Measuring Metabolites of Dysbiosis and Gut Function to Create Targeted Interventions

As we gain insight into the microbiome’s impact on our health, we need accurate tests that tell us not only what and how much is there, but also which metabolites or post-biotics can have downstream effects. So today I’m thrilled to welcome the brilliant Dr. Erika Ebbel Angle from Ixcela to discuss their fingerstick metabolomic testing that can do just that. We’ll discuss key markers, the value of a blood sample over urine, and the impact of endurance sports and chronic stress on health markers as revealed by the test.

And we also chat about my own results, how impressed I was by the insight provided – and how they clearly identified changes I could make to improve my markers. Listen and take notes — I know I did! ~DrKF

The importance of a balanced microbiome and healthy gut function cannot be overstated when it comes to our overall health. Having accurate tools to measure the factors that lead to dysfunction is the key to better protocols and outcomes.

In today’s episode of New Frontiers, Dr. Erika Angle, PhD, biochemist, CEO, and co-founder of Ixcela, joins us to discuss their fingerstick gut microbiome test. We dive into the 11 key metabolites they test to evaluate the microbiome, digestion, and absorption. She’ll also explore the downstream effects of high and low markers on inflammation, disease progression, dysbiosis, sleep, emotional balance, energy production, overall health, and common changes seen in high-physical and -mental performers.

In this episode of New Frontiers, learn about:

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 thrilled to be talking with the brilliant Dr. Erika Angle. I’m going to give you her background and we are going to jump right in. She is CEO and co-founder of Ixcela, the internal fitness company. She received her PhD in biochemistry in 2012 from Boston University School of Medicine, and she holds a BS in chemistry from MIT. Erika is also the Founder and Executive Director of Science from Scientists, an award-winning national nonprofit that sends charismatic scientists into the classroom to improve the attitudes and aptitudes of three to eighth grade students in science, technology, engineering, and math. The STEM for you.

In 2018, she was awarded the Young Alumni Award from Boston University. In 2017, she received the Distinguished Alumni Award from Boston University School of Medicine. And in 2014, the Boston Business Journal selected Erika as one of the top 40 under 40. In 2013, the Boston Chamber of Commerce selected her as one of the 10 outstanding young leaders in Boston. Erika, welcome to New Frontiers.

Dr. Erika Ebbel Angle: Thank you so much for having me.

Dr. Kara Fitzgerald: Yeah. It’s been nice getting to know you as a human, but just also getting to know what your lab is all about. And it’s cool that you’re in my neck of the woods here on the northeast. Your lab does metabolomics, and you and I have dialogued a little bit about me coming from functional medicine and having a background in what I call, almost like the pre-metabolomics era or the pre-omics era where we were and still are really looking at organic acids and using some of the tools that you have taken along with your co-founder, Wayne Matson. You’ve refined, you’re putting some more solid science behind them and you’re making metabolomics available to us. So that’s going to be the heart of our conversation. And I want to know how Ixcela started, how you got on this journey?

Dr. Erika Ebbel Angle: Absolutely. So the company at this point is about 11 years old, so formerly incorporated in late 2012, early 2013. But the science itself that underpins what we do dates back significantly further. So my co-founder Wayne Matson, he’s in his early 80s right now, and this has been his career, his life. He’s been doing this. He can tell stories back in the days when he was working with Jeff Bland, and he would joke that back in those days they would measure lots of these small molecule metabolites in, whether it’s blood or urine or any_ And you couldn’t get funding from the NIH by saying, “We’re measuring lots of stuff.” So they ended up calling it metabolomics. So I think he is considered to be one of the pioneers, the fathers in this field of metabolomics. So yes, we’re metabolomicists by training. Throughout the course of his, now probably 50 years in the industry, we’ve looked at many, many different health and wellness states.

So everything, from the neurodegenerative diseases, Alzheimer’s, Parkinson’s, Huntington’s, pick one. Various cancers, GI issues, autoimmune conditions, concussions in athletes. I mean, it spans the gamut. And typically what happens is we do what we call shotgun metabolomics. So we look at all of the different small molecules that are present in a sample. And we try to compare what is different in a person who either has that condition to a normal control. Or if you’re at risk for that disease, what does that look like against a normal control? And what you find in using the platform that we use, which is electrochemistry, which is actually, it was invented by Wayne at his previous company, which he then sold. Now Thermo Fisher Scientific actually owns the tech. But using that platform, we were able to look at thousands of different molecules and say, “All right. What is different biochemically in a person who is either at risk or has this particular condition?”

And then, drug companies do this all the time to try to figure out, “Well, what am I targeting in order to try to help solve this?” So 50 years of getting all this data, I met Wayne serendipitously at sort of in between my undergrad and grad career life. And what was really compelling was that both of us are interested in helping people who are uncomfortable, haven’t been able to find the root cause of their very symptoms and pain points, and how do we improve quality of life by giving people more information that is actionable. So we said, “All right. We’re going to do this. We’re going to start a business that takes a small volume of blood and that looks at certain molecules based on Wayne’s studies that have been shown repeatedly time and time again to be risk factors, disease progression markers, overall markers of general health and wellness.”

And when we stood back and said, “All right. Well, what kind of company are we going to become?” These markers, of which 11 are those that we are currently measuring were related to the gut microbiome, they were all either generated specifically by certain bacteria in the gut, regulated by the gut, or were a phenomenon based on how much was your gut able to digest, absorb, and then ultimately spit out right into the circulatory system.

Dr. Kara Fitzgerald: I’m going to just ask you, and then just cut right back in. So you didn’t intentionally set out to be focused on the gut, but those analytes that were just most relevant in Wayne and your research turned out to be gut associated either directly or a little bit less directly.

Dr. Erika Ebbel Angle: Correct. And I think that’s actually a very important part of the story because I think people sometimes, “Well, how did you decide this?” Well, there’s money here or there’s funding there or whatever. And people develop their business model around a different set of criteria. For us, it really was about which metabolites are the most significant across 50 years of research. And then, gee, how cool, where do they come from? They are related to the gut microbiome. So we are a gut microbiome company because the science pointed to that.

Dr. Kara Fitzgerald: Yeah. It’s so fascinating to me. I guess we should just talk about those, talk about the 11 analytes that you’re measuring and maybe a little bit of information around them, and then how you’re looking at them as a whole. And then, folks, we’ll jump into my own analysis, which was super fun and interesting. And by the way, you guys on our show notes page we’ll link to the science, to the papers that Erika thinks is most relevant for us to check out and their website and so forth. So let’s talk about these analytes, these amazing 11.

Dr. Erika Ebbel Angle: Sure. So they sort of high level, they are in the tryptophan, tyrosine and purine pathways. And tryptophan is a very central one because it’s, well, it’s at the center of everything in many ways. So we look at tryptophan, a variety of different indoles. So indole-3-propionic acid, indole lactic acid, indole acetic acid. The indoles are very important to looking at the health and diversity of the gut microbiome. So for example, IPA is very important to intestinal permeability. So if you have low levels of IPA, you might have greater issues with leaky gut or intestinal permeability, whatever, indole lactic acid is actually a precursor.

Dr. Kara Fitzgerald: Let me just restate that. So IPA, that’s indole propionic acid. Low levels are a problem. This is a metabolite from tryptophan. Bacterial action on tryptophan converts it to IPA. All of these convert it. Okay. And before you jump into the next indole. Tryptophan is at the center you said, you said that provocatively and then jumped in like we all knew. I mean, and that’s because why? Why? Just because it’s such a fundamental amino acid and so many pathways and mechanisms and so forth, like proteins?

Dr. Erika Ebbel Angle: Yeah. Yes. So I mean, first of all, it comes from your diet, which is very important. You have to get it from your diet. And the microorganisms in the gut will take in tryptophan and convert it to, there are many different pathways. So if you like to geek out, you can go on the KEGG PATHWAY site and type in tryptophan and you’ll see tryptophan and a thousand other things coming off of it. So it’s regulated in different ways depending on what the body needs or doesn’t need, right? Pathways go in different directions, but it is very central to everything from the brain gut connection and serotonin, which is derived from tryptophan, which melatonin is then derived. So your sleep, your emotional wellbeing, your emotional health to gut permeability with the indoles to inflammation markers and excretion of those inflammation markers. And so tryptophan is a very, very key and central marker to all of these different things. So I always start there.

Dr. Kara Fitzgerald: Yeah. I get it. And not just gut, but well, as you said brain, like pro-inflammatory and protective in the anti-inflammatory. Okay. Okay. Keep going.

Dr. Erika Ebbel Angle: Right. And tryptophan is converted to indole, indole if it’s goes down the wrong path is actually inflammatory, which is our conversation earlier about indican and what that means if the levels are too high or too low. So again, it’s very interesting that it sits in the middle there of a very important role. So you’ve got tryptophan, you’ve got the indoles, so indole propionic acid, IPA, indole lactic acid, ILA, and IAA, indole acetic acid. So IPA, like we mentioned is a gut permeability marker. It’s also one of the most powerful antioxidants in the body, and it is generated by bacteria, very specific species, Clostridium sporogenes. Sadly, when the body is under stress or when there’s a dysbiosis, often that’s the species that tends to be influenced right up front. So people who live stressful lives, who have poor diets, all these different things, they’re Clostridium sporogenes tend to take a hit on that, which is bad because their IPA levels tend to be low. IPA low means intestinal permeability, means all the lousy things that come with it.

Dr. Kara Fitzgerald: All the downstream with IP, with permeability. Yeah.

Dr. Erika Ebbel Angle: That’s allergies and sensitivities and inflammation.

Dr. Kara Fitzgerald: Sure. Autoimmunity. Yeah. The whole gamut.

Dr. Erika Ebbel Angle: The whole gamut.

Dr. Kara Fitzgerald: Like, what isn’t? Yeah.

Dr. Erika Ebbel Angle: Right. So ILA, indole lactic acid is actually a precursor to indole propionic acid. You find it in foods like fermented foods, so kimchi, pickles, et cetera. It actually is the fuel that fuels the generation of IPA. So the bacteria will take in ILA and convert it to IPA. So it’s the precursor. It is important to have enough of that in the system in order to keep everything going as it should. IAA, indole acetic-

Dr. Kara Fitzgerald: Let me ask you a question. I’m sorry. I want to apologize. I know this is super interesting. So it’s a marker of a need for fermented foods, and then bacteria act on it and convert it to the really important IPA. Is it or can bacteria in our gut actually take tryptophan itself and convert it to indole lactic-

Dr. Erika Ebbel Angle: Yeah.

Dr. Kara Fitzgerald: Okay.

Dr. Erika Ebbel Angle: Yeah. So this is where the [kinetics]. It gets really tricky, right? So if you were trying to create a supplement for IPA, and we’ve toyed with this, which is like, it’s a weird thought, “What would you give to the body?” Right? Would you just give IPA? Probably not, because that would cross compete with your bacteria’s creation of it. You’d have to give them some of the precursors instead. So you would give them ILA predominantly, but if you give them too much ILA, then again the body will stop generating its own IPA. So unfortunately, none of this is like do X, Y happens. There are all these different mechanisms and ways that things fuel the system. But ILA is a direct, they take ILA and they convert it to IPA. So otherwise you have to generate ILA, which is harder than doing it the other way by eating food directly.

Dr. Kara Fitzgerald: Okay. Okay. Okay. So you can take together and you can just infer whole foods diet, compliment of fermented, adequate tryptophan, et cetera, et cetera. And I know you’re very diet forward and the complex interactions would be a piece of that.

Dr. Erika Ebbel Angle: Very much so. We try to do everything, we call it the food first approach. Right. So those two are connected and they tell a story. So if one is too high and one is too low, then maybe you’re getting enough in your diet, but you don’t have the right bacteria to convert the ILA into the IPA. So then, you have a dysbiosis, you have to help the Clostridium sporogenes to come back, or if you don’t have enough ILA, or maybe both are low, maybe you don’t have enough of the precursor. So you can help that process with the right types of foods and maybe that’ll kickstart it.

So again, together they tell a little bit of a story as to where you should begin with a client. IAA is kind of a cousin, it’s not directly in the same line, but it’s often secreted by more invasive species in the gut. And so again, if you have really high and elevated levels of IAA, there’s a question of, yes, you probably have a gut dysbiosis and we need to do something here to help to restore the right types of bacteria in the gut. So that’s what that one sort of tells us.

Dr. Kara Fitzgerald: All right. Let’s keep going. I mean, again, it’s interesting. By the way, folks, you can link to the website, in fact, you may want to do that while we’re talking and pull up the cheat sheet of all of these compounds, and then there’s a nice dropdown discussion of each of them and really plain language. And so you can get a sense of it. Okay. Keep going.

Dr. Erika Ebbel Angle: So then we have serotonin. I think this is one of the ones that everybody has heard about. 90% of  peripheral serotonin is secreted by cells in the gut. So again, typically people think serotonin brain health, it must be the brain. But in reality, serotonin, a lot of it is actually produced in the gut. It’s responsible for intestinal motility, again, things that people don’t know. So if you have low levels of serotonin, you might be chronically constipated. We see that a lot in folks. There’s, of course, the connection with the brain and the gut, and low levels of serotonin leading to anxiety, depression, all of these mental health related symptoms. But serotonin is really interesting. It plays all kinds of roles in the body. And I think that the motility issue is actually very, very important. Most people do not understand that is one of its predominant functions.

Dr. Kara Fitzgerald: And there’s a sweet spot for serotonin, and that’s what you want to achieve?

Dr. Erika Ebbel Angle: Right. If it’s too little, you have the mental health repercussions, constipation. If you have too much, you have a different feeling, not very good either. And both emotionally, but also there’s this other sensation plus other issues with your gut.

Dr. Kara Fitzgerald: A rapid transit I would imagine the feeling.

Dr. Erika Ebbel Angle: Rapid feeling. That’s right.

Dr. Kara Fitzgerald: Yeah. Okay. Keep going.

Dr. Erika Ebbel Angle: Tyrosine is another amino acid. You do get it from your diet. Your body also can make it so it’s not only dietary, the body can convert it from other amino acids. But very important because it’s the beginning of many of the neurotransmitters, dopamine, adrenaline, epinephrine, these all come from tyrosine. So again, we often see people who have low levels of tyrosine just having like a sluggish, I’m tired all the time, I don’t have energy, I don’t have any, the initiative-oriented behavior we call it. People are just feeling blah. So important. But does, again, comes from diet as well as being able to be synthesized from other things. So your body does try, but not tryptophan, which you have to consume it.

And then we have the purines. So you’ve got xanthine, 3-methylxanthine and uric acid, and all very, very interesting because if they’re too high, there’s a problem. If they’re too low, there’s a problem. There is a sweet spot for all of these. But they’re inflammatory markers, right? So folks have heard of uric acid typically because of gout. If your levels are too high, there’s an inflammatory response. So you want to try to keep it obviously within range. Xanthine is actually very, very interesting in that it is, what we have seen is it’s an inflammatory marker. So people under physical, emotional stress, you typically see this elevated. Why? Because in the conversion process where ADP is actually converted to ATP, if your body is doing that and it’s almost happening too quickly for you to be able to keep up with it, the fallout product is xanthine. So as levels of xanthine accumulate, levels are really, really high it means that you’re spinning your wheels too much. So we see this a lot in performance athletes that are like runners, cyclers, triathletes, swimmers, people doing endurance sports.

We see this in people with high stress jobs, who are just constantly thinking. Your body thinks you’re running that marathon even though you might not be, which I always thought was so fascinating.

Three MX is in that pathway. It is also a caffeine metabolite. 3-MX is 3-methylxanthine. We can ask that question because sometimes people will say, “Well, is it because I consume caffeine that I’m having these sensations and feelings?” And we can get a sense about that based on the levels of 3-MX. So if 3-MX is fine, typically we say, “Nope. I don’t think it’s unfortunately you don’t feel this way because of your caffeine.” Sometimes it is, sometimes it is elevated. But again, everybody has a different tolerance for that. So it’s a useful molecule to have in order to be able to rule out what could be contributing to some of these sensations that people have.

The IDS or total indoxyl sulfate also known as indican, as we’ve chatted before about it is very interesting. So it’s tryptophan. Its tryptophan is converted into indole, indole is then converted into, it’s sulphonated before it’s excreted. So the liver does that and it’s excreted. We do consider it at high levels to be a kidney and liver damage marker. So again, high stress, we see this a lot in our bodybuilders actually for whatever reason, probably because they’re taking in a lot of protein. So often it’s just an indicator that there’s too much protein in the diet. So if you’re a lot of shakes that you’re taking in and just too much protein, total indoxyl sulfate will be elevated. Also, if you’re not drinking enough water and you’re not properly hydrated, because typically if you’re drinking enough water, you’re flushing it out. There are studies that are talking about it as an inflammatory marker. So people who have high levels of IDS are looked at for different types of coronary inflammation, obviously gut inflammation, joint inflammation. So there is a connection with that.

Dr. Kara Fitzgerald: I want to just underscore that. I mean, I think it’s cool that you’re taking what was an old school analyte that while we were looking, we’ve been looking at it forever in organic acids. But even before labs were measuring it, it was I think old school, like nature cure doctors could do some basic colometric assay in their offices and see if indican was around. So I think it’s neat to have it really so so so validated. And I was on PubChem today reading about it. It increases reactive oxygen species. It’s associated with really spending glutathione, our incredibly essential endogenous antioxidant, like mother antioxidant. So to your point, I think it’s a very valuable marker. And then you and I were talking about earlier offline about the newer research looking at gut brain- So indican being associated with Parkinson’s disease, I think primarily Parkinson’s disease, but maybe other neurodegenerative conditions as well. But it’s this marker that’s just demonstrating an association in a broad variety of really clinically relevant problems, even osteoporosis. It’s suppressing osteoblast activity, I thought that was super fascinating.

Dr. Erika Ebbel Angle: It’s funny that you say that, because I actually made a list for myself of all the different studies and things pertaining to it. Because I knew we had talked about it and it was fascinating, but I mean, literally it’s like coronary artery disease, calcification, modification of the… High levels of it circle back and modify the microbiome in a negative way. So there’s like a connection to the gut to bone health, to inflammation, to heart health, I mean it was-

Dr. Kara Fitzgerald: Across the board. So I guess my question would be, and I don’t know that you know the answer, but just rhetorically wondering. With excess protein intake and an increased gastrointestinal production of this compound, is it a problem? I mean, do we want to drop our protein down to keep this one in line, or maybe toggle our protein, or just pay attention to see if we have the microbiome to produce this? Because I know there’s an argument for ingesting high protein and it’s essential for muscle mass, it’s essential for longevity, et cetera. But there’s that balance.

Dr. Erika Ebbel Angle: This is going to sound so cliche, but this is why everything is a balance, right? Because if you don’t get enough then you don’t build the building blocks and you don’t have the pieces that you need. If you take too much, then the body doesn’t know what to do with it and converts it in weird ways and has to excrete it, and it puts pressure on the organs that do that. So again, we get asked, “Who should take this test?” I mean, at the end of the day, these are things that everybody should do. Because you can select groups who would benefit for specific reasons and causes. But in many ways, molecules like this, I think they should be on a panel that people just run to say, Okay. Where are we at with our dietary-

Dr. Kara Fitzgerald: Yeah. An annual evaluation.

Dr. Erika Ebbel Angle: Yeah. Because it makes sense.

Dr. Kara Fitzgerald: Yeah. Or semi-annual. Yeah. And I mean, When we were looking at mine, there was evidence, it was funny, your nutritionist was able to see that I’m not resting and digesting sufficiently. So some of my tryptophan was actually being… My indican is a little bit higher than optimal than where it should be. Actually most of my markers, I’m happy to say were in fabulous range, but we could see that I was not sufficiently resting and digesting. And that was probably the reason tryptophan was getting converted downstream into indican, and it’s fascinating. My fix could be some digestive enzyme support, but really more importantly, I was confessing to both of you guys on that call that I had stood there in the kitchen eating a steak the day before I took the test, or something like that.

I didn’t sit. But there’s a lot of information one can infer, maybe I need some enzymes, maybe I need to rest and digest. Maybe somebody else is just really in an inflammatory burden and has a certain kind of dysbiosis. But you can really sort of interplay, you can look at the pattern of metabolites and draw some conclusions. And in the case for me it was really accurate. It was somewhat irritatingly accurate actually. I was like, “Yeah. Yeah.”

Dr. Erika Ebbel Angle: That’s weird. It’s weird. We get that a lot, which is cool because I think these are questions that people don’t normally ask either, right? When you have a conversation or you’re looking at your test results or whatever, we don’t typically take a step back and say, “Well, what are the conditions around how you live?” Not to be judgmental, but what happens, your blood in a vacuum is one thing, but what is the context behind that person’s life and choices? Because it really paints a comprehensive picture of that person. And then as you’re trying to create a program that’s going to work for them, right? You might be saying, “I’ll do all these things.” The person is like, “I don’t do any of those. That’s not how I live and I can’t.” So we always find it to be really interesting to spend that time to have that dialogue and to learn about what’s going on. And sometimes those are the habits that you have to change. It may not even just be your diet. It may be just sitting down for 30 minutes and chewing your food.

Dr. Kara Fitzgerald: Yeah. I mean, I think it was beautifully reflective of eating a good quality whole foods diet. I mean, I follow basically the eating pattern that I’ve published on. I think it really works and it did reflect, but you were able to pick up that I need to rest and digest and maybe a digestive enzyme, but without question, more meaningful for you and Rachel, the nutritionist, was needing to chill out. There was more evidence for just allowing parasympathetic drive to kick in and digest my food. And the other extraordinary piece that you picked up also in the too stressed camp, and exercising, was my xanthine was really high.

And I have been doing resistance training and I noticed that I’ve been a little bit more sore than usual. So that’s one thing that was flagged I think with that finding. But it’s no secret that I have a pretty intense job as well. So those two pieces, it was really quite clear. I mean, you had my number. I wasn’t quite ready for the level of insight that the test had, I mean, yeah, I wasn’t quite ready. You really had got in, you went right in there and found it, but it was also nice to see what was in the right column as well. And there was good, a lot of it.

Dr. Erika Ebbel Angle: Yeah. Which was awesome. I think that often the indoles are shifted. It’s very common. So the fact that your IPA and your ILA, and I think that was great because when those are off, typically that’s where it all begins. I’d say again, and the dieticians are working with people to try to figure out, where to start? Where do you begin? Right? So if your gut is dysfunctional, no matter what food you’re putting into it doesn’t matter. So things always start there, sometimes in parallel with de-stressing and mindfulness and all of that. But it all begins there. So that was all fine. So most of this is lifestyle, a reminder.

Dr. Kara Fitzgerald: Yeah. It is.

Dr. Erika Ebbel Angle: And to just stay in touch with your body. I mean, that sounds cliche.

Dr. Kara Fitzgerald: It’s just what we need to hear it over and over again. I mean, I need to hear it and it’s part of what I’m researching, it’s certainly what I prescribe to my patients and it’s what I try to practice myself. Albeit, I’m human and I do it imperfectly, but I certainly do the best that I can. But this was obvious, I need to turn the volume up in that arena a little bit more and dial back. In fact, my prescription when she emailed me was to take a real rest day and sit down when I’m eating. So I was thinking, well geez, I could just get in there with the digestive enzyme too. And I might consider trying that because I will do a follow-up test. I’m curious about it. But obviously the lifestyle, I think the lifestyle pieces are really important. When are supplements indicated? When would she have advised? Or how do you think about prescribing them?

Dr. Erika Ebbel Angle: Interesting. Supplements are, as I’m sure you know are always the topic of either great supporter or great consternation. And I haven’t used that word in a long time, but there’s people very opinionated about them. And in the starting of the company, it can’t just be about a supplement because that always drives me nuts. So we want people to change their habits, we want them to eat well, we want them to lifestyle first. That being said, I mean there are people who definitely benefit from supplements and there’s things that we take that can help us. So I think in the selection of those that we offer, I mean we’re always very transparent about why you take this because of this. Here’s the citation showing why it works, and most of our stuff is very common. There’s nothing, some berry that’s only found on one island east of Madagascar, you don’t see that because there’s typically not a lot of data that substantiates efficacy.

So we give recommendations to things we don’t even offer, because we just haven’t gotten around to adding it to the portfolio. And at the end of the day, we’re not a supplement company. We had a lot of people come and ask us, “Hey, do you guys make a probiotic,” and finally I said, “Look, we’ll make some of these just so that we can package them in the most important ones, so that people are doing something if they’re in a program.” But it was definitely not the primary purpose of why we began. So in terms of what we offer, there is a probiotic. That probiotic has been really carefully designed, strain-by-strain by the science team, looking at outcomes and efficacy. And what strains are specific that can help with the various different issues that people have from inflammation to GI issues, et cetera.

Candidly, during the supply chain troubles during COVID, we had some trouble getting it and then we were like, okay. Well, we should just refer folks to another product if they need one, we couldn’t find one that was the same. So I think people love it, they swear by it. I’d say 90% of the people who take it really like it when they do.

Dr. Kara Fitzgerald: What are the strains?

Dr. Erika Ebbel Angle: Oh, there’s 17.

Dr. Kara Fitzgerald: Do you remember? Oh, there’s 17. Okay.

Dr. Erika Ebbel Angle: Yeah, there’s quite a few.

Dr. Kara Fitzgerald: We’ll link to it. We’ll link to it. So people take a look at.

Dr. Erika Ebbel Angle: Take a look. I don’t want to misquote that one, but again, it’s popular. For xanthine levels, typically we do a vitamin C. Vitamin C actually can help to reduce xanthine. The probiotic of course can help if your indoles are out of whack or you have a gut dysbiosis issue, especially diarrhea and constipation. So people who really have severe GI issues tend to benefit from it. We have a 5-HTP, which is, again, it’s a precursor to serotonin. And so for people who have low serotonin or for people who don’t sleep well, because serotonins converted into melatonin, sometimes that’s really helpful. We do have a melatonin. It’s a relatively low dose melatonin. Again, that’s variable. Some people do well on melatonin, some people do not. So we always say, “Look, try it, if it doesn’t work, don’t kill yourself doing this.” But some people really swear by it and it really helps them if they can’t sleep in other ways. We have a B complex supplement. Again, it depends on what your specific issue is.

Dr. Kara Fitzgerald: What would the pattern be for you to suggest a B complex? Just out of curiosity.

Dr. Erika Ebbel Angle: You mean the marker?

Dr. Kara Fitzgerald: Of the 11 markers, what would make you think B? You would have some history plus the 11 markers?

Dr. Erika Ebbel Angle: It’s going to be serotonin, maybe the person’s going to say they have energy issues. So again, there’s the questionnaire, there’s a health questionnaire plus the metabolites. But I’d say any issue with fatigue, just exhaustion, of course we would recommend the B’s general inflammation. So it might be that we look at some of the inflammatory markers and prescribe that. I’m trying to think of what else.

Dr. Kara Fitzgerald: I would say, I think our gut makes a multivitamin and so if you have evidence of dysbiosis, certainly one of the first things that would suffer from that would be B synthesis. Biotin, B12, folate-.

Dr. Erika Ebbel Angle: Yeah. So it could be like [IBA] would trigger it. So there’s very specific things, again, because we don’t just want everybody taking everything. I mean, I still think supplements are medications, so if you don’t need it, there’s no point in recommending it. I mean, things that we don’t do, we often suggest that people take an omega, especially with serotonin. If serotonin is low, we don’t offer one. But I know there are recommendations that the team can provide for high quality ones. So there are other things. There’s a CoQ10. So again, again with xanthine, CoQ10 can help to lower levels of high xanthine, and we don’t offer that one, but they do exist.

Dr. Kara Fitzgerald: I’m thinking about that for myself. Actually, I have vitamin C at home. I don’t know if I have, I probably CoQ10 here in the office, but I know I need to do the lifestyle pieces.

Dr. Erika Ebbel Angle: It’s funny, it actually works because I also have very high xanthine. So there’s things that I’ve tried as well and that’s a good one.

Dr. Kara Fitzgerald: Awesome. That’s really good to know. All right. So what else did I want to ask you about? Did we get through all 11?

Dr. Erika Ebbel Angle: It’s funny, I was trying to think in my head. I mean, there’s tyrosine, tryptophan, total indoxyl sulfate, the three indoles, the three purines, serotonin. What am I missing?

Dr. Kara Fitzgerald: Kynurenine.

Dr. Erika Ebbel Angle: Kynurenine. Okay.

Dr. Kara Fitzgerald: We haven’t talked about that. Yeah.

Dr. Erika Ebbel Angle: We haven’t? Okay.

Dr. Kara Fitzgerald: It’s an interesting one.

Dr. Erika Ebbel Angle: How could I forget that one? Interesting that one.

Dr. Kara Fitzgerald: And uric acid. We did talk about uric acid.

Dr. Erika Ebbel Angle: We did talk about uric acid briefly. So kynurenine’s interesting because it’s in the tryptophan family, but it’s an inflammatory, typically an inflammatory marker. So when things go haywire down the wrong path, kynurenine is generated. What’s really interesting also to look at is the ratio, sort of the tryp-kynurenine ratio. Things like cancers are sometimes when kynurenine is really elevated, super elevated kynurenine is not awesome. You don’t want that. And I’m not saying if you have elevated kynurenine that you have cancer, just to be clear. But it’s not awesome to have high kynurenine. And especially if the ratio is wonky and we do look at that. Because if the ratio is fine, then maybe you just have too much tryptophan. And so both of them are elevated, but if the ratio is weird, then it can have meaning. And we’ve seen that, it’s not common, but we’ve seen it. So that one is like the dark horse that we pay attention to, but people don’t always understand its significance.

Dr. Kara Fitzgerald: Yeah. I get it. Well, on organic acids we do look at kynurenine derivative quinolinic acid actually, which we talked about that you can measure that in urine and maybe if it’s very high, you would expect to see it quinolinate high as well as a pro-inflammatory marker. I have no experience measuring kynurenine, so I think it’s really interesting to me that you’re doing that. Why did you opt for blood? By the way, collecting the specimen was incredibly, it was the easiest fingers that I’ve ever, ever, ever done. The device that you use that, those little sponges are awesome, just super, super easy.

Dr. Erika Ebbel Angle: Yeah. So because these things are, you find them in blood.

Dr. Kara Fitzgerald: Yeah. Well, versus urine or better?

Dr. Erika Ebbel Angle: Yeah. And I also candidly, that’s what we had a lot of experience doing, right? So we knew that they were there, we knew the concentrations.

Dr. Kara Fitzgerald: Oh, awesome. Yes.

Dr. Erika Ebbel Angle: Fifth year the data came from the blood and not everything is measurable in the urine. That’s another thing.

Dr. Kara Fitzgerald: That’s right. Yeah. You’d have to omit some of these, and they’d be way less reliable, right? Well, you couldn’t do uric acid, I imagine.

Dr. Erika Ebbel Angle: Yeah. I don’t think you can actually measure all of them candidly. I don’t know which ones specifically, but I think part of the challenge is that you just can’t get an accurate result reading.

Dr. Kara Fitzgerald: Yeah. I know blood is better for the amino acids as well. Yeah. So it makes sense. And again, you just knocked it out of the park with a collection device. Usually I find blood spot or blood stick collections to be a pain. So bravo you guys.

Dr. Erika Ebbel Angle: It’s very important. If the experience is bad or if it requires collecting gallons of blood through, I mean, I always, when they’re like, “Oh you need to fill this tube,” and you’re like, “Wow. That’s a lot of squeezing with my poor little finger, which is now blue.” And then you end up having to poke other fingers. So this device is really needed. It literally, I think it’s like 20 microliters of blood, which is about four drops.

Dr. Kara Fitzgerald: Oh really? That’s cool. Yeah. It was easy. It was easy-peasy. Clinicians can use this, so I could get this information, I could get, and I think… Do I have access to the questionnaire? If I have those two pieces of information, obviously I’m going to be able to design a decent protocol.

Dr. Erika Ebbel Angle: Totally. There’s different ways that folks work with us. It depends on if they want to do the review themselves, in which case we provide information, training, so that you know what you’re looking at. And then, there’s a pro-portal so that our pro-partners or our physician partners can log in, access all the data, you have control over the report. So if you want to only show certain sections of it, sometimes just sending the whole 80-page report is overwhelming. So you could say, “We’re going to focus on diet for the next two weeks,” and you give them the results and you focus on one section and you can release that only. So you can really custom filter what you want that person’s experience to be. Or we have people who say, “Look, I don’t have time. I want you guys to just deal with it.” So we do the report, but we always send an executive summary. The physician has access to the data and all that, but it’s just two different models depending on how the person wants to work with us.

Dr. Kara Fitzgerald: And somebody could go direct to you. So if a consumer wanted to get it, they have access?

Dr. Erika Ebbel Angle: Absolutely. So I mean, you could always go to the website and do whatever they want. I’d say when we work with a physician, we always have to establish the relationship. What do you want us to say? Right? Because oftentimes physicians might say something like, “Once you have your results, let’s discuss them first before you decide what to do next.” So in the report or the result review session, we will say to the person, “Here are the results, now go and take this and talk to your doctor about what he or she wants you to do. We’re here if you have any questions, but go and talk with him or her in order to make a plan,” right? Because we don’t always have the full picture of what else is going on in that person’s life and we want to make sure that we’re understanding of that.

Dr. Kara Fitzgerald: I appreciated my consult. I thought that a lot of good information was imparted, as I’ve already stated. I thought that I was accurately, as those 11 analytes captured what was going on with my life. And I think Rachel did a good job folding it into my history that she had. So I think either as… So I could see using it as a clinician and having my clinician hat on and talking to whoever I was working with about them. And I could also see it being actually really pretty effective for one to go straight and work with you directly. As we head towards close here, you’re engaged in research. I know you’ve been doing work with elite athletes, and I want to hear a little bit about your research efforts and interests, and future thinking as well with the company and the work.

Dr. Erika Ebbel Angle: Yeah. So we’ve had the opportunity to work with a lot of different types of groups and especially last year spent a fair amount of the year running trials, right? Efficacy trials, right? Because there’s this question, you go on all these product websites, how effective is the thing? And so last year we focused on three cohorts. So there was the athlete group, so we call them the physical performers. And we did, I don’t even know, quite a few, I don’t remember 20, different people who did our 90-day program and every day we interviewed them, we had them fill out surveys and forms and, “Did you do what you were supposed to do?” So we were pretty consistent about making sure that they weren’t fibbing us, right? So at the beginning and at the end there was, “What changed?” And the data was pretty remarkable about, especially for GI related issues, diarrhea, constipation, runner’s gut.

Many of our folks were runners, triathletes who are constantly dealing with this. We were able to get rid of a lot of those problems. We had people who were missing the podium because they were spending two and a half minutes in a porta-potty who suddenly didn’t have to do that anymore. And so some pretty compelling data and that’s on the website, but also happy to share that. I think we may have shared a document with you, but again, if we need more of that, that folks want to see, I can share that with you as well. So there was a cohort of those individuals. There was a cohort called the Mental Performers, so people in high stress jobs who would report issues with mood imbalances, anxiety, fatigue, and just exhaustion. A lot of it was just physical and mental exhaustion, and mood issues and sleep, right?

So a lot of that data came from there. Again, improvements where they were 2 out of 10 went to a 9 out of 10, or now they were sleeping, maybe not a 100% perfectly, but before they were sleeping one day out of the week and now they’re sleeping six days out of the week. So there was some pretty amazing data that came from that. And the third group was, we call them the Wellness Group. So these are people with very specific health related issues and concerns. Thyroid issues, perimenopause and menopause, that’s a tough one and a weird one, because it’s not always clear where to begin and what to target. Cholesterol, high cholesterol levels, people who like, “I’ve tried eating this and I’ve done…” “Okay. Well, here’s what we think you should do.”

Issues like that where people had a very specific problem and we were working with a physician, right? So it wasn’t like we were just prescribing and doing medically oriented things, but working with them and their healthcare practitioners in order to try to help solve these problems. And we had people saying, “Look, I’ve spent so much money in my life on this and suddenly I can sleep. I have enough energy to go out for a walk.” And they’re in the program still, I mean, these people have been with us for years because they’re like, “For me to spend a few hundred dollars on my life, on my happiness, this is the best investment I could possibly make,” right? And those are the stories that are compelling and that’s why we do this.

Dr. Kara Fitzgerald: Yeah. Awesome. Yeah. We can link to the show notes. My team will get them from you and link to the show notes. I’m super curious, I know we’ve got to wrap up here, but patterns in these individual cohorts where there were clear patterns that corroborate what you’ve been talking about?

Dr. Erika Ebbel Angle: Yes. And to some extent you say, “How did you pinpoint me?” And what’s really interesting is there are definitely trends. So in the athlete group, I mean, elevated xanthine, elevated IDS, low IPA. Low IPA is just, in our NFL athletes that we’ve worked with, in our sailors from America’s Cup that we work with, and athletes in general, low IPA. Serotonin, low serotonin is also on the list. So those are very, very typical. Then you have your elevated urinate, you have your elevated kynurenine, typically your athletes are taking in a lot of proteins, so sometimes that’s elevated as well. Not always, but sometimes, typically more in men than in women, which is, again, it just depends on how much you’re consuming. So that was that group.

On the mental performer group, I mean, xanthine again, for a different yet similar type of reason despite the indoles. Typically, all the indoles are wonky, whether the IAA is high and your IPA is low, but indoles. So high stress people get a messed-up gut microbiome. They just do. So there’s that serotonin again is in there. Depending on how much caffeine they’re ingesting, their 3-MX could be off the charts depending on that situation. I’m trying to think of what else did I missed. Tyrosine, tryptophan is usually low because they’re not eating, they’re not eating enough food or not digesting, spending the time to do that properly. So you’ve got low amino acids versus high for the athlete. And then, the Wellness Group is very variable depending on the specific problem.

Dr. Kara Fitzgerald: Of course.

Dr. Erika Ebbel Angle: Specifically, the indoles are often off. One of the most interesting groups we’ve had, we have a limited number of data points, but enough to see trends, are with the pregnancy group. So we had a bunch of pregnancies in the office, and then we had a bunch of our athletes and such get pregnant. So I don’t know, 10 people at this point. So it’s not huge, but amino acids, tank, tank-

Dr. Kara Fitzgerald: They’re building a human.

Dr. Erika Ebbel Angle: They’re building a person. And that’s what this is so cool when we saw this. The tyrosine, tryptophan went from eight to two. I mean it was unbelievable, right? And you’re like, “I should probably be eating more protein. Someone is sucking this out of me.” So that was there. Tyrosine, so for the people who had emotional issues, serotonin, tyrosine, because they were in fatigue, tyrosine is a big one for fatigue as well. So if you were chronically tired, you were seeing that.

Dr. Kara Fitzgerald: Sure.

Dr. Erika Ebbel Angle: So there are these kinds of trends.

Dr. Kara Fitzgerald: And will you publish on this? Will you guys write some of this up for?

Dr. Erika Ebbel Angle: We probably should. Yeah. We should.

Dr. Kara Fitzgerald: You know what else would be cool, just because you have this little pregnancy cohort to track birth outcome based on adhering the program. And anyway that’d be interesting. It’s a small cohort, but it would be kind of cool.

Dr. Erika Ebbel Angle: But we get asked a lot of questions about it, and what’s really interesting is every single person, every single person who went through that had some of these things that were aligned. And then we’re still following some of these folks because, again, some of them are in-house, but some of them are some of our influencers. We have a couple of athletes that work with us and they all have babies and now we’re still working with them. So we have years of longitudinal data to look at what happens and when does it revert and how does it revert. But that was just something that was really compelling to me.

Dr. Kara Fitzgerald: So interesting, so interesting. I’m thinking about, there’s been a hot dialogue in our space around really radically increasing protein, or there’s the counter-argument that we should be consuming lower protein diets, like the intermittent fasting model, fasting mimicking diet. But I just wanted to say, so there’s camps and there’s been a lot of conversation in our space. But certainly looking at these to see how our body’s processing protein, how our microbiome is acting on the protein that we’re consuming would be a helpful guide towards who’s safe to consume higher amounts of protein. Or how you might change the way that it’s processed if you want to consume a higher amount of protein, if you need to for whatever reason. But it’s a cool way to use this information for a hot topic in our space these days. But yeah, go ahead, what were you going to say?

Dr. Erika Ebbel Angle: No. We believe in measuring it, right? Because there’s no way to really know. You can’t look at a person and be like, “Yeah. That person probably needs X.” So the tests, you measure it and see what their level actually is.

Dr. Kara Fitzgerald: See what they’re doing?

Dr. Erika Ebbel Angle: Yeah. Again, sometimes you think that person, “Hey, they’re exercising all day, they need more protein,” but it turns out their protein is off the charts and they’re chronically inflamed. They’ve got GI issues up the wazoo. And often, I mean candidly, if you’re a woman, if you’re a vegetarian or vegan, you’re not getting enough protein and so you’re tired, you’re fatigued. “Why do I feel down all the time?” Right? And especially if you’re over 40, I’d say we tend to ascribe to the protein is good. A little bit more is okay, but you don’t want to just do that in a vacuum.

Dr. Kara Fitzgerald: That’s right. Yeah. I mean, some of these compounds are really potently damaging. I mean, just going back to our conversation on indican, and it’s produced from tryptophan. And certainly high protein eaters tend to down the tryptophan dense, meats, turkey, chicken, and so forth. Yeah.

Dr. Erika Ebbel Angle: Right. Exactly.

Dr. Kara Fitzgerald: Well, listen, Erika, it was really nice to get to hang out with you again. And I think this is our third time getting to connect and talk about this really, really interesting topic. Yeah. I’ll just look forward to seeing what you guys are up to and I hope that our paths continue to cross.

Dr. Erika Ebbel Angle: Absolutely. I think just one last thing people often ask us, “Who is good for this?”

Dr. Kara Fitzgerald: Oh, of course.

Dr. Erika Ebbel Angle: And you asked that earlier and it’s a hard question to answer. I mean, in many ways, I think it’s something that many of these markers should just be measured in people. They should just be measured in general.

Dr. Kara Fitzgerald: Are there annual exam? Are there semi-annual exam? Yeah. All of us.

Dr. Erika Ebbel Angle: Right. For sure. But I think if I had to say… I mean, we do GI really well. So if people are, gas, cramping, bloating and they’ve tried many things and there’s just been no hope. We tend to help a lot their sleep, energy, inflammation obviously. I mean, weight loss is such a touchy and difficult topic, but in reality if you adjust your lifestyle and you eat better, typically things like weight loss and cholesterol, they get fixed on their own because you’ve solved some of these other underlying issues. And especially if you have GI issues, solve those first, it makes solving these other problems a heck of a lot easier. So really there are many different types of folks who could benefit, but these are some of the pain points that we’re great at.

Dr. Kara Fitzgerald: Awesome. Thank you for that.

Dr. Erika Ebbel Angle: No worries. Thank you.

Dr. Erika Ebbel Angle is the CEO and co-founder of Ixcela, the Internal Fitness Company. She received her Ph.D. in Biochemistry in 2012 from Boston University School of Medicine and holds a B.S. in chemistry from MIT. Erika is also the founder and Executive Director of Science from Scientists, an award-winning national nonprofit that sends charismatic scientists into classrooms to improve the attitudes and aptitudes of 3rd-8th grade students in Science, Technology, Engineering, and Math (STEM). In 2018, she was awarded the “Young Alumni” award by Boston University. In 2017, she received the “Distinguished Alumni Award” from the Boston University School of Medicine Division of Graduate Medical Sciences. In 2014, the Boston Business Journal selected Erika as one of the “40 Under 40.” In 2013, the Boston Chamber of Commerce selected her as one of the “Ten Outstanding Young Leaders” in Boston. Read full bio here.

How tryptophan relates to many of the metabolites Ixcela tests

Ixcela

Research studies relevant to the Ixcela Metabolites

KEGG Pathway Site

Ixcela Metabolite Cheatsheet

Metabolites tested by Ixcela

Ixcela Dropdown Discussion of Metabolites

Ixcela Supplements mentioned: Probiotic, Vitamin C, 5-HTP, Melatonin, B Complex

Ixcela Pilot Studies and Company Overview

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