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Saul,  low-dose aspirin is not an analgesic, period.   You need higher doses to get any analgesic effect.

Regarding GI bleeding,  no one is saying that l.d. aspirin doesn't increase the risk of significant bleeding at all, but the absolute risk  remains quite low,  and is reduced much further in those  who don't  have any  predisposing GI bleeding risk conditions and take protective action.    But this is not the place  to debate it,  and I'm not recommending anything anyway,  so I'll  leave it at that for now.

 

Edited by Sibiriak

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Thank you, Sibirak, for all your work finding studies and linking to sources for the choline/TMAO nexus. I will delve into all those in due time, for now I'm cautious. My biggest sources of choline are fish - salmon once a week and either herring or sardine once a week. I'm not worried about TMAO from the fish. The other big source is eggs, which I consume 3 times a week (one egg each session), which I suppose is the most worrisome from TMAO point of view. However, I consume a ton of brassica veggies with it, which hopefully counteracts the TMAO formation (plus berries every day). The balance of nutrients vs downsides, has me consuming eggs after careful consideration - and as far as I can see 3 (or even 4) a week is a tolerable risk/reward.  

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Hi Tom!

Dietary TMAO is not the source of your gut TMAO.  For example, fish are higher in TMAO than land animals and animal parts, such as chickens, eggs and cows.  But people who eat fish and are otherwise vegan (such as myself) have an excellent gut microbiota.

People who eat excessive red meat and/or eggs usually do not have a good gut microbiota.  TMAO is in their gut that comes from through a chain of reactions with unfavorable gut bacteria that act on the meat byproducts (I don't believe many of the steps are fully known yet, if ever), which leads to serum TMAO and eventually atherosclerosis.

Sibiriak may be right that low dose aspirin may have some mild protective effect -- I don't know.

But there's no question that improving your diet is the right way to go.

  --  Saul

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If you eat a lot of whole grains, legumes, and greens, you will get a lot of betaine. Betaine is one of the metabolites of choline used for methylation, so eating it directly contributes to the choline requirement. According to Chris Masterjohn it's good for up to half of the requirement, so you'd only need 275 mg choline. 

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Chris Masterjohn:   https://chrismasterjohnphd.com/blog/2019/04/17/the-choline-database/

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People with low MTHFR activity should consume 900-1200 mg/d

 

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Phosphatidylcholine is also least likely to generate TMAO.

I'd like to know the scientific bases for those assertions.   I'm not saying they don't exist,  but he doesn't provide references.   I've had this problem before with some of his assertions (eg. his claim about ideal homocysteine levels).

Edited by Sibiriak

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Thanks, Ron and Sibirak. Indeed, I have not noticed any adverse effects of my homozygous MTHFR variant condition thus far - I have gone through the various lists of supposed effects, and I can honestly say, I have not experienced them, nor does any of my bloodwork reflect it (as mentioned, my homocysteine is quite low). I am not super paranoid about this condition, but I do wonder if it might have some impact down the road, perhaps when I'm quite old - but I guess there's still some time, and the research is ongoing. 

In any case, I'm keeping an eye on the choline situation, but I don't see enough evidence either way to alter any of my health behaviours. 

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Dean Pomerleau:   Per Jack Norris' reading of the literature (here) the DRI for choline was set based on a single study which found people developed signs of choline deficiency (i.e. markers of fatty liver / liver dysfunction) when placed on a diet for six weeks that had less than 50mg of choline per day. Their deficiency was corrected by a diet with ~500mg of daily choline, so they set the DRI at ~500mg. But that begs the question of how much choline is actually needed to avoid deficiency.



Btw,  the European Food Safety Authority (EFSA) set an Adequate Intake (AI) level for choline  at 400 mg/day  for all adults.

 

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Summary

Following a request from the European Commission, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) was asked to deliver a Scientific Opinion on Dietary Reference Values (DRVs) for the European population, including choline.

Choline is a quaternary amine (2‐hydroxyethyl‐N,N,N‐trimethylammonium) present in food in free and esterified forms. The main forms present in foods are phosphatidylcholine (PC, lecithin), which is also the main form present in animal tissues, free choline, phosphocholine (PChol), glycerophosphocholine (GPC) and sphingomyelin (SPM), and minor amounts of cytidine‐5‐diphosphate‐choline (CDP‐choline) and acetylcholine. Choline, PChol and GPC are water‐soluble choline compounds, whereas PC and SPM are lipid‐soluble compounds.

Although choline can be synthesised de novo by the human body, this synthesis may become insufficient, making choline an essential component of the diet. Choline is predominantly provided via the diet. The human body can form choline either de novo by methylation of phosphatidylethanolamine (PE) via the hepatic phosphatidylethanolamine N‐methyltransferase (PEMT) pathway, or by hydrolysis of PC formed in the CDP‐choline pathway in all cells of the body. The PC formed in the PEMT pathway contains substantial amounts of long‐chain polyunsaturated fatty acids, like docosahexaenoic acid and arachidonic acid. Both pathways can be stimulated by dietary choline and the PEMT pathway is sensitive to the presence of oestrogens.

Choline is an integral part of some phospholipids, which play an important role in the structure and function of membranes. Choline (as PC) plays an important role in the metabolism and transport of lipids and cholesterol by lipoproteins, and is needed for the assembly and secretion of very low‐density lipoproteins by the liver. Choline is a precursor of the neurotransmitter acetylcholine, and of betaine, an osmoregulator to which choline is irreversibly oxidised in the liver and kidney. Via betaine, choline is involved in the folate‐dependent one‐carbon metabolism. Dietary deficiency of choline can cause fatty liver or hepatic steatosis that can result in non‐alcoholic fatty liver disease (NAFLD), and can cause liver and muscle damage. This shows that de novo production can be insufficient.

Dietary free choline is quickly taken up by a carrier‐mediated saturable transport system. PC and GPC from the diet or secreted in the bile, and dietary SPM are hydrolysed by phospholipases (PLs) to liberate choline. Choline and water‐soluble choline compounds (PChol and GPC) are rapidly absorbed and appear in plasma predominantly as free choline. Phospholipids (PC and SPM) that have escaped PLs enter the lymph incorporated into chylomicrons.

The available data do not allow defining the percentage of intestinal absorption of choline in humans, and the total amount of choline in the human body. Non‐absorbed choline is a precursor of trimethylamine (TMA) produced in the gut by anaerobic symbiotic microbes. TMA is efficiently absorbed from the gastrointestinal tract and then converted in the liver to trimethylamine‐N‐oxide (TMAO). Both TMA and TMAO (i.e. total trimethylamine (TTMA)) are eliminated in the urine. Urinary excretion of choline is low in relation to usual dietary intakes, while no human data are available on faecal excretion of choline or choline compounds in relation to dietary intake. Breast milk mainly contains PChol and GPC, besides free choline, PC and SPM, in concentrations depending on the progress of lactation, maternal diet and genotype.

The Panel reviewed possible biomarkers of choline intake and/or status. The Panel considers that the available data do not allow conclusions to be drawn on a dose–response relationship between choline intake or status and plasma choline concentration, and that plasma choline concentrations cannot be used to set DRVs for dietary choline. Plasma concentrations of PC, betaine, dimethylglycine, total homocysteine or TMAO, erythrocyte PC concentration, or urinary betaine and TTMA urinary excretion also cannot be used to set DRVs for dietary choline.

The Panel also notes that single‐nucleotide polymorphisms in genes coding for enzymes involved in choline metabolism, some of them present with high frequency in the population, can influence the dietary requirement for choline and determine the susceptibility to dietary choline deficiency, but data are insufficient to predict variations in individual choline requirements based on genetic polymorphisms. The Panel considers that the available data on choline intake and health consequences (NAFLD, cardiovascular disease, cancer, birth defects, cognition) cannot be used to set DRVs for dietary choline.

The Panel considers that Average Requirements and Population Reference Intakes for choline cannot be derived for adults, infants and children, and therefore defines Adequate Intakes (AIs).

Dietary total choline intake was calculated based on individual food consumption data that were available to the European Food Safety Authority (EFSA) and classified according to EFSA's food classification system, from healthy populations investigated in 12 national surveys undertaken in nine countries of the European Union (EU), between 2000 and 2011. In the absence of food composition data on choline in Europe, composition data on free choline and choline compounds from the US Department of Agriculture were used.

The total choline intake mean estimates ranged from 75 to 127 mg/day in infants, from 151 to 210 mg/day in children aged from 1 to < 3 years, from 177 to 304 mg/day in children aged from 3 to < 10 years, and from 244 to 373 mg/day among children aged from 10 to < 18 years. The total choline intake mean estimate was 336 mg/day in pregnant adolescents and 356 mg/day in pregnant women. The total choline intake mean estimates ranged from 269 to 444 mg/day and from 332 to 468 mg/day in women and men, respectively, i.e. for all adults: 269–468 mg/day.

The Panel reviewed 11 choline depletion/repletion studies with similar design. Only one reported the amounts of choline needed to replete depleted subjects who showed signs of organ dysfunction. The Panel concludes that choline depletion/repletion studies do not provide sufficient data to calculate Average Requirements for choline, but may be used to inform data on observed choline intakes to set AIs for choline.

For all adults, the Panel set an AI of 400 mg/day. This is based on the midpoint of the range of observed mean intakes in healthy populations in the EU (about 370 mg/day), and in consideration of the results of a depletion/repletion study in which about 70% of the depleted subjects who had developed signs of organ dysfunction were repleted with an intake of about 400 mg/70‐kg body weight (bw) per day. Although premenopausal women may have a lower requirement for dietary choline (than postmenopausal women or men) in connection with a potential stimulation of the PEMT pathway by oestrogens, and ranges of estimated mean total choline intake in Europe are slightly lower in women than men, the Panel considered it unnecessary to give sex‐specific AIs for adults.  [ETC.]

 

 

The EFSA lays out its rationale in excruciating detail in a seventy page report:

Dietary Reference Values for choline

First published: 17 August 2016

 

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Thanks, Sibiriak. Very informative and rather convincing, to me at least.

I've reduced my Alpha CPG dose to 150 (from 300 over the past six months or so), but will continue taking it, since by my count, there are plenty of days I don't hit 400.

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