Guests: Dr. Jonathan Bortz, Balchem Corporation; Dr. Mark Manary, Washington University School of Medicine; Dr. Rima Obeid, Saarland University Hospital; Dr. Susan Smith, University of North Carolina Nutrition Research Institute; Dr. Isis Trujillo-Gonzales & Dr. Evan Paules, University of North Carolina Nutrition Research Institute; Dr. Bryan White, University of Illinois; Dr. Julia Maeve Bonner, Sanofi; Dr. Stephen Hursting University of North Carolina Nutrition Research Institute Today’s episode was filmed at the Future Directions in Choline Symposium put on by the University of North Carolina Nutrition Research Institute.
Today’s episode was filmed at the Future Directions in Choline Symposium put on by the University of North Carolina Nutrition Research Institute.
Our day two episode opens with Dr. Eric Ciappio and Dr. Jonathan Bortz of Balchem, summarizing day one’s focus on pregnancy and early life and previewing day two’s focus on the latest choline research targeting adult nutrition. (1:03)
The next guest on our roster is Dr. Mark Manary, a professor of pediatrics at the Washington University School of Medicine. Mark’s symposium talk discusses choline and food aid. Food aid products are specially designed to address needs from crisis situations. These specialized food aid products are standardized to meet great deficiency or inadequacy needs. On the most extreme side, there is a product called ready-to-eat therapeutic food for children who are starving to death. Other food aid products include those for severely underweight children. Dr. Manary’s research consists of clinical trials in sub-Saharan Africa that include different nutrients in food aid to see if there are improvements in children’s responses. One trial with the inclusion of DHA found a 6-15 IQ point difference by adding fish oil or DHA. Mark hypothesizes that a doubling of that effect will be observed when choline is added. (6:42)
Dr. Rima Obeid from Saarland University Hospital in Homburg, Germany, joins us next. Her symposium presentation focused on choline and pregnancy outcomes. Their research group has found that low or insufficient amounts of choline in the mother’s diet during pregnancy are associated with a higher risk for serious birth defects in babies and that the liver health of the infants is also negatively affected by low choline intake of the mother during pregnancy. Rima’s future research includes investigating the impacts and interactions of folate and choline consumption during pregnancy on neural tube defects such as spina bifida. In another study, she will focus on the relationship between the severity of congenital heart defects compared to neural tube defects. In particular, they wish to look at the association with low choline in the blood of the children, the mother and the father, because a pilot study suggests a family pattern, which could be due to some genetic background. (17:18)
Our next guest is Dr. Susan Smith, Deputy Director of the University of North Carolina Nutrition Research Institute. One of her presentations centered on choline genetics and cognition. Her research has found genetic variation in choline uptake from the diet. One research question was, “Are there choline variants that affect how powerful that choline is in treating a disease condition?” In particular, Dr. Smith was investigating if choline could be used to treat children who have brain damage from prenatal alcohol exposure, and the answer is yes, it’s very helpful. Then, they evaluated if some children benefit more than others and found that there is a gene variant that affects how efficiently choline is absorbed from the diet. Children with the variant that reduced choline uptake benefitted the most from supplemental choline. In addition, there was an impact of the gene variant on cognitive function regardless of prenatal alcohol exposure. Children who carried one or two copies of this particular variant had reduced cognitive performance as compared to those children who were lucky enough to be born with the other variant. While we still don’t have a blanket recommendation for how much choline pregnant women should consume, Dr. Smith’s message to pregnant women is that eating enough choline lets your baby achieve its full potential. (23:32)
Dr. Isis Trujillo-Gonzales and Dr. Evan Paules, both with the University of North Carolina Nutrition Research Institute join us. Isis focuses on choline and brain/eye development, while Evan focuses on choline and metabolic health. Dr. Trujillo-Gonzales’s research has found that the neurons in the eye that receive light and connect to the rest of our brain are impacted by choline absorption. Her lab has also investigated the mechanism of action for choline’s effect on brain development. The stem cells in the brain that give rise to neurons are very sensitive to choline availability. If a pregnant mom is not consuming enough choline, these cells in the baby’s brain are not proliferating adequately. Choline is important in the microRNA that fine-tunes the regulation of this pool of stem cells. Dr. Paules’s research is focused on the metabolic symptoms of obesity and the impact of choline on them. For example, giving choline to someone who is deficient can ameliorate the symptoms of fatty liver disease. One area emerging in his work is the loss of lean mass as people age. It appears that increased loss of lean muscle is observed in people who aren’t consuming adequate choline. This suggests that as we age, making sure we have sufficient amounts of choline intake may help prevent the loss of lean muscle tissue. (32:58)
Dr. Bryan White with the University of Illinois is our next guest, and his area of interest is the microbiome. In particular, he discusses the role of the microbiome in TMAO production. TMAO (trimethylamine N-oxide) is a metabolite that has been associated with cardiovascular disease. In short, the microbiome produces TMA (trimethylamine), which is converted to TMAO in the liver. Some of the seminal TMAO literature suggests that there is a diet effect on the production of TMAO and that diet changes the microbiome so that more TMAO is produced in the bloodstream. When it comes to microbiome research, there are generally four questions that can be asked about the microbial community: 1) Who's there? 2) How many of them are there? 3) What can they do (given their genetic potential)? and 4) What do they do? The seminal research used 16s ribosome technology to evaluate which microbes were present and their abundance in the microbiome of people consuming omnivorous versus vegetarian diets. It stated that there was a correlation between diet and blood levels of TMAO. Dr. White took the small read archives of that manuscript (the sequencing they did of 16s ribosomes) and got the opposite results of the original paper. (42:25)
Our next guest is Dr. Jonathan Bortz with Balchem Corporation, whose presentation was titled, “TMAO and Choline: A Mechanistic Perspective.” In the last several years, there have been concerns about choline advanced by a group of investigators who have claimed that excessive intake of meat, eggs, and other animal-source foods (resulting in choline and/or carnitine upon digestion) generate a substance in the blood called TMAO, trimethylamine oxide. Their hypothesis has been that TMAO has a negative effect on the cardiovascular system and has been associated with a high incidence of cardiovascular disease. However, Dr. Bortz presented multiple examples of how the concerns about choline with respect to TMAO having a causative effect on cardiovascular disease really cannot be supported. In other words, choline does not represent a risk to any users, young or old. (51:42)
Dr. Julia Maeve Bonner with Sanofi joins us next to give an overview of her presentation about choline and Alzheimer’s disease. In her postdoctoral work at MIT, Dr. Bonner focused on the apolipoprotein E (APOE) gene, which is involved in making a protein that helps carry fat in the bloodstream. Dysfunction in this process is thought to contribute to the development of Alzheimer’s. APOE4 is the most highly validated risk factor for Alzheimer’s. Dr. Bonner wanted to understand what is happening in APOE4 high risk allele compared to the APOE3 neutral risk allele of this gene in brain cells (astrocytes) in culture. She found that the APOE4 astrocytes accumulated neutral lipids, particularly triacylglycerols, to a much higher degree than APOE3 cells. These lipid droplets is associated with many different dysfunctions in the cell that can be associated with neurodegeneration. If APOE4 cells were grown in a choline-rich media, the lipid imbalance was shifted much closer to the APOE3 cells. Dr. Bonner’s group was able to pinpoint that phosphatidylcholine synthesis is the mechanism of action by which choline supplementation had the lipid-shifting effect in APOE4 cells. She has also studied choline supplementation in mice that have Alzheimer's disease genes knocked in where they accumulate the plaques that we see in human brains in Alzheimer's disease. In the background, they also have the human APOE knocked in, which means that they're expressing either APOE3 or APOE4. Again, they saw a protection against the accumulation of some of the Alzheimer’s-related damage as well as a lipid shift similar to the brain cell cultures. (1:03:00)
To summarize the Future Directions in Choline Symposium, Dr. Dr. Stephen Hursting and Dr. Susan Smith with the University of North Carolina Nutrition Research Institute join us. They give their perspectives on the advancements of the field of choline research and leave us with the take-home message that choline is a critical nutrient for the entire healthspan. (1:22:27)
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Scott (00:00:14):
Good evening everyone, and welcome to the Real Science Exchange, the pubcast where leading scientists and industry professionals meet over a few drinks to discuss the latest ideas and trends in the world of nutrition. Today is day two of the directions in future Directions in Choline Symposia here with the University of North Carolina. And I have two guests with me. First is Dr. Jonathan Bortz. Jonathan is the VP of Nutrition Science at Balchem. And Dr. Eric Ciappio, he's a manager of Nutrition Science, also at Balchem. Gentlemen, we had a great day yesterday here at the Symposia. Learned a lot, Eric. The first day was all about choline and prenatal nutrition and choline and early life and childhood nutrition. What were some of your key takeaways from day one?
Eric (00:01:03):
You know, I think for me, it is just so incredible to see how far the field has advanced even in my time with just my time with Balchem. You know, we're fortunate to be in a world now where there's been a lot of randomized controlled trials showing the benefits of choline supplementation during pregnancy, and how that impacts offspring development. So what we saw yesterday at the sessions, was the benefits of choline supplement maternal choline supplementation in terms of baby's cognition both immediately after birth and persisting up to seven years in life. Improvements in DHA status as well when choline and DHA were given together. We also saw a lot of incredible data on the ability of choline to support, we call fetal resilience. It's ability to sort of adapt and, and deal with external stressors, be it emotional stressors that mom faces, be it exogenous toxin stressors that mom may consume.
Eric (00:01:58):
The abilities that choline seems to demonstrate in early life are really Rimarkable. We also had a good discussion on choline and lactation and how some of the specific metabolites of choline were present in breast milk and some of the differential effects of that, which is an area that does not get enough attention, sadly. So just a lot. We also had a good discussion on the role of choline and food aid and how adding choline to certain food aid programs might benefit in terms of areas of severe acute malnutrition. So, a really broad range, and, and we really took the charge of trying to identify the role of choline in early life nutrition broadly, and I think that's reflected by its really varied roles and, and the varied clinical trials that are out there. So, a really, really exciting day yesterday.
Scott (00:02:52):
Yeah, it was a great day. Just as a reminder to our audience that we released day One's podcast last week, please go back and listen to that one full of great details and information there. Dr. Bortz day two's coming up. We're gonna shift gears just a little bit, and we're gonna be talking about choline and adult nutrition. What's some of the things the audience gonna expect to hear from today?
Jonathan (00:03:15):
Well, Scott, first of all, let me say this, about five years ago when some of the very exciting information was being developed and generated by the, our clinical investigator collaborators about the benefit during pregnancy and children, and so on and so forth, I remember having a meeting with some potential customers who were impressed with all the data. And when everything was said and done, they turned around and said to me, well, what about us? And what that did was it opened my eyes at that time to say we really needed to expand our vision into childhood young adulthood and, and beyond adolescence and into you know, into the benefit for, for mature, you know humans. And I think what we're gonna see today with the focus yesterday being on the prenatal early childhood and childhoods, what we're gonna focus on are some of the challenges that we see in our health environment today with obesity, with the development of radio silent epidemic, with fatty liver, with cognitive decline. So we've invited really the world's leading investigators in these areas to come and share with us their science, and they're literally breaking news or how they're looking at things. So I, I'm anticipating a very exciting day in a new chapter, and that is how coding affects all of us from prenatal all the way through to old age.
Scott (00:04:57):
Yeah. Great summary. Great way to kick off day two. Looking forward to it. Thank you, gentlemen. So our next guest is Dr. Mark Manary. He's a professor of pediatrics at Washington University School of Medicine in St. Louis, Missouri. Dr. Manary you gave a presentation, we'll be given a presentation later today called Choline and Food Aid. Gonna start off by telling us just a little bit about food aid and, and what that is and what's it, what it does it entail.
Mark (00:05:32):
Well, food aid products are specially designed to address needs from crisis situations. So, you know, right now we have a huge crisis in Gaza. And so the, what's needed there are these specialized food aid products. They're, they're standardized, okay. For, to basically to meet needs of great deficiency or inadequacy. And so on the most extreme side, we've got something called ready to use therapeutic food for children who are starving to death. And we're not talking about people who are poor or don't have shoes or, you know, may, may not be eating like they should. We're talking about people that face a serious compromise, even death in a few months if they can't get the proper food. So that's one of the food aid products. And then for children who are just morally underweight in the process of starving, we have other food aid products. Choline is not prescribed in any way in these products. And as an essential nutrient choline seems to be kind of, you know, is a lap behind many other nutrients, you know, in catching up. And so our goal of this investigation is to place co choline in food aid and say, Hey what happens?
Scott (00:06:54):
Okay. So it's kind of a research project then, is what you're doing with food aid?
Mark (00:06:58):
It's a, yeah It's a clinical trial. So in other words, thousands of children who are receiving this food aid will be given either food aid with choline or the standard food aid. Okay. And will and will measure in some cases, cognition in other cases. What, how well they recover.
Scott (00:07:20):
And where's this research taking place?
Mark (00:07:22):
This is gonna take place in Malawi, a place that I've been so parenthetically I'm introduced as someone from St. Louis, but where I work is in Sub-Saharan Africa. Okay. And that has been the case for a really long time. Okay. 1985. And so I have four teams each in different countries, about 200 people who work for me, and we're doing trials and food aid is one of our primary focuses.
Scott (00:07:55):
Okay. And so when you put this trial together, what's your hypothesis? What, what are you anticipating that you'll see?
Mark (00:08:01):
I anticipate that we will see we saw a six to 15 IQ point difference by adding fish oil or DHA. And when we combine that with choline, I'm expecting we'll see a doubling of that.
Scott (00:08:17):
And is that a certain age that you administer the choline, or does it matter?
Mark (00:08:20):
It's administered when they're, when they're severely malnourished. Okay. So it doesn't, it isn't a well population, it's a population that's starving to death. And typically most of those kids are under two but they're almost never under six months.
Scott (00:08:37):
And so your presentation is gonna be basically just kind of outlining the research that you're doing and the expected outcomes
Mark (00:08:45):
Yeah. And talking about the stuff we've done in the past. Okay. So the, the A trial with DHA, one of the really exciting things about doing trials like this that are in in the vernacular, they would say, well powered, which means that there's thousands of participants, which means that the outcomes of any 10 participants can't really bend the data one way or another. Is that then you're in line to change policy. Okay. So what we did with the DHA trial was we took that to the WHO, then we took it to Codex Aria. So that is the FDA of the world, if you will, the international FDA. And now every child who gets ready to use therapeutic food has to have DHA in it. Or the balance of the kind of fatty acids that constitute DHA Omega-3 polyunsaturated fatty acids.
Scott (00:09:42):
And so boy, I had another question here. Go ahead, Tom. Yeah,
Tom (00:09:46):
No, thank you. Documentary. I have an interesting question based on, we've seen, and actually we'll see from other presentations here at the symposium, that there's definitely a prenatal impact of DHA and choline combined in terms of providing greater DHA status or, or more beneficial. Do you think that's true postnatally as well? Does that hold firm, or,
Mark (00:10:09):
I don't know. I mean, we were talking about the trial just now having to do with children, but we also are doing a trial with malnourished pregnant women. Okay. Right now in Sierra Leone, we're adding DHA and choline to malnourished women. Okay. So women not, no, not all pregnant women, but just the ones that are, that are starving and looking at cognition in the babies. I mean, certainly the
Mark (00:10:43):
You know, it's hard, do I have an opinion on whether this is just a developmental issue, I think is what you're asking. So if you don't get it at the time, development's going on Yeah. Versus an ongoing issue. I'm gonna guess that it's, that it's an ongoing issue. Choline's the kind of metabolite that's used every day for everyday work of the brain. And, and so having periods of your life when you don't have choline, I imagine if you then added it back into your diet, you would see better performance or something. Whereas I think, I don't think, you know, you would, you can have things that happen during very formative points in, in your life, your, those like being in the womb, being in the first six months of life and so forth, that stick with you forever.
Tom (00:11:37):
Okay.
Scott (00:11:37):
You know, one of the questions you are, one of the, the statements you made is that your research you're hoping that it'll help direct policy. Now, is that gonna be a policy just for malnourished children, or, or is this gonna be broader in looking at other children that are not necessarily severely malnourished?
Mark (00:11:56):
No, I mean, the policy we're talking about has to do with what is in food aid products, food aid. Got it. So food aid products have a certain, you know specification and you can't say that something is RUTF when it doesn't meet these 335 specifications. And choline is going, as we're hoping is going to be one of those.
Scott (00:12:19):
Okay. Alright. Very well, Tom, anything else?
Tom (00:12:24):
Just that I, I think one of the things we've seen, we've talked a lot about cognitive is do you think there's gonna be benefits? Because one of my understanding is that one of the consequences of low choline is potential liver problems. So do you see that as something that you're looking at or
Mark (00:12:40):
We're not specifically looking at it. I mean we have very strongly believe that fatty liver will be diminished with choline supplementation. The populations we work with in Sub-Saharan Africa just really aren't obese at all. Right. And so, you know, why do we say, oh, well, fatty liver's such a big problem going up Oh, in our society has to do with obesity. Right,
Tom (00:13:09):
Right. Yeah. Okay.
Scott (00:13:11):
Very well appreciate you joining us today. Just kind of one final question. Would you mind kind of giving us just one key takeaway for consumers out there? One takeaway from the research that you've done, whether it's DHA with choline, what would be one message you'd give them?
Mark (00:13:29):
Well, I guess the message I, the message I would, would impart for consumers is that getting ample amounts of choline from commonly used foods, particularly plant-based foods, is difficult. And so there has to, you know, the consumers need more help in how to achieve that
Scott (00:13:56):
Very well. Maybe just kind of as a follow up, that, so it's difficult getting it for plant-based foods. So what are some foods that are, perhaps rich in choline, that we should be consuming?
Mark (00:14:08):
So the bugaboo with that particular question is that, yes, there's some choline in milk and there's choline in peanut, but if you had to increase your consumption high enough in those foods to get to these levels that are being talked about next door, that's not realistic. Got it. You, you know what I, I'm saying that that's why my message was, it was tricky to get there. Yeah. And, and I'm not using the word supplement on purpose Okay. But, I am intimidating behind that, that it might be something that is better addressed for many people through a supplement.
Scott (00:14:47):
Yeah. Very well. Yeah.
Tom (00:14:49):
Yeah. I think that's a really good point, because what we've seen definitely is anyone who's on a plant-based diet, just like they have to worry about B12, they worry about choline as well. And so I think, you know, it's always going to be food first when you talk about policy, and I get that, but liver just isn't eaten in great quantities anymore, and eggs are often very challenging, you know, for people. So,
Mark (00:15:12):
Yeah. Yeah. And the populations I've worked with in Sub-Saharan Africa are eating animal source foods once a week. Yeah.
Tom (00:15:20):
Yes. That kind of thing.
Mark (00:15:21):
It’s not, yeah. It's just not part of the, yeah.
Scott (00:15:25):
Great. It's been a great discussion. Dr. Manary, thank you for joining us today and thank you for everything you do.
Mark (00:15:31):
You’re welcome.
Scott (00:15:39):
And we're back at the future directions in Coaling with my co-host Tom Drew. Our guest for this session is Dr. Brian White. He's professor emeritus from the University of Illinois. Now, this week we've been having a two day symposium. We're in the middle of that. After the symposium, we're gonna have a scientific advisory board, and Brian's gonna be giving a talk to that advisory board. Brian wants to give a just a kind of brief overview, kinda the big rocks of what your presentation's gonna entail.
Brian (00:16:10):
Sure. So, the microbiome has been implied into TMAO production, and then the negative effects of TMAO that primarily in cardiovascular disease, that cardiovascular disease side of the story, is way outside of my expertise. My expertise is in the microbiome and the gut. And so the question comes, what is the role of the gut in the production of TMAO that gets into the bloodstream of humans. And so there's been a lot of work out of primarily Stan Hayden's lab. That's shown a few things that are indisputable. So the indisputable thing is that microbes produce TMA. Yeah. TMA is taken up across the gut wall, and then in the liver is converted to TMAO.
Brian (00:16:58):
Can't dispute that. What you can dispute from the literature is that there's a diet effect on the production of TMAO. And that the effect of that diet changes the microbiome in such a way that more TMAO is produced in the bloodstream. Okay. And when I've looked at the literature for this effect, there's a couple of published papers that really were not reviewed very well.
Brian (00:17:31):
So the manuscript in, in most questions, the COS 2013 paper and figure two is, is really very poorly, was very poorly reviewed. And the data that I have taken from their small read archives. So I look at the microbiome, and the microbiome is a community, and you can ask a couple of questions. You can ask four questions, really. You can ask who's there, you can ask how many of 'em are there, you can ask what they can do that's genetic potential? And then you can ask, what do they do? And the simplest thing to do is to find out who's there. And in a rough sense, how many are there? That's using 16 s ribosome technology, which is what is done in the coast paper. And so they took individuals giving different diets, omnivores versus herb or versus vegetarians, and asked who was there and how many there?
Brian (00:18:29):
And then they tried to correlate that to blood levels of TMAO. And in the paper, it looks pretty reasonably clear that there's a correlation between diet and blood levels. But if you take apart that, that figure too carefully, and then I took the, their small read archive, the, the sequencing that they did of 16 s ribosome A and I did the analysis myself, and I got different results, and my results would be completely opposite of theirs. That there's a diet effect, and that there's a correlation between the microbiome in those diets and blood levels of TMAO. So through that exercise, I've contacted the authors. The authors have, in some cases, been cooperative in saying, yes, we can give you data, which is fine. Don't necessarily agree with me, with my results. They said I did different methodologies. So I went back and I did their methodology. Now, the problem is that paper was done in 2013. I can do probably 80% of exactly what they did, the other 20%, because databases have changed. Technologies have changed. I can't reproduce. But the bulk data does not match their data. There's no correlation between diet and there's no correlation between TMA levels in the blood with, with their cohorts.
Tom (00:20:04):
Would you say Dr. White, that it's like, is it a, you now have finer tools to analyze, or was it a matter of what they had at the time, you know, wasn't necessarily drawing the same conclusions? Or have you learned things since, I guess is my question?
Brian (00:20:21):
We have learned the same things since, but they to me, and I, I've been doing this since 1987, before a lot of people were doing it, they didn't present two critical pieces of data or one, one critical piece of data, let's say. And these are called PCO, and they are dots, the dots in space, if you've looked at a microbiome paper, they're the dots in space. And you draw a circle around the Dotson space and, and you can get two distinct sets of dots in space. Those pcos are based upon sequence similarity between communities. They did not present those pcos. They did a rough statistical model, which you can do on a computer, and it throws out numbers and says they're different. I never publish a paper, submit a paper. And, and this is, goes back to before they submit theirs without pcos.
Brian (00:21:13):
If your PCO don't show clear circles, then there's no difference. And, when I redid their data and then generate PCO there's no difference. And the statistics show there's no difference. It's a finer level of analysis, but they had all the data to do it. It's literally a push of a button in about 48 hours of CPU time unsupervised. Why they either, they say they did not do that. They just used the statistical model. I have no idea. But if, but if you saw those, you'd go.
Scott (00:21:53):
So it's created a, a bit of a controversy,
Brian (00:21:56):
A big controversy. Yes.
Scott (00:21:57):
And so what are the next steps to get to the bottom of this? Right. 'cause I'm assuming they're saying they're right, and you're saying you're not so sure.
Brian (00:22:06):
So the literature since that is, is, is mixed as well. Okay. I mean, you can find probably as many papers out of the literature that say that TMAO levels in the serum is linked to the biome, as you can say, is not again, the indisputable thing is, is that that microbes in the gut produce TMA, but is that, can you correlate that to blood levels? And I haven't seen much in the literature that convinces me that the community structure, the presence of those organisms that do produce TMA is correlated or associated with blood levels of TMAO.
Brian (00:22:45):
So it's, it's the, the hazing group has taken their set of data and they've gone to march with it. And there's plenty of data out in the literature, which is contradictory to that, contradictory to that. But it's, they're, they're going with their story. Yeah. Now, he just recently post a paper, and I'll present a little bit of this CSAB meeting where he tried to correlate or Purdue predictive modeling of the organisms in the gut and their genes, and try to say, can we use a study where we have cohorts that have high TMA versus low O? And can we look at the gene content and the organism content in the gut, this community structure analysis, who's there and what's their potential to predict blood levels of TAO? And guess what they couldn't. Now the fallback is you're not looking at activity, which is the last piece of that puzzle, just because they're not, they're, you don't have a correlation of the gene content. Right. Doesn't mean you don't have a gene, a correlation of the activity. I would suspect that they're not gonna find that if they look at it.
Tom (00:23:58):
Yeah, well, this is, this has been super fascinating. I think we're gonna hear a lot of other talks about TMAO and some of the causality versus the association and all that. But it's fantastic to hear some of this deep dive into the microbiome piece, which clearly is your area of expertise.
Brian (00:24:13):
So we appreciate it. Well, one thing with almost all the microbiome studies out there causation is the gorilla in the room, and there's really only one disease that has been absolutely correlated to the gut microbiome. And that's c diff.
Brian (00:24:31):
All the rest of them, there's, there's associations, but the causation root has never been defined for any other disease. So is it the microbiome that causes the disease or does the disease change the microbiome? And the only one that's been established for is c diff out of all, all the ones that are out there. So it's
Tom (00:24:51):
Great context.
Brian (00:24:52):
Yeah.
Scott (00:24:53):
Well, thank you for your time today. Thank you for being a part of our advisory board. And look forward to talking to you later on today. Thanks very much.
Brian (00:25:01):
Thank you. Appreciate it. Thank you.
Speaker 7 (00:25:10):
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Scott (00:26:20):
And we're back with Rima Obeid from Saarland University Hospital in Holberg, Germany, I believe it or not. Rima, I'm also somewhat from Germany. I was born in Frankfurt. Did not stay there very long. My father was in the service. But I've got that little bit in common. You gave a presentation earlier today called choline and pregnancy outcomes. Can you kind of just give us a real top line overview of some of the things you covered in your presentation?
Rima (00:26:49):
Yes, indeed. We have shown that if the choline amount in the diet of the mother is low or insufficient this will mean higher risk for getting a child with serious birth defects. And this will also affect the liver health of the fetus and the infants.
Scott (00:27:12):
Oh, that's very interesting. Now, did you happen to follow some of the health impact on the babies after they were born? Like the immune function or anything like that?
Rima (00:27:23):
No, indeed not. But the study that we published is showing that if choline is sufficient during lactation, this will be good for the liver of the infants, the breastfed infants, of course.
Scott (00:27:42):
Okay. And did you share with the audience some research that you've done personally there?
Rima (00:27:49):
Yeah, we have done a recent systematic review and meta-analysis on the association between the dietary intake of the mother of choline and the risk of neural tube defects.
Scott (00:28:04):
Okay.
Rima (00:28:05):
Like spina bifida, for example.
Scott (00:28:07):
Okay. Tom, do you have anything?
Tom (00:28:10):
Yeah, I think just one of the things that we, we actually talked about with someone else is, I think we hear a lot in pregnancy circles about obviously the risk of preeclampsia or in some cases, gestational diabetes, these types of things. Do you think potentially, you know, given the discoveries you've had with liver health, could that be an issue for mom too with you know, having liver issues during pregnancy? Because obviously a lot of that choline is going to the baby.
Rima (00:28:34):
Yeah, indeed. We speculate about this right now, and there is a biome mechanism or biochemical pathway justifying that if you give more choline, then the risk of diabetes or preeclampsia could be lower. But we don't have concrete studies on this right now.
Tom (00:29:00):
So more research still needed. Yeah. Okay. Well, that's interesting.
Scott (00:29:03):
So, along those lines, what kind of research do you have planned for the future?
Rima (00:29:08):
Well, for the near future, we are doing more research on neural tube defects, like spina bifida and the interaction between choline and folic acid or folate, because, you know, folic acid is standard in prenatal nutrients or supplements, but not yet choline everywhere it should be. And we are looking at the interaction between them so that if the status of folate in the mother is low, then the importance of choline would be even more. So this is one study. The other study is on the relation between the severity of congenital heart defects, which is very common compared to neural tube defects. So we have 1% of the bursts with heart defects, and this is a real problem with long term and high costs. So we are looking at the association with low choline in blood of the children, the mother and the father, because we have seen in a pilot study that there is a family pattern, which could be due to some genetic background.
Scott (00:30:25):
Hmm. Oh, that's very interesting.
Tom (00:30:27):
Yeah. Yeah. I think given the fact that you've been doing a lot of research, it sounds like we know that choline adequacy during pregnancy is really, really important both to the health of mom and the baby. If you met a mom on an, on the elevator on your way outta here what would you say just to her in a few sentences about choline and things you've learned? What, what recommendations might you have?
Rima (00:30:47):
Well, indeed, we know that from population studies that in general, women in pregnancy age are not achieving the adequate intake of choline. And that's why I would advise all women to take choline from pre-pregnancy until the end of lactation if they are not able to achieve this through the normal diet.
Tom (00:31:10):
Right. 'cause that can be a challenge.
Rima (00:31:12):
I know. Yeah. It is a challenge, especially because the natural sources of choline are rich in, in lipids or in fats, and this is not the kind of diet usually consumed during pregnancy. You know, women try not to gain too much weight and so on. Yeah. So supplements could be a good alternative.
Tom (00:31:34):
That’s great.
Scott (00:31:35):
Yeah. Great advice. Just kind of wanna follow up with one final question. So what is the recommended rate that, that, that you recommend in Germany?
Rima (00:31:42):
The total intake is currently, it's not my recommendation. I mean, we, we, we have, like, the recommendations are set by authorities, and it's in Germany, like similar to the US 450 milligram per day during pregnancy and 550 during lactation.
Scott (00:32:03):
Okay. Very good.
Tom (00:32:04):
Yeah. So that's the minimum amount should be getting,
Rima (00:32:06):
That's, that's the, the minimum amount. What is the meaning of minimum amount. I mean, even for this adequate intake level, we don't have so strong evidence, but at least this amount should be achieved. Yeah. Right.
Tom (00:32:23):
Okay. Great.
Scott (00:32:25):
Rima, it's been pleasure meeting you. Thank you for joining us today.
Rima (00:32:27):
Thank you very much.
Scott (00:32:29):
You’re very welcome. Thanks.
Rima (00:32:29):
Thank you.
Scott (00:32:38):
And we're back with Dr. Susan Smith. Susan is the Deputy Director of UNCs Nutrition Research Institute. Susan, you gave two presentations today. One was titled Choline and Genetics and Cognition. The other is the blanket recommendation. So why don't we start off with the first one. What was kind of the overall thesis of, of, of the talk that you gave there today?
Susan (00:33:02):
Sure. So we know that genetic variance in choline metabolism is important. What people don't realize, you know, we talk about genetic variants, and we think these are rare things out there, and most of them, fortunately, are rare, but in nutrition, they're actually fairly common in our population. And they reflect what the geographic location were we involved in, and what our dietary practices were in that location. Maybe we were within a group that had a high fish consumption, or maybe we had low access to meat, or maybe high access to milk and meat products. So that can capture gene variants and allow them to be spread in that population because of their diet practices. That was great, maybe 12,000 years ago. But today, with our modern McDonald's diet, we now have this mismatch between what we were consuming then and what we're consuming now. So we worry about this a lot because we all carry these variants.
Susan (00:34:11):
They can be anywhere from 1% to 10% to 50% in a population, and we're only just now discovering what these are. And they affect a whole range of risk factors. For example, Alzheimer's disease, our heart disease may be at risk for kidney failure. So we've all heard about these, but a lot of us don't understand or don't know that they also affect our nutritional needs. So that's the avenue that my work is entering from. And we were looking at choline and asking, are there choline variants that affect how powerful that choline is in treating a disease condition? And the situation, we were looking at our children who had unfortunately prenatal exposure to alcohol. Mm-Hmm.
Susan (00:35:22):
And a very important nutrient that we already know about for this is choline. And we've talked a bit about in the podcast, and you've chatted with others about how important choline is for brain health. So we asked a little portion of that question and said, in children who have, you know, brain damage from alcohol exposure, can we use choline to treat this? The answer is yes, it's very helpful. And what we did was we looked at the genetic piece. Are there some children who benefit more? And the answer was definitely yes. And so there is a gene variant that affects how efficiently we absorb choline from the diet. Okay. Alright. And this variant, some people absorb it better, and some people absorb it worse. And it's a common variant. It's between five to 40% of the population in the us. And it turns out that people who had the variant that reduces your ability to take it up, they benefited the most from the choline.
Tom (00:36:33):
There was a bigger gap to fill
Susan (00:36:34):
Because there was a bigger gap to fill. That's exactly right. Right. And so that was a very exciting to see. So now we know who to target this to.
Tom (00:36:44):
I think what's so encouraging about that to me is, you know, it's, it's hitting it from two points. Number one, I think a lot of times people think, well, what you do during pregnancy, that's, it's done. You know, there's nothing you can do. And I think you're giving us hope to say there are things you can do after the baby's born Absolutely. To help improve brain development, et cetera, and recover from some of those things. But then on the other level, we're gonna get more information as time goes on, about the specific needs of each person. Yeah. Is that something someone might get from like a 23 and Me eventually? Or is it specialized now?
Susan (00:37:17):
Possibly. I will tell you that 23 and Me is getting most of their information from folks like me.
Tom (00:37:22):
Yeah. Okay. That's good to know.
Susan (00:37:23):
So, it's out there and the information base is growing. I don't think they've got this one yet.
Tom (00:37:32):
Fascinating. Yeah.
Susan (00:37:32):
So the other piece we then looked at in that question was we said, okay, if this gene really helps fill the gap, then the prediction is that people who aren't getting choline will have poorer cognitive function because that gap isn't getting filled. Right. So we went and we looked at that, and to our surprise, it, that gap exists. But it wasn't just for the alcohol exposed children, it was for all the children.
Susan (00:38:07):
To all the children. And the children who carried one or two copies of this particular variant had reduced cognitive performance as compared to those children who were born lucky enough to have the other variant.
Tom (00:38:24):
Wow.
Susan (00:38:25):
Even though they were all eating the same diet, presumably.
Tom (00:38:31):
So this kind of ties interestingly into the title of your second you know, to talk, which I know is the blanket recommendation and the idea of, well, how much should mom be getting? Maybe talk a little bit about that part of your speaking.
Susan (00:38:44):
Sure, we don't have a good answer yet, unfortunately, but we know that it's very likely that of all the moms in this study, we're not getting enough. Just because we know in the US population, most pregnancies are not consuming enough choline. The message hasn't gotten out the way we should. So on average, they're getting maybe 50-60% of what they really need. So maybe the, the, the pregnancies where they have the, the good, I don't wanna call it really a good variant or a bad variant, but the variant that has strong choline uptake, you can muddle through on that. And they're okay. But the pregnancies where they have the allele that, or the variant that isn't so good at absorbing choline. Now if you've reduced the intake, that's a double whammy. And maybe those pregnancies would have a much better outcome if those pregnancies were able to hit that requirement and hit that target. And we think that's correct from other studies that have been done in humans showing that when the women consume enough pr choline to hit that target, that there's significant improvement in the outcomes. So we think some of those pregnancies are probably this variant.
Tom (00:40:08):
This is really fascinating research, and I think, you know, for those of us who are in the field and understand a little bit about choline, it's super exciting. One of the challenges we always face is how do you translate this to a message that just everybody can, if you were to run into a mom, for example, walking outta the conference today, and she were to ask you you know, what do I need to do with choline? Why should I be concerned? What might your few messages be in layman's terms?
Susan (00:40:32):
I mean, the best message is that eating enough choline lets your baby achieve its full potential.
Tom (00:40:39):
That's a great message.
Susan (00:40:40):
You don't wanna limit that potential.
Tom (00:40:42):
Yeah. That's good. That's good. I think we had a, we had a really interesting talk when we went to the ACOG earlier in the year. And one of the things was you know, we basically said to our you know, as the message on our board, we said, imagine a nutrient that could change your baby's life, but 90% of moms aren't getting enough. Yeah. So I think that's really the message we gotta get out there.
Susan (00:41:04):
Yeah. Yeah. I mean, in pregnancy, of course, it's a really hard time because everybody's messaging, you do this, do that, don't do this, don't do that. This is one where it's so simple. Yeah. And it's a huge, if you will, bang for the buck, there's such a large benefit, and the risk from it is very, very, very small. So it's, you know, a can't lose situation.
Tom (00:41:30):
Yeah. That's great to hear. Yeah. Dr. Smith, you're a great
Scott (00:41:32):
Ambassador for the cause and thank you for helping us get the word out there. Right. We're doing the best we can. And I'll ask if you will forward this podcast around when it comes out. Sure. Will do. Sounds good. Thank you for joining us. Thank you for inviting me.
Speaker 10 (00:41:47):
Thank you so much.
Scott (00:41:55):
And we're back. And this time we've got two guests and a new co-host, Dr. Eric Ciappio, gonna serve in the co-pilot seat on this one. My two guests are Isis Trujillo-Gonzales and Evan Paules. And Isis, this is not your first time working with us before. I think you've been at the Real Science Exchange before a couple years. No, it might have been pre Covid. Even pre Covid. Yeah. Yeah. So, so welcome back. It's good to have you here. Isis, would you mind kind of just start us off by giving us an overview of the presentation that you gave yesterday?
Isis (00:42:25):
Yeah, of course. Well, first, thank you so much for having me here. It's a pleasure for me. Yesterday I talked about how important choline is during pregnancy, and mostly I focus on brain development and eye development. And I share some of our findings on how important it is when pregnant woman is taking enough choline.
Scott (00:42:48):
That was interesting. The one thing I hadn't heard before was about the eye development. So what's unique about the eye that's different than the brain that, that, that allows that, that helps with eye development and choline?
Isis (00:43:00):
Well, actually, the cells are coming from the same origin, so the brain and eye are gonna develop from the same cells. Okay. So basically we found this eye development to be happening more or less at the same time that the cerebral cortex, that is the top part of our brains. And we saw that actually the neurons in our eyes that are receiving the light and connecting to the rest of our brain are also very important to receiving choline.
Scott (00:43:32):
Okay. Let me ask you this. Is it only allocated to the brain or, or can it help with other organs as well as they develop?
Isis (00:43:39):
Well, that's a very interesting question. And we are not sure yet. But we think that it may have an effect on the liver, but I think Evan can talk more about that in adults. But in embryonic development, we think that probably it will have some effect in the liver. Yeah.
Scott (00:43:58):
So that's a great segue to Evan. Evan, give us kind of an overview of, of your presentation and then if you will, kind of talk about liver development. Yeah,
Evan (00:44:07):
Definitely. Thank you so much for having me here. So my presentation focused primarily on looking at this intersection between coin availability and obesity, and specifically the manifestations of some of the associated chronic disease states that we see with obesity. And really trying to get to an understanding of can choline and its metabolites help ameliorate some of the symptomologies of obesity. And one of the main ones that we are focusing on right now is non-alcoholic fatty liver disease, or just fatty liver disease. And so, at least with respect to liver development, although I focus more on the adult side and we know it's very, very well documented that giving choline to someone who's deficient in it really helps ameliorate that fatty liver in development. We know that at least I think there's been a lot of evidence on specifically for the mother in which, if she's not supplied a sufficient amount of choline not only is she donating a a lot of her own stores of choline to the fetus so that it can develop properly, but also she's put at a much higher risk of developing fatty liver.
Evan (00:45:24):
So I, I think that's a really interesting area and really needs a lot of focus to make sure that everyone has enough cho in their diet,
Eric (00:45:33):
You know, so, so Isis. What I love about your work is it feels like in choline for so long. It's been a little bit of a situation where the mechanism is described as, you know, there's sort of an adequate choline, epigenetics, and then some problem occurs. Right. But you've really shed a lot of light on that, particularly as it relates to brain and eye development. So can you maybe walk us through, you know, kind of a high level of what you found in these last, well, I don't know what, two, three years about the mechanism of how choline deficiency can impact brain development?
Isis (00:46:05):
Yeah. Actually what we found is that the stem cells of the brain, and these are very particular cells that are gonna give rise to neurons, to all the types of cells in the brain are very sensitive to colon viability. So what we found is that if we don't have enough colon, if a moderate doesn't is not eating enough, cho these cells in the baby brain are not proliferating enough. So basically the mom needs to eat enough for the baby to build a better brain, and then these cells are gonna proliferate, have a really good pool of this number of cells, and they are gonna become neurons eventually. So part of what actually was also his dissertation was to find what was happening, what, how choline was making those cells to proliferate more. And we found that it's through microRNA that it's a small RNA that does fine tuning reg regulation. And that is what is regulating this pool of stem cells.
Eric (00:47:11):
So interesting. And so I think another message that I learned about the conference overall, but especially I think the both of you sections, was that it's not just important for expecting moms. I mean, there is a significant role of choline as we age. So, you know, Evan, for your work, especially this interaction between obesity and, and choline deficiency and choline levels, I mean, could you sort of elaborate on that and how that interplay might impact specific aspects of health?
Evan (00:47:38):
Yeah, definitely. I think one of the big things that we're really focused on, and at least we see emerging in our work, is that this idea of lean mass in body body mass fat mass, excuse me. And so we know as we age, one of the large concerns is loss of lean muscle mass. And so one of the things that we've seen, particularly in ma pre-clinically in males is that we have this loss of lean mass in these preclinical models that aren't consuming a sufficient amount of choline. And so, particularly in our older population, and as we age we're starting to think that perhaps like making sure that we have sufficient amounts of cloning, perhaps having fairly high levels of coin intake may help prevent that loss of lean mass.
Eric (00:48:35):
Wow. Wow. So one of the goals that we've had for this conference overall is trying to create just short messages that we can sort of communicate externally. So maybe what we can do, Isis, if you wouldn't mind giving like a two to three sentence summary of just kind of what the state of the union is as it relates to choline and early life nutrition. And perhaps Evan, you could do the same for, let's just call it adult nutrition overall.
Isis (00:49:02):
I will say that if a woman is planning to get pregnant or is pregnant, and needs to eat enough calling to make a baby with better cognition, that will be a very straightforward recommendation. The other thing is that it's important to consider also during nursing or lactation to keep consuming choline. 'cause The development of the baby, even of course the baby's brain, of course, after birth. So keeping the breast milk with enough choline, it's gonna be very important.
Eric (00:49:41):
Of course.
Evan (00:49:43):
I think one of the really interesting things that I didn't touch on too much in my talk, but I had sort of the backslide a little bit. A lot of evidence is emerging that, you know, what is a diet to maintain health, right? And so a lot of people are looking for a lot of, perhaps you could say like quick fix fixes, but ultimately there is nothing that is going to outweigh a healthy lifestyle. And really what we think of is really high diet quality. And so we are surrounded in an environment of a lot of processed and ultra processed foods. And so what we really need to focus on is just having a really high diet quality and ensuring that we get that high quality and that high quality diet includes choline, of course, because coin is a part of that really high quality diet.
Eric (00:50:38):
Exactly. That. I think that's what I love about nutrition overall, is there's love and hate, is that there's just a hundred boxes that you need to check in order to live that optimal lifestyle. You know, choline of course is an incredibly important part, but it's part of this bigger picture of overall health and diet, and I think you captured that really well. So thank you. Yeah.
Scott (00:50:56):
Thank you. I wanna thank both of you for joining us today. I failed to mention early on that you're both employees of University of North Carolina here with the Nutrition Research Institute, I believe isis, you're a, a researcher and you're a postdoc, correct? Alright. Thank you guys for joining us today. It's been, it's been great.
Evan (00:51:16):
It's been, it's been great. Thank you.
Scott (00:51:24):
Our next guest is Dr. Jonathan Bortz with Balchem. He's the VP of Nutrition Science here at Balchem. Jonathan, you gave a presentation today called TMAO and choline a mechanistic perspective. So give us kind of a bit of an overview of what your presentation was all about.
Jonathan (00:51:42):
Sure, Scott. So first of all in the last several years, there's been attention being paid to some concerns about choline really advanced particularly by one group of investigators who have claimed that excessive intake of meat and eggs and animal source foods that land up contributing either choline or carnitine land up generating a substance in the blood called TMAO, trimethylamine oxide. And what their hypothesis has been is that this has a negative effect on the cardiovascular system and has been associated with a high incidence of cardiovascular disease. What I demonstrated or at least try to share with my audience today was that we have taken this concern, the safety concern very seriously, have looked into the the with, with tremendous breadth and depth into the studies that have been performed to try and ascertain whether there was some real safety issues associated with choline, which is our product that we market. And fortunately was supported by our senior management to say, explore the science, let the science speak, and tell us whether there are issues to be concerned about or not. And I'm happy to say that what I presented were multiple examples of how the concerns about choline with respect to TMAO really cannot be associated, cannot be supported. The claimants maintain that there is a causative effect between choline TMAO and cardiovascular disease. But what I was able to present to the audience was that this is really not the case
Scott (00:53:42):
Now, is there new research or additional research that's gonna be required to demonstrate that, or,
Jonathan (00:53:48):
So the answer is some of these studies that were initially published in support of this hypothesis have been repeated and have failed to demonstrate the association. And furthermore, we have continued to look for and support any science that can tease out and evaluate the whole body of information and literature to determine whether there's anything there or not. So there is gonna be some ongoing work. We don't believe that this is gonna go away overnight, at least the concern, but we are very satisfied that choline does not represent a risk to any users, young or old.
Scott (00:54:36):
Makes sense.
Eric (00:54:37):
I mean, for most folks, we've been asking them to summarize sort of the state of the Union in their particular area in a couple of sentences. I think you just said that really nicely. I mean, is there anything else, or anything else you'd like to elaborate on this area briefly for anyone who might be listening ? You know, kind of confused by all this stuff that's out there. I mean, how do they make heads or tails of this connection?
Jonathan (00:54:58):
Sure. Well, let a very easy and clear example is that TMAO, which again, is the substance that is found in high concentrations in deep sea fish when a a meal is had of card or halibut or whatever. Okay? The amount of TMAO that gets ingested by eating this meal is in the several thousand fold higher than what would be generated by eating an egg or, you know, having a rib steak. So the question is, if this is the case, if TMAO is noxious and toxic to the cardiovascular system, Eric, then why is it that in multiple, multiple studies, the consumption of fish has been associated with actually a decrease in cardiovascular risk? So for example, in a meta-analysis of over 360,000 patients, okay, it's been found that this reduction is nearly 20% Okay. On fish eaters who consume much higher amounts of TMAO than what is contained in food substances that are rich in choline and canine.
Eric (00:56:18):
Yeah. And, and so I, I guess what you're trying to say is, or what I'm understanding from you is that this connection doesn't really make a lot of sense when you consider that fish consumption is really kind of a bedrock principle of dietary guidance for cardiovascular disease prevention. And that doesn't really match with the elevated TMA concentration that's found in fish. Right? Right. These two things are
Jonathan (00:56:40):
Right. It doesn't match at all. And and even though, and even, you know, what, what I anticipate is that when people hear about this, they say, well, what's there to talk about? Mm-Hmm.
Eric (00:57:36):
Are there any other big factors that might be confounding this relationship between TMAO and disease, maybe perhaps in the study populations that have been?
Jonathan (00:57:43):
Yeah, so that's a, it's a great question, and the answer is yes. TMAO is extraordinarily sensitive to even minuscule decreases in normal renal function. Mm-Hmm. So, in other words, give you an example. The normal renal function healthy adult is about a hundred milliliters per minute. Okay. That flows through the kidneys when there's a drop to less than 90, which by the way, is pretty normal for a lot of people in their late fifties and sixties. Okay. The amount of TMO that goes up is dramatic much more, it's a much more sensitive marker than even typical medical markers of renal insufficiency, which is blood urea nitrogen and, and, and creatinine. So, TMO is extraordinarily sensitive to that. And the population that was studied, that was found to have TML elevated also happened to be in, in patients who were diabetic, who were smokers, who were hypertensives, who had kidney disease, who had low kidney function, much lower than 90 milliliters per per minute. And as a result, you would expect to find elevated TMAO. That doesn't mean that TMAO has caused the cardiovascular disease, which is very commonly found in smokers, diabetics, hypertensive individuals. So the population that was studied in which this was brought out, okay, as proof of TMOs role in cardiovascular disease, it's really a sick population.
Jonathan (00:59:15):
Many of whom had, I mean, 40-50% of whom would have cardiovascular disease diagnosed heart attacks, strokes. Okay. So gimme a break. Okay. TMO is not a risk factor. Okay. A risk factor, something that you identify in a healthy population track and then see that, oh, wow, people who've had this particular risk factor have a higher chance of developing the disease. They did it the other way around. They looked at a sick population, picked out TMAO, and then looked for the reason for it.
Eric (00:59:47):
So it sounds like, you know, a quick summary of that, I guess would be there's, we'll call it mechanistic issues with the hypothesis on how TMAO might impact health. There's also some confounding biases, perhaps in some of the EPI data that's out there connecting TMAOTA to cardiovascular disease endpoints. And, you know, I think at this stage it seems, you know, difficult to really make a solid conclusion about that or the solid conclusion that there is this significant concern about understanding, right.
Jonathan (01:00:17):
Well, well, we have, I think, done more than our due diligence. We've also invited experts to come in. One of the areas that, one of the things that's been interesting is that these studies that have published these, this hy hypothesized construct really go into multiple different non-overlapping areas of expertise that most people, very few people actually con, contain or have all the tools in order to understand all the components. So when we've actually spoken to experts in all of these areas, what we have found is that not only are there real challenges in the way in which the science has been performed, but the so, so we are very comfortable that we've done our due diligence to make sure that choline is a absolutely safe nutritional you know, nutrient, it's essential for so many things. How can it be toxic? Okay. It's suggesting it in much lower le levels than what's been agreed to by the Institute of Medicine as the upper limit. So it doesn't make sense. However in a sense the genie's been led out of the bottle. You know, it's not that easy to put it back in. Okay. Even though we're comfortable that the veracity of the science, I think doesn't stand up to what is being claimed,
Scott (01:01:44):
Dr. Bortz it's obviously an important issue. And I wanna thank you for your dedication to understanding and explaining the data and coming on with us to set the record straight. So, thank you for joining us today.
Jonathan (01:01:56):
My pleasure, Scott.
Scott (01:01:56):
Thank you. Very welcome.
Scott (01:02:05):
Alright, our next session is with Dr. Julia Maeve Bonner. Dr. Bonner has a PhD in molecular genetics from the University of Toronto, and she did her postdoc at MIT. She's now the principal scientist at Sanofi. Dr. Bonner, I gotta tell you out of all the amazing presentations that we saw at the new directions in choline symposia, yours was my favorite. And I think that's probably because, you know, it was a bit personal for me. I've got two grandmothers that passed away with Alzheimer's. My mother passed away a couple years ago with Alzheimer's, and I have a younger brother that's got the the early onset version of that. So I was obviously very intentive in listening to your presentation. Found it very interesting. If you wouldn't mind, kind of just give us a general overview of, you know, kind of the high points of what your presentation was about.
Julia (01:03:00):
Sure. First, you know, I'm sorry to hear about your grandmother and your mother and your brother. You know, this, this is why we do this work. It's a devastating disease. So I'm sorry to hear about that. I hope you know that we can, we can use some of this work to, to move the field forward. So, the summary of my yeah, thank you. Research is at m mit. So in the lab of Dr. Leeza, I was working on a genetic mod risk factor for Alzheimer's disease, an OE four. So, APOE four is the most validated, highly validated risk factor. Genetic risk factor for Alzheimer's disease occurs in about 14% of the population, the control population, and is enriched to about 50% of Alzheimer's disease patients. So, and it is dose dependent.
Julia (01:03:50):
So, you know, if you get one copy of a POE four you have an increased risk of about fourfold. If you have two copies, it's about 10 to 12 fold. So it's clearly very closely linked to Alzheimer's disease risk. And we wanted to understand you know, what is, what is happening in a OE four compared to the non-risk or neutral risk allele rather, which is a OE three what's happening in the risk version versus the non-risk that's changing the cellular state, changing the brain ultimately to create this sort of early system of risk. So we were characterizing this gene and this variant of the gene, the risk variation in the cell type in the brain that makes the most of this protein. So these are astrocytes, these are glia. They support neuronal cells.
Julia (01:04:41):
They also have many functions in the brain, one of which is to sort of it's a major modifier of lipid homeostasis. So this is the, the fats in the brain that are, you know, the cell surface, the, the, the membranes of the brain, the intracellular organelle membranes, and, you know, many important components that get transferred that are important for cell function and then get transferred between cells and apoe. The protein is one of the major facilitators of transport of, of these kind of lipids, these fats between cells. And so what we found is that in this brain cell type astrocytes there was a really distinct shift in the lipid do. This is all the kinds of lipids that are being made or accumulated in the cell. And the APOE four, the risk version, accumulated neutral lipids to a much higher degree, a particular kind of lipids.
Julia (01:05:37):
Especially these tri glycerols. These are the kind of lipids that accumulate in these intracellular compartments called lipid droplets. These this accumulation was associated with dysfunction of many different kinds of functions in the cell. We found that using astrocytes as well as from work that we started initially in Susan Lindquist lab at the Whitehead in yeast, that we were able to pinpoint a node a biochemical node where we could kind of influence this lipid dyshomeostasis and the outcome, the resulting outcome for the cells. So we were able to discover that if these cells were grown in a media that was supplemented with choline and are rich in choline compared to media that was deficient or minimal in choline, that we could really alter this lipid imbalance and move it a lot.
Julia (01:06:41):
If in the media that was supplemented for choline move these cells quite a bit closer to the cells that were in this non-risk state, the APO E three, we could move that lipid. So all the kinds of lipids it's making, but especially these neutral lipids that we're accumulating these triglycerol, we could move them a lot closer to sort of APOE three or non-risk levels. And then through a lot of genetic work, we were able to pinpoint that this was actually phosphatidylcholine synthesis. So we saw that the Kennedy pathway of phosphatidylcholine synthesis was critical for this effect of choline on modifying the lipid balance. We have been since then, that work was published in Science Translational Medicine. And since then we've done a lot of work to try and see could we move this into a potential, you know therapeutic and an, and an in vivo and an intact animal.
Julia (01:07:39):
So we were looking at mice that have Alzheimer's disease genes knocked in. So these are pro amyloid Amy immunogenic genes. This means that these mice have mutations, human genes with mutations in them that cause them to accumulate the plaques that we see in human brains in Alzheimer's disease. And also in the background of this, they have the human apoe knocked in, which means that they're expressing human apoe either three or four. And in this April E four background with this amyloid genic mouse model, we fed them diet that was higher, low in choline. And we saw a really nice protection against the accumulation of some of this Alzheimer's related damage as well as a shift in the lipid of the cells that we looked at and some of the tissues we looked at. And we're still characterizing these outcomes. But we're excited. We think that, you know, it's possible that something that is as simple as, as as a dietary supplement could, could maybe merely make a difference, especially for those who, who have a copy of this, this particular risk allele. So could be basically through modifying this lipid imbalance, we're hopefully kind of restoring a little bit of the norm or non-risk state to the cells that might otherwise kind of be in this imbalance or risk state. So that's the, that's the big, the gist.
Scott (01:09:16):
Yep. That's the big picture. I'm kind of curious. So if, if and I'm gonna ask you a question I know you don't know the answer to, but I'm gonna ask you to speculate, is, so if you were to use choline supplementation to kind of stave off Alzheimer's, if, if you had the A POE gene would you have to be taking that or supplementing throughout lifetime? When, when, when would be the best time to be making sure you had enough choline supplementation in your diet? So,
Julia (01:09:45):
You know, we can't say these are mice and cells in a dish. We have human cells in a dish and they're mice. So we of course have to be very careful about making any claims that this, you know, can have a beneficial effect on humans that we would hope. There have been previous clinical trials looking at choline supplementation in Alzheimer's disease with some mixed results. A lot of those weren't stratified for an OE status, like whether they were an E four versus an OE three. And there is one study where it does look like when they did stratify that the four responder or carriers responded a little bit better. But, you know, we'd need to do a more careful, you know, very on purpose intentional study in humans looking at, you know, different levels of choline with, you know, in E four carriers having tracked, you know, ideally looking at sort of certain lipid markers maybe in their blood.
Julia (01:10:54):
And following that you know, a clinical trial is required to be able to say this. And, and we need to be careful to make sure we don't, we don't overstate claims, but I think that, you know, our science suggests that, that it should be possible and that that it's worth doing these kind of studies to identify if there is, you know an intervention like a supplement like food, like, you know, eating hot choline rich foods, that, that could make a difference because of course this would be a wonderful thing. One thing I can say is that in general, according to the sort of nutritional studies you know, people tend not to get enough going just by, you know, surgeon general recommendations. So I think that it's probably safe to say that you should get as much as is recommended currently. And then hopefully we can, you know, do more studies to, to really identify if it has a specific benefit for, for AE four carriers.
Scott (01:11:59):
And can you talk a little bit about, maybe are there future research studies planned either by yourself or others?
Julia (01:12:05):
So there is a small study currently being planned in collaboration with MIT and the Neurodegeneration Consortium out of MD Anderson. And I think with Alchem that have sort of been working together to try and get not, you know, a full phase one clinical trial or phase two, but a clinical study in humans to try and identify biomarkers that would change on different levels of choline. And then this would create, you know, the kind of readouts we would need to know before going into a clinical trial, but of course, clinical trials that are then very expensive. So we'd have to sort of see what happens after that. But this would be, you know, hopefully a proof of principle that we can change important and relevant biomarkers and then those can serve as readouts in a potentially bigger study.
Scott (01:13:04):
Eric, you have any questions?
Eric (01:13:07):
Yeah, I'm just curious if maybe you can comment on what the relationship is between say, choline intake and neurodegeneration and epidemiological literature. Is there a connection between these two things?
Julia (01:13:23):
I mean, so there's, there's correlative evidence, which is that groups that are at risk for low choline, there's all, you know, an overlap of, of groups that are at risk for low choline versus groups that are at high risk for ad. So for instance, women are high at high risk for low choline you know, both from in the potential child bearing times when, when there's, 'cause choline is also in the folate cycle folate metabolism pathway. So there's a much higher requirement for choline in women. And so then you could they are potentially at risk for being older people. It's been reported that the elderly, there's a decrease in their ability to uptake choline, even, you know, to whatever level that they have circulating from their diet. But there's a decreased ability to take it up. So this could also increase risk. And of course, we know that age is the biggest risk factor for, for ad. And there are some studies that suggest that 80 patients are, you know, have lower levels of choline, but it's not, it's not super consistent. So that would, you know, those studies kind of depends on, on what's being measured.
Eric (01:14:43):
Definitely an interesting emerging area for sure. Really need to see some of this pioneering work you've done. Mechanistically, I think the picture is very complex. I mean, as you said, this relationship between a POE four and other dietary factors is tricky. And I think something that's only been appreciated in the last, I don't know, let's say 10 years or so, really to a certain degree. I mean, I do, the reason I love your work in particular, one of the reasons is because I do think this appreciation for specific genetic markers and how specific dietary interventions might help people with those genetic markers, I think is incredibly important. You know, we're, we're definitely at a stage, I think in the field of nutrition where a lot of the sort of big picture general population recommendations are, have definitely been covered. And I think this area of nutrigene genetics, precision nutrition, personalized nutrition, whatever buzzword you want is definitely the future.
Julia (01:15:42):
So I really, well, thank you. And I think I agree. I think that you know, similarly from, you know, a field of Alzheimer's research, you know, we've done a lot where we try and look at sort of a broad scope of Alzheimer's disease suffering patients and compare, you know, all and against all control. And, you know, the more we learn, the more we understand that there might be subtypes within the disease, there might be, you know, within that all kind of converge on a clinical presentation of memory defects and neuronal loss. But you know, there might be underlying mechanisms that are slightly different or have slightly different sorts of origins or starting points. And if we can identify that that's, that's the case, if we understand whether or not that's the case, and then we can potentially understand that there are more targeted therapies that might be more, more amenable to some ad patients versus others, and, and that if we understand sort of how they're getting to their clinical presentation, we can, we can have a more effective series of therapies
Eric (01:16:48):
In your animal study. Do you know what the equivalency would be to a human diet, for example, in the supplemented mice where they get in?
Julia (01:16:58):
Yeah, so yeah, so the mouse recommended the choline, dietary recommendations for mice are very high, much higher than for humans. So the, we went basically our dietary paradigm. We wanted to kind of try and keep, as you know, within the scope of what a sort of healthy mouse would see. So we went to sort of the National Research Council minimum and maximum. And those were about fivefold different between the minimum choline and the maximum choline about fivefold different amounts of choline. But you know, those are much higher. You know, they're, you know, in grams per kg amounts of choline in the diet compared to, you know, 450 mgss per day that is recommended for adult males or adult females four 50 mgs per day, somewhere in that range. There are much higher requirements in mice. So we were within the sort of healthy mouse range and then a fivefold increase in the supplemented diet.
Eric (01:18:08):
I do think your comment is very prudent, right? I mean, I think that we know of course that before making any kind of, you know, strong claims about the connection between choline and the disease, of course we need, you know, rigorous RCTs. But I do think as a prudent dietary piece of advice, it's probably smart to at least stick to trying to get your daily requirement. So I think you're, I would agree. I think you're spot on with that recommendation. Just tough. Not a lot of people do that, right? I think you said you, you know, depending on the source, it's what, six to 10% of people get enough? I mean, it's really not a lot. So a lot of work to be done in terms of education and awareness
Julia (01:18:51):
That it's tough to get the appropriate dietary amount of choline. So humans do make some cooling but not enough. We, it is a, a required nutrients, so it can't, you know, it's depending on your diet, I think, you know, that the recommendations that are always the case for most diseases of aging, most healthy living in general, which is, you know, a good, a good balanced diet and, and, you know, taking care of yourself in, in every way that you're able to are always safe recommendations. But again, in terms of specific recommendations for, you know, choline intake beyond the we already have, we would need to do the careful studies, but yeah, most people don't, don't even achieve that much. So so it seems, it seems prudent to watch what you're eating and do your best,
Scott (01:19:44):
Dr. Barns, we get ready to close out here. Any key takeaways you'd like to leave with our audience?
Julia (01:19:49):
Well, I appreciate, you know, that, that this is an, one of the sort of newer angles of looking at Alzheimer's disease is looking at it from a sort of metabolic you know, potentially nutritionally accessible viewpoint key. One of the things that will help, I think, to understand different kinds of interventions and how they can be most helpful is these kinds of mechanistic studies, these kinds of this work where we can, we can understand, you know, there are broad benefits to the things that we know our body needs. But if we can actually, you know, start linking those to specific pathways, to specific mechanisms to specific, you know, requirements that may be greater or lesser in certain risk states, then I think, you know, there's a much greater case. It's much easier to, to convey that information to a general public, but also hopefully to convince you know, medical, the medical field that, that these are valuable insights. And of course with that, I just would also like to say that all this work is, you know, publicly funded. We are excited to share it. We hope that people can learn from it. And you know, the most important thing is if we can try and make a difference for people who are suffering from this terrible disease.
Scott (01:21:17):
Yeah. Well said. Wanna thank you for your work on this important subject. And I want to thank you for joining us
Julia (01:21:22):
Here today. Thank you. Yeah. Happy too. Appreciate it. Thank you.
Speaker 7 (01:21:24):
Tonight's last call question is brought to you by NitroShure Precision Release Nitrogen. NitroShure delivers a complete TMR for the room microbiome, helping you feed the microbes that feed your cows. To learn more about maximizing microbial protein output while reducing your carbon footprint, visit balchem.com/nitroshure.
Scott (01:21:54):
Well, folks, we've just concluded the future directions in choline. I, I hope you've been able to, to join us for all of the interviews so far. If not, please go back and listen to the first one. We started off the conference with Dr. Steven Hurst and Dr. Susan Smith, both with UNC here. And we, we asked you, you know, what does success look like? And so, and I'm not gonna ask that exact question, but was it everything you expected?
Steven (01:22:27):
You know, it was more than I expected, actually. So we had more like 90 people here. One, one I think we were really looking forward to was showing our campus off, and our facilities. And so that was so much fun for us to do. But also the science was just unbelievably good. And the progress that has been made in the, we, we talked about this 25 years since really choline was established as a nutrient. The progress over that 25 years is Remarkable. And we heard just so many exciting talks. And to me, we, you know, you expect that from some of our senior folks that were here. To me, the highlight was our, our emerging stars and the excitement they have in this, the new ideas that they're bringing to the field the field's fantastic shape. And so that was really exciting. So I, I think I said we, you know, we were looking what would be a touchdown? What would be, what, what could we spike the ball on? Well, I think we, I think we scored eight touchdowns in this event.
Scott (01:23:30):
Well said Susan, based on what you heard this week, so what are the future directions of choline?
Susan (01:23:37):
So it was interesting reflecting upon where we were and where we are now. And so we came into the conference. What had set up choline as an essential nutrient was the fact that it promotes liver health and it promotes skeletal muscle health. And what we heard about this time was we saw tremendous cognitive effects when given during pregnancy and early childhood. It's building smarter brains in babies. We learned about a potential role in Alzheimer's disease. We learned about roles in litter health, but also its potential for obesity and helping to overcome some of the side effects that accomp the ill health that can accompany obesity. Just so much exciting information.
Scott (01:24:28):
Yeah. I couldn't help but reflect on after hearing a lot of these presentations and, and all the amazing benefits of, of adequate sub choline supplementation. Why is it so, why is it the nutrient nobody's heard of, right. It's just, that's a little confounding to me. I dunno if you guys have an answer for that. But
Steven (01:24:48):
One thing I have learned is that there haven't been many opportunities for the broad field to get together. It's been in various, those that work on early development, maybe go to pediatric meetings, those that work on later in life are going to more the aging or the Alzheimer's types of conferences. But this, this may be the first time for, for many in the field that have gotten together with the whole breadth of the field. And so I think that that's it, we're gonna do it again. By the way, in two years I made, I made the commitment that let's start this party again in two more years and and, and invite some of our friends at N-I-H F-D-A some of the other decision makers in, in the, in the area of nutrition and disease, health, you know, promotion to, to come and listen to this progress. Yeah. And so we're, we're looking forward to that already.
Scott (01:25:42):
And if I might, I'd, I'd please invite some of our researchers and animal nutrition. Yes. There's a lot of bright people out there doing some pretty cool stuff now. It's not exactly what you guys are doing, but I think there might be some synergies there where, where you can learn from each other. A
Steven (01:25:57):
Hundred percent. We had actually a couple of veterinary medicine researchers here that shared some of their results in the animal health area. Fascinating. And I think that's exactly right. We'll have a whole session, I think, in around that topic next time. Yeah.
Scott (01:26:14):
Perfect.
Tom (01:26:15):
Yeah, I'm really excited about the opportunity to come back in two years, I think, and show all the progress we've made. Obviously there's been a lot since 1998, but I think back even five years ago, we held this round table with some of the leaders in, you know, like people from NIH and from USDA. And I remember one of the fellows putting up on the screen, you know, a picture of choline with 500 miles to go before getting to the science that they needed for A DRI. And I think in two years, when we bring those guys back, we're gonna be able to show that we've been driving through the night. Yes. We got,
Steven (01:26:49):
We're a lot closer than they think. That's a great, great way to put it. I love that. Yeah,
Susan (01:26:53):
I think that's true because when we were organizing the conference, it was so hard to pick and choose Yeah. What work we could feature. We could have filled a week easily. And so in two years time, it's gonna be really exciting too, so hopefully we can expand this a little and hear even more about it.
Scott (01:27:09):
Yeah. Super.
Tom (01:27:10):
I also love the opportunity, and you brought it up of the young scientists to present. It was great to see the posters and really celebrate some of the up and coming work. So lots to build on and more exciting things to talk about.
Scott (01:27:22):
You know, one of the things you did right at the end of the conference is you had these breakout sessions where everybody got together and was sharing ideas and there was a lot of sparks flying and innovation going on. I really enjoyed listening in on those. You know, can you share some of the ideas that, that the, that the teams came back with
Steven (01:27:42):
Eat more choline
Scott (01:27:43):
That was the theme.
Susan (01:27:46):
I think one unexpected discussion circled around the effects of climate change and heat stress and the impact that could be having upon both choline needs as well as the choline content of foods. We know that it's having an impact, say upon the protein content of certain plants and the like, but we don't know what that impact is going to be with choline. And so there's an area of research to think about.
Tom (01:28:13):
Wow. Yeah.
Scott (01:28:14):
Interesting.
Steven (01:28:15):
I was, I was struck by the, I think it's a sign of the maturation of the field of efforts to really align research and standardize really so that data can be pooled and future and get more powerful summaries of data such as meta-analyses that where, where you can put multiple studies together and, and get a much stronger signal than a single study. And so there were, there were efforts in that regard of aligning on biomarkers, on standardizing dosing and type of choline administered and study design, so that those types of pooling efforts can, can occur in a few years. And I think that will really move things forward. So I was, I was struck by that. Yeah.
Tom (01:28:59):
Well, on behalf of the Balchem team, 'cause I just wouldn't be fair to close this without saying we really appreciate all the leadership from UNC and the Nutrition Research Institute over the past years, and we are really excited to have started this ball rolling and to continue it. So thank you so much for hosting us.
Scott (01:29:16):
Yeah, thank you very much. Yeah, well said. Tom, one final question for each of you guys. Dr. Ciappio did a nice job of summarizing things there toward the end. And what he did was he wanted, he asked everybody in two to three sentences, you know, tell us, tell us what the key takeaways are, and so, you know, use this opportunity right to, to, to share this succinct message to, to a wider audience. So I don't know which of you guys would like to start, but I,
Susan (01:29:41):
I'll, I'll say choline is, is looks like an easy way to work toward a healthy lifespan. And, and not just lifespan, but a health span, healthspan, it's touching everything from fetal development through early childhood adolescence, adulthood, and into aging. And it's just such a huge spread and an easy way to address that. Eat more eggs, take more choline.
Scott (01:30:08):
Well said. Well said.
Steven (01:30:09):
I can't add anything to that. Perfectly said.
Scott (01:30:13):
So we're gonna leave it there. Alright, Thank
Tom (01:30:15):
You know, folks eat more cold. Eat
Steven (01:30:18):
More cold. That's, that's right. That's exactly right.
Scott (01:30:20):
Well, listen, this has been a great conference. I want to thank you guys for putting it together. Thank you for joining us. This has been a blast. Also want to thank our loyal audience for joining us once again. I hope you learned something, hope you had some fun, and we hope to see you next time here at the Real Science Exchange, where it's always happy hour and you're always among friends.
Speaker 7 (01:30:40):
We'd love to hear your comments or ideas for topics and guests. So please reach out via email to anh.marketing@balchem.com with any suggestions and we'll work hard to add them to the schedule. Don't forget to leave a five star rating on your way out. You can request your Real Science Exchange t-shirt in just a few easy steps, just like or subscribe to the Real Science Exchange. And send us a screenshot along with your address and t-shirt size to a and h.marketing at alchem.com. Balchems real science lecture series of webinars continues with ruminant focused topics on the first Tuesday of every month. Monogastric focused topics on the second Tuesday of each month, and quarterly topics for the companion animal segment. Visit balchem.com/realscience to see the latest schedule and to register for upcoming webinars.