Using Metabolomic Analysis For Clinical Insight

So many of us in functional medicine use standard organic acid interpretations, but newer research is using them in a broader metabolomics assessment (the vast landscape of clinically relevant metabolites). A great example is the assessment of in-born errors of metabolism. Utilizing metabolomics resulted in a six-fold higher diagnosis rate and identification of new in-born errors, compared to traditional organic acid assessment methods. Impressive, isn’t it? Think of what it could do in a full assessment.

I’m thrilled to be joined by my dear friend and metabolomics enthusiast Dr. Betsy Redmond in today’s podcast. I worked with Dr. Redmond back at Metametrix and deeply admire her passion and skill in bringing metabolomics into clinical practice. With years of experience in functional lab testing and a doctorate degree in nutrition, Dr. Redmond shares exciting pearls from the latest metabolomics research, including using urinary dicarboxylic acids to identify early cognitive decline and strategies to modulate the kynurenine tryptophan ratio (KTR) – a novel biomarker associated with inflammation, cognitive decline, and kidney disease. I was excited to hear that this ratio could also be used as an innovative biological age marker – a topic at the center of my recently published study on reversing epigenetic aging, and focus of my book, Younger You. Thanks for listening to New Frontiers; please leave us a review and comment to let us know what you think! ~DrKF

The field of metabolomics is rapidly evolving and grabbing the scientific community’s attention beyond the world of functional medicine. Apart from making tremendous contributions to the medical body of knowledge, metabolomics can be of great clinical value and help capture the very early stages of dysfunction and disease. In this episode of New Frontiers, we are joined by Dr. Betsy Redmond, senior education specialist at Diagnostic Solutions Lab and a clinical nutritionist with extensive experience in functional laboratory research. As an expert at translating current research into clinical application, Dr. Redmond guides us on how to assess metabolomic pathways in order to identify early patterns of chronic conditions such as Alzheimer’s and depression. Dr. Redmond also shares the latest evidence-based clinical interventions that can have a significant impact on patients’ metabolomes.

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.

New Frontiers with Dr. Betsy Redmond: The Ultimate Metabolomics Panel for Clinicians

Linus Pauling Institute

Studies/Articles referenced:

Effects of B-Group Vitamin Administration on Daily Change in Urine 2-Oxo Acids in Young Japanese Women

Tryptophan Metabolism in Inflammaging: From Biomarker to Therapeutic Target

Urine dicarboxylic acids change in pre-symptomatic Alzheimer’s disease

Stress and serum cortisol levels in major depressive disorder

Effect of S-equol and Soy Isoflavones on Heart and Brain

Comparison of Untargeted Metabolomic Profiling vs Traditional Metabolic Screening to Identify Inborn Errors of Metabolism

Metabolic phenotyping reveals a reduction in the bioavailability of serotonin and kynurenine pathway metabolites in both the urine and serum of individuals living with Alzheimer’s disease

Dr. Kara Fitzgerald: Hi everybody. Welcome to the New Frontiers in Functional Medicine where we are interviewing the best minds in functional medicine, and today is no exception. I am thrilled to be here with my very good friend, Dr. Betsy Redmond. She’s going to be talking to us today about all things metabolomics. Background on Betsy, I actually worked with her at MetaMetrics Laboratory many moons ago and we’ve stayed close in the years since that time.

She’s in private practice as a nutritionist. She’s a senior education specialist at Diagnostic Solutions Lab. She’s got her master’s degree in clinical nutrition from Emory, and she’s got a doctorate in nutrition from the University of Georgia. She’s got a lot of experience in functional laboratory research. Again, starting back at MetaMetrics with me over 15 years ago, Betsy tries to provide translational application by relating known and current research with clinical application.

And in fact, you’re really good at this. Before working in functional medicine, Dr. Redmond worked in university research and public health programs. You can find her on social media at Nutrition Provisions or, you can find her at Diagnostic Solutions. Betsy Redmond, welcome to New Frontiers.

Dr. Betsy Redmond: Thank you.

Dr. Kara Fitzgerald: It’s great, great to be with you. And I look forward to learning from you today, as you talk to us about… Really, this is a part two of the podcast. We’ll link part one in the show notes for those who are interested in bringing metabolomics into clinical practice. Betsy’s, this is her passion project. She’s put a lot of energy and sunk deeply into the science around this. So last time we talked and again, this will be in the show notes and any accessory, diagrams, papers, et cetera, to guide you in this podcast with Betsy, will also be in the show notes.

We talked about applied metabolomics and how it’s different than just looking at a list of organic acid markers. So many of us in functional medicine use urine organic acids, and you’re really arguing for us to move on beyond that. So let’s start about how you look at metabolomics in practice. In fact, let’s start with maybe a definition of metabolomics and then let’s move into, how you’re using them in practice.

Dr. Betsy Redmond: Okay. And you can pull me back anytime I go to into the weeds. So if you look at the NIH just defines metabolomics as the scientific study of chemical reactions that occur in organisms cells and tissues. So we’re just looking at all the different small molecules in body fluids and what they’re telling us. You throw a wide net and then see, what stories are being told with those.

And before I go into other kinds of processes, there’s an article that just came out. It was July 21 in JAMA, and it’s a study, and they compared traditional assessment of inborn errors of [metabolism] like inborn errors. And they compared that to metabolomics. So they looked at traditional assessment and then using metabolomics. So in traditional assessment of inborn errors, they look at symptoms, they do routine laboratories. If they notice something, they’ll do a follow-up, a biochemical testing or genetics, if you see something. So that’s how they normally do it.

So metabolomics uses this broader view of all the small molecules. So you’re throwing a wide net. So when they did it, they looked at 4,500 people while they were newborns, essentially. It’s 92% newborns, but the age range was zero to 80. And they looked at 2000 newborns with metabolomics. And using the traditional method, they found a diagnosis rate of 1.3%, and they identified 14 inborn errors of metabolism, that’s standard. But when they use metabolomics, they had a diagnosis rate of 7.1 and found 70 inborn errors. So six-fold higher, and it includes 49 conditions not currently included on the standard screen.

Dr. Kara Fitzgerald: That’s amazing.

Dr. Betsy Redmond: So they might not be those things that, you see all the time, like MSUD (Maple Syrup Urine Disease) or something that’s going to be really significant, but they might be things that affect people over a lifetime.

Dr. Kara Fitzgerald: So things that could be adult onset. So MSUD, maple syrup urine disease, the classic inborn error that might be identified. A lot of these early identifications, well with the old method, which is very insensitive. So it’s only going to capture 1%. They result in really egregious neurodevelopmental conditions. Isn’t that right, Betsy?

Dr. Betsy Redmond: Yeah. So there’s those things that stand out the most.

Dr. Kara Fitzgerald: Yeah. But here you’re arguing, so these reference ranges, so A, they’re looking at way more molecules in the metabolomic assay. And I would bet the reference ranges are much more sensitive. Is that right?

Dr. Betsy Redmond: Yeah. So they’re looking at much more detail. So they can tell more of a whole story. They looked at a specific pyruvate dehydrogenase alpha 1 impairment, and they looked at pyruvate lactate alanine. So that was something that’s  not going to affect you day to day. You’re going to make it to 10 years old.

Dr. Kara Fitzgerald: That’s so fascinating. Yes. Pyruvate is going to be converted into Krebs cycle intermediate. It’s hanging out there in the mitochondria. It’s associated with energy. So maybe this would be missed under standard analysis and cause problems, likely later on. I mean, back when you and I were at the lab, we were thinking about, we were looking at mitochondrial markers. I mean, we had a limited group of them that we could look at, but we were thinking about the so-called acquired mitochondriopathy, those things that happen because of life and medicine exposures, or toxin exposures, et cetera.

But really what you’re suggesting here in this JAMA paper, and again, what we will link to this in the show notes is ridiculously exciting. Is that with more sensitive reference ranges and looking at a broader panel, we could be picking up really important stuff early on. Are these things actionable?

Dr. Betsy Redmond: Yeah. You figure that they are. One of the things they looked at was short-chain acyl-CoA dehydrogenase deficiency, SCAD. And if you look in some of those databases, it’s like, well, it’s a benign condition. We don’t really care about it. Essentially that was my thought. But it’s like, it may not affect you. You may have a few markers. You may have some ethyl malonate or methylsuccinate or butyrylcarnatine.

But, I think that there may be a difference in those people, they might want to have different macronutrients. Maybe they’d benefit from some carnitine or, some B2 or something. But there are things that you could do. And if we don’t know what those are, we need to find out what those are. So kind of those mild things that we could look at.

Dr. Kara Fitzgerald: And often, so you just talked about fatty acid metabolism, via a handful of different polysyllabic molecules. But basically you’re talking again about mitochondria and making energy. And so the obvious issue could be, fatigue, or where there’s a lot of cell turnover issues there. So I always think of the gastrointestinal tract and problems there where it’s very highly energy demanding, or even heart health or brain where we use a boatload of energy again, and we’re using ketones and fatty acids and so forth. So maybe subtle perturbations.

Dr. Betsy Redmond: Right. I mean, to me, this article was just so exciting. It’s kind of-

Dr. Kara Fitzgerald: Yeah, it is.

Dr. Betsy Redmond: Conventional medicine is now like, hey, let’s look at this functional take on things. So conventional medicine is starting to see these. And so functional medicine needs to be ready. We need to get out there, get in with the researchers and see what, this is what you might be looking at or we’ve studied this. Or this is what’s said, but we need to prove that. So I think that just a good kind of… When they’re moving that over, it’s from birth on, you can start with a good metabolomics review.

Dr. Kara Fitzgerald: It’s so fascinating. So you’re arguing that we blast forward into a broader analysis than relying on our tried and true collection of about 40 markers?

Dr. Betsy Redmond: Yeah. I mean, when I look at the metabolomics process, I look at, looking at the whole pathways. So the more markers you can get in a pathway, you can see. And usually those are amino acids and it’s easy to see those breakdowns. Are there any bottlenecks in the pathway? It helps to have pathways in order so you can see them. But I also look at patterns of disease associations outside of that, because I think that’s a lot of research that’s coming out. Can you discriminate between types of depression or cognitive impairment and Alzheimer’s disease or specific metabolic disease?

Dr. Kara Fitzgerald: That’s so interesting. Can you give me… Listen, I just want to say something because it’s going to bug me otherwise. I just want to back up and say that this metabolomic analysis, the interventions that you mentioned are super safe and it’s not going to be risky for us to try to tweak these pathways, whether there’s good outcome or not. So I just want to hit that home. So if you give that.

Dr. Betsy Redmond: Right. Yeah. And-

Dr. Kara Fitzgerald: Right.

Dr. Betsy Redmond: … it may explain, like I wonder why this happens when I do this. All right.

Dr. Kara Fitzgerald: Yeah. Right.

Dr. Betsy Redmond: So I think they just give some insight.

Dr. Kara Fitzgerald: So a pathway that you’re looking at in your practice, can you give me just a basic over… Just give me the theme of what that pathway might-

Dr. Betsy Redmond: So is that same thing we’ve always been looking at A to B. So substrate to product, and what takes it over there is likely an enzyme, and that enzyme likely needs a co-factor, which is probably a nutrient.

Dr. Kara Fitzgerald: And the substrate is, as you were just saying, often an amino acid.

Dr. Betsy Redmond: Right. So like a tryptophan or a branched-chain amino acid, and looking at the substrate as part of the pathway, is that enough? Do you have enough? Is there too much? Does that substrate have lots of different pathways that can go in. Something I find interesting that I didn’t realize before – the branched-chain amino acids, they go through a transamination to become alpha-keto acids. And then the alpha-keto acids go through branched-chain keto acid dehydrogenases to move on into the Krebs cycle. But that branched-chain transamination reaction it’s reversible.

Dr. Kara Fitzgerald: So they can go back to keto acids or onto the Krebs cycle. But yeah, go ahead.

Dr. Betsy Redmond: Well, I mean, I think knowing all those specifics about the pathways makes a big difference.

Dr. Kara Fitzgerald: Give me an example. So you talked about the patterns associated with diseases and being able to suss out different pathophysiology. Using depression, can you give me how you might use these tools to identify different causes of depression?

Dr. Betsy Redmond: Well, I have some articles, but I can talk about that. I think that it’s a combination of different stuff. I think that one of the best examples of just looking at these pathways, are the co-factors. It’s the effect of B-vitamin groups. So I think I have that article posted in there. So it’s the fact of B vitamin administration on daily change in urine 2-oxoacids in young Japanese women.

And it’s a great article. And 2-oxo is alpha-keto. So it’s the same thing. Alpha-keto acids or 2-oxoacids. And I don’t know if maybe that’s like why, they have an earlier one in 2-16 and why it was missed by all of us. So they are going to what… They’re actually proving what functional medicine has been saying.

So we’ve been saying it without real human studies evidence and they happen to prove it. So hopefully we can bring on proof for everything else we’re saying. So what they did was they had a group of college women and they divided them to three categories based on their urine excretion of branched-chain alpha-keto acids, alpha-ketoglutarate, alpha-ketoadipic acid and pyruvic acid.

So they took their excretion, they added them up, and then they were placed in three groups. So the top tertile group had the most excretion and then the middle, and then those that really had minimal excretion. And they gave them B vitamin supplements and checked their urine every day for seven days. And in the upper tertile, the branched-chain keto acids decreased significantly in one day. They just came right down.

And in the middle tertile, they came down a few days later, and there was no change in the group that started with low alpha-keto acids. And then the other markers came down subsequently. But what I found really interesting was after seven days, they stopped the supplements and they waited a month and then they recollected the urine. And the total branched-chain keto acids had reverted right back up to the basal levels in the people who had the same high levels.

Dr. Kara Fitzgerald: What did they conclude?

Dr. Betsy Redmond: They conclude that there may be some minor enzyme alterations that aren’t, they’re not going to call it a true, what we think of as inborn error. They’re going to be fine, but maybe they’ll be a little more fatigued, like you said.

Dr. Kara Fitzgerald: Well, what about their diet though, did they do any dietary analysis? I’m assuming they were healthy at baseline, so maybe not like a malabsorption issue. But yeah, go ahead.

Dr. Betsy Redmond: Yeah. So they also, the same group has a 2-16 study, and it’s a really nice review of how the diet impacts. So they did the same thing where they grouped women into three groups based on alpha-keto acid excretion and gave them B vitamins. But when they first put them into groups, they looked at their diet. So they found that the intakes of calories, macro nutrients, and B vitamins intake and the excretion of B vitamins in the urine didn’t differ between the groups. You’d only find the women who benefited the most from the supplements by knowing their total alpha-keto acids excretions. So it’s not…. go ahead.

Dr. Kara Fitzgerald: Did they clinically notice any change with supplementation that they reported?

Dr. Betsy Redmond: They didn’t report it and it wasn’t a long study. And it’s not necessarily something that’s like, well, I never thought about. We talk about it, but the fact is that they had proved it. So it just feels better. When you know there are human studies.

Dr. Kara Fitzgerald: Absolutely. It’s very exciting because we’ve been thinking about this, well, going back to really like Linus Pauling, arguably the father of functional medicine has been talking about orthomolecular doses of nutrients to push biochemical pathways. And then Bruce Ames came and has, of course written and published on it extensively. And we adopted these ideas and then some in functional medicine, with the intuition that it’s right. But I agree with you, Betsy, it’s absolutely imperative that we put some solid controlled science behind it.

Dr. Betsy Redmond: Yeah. I think as it’s, we move forward and I feel like I should give a little shout out to the Linus Pauling Institute. They have a nutrition center and they give great information.

Dr. Kara Fitzgerald: Absolutely. I’m with you. I’m with you on that.

Dr. Betsy Redmond: And….

Dr. Kara Fitzgerald: I love it.

Dr. Betsy Redmond: … they give a lot of good pathways and summaries.

Dr. Kara Fitzgerald: Yep. They do. They really do due diligence in their investigation. We’ll put a link on for the Linus Pauling Institute, so you can find it if you haven’t been over there. All right. So what else do I want to ask you about? We were moving towards discussing how you’re doing this in practice. You’re looking at disease patterns, and talk about some of those patterns that you’re looking at.

Dr. Betsy Redmond: And so I’m trying to take the research that’s out there and what am I seeing in the results that I’m getting. Branched-chain amino acids and metabolic disease, I think that’s pretty much out there. I mean, it’s continuously noted, particularly with elevated branched-chain amino acids and metabolic signature, and it’s associated with diabetes.

Dr. Kara Fitzgerald: Why is that? Do you know the why? I’m sorry. I’m completely cutting you off. Keep going.

Dr. Betsy Redmond: Well, when I first heard it I thought, “Well, it’s related to obesity. Maybe people are just eating more. And so they’re getting higher blood levels.” They don’t think that’s it. So they’re looking more into it. But I think that’s like the first one that I really noticed. And then the other one that I’m looking at now is the tryptophan pathway, and I’m looking at the kynurenine to tryptophan ratio.

Dr. Kara Fitzgerald: Awesome.

Dr. Betsy Redmond: KTR…

Dr. Kara Fitzgerald: Do educate.

Dr. Betsy Redmond: I know. I’m always like, I’m hearing about this and it’s been around. So the KTR ratio. And it’s helpful to have that full pathway when you look at tryptophan breakdown with kynurenine. So last time, and we had talked about this, we talked about the end of the pathway in NAD. But the beginning of the pathway has some key regulations.

Dr. Kara Fitzgerald: Well, talk to me about it that. Just sketch out. So tryptophan is an amino acid, and talk about the kynurenine pathway and then give me the-

Dr. Betsy Redmond: So tryptophan, you get it from diet. It can go three main ways. It can go to serotonin. It can go to kynurenine or get changed into indoles. And most goes down, the vast majority goes down that kynurenine pathway. So when you’re deciding what’s… And usually it’s TDO is the enzyme, the tryptophan 2,3-dioxygenase is the enzyme that takes it down that pathway. So during inflammation, it’s going to be under the control of [IDO] (indoleamine 2,3-dioxygenase). So the kynurenine to tryptophan ratio has been calculated to estimate IDO activity.

Dr. Kara Fitzgerald: Interesting.

Dr. Betsy Redmond: So a lot of people probably, oh okay, that makes sense. But wait, it’s going to get more exciting.

Dr. Kara Fitzgerald: I don’t know that a lot of people would say that. This is a really unusual and exciting way to look at inflammation. Keep going.

Dr. Betsy Redmond: So it’s related to excessive chronic inflammation. And this is kynurenine not to be confused with kynurenic acid, kynurenic acid or kynurenate. That’s downstream. This is kynurenine. Kynurenine, it’s the main product. It’s the first stable product of the pathway. It’s the central node of the pathway. And so it can go in three major ways also. So it can get converted to 3-hydroxy kynurenine, which is a more neurotoxic pathway, which then goes onto quinolinate and xanthurenate.

It can get degraded to anthranilic acid with a B6 dependent enzyme. Or it can get deaminated to kynurenate via another B6 enzyme, which is more neuroprotective. So it can go all sorts of different ways. And then anthranilic acid can go back down into the 3-hydroxy kynurenine pathway. So there are a lot of ways. I always think, “Oh, I know this pathway.” And then when you start looking at some Kegg pathway, it’s going all ways.

Dr. Kara Fitzgerald: Yeah, I agree with you. The science in the tryptophan-kynurenine pathway is always evolving. I just wanted to say that people who are using organic acids, you look at kynurenate all the time. I think it’s on probably all of the panels in functional medicine. And when it’s elevated, we think about it being a B6 deficiency, when kynurenate is elevated. And I just want to AKA kynurenic acid. So it could be listed as either name, depending on the panel that you’re looking at. So kynurenate or kynurenic acid. And this is a downstream compound in the kynurenine pathway. Betsy’s talking about the kynurenine pathway overall. So she’s not specifically talking about kynurenic acid or she did just mention it.

Dr. Betsy Redmond: So it goes tryptophan to kynurenine, and then it goes to kynurenic acid or anthranilic acid or 3-hydroxy kynurenine.

Dr. Kara Fitzgerald: So it’s got three different fates.

Dr. Betsy Redmond: Yeah. And break down further. So I think it’s that tryptophan to kynurenine. So you can’t really take it right to the other one. I mean, there are some other good articles that look at that. There’s tryptophan metabolism and inflammaging, which is a biomarker of a therapeutic target. It’s Frontiers in Immunology came out October 2-19. And it’s a cool article too. It looks at two things, tryptophan depletion, that are related to the KTR.

And so necessary to control inflammation. So it’s looking at tryptophan depletion and kynurenine activation. So tryptophan depletion is going to influence nutrient sensing. So it’s something like GCN2 kinase is activated and that produces anti-inflammatory kinases, cytokines, and then activation of the IDO enzyme, which can prevent inflammation and promote tolerance.

And then mTOR is activated during tryptophan sufficiency. So they’re both important for metabolic control. So you’re looking at changes in tryptophan and then activations, increases kynurenine. So kynurenine can activate the AHR, the transcription factor to control local and systemic immunity. So there’s a lot of involvement here with the immune system. So higher kynurenine increases T reg cells and that’s via the AHR pathway. So essentially you want to lower the KTR ratio. You don’t want tryptophan to get depleted or kynurenine to build up.

Dr. Kara Fitzgerald: Can we measure kynurenine directly?

Dr. Betsy Redmond: Yes, yes. You can measure in the blood and in urine. So you can measure it directly. And the KTR levels, they’ve been associated with all sorts of things in research. This is what made me think like, why isn’t this out and about? BMI, obesity, inflammation, renal failure, chronic kidney disease, cancer, sepsis, pregnancy.

Dr. Kara Fitzgerald: Oh my goodness.

Dr. Betsy Redmond: Reduced cognition. So a high KTR in plasma or urine in a study of older adults was related to all-cause mortality.

Dr. Kara Fitzgerald: So you just got through introducing us to the kynurenine pathway with how complex it is and the different arms that it can take, like the different metabolic end points it can go to. Some beneficial, others not. But then you’re circling back to the very beginning of the pathway, which is tryptophan being converted to kynurenine. And that ratio, so when kynurenine is higher than tryptophan, even though some of those derivative molecules might be beneficial, over-arching when that ratio is skewed, it is pro-inflammatory and associated with everything from obesity to cognitive decline, et cetera. Is that correct? Am I understanding that?

Dr. Betsy Redmond: You are understating it correctly.

Dr. Kara Fitzgerald: Awesome. All right. I agree with you. I think, it would be really nice to have that ratio and to really infer, or have another solid biochemical metabolomic marker for inflammation, beyond some of the standard tried and true things that we look at that aren’t that sensitive. Like CRP is great when it’s great. The sed rate is great when it’s great, but we obviously miss a lot of inflammation with those two markers. I think it’s just as you said in the very beginning, we need to be casting this wide net. And it’s exciting. I mean, it’s exciting that there’s so much science behind it.

Dr. Betsy Redmond: I mean, certainly the KTR ratio, they propose it as meeting the criteria for biological age marker. So the kynurenine to tryptophan ratio, the KTR, they’ve proposed it as meeting the criteria as a biological age marker. And what’s interesting in other studies is like vitamin B6 has been negatively correlated to the ratio. So it may be higher if you’re B6 deficient. Weight loss has resulted in a decrease of the ratio.

So along with a decrease of tryptophan, kynurenine, and CRP and an increase in vitamin B6. So that was a single study. But they have preclinical and clinical studies that have revealed that there’s are also a variety of probiotics, that have lowered the kynurenine to tryptophan ratio.

Dr. Kara Fitzgerald: That’s fascinating.

Dr. Betsy Redmond: There was a study that they find it did that. And it also alleviated depression symptoms.

Dr. Kara Fitzgerald: I wanted to circle back to that and spend a little time on our opener, just the fact that tryptophan makes serotonin, and if it’s all being diverted down this, the kynurenine pathway, it’s like a serotonin steal. Would you say that’s accurate?

Dr. Betsy Redmond: Yeah. I mean, I think it’s a percentage. I mean, I think that’s the thing that they’ll say, that there’s no tryptophan to make serotonin, which can also be impacted with gut. So I had another article that I was looking at of the ratio looking at tryptophan with Alzheimer’s disease. I’m not at all an Alzheimer’s expert, but I know that we’re all concerned about it because, we’re headed that way. So there’s going to be so many people who develop Alzheimer’s as the decades go on and the population ages, and then they think there may be an impact with COVID.

So there’s an article, and I think it’s linked in there that metabolic phenotyping reveals a reduction in the bioavailability of serotonin and kynurenine pathway metabolites in both urine and serum of individuals living with Alzheimer’s disease. And that came out in January, 2021. And they looked at metabolic phenotyping. They looked at 560 people urine metabolites, and 350 with serum. And they had people divided into Alzheimer’s disease, mild cognitive impairment, and normal cognition. So you kind of want to get yourself earlier on that spectrum.

But Alzheimer’s disease was associated with impaired kynurenine pathway and inflammation. And disruption in serotonin signaling, both pathways. It’s just the same with depression. I mean, they both get impaired. So overall with the Alzheimer’s patients, there was an overall trend for lower tryptophan metabolites in those with Alzheimer’s disease compared to mild cognitive impairment and normal. So it was graded in all of them. So all those tryptophan markers were going to be lower in Alzheimer’s disease.

So it was most significant in serum tryptophan, kynurenine and xanthurenatic acid. And then serum kynurenine and urine 5HIAA. So the breakdown product, 5-hydroxy indole tryptophan, the breakdown product of serotonin. Both of those correlated positively with age. I mean, I think the earlier study I talked about, their big thing is as you age, inflammaging, kynurenine is going to go up and tryptophan is going to go down

Dr. Kara Fitzgerald: Because it’s just being pushed into the kynurenine pathway.

Dr. Betsy Redmond: Yeah. There’s inflammation just with aging.

Dr. Kara Fitzgerald: So the indoleamine dioxygenase enzyme is turned on in the inflammatory journey, pushing tryptophan towards a pro-inflammatory kynurenine pathway.

Dr. Betsy Redmond: Mm-hmm (affirmative).

Dr. Kara Fitzgerald: Versus the other enzyme that’s kind of the, if I’m using it correctly, the constitutively active enzyme, the TDO enzyme that will take kynurenine to NAD. So that TDO is going to be overwritten by IDO in the inflammatory journey?

Dr. Betsy Redmond: Right.

Dr. Kara Fitzgerald: Is that right?

Dr. Betsy Redmond: Yeah. So I think, just, yes. So I mean, in their study, they even found that the urine kynurenine to tryptophan ratio was higher in Alzheimer’s patients, and it positively correlated with MMSE, the mini mental state exam.

Dr. Kara Fitzgerald: Interesting. And what about the mild cognitively impaired folks, were you able to pick up some of these perturbations on a continuum?

Dr. Betsy Redmond: Yeah.

Dr. Kara Fitzgerald: Were there some more abnormalities, so we could use this as an early investigation?

Dr. Betsy Redmond: Exactly. It was graded. All the markers were graded. They just tanked down.

Dr. Kara Fitzgerald: Interesting.

Dr. Betsy Redmond: They also talked about, which I thought was interesting, the fecal calprotectin, which is a marker of intestinal inflammation. They found it to be negatively associated, they’re talking about other studies, with serum essential amino acids in people with Alzheimer’s disease. So they’re wondering, is there a disturbance in the intestinal barrier, that function leading lowering of the ability to absorb essential amino acids.

Dr. Kara Fitzgerald: Interesting. So calprotectin, which is a marker of inflammation, when it’s very, very high, we want to be thinking about cancer, but it is evidence of inflammation in the gut. So when that creeps up, it was associated with lower circulating essential amino acids?

Dr. Betsy Redmond: Yeah. I mean, part of it they’re wondering like, when people have Alzheimer’s they have altered appetite and things. But was this making an impact? You wonder about serotonin, that’s all in the gut and how that’s also being impacted.

Dr. Kara Fitzgerald: Well, and just the fact that you said earlier that probiotics could favorably influence the tryptophan-kynurenine ratio.

Dr. Betsy Redmond: Yeah.

Dr. Kara Fitzgerald: So that just linking those together, starting with the gut, again, a key area. I guess, I think of to, just knowing that some of the microbes, and if they’re out of balance, will act on tryptophan and gobble it right up. And so it makes sense to me that, a good probiotic protocol could perhaps shift that. Right?

Dr. Betsy Redmond: Yeah. I think that it’s the whole picture.

Dr. Kara Fitzgerald: Well, listen, let me ask you something that just going back to this. So you’re working with a patient. I mean, how are you going to… And you see that they’ve got an elevated kynurenine and tryptophan ratio, maybe we’ll throw in an elevated calprotectin or some… I mean, how are you thinking about them clinically? What are you doing with them?

Dr. Betsy Redmond: Well, I’m going to think that I want to bring it down. I’m going to look at, where they’re at, what they’re actually doing. But then I’m going to look at, the things that have been proven. Do they need any weight loss? That seems to be helpful. Do they have any need for B6? How is their nutrient status, their level of inflammation? And then just overall gut bacteria. I mean, I think that, my thing, and I think we’ve probably discussed this.

One day you’re going to get all your SNP’s and all your gut bacteria markers, and all your amino acids and organic acids, and you’re going to file everything, inflammation and file it into a big AI thing and it will tell you what you need to do. And that probably will only last until you bring things in balance, just given your environment and everything.

Dr. Kara Fitzgerald: So we’ll use artificial intelligence to crunch many, many, many, many data points and spit out the decidedly individualized plan for us at that moment at that snapshot.

Dr. Betsy Redmond: Right. It gets to be a lot when you were trying to pull all these things together.

Dr. Kara Fitzgerald: Well, you’re a real, you’re not artificial intelligence. You’re real intelligence. Yes. You’re doing it. You’re RI. You’re the RI right now.

Dr. Betsy Redmond: I mean, I was going to say one of the other things that I always look at is that, that glutamine to glutamate ratio.

Dr. Kara Fitzgerald: Well, before, I want to talk about that ratio. But I’m curious about the probiotics that brought down the KTR. What are they? Do you know? Do you remember? Or can we link to that paper?

Dr. Betsy Redmond: Yeah. I’ll link to that.

Dr. Kara Fitzgerald: Let’s link to that paper. I’m curious about that.

Dr. Betsy Redmond: You’re having trouble staying focused. You want to run and get that article right now.

Dr. Kara Fitzgerald: No. But I meant to circle back to it. It sounds to me like you’re doing pretty good. You’re taking a good functional medicine approach. So the patient presents it to you with complications X, Y, and Z. And of course you’re considering those, but then obviously you’re thinking about gut health. You’re thinking about absorption and digestion, et cetera. You’re thinking about nutrients and what they might need to do if they need to lose weight, or if they need to be engaging in exercise, et cetera, et cetera. But it sounds like it’s a good systems/functional medicine approach.

Dr. Betsy Redmond: Yeah. I mean, you may end up doing the same things that everybody needs to do. It’s with more evidence of its requirement.

Dr. Kara Fitzgerald: There’s a refinement there. I mean, as you pointed out, who doesn’t want to be correcting a very evidence informed underlying cause of Alzheimer’s, that’s going to walk you strongly on that trajectory. And the myriad associated conditions like diabetes and depression and obesity, et cetera.

Dr. Betsy Redmond: Yeah.

Dr. Kara Fitzgerald: And as you said, before aging.

Dr. Betsy Redmond: Yeah. Everybody comes in with aging and then whatever else they bring along with it.

Dr. Kara Fitzgerald: All right, I do indeed want to know about the GSG index. So talk to me about that ratio.

Dr. Betsy Redmond: I mean, I think that’s just one I like to look at. I think I’ve written that blog years ago on that. And it just, the GSG index was positively correlated with liver enzymes, and it was able to discriminate stage of liver fibrosis. And so it may help and identify severity of liver disease. So I think that’s just a nice one. I mean, obviously it’s not, they’re not diagnostic, but they do go a direction.

And then the other one I look at is what I call the castor ratio. So that ratio, it’s proposed by somebody who wrote an article, their last name was Castor. So I’ve been calling it that. And the article they had was urine dicarboxylic acids change in pre-symptomatic Alzheimer’s disease reflect a loss of energy capacity and hippocampus volume. It’s from Plos one, 2020. I thought this one was really exciting too.

Dr. Kara Fitzgerald: That’s really interesting.

Dr. Betsy Redmond: So what they did was they looked at urine dicarboxylic acids of carbon lengths of three to 10, and then they did an MRI in the group of older adults. And the study participants were divided into two main groups, neurological study. They did some neurological studies and they put them in two… And then they also did beta amyloid and tau ratios based on cerebral spinal fluid. And they had them in cognitively healthy and clinically probably Alzheimer’s disease.

But then they took the healthy group. And then they sub divided that into asymptomatic, low risk individuals. So who had normal amyloid tau ratios. And then asymptomatic high-risk individuals who were cognitively healthy, but had pathological amyloid tau ratios. I’d be scared to be in that group. I know you’re good now, but… So it’s the same thing with looking at the KTR ratio and Alzheimer’s mild cognitive impairment.

So they wanted to see, what happens with that? So they found that the DCA’s, the dicarboxylic acids had an 82% ability to predict cognitively healthy participants. So with normal spinal fluid amyloid tau. And that they reported that in Alzheimer’s disease compared to the controls… This is where it gets interesting if I’ve lost you.

Dr. Kara Fitzgerald: No, we’re here. I’m here.

Dr. Betsy Redmond: That urine, so when they looked at it, the C4, which is succinic acid and C5, which is glutaric acids were both individually and together lower in Alzheimer’s disease. And C7, which is pimelic acid, C8, which is suberic and C9, which is azelaic acid, were all individually and as a group higher in Alzheimer’s compared to healthy controls. And it’s associated the ratio, with an accumulation of amyloid. So what they’re saying is to look at the mean values of C4 and C5, and then have that a ratio with the mean values of C7, 8, and 9. So what you really want is higher, lower short chain C4 and C5.

Dr. Kara Fitzgerald: Higher smaller ones.

Dr. Betsy Redmond: Yeah. And lower C7, 8.

Dr. Kara Fitzgerald: But what if you don’t, what do you do? What’s the intervention?

Dr. Betsy Redmond: I think that they, it’s more of identification and those kinds of things that you’re going to find like where-

Dr. Kara Fitzgerald: So you are-

Dr. Kara Fitzgerald: … using it as a diagnostic tool.

Dr. Betsy Redmond: Yeah. I mean, it’s obviously not diagnostic of Alzheimer’s disease.

Dr. Kara Fitzgerald: Or suggestive. Suggestive of early, potentially early, another early perturbation that we could identify.

Dr. Betsy Redmond: Right. So they’re looking at the difference with it. So if you have an impairment, when you look at C4 and C5, those are maybe dysfunctional brain mitochondria may account for that dysfunction. I mean, succinate and gluturate are going to contribute to energy metabolism. And so that may impact mitochondrial function. You look at the group as a whole, and if you download the article, which is a great article and it has good diagrams, which I always appreciate. And when they break them down, succinate by far is the highest. It’s 40%. And all the other ones are anywhere from one to 14%.

Dr. Kara Fitzgerald: And what’s the carbon length of succinate?

Dr. Betsy Redmond: Succinate is the four.

Dr. Kara Fitzgerald: Four. So then the way that I would use it, because again, just thinking about translating this into clinical practice is, you’ve got this abnormal ratio, the castor ratio in a cognitively solid individual, or maybe there’s some early cognitive shifts, really regardless, I guess, of where you are on the continuum. But if we were using this as a preventative analysis, I mean, we’re going to get in there with all of the other usual functional medicine areas. So you talked about the tryptophan-kynurenine ratio being off, or it’s kynurenine-tryptophan ratio. You’re just going to cast

Dr. Betsy Redmond: KTR.

Dr. Kara Fitzgerald: But you’re going to just cast that wide net. So even if there isn’t necessarily a specific intervention for the castor ratio, you’re going to be doing everything else and then retesting.

Dr. Betsy Redmond: Right. And you’re going to look, are those energy things. And there’s also, when they look at the long ones, the C7, 8, and 9, and those are like suberic, pimelic. So that’s the once you often look at. So they are looking at, it’s proposed that there’s this fragile double bonds and unsaturated fatty acids within the brain, and that those are going to increase. So that you’re going to have tissue loss progresses and it’s been proposed that those fragile double bonds… I get also excited.

And unsaturated fatty acids are going to increase and it’s going to because them to break down. And that ultimately those are going to get excreted in the urine. So they’re proposing that those DCAs are formed from oxidation of the breakdown of unsaturated fatty acids. So urine levels of the C7 and C9 positively correlated with cerebral spinal fluid tau levels. And higher level of those were also associated with lower hippocampal volume.

Dr. Kara Fitzgerald: That’s so fascinating.

Dr. Betsy Redmond: C4 and C5 is associated with more energy efficient balance. So you can then like what is that oxidative stress? What are those things? How can you fix any energy efficient balance? As much-

Dr. Kara Fitzgerald: I like it.

Dr. Betsy Redmond: … as you can, but I think it’s just really nice to give you, and it’s also graded. So the people who have the normal cognition are going to have those high C4, C5 and low 7, 8, 9, and then that flips when you look at Alzheimer’s. But they’re about equal when you look at the people in the middle, who are normal cognitive.

Dr. Kara Fitzgerald: So let me just ask you, I mean, your head is in the science. So you have a clinical practice, but you’re spending a lot of time tweaking these and thinking about them and then, applying them as much as you can in clinical practice. I know we haven’t had these tools at the ready just yet. I obviously, I hope so soon and I know people listening, everybody’s ears are perking up because we have a Alzheimer’s epidemic.

I mean, I’m thinking about Dale Bredesen, who, I’ve been chatting with recently. I did a, published our own study, looking at aging that I was talking to you about before. And he is interested in whether his Alzheimer protocol reverses biological aging as well. And they’re doing a broad functional/systems approach and getting remarkable turnaround.

And I can’t help but wonder about what’s happening in the metabolome with the participants. Since they’re improving, they must be turning these around. And it just would be a cool thing to use there. But I digress from my original point here, which was, we need assistance. We’re all, not an AI brain like yours. We’re not spending our time in the literature on these. And so we’re going to need some handholding, some easy turnkey tools to be able to identify the ratios, to identify the associations and the imbalances. So I just, do you have any thoughts on that? Like how are we going to use this in a very busy clinical practice, with two minutes to digest this?

Dr. Betsy Redmond: I wouldn’t say because it’s my brainiac, it’s probably because I’m at home reading articles and you guys are out living hip lives.

Dr. Kara Fitzgerald: You’re so funny. Indeed. No doubt.

Dr. Betsy Redmond: That’s right. I see you in the club scene. So I break it down when I look at it, I look at six main areas that I’m really looking for. So I look at all those markers that are associated with metabolic issues, like the key metabolic issues getting into the Krebs cycle. I look at the breakdown of all the amino acid pathways like what are those? So those pathways. I look at, are there any key nutrition things that I think that are relating to those? Just the toxins, I look at stress and mood, and then I look at the metabolites that the microbial might be given off. So I just try to-

Dr. Kara Fitzgerald: You break it down.

Dr. Betsy Redmond: Yeah. I break it down-

Dr. Kara Fitzgerald: Soundbite it.

Dr. Betsy Redmond: … to those kind of… Yeah, soundbite it so I can see what’s going on where. I mean, there’s not one easy way. That’s why it takes a lot. So I’m trying-

Dr. Kara Fitzgerald: Well, you’re going to make this doable for us when we’ve got a real-time metabolomics assay, you’re going to be… We’ll meet again, and you’ll walk us through an easy interpretation. I’m thrilled about it. I mean, gosh, Betsy, you have such a command of the literature and I’m as excited about you as you are with the possibility, especially given the fact that there’s human studies and I know forever your entire career you’ve been really wanting to find the human data and encouraging people to research it.

And these aren’t little numbers. We’re not talking about N of six. I was looking at the number of participants in an earlier study you referenced, and there were almost 8,000 people, in one of the kynurenine and tryptophan ratio study. So it’s just, this isn’t chump change research, and I appreciate you bringing it front of mind. So let’s see, as we did… Well, actually, I’ve got two more questions for you. So you’ve got these six areas that you look at, which seems essential to have some kind of a easy pattern analysis. But do you see a lot of overlap within these areas?

Dr. Betsy Redmond: Yeah. I do. I do see significant overlap. Certainly, they don’t just go straight down by themselves. So you’re going to have to see what’s going on. I think something I like to look at, try to find out is, is looking at cortisol and its impact in some of these. Certainly cortisol it’s going to have an impact on tryptophan breakdown on-

Dr. Kara Fitzgerald: Sure.

Dr. Betsy Redmond: … methylation down, with phenylalanine. So those are also related to mood. I think I listed… There’s a nice, small, simple 2020 study about stress and serum cortisol levels in major depressive disorder. And it’s not groundbreaking, but it’s nice that they just look at high cortisol as one of the relevant mechanisms involved in response to stress, and it’s present in people with major depressive disorder.

And they find that in people and unfortunately in animals subjected to stress. So they really aim to investigate, what the levels of stress and cortisol in major depression. And I like the study, partly because it was done at the laboratory of translational psychiatry. And it’s done in Brazil and then partly at university of southwest Texas. And I thought, “I want a laboratory of translational, internal medicine of gastroenterology. I want everybody to have that.”

Dr. Kara Fitzgerald: Yeah.

Dr. Betsy Redmond: So just higher cortisol levels. And so I think that’s a good one to throw in. So urinary..

Dr. Kara Fitzgerald: Well, there’s an inverse relationship and cortisol and brain size, I believe. Right? And specifically like the hippocampus.

Dr. Betsy Redmond: Yeah. Looking at that whole HPA axis, I’m a big believer in, just the whole circadian rhythm. And circadian rhythm is not one rhythm. It’s all those sleeping, eating, all those kinds of things. And looking at the HPA axis too. And then just, where is their cortisol levels? What’s happening at that point? Are they getting any elevated cortisol or-

Dr. Kara Fitzgerald: Sure.

Dr. Betsy Redmond: … corticoid resistance? Like when you look at cortisol, there’s the urinary cortisol measurements and that can look at cortisol secretion over time. Maybe, as more reliable than plasma or salivary, which are going to be subject to diurnal variations, fluctuations. And unless that’s what you want to look at. So about 1% of the plasma cortisol-

Dr. Kara Fitzgerald: Well, it’s easier to collect. And then arguably, I’ll just put you on the spot. Isn’t the collection itself potentially stress inducing if you’re getting a blood draw?

Dr. Betsy Redmond: I guess, for some people. Yeah.

Dr. Kara Fitzgerald: Anyway.

Dr. Betsy Redmond: For some people certainly, and having to get up and go.

Dr. Kara Fitzgerald: And go. Yeah. Who wants to go to-

Dr. Betsy Redmond: the lab.

Dr. Kara Fitzgerald: Right.

Dr. Betsy Redmond: they want to stay home

Dr. Kara Fitzgerald: That’s right. Especially if it’s fasting, you can’t have your coffee. I won’t say whose issue that is.

Dr. Betsy Redmond: It’s probably equal.

Dr. Kara Fitzgerald: Well, then coffee would influence your cortisol as well.

Dr. Betsy Redmond: It would. And it’s going to make a lot of downstream things. I think it’s about 1% of the plasma cortisol is excreted in the urine. But I’ve also seen studies where a spot urine gave comparable results to 24 hours. Which I think is stress-inducing to have to carry that jug around for 24-hours.

Dr. Kara Fitzgerald: That’s right. That is so funny. We need to do a study on the influence of different collection methods. I mean, I remember at the lab when we would be working on a different analysis and there’d be urine jugs, everybody would be testing. Everybody would be involved in sample collection, all of us.

Dr. Betsy Redmond: Which worked fine if you’re working in a lab.

Dr. Kara Fitzgerald: If you’re actually in a lab, nobody cares that there’s urine jugs.

Dr. Betsy Redmond: If you’re out to dinner and you have to run get your jug.

Dr. Kara Fitzgerald: You have to get your urine jug.

Dr. Betsy Redmond: I’ll be right back.

Dr. Kara Fitzgerald: That’s right. Oh my goodness. That’s so funny.

Dr. Betsy Redmond: So just that there’s research that the amount of cortisol in the urine reflects the average cortisol in the blood. So I like that study because it was simple.

Dr. Kara Fitzgerald: That’s cool.

Dr. Betsy Redmond: Cortisol is a good marker to help bring some other things together.

Dr. Kara Fitzgerald: I think it is a useful marker. All right. So we’re on the home stretch here and I just want to ask you one more question. I mean, we know from back in the day that there are, that our gut microbe makes all sorts of metabolomic compounds, the compounds have their own, metabolic activity. And some of these are relevant and some of these are probably pretty useless and just being eliminated in our urine as they should be. But what are some of the markers that you’re looking at thinking about these days?

Dr. Betsy Redmond: For microbial stuff, it’s my new favorite. I look at everything. I want to look at amino acids or polyphenols are going to get metabolized. But specifically I’m looking at like isoflavones. I think, equol, when you look at that research, just looking at urinary equol was really helpful clinically to get some direction. I mean, it’s the assumption that, some clients, they’re going to take isoflavones or some are going to eat soy, and are they getting a benefit from it? And you just don’t know.

Dr. Kara Fitzgerald: Well, give me the background. Why do we care about equol?

Dr. Betsy Redmond: Well, there’s a lot of research. Research suggests, equol is anti-atherogenic. It improves arterial stiffness. It may prevent coronary heart disease. It’s been related to cognitive impairment and function. There’s actually a NIH study of equol producers in Alzheimer’s disease that started in 2-17 and it finishes next month. So that’ll be interesting. Equol producers compared to non-producers. It’s like, ah, fingers crossed. You’re an equol producer.

Had significantly lower prevalence of coronary, the calcium score, the CT score. There’s a big study in 743 women, and equol producers had significantly lower brachial ankle pulse weight velocity, lower femoral pulse velocity, and coronary artery calcium score. So they are all going to help predict future coronary vascular events. It may have greater cognitive benefit than just dietary soy, because equol has higher antioxidant properties. It’s got greater or similar affinity for estrogen receptor beta. It’s got longer bioavailability and the ability to increase mitochondrial activity than just dietary sources. So it has a lot of benefits, but-

Dr. Kara Fitzgerald: This is awesome. We have to actually… So it’s bacterial or gut microbiome acts on the soy that we’re consuming, whatever that is and converts or doesn’t to equol?

Dr. Betsy Redmond: Right. It’s gut bacteria. It’s not genetics. So when they look at Western populations, only 20 to 30% are equol producers, but it’s much higher up to 75%, maybe even higher in Asian populations, but it’s not genetics. It’s gut bacteria.

Dr. Kara Fitzgerald: It’s amazing.

Dr. Betsy Redmond: Once you get there, it’s pretty stable, they find. And I’ve seen some reports that vegans and vegetarians are going to be higher, maybe not quite as high as aging populations, but, Westernized vegans and vegetarians are going to be higher. And there are some studies that have converted people. You’d be an equol converter. It takes a little bit of time and it may be that vegans and vegetarians are getting soy and they’re building their gut bacteria.

Dr. Kara Fitzgerald: That makes sense. Well, it’ll be pretty interesting to see… The bugs that are able to produce equol, we don’t know who those guys are. Do we?

Dr. Betsy Redmond: No.

Dr. Kara Fitzgerald: That’s so interesting.

Dr. Betsy Redmond: I mean, I didn’t see them in the literature, and that’s where AI learning’s going to find that.

Dr. Kara Fitzgerald: That’s going to be super. Well, not only that, but maybe the other nutrients being consumed with soy. If you’re eating a veggie burger McDonald’s equivalent and a whole bunch of processed garbage, are you going to be making equol as efficiently from that veggie burger soy meal versus somebody who’s consuming like a fermented soy with a ton of greens. It’ll be interesting to see how the soy needs to be consumed. I guess we could look to Asia. We could look to soy preparation there, which is interesting. Like fermented or not, fermented or with what.

Dr. Betsy Redmond: The young kids who were starting to have a coke…

Dr. Kara Fitzgerald: Are they making Equol? Fascinating. I’m with you. I’m a big fan of the possibility of equol. I know there’s a stable equol form is available now as a supplement. But what does that… I think that they did a study looking at hot flashes. I don’t know how large it was or anything like that, but it showed some benefit. And I don’t know whether we’ll start to use supplemental equol. But I am a big fan of soy-based isoflavones. I mean, I think they’ve got a lot of potential. And I’m paying attention to whether or not we can activate to this all-important equol. I think is really pretty cool.

Dr. Betsy Redmond: And maybe if you are a producer, you can take advantage of that. And if you’re not, maybe, I think there’s certainly should be more research on it.

Dr. Kara Fitzgerald: We need more research because it’s not the only-

Dr. Kara Fitzgerald: It’s not the only player from soy that’s beneficial. So I don’t know that we would say you can’t make good equol, therefore don’t consume soy, but maybe we would lean heavier on different polyphenols, flavonoids compounds

Dr. Betsy Redmond: I think we’re going to find the pathway to become a producer. And certainly like soy has protein. It has isoflavones. And both have different benefits. And maybe, the September 30th, when the NIH trial comes out, they’ll have some more information. So that’ll help find how to convert.

Dr. Kara Fitzgerald: That’s fascinating. Good call. We’ll pay attention. Let me know. Keep us posted. I’d love to post. Keep us posted and we’ll post on it when that study comes out. Well, listen, Dr. Redmond, it’s always good to get to connect with you and hang out with you in cyberspace and pick your amazing brain and get up on the current omics. So do keep us posted. And again, folks, you will find the many citations Betsy referenced in the show notes as well as a link to our first conversation. And anything else that she finds along the way that she feels she needs to post.

Dr. Betsy Redmond: That could be dangerous.

Dr. Kara Fitzgerald: It could be dangerous.

Dr. Betsy Redmond: It’s fascinating.

Dr. Kara Fitzgerald: I’m sure it’ll be valuable and maybe funny too. All right, Betsy, thanks again for joining me.

Dr. Betsy Redmond: Okay. Thank you.