When High Protein Backfires in the Gut | Dr. Tom Fabian

It feels like every patient walking into our offices right now is hearing the same message: eat more protein. But maybe the more important question isn’t just how much protein someone is eating, but whether their gut can actually digest and absorb it effectively. Dr. Tom Fabian, science advisor at Diagnostic Solutions Laboratory, joins me again to unpack the emerging science around the gut–muscle axis and what it may mean for our patients. And in a moment when so many people are on GLP-1 medications that suppress appetite and slow digestion, that becomes an especially important clinical consideration. It’s a fascinating shift in how we think about GI function and muscle health. ~DrKF

In this episode of New Frontiers in Functional Medicine, Dr. Kara Fitzgerald speaks with Tom Fabian, PhD, Senior Educator and Research Specialist at Diagnostic Solutions Laboratory, about why higher protein intake doesn’t always translate to better muscle size and performance. While protein is widely recommended to support muscle maintenance with aging, emerging research shows that digestion, microbiome balance, and immune signaling influence how effectively the body can utilize it.

Dr. Fabian explores the emerging science of the gut–muscle axis and how microbiome-derived metabolites and regulatory T cells impact tissue repair and recovery. Clinicians will learn why variability in protein digestion and absorption matters, how gut ecosystem balance may shape muscle health, and when evaluating GI function can help determine whether patients are positioned to benefit from higher protein intake.

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Dr. Kara Fitzgerald: Hi, everybody. Welcome to New Frontiers in Functional Medicine, where we are interviewing the best minds in functional medicine. And of course, today is no exception. I’m welcoming back Dr. Tom Fabian. He is a familiar and trusted voice on this podcast. He’s somebody who consistently helps us translate complex microbiome science into meaningful, actionable clinical strategy. He’s a leading expert on the microbiome, immune function, chronic disease, and aging. He’s got a PhD in molecular biology and decades of experience in translational science. He now serves as the science advisor at Diagnostic Solutions Laboratory.

Dr. Kara Fitzgerald: I’m particularly excited about this conversation of the many great convos I’ve had with Tom because we are talking about the gut-muscle axis in part. This is something that you probably haven’t spent a lot of time thinking about, how gut influences muscle development and maintenance. We’re also talking about protein, the impact of protein on the gastrointestinal microbiome and beyond. Who is a candidate for a carnivore-leaning diet? Who needs to be mindful around that? As always, Tom brings a lot of clarity to the conversation, actionable insights, stuff that we can use tomorrow in clinical practice. I hope you enjoy the conversation.

Dr. Kara Fitzgerald: As always, Tom, it’s awesome to get to learn from you, pick your brain, just hear about the new frameworks that you’re always developing that ultimately serve us as clinicians to deliver better care to our patients. I mean, that’s the end goal here, to be the best clinicians, to be the best informed, to be really taking in as much data as we can and translating it into clinical practice. And I know that that’s your mission and passion as well.

Dr. Kara Fitzgerald: So today we’re going to be talking about protein. Of course, everybody’s obsessed with protein these days. Our patients are coming to us on carnivore diets. Maybe we ourselves are experimenting with very high protein dietary patterns. I just had an awesome conversation with Gabrielle Lyon, and of course, she is on team protein big time, although she doesn’t discount all of that other food information. But we know the information coming from protein, those amino acids, influence the gastrointestinal microbiome and a high protein diet, which can be, I think, really up to a gram per pound body weight is kind of the upper limit. Or if you think in kilograms, 2.2 grams per kilogram body weight is the max where people are generally hitting these days.

Dr. Kara Fitzgerald: So we’re using this a lot, but that kind of protein consumption will be the dominant information on your plate. Fiber will go to the wayside unless you’re really, really careful. Certainly the polyphenol information that I’m extremely bullish on and have researched can be compromised in this kind of a dietary pattern. So we want to be prescribing high protein. We get that it’s important. We want to be prescribing it healthfully and correctly, so talk to me about it. Talk to me about your thoughts on this new high protein, this high-protein era we’re in and how we can do it and individualize it.

Tom Fabian, PhD: Yeah, I definitely think that especially being in the functional medicine field where we’re typically taking kind of that big picture, more holistic view with patients and clients, we definitely want to zoom out beyond just the core recommendations and debates about what might be the most optimal level or range of intake for a given patient. When you zoom out, we definitely know that there are key factors when it comes to digestion and absorption. Particularly with stool testing, and we’re looking at gut health and a lot of different markers, typically. With digestion markers and direct and indirect markers reflecting digestion and the impacts, we’re definitely seeing a lot of patients who do have compromised digestion in one way or another.

Tom Fabian, PhD: So that can be things like hypochlorhydria, that can be issues like digestive enzymes, pancreatic function. Even in the small intestine that can be related to just overall small intestinal health, brush border enzymes, for example. I think that’s a key piece of the puzzle when you’re looking at what is going to work for an individual patient, you definitely want to take a look at that digestion picture.

Dr. Kara Fitzgerald: Can they actually receive this protein and break it down and absorb it, is what you’re saying. And we should establish that.

Tom Fabian, PhD: Yeah, so there’s always been this long-standing assumption that the GI tract is generally really efficient with digesting and absorbing amino acids. The amino acids, of course, are from protein. It turns out that in reality, there are pretty significant individual differences in both the digestive side and the absorptive side. And these days with so many patients and individuals having various GI imbalances and even conditions that can interfere with that process, just to give one example would be H. pylori colonization. We know that H. pylori as a chronic infection can generally interfere with some of the stomach functions when there’s significant inflammation, and one of the key implications or key impacts is on stomach acid.

Tom Fabian, PhD: So long-term H. pylori overgrowth is associated with hypochlorhydria. And when you think about protein, that first step in terms of just the acid levels in the stomach that help to denature the proteins, but also help to activate the enzyme precursor, pepsinogen, into the active form, pepsin, that’s a key step in digestion, of course. So looking at digestion, just think is such a key step and some of the factors that interfere with digestion, which of course we can do with gut testing. And that is how it’s largely been done along with just sort of the overall symptomatic picture for patients in our field.

Tom Fabian, PhD: I do think that is a really big piece of the puzzle: Is it just a matter of increasing your protein intake, which may or may not have the desired effect based on how well you can handle that protein. So as far as like an initial patient workup, I think that’s such an important key component to figuring out do we need to do some work here first to make sure they’re getting the optimal amount from their diet.

Dr. Kara Fitzgerald: Well, first of all, I want to understand that workup. I know we’re going to go into some pattern analysis later on, but since we’re talking about it now, we might as well just cover what we want to look at to confirm that there’s good digestion happening or begin to initiate treatment to support digestion. And I just want to layer into that the data around compromised digestion just being a thing of aging. I don’t accept aging needing to be the cause of all of these things, but we do see a net decrease in elastase in the key pancreatic enzyme as we age. It just continues to drop I see it all the time in my patients, but of course now I’m seeing it in younger and younger individuals. Anyways, so talk about the workup and how we evaluate for it.

Tom Fabian, PhD: On typical gut testings, of course, in this case, we’re focusing primarily on GI MAP as a key example for assessing gut health overall, so typical markers on comprehensive stool tests like GI MAP are the direct digestion markers. Those are going to vary from test to test, but a really important one, obviously, a very well validated marker is elastase, which is a marker for pancreatic enzyme production. So that’s really important, and there’s two ways to look at that. One is if you’re really down into the potentially insufficiency range, which is roughly below about 100 or so on a test, with a cutoff being usually around 200 for being considered low. Below 100 is considered quite low, and they may need a further work up for insufficiency. Usually there’s other symptoms, of course, and signs.

Tom Fabian, PhD: Above that, though, and especially above 200, a lot of the tests such as GI MAP will indicate a range that’s suboptimal, usually somewhat below say 500. Over 500 is generally considered optimal. So that’s certainly one that we want to look at. In terms of digestion, we know even below 500 when it’s not officially low, certainly is part of that picture of what you want to look at. Then I would say beyond that we have indirect indicators of low stomach acid. I just mentioned H. pylori is one example as a common contributor. That is a difficult thing to measure directly. It’s typically not measured directly outside of a gastroenterologist’s office. But we have various ways to kind of get at that picture from symptoms, from signs, certain nutrients deficiencies, and even the microbiome.

Tom Fabian, PhD: That’s certainly where gut testing can be helpful because there are pretty well-defined patterns related to reduced digestion overall. And that would be typically an overgrowth type pattern, both in terms of the commensals—So you’re looking for high levels in general of commensals, especially at the phylum level. One of the common upstream causes of high commensals is reduced digestion and that’s what well established in the research.

Tom Fabian, PhD: Same with some of the opportunists. We do have a defined pattern there as well, particularly with some of those that are kind of in the top of that opportunistic section on page three. That would be Streptococcus, Staphylococcus, Enterococcus, those types of bacteria. Research study after study shows that poor digestion, especially low stomach acid, is a key cause of those being elevated. So we get some hints and we also have some direct markers for digestion in terms of looking at that assessment again in the context of the overall patient.

Dr. Kara Fitzgerald: That’s really useful. That’s kind of an at-a-glance analysis. It makes sense. If there’s all sorts of substrate, if you have all sorts of food going in or if you’ve moved into a high-protein dietary pattern, that’s a lot of substrate for bacteria to act on and thrive on and you’re going to see a dysbiotic pattern, I think, if digestion isn’t adequately breaking them down to their derivative and absorbable bioavailable compounds.

Dr. Kara Fitzgerald: We were talking off record and I just wanted to bring up that this kind of scenario can increase risk for allergies, food sensitivities, et cetera. And there’s research on that actually, just inhibiting stomach acid production and increased incidence of allergies. Or if you already have food allergies, increased intensity. And I would say sensitivities would be in there as well. But then the other thing is the clinical picture that we all know really well: We want people to eat more protein and they can’t because they’re left with a basketball in their stomach. What are your thoughts there?

Tom Fabian, PhD: Exactly. Yeah, so those are really common challenges when patients are trying to optimize their diet. Not even just for protein, but of course for lots of other goals in terms of just improving the health of their diet. I would say those are some of things you just want to consider and address them as you can. That’s where gut health testing can be very helpful. But obviously we know that food reactions are becoming, unfortunately, more and more common over time, probably because of some of these insults to the microbiome. We’re learning more and more about microbiome imbalances that can contribute to that. But also just coming back to the picture of digestion, as you mentioned, there are number of studies showing that poor digestion, in various ways, can increase the risk for food reactions.

Tom Fabian, PhD: When you think of the sources of proteins and especially the sources of antigens, antigens typically that stimulate the immune system are proteins. So that’s again, really illustrating why breaking down those proteins more completely and efficiently so that they no longer have those antigenic properties really can be very important for helping to reduce that potential for reactivity. And then, as always, looking at the bigger picture, microbiome imbalances in other ways that can affect the immune system. The immune system imbalances due to dysbiosis also can increase that risk of food reactions. So that really is a big part of the picture. I’ve seen that lots of times in practice when patients are trying to find sources of protein that they can handle from a digestive standpoint and that they can handle from a food reactivity standpoint to try to meet those goals that they want to reach.

Dr. Kara Fitzgerald: Yes, it’s a big problem. Just thinking about my own clinical experience and when we talk about this in rounds, in trying to move people over to a higher protein diet, especially in an older population, as protein really drops considerably. And I think we have to be very creative on what we can get in. Also to your point, digestion is essential and H. pylori is pretty ubiquitous. Not that it’s a level that would be necessarily profoundly clinically relevant, but I have to wonder whether that background H. pylori isn’t influencing digestion somewhat. What would you say?

Tom Fabian, PhD: There’s certainly good evidence that the chronic infections, when it’s at a high enough level to cause significant gastritis—Now the significant gastritis really would have to be assessed with an upper GI endoscopy because patients don’t always have direct symptoms from the gastritis, but they can have indirect symptoms. So the inflammation, for example, is known to affect parietal cells that are involved in producing stomach acid, so that’s a very common one that we see. If it’s in the lower ranges, it’s detected but lower, it is kind of a clinician judgment scenario. For this patient is that level really causing problems? Or maybe they don’t seem to have any issues with that particular level. So it may not necessarily be something that they feel they need to treat in all cases, particularly when the levels are lower.

Tom Fabian, PhD: The rest of the picture that we see on GI MAP that is validated based on research studies would have to do with this downstream effect of hypochlorhydria. And of course there can be other causes of hypochlorhydria. Even chronic stress, for example, may reduce overall digestion. But the overgrowth often happens with both the commensals—it can kind of throw off the balance downstream of the commensals that are primarily in the colon—and then also the opportunists. Most of those opportunists do start to overgrow in the small intestine and we know that a lot of those opportunists, by definition, can cause some issues, whether they’re participating in stimulating inflammatory responses, et cetera. But I think the biggest issues that are coming to light more recently are actually further downstream in the colon in terms of that protein fermentation scenario.

Dr. Kara Fitzgerald: Well, let’s talk about it. There’s quite a few categories of players that protein maldigestion can result in that can contribute to systemic inflammation. In fact, there’s a phenolic compound that you’re, of course, familiar with. I think it might be indoxyl sulfate that is associated with Parkinson’s?

Tom Fabian, PhD: That’s a good question. I’m not sure. It might be one of the ones. There are quite a few actually that are produced from amino acids. I know that’s one.

Dr. Kara Fitzgerald: There are quite a few. Yeah. Well, let me just say that these are indole-based derivative compounds coming from the aromatic amino acids that are super pro-inflammatory. There’s actually a whole collection of them that are actually really safe, but there’s some that are potently pro-inflammatory and associated with all sorts of mischief. There’s actually a lot of compounds that a dysbiotic gut, when exposed to a whole bunch of protein, can produce that are negative. So can you talk about that? Just give me your thoughts.

Tom Fabian, PhD: Yeah, there’s actually a pretty wide range. So just to kind of back up and take a look at the bigger picture of this idea of protein fermentation phenomenon and protein fermentation. We know that when you get more than the typical amount of protein that gets into the colon, usually it’s a very small amount. But of course, when you have these poor digestion scenarios upstream, that can lead to more protein getting into the colon, but that can also happen with higher protein intake.

Tom Fabian, PhD: Studies vary a bit, and it is going to be individual, but on average, when you get roughly into that two gram per kilogram range—something like that and it is very individual—but once you get above a certain amount, patients are more likely to start getting this excess protein fermentation. And then when you factor in this digestion picture, certainly that can lead to significantly more amounts of protein getting into the colon. And in the colon, it has to do with the balance—which we’ll get to in a minute—between fiber fermentation and then fermentation of these proteins that get into the large intestine. The microbes also produce proteolytic enzymes, proteases, that can break down proteins into amino acids, which they use either for their own growth or they use them to convert them to other metabolites.

Tom Fabian, PhD: That takes me to this list of metabolites, of which the main categories would be branched-chain fatty acids, that of course are made from the branched-chain amino acids. The phenols in general, with one of the biggest known being p-Cresol. You’ve probably heard of that one. That’s known to be mostly an issue for say chronic kidney disease, but may contribute to other issues. It’s been loosely linked to things like autism. I’m sure there may be some other issues there with elevated p-Cresol. A variety of biogenic amines, everything from histamine to something called tyramine, tryptamine, et cetera. Then there are these tryptophan metabolites. I think indoxyl sulfate might be one of those in that category. Those are a little more diverse.

Tom Fabian, PhD: There are some that are actually known to be beneficial in certain contexts and others that may be detrimental, and then there are a range of others. There are sulfur compounds, especially hydrogen sulfide, which has some really interesting information around it; ammonia, which of course can be toxic at high levels, et cetera; and just other nitrogen compounds that may cause some issues. As far as the impacts that are documented go, affecting the immune system and in some cases causing inflammation can be one. One of the most common would be intestinal barrier dysfunction and stimulating increased intestinal permeability.

Tom Fabian, PhD: Some may even function as neurotoxins once they get into circulation. So there may be some level there and they think that might be one of the reasons why it’s linked to some of these gut-brain scenarios such as autism, through this neurotoxin-type scenario. And then again, there’s the hydrogen sulfide, which is really controversial in terms of the research that’s out there. Some showing some really beneficial roles and then some showing some potentially detrimental effects.

Dr. Kara Fitzgerald: It’s very interesting. It’s really interesting. And that’s where the Parkinson thought comes in. I’ll see if I can chase down that specific compound, but it is a tryptophan derivative. But to your point, yeah, there’s good guys and there’s bad guys. It seems to me that it’s pretty clear that in a dysbiotic environment, maldigestion, malabsorption, brush border damage, and a dietary pattern that’s promoting these imbalances. To your earlier point, perhaps there’s a stressful scenario kind of contributing or other untreated issues, maybe hypothyroidism, et cetera, that could influence digestion. The bias would be towards the less helpful, more pro-inflammatory compounds.

Dr. Kara Fitzgerald: That’s my question to you. And just again, wearing my clinician hat, it might be inappropriate for that particular individual, even if they’re sarcopenic, to start on a high protein dietary pattern. We have to clear the hurdle first and get their body able to receive the information. Not that we go protein free, but we’re not going to be doing a gram per pound body weight. What are your thoughts?

Tom Fabian, PhD: Yeah, I definitely think just making sure that they do have these various factors in line or at least knowing the situation. If they have some of these factors that might increase their risk for excessive protein fermentation, and that actually can be assessed with another test that’s an add-on to GI MAP, which I’m sure we’ll get to in a little bit. But to your point, some of the key things upstream, certainly starting with diet. The amount of protein and, to some extent, the type of protein might affect that.

Tom Fabian, PhD: Despite the fact that plant proteins can be more difficult to digest, studies show that there’s usually less protein fermentation when the proteins are coming a little bit more predominantly from plant sources. They debate why that may be the case, it’s not really established, but it could just be the fact that plants have other compounds that can mitigate some of that protein fermentation. So that takes me to the fiber content of diet. The amount of fiber is the best studied and best established—both in animal studies and in human clinical trials—for reducing protein fermentation from a given amount of protein intake.

Tom Fabian, PhD: There are various reasons for that likely. Probably one of the best studied is that in your microbiome in the large intestine, most of those beneficial microbes really thrive on fiber. They don’t really prefer protein as a source, they prefer fiber. So if you give them fiber along with the protein that’s in the diet, they’re going to use the fiber to generate energy and fuel their growth, but they do need amino acids.

Tom Fabian, PhD: They can certainly make a number of amino acids themselves, but also amino acids from the diet can be used to fuel their growth. So essentially a growing microbiome that has plenty of fiber acts like a sponge for these excess amino acids in the large intestine, so they’re less likely to contribute to protein fermentation. And then there are other potential benefits of fiber, including effects on pH that also might reduce protein fermentation.

Tom Fabian, PhD: Polyphenols, as always, really in synergy with fiber. Of course, both those come from plant foods. Once again, studies show repeatedly that higher polyphenol intake can mitigate protein fermentation. So the overall picture of the diet is really important in making sure there’s adequate amounts of fiber. We’re talking really about the fermentable fibers, of course. But having a certain amount of the harder to ferment fibers, like cellulose, for example, just other plant components, that can draw out that fiber fermentation further along the colon and help to reduce that protein fermentation that’s more likely in the latter part of the colon. So it’s also the type of fiber and the variety of fiber that’s being included. So diet, certainly important, and we talked about digestion.

Tom Fabian, PhD: The one other thing we haven’t talked about that’s a big factor that you want to consider when it comes to risk for excessive protein fermentation is simply transit time. Patients who have the slower transit or constipation, that sets the stage for various reasons, for depletion of fiber because there’s just this longer transit time, more time to deplete that carb fermentation, and then an increase in protein fermentation just from slow transit. So when you combine those two, slow transit, and especially if there’s poor digestion, insufficient fiber, but then the higher protein intake, that can set the stage for pretty significant excessive protein fermentation.

Dr. Kara Fitzgerald: I think when our goal is building muscle, and when we’re introducing a higher protein dietary pattern into an individual, we might do that initial workup. I think it’s worth it. Certainly new patients in our practice are going to be getting stool testing and as you know, I’m becoming a fast fan of the StoolOMX test, so we should talk about that in a minute too and why I would be a fan. But just know that we’re going to be able to introduce that potentially radical shift into the best possible environment. And if we need to tweak the environment, which arguably we will, we can do that concurrently. I think we can work on the GI with a 5R protocol and still turn the volume up on protein, although we probably aren’t going to be able to hit the gram per pound body weight at that point. We’re going to have to do some serious cleanup.

Dr. Kara Fitzgerald: And by the way, folks, we may never be able to hit a gram per pound body weight. That just might not be possible in our patients. I mean, I don’t know how many of you have tried it in the audience, but it’s difficult to sustain it. It really is. Gabrielle Lyon recommends hitting 90 grams or maybe opening the day with 50 grams and then closing the day with 50 grams and that’s still good chunk of protein. But I think it’s more doable than the higher amounts. But we might not be able to hit it. And I just want to throw it kind of as a side note that we can look at body metrics, we can do a BIA, or maybe get a DEXA. We can actually evaluate our patients for muscle mass and if they’re actively increasing it, we’re doing something right. They’re hitting decent targets and we don’t need to worry about the numbers that are being bandied about on social media these days.

Dr. Kara Fitzgerald: Are there any of these compounds that really jump out for us to think about? Any of these products of protein fermentation that come to mind in particular? We’ve talked previously about hydrogen sulfide, hydrogen sulfide-associated SIBO and whether or not we need to be quite as concerned about it. Tell me about it and whether there are any other compounds that kind of come to mind for evaluation.

Tom Fabian, PhD: Yeah, I would say definitely hydrogen sulfide has gotten a lot of focus and the SIBO field has a pretty negative image in terms of the potential downsides. There are some downsides that have been documented and certainly we know at sufficiently high levels, it can be toxic overall. In the gut, we actually don’t really know what those levels are though. Those are not well established in terms of levels of hydrogen sulfide that may be toxic. Routinely in a typical healthy gut, we generate hydrogen sulfide both from the microbiome, but even our own cells, the cells that line the gut. Just systemically, our cells can produce hydrogen sulfide and we know that has a number of beneficial effects that we’ve talked about at a high level in a previous podcast from a while back.

Dr. Kara Fitzgerald: And we’ll link to that.

Tom Fabian, PhD: Some of the biggest validation there is that hydrogen sulfide, in numerous studies now, mostly animal studies, of course, to date, seem to show that hydrogen sulfide even increased levels up to a point based on hydrogen sulfide generated from a lot of plant compounds like garlic, ergothioneine, even taurine, may help to promote healthspan and potentially longevity. So for example, higher hydrogen sulfide is linked to the effects of caloric restriction. So we know that there’s well-documented positive effects on antioxidant status and even in terms of promoting muscle health.

Tom Fabian, PhD: So we know that there’s a connection, to a point, of increasing hydrogen sulfide. That takes me to the gut though, where you can have scenarios where this increase in protein intake, which typically includes the sulfur amino acids coming from primarily animal sources. That would be methionine and especially cysteine, so those can be also elevated in the colon. Those are now thought to be the main contributors to excess hydrogen sulfide.

Tom Fabian, PhD: It used to be thought that it was these sulfate-reducing bacteria that actually take the sulfates directly either from sulfated mucus in the colon or from dietary sources. Those do produce hydrogen sulfide, but the levels generally are not thought to be anywhere near what can be generated from these sulfur amino acids by certain bacteria. So that’s thought to be the main concern, and once again, in this slow transit scenario, where you have an increase in protein coming into the colon, that has been shown to be a primary scenario for potentially generating excess hydrogen sulfide. The key there is the production versus your mucosal ability to detoxify it.

Tom Fabian, PhD: Your cells that line the colon, the colonocytes, most of that detoxification happens in the mitochondria. So you want healthy mitochondria, which takes us to butyrate and we know butyrate is a really important factor for mitochondrial energy, but there are also other factors. Just to mention a couple, we know that process of detoxifying sulfur in the gut is enhanced by butyrate, so you want good levels of butyrate producers. But the process requires CoQ10 and glutathione among the other factors. So these are just some other things that you want to check in with on patients that may be a risk for one reason or another if you have insights into whether they may be producing excess hydrogen sulfide.  And that way, you’re dealing with this scenario in a more holistic way, beyond just the amount of protein and fiber in the diet. You’re also looking more specifically at that gut health scenario and the nutrients that are going to support detoxification of the hydrogen sulfide.

Dr. Kara Fitzgerald: It would be interesting for me, again with my clinic hat on, if I’m concerned about a potential hydrogen sulfide SIBO—and I think you’ve argued pretty convincingly that we might be over-diagnosing it—But you could pull somebody off of red meat for a few days, and see how they respond, right? You could just do a quick little N-of-1 trial and see whether they feel better. You know, whether their gas, bloating, basketball sensation resolves, and then that might point to the fact that you need to work on digestion and maybe work on the microbiome. What about TMAO?

Tom Fabian, PhD: Trimethylamine N-oxide (TMAO) certainly has some documented negative effects. It’s been mostly linked to both cardiovascular disease risk and to some extent, I believe also to chronic kidney disease and possibly other conditions. That is another consequence indirectly, usually with a higher protein diet. Of course, most people are consuming higher amounts of meat, in many cases red meat, which is higher in carnitine. Carnitine tends to be one of the key factors that can be converted by certain microbes in the microbiome to TMA, which is then absorbed. So TMA just stands for trimethylamine that’s derived from carnitine. That goes into circulation, gets converted to TMAO in the liver and then that can go back into circulation and then potentially contribute to these issues.

Tom Fabian, PhD: In terms of the microbes that contribute to that, once again, it tends to be these dysbiotic microbes. A lot of that comes down to your balance in microbes. I’d say my own testing is kind of a good example of that. Cardiovascular disease is one of the family risks that I have, so that’s something I monitor. I’ve had my TMAO levels measured and they’re really low, both the actual levels in circulation, but also predicted levels from the microbiome. And it’s likely because I have the profile where I don’t have an overgrowth of those dysbiotic microbes that are known to produce it. So I think that’s one of the factors. It doesn’t mean that you cannot eat those sources or consume those sources, but you want to make sure you’re setting the stage in terms of gut health and the microbiome. And of course I eat a lot of fiber as well to reduce a lot of the negative effects of excess protein.

Dr. Kara Fitzgerald: Right, so a TMAO could be really like a surrogate marker of dysbiosis. It’s just being produced heavily in a more dysbiotic-biased gut. So it’s not necessarily about stopping that protein source because it’s important. Yeah, and it makes me think of choline too. Choline has been associated with TMAO as well. And choline, of course, is incredibly, incredibly important for optimal health. Why don’t you talk about how we would use StoolOMX? How would you think about bile acids in context with this? And then, yeah, go ahead.

Tom Fabian, PhD: Yeah. I think this is a good segue to talk about this add-on to GI MAP. So it’s essentially a metabolomics test where we’re primarily looking at the bigger picture of the short-chain fatty acids, we’re also looking at branched-chain fatty acids, which are considered a marker for protein fermentation, and then we also have a variety of bile acids, which I’ll also talk about. But since a lot of this protein fermentation scenario comes down to the balance of carbohydrate fermentation in the gut versus the protein fermentation, and then the short-chain fatty acids primarily reflect this carbohydrate fermentation, right? So they’re produced primarily by the healthy microbes that are producing these from fiber. And then they have a lot of well-documented beneficial effects, including some anti-inflammatory effects.

Tom Fabian, PhD: And then at the other end of the spectrum, if you have too much protein getting to the colon, you have these conditions that are ripe for more protein fermentation, especially slow transit and also lack of the good guys and lack of fiber. Then you’re much more likely to see an increase in those branched-chain fatty acids. And so the StoolOMX report not only includes the details of each of the individual ones that are measured in absolute quantities, but you also get to see it from this sort of balance indicator, where you’re looking at the short-chain versus the branched-chain ratio. So it’s a really easy metric to look at if it’s on the low end, that’s indicating that short-chain fatty acid production scenario is low relative to the protein fermentation. So in my mind, that’s a really important indicator to look at to gauge where a patient is in that spectrum. And then you know, are they really skewed in terms of not just predicted scenario, but are they actually producing too many of these products of protein fermentation?

Dr. Kara Fitzgerald: Yeah. And as far as correction, what would be the interventions you would think of?

Tom Fabian, PhD: So again, starting with the diet, we have seen this sometimes in patients that seem to be eating a pretty healthy diet overall so that seems like that may not be the scenario. But if it is, then making sure there’s additional fiber added to the diet. I think the variety is really important. So if you’re looking at a patient that’s taking oligosaccharide supplements, a prebiotic like an FOS or GOS, those are good in some ways. They can stimulate beneficial bacteria, but they’re also readily and rapidly fermented. So you’re not going to get this situation where you have that fermentation stretching out all along the large intestine. That’s ideally what you want. So a variety of fiber really, I think, is important there. And then polyphenols. Many, many studies have shown that a variety of polyphenols counteract that.

Tom Fabian, PhD: Again, looking at the digestion and then transit. So transit, especially when it comes to constipation, that’s a whole other topic to discuss because that can be very challenging in some cases to try to address. But those would be really the main things to look at. And then in terms of this overall picture in StoolOMX, we also have the bile acids. And so when you kind of put those together with the short chains, one of the things you want to look at in addition to this protein fermentation scenario is really looking at the balance in terms of how that might affect the immune system. A lot of research shows that good levels of short-chain fatty acids, especially butyrate, can promote regulatory T cells. And the same goes with the bile acids. We know that the production of secondary bile acids by a healthy microbiome also can promote these regulatory T cells.

Tom Fabian, PhD: So an interesting connection, which I’ll just kind of touch on here, is this idea of the concept of the gut-muscle axis.

Dr. Kara Fitzgerald: Yeah, you read my mind.

Tom Fabian, PhD: A number of studies have shown that T reg cells produced in the gut can travel to various sites around the body to promote tissue repair and regeneration and that’s especially been shown in muscle. This really, really interesting study published one of the top journals, Cell, recently showed that Treg cells coming from the gut, and again, those are stimulated by good levels of short-chain fatty acids and secondary bile acids, affect the balance of the immune tone, I think is the term that they use, which is the balance of inflammation and the anti-inflammatory part of the equation. That was really key to optimizing the regeneration, repair, recovery of muscle after stress or injury to the muscle. It’s totally aside from this protein component.

Tom Fabian, PhD: This is another window into how are you optimizing—Muscle health is our main focus here, but that applies to other organs as well. They looked at liver, for example, skin. So that balance, when you’re looking at the balance of short chains and secondary bile acids, that’s a major readout of what’s going on with that gut microbiome, but also you can infer the impact on the immune system, since that’s been established in the research. And then if that balance is off, that may be one of the factors inhibiting the benefits you’re getting from a certain amount of protein in the diet.

Dr. Kara Fitzgerald: There’s a lot more going on than just the one-to-one relationship of protein equals more muscle, protein equals more muscle. Yeah, there’s more information that the body can lean on. So the secondary bile acids are coming from a good microbiome being able to produce them, and that microbiome is being stoked by fiber and polyphenols, and the dietary pattern beyond protein. Is that correct?

Tom Fabian, PhD: Yeah, I mean, we’re talking about a lot of science here and some complicated pathways, but it really does come down, kind of simplistically, to what does the diet look like? Do you have a good balance between the protein and the fiber and polyphenols? Do you have evidence from testing that you’re actually achieving a balance, which I think is really important to know. Is this diet actually working in this person and do we need to tweak it somehow? And then in between is that digestion-absorption component, which we can also look at.

Dr. Kara Fitzgerald: Yes, and the end result—Is muscle mass improving? Is there appropriate strength training and all of the other essential tools for doing this key longevity intervention. Any cases come to mind? You’ve had a better opportunity than probably all of us looking at GI MAP combined with the StoolOMX, looking at bile acids. Insights that you can share with us? Common scenarios?

Tom Fabian, PhD: Yeah, I would say I just happened to have a couple cases that came across. We do these 30-minute consults to look at individual cases and we’re talking with practitioners about their patients. I had a couple cases, both individuals in their 60s and kind of representing two different ends of the spectrum. So I’ll start with the woman who unfortunately had a long history of inflammatory bowel disease. It was off and on and well controlled, but she’d had a recent bout where it flared up for no obvious reason that they could really come up with. That’s one of the reasons they decided to run GI MAP plus StoolOMX to take a deeper look.

Tom Fabian, PhD: Long story short, I mean, there’s a lot to this case, but the bottom line is we did see the classic imbalance that you’d see in a flare of IBD with lack of the good guys, especially low butyrate producers, low Akkermansia, and an especially significant overgrowth of many of the inflammatory species. And then in terms of the StoolOMX, we did see that the short-chain fatty acids were definitely out of balance with really low butyrate compared to the other products. Protein fermentation in that case wasn’t as bad as we would think it is, but it was definitely higher than optimal relative to those short-chain fatty acids.

Tom Fabian, PhD: This patient had unusually low butyrate. One of the other telling features, though, was when we looked at the bile acid. Now that we have this add-on that’s looking at the primaries and the secondaries, we could see that this patient had an excess of the primaries, deficiency of the secondaries, so she wasn’t really converting, and then a high total. That picture is really characteristic of what’s called bile acid malabsorption, and recent studies show that that further fuels this dysbiosis. It becomes a vicious cycle. So the key there, of course, is to continue to work on managing the disease and the flare, but from a gut standpoint, looking at ways to try to get the short-chain fatty acids and butyrate increased and then managing that bile scenario, for example. So often, practitioners will use things like bile acid binders, et cetera,  and then they’ll look upstream when we know there is a poor digestion part of that picture, et cetera.

Tom Fabian, PhD: The other scenario was a very healthy individual in his 60s who was just kind of looking for optimal longevity-type scenario. The only imbalance that we really saw that stuck out was a bit of a decrease in digestion which, as you noted, is one of the common features of aging to have, although it’s variable. At some point, some of the digestive capacities can start to decline and patients may just need a little bit more support there. But when we looked at the microbiome it was generally well balanced. We looked at the products, short-chains, and it was textbook. Everything just looked like it was right in middle of where it’s supposed to be and then the same with the bile acids.

Tom Fabian, PhD: So in that case, if this individual wanted to increase their protein, for example, certainly addressing the digestion picture might be helpful. But at that point in time, we’re not seeing any evidence of excessive protein fermentation or deficient secondary bile acids or short chains. So this looked to be a case where this patient probably metabolically-gut health-microbiome-wise could easily handle additional protein with a little bit of digestive support.

Dr. Kara Fitzgerald: That’s awesome. And conversely, you can identify the gut that’s going to be vulnerable, that could produce some of those downstream toxic pro-inflammatory metabolites unless we do that underlying work. I have seen some of those in my own patients with IBD. What about the carnivore diet? I’m just curious if you’ve seen people who are really leaning into high protein without a lot of additional nutrient information. Any interesting patterns kind of like what we’ve been talking about?

Tom Fabian, PhD: I haven’t seen anything for a while. Since StoolOMX was introduced last year I have not personally had any cases so I can’t really comment on that from a StoolOMX, bile acid, short-chain fatty acid standpoint. Based on the ones I did see previously, there was definitely a general trend, and I think this is probably a total of maybe four or five individuals, tops. So not a big sample size, but we definitely did see a general trend towards a pretty big increase in the opportunists overall. And these are individuals that symptomatically felt okay. That was the reason why they went on the carnivore diet because it was helping to improve some of their GI symptoms.

Tom Fabian, PhD: Commensals really did not look good, so it seemed to be throwing off—I mean, in some cases we didn’t have a before and after, so we didn’t know what did this look like before. But at least in the context of a carnivore diet, it did not look like they had a very healthy balance of microbes. Generally the thought is that if they do well by cutting out plant sources of carbohydrates, maybe they just have carbohydrate intolerance and that’s a separate thing that should be addressed so that they can start to handle at least some level of fermentable carbohydrates.

Dr. Kara Fitzgerald: Yeah. I like couching food as information. To me, it’s meaningful that our body needs that collection of complex information to run the show. For sure. And I think it’s been has been observed that a long-term carnivore dietary pattern can definitely lead to some some fallout.

Dr. Kara Fitzgerald: What about GLP-1? I’ve seen GLP use lead to poor dietary pattern because there’s no appetite and the foods that are chosen are just easily digested, ultra-processed stuff and so we can see fallout with that. But we, in functional medicine, want our patients using GLP at whatever dose to consume sufficient protein to maintain muscle mass and that is obviously hard because GLP is kicking in satiety, but it’s also slowing down gastric emptying, et cetera. It would seem to me that this would be another just really smart check-in tool once in a while, because that population could be super vulnerable to some of those negative metabolites, the dysbiotic pattern that we’re talking about here.

Tom Fabian, PhD: Yeah, and I think one of the best established effects of the GLP-1 drugs is on overall motility. It’s certainly best documented more for the upper GI, but there is evidence that it can also slow transit all the way through the small intestine and the colon, which is one of the factors that can set the stage. Plus if they just don’t have much of an appetite, which is kind of the point of those drugs is to reduce appetite, as you note, in some cases they may not be not selecting the healthier choices with fiber and polyphenols and that can compound the problem.

Tom Fabian, PhD: To my knowledge, what we don’t really have a great handle on yet is the effects of the drugs on the microbiome. I’ve heard some things more anecdotally from other clinicians that it seems like it does have a negative effect in some cases. I’m still waiting to see what the consensus is about effects on the microbiome and does it shift the microbiome more towards something that might make protein fermentation more likely. But in the meantime, certainly checking in with StoolOMX and seeing what’s going on there, once they’re on it, is it shifting things in a bad direction in terms of increased protein fermentation?

Tom Fabian, PhD: But at the same time, I think it’s important, especially for those who may not want to be on the drugs long-term, we know that short chains and secondary bile acids stimulate the GLP-1 receptor. So they could potentially help to compensate a bit. And if they’re optimizing things on that end and getting good short chains, especially butyrate and secondary bile acids, there are certain ones that are better known to stimulate GLP-1 and we do have some of those on StoolOMX. Those would be great ways to check in to see if they have the signature suggesting that they will be more likely to produce their own, or stimulate their own GLP-1 more effectively through the microbiome.

Dr. Kara Fitzgerald: Right, right. And if they don’t, if they don’t have that healthy pattern, what are we going to do to shift things towards that so they can successfully taper their GLP? Or as a piece of what we would do, I should say.

Tom Fabian, PhD: Yeah, there’s a number of things. In addition to the ones that we talked about in terms of diet, balance, digestion, and motility, there are some specific things to consider beyond that. Nowadays, we’re looking at this picture that’s generally referred to as postbiotics, although there’s a formal definition of that that’s a little more restrictive. So we can refer to them as just the microbiome products that are available for clinicians to make use of in their practice. Butyrate is probably the top one so if you have a scenario where patients may need some additional assistance there, butyrate supplementation may be helpful. There are other post-biotics like Urolithin A that can also help shift things in a good direction.

Tom Fabian, PhD: We talked about hydrogen sulfide as another aspect that can help promote that gut muscle aspect. Some of the best evidence is for these plant-sourced sulfur compounds, so ergothionine would be one that we have some research. Also various garlic extracts and cruciferous vegetable extracts. One in particular, I don’t know if you’ve heard of it, it’s actually mostly from arugula and it’s called erucin. And then, of course, bile acid. Right now I would say the only individual product that’s relatively widely available is TUDCA, or  tauroursodeoxycholic acid, which has a lot of data showing it may be helpful in a number of ways. So there are some specific products, I think, that may also help to either compensate or correct for that situation to some extent.

Dr. Kara Fitzgerald: Awesome. Well, this was a tour de force as usual of really interesting, useful work. As always folks, we will corral together the many references that Dr. Fabian sent over and we’ll put those on the show notes. The whole transcript will be on the show notes. A summary will be on the show notes. I know this was very clinically actionable. I think this has probably prompted a lot of aha moments for doctors listening and clinicians using stool testing and just how to best support our patients in this era of high protein dietary patterns.

Dr. Kara Fitzgerald: And I hope, folks, that you also found the conversation around bile acids and secondary bile acids useful. We will link in the show notes to the other conversations that I’ve had with Tom over the years. We have talked about secondary bile acids. They’re incredibly interesting from the longevity lens and we’ve got a whole conversation on that that we’ll link to. There’s a good reason for those of you thinking about longevity medicine or practicing longevity medicine that we want to be paying attention.

Dr. Kara Fitzgerald: Thanks again for joining me today, Tom, as always.

Tom Fabian, PhD: All right, thanks so much, Kara. Enjoyed the conversation as always.

Dr. Kara Fitzgerald: I hope you enjoyed the conversation I had today with Tom Fabian. Always, always an interesting guy to talk to, actively translating the science more intensely, more rigorously than almost anybody I know. I appreciate that he brings a new lens to topics that we’re familiar with. In this case, we talked about the gut-muscle axis. We looked carefully at the influence of protein on the gastrointestinal microbiome. It’s not always what we think and it’s not a one-size-fits-all. We can’t march everybody onto a very high protein diet and expect a good outcome.

Dr. Kara Fitzgerald: For those of our patients who we want on a high protein diet and they’re not tolerating it, what do we need to be paying attention to to enable it? What do we need to be looking at with regard to digestive function, absorption, et cetera, et cetera. So I hope this conversation sparked some interesting ideas, some shifts that you’ll bring into the clinic and I’d love to hear from you. This community is such an important part of what keeps this work going, what keeps it evolving, and what keeps it interesting.

Dr. Kara Fitzgerald: Don’t forget to check our show notes. They are packed with citations, you can get the full transcript, you’ll get links, et cetera, and all of this is free. We’ll see you next time on New Frontiers in Functional Medicine.

Tom Fabian, PhD, CNTP is a leading expert on the role of the microbiome in health, immune function, chronic disease, and aging. His primary focus is on the clinical application of research in the microbiome and mucosal immunology fields in integrative and functional medicine. After receiving his PhD in molecular biology from the University of Colorado, Boulder, he conducted aging-related research in the biotechnology industry. More recently, he has served as a consultant in the microbiome testing field. Currently, Dr. Fabian serves as a translational science consultant and science advisor with Diagnostic Solutions Laboratory, and is a Science Advisory Board member with Designs for Health.

GI-MAP Interpretive Guide

StoolOMX Reference Guide

Journal Articles Mentioned

Lithocholic acid phenocopies anti-ageing effects of calorie restriction

The gut microbiota promotes distal tissue regeneration via RORg+ regulatory T cell emissaries

Role and Mechanism of Short-Chain Fatty Acids in Skeletal Muscle Homeostasis and Exercise Performance

The histone deacetylase inhibitor butyrate improves metabolism and reduces muscle atrophy during aging

Association of Gut Microbiome with Muscle Mass, Muscle Strength, and Muscle Performance in Older Adults: A Systematic Review

Aberrant bowel movement frequencies coincide with increased microbe-derived blood metabolites associated with reduced organ function

Interference of dietary polyphenols with potentially toxic amino acid metabolites derived from the colonic microbiota

The fate of dietary protein in the gastrointestinal tract and implications for colonic disease

The Role of Gut Microbiota and Leaky Gut in the Pathogenesis of Food Allergy

The Role of Short-Chain Fatty Acids and Bile Acids in Intestinal and Liver Function, Inflammation, and Carcinogenesis

Regulation of short-chain fatty acids in the immune system

Research on Hydrogen Sulfide

Bismuth subsalicylate profoundly alters gut microbiome and immunity with increased susceptibility to infection (Preprint)

Differential hydrogen sulfide production by a human cohort in response to animal- and plant-based diet interventions

Enhanced non-enzymatic H2S generation extends lifespan and healthspan in male mice

People Mentioned

Gabrielle Lyon

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

Podcast: The Bile Acid Imbalance Accelerating Aging: How to Detect & Fix It

Bio Age Self Assessment Quiz

Younger You book

Better Broths and Healing Tonics book