example of where diversity does matter. You want to basically make sure that your microbiome is healthy and you have a good overall balance of commensals but you also want to have diversity. We kind of summarize some of the most important ways, the best research ways, to do that is the four P’s. Of course there’s fiber, prebiotics, and the key there is really a range of different fibers and fermentable carbs, not overly focusing on any particular one.

Dr. Tom Fabian, PhD: Polyphenols, as always, and a range of polyphenols. Probiotics can be helpful, depending on the details of that individual’s microbiome. Postbiotics, so that’s kind of the new category, that’s the fourth P. Lots of research now is indicating if you’re deficient overall in your microbiome, particularly in the butyrate producers, taking butyrate might help your microbiome kind of jumpstart its recovery. You know, you may look at a patient that’s really deficient and figure that they’re going to need a multifactorial approach. Throwing a bunch of fiber at a patient whose microbiome can’t really metabolize it, at least not yet, may not be beneficial at that point in time, so kind of that idea of low and slow, combining it with polyphenols, maybe some butyrate. A lot of practitioners go that direction. That seems to work quite well in many cases.

Dr. Tom Fabian, PhD: I think promoting the microbiome, as long as the upstream parts are optimized, is the best way to ensure both short-chain fatty acid production and also adequate levels of these various secondary bile acids.

Dr. Kara Fitzgerald: It’s going to be fun to really explore it and another compelling reason that a diversified gut is so essential, as if we need more. But we know that’s also the hallmark of the centenarian gut, and probably why they’re able to make all these awesome derivative compounds associated with longevity. Also talk about muscle and GLP-1 and some of these secondary bile acids, because they play a role there too.

Dr. Tom Fabian, PhD: Yeah. I mean, certainly short-chain fatty acids do and butyrate is pretty well characterized as being one of the factors that can stimulate these L cells, which are these enteroendocrine cells in the gut that can basically release GLP-1. So that pathway is pretty well known. Others may participate as well. But as far as the secondary bile acids, to date there’s a handful that have been shown, mostly in animal models, to improve the release of GLP-1 from the L cells. Mostly that’s thought to be due to this receptor that I mentioned, this TGR5. L cells have all these different receptors on them to basically sense these microbial products and also nutrients. Certain secondary bile acids are among the ones that they can basically respond to.

Dr. Tom Fabian, PhD: Specifically, there’s one called TDCA, that’s taurodeoxycholic acid. There’s also another one that’s really not well known at this point. There’s actually some interesting research on it and it’s called hyocholic acid. I would imagine most people in our field have not heard of that. Hyocholic acid has also been shown to be one of the factors that can bind to this TGR5 and then stimulate GLP-1 release. They actually found in the study that I mentioned earlier on this lithocholic acid, and it’s link to promoting longevity, they looked at a variety of animal models. In lower animals that they studied, like Drosophila and C. elegans, basically LCA, lithocholic acid, was able to extend lifespan. When they looked at a mammalian model, so in this case a mouse, it didn’t extend lifespan, but it improved what we would consider to be healthy aging, right? So metabolic health.

Dr. Tom Fabian, PhD: They actually found that unlike other GLP-1 agonists, where one of the concerns there, kind of a side effect, is that it may compromise muscle strength or muscle content, whereas the LCA, lithocholic acid, did not seem to have that negative side effect.

Dr. Kara Fitzgerald: So the LCA, in stimulating GLP activation, didn’t have the same associated fallout on muscle that using the drugs does. Yeah. Yeah.

Dr. Tom Fabian, PhD: Exactly. And again, that was in an animal model. So certainly want to see more research about that and how that applies in people. But once again, we know adequate muscle is such a key aspect for metabolic health as we get older and if that’s associated with centenarians, maybe even if they’re not working out, that they’re still able to preserve more muscle mass because they have this particular microbial product.

Dr. Kara Fitzgerald: Yes. That’s interesting and I don’t think that’s so far-fetched. You know, when we look at some of the cool research on the postbiotic Urolithin A and its ability to preserve and even increase muscle mass as a standalone– this postbiotic compound. I mean, we’re in a whole other world of understanding now. It’s not just like, eat your weight in protein and lift heavy stuff. That is, of course, a piece of it. It’s a big piece of it, but all these signal molecules kind of telling the body what to do. I’m just very interested, obviously, in the whole longevity conversation and it’s nice to look at people who are alive now and healthy and explore their metabolome and see what’s going on.

Dr. Tom Fabian, PhD: Yeah, and I think this topic is, again, there’s these sort of cutting edge research studies, but it’s really growing rapidly. And I know I’m going to be working on producing more content a little bit later in the year on that connection between the microbiome and musculoskeletal health, because I think that’s becoming more more recognized as the key piece of healthy aging. Especially muscle health for overall metabolic health.

Dr. Kara Fitzgerald: Yeah, awesome. Well, I hope you include us in sharing some of your content.

Dr. Tom Fabian, PhD: Absolutely. I’d be happy to.

Dr. Kara Fitzgerald: We’ve covered a lot and we’ve talked about therapeutic applications. What else? You always get prepared more than anybody. What else do you want to touch on now? And I’m just reminding people that you can go ahead and access the downloadable information, all the papers that Tom’s been referencing, but you can also get the interpretive guide that will have a discussion on these. And know that this will be an easy-peasy add-on, like a box check for the GI-MAP extremely soon. So what else do we need to know today, Tom, that we didn’t get to?

Dr. Tom Fabian, PhD: I think we covered quite a bit there and really touched on the clinical value of knowing this information and how you put that together with what you see with GI-MAP, for example, to give you a more complete picture. That’s really what I would want to say about this new StoolOMX test and just kind of the bigger picture of focusing more and more on the metabolites that they’re producing. It’s such a key part of the puzzle and there’s so many ins and outs to it that can help you put the pieces together.

Dr. Tom Fabian, PhD: So we’ve of course we just touched the tip of the iceberg here. We did cover a lot, but there’s still a lot more to that story and so through our ongoing educational materials, consults, etc. Practitioners will have plenty of opportunities to learn how to connect the dots with this new information. I think again, short-chain fatty acids, fortunately everybody has kind of a baseline level of knowledge around that. This will really kind of expand it from there.

Dr. Kara Fitzgerald: So much, so much. I can see using it in my real tough refractory gut patients. It’s just kind of a new way of exploring what’s going on and what to do, which we’re in need of, I would say, pretty desperately at this point. But also expanding into the wellness space, into healthspan, healthy aging, etc. So really the continuum, it sounds like we might be able to benefit from these, which I’m sure motivated you to do the hard work on bringing these out.

Dr. Tom Fabian, PhD: Yeah, it’s definitely something I’m really excited about and I’m excited to get a lot of the educational information out there about it because I think it can help a lot of practitioners with a pretty wide range of patient cases.

Dr. Kara Fitzgerald: Cool, well next time we come back we’ll both have some clinical experience and it’ll be fun to talk about it. Alright, well as usual Tom, thanks for joining me on New Frontiers today.

Dr. Tom Fabian, PhD: Thank you so much, Kara. It’s been my pleasure as always.

Dr. Fabian is a leading expert on the role of the microbiome in health, immune function, chronic disease, and aging. As a translational scientist, his primary focus is on the clinical application of microbiome research in the integrative and functional medicine space. He received his PhD in molecular biology from the University of Colorado, Boulder, and has worked as a biomedical researcher in the biotechnology industry, and more recently, as a consultant in the microbiome testing field. Currently, Dr. Fabian serves a consultant and science advisor with Diagnostic Solutions Laboratory, and he is also a Science Advisory Board member with Designs for Health. In addition, he is certified as a Nutrition Therapy Practitioner by the Nutrition Therapy Institute in Denver.

Dr. Fabian’s Email Address: tom.fabian@diagnosticsolutionslab.com

Diagnostic Solutions Laboratory web link: www.diagnosticsolutionslab.com

Diagnostic Solutions Laboratory Phone Number: 877-485-5336

Dr. Tom Fabian, Ph.D., CNTP

Diagnostic Solutions Laboratory

NEW GI-MAP Interpretive Guide with StoolOMX™ Add-on

Study: Bile acids as modulators of gut microbiota composition and function

Study: Bile Acids Signal via TGR5 to Activate Intestinal Stem Cells and Epithelial Regeneration

Study: Lithocholic acid phenocopies anti-ageing effects of calorie restriction

Study: Microbiome-encoded bile acid metabolism modulates colonic transit times

Study: Short-chain fatty acid metabolites propionate and butyrate are unique epigenetic regulatory elements linking diet, metabolism and gene expression

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Novel bile acid biosynthetic pathways are enriched in the microbiome of centenarians

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