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Phosphatidylcholine and risk of cardiovascular disease
#61
Posted 23 April 2011 - 06:17 PM
ScienceDaily (Apr. 21, 2011) — In the future, when you walk into a doctor's surgery or hospital, you could be asked not just about your allergies and blood group, but also about your gut type. Scientists at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, and collaborators in the international MetaHIT consortium, have found that humans have three different gut types.
The study, published in Nature, also uncovers microbial genetic markers that are related to traits like age, gender and body-mass index. These bacterial genes could one day be used to help diagnose and predict outcomes for diseases like colo-rectal cancer, while information about a person's gut type could help inform treatment.
We all have bacteria in our gut that help digest food, break down toxins, produce some vitamins and essential amino acids, and form a barrier against invaders. But the composition of that microbial community -- the relative numbers of different kinds of bacteria -- varies from person to person.
"We found that the combination of microbes in the human intestine isn't random," says Peer Bork, who led the study at EMBL: "our gut flora can settle into three different types of community -- three different ecosystems, if you like."
Bork and colleagues first used stool samples to analyse the gut bacteria of 39 individuals from three different continents (Europe, Asia and America), and later extended the study to an extra 85 people from Denmark and 154 from America. They found that all these cases could be divided into three groups, based on which species of bacteria occurred in high numbers in their gut: each person could be said to have one of three gut types, or enterotypes.
The scientists don't yet know why people have these different gut types, but speculate that they could be related to differences in how their immune systems distinguish between 'friendly' and harmful bacteria, or to different ways of releasing hydrogen waste from cells.
Like blood groups, these gut types are independent of traits like age, gender, nationality and body-mass index. But the scientists did find for example, that the guts of older people appear to have more microbial genes involved in breaking down carbohydrates than those of youngsters, possibly because as we age we become less efficient at processing those nutrients, so in order to survive in the human gut, bacteria have to take up the task.
"The fact that there are bacterial genes associated with traits like age and weight indicates that there may also be markers for traits like obesity or diseases like colo-rectal cancer," Bork says, "which could have implications for diagnosis and prognosis."
If this proves to be the case, when diagnosing or assessing the likelihood of a patient contracting a particular disease, doctors could look for clues not only in the patient's body but also in the bacteria that live in it. And after diagnosis, treatment could be adapted to the patient's gut type to ensure the best results.
http://www.scienceda...10421141632.htm
ScienceDaily (Apr. 22, 2011) — The human gut is filled with 100 trillion symbiotic bacteria -- ten times more microbial cells than our own cells -- representing close to one thousand different species. "And yet, if you were to eat a piece of chicken with just a few Salmonella, your immune system would mount a potent inflammatory response," says Sarkis K. Mazmanian, assistant professor of biology at the California Institute of Technology (Caltech).
Salmonella and its pathogenic bacterial kin don't look that much different from the legion of bacteria in our gut that we blissfully ignore, which raises the question: What decides whether we react or don't? Researchers have pondered this paradox for decades.
In the case of a common "friendly" gut bacterium, Bacteroides fragilis, Mazmanian and his colleagues have figured out the surprising answer: "The decision is not made by us," he says. "It's made by the bacteria. Since we are their home, they hold the key to our immune system."
What's more, the bacteria enforce their "decision" by hijacking cells of the immune system, say Mazmanian and his colleagues, who have figured out the mechanism by which the bacteria accomplish this feat -- and revealed an explanation for how the immune system distinguishes between beneficial and pathogenic organisms.
In addition, the work, described in the April 21 issue of Science Express, "suggests that it's time to reconsider how we define self versus non-self," Mazmanian says.
Like other commensal gut bacteria -- those that provide nutrients and other benefits to their hosts, without causing harm -- B. fragilis was thought to live within the interior of the gut (the lumen), and thus far away from the immune system. "The dogma is that the immune system doesn't respond to symbiotic bacteria because of immunological ignorance," Mazmanian explains. "If we can't see them, we won't react to them."
But using a technique called whole-mount confocal microscopy to study the intestines of mice, he and his colleagues found that the bacteria actually live in a unique ecological niche, deep within the crypts of the colon, "and thus in intimate contact with the gut mucosal immune system," he says.
"The closeness of this association highlights that an active communication is occurring between the bacteria and their host," says Caltech postdoctoral scholar June L. Round.
From that vantage point, the bacteria are able to orchestrate control over the immune system -- and, specifically, over the behavior of immune cells known as regulatory T cells, or Treg cells. The normal function of Treg cells is to prevent the immune system from reacting against our own tissues, by shutting down certain immune responses; they therefore prevent autoimmune reactions (which, when uncontrolled, can lead to diseases such as multiple sclerosis, type 1 diabetes, lupus, psoriasis, and Crohn's disease).
Bacteroides fragilis has evolved to produce a molecule that tricks the immune system into activating Treg cells in the gut, but in this case, Mazmanian says, "the purpose is to keep the cells from attacking the bugs. Beautiful, right?"
In their Science paper, Mazmanian and colleagues describe the entire molecular pathway that produces this effect. It starts with the bacteria producing a complex sugar molecule called polysaccharide A (PSA). PSA is sensed by particular receptors, known as Toll-like receptors, on the surfaces of Treg cells, thus activating those cells specifically. In response, Treg cells suppress yet another type of cell, the T helper 17 (Th17) cells. Normally, Th17 cells induce pro-inflammatory responses -- those that would result, for example, in the elimination of foreign bacteria or other pathogens from the body. By shutting those cells down, B. fragilis gets a free pass to colonize the gut. "Up until now, we have thought that triggering of Toll-like receptors resulted solely in the induction of pathways that eliminate bacteria," says Round. "However, our studies suggest that multiple yet undiscovered host pathways allow us to coexist with our microbial partners."
When Mazmanian and his colleagues blocked this mechanism -- by removing the PSA molecule, by removing the Toll-like receptor for PSA, or by eliminating the Treg cells themselves -- the bacteria were attacked by the immune system and expelled. "They can no longer co-opt the immune system into inducing an anti-inflammatory response, so the formerly benign bacterium now looks like a pathogen," he says, "although the bug itself is exactly the same."
"Our immune system arose in the face of commensal colonization and thus likely evolved specialized molecules to recognize good bacteria," says Round. Mazmanian suspects that genetic mutations in these pathways could be responsible for certain types of immune disorders, including inflammatory bowel disease: "The question is, do patients get sick because they are rejecting bacteria they shouldn't reject?"
On a more philosophical level, Mazmanian says, the findings suggest that our concept of "self" should be broadened to include our many trillions of microbial residents. "These bacteria live inside us for our entire lives, and they've evolved to look and act like us, as part of us," he says. "As far as our immune system is concerned, the molecules made by gut bacteria should be tolerated similarly to our own molecules. Except in this case, the bacteria 'teaches' us to tolerate them, for both our benefit and theirs."
The work was supported by the National Institutes of Health, the Damon Runyon Cancer Research Foundation, and the Crohn's and Colitis Foundation of America.
http://consumer.heal....asp?AID=652138
Gut Bacteria Falls Into Three Major Types
Every human appears to have a distinct intestinal ecosystem, European researchers report
By Jenifer Goodwin
HealthDay Reporter
THURSDAY, April 21 (HealthDay News) -- Just like eye color or blood type, the bacteria that flourish in the gut can also be used to categorize humans, new research finds.
European researchers have determined that there are three distinct types of microscopic ecosystems that exist in the human intestine. What differentiates each type is which species of microbes are present and which are the most abundant, researchers said.
Although there's far more to learn about what those microbes do, researchers say your bacterial type may tell a whole lot about you, including how you metabolize food, how you synthesize vitamins and how you might respond to certain medications.
"We think humans can be categorized based on the micro-composition in their gut," said study co-author Manimozhiyan Arumugam, a research scientist at the European Molecular Biology Laboratory in Heidelberg, Germany. "We also have reasons to believe these are not specific to any continent, country, ethnicity or any other obvious factor."
The human gut is host to an estimated 500 to 1,000 species of bacteria, Arumugam said. Those species compete and cooperate with each other in microscopic ecosystems that remain relatively stable in a balanced, symbiotic relationship with the host -- the human body.
"They are not working alone, they have to work as a community," Arumugam said. "And they have to adapt to the host, such as what we eat."
In the study, published in the April 20 issue of Nature, researchers took stool samples of 22 people from four European countries (Denmark, France, Italy and Spain), extracted the DNA and determined which species of bacteria resided there. They combined their data with the results of earlier data on the gut microbes of 13 people from Japan and two Americans. They then added data from another 85 Danish people and 154 Americans.
Their analysis showed that the microbiota could be grouped into three categories. People with type 1, for example, had high levels of the bacteria Bacteroides. In type 2, Bacteroides levels were lower, but the Prevotella was prevalent. Ruminococcus was a big factor in the third enterotype.
"In the data sets we looked at, we found three types. Would it remain only three if you sampled 100,000 people? We don't know," Arumugam said. "It could also be that maybe these enterotypes could be refined more and that there are subtypes."
Since researchers began to understand that gut microbes play a significant -- and underestimated -- role in human health, one question that's been vexing the field is just how many versions of intestinal microbiota there are, said Justin Sonnenburg, an assistant professor of microbiology and immunology at Stanford University School of Medicine.
If there were an infinite number of variations, then using the information in the real world would be impossibly complex, Sonnenburg added.
"There's been this increasing realization over the past several years that the microbes that live in and upon us are wired into many facets of our biology, and it's also becoming clear that these microbes are going to be a major determinant of variation between individuals, both in relationship to our health, predisposition to disease, progression of diseases and how they should be treated therapeutically," he said.
But by identifying the three types, the new research represents a significant breakthrough, he added.
"This paper really makes a huge leap in establishing that this variation is not a continual and infinite, but that there these finite enterotypes," Sonnenburg said.
Think of it like eye color, Sonnenberg added. There's brown, green, blue, hazel and a perhaps a few other variations, but there is no purple, chartreuse or other colors.
The researchers said they had found no evidence that such characteristics as age, gender or body weight correlated to the gut microbe types.
However, looking across the entire sample, age, gender and body weight did correlate with certain genetic markers in the bacteria, hinting that it may be possible to eventually use such information to diagnose disease or determine who is likely to get diseases, Arumugam said.
#62
Posted 23 April 2011 - 08:21 PM
There would need to be some sort of signaling between the site of injury and whatever system regulates choline levels. But choline levels have a non-huge effect on CVD; it seems to be mostly driven by TMAO. If the human body synthesizes choline, it must not be all that much, at least not enough to eliminate essentiality. If you created injury requiring cell repair, and you saw no change in choline level, it wouldn't rule the idea out but it would suggest that it was at least limited to certain situations. I'm not sure we know yet whether TMA/O is causal in CVD, is a correlate to something that is causal, or is a consequence.Isn't choline also needed to repair cell membranes ? Could elevated serum choline be a sign of attempted repair, similar to high Cholesterol levels ?
After all, the human body does manufacture choline...
How would we falsify this hypothesis ?
You're right, choline is essential:Thanks for the clarification niner. Still, there are many reasons why someone might supplement with choline and it is an essential nutrient so I am not going to toss it out over one study. CVD is a multi-factorial disease and I wonder if other lifestyle and diet factors would overwhelm anything negative from exogenous choline.
... so you certainly want to get the AI, and if your diet is low in choline, supplementation would be necessary. If there are certain forms of choline that are better than others, as Chris Masterjohn says, then that would seem to be the way to go. Anyway, considering the data, I don't think obsessing over choline is important. What's more important is determining your TMA/TMAO levels and getting those sorted.Nutr Rev. 2009 Nov;67(11):615-23.
Choline: an essential nutrient for public health.
Zeisel SH, da Costa KA.
Choline was officially recognized as an essential nutrient by the Institute of Medicine (IOM) in 1998. There is significant variation in the dietary requirement for choline that can be explained by common genetic polymorphisms. Because of its wide-ranging roles in human metabolism, from cell structure to neurotransmitter synthesis, choline-deficiency is now thought to have an impact on diseases such as liver disease, atherosclerosis, and, possibly, neurological disorders. Choline is found in a wide variety of foods. Eggs and meats are rich sources of choline in the North American diet, providing up to 430 milligrams per 100 grams. Mean choline intakes for older children, men, women, and pregnant women are far below the adequate intake level established by the IOM. Given the importance of choline in a wide range of critical functions in the human body, coupled with less-than-optimal intakes among the population, dietary guidance should be developed to encourage the intake of choline-rich foods.
PMID: 19906248
The bacteria that create TMA are anaerobes, as I understand it. As far as I know all probiotic species are aerobes.So we would need to know what bacteria generates the TMA (which always gets oxidized to TMAO) and which probiotic might supress this bacteria. I assume it is possible the wrong probiotic could make things worse!
The reference (#35?) that led to the speculation in the paper was using some sort of "humanized" mouse model. It would be easy to get before and after TMA levels in humans that were administered a probiotic. The enterotype concept that Hebeh just posted about is really interesting. Seems like getting a good understanding of that would have to be helpful for improving human health.Do we know what particular species are able to achieve this?probiotics are a way to alter the flora and reduce production of TMAO
#63
Posted 23 April 2011 - 10:47 PM
There would need to be some sort of signaling between the site of injury and whatever system regulates choline levels. But choline levels have a non-huge effect on CVD; it seems to be mostly driven by TMAO. If the human body synthesizes choline, it must not be all that much, at least not enough to eliminate essentiality. If you created injury requiring cell repair, and you saw no change in choline level, it wouldn't rule the idea out but it would suggest that it was at least limited to certain situations. I'm not sure we know yet whether TMA/O is causal in CVD, is a correlate to something that is causal, or is a consequence.Isn't choline also needed to repair cell membranes ? Could elevated serum choline be a sign of attempted repair, similar to high Cholesterol levels ?
After all, the human body does manufacture choline...
How would we falsify this hypothesis ?
Elevation of serum cerebral injury markers correlates with serum choline decline after coronary artery bypass grafting surgery.
Decreased serum choline concentrations in humans after surgery, childbirth, and traumatic head injury.
Endotoxin alters serum-free choline and phospholipid-bound choline concentrations, and choline administration attenuates endotoxin-induced organ injury in dogs.
If it's non-huge, it could simply mean that the situation it describes isn't likely, like an anaerobic infection in the circulatory system ?
Edited by rwac, 23 April 2011 - 10:54 PM.
#64
Posted 24 April 2011 - 04:18 AM
All of these suggest that choline is used up by cellular repair, but not that choline levels are increased as a result of repair. I don't know anything about choline biosynthesis in humans, other than to say it must not be enough to prevent essentiality.There would need to be some sort of signaling between the site of injury and whatever system regulates choline levels. But choline levels have a non-huge effect on CVD; it seems to be mostly driven by TMAO. If the human body synthesizes choline, it must not be all that much, at least not enough to eliminate essentiality. If you created injury requiring cell repair, and you saw no change in choline level, it wouldn't rule the idea out but it would suggest that it was at least limited to certain situations. I'm not sure we know yet whether TMA/O is causal in CVD, is a correlate to something that is causal, or is a consequence.Isn't choline also needed to repair cell membranes ? Could elevated serum choline be a sign of attempted repair, similar to high Cholesterol levels ?
After all, the human body does manufacture choline...
How would we falsify this hypothesis ?
Elevation of serum cerebral injury markers correlates with serum choline decline after coronary artery bypass grafting surgery.
Decreased serum choline concentrations in humans after surgery, childbirth, and traumatic head injury.
Endotoxin alters serum-free choline and phospholipid-bound choline concentrations, and choline administration attenuates endotoxin-induced organ injury in dogs.
If it's non-huge, it could simply mean that the situation it describes isn't likely, like an anaerobic infection in the circulatory system ?
#65
Posted 24 April 2011 - 04:47 AM
All of these suggest that choline is used up by cellular repair, but not that choline levels are increased as a result of repair. I don't know anything about choline biosynthesis in humans, other than to say it must not be enough to prevent essentiality.Elevation of serum cerebral injury markers correlates with serum choline decline after coronary artery bypass grafting surgery.
Decreased serum choline concentrations in humans after surgery, childbirth, and traumatic head injury.
Endotoxin alters serum-free choline and phospholipid-bound choline concentrations, and choline administration attenuates endotoxin-induced organ injury in dogs.
If it's non-huge, it could simply mean that the situation it describes isn't likely, like an anaerobic infection in the circulatory system ?
Yes, that is what it points towards. So have these people with high serum choline really been eating a lot of eggs and liver ?
I wouldn't have guessed that this was common these days.
How is a chronically elevated serum choline related to choline being elevated immediately after a meal ?
#66
Posted 24 April 2011 - 05:16 AM
From what people have posted upthread, it sounds like dietary choline isn't highly correlated with serum levels, unless the diet is profoundly low in choline. Some forms of supplemental choline might be a problem, though. But the relationship between choline and CVD isn't that strong anyway, so it's probably not the thing to focus on. The problem is really TMA, which leads more or less quantitatively to TMAO, from the sound of it. In this case, we'd want to address the gut biota, and try to alter that. I don't know if you can just walk into a doctors office and ask for a TMAO level, but I suspect not. The easy things to do are to choose choline supplements carefully and use probiotics. While not a proven fix, these things are at least sensible and lack an obvious downside risk.So have these people with high serum choline really been eating a lot of eggs and liver ?
I wouldn't have guessed that this was common these days.
How is a chronically elevated serum choline related to choline being elevated immediately after a meal ?
#67
Posted 24 April 2011 - 09:24 AM
As often posted I think it is all matter of moderation and being cautious on what we supplement. I think I have a relatively balanced diet (eat no liver, eggs moderately and regularly fish but on this the article says: "..Indeed, the massive increases in urinary trimethylamine and TMAO following meals rich in seafood suggests that our kidneys excrete these compounds very efficiently...") and as already supplementing with Cognitex (with its Alpha-Glyceryl Phosphoryl Choline (A-GPC) content) and ALC (carnitine is also a precurson of TMA) which I like to keep both, I feel even more comfortable now to cut on PPC (as well as TMG which was ineffective on my (relatively) high homocysteine).
As the article says: "...Perhaps future work will in fact elucidate a role for harmful gut bacteria in increasing TMAO levels and subsequent development of heart disease, in which case the clear implication would be that we should figure out how to normalize the gut bacteria...." and I keep supplementing with probiotics, I wonder which gut bacteria maybe harmful. Any information/comment on this? I am due to test again for dysbiosis by the year end (i had an imbalance few years ago) and might up my probiotics dose.
#68
Posted 03 May 2011 - 04:10 PM
There is a thread around somewhere about this. IIRC the thread starter was looking to create a program to do the randomization. No link sorry.I was thinking about randomizing supplementation somehow. What I mean is using a randomizing tool or even possibly flipping a quarter everyday ( heads I take it, tails I don't sort of thing) I know this may sound borderline crazy, but hey it
might work, right.
Any thoughts?
#69
Posted 12 October 2011 - 03:42 AM
This provides an interesting dicussion about the OP study. If you want access PM me. I'll summarize it when I have time.
#70
Posted 17 November 2011 - 07:07 AM
.......Plasma levels of choline and TMAO will be dependent on dietary habits, in particular the consumption of a proatherosclerotic phospholipid–rich diet, and are likely to be a risk factor rather than a direct marker of cardiovascular disease..... Are these plasma metabolites contributing to disease? Choline and TMAO feeding accelerated atherosclerosis in apoE-/- mice, a widely used mouse model of atherosclerosis. Reverse cholesterol transport differs
between mice and humans. A negative correlation was reported between hepatic FMO3 expression and plasma high-density lipoprotein concentrations in apoE-/- mice, but no correlation was observed between plasma levels of TMAO and high-density lipoproteins in subjects. Also, previous metabolomics analysis of atherosclerotic aortas from apoE-/- mice demonstrated a 2-fold rise in choline without significant changes in tissue concentrations of TMAO, suggesting that plasma TMAO may act systemically rather than locally in the atherosclerotic plaque. This would be consistent with the observation that TMAO feeding induced foam cell formation in peritoneal macrophages. The precise molecular mechanisms in which TMAO mediates its proatherosclerotic effect are currently unknown. Interestingly, TMAO was also measured in the study by Gerszten et al: According to their correlation matrix for plasma metabolite levels (see their Figure1),TMAO is positively correlated with N-monomethyl-arginine, a competitive inhibitor of nitric oxide synthase, providing an alternative explanation for the association of TMAO with cardiovascular disease....
In one of my previous posts: http://www.longecity...253#entry459253
Lecithin seemed to not raise TMAO, also Chris Masterjohn's post somewhere in this thread also gave explanations. I think for most it would be prudent to stop supplementing free choline.
Edited by Sillewater, 17 November 2011 - 07:07 AM.
#71
Posted 17 November 2011 - 04:00 PM
MR mentioned the rancidity issue and also contamination of lecithin, so I'll be dropping it. So gonna buy a concentrate, that is what MR takes.
#72
Posted 17 November 2011 - 07:47 PM
ie. Jarrow Ubiquinol, which are pretty large capsules. I expect they have around 600mg/each, so figure 1-2 grams/daily depending on dosage.
Which is pretty skimpy as far as lecithin dosing, but if possibly rancid, it's probably not something I'd want to consume.
#73
Posted 18 November 2011 - 03:32 PM
The second article provides some odd information...stating that those who had the highest levels of "Gammaproteobacteria" at the beginning of the study had less fatty livers.....if you look up the bacteria in that class, they are almost all pathogenic, including our good friend E. coli. The second class that was stated to indicate those at highest risk of fatty liver, was Erysipeoltrichi. Also pathogenic, mostly in animals.
Also cited as a possible contributing factor when combined with the bacterial colonies and ratios, was a deficiency in dietary choline.
Im going to call bullshit, if not poorly presented and contradictory. I wouldn't go so far as to say there is no potential at all for bacterial flora in the gut to affect an individuals health in ways not obvious and also the absorption of various nutrients, but this whole mess described in both articles just isn't making much sense.
#74
Posted 20 November 2011 - 02:56 PM
#75
Posted 22 November 2011 - 07:08 AM
From (1):
Creatine is present in the muscletissue of many vertebrates but ingestion of meat products did not significantly increase urinary methylamine levels. However, the majority of creatine in muscle is present in a combined form as phosphocreatine, with phosphoric acid blocking the terminal amino group, and thus may not be immediately available for methylamine production.
The study actually didn't find a large difference from food intakes (except for a couple like clams and stuff).
References
01. Clin Chim Acta. 2001 Oct;312(1-2):107-14.Methylamine in human urine.Mitchell SC, Zhang AQ.
Edited by Sillewater, 22 November 2011 - 07:09 AM.
#76
Posted 21 January 2012 - 12:10 PM
http://en.wikipedia..../Trimethylamine
I think the resarch put a lot of worry on TMG as supplement... beeing so TMG and TMA so close...
"Demethylation of TMG gives dimethylglycine. Degradation of TMG yields trimethylamine, the scent of putrifying fish..."
http://en.m.wikipedi...rimethylglycine
I found also this.... here TMG seems to be ok (confused...).
Some humans with a defect in the flavin-containing
monooxygenase-3 gene (FMO3) develop fishy body odor
because they accumulate trimethylamine, a breakdown
product formed from choline by bacteria in the gut (6-9).
A choline-restricted diet is useful in these patients because
it diminishes body odor (10); betaine does not need
to be restricted because it is not a substrate for these
bacteria.
http://breathandbody...rint&thread=191
Edited by brunotto, 21 January 2012 - 12:58 PM.
#77
Posted 21 January 2012 - 01:21 PM
#78
Posted 21 January 2012 - 02:40 PM
I think here is explained very well ....
http://www.westonapr...-heart-disease/
Nice find, brunotto; thanks for that! Chris Masterjohn addresses the Choline/TMAO issue and brings new data to the table; it's a must-read.
#79
Posted 06 July 2012 - 05:42 PM
I think here is explained very well ....
http://www.westonapr...-heart-disease/
Nice find, brunotto; thanks for that! Chris Masterjohn addresses the Choline/TMAO issue and brings new data to the table; it's a must-read.
It's a useful post. Two quick comments. First, while it tends to reinforce the view that dietary doses of PC, such as those present in reasonable servings of meat, will not substantially raise TMA(O) levels, these studies were done in people from the general population and thus in presumed omnivores. However, a study comparing people consuming vegetarian, low (60 g/day), and high- (420 g/day) red meat diets found that "creatine, carnitine, acetyl-carnitine, and trimethylamine-N-oxide (TMAO) [were] elevated in the high-meat consumption period."(1) Part of this differential may have been due to diet-induced shifts in the gut microbiome, causing greater metabolism of a given am't of PC to TMA(O) in high-meat eaters (or, less probably, a reduction of production of TMA(O) from a given am't of PC in vegetarian and low-meat diets) rather than the straightforward effect of the sheer PC content of the extra meat in the diet. Unfortunately, their study was "simply" a multivariate analysis of the patterns of metabolites resulting from the various diets , so they don't provide (and don't have) an absolute quantification of the levels of TMAO that resulted from eating each of the three diets -- just that an unspecified rise therein as one component distinguishing the high-meat diet from the rest.
Second, this still leaves free choline supplements (and badly-stored or old PC supplements) as potentially harmful.
Separately: I've subsequently discovered that carnitine also raises TMA(O) levels,((2) and numerous other refs), so higher than dietary levels (estimated roughly as 23-135 mg/d in a typical 150-pound Western omnivore (3)) would in turn "abnormally" elevate TMA(O).
References
1: Stella C, Beckwith-Hall B, Cloarec O, Holmes E, Lindon JC, Powell J, van der Ouderaa F, Bingham S, Cross AJ, Nicholson JK. Susceptibility of human metabolic phenotypes to dietary modulation. J Proteome Res. 2006 Oct;5(10):2780-8. PubMed PMID: 17022649.
2: Bain MA, Milne RW, Evans AM. Disposition and metabolite kinetics of oral L-carnitine in humans. J Clin Pharmacol. 2006 Oct;46(10):1163-70. PubMed PMID: 16988205.
3: Rebouche CJ. Carnitine function and requirements during the life cycle. FASEB J. 1992 Dec;6(15):3379-86. Review. PubMed PMID: 1464372.
Edited by Michael, 07 July 2012 - 12:59 AM.
#80
Posted 19 July 2012 - 02:28 AM
Next to net bioavailability of the in vivo yielded choline, those qualities must be what makes people rate the variation of choline forms differently, right?
In any case, I am reading left and right that it's from around 5 grams of choline a day when TMA would become problematic, which is 10 times the adequate daily dose for a male that is established.
If it wasn't for racetams I would probably not bother to make sure my choline levels are up to par so that my CNS can source it when several brain regions have faster ACh overturn, but given the evidence as I understand it... it would probably be better if I upgraded my choline source from the citrate to something different like lecithin... but omitting it altogether when taking racetams or Noopept doesn't seem like a good idea at all. (I realize nobody said that, but still - I'm weighing the options).
Edited by Solipsis, 19 July 2012 - 02:29 AM.
#81
Posted 19 July 2012 - 02:24 PM
In the paper that started this thread, they looked at 2000 humans, and found that serum levels of choline, TMA, and TMAO correlated (strongly) with CVD.
The causation may well be in the other direction, since CVD will mess up many other metabolic processes. For example, CVD is also strongly correlated with erectile dysfunction, but that doesn't mean that erectile dysfunction causes CVD.
Here is a paper that suggests that high levels of serum choline may be a consequence, not a cause, of CVD, related to plaque instability, clotting, and ischemia.
Expert Rev Mol Diagn. 2010 Mar;10(2):159-71.
Choline in acute coronary syndrome: an emerging biomarker with implications for the integrated assessment of plaque vulnerability.
Danne O, Möckel M.
Source
Department of Medicine, Internal Intensive Care and Nephrology, Charité - Universitätsmedizin Berlin/Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany. oliver.danne@charite.de
Abstract
Whole-blood choline, plasma choline and serum choline are emerging biomarkers in acute coronary syndrome related to coronary plaque instability with platelet thrombus formation and ischemia. Whole-blood choline is an early predictor for cardiac events, which adds to troponins, natriuretic peptides and inflammatory markers. Serum choline is highly predictive for myocardial infarction and discriminates high- from low-risk subgroups in troponin-positive patients. Choline is a candidate marker to aid decision making in the emergency room in the upcoming era of sensitive troponin tests and the growing need to differentiate between ischemic and nonischemic etiologies of troponin elevations. The integrated approach of in vitro choline measurement in combination with advanced techniques of in vivo choline imaging represents a novel future strategy for detecting vulnerable plaques. This paper provides an up-to-date review of choline in acute coronary syndrome including key aspects of pathophysiology, analytical methods, clinical studies and implications for the integrated assessment of plaque vulnerability.
Edited by viveutvivas, 19 July 2012 - 02:41 PM.
#82
Posted 06 December 2012 - 03:06 AM
Just out of interest and if this TMAO thing is really a worry:
Dietary restriction of: (1) trimethylamine (present in milk obtained from wheat-fed cows) and its precursors including choline (present in eggs, liver, kidney, peas, beans, peanuts, soya products, and brassicas [Brussels sprouts, broccoli, cabbage, cauliflower]), lecithin and lecithin-containing fish oil supplements, (2) trimethylamine N-oxide (present in seafood [fish, cephalopods, and crustaceans]), (3) inhibitors of FMO3 enzyme activity such as indoles (found in brassicas); use of acid soaps and body lotions to remove secreted trimethylamine by washing; use of activated charcoal and copper chlorophyllin to sequester trimethylamine produced in the gut; antibiotics (metronidazole, amoxicillin, and neomycin) to suppress production of trimethylamine by reducing bacteria in the gut; laxatives (e.g., lactulose) to decrease intestinal transit time; riboflavin supplements to enhance residual FMO3 enzyme activity.
Case Report: Riboflavin-Responsive Trimethylaminuria in a Patient with Homocystinuria on Betaine Therapy
Without changing diet or betaine therapy, riboflavin was given at a dose of 200 mg per day. An immediate improvement in her odour was noticed by her friends and family and urinary TMA was noted to be greatly reduced, although still above the normal range.
Gradual further reductions in TMA (and odour) have followed whilst receiving riboflavin. Throughout this period, betaine compliance has been demonstrated by the measurement of dimethylglycine (DMG) excretion, which has been consistently increased. Marked excretions of DMG when the odour had subsided also demonstrate that DMG was not the source of the odour.
While interesting I am still yet unconvinced by the whole connection but its prudent enough to not oversupplement on choline-related supplements (e.g. carnitine).
btw anyone have access to this paper:
Curr Drug Metab. 2005 Jun;6(3):227-40.
Trimethylamine: metabolic, pharmacokinetic and safety aspects.
Bain MA, Fornasini G, Evans AM.
Source
Centre for Pharmaceutical Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide SA 5000, Australia.
Abstract
Trimethylamine (TMA) is a volatile tertiary aliphatic amine that is derived from the diet either directly from the consumption of foods containing TMA, or by the intake of food containing precursors to TMA such as trimethylamine-N-oxide (TMNO), choline and L-carnitine. Following oral absorption in humans, TMA undergoes efficient N-oxidation to TMNO, a reaction catalyzed by the flavin-containing monooxygenase (FMO) isoform 3 enzyme. TMNO subsequently undergoes excretion in the urine, although, evidence also suggests that metabolic retro-reduction of TMNO can occur. Whilst the pharmacokinetics of TMA and TMNO has not been fully elucidated in humans, a number of studies provide information on the likely fate of dietary derived TMA. Trimethylaminuria is a condition that is characterized by a deficiency in FMO3 enzyme activity, resulting in the excretion of increased amounts of TMA in bodily fluids such as urine and sweat, and breath. A human FMO3 database has been established and currently twenty-eight variants of the FMO3 gene have been reported including twenty-four missense, three nonsense, and one gross deletion mutation. Whilst TMA and TMNO are generally regarded as non-toxic substances, they are of clinical interest because of their potential to form the carcinogen N-nitrosodimethylamine. PMID: 15975041 [PubMed - indexed for MEDLINE]
#83
Posted 09 April 2013 - 09:35 AM
From what people have posted upthread, it sounds like dietary choline isn't highly correlated with serum levels, unless the diet is profoundly low in choline. Some forms of supplemental choline might be a problem, though. But the relationship between choline and CVD isn't that strong anyway, so it's probably not the thing to focus on. The problem is really TMA, which leads more or less quantitatively to TMAO, from the sound of it. In this case, we'd want to address the gut biota, and try to alter that. I don't know if you can just walk into a doctors office and ask for a TMAO level, but I suspect not. The easy things to do are to choose choline supplements carefully and use probiotics. While not a proven fix, these things are at least sensible and lack an obvious downside risk.So have these people with high serum choline really been eating a lot of eggs and liver ?
I wouldn't have guessed that this was common these days.
How is a chronically elevated serum choline related to choline being elevated immediately after a meal ?
Don't forget your prebiotics. They can also make a difference in giving those probiotics a fighting start.
#84
Posted 09 April 2013 - 09:45 AM
http://www.jnutbio.c...0151-0/abstract
http://www.sciencedi...02191509405460Z
http://www.sciencedi...043661801908527
#85
Posted 13 April 2013 - 02:11 PM
Oh, yeah about that. Same research group, didn't read the paper:Separately: I've subsequently discovered that carnitine also raises TMA(O) levels,((2) and numerous other refs), so higher than dietary levels (estimated roughly as 23-135 mg/d in a typical 150-pound Western omnivore (3)) would in turn "abnormally" elevate TMA(O).
References
1: Stella C, Beckwith-Hall B, Cloarec O, Holmes E, Lindon JC, Powell J, van der Ouderaa F, Bingham S, Cross AJ, Nicholson JK. Susceptibility of human metabolic phenotypes to dietary modulation. J Proteome Res. 2006 Oct;5(10):2780-8. PubMed PMID: 17022649.
2: Bain MA, Milne RW, Evans AM. Disposition and metabolite kinetics of oral L-carnitine in humans. J Clin Pharmacol. 2006 Oct;46(10):1163-70. PubMed PMID: 16988205.
3: Rebouche CJ. Carnitine function and requirements during the life cycle. FASEB J. 1992 Dec;6(15):3379-86. Review. PubMed PMID: 1464372.
Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis
http://www.nature.co...ll/nm.3145.html
This makes one speculate: could we get TMAO reliably tested? Presumably this could measures the net impact of these "carninutrients" on one's blood levels, which might differ depending on one's microbiota.
#86
Posted 18 April 2013 - 01:37 AM
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#87
Posted 18 April 2013 - 04:06 PM
http://www.ncbi.nlm.nih.gov/pubmed/2253811
http://www-miljo.slu.se/Workshop%20Norge/organic_acids_canibe_et_al.pdf
http://ir.library.oregonstate.edu/xmlui/handle/1957/27113
SA inhibited the growth and subsequent TMA production in E. coli at or above 0.35 mM
Edited by revenant, 18 April 2013 - 04:27 PM.
#88
Posted 18 April 2013 - 05:28 PM
http://lib.bioinfo.pl/meid:38169
http://www.cabdirect.org/abstracts/20063104305.html;jsessionid=BE143C197D0DF64272ED04F2FF04DCBD?gitCommit=4.13.29
http://www.prairieswine.com/pdf/39091.pdf
#89
Posted 03 May 2013 - 08:11 AM
Is that right?
Also,is 30mg of PSP-choline per day in the form of a multivitamin a concern?
#90
Posted 28 September 2014 - 12:06 AM
All:
A few additional things on this subject:
-There is some suggestion that TMA(O) may also be procarcinogens(2).
-Contrary to all the advise out there to consume fermented foods or take probiotics to avoid TMA(O) formation, (4) seems somewhat unclearly to indicate that kimchi consumption was associated with greater TMAO levels.(4)
The pop sci article, and the headline & abstract of the report, focus on phosphatidylcholine (which is the form in lecithin and food), but the issue is that a small percentage of dietary or supplemental phosphatidylcholine (PC) can be degraded into free choline, which in turn is metabolized into trimethylamine (TMA) and trimethylamine N-oxide (TMAO). Unsurprisingly, then, taking dietary supplements composed of free choline have been shown in human studies (I've checked the references ((1,3) below)) to spike TMA levels much higher than phosphatidylcholine itself.
There is very little free choline in the diet, and despite this new study, previous reports show that very little naturally-occurring, food-bound PC is converted to choline in a way that leads to formation of TMA/TMAO:
Egg is usually regarded as a rich source of choline; egg yolk has been reported to contain as much as 1.3% (by weight) ... However, closer inspection of this work reveals that the egg yolk was alkali hydrolysed prior to quantification. Such severe chemical treatment may release bound choline (usually present as lecithin) and result in overestimation.
More recent studies suggest that eggs contain only small amounts of free choline (0.003% by wt), and indeed, that most of the choline we are presumed to eat is actually in the form of lecithin (Wurtman, 1979). Peanut and soyabean, foods that provide relatively large amounts of trimethylamine on alkali hydrolysis (unpublished data), also contain lecithin which, from the present investigation, is not a biological precursor of trimethylamine and its N-oxide. This is also true for meats, especially lamb (Zeisel, 1981). It has been estimated that the total daily intake of free choline is about 9 mg (Wurtman, 1979), suggesting that dietary choline is probably not a common source of urinary trimethylamine.(3)
But then, there's those darned supplements ...
Many supplement users already use PC supplements, for both justified and unjustified reasons, and clearly people taking choline now should be encouraged to move to PC. Unfortunately, that doesn't get us quite out of the woods, because the same studies op cit showed that nearly all PC supplements are (or were, at the time) contaminated with TMA!
It has been suggested that ingested lecithin is hydrolysed in the gut by phospholipase A, found in pancreatic juice, to produce lysolecithin, which is absorbed. Further degradation does not occur in the upper gut and there is no release of choline for further metabolism (Haslewood, 1967; Zeisel, 1981). Previous reports of increased urinary trimethylamine excretion after lecithin ingestion are most likely explained by the usage of lecithin which was contaminated with choline (Asatoor and Simenhoff, 1965; De La Huerga and Popper, 1952; Zeisel et al., 1983). Also, abnormally large intakes may enable unabsorbed lecithin or lysolecithin to pass to the colon where resident microbes ... may degrade the compounds and eventually liberate [TMA, as in this new study] ...(3)
It is, however, relatively easy to remove the great bulk of this contaminant, considerably decreasing systemic exposure:
Preparation of “clean” lecithin. Bolec Soy Lecithin was dissolved in ethanol and water was then added. After mixing, acetone was added to precipitate the lecithin. The supernatant was decanted, and the precipitate was washed two times with equal volumes of water. Lecithin prepared in this manner contained only 4% as much TMA (0.6 ımol/g) as the untreated compound (see table 1). …
When [normal volunteers] consume a normal diet their urinary output of ... TMA is approximately 1 mmol of each amine per day. After consumption of 27 mmol of choline chloride, humans excreted ... more than 17 mmol/day of TMA (P < .01 all values different from control). Ingestion of 27 mmol of choline stearate caused humans to excrete ... TMA (9.3 mmol/day; P < .01 different from controls). When humans ate 27 mmol of lecithin they excreted more ... TMA (3.8 mmol/day; P < .01) than did controls. Methylamine excretion was not increased as much when the humans ingested “cleaned” lecithin (...TMA, 2.2 mmol/day). ...
Lecithin is soluble in organic solvents, whereas the methylamines are soluble in water. Therefore, removal of these contaminants should be easy. It is possible that the methylamines are formed after the lecithin is manufactured, perhaps because of bacterial action during storage. We used all the lecithins in the form in which they are made available to humans and we stored them at 4°C. We suggest that lecithin manufacturers should determine which method of storage is optimal for their preparation. (1)
Note that 3.8 mmol/d, while much lower than 17, still constitutes a quadrupling of normal diet-derived exposure -- and the study in Nature seems to suggest that even in the range present in the population at large, where nearly all choline will come from dietary PC rather than free or PC-bound choline supplements, even the higher end of that much narrower range is enough to increase risk of CVD.
Bolec Soy Lecithin started out with amongst the highest levels of TMA of all tested supplements, suggesting that in most supplements, the same protocol could lead to even greater reductions in exposure relative to free choline.
References
1: Zeisel SH, Wishnok JS, Blusztajn JK. Formation of methylamines from ingested
choline and lecithin. J Pharmacol Exp Ther. 1983 May;225(2):320-4. PubMed PMID:
6842395.
2: Bain MA, Fornasini G, Evans AM. Trimethylamine: metabolic, pharmacokinetic and
safety aspects. Curr Drug Metab. 2005 Jun;6(3):227-40. Review. PubMed PMID:
15975041.
3: Zhang AQ, Mitchell SC, Smith RL. Dietary precursors of trimethylamine in man:
a pilot study. Food Chem Toxicol. 1999 May;37(5):515-20. PubMed PMID: 10456680.
4: Mi Park E, Lee E, Jin Joo H, Oh E, Lee J, Lee JS. Inter- and intra-individual variations of urinary endogenous metabolites in healthy male college students using (1)H NMR spectroscopy. Clin Chem Lab Med. 2009;47(2):188-94. doi: 10.1515/CCLM.2009.040. PubMed PMID: 19191725.
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