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[Admin Note: I made this new thread as a collector for posts about the recently discovered and previously discussed apparent link between diet, micronutrients choline and carnitine, TMAO production by gut microbes that feed on these micronutrients, and elevated risk of cardiovascular disease. Four posts down is the new post (by me) on the topic. The first four posts come from a different thread. --Dean]

 

In his post about supplements for vegetarians, Michael Rae said:

 

For now, prudence seems to require that vegetarians err on the side of a generous and definitely supplemented intake of choline, ensuring that dietary (to the extent that it can be known) plus supplemental choline is meaningfully higher than the AI of 550 mg for men and 425 mg/day for women. Functional status is still tricky, but one obvious set of markers is the same panel used to establish signs of deficiency in Zeisel’s depletion-repletion study:iv a fivefold or more increase above normal of the muscle-damage enzyme creatine phosphokinase (CPK),  or a one-and-a-half or more times normal reading of the liver enzymes aspartate aminotransferase (AST)gamma-glutamyltransferase (GGT), or lactate dehydrogenase (LD). Fatty liver, unfortunately, requires a harder-to-access MRI of fat deposits in the organ, to which your doctor is unlikely to consent.

 

 
The below papers may be a reason dietary choline can be bad for us.
 
NATURE | RESEARCH HIGHLIGHTS
CARDIOVASCULAR BIOLOGY
Gut microbes raise heart-attack risk
Nature 531, 278 (17 March 2016) doi:10.1038/531278b
Published online 16 March 2016
 
Subject terms: Microbiology Cardiovascular biology
 
Gut microbes produce a chemical that enhances clotting in the arteries, increasing the risk of heart attack and stroke.
 
Stanley Hazen of the Cleveland Clinic in Ohio and his colleagues treated human platelets, which form blood clots, with a compound called TMAO. This is made in the body from a waste product of gut microbes, and has been linked to heart disease. The team found that TMAO made the platelets form artery-blocking clots faster. The researchers increased blood TMAO levels in mice by feeding them a diet that was rich in choline, a TMAO precursor, and found that the animals formed clots faster than did those with lower TMAO levels.
 
This effect was not seen in animals that lacked gut microbes or that were treated with antibiotics. When intestinal microbes from mice that produced high levels of TMAO were transplanted into mice with no gut microbes, the recipients' clotting risk increased. The results reveal a link between diet, gut microbes and heart-disease risk, the authors say.
 
 
Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk.
Zhu W, Gregory JC, Org E, Buffa JA, Gupta N, Wang Z, Li L, Fu X, Wu Y, Mehrabian M, Sartor RB, McIntyre TM, Silverstein RL, Tang WH, DiDonato JA, Brown JM, Lusis AJ, Hazen SL.
Cell. 2016 Mar 9. pii: S0092-8674(16)30113-1. doi: 10.1016/j.cell.2016.02.011. [Epub ahead of print]
PMID: 26972052
 
Abstract
 

 

Normal platelet function is critical to blood hemostasis and maintenance of a closed circulatory system. Heightened platelet reactivity, however, is associated with cardiometabolic diseases and enhanced potential for thrombotic events. We now show gut microbes, through generation of trimethylamine N-oxide (TMAO), directly contribute to platelet hyperreactivity and enhanced thrombosis potential. Plasma TMAO levels in subjects (n > 4,000) independently predicted incident (3 years) thrombosis (heart attack, stroke) risk. Direct exposure of platelets to TMAO enhanced sub-maximal stimulus-dependent platelet activation from multiple agonists through augmented Ca2+ release from intracellular stores. Animal model studies employing dietary choline or TMAO, germ-free mice, and microbial transplantation collectively confirm a role for gut microbiota and TMAO in modulating platelet hyperresponsiveness and thrombosis potential and identify microbial taxa associated with plasma TMAO and thrombosis potential. Collectively, the present results reveal a previously unrecognized mechanistic link between specific dietary nutrients, gut microbes, platelet function, and thrombosis risk.

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Thanks Al, 

 

I too wonder what Michael thinks now about dietary or supplemental choline (as phosphatidylcholine), especially for veg(itari)ans. Here is what he wrote back in 2013 (on the old CR email list):

 

Michael wrote (my emphasis):

All:

Cliff Conwell wrote:

    So obviously the next question is what do you think about choline (supplement form) + vegetarian/vegan diet?

 

choline is an essential nutrient, unlike carnitine, and deficiency (and in a surprisingly large number of people, even ostensibly adequate intakes) leads very clearly to harm (insufficent intake rapidly results in elevated liver enzymes and creatine phosphokinase (indicative of muscle damage)). So even if it contributed to atherosclerosis, you just have get enough of the stuff -- by food if you can, by supplement if you can't.

It would be nice if the USDA food databases' coverage of choline was more complete than it is: they've only tested a relatively small number of foods for choline content, so one's COM-stated intake will be low, but by an unknown amount. One could in principle eat an intentionally choline-deficient diet for a while and then slowly keep adding more choline until one's CPK and liver enzymes plateaued, but that would be an expensive PITA and also risky business IMO.

 However, despite what the pop press and even the study abstract from the original PC-TMAO study report, PHOSPHATIDYLcholine (and dietary choline, which is almost entirely PC) really is not strongly prone to forming TMAO (tho' I've not yet looked at the NEW report). However, there is evidence that the supplements can degrade and form TMAO even prior to ingestion, due to the presence of bacterial contamination in the underlying lecithin or PC conentrate. So as regards supplements, one should take several steps to protect oneself, namely: buy your PC from a reputable /manufacturer/ ; to try to get it as fresh as possible (check expiry dates, but don't take them too seriously if they're not from a high-turnover operation: most manufacturers are now complying with regs requiring a proper expiry date and in many cases a manufacturing date -- BUT, unfortunately, that just tells you when the ingredient was put in the pill, and not how old the ingredient was when they put it there); to buy it from a /vendor/ with high turnover; to keep it in the fridge; and to spread your PC out into several doses over the course of the day.
 

Avoiding eggs and red meat are one thing, but I'm more perplexed about the underlying intestinal bacteria matter.

 

It's not clear to me whether veg(etari)ans may be protected against the PC effect or not, as it depends whether the same critters whose growth is stimulated by meat and/or carnitine are also responsible for PC conversion.

However, it's clear that I personally have been subjecting myself to high TMAO for more than a decade, thanks to choline (bitartrate or citrate), citicoline, and carnitine supplementation, so I am really kicking myself.

 

-Michael

 

As suggested by the bolded passage above, at the time it seemed like Michael thought that dietary choline or supplemental choline, both of which come mostly in the form of phosphatidylcholine (PC - as Michael references it above) might not be so bad for this ↑ TMAO → ↑ heart attacks link.

 

But it appears to me that subsequent research (e.g. [1]) have found otherwise - that dietary and supplemental PC does indeed raise TMAO levels, and as your new study reinforces, cardiovascular risk. For those of you who haven't heard about this before, or have forgotten, here is the instructive graphical abstract from [1] showing the pathway between PC-rich animal products in one's diet and increased risk of cardiovascular disease, via gut microbe digestion of PC to form a blood clot-promoting compound called TMAO. 

 

EqzIQYo.png

 

So this seems to reinforce the fact that animal products don't raise one's risk of cardiovascular disease exclusively through raising cholesterol levels, but through this TMAO pathway as well. All the more reason to go vegan☺.

 

--Dean

 

------------

[1]  N Engl J Med. 2013 Apr 25;368(17):1575-84. doi: 10.1056/NEJMoa1109400.

 
Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk.
 
Tang WH(1), Wang Z, Levison BS, Koeth RA, Britt EB, Fu X, Wu Y, Hazen SL.
 
Author information: 
(1)Department of Cellular and Molecular Medicine, Lerner Research Institute,
Cleveland Clinic, Cleveland 44195, USA.
 
Comment in
    Nat Rev Cardiol. 2013 Jul;10(7):363.
    N Engl J Med. 2013 Apr 25;368(17):1647-9.
    Rev Clin Esp (Barc). 2014 Jan-Feb;214(1):46-8.
 
 
BACKGROUND: Recent studies in animals have shown a mechanistic link between
intestinal microbial metabolism of the choline moiety in dietary
phosphatidylcholine (lecithin) and coronary artery disease through the production
of a proatherosclerotic metabolite, trimethylamine-N-oxide (TMAO). We
investigated the relationship among intestinal microbiota-dependent metabolism of
dietary phosphatidylcholine, TMAO levels, and adverse cardiovascular events in
humans.
METHODS: We quantified plasma and urinary levels of TMAO and plasma choline and
betaine levels by means of liquid chromatography and online tandem mass
spectrometry after a phosphatidylcholine challenge (ingestion of two hard-boiled 
eggs and deuterium [d9]-labeled phosphatidylcholine) in healthy participants
before and after the suppression of intestinal microbiota with oral
broad-spectrum antibiotics. We further examined the relationship between fasting 
plasma levels of TMAO and incident major adverse cardiovascular events (death,
myocardial infarction, or stroke) during 3 years of follow-up in 4007 patients
undergoing elective coronary angiography.
RESULTS: Time-dependent increases in levels of both TMAO and its d9 isotopologue,
as well as other choline metabolites, were detected after the phosphatidylcholine
challenge. Plasma levels of TMAO were markedly suppressed after the
administration of antibiotics and then reappeared after withdrawal of
antibiotics. Increased plasma levels of TMAO were associated with an increased
risk of a major adverse cardiovascular event (hazard ratio for highest vs. lowest
TMAO quartile, 2.54; 95% confidence interval, 1.96 to 3.28; P<0.001). An elevated
TMAO level predicted an increased risk of major adverse cardiovascular events
after adjustment for traditional risk factors (P<0.001), as well as in lower-risk
subgroups.
CONCLUSIONS: The production of TMAO from dietary phosphatidylcholine is dependent
on metabolism by the intestinal microbiota. Increased TMAO levels are associated 
with an increased risk of incident major adverse cardiovascular events. (Funded
by the National Institutes of Health and others.).
 
PMCID: PMC3701945
PMID: 23614584

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Michael wrote (my emphasis):

However, despite what the pop press and even the study abstract from the original PC-TMAO study report, PHOSPHATIDYLcholine (and dietary choline, which is almost entirely PC) really is not strongly prone to forming TMAO (tho' I've not yet looked at the NEW report). However, there is evidence that the supplements can degrade and form TMAO even prior to ingestion, due to the presence of bacterial contamination in the underlying lecithin or PC conentrate. So as regards supplements, one should take several steps to protect oneself [...]

 

Avoiding eggs and red meat are one thing, but I'm more perplexed about the underlying intestinal bacteria matter.

It's not clear to me whether veg(etari)ans may be protected against the PC effect or not, as it depends whether the same critters whose growth is stimulated by meat and/or carnitine are also responsible for PC conversion.

 

However, it's clear that I personally have been subjecting myself to high TMAO for more than a decade, thanks to choline (bitartrate or citrate), citicoline, and carnitine supplementation, so I am really kicking myself.

 

As suggested by the bolded passage above, at the time it seemed like Michael thought that dietary choline or supplemental choline, both of which come mostly in the form of phosphatidylcholine (PC - as Michael references it above) might not be so bad for this ↑ TMAO → ↑ heart attacks link.

 

But it appears to me that subsequent research (e.g. [1]) have found otherwise - that dietary and supplemental PC does indeed raise TMAO levels, and as your new study reinforces, cardiovascular risk. For those of you who haven't heard about this before, or have forgotten, here is the instructive graphical abstract from [1] showing the pathway between PC-rich animal products in one's diet and increased risk of cardiovascular disease, via gut microbe digestion of PC to form a blood clot-promoting compound called TMAO.

First: most supplemental choline is not in the form of phosphatidylcholine, but free choline salts (bitartrate or citrate). As the authors note, "(TMAO) [is] an intestinal microbiota-dependent metabolite of the choline head group of phosphatidylcholine". And the question is not whether dietary and supplemental PC raises TMAO levels — it does, of course — but "compared to what?" (1,2) show very clearly that the production of TMAO from the choline moiety from supplemental PC or food is vastly lower than the production from equivalent amounts of choline from choline salts, even when therethe PC supplement itself is contaminated with some TMAO from bacterial degradation of the supplement itself, before it's even ingested.

 

And the whole question has to be kept in its full perspective. I find the work overall body of evidence on the TMAO-atherosclerosis risk persuasive, but it remains primarily based on associational studies (it might, for instance, instead be due to variations in FMO3 SNPs that affect the metabolism of some other, genuinely causally-associated food or endogenous metabolite) as well as some in vitro work. By contrast, choline is absolutely essential to life, and there is clear evidence of harm from deficiency, and that even the RDA is not enough to meet the needs of a substantial fraction of the population.

 

So one should make sure that one is getting enough choline — likely achievable mostly or exclusively from food if you're omnivorous, but requiring supplementation if you're veg(etari)an. And the form of such supplements should be PC, and PC selected based on the criteria laid out above.

 

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: 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.

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All,

 

This is the first new post to this collection thread about TMAO and cardiovascular disease.  It highlights a new study [1] on the topic just posted by Al Pater to the CR-community email list.

 

Background - Recall that the previous findings discussed above seem to show a link between choline or creatine intake from diet (mostly animal products) or supplements, production of a substance called TMAO by gut bacteria that feed on these two micronutrients, and elevated risk of cardiovascular disease and heart attacks, likely through a TMAO-induced increase in blood clotting / thrombosis.

 

In his previous post above, Michael cautioned that this whole TMAO story should be kept in perspective, saying:

 

And the whole question has to be kept in its full perspective. I find the work overall body of evidence on the TMAO-atherosclerosis risk persuasive, but it remains primarily based on associational studies (it might, for instance, instead be due to variations in FMO3 SNPs that affect the metabolism of some other, genuinely causally-associated food or endogenous metabolite) as well as some in vitro work.

 

Although not definitive, study [1] seems to lend more credence to the causal linkage between TMAO and cardiovascular events. It followed people with pre-established cardiovascular disease, and found that in raw analysis, patients with the highest level of circulating TMAO had a 4x higher likelihood of a heart attack during the 5 year follow-up period. After controlling for other risk factors, circulating TMAO level remained highly predictive of subsequent heart attacks, with a 1.7x to 2x increase in heart attack risk after all adjustments were made.

 

While not an intervention study in humans, which would be required (but unethical) to definitively prove the TMAO → heart attack link, study [1] was a prospective cohort design (measured people's TMAO at the beginning and followed them over time), which is pretty good evidence for the linkage.

 

For me this translates into yet another reason to remain vegan, and to keep my recently-begun creatine supplementation very modest, simply to avoid deficiency as Michael suggests, and potentially boost cold-induced thermogenesis. Here is another potential reason to avoid overdoing it with creatine.

 

--Dean

 

------------

[1] Intestinal Microbiota-Generated Metabolite Trimethylamine-N-Oxide and 5-Year

Mortality Risk in Stable Coronary Artery Disease: The Contributory Role of
Intestinal Microbiota in a COURAGE-Like Patient Cohort.
Senthong V, Wang Z, Li XS, Fan Y, Wu Y, Tang WH, Hazen SL.
J Am Heart Assoc. 2016 Jun 10;5(6). pii: e002816. doi:
10.1161/JAHA.115.002816.
PMID: 27287696 Free Article
http://jaha.ahajournals.org/content/5/6/e002816.full
http://jaha.ahajournals.org/content/5/6/e002816.full.pdf+html

Abstract

BACKGROUND:

Trimethylamine-N-oxide (TMAO), a metabolite derived from gut microbes and
dietary phosphatidylcholine, is linked to both coronary artery disease
pathogenesis and increased cardiovascular risks. The ability of plasma TMAO
to predict 5-year mortality risk in patients with stable coronary artery
disease has not been reported. This study examined the clinical prognostic
value of TMAO in patients with stable coronary artery disease who met
eligibility criteria for a patient cohort similar to that of the Clinical
Outcomes Utilizing Revascularization and Aggressive Drug Evaluation
(COURAGE) trial.

METHODS AND RESULTS:

We examined the relationship between fasting plasma TMAO and all-cause
mortality over 5-year follow-up in sequential patients with stable coronary
artery disease (n=2235) who underwent elective coronary angiography. We
identified the COURAGE-like patient cohort as patients who had evidence of
significant coronary artery stenosis and who were managed with optimal
medical treatment. Higher plasma TMAO levels were associated with a 4-fold
increased mortality risk. Following adjustments for traditional risk
factors, high-sensitivity C-reactive protein, and estimated glomerular
filtration rate, elevated TMAO levels remained predictive of 5-year
all-cause mortality risk (quartile 4 versus 1, adjusted hazard ratio 1.95,
95% CI 1.33-2.86; P=0.003). TMAO remained predictive of incident mortality
risk following cardiorenal and inflammatory biomarker adjustments to the
model (adjusted hazard ratio 1.71, 95% CI 1.11-2.61; P=0.0138) and provided
significant incremental prognostic value for all-cause mortality (net
reclassification index 42.37%, P<0.001; improvement in area under receiver
operator characteristic curve 70.6-73.76%, P<0.001).

CONCLUSIONS:

Elevated plasma TMAO levels portended higher long-term mortality risk among
patients with stable coronary artery disease managed with optimal medical
treatment.

KEYWORDS:

optimal medical treatment; prognosis; stable coronary artery disease;
trimethylamine N-oxide

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Hmmm.....

 

Hi Dean!

 

The study is inpeople with coronary artery disease -- hardly very similar to us.

 

Concerning the advantage of being vegan (wrt TMAO levels):  As Michael noted, you have to get your choline (or PCh) from something -- the choline supplement taken by a vegan has zero advantage (wrt TMAO levels) than eating a small amount of animal protein  -- arguably, it might be best to do just that (getting ones needs from food rather than supplements). So it mightbe best (wrt getting adequate choline while keeping TMAO low) to be "almost a vegan".

 

;)xyz

 

  --  Saul

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Saul,

 

So it might be best (wrt getting adequate choline while keeping TMAO low) to be "almost a vegan".

 

I've never argued that a small amount of animals products is necessarily unhealthy. Just that, as Sthira put it so eloquently:

 

I don't eat animals not because I believe eating animals is necessarily unhealthy; I don't eat animals because animals are cool and animals "deserve" to not be treated like shit, tortured, then eaten for fun. They live their own lives. We can eat just fine without sacrificing animals for greedy earth-gobbling human appetites -- so why sacrifice land and trees and jungles and pollute streams and air and foul up water for everyone when vitamin B12 is cheap and easily bought?

 

As with B12, the same goes for getting one's modest daily requirements for choline and creatine from supplements rather than the flesh of dead animals.

 

--Dean

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Hi Dean!

 

Admirable compassion for animals.  (Of course, fish, and some shellfish don't have the same cognition as birds and mammals.  Exception:  The octopus and squid are unusually intelligent.)

 

Do you approve of studies that sacrifice rodents?

 

  --  Saul

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Saul,

 

Do you approve of studies that sacrifice rodents?

 

Nice try Saul. But you won't create cognitive dissonance in me, or assuage your own, quite so easily.

 

I regret when any sentient creatures (including rodents) suffer needlessly. I'm conflicted about animal experiments in the name of science, particularly when those animals aren't treated well.

 

But at least most science experiments seek to minimize the suffering of the animals involved, and importantly, have a worthy goal in mind - they represent suffering and sacrifice with a worthwhile purpose.

 

I view my own life in much the same way - as an N-of-1 experiment where I engage in practices that others might consider intolerable in order to help contribute to the scientific understanding of how the human body works, and what it is capable of. That's my purpose.

 

I view eating animals as inappropriate and immoral not because I think suffering can never be justified. Eating animals is wrong because it creates suffering and serves only to satisfy your selfish, personal appetite. While satisfying your desire for the taste of animal flesh is undeniably fufilling a purpose, it is one that I consider petty, selfish and low. We human beings are better than that, or if we're not now, we should strive to become better than that. A good place to start is with our barbaric habit of eating animals.

 

If you'd like to continue this line of discussion, we should probably take it over here.

 

--Dean

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All,

 

The TMAO saga continues, with the discovery by Mike Colella of this recent study (PMID 26016867) discussed on this thread.

 

It found 8 weeks of krill oil supplements dramatically impaired insulin sensitivity, elevated serum cholesterol and increased carotid artery wall thickness in overweight but otherwise healthy men. Krill oil is very high in phosphatidylcholine, the effects of which Michael and I were debating about above. I think I'm winning this one. ☺

 

--Dean

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Either Al Pater is watching this and the krill oil thread, or it's a mighty big coincidence. But either way, thanks Al for posting [1] a study investigating the association between dietary phosphatidylcholine and mortality. Recall phosphatidylcholine is high in krill oil, as well as other animal products and seafood, and it appears to feed TMAO-producing bacteria in the gut, potentially increasing risk of cardiovascular disease. 

 

It was a prospective cohort study that followed ~80K women from the Nurse's Health Study and ~40K men from the Health Professionals Follow-Up Study for 30 years to see how people's repeatedly-reported dietary intake of foods containing phosphatidylcholine related to how long they lived, and how they died. 

 

Sure enough, higher consumption of phosphatidylcholine-containing foods was associated with a 26% increase in CVD mortality (P < 0.0001) and 11% increase in all-cause mortality (P < 0.0001), even after controlling for a host of other potential confounding risk factors. In fact the authors had enough data to do some interesting additional analysis, by breaking down the relationship between dietary phosphatidylcholine and all-cause mortality among various subpopulations. This interesting analysis is depicted in this figure from the full text:

 

fe0tYxl.png

 

The biggest spike towards the left is for obesity. If you were obese, than dietary phosphatidylcholine was dramatically more detrimental. The second biggest effect, and the bigged food-related effect, was from being a fish eater. If you eat a lot of fish, it looked like dietary phosphatidylcholine may be a bit worse for you than if you don't - but the difference was not statistically significant.

 

The most interesting thing is the scale of the Y-axis - all-cause mortality hazard ratio per 100 mg of phosphatidylcholine . Here is a related statement from the text:

 

Each 100-mg/d higher phosphatidylcholine intake was significantly related to a 13% (95% CI: 7%, 19%) increment in CVD-specific mortality after adjustment for covariates from women and men combined.

 

100mg is not very much. Recall the RDA for choline is ~400 mg/day, and the poor guys in the krill oil supplement study (PMID 26016867) discussed on this thread were taking 1400 mg/day.

 

It seems the evidence continues to mount suggesting it's a bad idea to get too much phosphatidylcholine from either foods (mostly of animal origin) or supplements.

 

--Dean

 

----------

[1] Dietary phosphatidylcholine and risk of all-cause and cardiovascular-specific mortality among US women and men.
Zheng Y, Li Y, Rimm EB, Hu FB, Albert CM, Rexrode KM, Manson JE, Qi L.
Am J Clin Nutr. 2016 Jun 8. pii: ajcn131771. [Epub ahead of print]
PMID: 27281307
http://sci-hub.bz/10.3945/ajcn.116.131771

Abstract
BACKGROUND:
The trimethylamine-containing nutrient phosphatidylcholine is the major dietary source for the gut microbiota metabolite
trimethylamine-N-oxide (TMAO), which has been related to cardiovascular diseases (CVDs) and mortality. Previous research
suggested that the relation of TMAO with CVD risk might be stronger in diabetic than in nondiabetic populations. However,
the evidence for an association of dietary phosphatidylcholine with CVD and mortality is limited.
OBJECTIVES:
We aimed to examine whether dietary consumption of phosphatidylcholine, which is mainly derived from eggs, red meat, and
fish, is related to all-cause and CVD mortality in 2 cohorts of US women and men. In particular, we also tested if such an
association was modified by diabetes status.
DESIGN:
We followed 80,978 women from the Nurses' Health Study (1980-2012) and 39,434 men from the Health Professionals Follow-Up
Study (1986-2012), who were free of cancer and CVD at baseline, for mortality. Dietary intakes and potential confounders
were assessed with regularly administered questionnaires. We used Cox proportional hazards models to estimate HRs and 95%
CIs.
RESULTS:
We documented 17,829 all-cause and 4359 CVD deaths during follow-up. After multivariate adjustment for potential
confounders, including demographic factors, disease status, lifestyle, and dietary intakes, higher phosphatidylcholine
intakes were associated with an increased risk of all-cause and CVD mortality. HRs (95% CIs) comparing the top and bottom
quintiles of phosphatidylcholine intake were 1.11 (1.06, 1.17; P-trend across quintiles < 0.0001) for all-cause mortality
and 1.26 (1.15, 1.39; P-trend < 0.0001) for CVD mortality in the combined data of both cohorts. The associations of
phosphatidylcholine with all-cause and CVD mortality were stronger in diabetic than in nondiabetic participants (P-
interaction = 0.0002 and 0.001, respectively).
CONCLUSION:
These data suggest that higher phosphatidylcholine consumption is associated with increased all-cause and CVD mortality in
the US population, especially in patients with diabetes, independent of traditional risk factors.

KEYWORDS:
TMAO; cardiovascular disease; choline; diabetes; mortality

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Hey Dean & Al I think you are going to save me some money on supplements. This looks like a good reason to dump LEF Mix, as it has quite a bit of choline in two different forms including phosphatidylcholine. Perhaps I'll switch to taking just 1 tablet of their simpler and much cheaper 2 per day product.

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Guest LeoH

Maybe just testing TMAO is the way to monitor one's risk. The gut microbial community differs in each person, as does the diet, And the integrated read out of whether one has too much precursor or not in their diet is best seen by monitoring the end product that is the biologically active participant in the pro-atherosclerotic and pro-thrombotic processes.....TMAO.

Dean P - you seem to be an astute reader of the literature. Does this seem to make the most sense ?....

Maybe we should ask Dr Hazen. He seems to be at the forefront of this field and doing both the large scale human studies and mechanistic intervention studies in animal models. I know I am not a rodent.... and we can only learn so much from mouse studies. But there also appear to be a large (and ever growing) number of sizable (eg >1000 subjects) clinical association studies  that keep showing higher blood levels of TMAO are associated with higher cardiac event risk.

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Hi Leo!

 

Welcome to the CR Forums. We'd love to have you stay awhile and engage in our discussions. If you decide to, would you please register? Your post didn't show up immediately because guest posts are automatically set up for screening by moderators, and I didn't see your post until today.

 

Regarding your suggestion, it does seem like someone who is concerned about their TMAO level might want to get it tested. Unfortunately up until recently (earlier this year), there wasn't an easy way to do this in a clinical setting.

 

But earlier this year, the Cleveland HeartLab (associated with the famous Cleveland Clinic) began offering a TMAO test. Here is a press release with a good overview of TMAO and heart disease. It almost certainly won't be covered by anyone's insurance, and they don't say on the provider page how much the test costs. You (or more likely, your prescribing physician) would need to contact the Cleveland HeartLab to get more details and to order the test.

 

--Dean

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https://health.clevelandclinic.org/2016/03/whats-gut-can-affect-heart-health/?_ga=1.124627022.572871292.1450131893

 

The Cleveland clinic weighs in on TMAO and they are concerned about it. Bottom line on their take is eat more plants and throw out the eggs and dairy, meat. It is noteworthy imo that the most prestigious institution for heart care makes a bold statement on this issue.

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Mike,

 

Note that the study your article links to by Hazen et al from the Cleveland clinic is the study we opened up this thread with. So the fact that the Cleveland clinic is weighing in on the TMAO → CVD link in the material it sends out to general public probably shouldn't be considered additional support for the hypothesis, since they are the ones (along with several other groups) who have been investigating the link in the first place. But the fact that the Cleveland Clinic is one of the most respected CVD research and treatment facilities in the country does lend the theory additional credibility, IMO.

 

--Dean

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All,

 

This new study [1] (press release) seems to add to the heat, but perhaps not a whole lot more light to the story about TMAO and cardiovascular disease. It was an intervention study, which fed a few 40 young healthy (non-vegetarian) men 4 different meals with a one-week washout period between each. The meals either contained 6oz of codfish, 3 whole eggs, or 6oz of beef (hamburger), or two servings of apple sauce. Right before and for six hours after each meal, the took blood samples and measure serum TMAO levels in the subjects.

 

Here is part of the protocol I didn't know, which was very interesting. They instructed subjects not to eat certain foods as follows:

 

The day prior to the study session, participants were advised to avoid consumption of grapefruit juice and indole-containing vegetables (i.e., broccoli, Brussel sprouts, cabbage, cauliflower, kale and bok choy) as these foods can decrease FMO3 enzyme activity and alter TMAO metabolism [2].

 

Basically, grapefruit and cruciferous vegetables decrease the activity of the enzyme that converts TMA to (potentially CVD-inducing) TMAO. So that is good to know.

 

But what the found was even more surprising, to me anyway. It turns out, not surprisingly, that the apple sauce meal didn't raise the TMAO level. Beef and eggs raised TMAO by about 20%. The beef and egg-induced TMAO increase was delayed, and appeared to be mediated by the metabolism of TMA to TMAO by gut bacteria, as we've seen previously in this thread. In particular, those subjects whose serum TMAO went up a lot in response to beef and eggs had a preponderance of firmicutes relative to bacteroidetes in their gut. 

 

But was what was most surprising of all to me was the huge and immediate spike in serum TMAO observed after the fish meal in all subjects:

 

Fish yielded higher circulating
and urinary concentrations of TMAO (46-62 times; p < 0.0001), trimethylamine
(8-14 times; p < 0.0001), and dimethylamine (4-6-times; P<0.0001) than eggs,
beef, or the fruit control. Circulating TMAO concentrations were increased within
15 min of fish consumption, suggesting that dietary TMAO can be absorbed without 
processing by gut microbes.

 

Holy schmoly! The fish meal induced a TMAO spike more 50x greater than the other meals, which lasted for the full 6h of sampling. I was only vaguely aware of this, but apparently (based on their measurements), the codfish contained about 600x the preformed TMAO than the other foods. From Table 2:

 

Food content (mg)   Fruit         Egg           Beef             Fish                P-value

TMAO                     0.0      0.8 ± 0.1a   0.9 ± 0.1a    528.9 ± 9.4b      < 0.0001

 

Here is the authors' graphical representation of their results, for those who like pictures:

 

0wQf20a.png

 

Beef and fish raise circulating TMAO by feeding TMA-producing gut bacteria the carnitine and choline they live off. The TMA gets converted into TMAO by the liver. A fish meal skips all that and simply dumps a big load of TMAO directly into the bloodstream.

 

Notice they put a '?' on the link from TMAO to heart disease. In their commentary on the paper, the authors suggest the TMAO → CVD link may be correlational not causal, since fish eaters aren't at a higher risk of CVD than the general population (if anything they have lower risk) despite all that TMAO.

 

So who knows. But for those who'd rather not risk the possibility that TMAO contributes to CVD, a diet low in animal products, especially fish and choline/carnitine containing eggs/beef, along with lots of cruciferous vegetables appears to be a pretty good prescription.

 

--Dean

 

-------------

[1] ol Nutr Food Res. 2016 Jul 5. doi: 10.1002/mnfr.201600324. [Epub ahead of print]

 
Trimethylamine-N-oxide (TMAO) response to animal source foods varies among
healthy young men and is influenced by their gut microbiota composition: A
randomized controlled trial.
 
Cho CE(1), Taesuwan S(1), Malysheva OV(1), Bender E(1), Tulchinsky NF(1), Yan
J(1), Sutter JL(2), Caudill MA(1).
 
Author information: 
(1)Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA.
(2)Department of Microbiology, Cornell University, Ithaca, NY, USA.
 
 
SCOPE: Trimethylamine-N-oxide (TMAO), a metabolite linked to the gut microbiota, 
is associated with excess risk of heart disease. We hypothesized that (i) TMAO
response to animal source foods would vary among healthy men and (ii) this
response would be modified by their gut microbiome.
METHODS AND RESULTS: A crossover feeding trial in healthy young men (n = 40) was 
conducted with meals containing TMAO (fish), its dietary precursors, choline
(eggs) and carnitine (beef), and a fruit control. Fish yielded higher circulating
and urinary concentrations of TMAO (46-62 times; p < 0.0001), trimethylamine
(8-14 times; p < 0.0001), and dimethylamine (4-6-times; P<0.0001) than eggs,
beef, or the fruit control. Circulating TMAO concentrations were increased within
15 min of fish consumption, suggesting that dietary TMAO can be absorbed without 
processing by gut microbes. Analysis of 16S rRNA genes indicated that high-TMAO
producers (≥20% increase in urinary TMAO in response to eggs and beef) had more
Firmicutes than Bacteroidetes (p = 0.04) and less gut microbiota diversity (p =
0.03).
CONCLUSION: Consumption of fish yielded substantially greater increases in
circulating TMAO than eggs or beef. The higher Firmicutes to Bacteroidetes
enrichment among men exhibiting a greater response to dietary TMAO precursor
intake indicates that TMAO production is a function of individual differences in 
the gut microbiome.
 
© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
 
DOI: 10.1002/mnfr.201600324 
PMID: 27377678
 
---------
[2] Biochem Pharmacol. 1999 Sep 15;58(6):1047-55.
 
In vitro and in vivo inhibition of human flavin-containing monooxygenase form 3
(FMO3) in the presence of dietary indoles.
 
Cashman JR(1), Xiong Y, Lin J, Verhagen H, van Poppel G, van Bladeren PJ,
Larsen-Su S, Williams DE.
 
Author information: 
(1)Human Biomolecular Research Institute, San Diego, CA 92121, USA.
ledcash@aol.com
 
The effect of consumption of glucosinolate-containing Brussels sprouts on
flavin-containing monooxygenase functional activity in humans was investigated in
10 healthy, male, non-smoking volunteers. After a 3-week run-in period, 5
volunteers continued on a glucosinolate-free diet for 3 weeks (control group),
and 5 others consumed 300 g of cooked Brussels sprouts per day (sprouts group).
Human flavin-containing monooxygenase activity was measured by determining the
levels of urinary trimethylamine and trimethylamine N-oxide. In the control group
similar trimethylamine to trimethylamine N-oxide ratios were observed, while in
the sprouts group the trimethylamine to trimethylamine N-oxide ratios were
increased 2.6- to 3.2-fold, and thus flavin-containing monooxygenase functional
activity was decreased significantly. To investigate the molecular basis for the 
in vivo inhibition of functional human flavin-containing monooxygenase activity, 
in vitro studies were carried out examining the effect of acid condensation
products of indole-3-carbinol, anticipated to be formed after transit of Brussels
sprouts through the gastrointestinal system, on the prominent cDNA-expressed
human flavin-containing monooxygenase form 3 enzymes. Two indole-containing
materials were observed to be potent inhibitors of human flavin-containing
monooxygenases, having Ki values in the low micromolar range. The results
suggested that acid condensation products expected to be formed upon transit of
Brussels sprouts materials through the gastrointestinal system were potent
competitive inhibitors of human flavin-containing monooxygenase form 3 enzymes.
The findings indicate that daily intake of Brussels sprouts may lead to a
decrease in human flavin-containing monooxygenase activity, and this may have
consequences for metabolism of other xenobiotics or dietary constituents.
 
 
PMID: 10509757

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Dietary allicin reduces transformation of L-carnitine to TMAO through impact on gut microbiota

Journal of Functional Foods 15:408-417 · May 2015

 

Abstract
 
Trimethylamine N-oxide (TMAO) was recently discovered as a novel and independent risk factor for promoting atherosclerosis while it has been found to be generated from dietary carnitine through metabolism of gut microbiota for decades. Antibiotics were found to successfully inhibit the pathway of gut microbiota-dependent TMAO formation, as well as prevention of atherosclerosis. However, the side effects and resistance potential of antibiotics limit their potential application.
 
Allicin is a well-established antimicrobial phytochemical naturally found in fresh blended garlic and easily acquired from diet. Here we demonstrated that the plasma TMAO levels in C57BL/6 mice fed with dietary carnitine were 4-22 times greater than that in the control chow diet group during carnitine challenge test. Interestingly, the differences of plasma TMAO level were not seen when comparing mice in carnitine plus allicin diet group with the control chow diet group.
 
The results of this study suggest that dietary allicin may be capable of protecting the host from producing TMAO when carnitine is consumed through its impact on gut microbiota. Allicin and dietary fresh garlic containing allicin may be used as functional foods for the prevention of atherosclerosis.
 

 

1-s2.0-S1756464615001735-jff1063-fig-000

 

https://www.sciencedirect.com/science/article/pii/S1756464615001735

 

https://www.nutraingredients.com/Article/2015/05/26/Garlic-compounds-may-boost-cardio-health-indirectly-via-gut-microbiota

Edited by Sibiriak

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Dean Pomerleau:   Notice they put a '?' on the link from TMAO to heart disease. In their commentary on the paper, the authors suggest the TMAO → CVD link may be correlational not causal, since fish eaters aren't at a higher risk of CVD than the general population (if anything they have lower risk) despite all that TMAO.

 

The following article proposes an explanation for the "TMAO bad but fish good"  paradox:

Microbial trimethylamine-N-oxide as a disease marker: something fishy?
According to the group of Hazen [3], there exists ‘a mechanistic link between intestinal microbe-dependent generation of trimethylamine-N-oxide(TMAO) and increased risk for future cardiovascular events (death, myocardial infarction, and stroke) by a pathway involving dietary nutrients such as phosphatidylcholine, choline, and carnitine.' Fish and other seafoods contain significant quantities of free TMAO,in addition to the TMA precursors (phosphatidylcholine, choline, and carnitine) found in meat, eggs, and milk products. The role of this free TMAO has apparently been neglected or overlooked in the discussion on the possible causal link between plasma TMAO and risk of cardiovascular disease.

 

[...]  free TMAO in seafood is quantitatively significantly higher than the amount of TMAO that can be generated by the gut microbiota from choline and carnitine in red meat and eggs

 

If there should be any direct causal link between plasma TMAO and the risk of cardiovascular disease, it seems like a paradox that more fish in the diet reduces this risk [19,20]. Recent randomized group trials indicate that this effect goes beyond what can be associated with intake of marine lipids, since a diet with a large proportion of lean white fish (rich in TMAO) also reduces the risk [21]. There is, accordingly, an obvious need to clarify the significance of plasma or urinary TMAO as a disease marker, but it seems highly unlikely that free TMAO is the direct cause.

 

Instead, increased risk of atherosclerosis may be associated with the abundance of TMA-producing bacteria in the gut, and hence indirectly with the TMAO generated by oxidation (i.e. detoxification) of TMA in the liver, as suggested also by Cho et al. [17]. The same authors showed that the ratio of Firmicutes to Bacteriodetes in the gut microbiota was notably higher in individuals producing high TMAO levels than in low TMAO producers, hence supporting the idea that the correlation between TMAO and atherosclerosis is indirect and likely to be the result of dysbiotic gut microbiota.

 

The phenolic antioxidant resveratrol, often referred to as the anti-atherosclerosis principle in red wine, inhibits TMAO production by reduced TMA production after remodelling the gut microbiota [22].

 

Optimism has been expressed regarding the prospect of using TMA-lyase inhibitors as new pharmaceutical drugs against cardiovascular disease [5].The concept is to reduce TMAO production in the liver by inhibiting the production of precursor TMA in the gut. If, however, TMAO as such is a primary risk factor for atherosclerosis, then such drugs would be of little help for seafood lovers. They would have an ample supply of ‘toxic’ TMAO from the healthy food they eat. On the other hand, free TMAO from seafood may act as an electron acceptor for facultative anaerobic bacteria able to respire with the aldehydes resulting from the TMA elimination reactions of choline and carnitine.

 

It may well be that TMAO-rich seafood would have the same effect–indirectly–as the TMA-lyase inhibitors, not by inhibiting TMA-lyase, but by supporting growth of more beneficial TMA-producing species. This is, of course, speculation, but seafood is, after all, also known to counteract negative effects of other foods.

Edited by Sibiriak

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