95 replies to this topic

[RoadToAwe]

Interesting research on how PC's metabolites could potentially promote atherosclerosis.

Common Dietary Fat and Intestinal Microbes Linked to Heart Disease

http://www.scienceda...10406131814.htm

Attached Files

•  Phosphatidylcholine_Nature_Paper.pdf   1.09MB   368 downloads

[aLurker]

Thanks for sharing. I'm guessing a lot of us are interested to know that since it makes choline look pretty bad. Speaking of which I ordered some CDP-choline yesterday, bad timing. Before reading this I assumed that choline supplementation was generally safer than AChEIs but now I'll have to reevaluate that. Well, I've still got the ALCAR I guess.

[niner]

Wow, that's an amazing paper. Considering the huge odds ratios they saw for choline metabolites vs CVD, it looks like we're going to be re-thinking a lot of things. Like hyperlipid paleo diets, some of the supplements we take, the choline in Vimmortal, or the amount of animal products we eat. Probiotics are protective here. There are also some new diagnostic and therapeutic possibilities- drugs that block the microbial liberation of trimethylamine, inhibitors of hepatic FMOs to block the oxidation of trimethylamine; tests for plasma concentration of TMA N-oxide as a gauge risk.

[triplecrown]

I really hate how these studies comes out right after I order a supplement containing a good quantity of phos-choline. Ugh

[Jay]

I'd be awfully suspicious of a paper that starts out by saying:

A known environmental risk factor for the development of CVD is a diet rich in lipids. A relationship between blood cholesterol and triglyceride levels and cardiovascular risk is well established.

Eggs, liver, and animal fat are quite unlikely to cause CVD. We've been through all this before... Wholehealthsource, dailylipid, etc are great places to start for newbies. For those that have been around a while, not quite sure why you'd be so quick to turn on choline. I think many people have far too little of it.

Edited by Jay, 07 April 2011 - 03:36 AM.

[niner]

Eggs, liver, and animal fat are quite unlikely to cause CVD. We've been through all this before... Wholehealthsource, dailylipid, etc are great places to start for newbies. For those that have been around a while, not quite sure why you'd be so quick to turn on choline. I think many people have far too little of it.

I think the paper is a call for moderation, assuming their results hold up. We certainly don't want to eliminate choline. We just don't want way too much. We just had a thread regarding some ugly data on egg consumption.

[Mortuorum]

Would this be as readily applicable, theoretically, to DMAE and CENTROPHENOXINE as PhDMAe is PC however it is minus one methyl group.......? Research data has indicated that 40% of PhDMAE persists in the membrane after 24 hours, in place of choline, then the PhDMAE actually works in membranes as an effective site-specific antioxidant, so prior research suggests......

[s123]

Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease
Metabolomics studies hold promise for the discovery of pathways linked to disease processes. Cardiovascular disease (CVD) represents the leading cause of death and morbidity worldwide. Here we used a metabolomics approach to generate unbiased small-molecule metabolic profiles in plasma that predict risk for CVD. Three metabolites of the dietary lipid phosphatidylcholine—choline, trimethylamine N-oxide (TMAO) and betaine—were identified and then shown to predict risk for CVD in an independent large clinical cohort. Dietary supplementation of mice with choline, TMAO or betaine promoted upregulation of multiple macrophage scavenger receptors linked to atherosclerosis, and supplementation with choline or TMAO promoted atherosclerosis. Studies using germ-free mice confirmed a critical role for dietary choline and gut flora in TMAO production, augmented macrophage cholesterol accumulation and foam cell formation. Suppression of intestinal microflora in atherosclerosis-prone mice inhibited dietary-choline-enhanced atherosclerosis. Genetic variations controlling expression of flavin monooxygenases, an enzymatic source of TMAO, segregated with atherosclerosis in hyperlipidaemic mice. Discovery of a relationship between gut-flora-dependent metabolism of dietary phosphatidylcholine and CVD pathogenesis provides opportunities for the development of new diagnostic tests and therapeutic approaches for atherosclerotic heart disease.

http://www.nature.co...ature09922.html

I haven't read the full article yet but the News and Views says:

"They also report that, in mice prone to atherosclerosis, increased dietary choline leads not only to increased plasma levels of TMAO, but also to greater plaque development in the animals' arteries. To demonstrate the role of the gut microbiota in this process, the researchers treated mice with broad-spectrum antibiotics, effectively abolishing the animals' internal flora. In this setting, phosphatidylcholine administration did not result in TMAO in the blood and, more strikingly, a high-choline diet did not increase the severity of atherosclerosis."

http://www.nature.co...ll/472040a.html

Sven

[Mortuorum]

Just poking around relative to this awful news and, according to this data from the late James South article:



"CPX is a compound of two biochemicals- diethylaminoethanol (DMAE) and parachlorophenoxyacetate (pCPA). DMAE is a natural food component, found especially in fish, and is also a natural metabolite of the human body, CPX's other half, pCPA, is a synthetic compound similar to a variety of plant hormones called "auxins."


The chief component of CPX is DMAE. DMAE is part of the choline betaine cycle, natural to human and animal cells.

By adding a methyl group (CH3) to DMAE, choline (also called trimethy-laminoethanol) is formed. The choline thus formed may then be used to make other valuable biochemicals, such as the major neurotransmitter acetylcholine, or the essential membrane constituents phosphatidylcholine and sphingomyelin.

Choline can also be oxidized to make betaine (trimethylglcine), important for ridding the body of heart and artery toxic homocysteine, now considered one of the most important risk factors for heart disease.

Under fasting conditions, normal blood levels of choline range from 8 to 12 micromoles. When blood choline levels are below 14 micromoles, choline flows from brain cells into the bloodstream. When blood choline levels are above 14 micromoles, choline flows from the blood into the brain.

Unfortunately, when choline enters the blood from brain cells, it is derived from auto-cannibalisation, the choline containing phospholipids (which are critical brain cell membrane components) are broken down to provide the choline entering the blood. There is evidence that excessive neuronal choline auto-cannibalisation over a lifetime may contribute to Alzheimer's disease.

Centrophenoxine - The need for supplementation

While a natural foods diet, such as liver, meat and eggs provides high dietary levels of choline, the modern processed junk food/ synthetic diet provides little choline, as do vegetarian diets.

Simple choline supplements, such as choline chloride or bitartrate are often broken down, as much as 60%, by gut bacteria. Thus, CPX derived DMAE is an especially ideal source of blood and brain choline for several reasons.


Gut bacteria do not digest DMAE, thus avoiding that wasteful trap.


The liver quickly and easily converts DMAE to choline as needed. Also, DMAE prevents choline from being irreversibly oxidized to betaine, further raising blood choline levels. Lastly, DMAE passes through the blood brain barrier far more easily than choline.

DMAE may be incorporated into brain cell membranes, where it functions as a powerful hydroxyl free radical scavenger. Or the brain cells may convert the DMAE to choline for their needs. With the help of an enzyme called "CAT", choline is converted to the learning/ memory neurotransmitter acetylcholine (ACh)."


It's possible that CPX and DMAE, therefore, may avoid this pernicious metabolic gut situated pitfall that now casts a pall upon more straightforward Choline derivatives intake as it is not digested, is rejected, by gut bacteria....?

Edited by Mortuorum, 07 April 2011 - 06:12 PM.

[nameless]

Interesting... Some quick questions:

Would probiotics be a good or bad thing if this paper holds up?

I believe they more or less wrecked the mice's flora using antibiotics, and said mice didn't show increased atherosclerosis due to choline. So would taking probiotics worsen this? Or would certain strains of bacteria be protective?

And as Niner mentioned, if nothing else, it does lead to re-evaluation of some diets. And Vimmortal... some folks already had hesitations over its choline content to begin with. I can't see this paper helping much.

Edited by nameless, 07 April 2011 - 06:53 PM.

[Sillewater]

If TMOA is indeed a problem, fish intake may pose a risk also (1). While choline and carnitine elicited an increase, betaine, creatine, and lecithin did not. Here is a scary paragraph from study (2):

The clinical significance of TMA and TMNO may be related to their potential to form the carcinogen N-nitrosodimethylamine and their association with abnormal neurological symptoms observed in patients with ESRD [15]. Other studies have shown higher levels of N-nitrosodimethylamine in the gastrointestinal tract of patients with ESRD compared with healthy controls [16] and, therefore, its potential contribution to an increased incidence of cancer in ESRD patients [17] should be carefully examined. N-nitrosodimethylamine does not elicit its carcinogenic effects directly, but requires metabolic activation in the liver, particularly by the cytochrome P450 2E1 isoenzyme, to form highly reactive alkylating intermediates that have the ability to methylate target organ DNA [18]. Mildly acidic conditions are conducive to the formation of N-nitrosodimethylamine from TMA and TMNO and, therefore, the acidic conditions of the stomach provide the most likely site for its formation in the body [18]. Whether elevated plasma levels of TMA and TMNO translate to increased levels in gastric fluid is not known. However, compounds with similar structural properties to TMA and TMNO are excreted from blood to gastric fluid [19]. The presence of bacteria or chronic inflammation has also been highlighted in other research as favouring the formation of N-nitrosodimethylamine from TMA and TMNO, implying that other sites of the body have the potential to form this carcinogen [18]. In our study, the pre-dialysis plasma concentrations of TMA and TMNO were significantly greater than those in healthy subjects (P<0.00001 andP<0.0001, respectively). There was also a significant reduction (P<0.001) in the pre-dialysis plasma concentrations of these substances following a haemodialysis session. Whether the accumulation of TMA and TMNO in the interdialysis period is associated with adverse effects is not currently known.

Also TMOA may have a protective effect in terms of protein folding and denaturation (3) [I put study (4) in the references, maybe someone can interpret it I don't have time to read the whole thing]. Maybe this explains why it is found in food products containing lots of protein (e.g. meat, beans). There is also previous research to show that TMOA has detrimental effects on cardiovascular health (5). There is a metabolic disorder known as Trimethylaminuria which may lead to problem beyond just smelling fishy (5).

In study (2) they also mention that ESRD patients have higher amounts of gut flora (but different types). And ESRD patients have higher TMOA levels (just like the nature study in the OP).

Could Vitamin K increase TMOA metabolism? (7).

If anyone can read russian and can access this older paper if would be great (6).

References


1. Food Chem Toxicol. 1999 May;37(5):515-20.Dietary precursors of trimethylamine in man: a pilot study.Zhang AQ, Mitchell SC, Smith RL.
2. Nephrol Dial Transplant. 2006 May;21(5):1300-4. Epub 2006 Jan 9.Accumulation of trimethylamine and trimethylamine-N-oxide in end-stage renal disease patients undergoing haemodialysis.Bain MA, Faull R, Fornasini G, Milne RW, Evans AM.
3. Biochem Biophys Res Commun. 1998 Sep 29;250(3):726-30.Natural methylamine osmolytes, trimethylamine N-oxide and betaine, increase tau-induced polymerization of microtubules.Tseng HC, Graves DJ.
4. Biochemistry. 2006 Mar 21;45(11):3684-91.TMAO promotes fibrillization and microtubule assembly activity in the C-terminal repeat region of tau.Scaramozzino F, Peterson DW, Farmer P, Gerig JT, Graves DJ, Lew J.
5. Lancet. 1999 Sep 4;354(9181):834-5.Mild trimethylaminuria caused by common variants in FMO3 gene.Zschocke J, Kohlmueller D, Quak E, Meissner T, Hoffmann GF, Mayatepek E.
6. Klin Med (Mosk). 1959 May;37(5):129-32.[Changes in the level of prothrombin and fibrinogen of the blood in atherosclerosis in treatment with ascorbic acid, choline and iodine preparations].[Article in Russian]
7. Arch Microbiol. 1990;154(1):60-6.The specific functions of menaquinone and demethylmenaquinone in anaerobic respiration with fumarate, dimethylsulfoxide, trimethylamine N-oxide and nitrate by Escherichia coli.Wissenbach U, Kröger A, Unden G.

[Mortuorum]

Interesting... Some quick questions:

Would probiotics be a good or bad thing if this paper holds up?

I believe they more or less wrecked the mice's flora using antibiotics, and said mice didn't show increased atherosclerosis due to choline. So would taking probiotics worsen this? Or would certain strains of bacteria be protective?

And as Niner mentioned, if nothing else, it does lead to re-evaluation of some diets. And Vimmortal... some folks already had hesitations over its choline content to begin with. I can't see this paper helping much.

According to the study data as manifest, the healthier and more "normal" your intestinal flora is, that is what is required and optimal to facilitate this resultant pathological process. So, yes, probiotics, presuming they are of integrity and being assimilated properly, will bolster and enhance the dark contentions of this research.

[rwac]

According to the study data as manifest, the healthier and more "normal" your intestinal flora is, that is what is required and optimal to facilitate this resultant pathological process. So, yes, probiotics, presuming they are of integrity and being assimilated properly, will bolster and enhance the dark contentions of this research.

Well, for one thing, it's hard to argue that the intestinal flora of lab mice is "normal" in any sense of the word.
It would be interesting to see if all strains of bacteria do this, or only specific strains.

Edited by rwac, 07 April 2011 - 08:24 PM.

[Mortuorum]

According to the study data as manifest, the healthier and more "normal" your intestinal flora is, that is what is required and optimal to facilitate this resultant pathological process. So, yes, probiotics, presuming they are of integrity and being assimilated properly, will bolster and enhance the dark contentions of this research.

Well, for one thing, it's hard to argue that the intestinal flora of lab mice is "normal" in any sense of the word.
It would be interesting to see if all strains of bacteria do this, or only specific strains.

Well, clearly, (...was I suggesting this? That is why I placed the word in quotations..haha...) another aspect of problematic transposing rodent models onto human ones, right? Also, I doubt the paper investigates nor goes into details regarding specific strains of microorganisms and their metabolic digestive breakdown roles. What is implicit is that, when the antibiotic ravaged control models had no sufficient gut flora with which to breakdown the PC, then the CVD did not actuate, to prove the role of gut bacteria's involvement. I would hardly assert yet upon any level that a specific strain of gut microbe could perhaps avert or prevent this unfortunate consequence, evidence thus far would seem to oppose this relative to gut flora breaking down intake matter in the way it is more or less supposed to. I don't think the study suggests that the causation of this mechanism resulting in CVD pathology has anything to do with a gut flora abnormality?

Edited by Mortuorum, 07 April 2011 - 08:45 PM.

[kismet]

At a glance:

I concur that a re-appraisal of choline is in order, but we must not get hysteric over the reported odds ratios for serum choline.

What does serum choline tell us about choline intake and how sensitive is it? this is a key question
since “there is no reliable blood biomarker for dietary intake of choline. As it is known from clinical settings, plasma concentrations of choline and betaine decrease when subjects are fed a low choline diet, but the amount of decrease is not highly correlated with susceptibility to develop organ dysfunction while on this diet”

The available cohort studies suggest a minimal risk from dietary choline if any.

"“During an average 14 years of follow-up (1987-2002), 1,072 incident CHD events were documented. Compared with the lowest quartile of intake, incident CHD risk was slightly and non-significantly higher in the highest quartile of choline and choline plus betaine, HR = 1.22 (0.91, 1.64) and HR = 1.14 (0.85, 1.53), controlling for age, sex, education, total energy intake, dietary intakes of folate, methionine and vitamin B6. No association was found between dietary choline intake and incident CHD when correcting for measurement error.”

BMC Cardiovasc Disord. 2007 Jul 13;7:20.
Usual choline and betaine dietary intake and incident coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) study.
Bidulescu A, Chambless LE, Siega-Riz AM, Zeisel SH, Heiss G.
http://www.ncbi.nlm....79/?tool=pubmed

"During a median follow-up period of 97 months, 717 women were diagnosed with CVD. After adjustment, neither folate, nor betaine, nor choline intakes were associated with CVD (hazard ratios for highest versus lowest quartile were 1.23 (95% confidence interval 0.75; 2.01), 0.90 (0.69; 1.17), 1.04 (0.71; 1.53), respectively). In a subsample of the population, high folate and choline intakes were statistically significantly associated with lower homocysteine levels. High betaine intake was associated with slightly lower high-density lipoprotein (HDL)-cholesterol concentrations."

Eur J Clin Nutr. 2008 Mar;62(3):386-94. Epub 2007 Mar 21.
Prospective study on dietary intakes of folate, betaine, and choline and cardiovascular disease risk in women.
Dalmeijer GW, Olthof MR, Verhoef P, Bots ML, van der Schouw YT.

As per: http://advances.nutr...70-c62da83b570e
"Deficiencies: Healthy humans with normal folate and vitamin B-12 status who were fed a choline-deficient diet developed fatty liver, liver damage [elevated plasma alanine (or aspartate) transaminase] or developed muscle damage (elevated creatine phosphokinase) that resolved when choline was restored to the diet (4,6). Elevations in markers of DNA damage (7) and alterations in lymphocyte gene expression (8) were also observed in choline deficiency. "

"Epidemiological studies have linked low dietary choline intake to higher concentrations of proinflammatory markers (36,37) as well as to increased risk of breast cancer (14)"


While zero choline as well as the ten-fold overdoses given to rats (and hyperlipid dieters?) will kill you, modest differences, e.g. 250mg vs 500mg, may involve only smallish trade-offs. Say, very, very small CVD risk vs neuro/cancer/inflamm. benefits. W/o all-cause mortality data it will probably remain guesswork.

Eggs, liver, and animal fat are quite unlikely to cause CVD. We've been through all this before... Wholehealthsource, dailylipid, etc are great places to start for newbies. For those that have been around a while, not quite sure why you'd be so quick to turn on choline. I think many people have far too little of it.

In which you and others have been corrected over and over again. Eggs drastically increase CVD in diabetics and may promote diabetes; some evidence suggests carcinogenic effects and overall effects on CVD are neutral-negative. They also worsen known risk factors and contain substances linked to diseases.
Same goes for saturated fat...
(mind you, I agree that the risks are exaggerated in the pop press, but you are going off the other side. Secondly, you correctly called the authors on their bullshit - fat per se is hardly involved in CVD, at least compared to other macros - but then use it to discount all their data by ad hominem reasoning: why?!)

Edited by kismet, 07 April 2011 - 10:02 PM.

[Sillewater]

Seeing as that in the ARIC cohort the majority of participants were not consuming the RDA (1) it doesn't seem higher choline intakes are protective of heart disease. Unless the protective effects occur at the AI (if there is one, most thing are J-shaped). Anyone read the chapter on choline in the RDA book?

But if TMOA is itself toxic then we really should rethink choline supplementation. Unless it plays an important role in preventing protein misfolding/function.

References
1. Nutr J. 2009 Feb 20;8:14.
Repeatability and measurement error in the assessment of choline and betaine dietary intake: the Atherosclerosis Risk in Communities (ARIC) study.
Bidulescu A, Chambless LE, Siega-Riz AM, Zeisel SH, Heiss G.

[kismet]

See appended data, In edited my above post. There is an AI ("RDA") for choline and there is not that much wiggle room at dietary intakes. The effect sizes are ridiculously small (one out of 2 studies found non-significant harm for CVD, yeah...), while there may be some real benefits to choline. (also note FFQs underestimate nutrient intakes)

Therefore it's difficult. "While zero choline as well as the ten-fold overdoses given to rats (and hyperlipid dieters?) will kill you, modest differences, e.g. 250mg vs 500mg, may involve only smallish trade-offs. Say, very, very small CVD risk vs neuro/cancer/inflamm. benefits. W/o all-cause mortality data it will probably remain guesswork."

Edited by kismet, 07 April 2011 - 10:05 PM.

[Sillewater]

Definitely seems u-shaped at least for all cause mortality in women. Higher then 205mg (total choline) Increased risk but it was nonsignificant and varied as to the type of choline. The AI for females right now is 405mg I think. I will have to reread that chapter on choline.

1. FASEB J. 2009 Nov;23(11):4022-8. Epub 2009 Jul 27.
High intakes of choline and betaine reduce breast cancer mortality in a population-based study.
Xu X, Gammon MD, Zeisel SH, Bradshaw PT, Wetmur JG, Teitelbaum SL, Neugut AI, Santella RM, Chen J.

[kismet]

And this is after a very low choline diet (550 to 50mg/d for 42 days!):

"Of the 57 participants, 68% developed organ dysfunction when fed the low choline diet and this resolved when choline was added back to their diets. Plasma betaine concentrations decreased almost 50% in response to the low choline diet (from 60±3 to 32±2 nmol/ml; P<0.001) and choline concentrations decreased almost 30% (from 9.8±0.3 to 7.1±0.2 nmol/ml; P<0.001). These decreases were irrespective of whether or not subjects developed organ dysfunction on the low choline diet. Plasma phosphatidylcholine concentrations were 9% lower when subjects were fed the low choline diet (1691±41 vs. 1868±45 nmol/ml than when on baseline diet; P<0.001); those subjects who developed organ dysfunction on the low choline diet had a 3-fold greater decrease in phosphatidylcholine (–228±47 nmol/ml) than those who did not (–64±31 nmol/ml; P<0.029 by t test)."
http://www.fasebj.or.../20/9/1336.full

Exogenous choline hardly budges serum choline, which going by this recent paper would suggest that dietary choline only confers a small risk; consistent with the cohort studies. We do not have TMAO data unfortunately...

Edited by kismet, 07 April 2011 - 10:34 PM.

[Sillewater]

Will have to wait for more data. The only thing we can conclude I guess is don't eat rotten fish (we knew that already though).

[Jay]

There are fist fulls of studies, in humans, some of them randommized placebo controlled trials, suggesting that folate and folic acid increase the risk of cancer. Yet, since folate is found in vegetables, many don't focus on this evidence. But, choline...

Now there is a study on dysbiotic mice and choline and we have a two page thread... Choline is of course found mainly in animal products... Since liver and other organs are out of fashion, human dietary intake of choline is primarily from eggs and coffee. And, people who ate the most choline just ate the most eggs, a dangerous thing to do if you believe your doctor... Paying attention to epidemiology where the variable goes against doctor's orders is not very reliable.

Now add in that serum cholilne is not so sensitive to dietary choline (in non-deficient people).

What do we have left from this paper? More or less completely defective human evidence and a wierd mouse study... Yup, let's stop eating liver and eggs and start eating the low-fat chow...

Edited by Jay, 08 April 2011 - 01:17 PM.

[aLurker]

There are fist fulls of studies, in humans, some of them randommized placebo controlled trials, suggesting that folate and folic acid increase the risk of cancer. Yet, since folate is found in vegetables, many don't focus on this evidence. But, choline...

There is a huge difference between dietary folate from vegetables and supplementing with folate. See this study for instance.

Now there is a study on dysbiotic mice and choline and we have a two page thread... Choline is of course found mainly in animal products... Since liver and other organs are out of fashion, human dietary intake of choline is primarily from eggs and coffee. And, people who ate the most choline just ate the most eggs, a dangerous thing to do if you believe your doctor... Paying attention to epidemiology where the variable goes against doctor's orders is not very reliable.

The problem with epidemiology is that there are too many confounding factors to see a cause and effect. An epidemiology study showing the dangers of egg intake could have many different explanations (such as oxycholesterol for instance).

Now add in that serum cholilne is not so sensitive to dietary choline (in non-deficient people).

Cite please.

What do we have left from this paper? More or less completely defective human evidence and a wierd mouse study... Yup, let's stop eating liver and eggs and start eating the low-fat chow...

I don't see anyone but you jumping to this conclusion.

Most of us seem to be reevaluating supplementary choline rather than changing our dietary habits based upon this. This reevaluation seems like a reasonable thing to do and I appreciate those here who have made an effort to investigate this further by citing studies and making logically coherent points.

[stephen_b]

There is a huge difference between dietary folate from vegetables and supplementing with folate. See this study for instance.

That's a bit apples and oranges. The study you linked supports the claim that folic acid supplements (which are synthetic) are problematic, but not necessarily supplementation of other forms of folate.

Folate is a water-soluble B vitamin that occurs naturally in food. Folic acid is the synthetic form of folate that is found in supplements and added to fortified foods.

(the quote above from the NIH).

[health_nutty]

And this is after a very low choline diet (550 to 50mg/d for 42 days!):

"Of the 57 participants, 68% developed organ dysfunction when fed the low choline diet and this resolved when choline was added back to their diets. Plasma betaine concentrations decreased almost 50% in response to the low choline diet (from 60±3 to 32±2 nmol/ml; P<0.001) and choline concentrations decreased almost 30% (from 9.8±0.3 to 7.1±0.2 nmol/ml; P<0.001). These decreases were irrespective of whether or not subjects developed organ dysfunction on the low choline diet. Plasma phosphatidylcholine concentrations were 9% lower when subjects were fed the low choline diet (1691±41 vs. 1868±45 nmol/ml than when on baseline diet; P<0.001); those subjects who developed organ dysfunction on the low choline diet had a 3-fold greater decrease in phosphatidylcholine (–228±47 nmol/ml) than those who did not (–64±31 nmol/ml; P<0.029 by t test)."
http://www.fasebj.or.../20/9/1336.full

Exogenous choline hardly budges serum choline, which going by this recent paper would suggest that dietary choline only confers a small risk; consistent with the cohort studies. We do not have TMAO data unfortunately...

To all: given this new study, what choline dosage seems optimal? If I remember correctly, the choline contenet of the immminst multi is pretty high.

[aLurker]

There is a huge difference between dietary folate from vegetables and supplementing with folate. See this study for instance.

That's a bit apples and oranges. The study you linked supports the claim that folic acid supplements (which are synthetic) are problematic, but not necessarily supplementation of other forms of folate.

Folate is a water-soluble B vitamin that occurs naturally in food. Folic acid is the synthetic form of folate that is found in supplements and added to fortified foods.

(the quote above from the NIH).

Thanks for mentioning that and for that informative link. It is true that the supplementation in the study I cited was mainly from folic acid intake as shown in this quote from the abstract:

Furthermore, although food folate intake was not significantly related to breast cancer risk, total folate intake, mainly from folic acid supplementation, significantly increased breast cancer risk by 32%.

What you wrote makes Jay's original hypothesis even less valid since there is an even starker difference between the dietary folate from healthy vegetables and supplementing with folic acid. As the NIH mentions:

Folate intake from food is not associated with any health risk.

Edited by aLurker, 08 April 2011 - 04:40 PM.

[stephen_b]

You know, I misquoted your original post -- I meant to quote Jay's statement, pointing out the distinction between folate from food and folic acid. Sorry about that.

[niner]

I concur that a re-appraisal of choline is in order, but we must not get hysteric over the reported odds ratios for serum choline.

I'm not hysterically concerned with the plasma choline ORs, (although they are non-trivial) but note that the TMAO ORs are twice as big, and are pretty big numbers. That's a hard thing to ignore.

What does serum choline tell us about choline intake and how sensitive is it? this is a key question
since “there is no reliable blood biomarker for dietary intake of choline. As it is known from clinical settings, plasma concentrations of choline and betaine decrease when subjects are fed a low choline diet, but the amount of decrease is not highly correlated with susceptibility to develop organ dysfunction while on this diet”

The available cohort studies suggest a minimal risk from dietary choline if any.

"“During an average 14 years of follow-up (1987-2002), 1,072 incident CHD events were documented. Compared with the lowest quartile of intake, incident CHD risk was slightly and non-significantly higher in the highest quartile of choline and choline plus betaine, HR = 1.22 (0.91, 1.64) and HR = 1.14 (0.85, 1.53), controlling for age, sex, education, total energy intake, dietary intakes of folate, methionine and vitamin B6. No association was found between dietary choline intake and incident CHD when correcting for measurement error.”

BMC Cardiovasc Disord. 2007 Jul 13;7:20.
Usual choline and betaine dietary intake and incident coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) study.
Bidulescu A, Chambless LE, Siega-Riz AM, Zeisel SH, Heiss G.
http://www.ncbi.nlm....79/?tool=pubmed

"During a median follow-up period of 97 months, 717 women were diagnosed with CVD. After adjustment, neither folate, nor betaine, nor choline intakes were associated with CVD (hazard ratios for highest versus lowest quartile were 1.23 (95% confidence interval 0.75; 2.01), 0.90 (0.69; 1.17), 1.04 (0.71; 1.53), respectively). In a subsample of the population, high folate and choline intakes were statistically significantly associated with lower homocysteine levels. High betaine intake was associated with slightly lower high-density lipoprotein (HDL)-cholesterol concentrations."

I think there's an explanatory role in the gut biota. We see little effect on CVD from dietary choline, but even there, the ORs are positive, though not significant. And that's with crappy FFQ data. When you look at plasma choline, you're getting better data, and you see a big jump in the ORs. This might represent differences in people's ability to transform PC to choline. Then consider that not everyone's gut flora is the same, and some are apparently more likely to convert choline to trimethylamine (TMA). The TMA is hepatically converted to TMAO, the putative ulitmate bad actor. There's probably some variation there, too. Each time we look further down the trasformation pathway, the ORs get worse.

While zero choline as well as the ten-fold overdoses given to rats (and hyperlipid dieters?) will kill you, modest differences, e.g. 250mg vs 500mg, may involve only smallish trade-offs. Say, very, very small CVD risk vs neuro/cancer/inflamm. benefits. W/o all-cause mortality data it will probably remain guesswork.

Classic inverted U, isn't it? We just need to sort out the parameters of the curve. But beyond that, I think the exciting messages are that a serum TMA or TMAO level would quickly tell you whether you had a problem or not. That should be simple to implement. Also, at the end of the paper, they mentioned the possibility of probiotic therapy. From their ref. 35, (Martin, F. P. et al. Probiotic modulation of symbiotic gut microbial–host metabolic interactions in a humanized microbiome mouse model. Mol. Syst. Biol. 4, 157 (2008).) they claim that probiotic supplementation can modulate TMAO levels. So get your gut microflora in the right shape and maybe you'll cut your risk of CVD and a growing list of other conditions.

[Jay]

A few studies on folic acid and folate:
http://jama.ama-assn...9/2119.abstract

http://jama.ama-assn...1/2351.abstract

http://jnci.oxfordjo.../101/6/432.full


http://www.bmj.com/c.../7479/1375.full

http://carcin.oxford.../29/9/1765.full

http://www.wjgnet.co...327/11/3834.asp

http://www.ncbi.nlm....8?dopt=Abstract

http://www.ajcn.org/.../4/895.abstract

http://jn.nutrition....9/2114.abstract

[Jay]

serum choline has nothing to do with choline intake (in healthy, presumably non-deficient people): http://www.ncbi.nlm..../pubmed/6699336

Edited by Jay, 09 April 2011 - 03:47 AM.

[Sillewater]

I don't think serum choline is the worry. If we could keep choline in the right range (whatever that range is) without producing TMAO that would be fine. Our body probably has very good homeostatic mechanisms fir regulating that ( considering the importance of choline). What we need is more data on the relationship between the various forms of choline and it's metabolism into TMAO (which has the relationship to CV risk)