Many of us have been using organic acids for decades. I am proud we were early adopters of the “OAT,” as the test is referred to sometimes. Historically, the inspiration for OAT came from inborn errors of metabolism, where a handful of compounds are (still) measured in newborns to rule out severe genetic diseases. Flash forward to the “Omics” revolution; you know, the genome, the epigenome, exposome, microbiome, etc. and we’re way beyond the organic acids of old and onto metabolomic data. For me, it’s about time, to be honest. Metabolomics research has been happening for years now, and today I talk with Betsy Redmond, PhD on the ultimate metabolomic panel for clinicians and what it might look like. What we can see, what the research shows us, and how we can use it in practice (both busy clinicians wanting easy interpretation, and rabbit hole clinicians who want all of the science). Listen, and leave us a review wherever you find this podcast! ~DrKF
Metabolomic testing can open the door to a deeper understanding of gut function, metabolite pathways, and predisposition to disease states — even years or decades in advance. Every year, experts gain new insights on metabolic pathways and what they mean for helping patients protect themselves from chronic conditions. In this episode of New Frontiers, Dr. Fitzgerald talks with Dr. Betsy Redmond about the latest advances in metabolic testing. Dr. Redmond is a private practice nutritionist and Senior Education Specialist with Diagnostic Solutions Laboratory. She uses a systems biology approach in diagnosing and treating nutritional issues. She’s conventionally trained with a master’s degree in Clinical Nutrition from Emory. She also has a doctorate in nutrition from the University of Georgia.
In this episode of New Frontiers in FxMed, you’ll learn about:
- Various organic acids that are produced in the gut and what they reflect about the activity happening in the gut and throughout the body
- Newer ways of thinking about gut activity
- Testing and interpretation of metabolites to determine each patient’s unique metabolic fingerprint
- Two avenues for continuous monitoring: consumer-grade wearables and clinic-phase precision medicine.
- Understanding the saccharolytic-proteolytic balance in the gut
- Health impacts of eating a high protein diet without sufficient fiber intake
- Hops-based vs. soy-based interventions for menopause symptoms (and how to use testing to determine who would benefit most from which intervention
- Metabolomic testing to determine which functional medicine interventions promote health for some people but harm other people
- Metabolomics to identify noninvasive strategies for diabetes
- Metabolomics for very early prediction of conditions like diabetes, kidney disease, liver disease, etc.
- Understanding specific metabolites including: 1-methylnicotinamide, nicotinic acid, betaine, lactic acid
- Urinary betaine as a marker of diabetes in cardiovascular patients
- The tryptophan pathway and the kynurenine pathway
- NAC, NAD and understanding anti-aging interventions
- Assessing pellagra and niacin deficiency
- Animal studies that associate high-dose nicotinamide with liver conditions
- L-FABP as a better marker for monitoring early treatment of chronic kidney disease.
Dr. Betsy Redmond is a private practice nutritionist and education specialist who uses a systems biology approach in diagnosing and treating nutritional issues. She is both conventionally trained with a Masters’ degree in clinical nutrition from Emory University and a doctorate in nutrition from the University of Georgia. Dr. Redmond has over 15 years’ experience in functional laboratory research and education, as well as involvement with Dietitians in Integrative and Functional Medicine. Betsy tries to provide translational application by relating known and current research with clinical application. She believes that clinical application should go beyond what is assumed and include current knowledge to better optimize health. She provides nutrition assessment and education workshops in her private practice, works in education at Diagnostic Solutions, and offers practical nutrition advice on social media at @nutrition_provisions. Before working in functional medicine, Dr. Redmond worked in university research and public health programs.
Dr. Kara Fitzgerald: Hi everybody. Welcome to New Frontiers in Functional Medicine where we are interviewing the best minds in functional medicine. Of course, today is no exception. I am talking to a really good friend of mine, Dr. Betsy Redmond, about metabolomics. Let me give you her background and then we’re going to jump right in.
Dr. Redmond is a private practice nutritionist and Senior Education Specialist with Diagnostic Solutions Laboratory. She uses a systems biology approach in diagnosing and treating nutritional issues. She’s conventionally trained with a master’s degree in Clinical Nutrition from Emory. She also has a doctorate in nutrition from the University of Georgia.
Betsy has over 15-years experience in functional research laboratory. Actually, that’s how she and I know each other; we worked together for years. Betsy tries to provide translational application by relating known and current research with clinical application. She believes that clinical applications should go beyond what is assumed and include current knowledge to better optimize health. Before working in functional medicine, Dr. Redmond worked in a university research and public health program. You can find her on social media at @nutrition_provisions or at Diagnostic Solutions.
Dr. Kara Fitzgerald: Welcome to New Frontiers, Betsy.
Dr. Betsy Redmond: Thank you.
Dr. Kara Fitzgerald: It’s great to have you here. I’m actually really excited that we’re talking about metabolomics. What a better person to talk about with. I can’t imagine. I’m glad that you’re turning your prodigious brain in this direction. You’re going to tease it out. The reason that I’m glad about it is because, of course, you and I worked at Metametrix. Metametrix is no longer, but I think it was the first lab to offer clinicians a broad organic acid panel and that was the precursor to metabolomics.
In the education department, you and I were always digging into the science around organics. What do they mean? How do we use them? Then leap forward into the omics revolution. Now we’ve got these amazing high throughput instruments where we go from 40 analytes that we were looking at back in Metametrix. We still use those today, but having the capacity that we’ll look at more analytes. There’s an explosion of science that has occurred. I keep one eye towards it. But I’m not steeped in it in the way that you are now. It’s just great to be able to pick your brain on it.
Let’s just start with defining metabolomics and then specifically applied metabolomics.
Dr. Betsy Redmond: Well, I think it’s really … It’s hard to get one definition. There are a lot of them. I would say that when you were mentioning that Metametrix did that years ago, that was like 30 years ago that came out.
Dr. Kara Fitzgerald: That’s amazing. Yeah.
Dr. Betsy Redmond: Now, there’s metabolomics and they seem to be going parallel and they need to come together more. But I guess when I think of metabolomics, I think it’s the study of metabolites and how your unique fingerprint. It identifies your cellular processes, your functional readout of your physiologic state. You can characterize it for cells, organs, tissues and biofluids. I tend to really focus on urine, because it’s so easy to get urine. It makes it a little more … Because eventually I’d like to see it when you do a baseline. Then you do more regular follow up with it.
But I think what it can help with it, looking at all the metabolomics, you can figure out what is related to different pathways, what’s normal. But then for each individual, what’s normal.
Dr. Kara Fitzgerald: I guess the extraordinary thing about it is you can get insight into pathological shifts or potentially pathological shifts way before the disease state actually develops. I think probably with these broader metabolomic tools versus what we were doing back in the lab, they’re all the more sensitive.
Dr. Kara Fitzgerald: We’re already talking about this, but how do we take this and make this into something that’s clinician friendly?
Dr. Betsy Redmond: Well, I think some of it because there is the big data sets that they put out there and really it’s going to take a lot of computing to get. But there’s a lot of individual markers that just haven’t really been put out there yet that have good research behind them. I think part of it is we just have to do to get it out there. That’s why functional medicine has really been pretty successful because they made these assumptions. They had research. They put it out there and started applying it clinically.
Dr. Kara Fitzgerald: Yeah, that’s right.
Dr. Betsy Redmond: We have a lot of that. I know when I first started at Metametrix, and you were already there in your office, and I remember …
Dr. Kara Fitzgerald: Down the hall.
Dr. Betsy Redmond: … down the hall.
Dr. Kara Fitzgerald: Yelling at the door.
Dr. Betsy Redmond: But looking at it and wondering, how is this true? I came from a research institution and I have not heard of all this stuff. That’s what got me into really researching it.
Dr. Kara Fitzgerald: Yeah. I mean, it’s pretty extraordinary. I know. I remember that. You’re such a research hound. You’re always so good with the data and bringing us more and more and challenging and expanding how we were thinking. But It is. It’s pretty extraordinary that the founders of our field had the presence of mind to think about, say, the old inborn error of metabolism research, which is pretty much where organic acids came from and think can we use these metabolites in healthy people and look for more subtle perturbations. I think that’s really how the party started in this arena. It was a stroke of brilliance. Now we’ve got the potential for looking at much, much more.
In your read on the literature, and where actually folks going to move through a bunch of the analytes that Betsy is thinking about today. Those citations will be on the show notes. She’s sent me just a quite a variety of references. Anything she mentions today will pop on the show notes and the things that she sent me prior to her interview will also pop on the show notes. If you’re interested in doing a drill down here and thinking about how you can use these in practice, just head over to the show notes.
Actually, I want to know what conditions it’s most helpful for. But talk to me a little bit about Ian Miller’s work, because I know you’ve been impressed with him. He’s out of University of Wisconsin. He’s looking at using urine metabolomic data for real-time health monitoring. Actually, we can just flow that into important conditions.
Dr. Betsy Redmond: Yeah. I mean, I think that really stood out to me. It’s 2019. It’s pretty current. But he was saying that there are really two avenues now for continuous monitoring, like consumer-grade wearables, and clinic phase precision medicine. What he did was he had two people in the study and they took all … everything about them, everything they ate, all their exercise, collected all their urine for 10 days. That must have just been really hard.
Dr. Kara Fitzgerald: Do you remember the day, it was when we were working on new tests in the lab and the whole hallway would be full of urine collection? Oh my goodness. Life in the lab.
Dr. Betsy Redmond: Yeah. I mean 24 hours, it’s hard to get. I guess you just have to wrap your head around. Okay. This is 10 straight days I’m doing this.
But he got a lot of stuff. He got a lot of detailed review like, “Oh, they had coffee.” One had coffee in the morning and they’ve seen this change and markers. One had it twice a day and the alcohol they would drink or what they would eat. It’s fascinating read. But it’s not practical. It’s not really even necessary to do all that.
I think it just really got me thinking that in this whole area that you need to find the markers that are going to be most clinically useful that are newer markers that maybe help you look at the whole pathway. Instead of just picking out individual markers and thinking, well this marker is high or low, we need to do this. Look at it and the whole pathway. Look at it in the cascade of tryptophan or methionine and those metabolites where they may cross through.
Dr. Kara Fitzgerald: Right. More in-depth, a little bit more granular. Your read on the current literature, what conditions most lend themselves to this level of analysis, do you think?
Dr. Betsy Redmond: Well, I think the metabolic conditions. Diabetes certainly has a lot of stuff going on. I think Zhang in 2013 had stuff coming out that their data suggested that robust metabolomics had a potential as a noninvasive strategy. That was seven years ago when I feel like that … Yeah, seven years ago, I was thinking, yeah. It’s not going to be an ideal. I don’t know if sometimes it just takes a long time because people want it to be diagnostic and that this is positive and you have this. It’s going to be metabolomics, applied metabolomics. It’s really going to give you a more underlying idea of pathways and areas to be concerned about. It’s going to show you perturbations long before.
It reminds me of thermograms, you can do a thermogram for breast assessment. If something shows up, it’s not diagnostic. It’s not going to say you have breast cancer. But there’s a concern and we need to go there. Metabolomics can do the same thing.
Dr. Kara Fitzgerald: Yeah. It sounds like it can narrow in the various pathways that are perturbed. Actually, you would say, you mean it begs the question. Perhaps one of the reasons these haven’t been widely adopted is because we have A1c. We have fasting blood sugar. We’ve got this workhorse selection of compounds that we’ve been analyzing forever. I think people are in the habit of doing it.
But what you’re saying is that if we were to consider metabolomics, we’ll see the imbalance before we see these imbalanced. We’ll just see the subtle transition towards disease.
Dr. Betsy Redmond: I think that when you think of that whole thing about if you want to get, if you want to transform modern medicine, which I do, then you need to make it as predictive, preventative, personalized, participatory. To have somebody come in with a normal visit, they’ll come into a clinician maybe once a year. Younger and they come once every five years. They get checked to see like, “How’s your blood pressure?” “It’s not high.” “You don’t have diabetes.” “Okay, bye.”
But that’s not really helpful if you have a family history or you want to know if something happening. Maybe you don’t have diabetes or even pre-diabetes. But maybe you have pathways or markers that might be elevated that you could actually do something about early on.
Dr. Kara Fitzgerald: That’s so cool. It may be a little bit more refined than just, okay, low-glycemic diet. I mean, this might actually provide a little more detail on how you’re going to prescribe for somebody their particular intervention plan. Again, just thinking back at the lab, even there were less sophisticated panels, but we would see imbalance of certain nutrients or maybe we would start to begin to think about toxins with a given panel.
I’m sure we could still apply that and then some to these more sophisticated metabolomic investigations. Would you say that that’s true?
Dr. Betsy Redmond: Well, I also think it helps people make changes because then they can see their changes. You don’t have diabetes, let’s do a change and see if we can move your A1c a little bit even though I already told you it was normal. If you can move back further, you can see.
Dr. Kara Fitzgerald: I think it’s exciting. Okay. Listen, let’s talk about some of the markers that you’ve been interested in. Any studies that have furthered your knowledge … Again, folks are going to be interested. I’m sure there are quite a few of our listeners who are using organic acids and would jump at the chance to look at metabolomics.
Dr. Betsy Redmond: Well, I think that there’s a study that I liked. It was in … just look in here. It was Diabetes and Metabolism from 2018. It was called identification of urine metabolites associated with five-year changes in biomarkers of glucose homeostasis. They had baseline assessment of A1c, fasting glucose, insulin resistance, and they also had some metabolomics markers. They actually whittled it down to 17 markers. They thought would make sense.
They looked at them in baseline and then they looked at it five years later. It’s a Dutch study. They just collect a lot of data and have that accessible for research. It was the civil registration system in Copenhagen. It had almost 4,000 people who were in the assessment.
It was quite a bit. But it has a really nice table in it and they broke it up into whole population, and then a subpopulation who were healthier people, and then by weight. But they found some markers were high across looking at all those A1c glucose and insulin resistance. 1-methylnicotinamide, which, no, I hadn’t heard of that before. I ran across some of these and started looking into it. I mean, I might have heard of it. But there’s quite a bit of research on it. They found that. They found betaine was really helpful, of course lactic acid.
Dr. Kara Fitzgerald: They found these guys were high, 1-methyl, nicotinic acid, betaine, lactic acid?
Dr. Betsy Redmond: Yeah. They were high at baseline, which gives you an idea that …
Dr. Kara Fitzgerald: In a pre-, pre-, prediabetic?
Dr. Betsy Redmond: Yeah. Five years earlier, they weren’t going to be … your A1c wasn’t going to be high till later.
Dr. Kara Fitzgerald: Blood sugar was fine. Our standard markers were within normal limits in these guys. But you’re seeing these other imbalances?
Dr. Betsy Redmond: Yeah. Over time, you’ll see them. Yeah.
Dr. Kara Fitzgerald: Start to rise up. Isn’t that fascinating? Why betaine? Have you teased out why betaine would be high? Why the methylation cycle would be …
Dr. Betsy Redmond: Well, there’s other studies that also … There’s a urinary assessment. There’s some good studies looking at betaine in relationship to diabetes. Well, once I get going, it’s like, “Oh no. Now, I can’t stop. I’m going to have to go.” There was another study that looked at specifically at assessment of urinary betaine as a marker of diabetes in cardiovascular patients. But it was part of the Western Norway B Vitamin Intervention Trial. They had about 2,300 people.
It is so interesting if you … What they found, they broke it up into three groups. They had people who had diabetes, people who had no diabetes but they had high glucose, and no diabetes and low glucose. At 99 was the cutoff of fasting glucose. They had those three groups and they were looking at urinary betaine.
The ones with no diabetes, if you just look at the spread of urinary betaine, they tend to be anywhere from 1 to 35 is what the urinary excretion. But with the people with diabetes, the range was so much higher. It was 1 to 200 plus. It just stopped, because that’s as high as their assessment. People tended to have a much higher marker. Their mean was probably 35 compared to 7 for the other group. Just as it was high was giving you an idea. They found that more in people with diabetes.
If somebody comes in and you see this, high urinary betaine, it can give you an idea. I mean, it has a lot of things that go on. But then when they changed it, and they also looked at other pathways, I mean, other markers of it, they compared it to A1c. They did like they have a chart and they have urinary betaine and A1c. There wasn’t much of a correlation until they got to A1c around six and a half. It was really 6.3 to 6.7. Once they did that, it was positively correlated, just kept going up together.
Dr. Kara Fitzgerald: Did betaine rise before A1c?
Dr. Betsy Redmond: No. It went straight across until it got to around 6. It was around 10. Then when A1c got to around six and a half the betaine took off.
Dr. Kara Fitzgerald: Interesting. Obviously, they confirmed they hadn’t just eaten a bunch of beets?
Dr. Betsy Redmond: I’m assuming they did that. Since they had such a big study group, with almost 2,500 people, it might negate the betaine …
Dr. Kara Fitzgerald: What about NMA and NNMT, some of the other methylation markers and diabetes or prediabetes?
Dr. Betsy Redmond: Yeah. I like the NMA marker because I thought that was so significant. I mean, because in the first study, it showed up as related to in every group and people who were obese and not obese, and the whole population of the healthy ones. It tended to be related to those markers.
Dr. Kara Fitzgerald: To early metabolic changes?
Dr. Betsy Redmond: Yeah. Again, it always bugs me when I haven’t heard of something. I am interested in this stuff and I haven’t heard of it. The 1-methylnicotinamide, it is the final breakdown products of tryptophan. Tryptophan goes down the whole kynurenine pathway. Certainly, with diabetes, that’s going to get pulled. Inflammation is going to push that TDO, IDO enzymes down the kynurenine pathway. It’s going to go down, makes niacin. But then the breakdown product of that is 1-methylnicotinamide or MNA. It gets called by, a lot of these get called by a lot of different names. Every study had different names.
But they have found higher 1-methylnicotinamide in patients with diabetes. Not just that study, some other ones. But originally, they thought that it was just the break clearance of excess niacin. Nobody really gave it much thought that that’s what it was.
The enzyme that takes it from nicotinamide to 1-methylnicotinamide is nicotinamide N-methyltransferase or NNMT. It was originally thought of as an inactive metabolite. That it was just there for clearance, to get the niacin out. But then they started thinking, well, maybe it’s related to more. Because when you look at it, it actually has to get methylated to get out. You have the NNMT enzyme, the nicotinamide and SAM, it’s methylated, and then it becomes 1-methylnicotinamide. There are some studies looking at it that it can deplete the body’s methyl-group pool.
Dr. Kara Fitzgerald: Interesting. Okay. Okay. Yeah. That’s why you’re probably starting to see some of those imbalances happen. There’s interesting research. Somebody who I podcasted with, David Sinclair, he’s a big gerontology scientist at Harvard. I don’t know if it’ll be out by the time of this podcast. But he and I were … He’s looking at this pathway in aging and manipulating it as regenerative Influence. He’s big in into nicotinamide riboside and other forms of nicotinic acid. He looks at in an animal model.
But I wouldn’t be surprised, Betsy as you tease through the science of these markers that you’re going to see some other areas to apply your work. Not just really early diabetes, which obviously is helpful and is obviously going to promote aging. But the corollary anti-aging and thinking about using some of those nicotinic acid interventions that are pretty popular now.
Dr. Betsy Redmond: Right. If you’re going to get rid of the pulling out the nicotinamide, you’re going to be pulling out NAD. NAD is used for so many things.
Dr. Kara Fitzgerald: Yeah, that’s right. Yeah, that’s right. That’s right.
Dr. Betsy Redmond: Dehydrogenase. I don’t think they’ve really looked into what does that mean? Certainly, they’ve found it increased in cancer, cirrhosis and other conditions when it’s really high. But then they also have some studies where they look at and low levels are a concern. They looked at whole blood, NAD, NADP in pellagra patients and controls. They proved that didn’t give that great., it gave an erroneously low estimate. But when they looked at spot urine of 1-methylnicotinamide, those concentrations were a little bit more sensitive and specific, in identifying people who actually had pellagra.
Dr. Kara Fitzgerald: Okay. That’s your classic niacin deficiency condition.
Dr. Betsy Redmond: Yeah.
Dr. Kara Fitzgerald: You’d be able to use this to not only assess excess as potential pathological diabetes or maybe accelerated aging. Also since you’re gunking up the methylation works big time, of course, detoxification, and all sorts of other possibilities that will be imbalanced. My area of interest right now, a study that we’ve just finished is looking at DNA methylation. Imbalances in biochemical methylation are obviously going to impact DNA methylation, and genetic expression, and in either deficiency or excess.
Cool. Low reference limits will indicate perhaps nutritional insufficiency. Excess, we need to be thinking about some of these other issues. All right.
Dr. Betsy Redmond: I’ve seen studies where low levels, they’re thinking may participate some allergic reactions …
Dr. Kara Fitzgerald: Interesting.
Dr. Betsy Redmond: Yeah. I think that … Yeah …
Dr. Kara Fitzgerald: Is that because of histamine N-methyltransferase, do you think, if methylation is gunked up? If there’s insufficient methyltransferase activity because SAM is depleted, they’re not able to get rid of histamine is that the mechanism?
Dr. Betsy Redmond: Yeah. I mean, I would go with that.
Dr. Kara Fitzgerald: Okay. All right.
Dr. Betsy Redmond: Yeah. I think there’s all these questions that they’re finding associations, and they’re just really funny.
Dr. Kara Fitzgerald: Isn’t that exciting. One of the things that’s always been a conundrum for me is that it’s certainly in functional medicine, it’s anecdotally recommended that we give people B vitamins in allergy season to help them metabolize histamine.
Now, I’ve done this plenty of times in practice, but I don’t really generally see any appreciable benefit. Probably a lot of people are sufficiently methylating and these are people who are coming to work with me as a functional provider. They’re doing a lot of things right.
But maybe if we have this metabolomic data sitting in front of us, we’re going to see the people who will actually respond to a B complex intervention in allergy season. We can stratify. Again, using the four Ps. It’s very personalized. Instead of throwing a B vitamin at everyone, which I’m less inclined to do, now that I’ve been in epigenetic data for a while, if we can stratify, and really individualize, it’s just the most satisfying medicine to practice. I can see that’s where we have the potential of going with metabolomics data. That’s pretty exciting to me.
Dr. Betsy Redmond: Yeah. No. I think it is. I’m so glad you’re excited. When I talk to my family, they’re not as excited.
Dr. Kara Fitzgerald: That’s so funny. Yeah.
Dr. Betsy Redmond: When it’s high, it makes me think that that tryptophan and methionine that those pathways are just coming down and that’s just moving too fast.
Dr. Kara Fitzgerald: Yeah, yeah, that’s right.
Dr. Betsy Redmond: When the nicotinamide gets methylated, it’s irreversible. It’s gone. That methyl donor is gone.
Dr. Kara Fitzgerald: You’ve spent out. Yeah.
Dr. Betsy Redmond: Yeah. They have studies where they give them supplementation of even just 1% in an animal study, just like rodent pups. That prevented their growth until they added some more methionine. Then they started growing again. Then with the adult rodents, the high doses increased liver conditions.
Dr. Kara Fitzgerald: Interesting.
Dr. Betsy Redmond: They gave some choline. Yeah. With people, the more you know, the better you can individualize it. You don’t have to know everything. You don’t have to know exactly this or that.
Dr. Kara Fitzgerald: Right. Well, a lot of people are intimidated because of either the test is full of acronyms or they’re all polysyllabic words, and they’re in the middle of biochemical pathways. People are either excited about that or just horribly intimidated.
I think a good metabolomics assay is going to have to pull the branch down. Having the data, I like having data at my fingertips so that I can look at it and do my own research and draw my own conclusions. But I definitely like being handheld through it. Because this field is actually going gangbusters, all of the -omics fields, the science is just bursting at the seams.
We need you and other people who are really spending time in the science and translating it for us, the clinicians creating how we’re going to use and interpret it. I want to ask you about glutathione. I mean, we know the methylation cycle, anybody who’s practiced functional medicine for a while knows the methylation cycle interfaces with the transsulfuration cycle and ultimately that produces glutathione.
If you’re looking at some of these imbalances, do you see glutathione actually being affected?
Dr. Betsy Redmond: Yeah. Well, I think so. Right. We’ve always been looking at specific markers with glutathione. There’s some good studies and pyroglutamate, alpha-hydroxybutyrate. When you look at those pathways, I’m trying to look at … if tryptophan comes down and the methionine comes down, and they meet at methylation, and then after that is going down to glutathione. What are all those things related to it?
Dr. Kara Fitzgerald: Let me just say, folks, for you, wondering why Betsy keeps saying going down. She’s got pathway charts in her.
Dr. Betsy Redmond: That’s true. It is. I’m going down the pathway. I tend to see, I guess, going down the …
Dr. Kara Fitzgerald: …it’s being metabolized. It’s the catabolic pathway and that’s why she keeps saying, as it’s catabolized.
Dr. Betsy Redmond: Yeah. All right. Yeah. It is where my head is.
Dr. Kara Fitzgerald: That’s so funny. I know that. Yeah.
Dr. Betsy Redmond: Looking at those markers that I would call standard in functional medicine. Yeah. Thinking of those, but then adding newer markers that may give us a little bit better insight into that. There’s a good study and their whole thing it’s called integration of traditional metabolomic biomarkers identifies prognostic metabolites for predicting responsiveness to nutritional interventions against oxidative stress.
What they did is they’re looking at what baseline markers, they did baseline markers. They looked at metabolomics. They also looked at standard oxidative stress and inflammation markers. They looked at glutathione, oxidized to reduced glutathione, MDA, IL-6. They looked at these markers in blood, except for the …
Dr. Kara Fitzgerald: MDA, that’s lipid peroxides, folks.
Dr. Betsy Redmond: Yeah.
Dr. Kara Fitzgerald: Then Il6. Yup.
Dr. Betsy Redmond: You need to be around my family when I keep talking. They’re like, “What are you talking about?” I don’t know why …
Dr. Kara Fitzgerald: That’s so funny. Yeah. Next time I’m in Atlanta, I’ll translate for you.
Dr. Betsy Redmond: Right.
Dr. Kara Fitzgerald: All right.
Dr. Betsy Redmond: They looked at those baseline and then they looked at some metabolomics markers. Then they followed them also. They gave them those. Then they gave them antioxidants. They actually, in this study, we’re looking at Korean blackberries. In the first part of the study, they compared them with North American blackberries. Korean blackberries turned out way better in their study. Now I’m going to go to the store and see if I can even find them.
Dr. Kara Fitzgerald: Find some?
Dr. Betsy Redmond: But what they found was that … This article stood out to me because it’s newer, and they did what some of those old studies do. They found that the people who had adequate higher glycine and a compound called phenylacetylglycine. If they had those two compounds, both of those higher, they tend to respond more positively to the treatment of the Korean blackberry that helped bring down the inflammation. It specifically did really well in bringing down the glutathione ratio.
Dr. Kara Fitzgerald: Okay. These guys, these two compounds predicted response to intervention in dropping inflammation and increasing glutathione?
Dr. Betsy Redmond: Mm-hmm (affirmative). It makes sense because if you have enough glycine, then you were going to probably do better. You can also make glutathione since it can be a limiting factor.
Dr. Kara Fitzgerald: Glycine can be a limiting factor. But we usually think about cysteine and N-acetylcysteine. It’s interesting that glycine is actually the amino acid we want to be thinking about.
Dr. Betsy Redmond: Well, I think it may also give a marker of where other markers are. That if somebody has super low glycine, that giving them all these antioxidants may not be as effective if you don’t also correct that area.
Dr. Kara Fitzgerald: Yep. That’s very interesting. Do you happen to know whether they had okay cysteine in this study? It’s just interesting. I always think of glycine as being more plentiful and I think of cysteine as being the rate limiting amino acid in the glutathione tripeptide. But this would suggest, “No, at least not in some people.” That’s helpful.
Dr. Betsy Redmond: Well, I mean, they were new to this and they wanted to say that in the study … They have a sentence in there which I found so odd. We only suggested that the subjects who had statistically higher mean value of background urinary glycine and phenylacetylglycine, PAG levels, may have good prognosis following nutritional intervention against oxidative stress.
It’s a weird sentence, we only suggested it. We’re not standing by that. If you guys are going to agree with it, they also should have called somebody in functional medicine. What do I do with this? I would have said, “pull back.” People who have adequate glutathione support probably are going to do better, when you’re doing treatment.
But I think being able to look at these markers together, along with the standard markers that functional medicine looks at, give you a fuller picture. It does help.
Dr. Kara Fitzgerald: A more sophisticated, more nuanced, more personalized. Yeah. No. I get it. It’s pretty exciting. I’m looking forward to getting to know some new analytes. I mean, I’m appreciative that what was created 30 years ago is still in use. I just really appreciate it how savvy the founders of this field were. But it’s also time for clinicians to have something a little bit more in-depth in their toolkit. I know …
Dr. Betsy Redmond: I think a lot of metabolomics research has gone on more conventionally or more conventional researchers and clinicians, and then functional medicines gone on. But really, I think it’s time to get together.
Dr. Kara Fitzgerald: Well, one of the reasons why I appreciate you actually putting your brain here is that I think there’s some overinterpretation on certain organic acids, and what they mean, and their utility. Yeah. I’ve certainly heard that in my years practicing functional medicine, really diagnosing conditions that can’t be diagnosed with the current, commonly used panels of organic acid.
Yeah. You’re always evidence-informed and you’re always reading the literature. I just look forward to seeing what you dig up as you move forward.
Dr. Betsy Redmond: Well, I was going to say the marker … Going back to the other study … that study looking at glycine and phenylacetylglycine, that phenylacetylglycine comes from glycine. They do tend to trend together. Phenylacetylglycine is glycine and phenylacetate together, which phenylacetate can come from phenylalanine. That breaks down to phenylpyruvate. If anything, if PAH enzymes are impaired then those markers get higher. Glycine jumps in there and grabs it. It also can come from the environment, from diet or …
Dr. Kara Fitzgerald: Yeah, from gut. It’s interesting. Yeah. I wonder if it’s neuroactive like phenylacetate can be neuroactive and glycine is a neurotransmitter also.
Dr. Betsy Redmond: I don’t know. When you look at phenylethylamine from food. Yeah. That gets metabolized into phenylacetate by MOA to try to keep things from reaching the brain. I don’t know.
Dr. Kara Fitzgerald: It doesn’t cross the blood-brain barrier. Okay. All right.
Dr. Betsy Redmond: Because if you can’t do that, yeah, then you get those symptoms. Maybe it’s not.
Dr. Kara Fitzgerald: But phenylketonuria people can have high phenylacetate?
Dr. Betsy Redmond: Yeah. Now that you’re saying that, I’m thinking, “Oh, I guess, because glycine could conjugate with that.” It’s like glycine conjugates with butyrate and becomes hippurate. It gives you a story of, “Oh, I need to go back. Where’s all that butyrate coming from? Oh, where’s all that phenylacetate coming from?
Dr. Kara Fitzgerald: Yes, that’s right. Yeah, that’s right. Okay. Let’s just talk about … I’m sure people are saying, “Yeah, yeah, yeah.” But in a well-designed panel, you’ll be able to geek out and go into the science and understand the rationale. You’ll also just be able to use it in a busy practice with interpretation done for you. I mean, yeah, I can see that. Hopefully, the evolution of artificial intelligence will catch up.
All right. Besides diabetes, what other conditions?
Dr. Betsy Redmond: There’s some good markers looking at kidney disease. There’s liver, liver type fatty acid binding protein. That seemed to have a lot of interesting research behind it. It’s L-FABP because there’s other ones too.
Dr. Kara Fitzgerald: Okay. Would this be something, again, that would suggest early changes?
Dr. Betsy Redmond: Yeah. It’s looking at things that are taking place earlier. It’s actually used in Japan. It just gives you a little more idea of what might be going on with kidney function. I was looking for the actual thing that Japan had on it. If you look at it when … You can get it. Albumin is going to bring in free fatty acids into the cytoplasm. The FABP will bind it and take it to the mitochondria.
But if there’s any type of ischemic profusion, or changes, the free fatty acid to peroxides, FABP will just take it out. It’s going to protect against oxidative stress. It’s really a better marker for monitoring early treatment of chronic kidney disease.
Dr. Kara Fitzgerald: Okay. It’s in the kidneys. I mean, where is this liver type fatty acid binding protein located?
Dr. Betsy Redmond: Yeah. It’s funny.
Dr. Kara Fitzgerald: Kidney specific?
Dr. Betsy Redmond: Mm-hmm.
Dr. Kara Fitzgerald: Okay.
Dr. Betsy Redmond: They also have some other really interesting studies looking at it with exercise. They looked at VO2max and grip strength. That they found it was inversely associated with the urinary FABP levels in middle-aged and older adults, even without chronic kidney disease.
Dr. Kara Fitzgerald: Oh my gosh. Isn’t that fascinating?
Dr. Betsy Redmond: I mean, you might have slight problem, things you don’t even know that you have. But it could be affecting your ability to exercise, which normally you just say, “Well, I’m a little older now.” But it’ll transfer all over.
Dr. Kara Fitzgerald: I could be an early marker of some deterioration, some loss of organ reserve and kidneys and beyond. God, that’s fascinating. All right. Listen, we’ve been looking at various organic acids that are produced in the gut. They give us an idea of activity happening there. What are some of the newer ways that you’re thinking about gut activity? What are the new gut metabolomic players that we want to think about or concepts that we want to be thinking about?
Dr. Betsy Redmond: Yeah. Way back when, I was really into proteolytic fermentation. A decade ago, there just wasn’t that much information. But now a lot more is coming out. That’s something I think I would really look at. I know when I’m looking at stuff, I want to know the balance.
Dr. Kara Fitzgerald: Of saccharolytic versus proteolytic. All right.
Dr. Betsy Redmond: Okay. What’s saccharolytic, proteolytic balance?
Dr. Kara Fitzgerald: Hey, baby.
Dr. Betsy Redmond: Hey, baby. What’s the balance like?
Dr. Kara Fitzgerald: But define them though. Just define them what this …
Dr. Betsy Redmond: Saccharolytic is going to carbohydrates. Those are going to be the things they actually have a lot of information on. That’s pretty well-established looking at short-chain fatty acids, butyrate, acetate, propionate looking at those things. But the proteolytic markers are the protein breakdown. There’s been less of that. There is new research coming out and they’re looking at what all that means.
Generally, it’s always been, like the old research was proteolytic fermentation, it’s bad. But now, maybe it’s not as bad.
Dr. Kara Fitzgerald: Interesting.
Dr. Betsy Redmond: I think that they’re just trying to figure out what’s good, what’s bad that they can … you could…
Dr. Kara Fitzgerald: You could look at a handful of saccharolytic and proteolytic gut produced markers. Bacterial action on carbohydrates or bacterial action on protein produces these organic acids and a balance of the … We can look at a ratio to suggest health or dysbiosis, I guess.
Dr. Betsy Redmond: Yeah. I think what I look for first is I would look for the proteolytic markers first.
Dr. Kara Fitzgerald: Okay. You’re not just going to look at a ratio between the two? You’re going to actually look at the …
Dr. Betsy Redmond: Yeah.
Dr. Kara Fitzgerald: … what they need.
Dr. Betsy Redmond: There hasn’t been developed a standard ratio, but that’s a good idea. You’d want to look at the proteolytic. Are those taking off? Because they’ve been involved in more metabolic disease. They have more likely to have negative stuff going on. But part of it is if they’re going to be related, number one, to your dietary protein. How much protein are you actually getting in your diet?
Dr. Kara Fitzgerald: What about specific types of protein? Would that make a difference?
Dr. Betsy Redmond: It does make a difference. There’s less research on that. But certainly, meat protein is going to get more fermented than, say, bean protein, because you got all the carbohydrates that come with it, and you’re going to have to break it down. It’s going to go with the other markers. But generally, it’s going to be just how much protein you eat. If you eat a lot of protein, we’re going to get higher levels and things.
Dr. Kara Fitzgerald: Okay.
Dr. Betsy Redmond: If two people eat the same amount of protein, but one gets a lot of fiber, it’s going to blunt that effect. If you just eat protein and you don’t have any fiber in there in a long-term, generally, you’re going to have decreased epithelial cell viability. It’s associated with increased intestinal permeability, DNA damage, decreased colonocyte proliferation.
Dr. Kara Fitzgerald: If you’re doing a high protein, low carb diet, which is frequently, if it’s not prescribed correctly …
Dr. Betsy Redmond: Right. You find that a lot people who just start eating a bunch of meat. Yeah. I think if you don’t follow it, if you’re not assessing those things, if you’re not getting any fiber, to speak of, or you’re eating a standard American diet and you decide to add more meat.
Dr. Kara Fitzgerald: Do you think that you’re going to be able to see more detail around … In terms of the saccharolytic markers around what foods might appropriately bump up. I mean, is there any butyric acid, for instance? I mean, do you think you’ll get that nuanced? You see a low butyric acid. But you can see the other saccharolytic. I don’t know. Is there any indication that you might … I mean, you’ll be able to define what’s going on with protein and whether you’re consuming too much protein or you’re not ingesting it with enough fiber, or I think some of the compounds that you guys are looking at are probably potentially toxic as you described, damaging.
I guess what I’m getting at is how detailed are these new metabolomic gut markers? I mean, how granular can you get?
Dr. Betsy Redmond: Well, I think looking at p-cresol, that’s going to be from tyrosine. You know where that’s coming from. It’s implicated in kidney disease, or in ASD severity. It can even identify it in some studies. But actually it’s excretion was significantly decreased after wheat bran extract, just 10 grams a day, which also increases bifidobacteria. It’s not just getting protein and fiber. It’s also what is your gut bacteria look like? Those kind of things you can look at. Tryptophan is another one indole-acetic acid, you can look.
If these markers are high, and then you’re going to look at other markers, then I would look at those type of amino acid breakdown markers, where are they? Then go and look at the dietary microbial metabolites. The ones that I think of looking at is phytoestrogens, lignan-derived, phenolic-derived, the ellagitannins, colon, carnitine metabolites. Those are all markers you can look at and give you an idea. Because if you look at them in groups, it may help you identify what area you might need to work on a little more.
If you’re going to give somebody some isoflavones, or try to look at those kind of changes, don’t you want to see if they’re an equal producer?
Dr. Kara Fitzgerald: Yeah, for sure. Okay. That’s really cool. This would be the person you’re prescribing soy to? Hopefully, it’s good quality, organic, maybe fermented. Are they going to be able to activate it or flaxseed? I mean, are they actually going to be able to transform it in the gastrointestinal tract to the compounds that we need those things to be transformed into?
Dr. Betsy Redmond: Yeah. I mean, you’re going to want to know those things.
Dr. Kara Fitzgerald: Yeah, for sure. We haven’t been able to know those things. I mean, I think … Probably, when we look at the pushback on soy in this country, I know sometimes it just has to do with the fact that some of our soy produced here is horrible quality and shouldn’t be eaten.
But it’s also probably because we don’t have the same gut microbiome as folks in Asia who’ve been consuming soy for time immemorial. But this is pretty cool. What you’re saying is that there are ways that we can look at the compounds produced by the microbiome and really see whether or not we’re activating some of these tried and true nutrients?
Dr. Betsy Redmond: Right. Yeah. Look at Equol, there’s also another one … you talk about pronunciation. I can never pronounce it. It’s 8-prenylnaringenin.
Dr. Kara Fitzgerald: Oh, yeah. Prenylnaringenin
Dr. Betsy Redmond: I prefer to call, yeah, 8-PN.
Dr. Kara Fitzgerald: Okay. Yeah. Call it 8-PN.
Dr. Betsy Redmond: Never been good with the pronunciation.
Dr. Kara Fitzgerald: I don’t pronounce well either, actually. Okay. What about it?
Dr. Betsy Redmond: That also has been noted as a really good phytoestrogen. Yeah. Interestingly enough, it comes from hops. But people who had higher levels tended to drink less alcohol.
Dr. Kara Fitzgerald: Interesting.
Dr. Betsy Redmond: You’d want to check that. I mean, they have had standardized extracts have been pretty good in some research. It’s alleviating menopausal symptoms. You would want to look where that is.
Dr. Kara Fitzgerald: In other words, you could predict whether your patient would respond to a hops-based intervention from menopause, or a soy-based intervention. If you’re using some of these for their other … the anti-cancer, the protective potential beyond just menopause, perimenopausal symptoms, these kind of metabolomic data would actually help there.
Dr. Betsy Redmond: Yeah. I mean, I think it would give you a picture that would give you direction. Yes, certainly, they have other … I put them into these categories in my head of phytoestrogens. But there’s so much overlap.
Dr. Kara Fitzgerald: There’s so much overlap. Yeah. It’s nice to actually have an understanding of that. Well, anything else that you want to add? As we just wrap up here, any other metabolites that are just really grabbing your attention in the literature these days?
Dr. Betsy Redmond: Well, the urolithins.
Dr. Kara Fitzgerald: Okay. Talk about those.
Dr. Betsy Redmond: Okay. They come down for the ellagitannins and ellagic acid. They get further broken down to urolithins and there’s A, B, and C. They just keep breaking down. But if somebody has a lot of the urolithins-A, it’s been associated more with ApoA and HDL. It has more of antiatherogenic impact. It has some good barrier function with AhR. That’s one you’d want as opposed to the B and the iso-A, those have been associated with increased risk of cardiovascular disease and dysbiosis. Even for response to statin therapy.
Dr. Kara Fitzgerald: Huh. That’s pretty interesting. Is that …
Dr. Betsy Redmond: Go ahead.
Dr. Kara Fitzgerald: You could be eating good foods, walnuts, pecans, what else is ellagic acid? Grapes, I guess that’s not so great. It’s very sugary. But some other berries. You could be eating a bunch of it and actually make a urolithin that’s not good for you. Is that what you’re saying?
Dr. Betsy Redmond: Yeah.
Dr. Kara Fitzgerald: Am I referring that correctly?
Dr. Betsy Redmond: Yeah. Urolithin-C and that’s going to be more in the small intestine. If you don’t end up metabolizing it, get to A or B.
Dr. Kara Fitzgerald: Wow. What’s extremely good for me …
Dr. Betsy Redmond: May not be extremely good for me.
Dr. Kara Fitzgerald: Depending on my gut. Depending on who’s living there. I mean, some really healthy foods, we think of ellagic acid as a good guy for all of us. It’s probably in berries.
Dr. Betsy Redmond: Yeah. But it’s really what is your gut bacteria
Dr. Kara Fitzgerald: What’s your microbiome look like?
Dr. Betsy Redmond: Maybe there’s bad guys live …
Dr. Kara Fitzgerald: Yeah, that’s pretty interesting.
Dr. Betsy Redmond: … living there. I mean, there’s also some other markers looking at enterodiol or enterolactone, those lignan-derived ones from cereal, seeds, berries. Those ones, they’re higher because it’s so difficult to make those a breakdown products. It’s really been used as a marker of just microbial diversity.
Dr. Kara Fitzgerald: They’re good guys? You want …
Dr. Betsy Redmond: They’re good guys. Right. Their conversion over is so dependent on all different activities and gut bacteria. That just by having them high, it indicates that you’ve already got pretty good gut diversity.
Dr. Kara Fitzgerald: Fascinating. Wow.
Dr. Betsy Redmond: It never stops.
Dr. Kara Fitzgerald: Well, I think … Yeah. It doesn’t stop. Yeah. Once you go into PubMed or Google Scholar or wherever you going, I think it’s exciting because it’s that much more precision. We can just tell that much more about the optimal diet.
Dr. Betsy Redmond: Right. It does, probably, just to hear people speak. It sounds confusing. But if it’s laid out well it won’t be confusing and you can figure out what products are the best or is it diet or do you need to move on and look at some gut activity. What’s actually living in your gut? I think, it’s not as overwhelming as it sounds.
Dr. Kara Fitzgerald: Well, I think a lot of people are going to be pretty jazzed up about it. Yeah. I think as long as … I mean I think, not everybody is going to be as geeked out as you are, Dr. Redmond. I mean, I think as long as we can bring the omics revolution to busy clinicians in such a way that it’s applicable in an informed but straightforward way, I think it’s where we’re going. It’s where we need to go.
All right. Well, listen. Again, folks on the shownotes, we will have loads of content for you. The papers that Betsy referenced and any of her … the papers that have really informed her thinking on these analytes, those will be on our show notes page.
Again, Dr. Redmond, it was just really nice to be able to chat with you today. I love it. I love what you’re thinking about right now and I look forward to seeing where it goes.
Dr. Betsy Redmond: Thank you. Yeah. I love having somebody who gets excited.
Dr. Kara Fitzgerald: Right.