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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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Unless you're homozygous for C677T MTHFR variant - which I am - in which case, also according to Chris Masterjohn, you need closer to 1 g of choline a day.

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

Quote

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

 

Quote

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.

 

Quote

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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I don't believe that's correct.   Garlic powder produces allicin when put in water,  for example. (Garlic powder, contrary to conventional wisdom, can even produce allicin when swallowed directly in capsules or tablets-- see sections 3.7.3, 3.7.4, 3.9.2, and 3.9.3 in the first article below.)

 

Allicin Bioavailability and Bioequivalence from Garlic Supplements and Garlic Foods (2018)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6073756/

Quote

The allyl thiosulfinates, of which allicin (diallyl thiosulfinate) is the most abundant and most studied member (Figure 1), are enzymatic products of alliin, S(+)-allyl-l-cysteine sulfoxide, and alliinase. They are rapidly formed when raw garlic cloves undergo cell rupture (Figure 1) or when dried and pulverized cloves (garlic powder) become wet [13,14].  

Garlic-Derived Organic Polysulfides and Myocardial Protection (2016)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4725427/

Quote

Raw garlic.

Raw intact garlic bulbs, although composed of 65% water, contain high amounts of γ-glutamylcysteine, which can undergo hydrolysis or oxidation to form inactive cysteine sulfoxides, alliin (14). During storage in cool temperatures, alliin naturally accumulates (up to ∼1%) in the garlic bulbs (14). Destruction of the intact garlic bulb by crushing, cutting, or ingesting it results in the activation of the allinase enzyme, promoting the conversion of alliin to the active metabolite allicin (diallyl thiosulfanate) (14). Allicin is an extremely unstable and odorless compound that readily breaks down into the organic diallyl polysulfides diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS) as well as ajoene (11, 14, 15).

Garlic powder and oil.

Garlic powder, a dehydrated, pulverized garlic clove, has a composition identical to raw garlic; therefore, it is capable of producing the biologically active allicin and its metabolites, the organic polysulfides DAS, DADS, and DATS (11).

Garlic oil is formed through steamed distillation of the whole garlic clove in organic solvents. Although allicin is not contained in the extracted oil fragment, both DADS and DATS are readily available (14).

Aged garlic extract.

Aged garlic extract (AGE) is prepared by storing raw sliced garlic in 15–20% ethanol for 20 mo in a stainless steel tank. The extract is then filtered and concentrated at low temperatures. AGE is sold in either a dry or liquid form, with the liquid form containing 10% ethanol. The aging process increases the activity of potent antioxidants, including S-allylcysteine and S-allylmercaptocysteine, giving AGE a greater antioxidant capacity than fresh garlic and garlic supplements (16). Moreover, the aging process modifies the harsh and irritating components found in raw garlic. Unlike raw garlic, AGE does not contain allicin, yet it does contain the diallyl polysulfides DAS and DADS (16).

 

I regularly drink garlic water made with crushed raw garlic or  with organic freeze-dried garlic powder. 

The biochemistry and biological effects of garlic are really quite complex,  and it would be a mistake to single out  one  compound as the sole health-enhancing agent. 

 

A Comprehensive Survey of Garlic Functionality (2010)

https://www.researchgate.net/publication/269100534_A_COMPREHENSIVE_SURVEY_OF_GARLIC_FUNCTIONALITY

Edited by Sibiriak

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5 hours ago, Sibiriak said:

I don't believe that's correct.   Garlic powder produces allicin when put in water,  for example. (Garlic powder, contrary to conventional wisdom, can even produce allicin when swallowed directly in capsules or tablets-- see sections 3.7.3, 3.7.4, 3.9.2, and 3.9.3 in the first article below.)

I hope you are right, but I am not certain (maybe it has to do with heating below 60°C). This is from one of the citations above:

"Since 1975 there have been more than 46 (from medline search) human studies on lipid-lowering effects of garlic and garlic preparations. These studies, were mostly randomized, double blind, placebo-controlled using garlic powder rather than raw garlic of 4–16 weeks, in hyperlipidemic patients. Most of these studies showed significant decrease in serum cholesterol and serum triglyceride. Only about one-third of these studies measured lipoproteins, where significant favorable changes in LDL-cholesterol level (11–26% decrease) were consistently observed. A few studies using garlic powder (having low allicin yields) failed to show any lipid lowering effects [24,25]. During the last one decade (1993–2002), 18 clinical studies have been published regarding the hypolipedemic effect of garlic. Nine studies showed negative results and garlic powder was used in seven of these studies (Table- (Table-1)1) [26-34]. The different composition and quantity of sulfur components of different garlic preparations used in various studies could account for the inconsistent findings." https://www.ncbi.nlm.nih.gov/pmc/articles/PMC139960/
 


And this is from Wikipedia:

"Allicin features the thiosulfinate functional group, R-S(O)-S-R. The compound is not present in garlic unless tissue damage occurs,[1] and is formed by the action of the enzyme alliinase on alliin.[1] Allicin is chiral but occurs naturally only as a racemate.[3] The racemic form can also be generated by oxidation of diallyl disulfide:[7]

(SCH2CH=CH2)2 + RCO3H → CH2=CHCH2S(O)SCH2CH=CH2 + RCO2H

Alliinase is irreversibly deactivated below pH 3; as such, allicin is generally not produced in the body from the consumption of fresh or powdered garlic.[8][9] Furthermore, allicin can be unstable, breaking down within 16 hours at 23 °C."    https://en.wikipedia.org/wiki/Allicin

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Alliinase is irreversibly deactivated below pH 3; as such, allicin is generally not produced in the body from the consumption of fresh or powdered garlic. (Wikipedia)

That's why  fresh garlic must be crushed  or garlic powder put in water   and not consumed immediately in order to guarantee the production of allicin outside the body.

I wrote specifically:

Quote

Garlic powder produces allicin when put in water.

And the first article I quoted stated:

Quote

[The allyl thiosulfinates, of which allicin (diallyl thiosulfinate) is the most abundant] are rapidly formed when raw garlic cloves undergo cell rupture (Figure 1) or when dried and pulverized cloves (garlic powder) become wet

(But read the first article I linked carefully--the "generally not produced in the body" rule may have exceptions.)

Quote

Ron Put:  Nine studies showed negative results and garlic powder was used in seven of these studies

 

Yes,  but  was the allicin in the garlic powder activated prior to consumption by putting it in water?  No,  it wasn't.

  • Ziaie et al.: " treated with daily doses of 800mg Garlet/day (n=50) or 800mg/day placebo (n=50) "
  • Superko et al.:  " subjects were randomly assigned to a placebo or 300 mg three times a day of a standardized garlic tablet for three months. "
  • Gardner et al.: " randomized to a placebo or a garlic botanical blend providing 500 or 1000 mg dehydrated garlic powder/day "
  • Byrne et al. 900 mg Kwai garlic or placebo was taken by moderately hypercholesterolaemic volunteers
  • McCrindle et al.: commercially available garlic extract (Kwai [Lichtwer Pharma, Berlin, Germany], 300 mg, 3 times a day)
  • Isaacsohn et al:  The active treatment arm received tablets containing 300 mg of garlic powder (Kwai) 3 times per day,
  • Simons et al:  subjects took Kwai garlic powder tablets 300 mg three times daily or matching placebo
  • Luley et al:   ... placebo and therapy periods of 6 weeks each. The doses administered were 3 X 198 mg in Study I (34 patients) and 3 X 450 mg in Study II (51 patients).

You can be sure the garlic and  placebos were administered in tablets (Kwai) or possibly capsules and that in  none of the cited studies was the garlic powder mixed into water prior to administration. 

Edited by Sibiriak

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Btw,  a standard method for determining the allicin content of garlic involves first blending it in water for a short time before testing.

Quote

The control for 100% ABB  [allicin bioavailablity or bioequivalence] was prepared by homogenization of 500 g of peeled raw garlic cloves [...] after addition of water at 0.60 mL/g, in an Osterizer blender at the highest speed for 2 min.

This allowed alliinase to transform all of the alliin to known amounts of allicin and other allyl thiosulfinates.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6073756/

 

Quote

2.4 Determination of allicin

Allicin concentration was determined in the raw garlic and processed products of the different cultivars [...]

* * * * *

Allicin standard preparation: Allicin was extracted by mixing 400 mg of fresh garlic with 10 mL of water and shaking for 2 min. Solid phase extraction (SPE) procedure was followed to obtain purified allicin from the aqueous extract from garlic.[...]

* * * * *

Sample preparation: to prepare the aqueous extract from the garlic samples, 0.7 - 0.9 g of samples were weighed and added to 25 mL of chilled water (4°C), stirred vigorously for 30 seconds; an extra 25 mL of cold water were added and it was stirred for 30 more seconds. The samples were filtered through a 0.45 µm filter membrane for HPLC analysis [...]

http://www.scielo.br/scielo.php?script=sci_arttext&amp;pid=S0101-20612014000300028

 

Quote

Ron Put:  ....maybe it has to do with heating below 60°C

 

Good point-- that's probably an important factor.    I'm not sure how much allicin potential is lost by high temperature dehydration processing ,   but to hedge my bets,  if I don't mix raw crushed garlic into water (the best option, imo),  I use freeze-dried powder in water as a convenient, quick , non-messy substitute.

Quote

...the antioxidant activity of several varieties of dehydrated freeze-dried garlic was measured and compared the results of fresh garlic. It was concluded that the process used to freeze-dry garlic at low temperatures did not alter the concentrations of antioxidants and the activity of allicin (Silva et al., 2010).  http://www.scielo.br/scielo.php?script=sci_arttext&amp;pid=S0101-20612014000300028

 

Edited by Sibiriak

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Back to choline, I've recently set my cronometer goal to 400 mg/day, as per EFSA reccomandations. This way it's easier to have a positive feedback without scrambling around trying to reach the higher and probably redundant IOM value of 550 mg.

Yogurt and some fruits are also good sources of choline beside the cited ones, providing that the amounts are significant. From what I've noticed, reaching the IOM value while on classic CR (few calories, a typical level being MR's 1800 kCAl) is just about impossible on a plant-based diet, unless we eat pounds over pounds of broccoli and spinach, for example (no EVOO added!).

I'm also going to take the occasional choline supplement. This seems to me a reasonable way to optimize the trade-off of supplements after what we've been discussing.

 

Edited by mccoy

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2 hours ago, mccoy said:

Back to choline, I've recently set my cronometer goal to 400 mg/day, as per EFSA reccomandations.....

How do you do that? I don't see choline listed as a nutrient in my Cronometer Diary Report. The only place I can find choline listed is in the Oracle dropdown.

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Ron, from the upper, right hand-side menu you can click 'diary settings'

image.png.9f4d5f667b377bd23d9e4da5297a8a3b.png

Then, click on 'targets'

image.png.ab2fb39ff87f89b829ac085e76c8979e.png

 

Then, click on 'vitamins' and you have a list of all the vitamins in cronometer, where you can choose to make visible whatever you want to in that group

 

image.png.6a60e859374d2d7056f26f2b25d0c847.png

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Dean Pomerleau (emphasis added):  

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.

https://www.crsociety.org/topic/11718-tmao-cardiovascular-disease/?tab=comments#comment-18159

 

I'm not sure if this has been noted before,  but there is a connection between FMO3 activity and beiging of white adipose tissue.
 

The TMAO-Producing Enzyme Flavin-Containing Monooxygenase 3 (FMO3) Regulates Obesity and the Beiging of White Adipose Tissue (2017)

Quote

SUMMARY

Emerging evidence suggests that microbes resident in the human intestine represent a key environmental factor contributing to obesity-associated disorders. Here we demonstrate that the gut microbiota-initiated trimethylamine-N-oxide (TMAO)-generating pathway is linked to obesity and energy metabolism.

In multiple clinical cohorts, systemic levels of TMAO were observed to strongly associate with type 2 diabetes. In addition, circulating TMAO levels were associated with obesity traits in the different inbred strains represented in the Hybrid Mouse Diversity Panel.

Further, antisense oligonucleotide-mediated knockdown or genetic deletion of the TMAO-producing enzyme, flavin-containing monooxygenase 3 (FMO3), conferred protection against obesity in mice.

Complimentary mouse and human studies indicate a negative regulatory role for FMO3 in the beiging of white adipose tissue. Collectively, our studies reveal a link between the TMAO-producing enzyme FMO3 and obesity and the beiging of white adipose tissue.

 

image.png.b152961ff6a16b70fba234b8c9e9b15d.png

 

The above study was discussed in the following excellent review of the TMAO issue:

 

Trimethylamine N-Oxide: A Link among Diet, Gut Microbiota, Gene Regulation of Liver and Intestine Cholesterol Homeostasis and HDL Function (2018)

Quote

As stated above, elevated systemic levels of TMAO have been associated with type 2 diabetes [91]. Moreover, FMO3 was increased in obese-/insulin-resistant human subjects. Interestingly, knocking down FMO3 prevented high-fat-diet-induced obesity in mice by stimulating the beiging of white adipose tissue [91]. Furthermore, knocking down FMO3 in liver-specific insulin receptor knockout mice prevented hyperlipidemia and atherosclerosis susceptibility concomitant with an increase in LDL receptors [92].

These findings concurred with the results of a previous report demonstrating the deleterious effects of FMO3 expression in glucose tolerance in liver-specific insulin receptor knockout mice [92]. Additionally, another recent study demonstrated that maternal hypercholesterolemia exacerbates the development of atherosclerosis with a positive association of aortic lesion size with both TMAO levels and increased FMO3 mRNA expression [93].

Overall, these data strongly indicate a role for FMO3 in modulating lipid and glucose homeostasis in vivo in a dose-dependent manner and, in some cases, independently of TMA/TMAO formation.

Edited by Sibiriak

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In summary, if you just eat the stuff all of us eat on a regular basis, you will be fine.  😉

grapefruit, broccoli, Brussel sprouts, cabbage, cauliflower, kale and bok choy

 

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Gordo: In summary, if you just eat the stuff all of us eat on a regular basis, you will be fine.

I  think that's right.  A healthy plant-based diet will (in most cases) naturally  produce a healthy gut microbiome and prevent FMO3 enzyme over-activity.

But what about the need for choline supplementation?

 According to Michael Rae:

Quote

...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.  

 

But according to Dean Pomerleau:

Quote

Is there any good evidence that a whole food plant-only diet with sufficient calories can and does lead to choline deficiency?

Based on Michael's crazy supplement regime, he seems to think some form of choline supplementation is necessary or at least prudent for vegans, but I see very little evidence to support this assertion. 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. In fact, one very small study (n=4) Jack cites showed that 138mg/day in 70kg men reversed their markers of choline deficiency in only 10 days. So the true daily requirement may be much less than 500mg.

* * *

 [...]unless I'm missing something, the USDA database and my own personal experience as a vegan suggests that a healthy plant-only diet should easily provide all the choline we need, without requiring choline supplements or animal product consumption, thereby alleviating the worry about TMAO formation

 

I agreed with Dean,  citing the authors of  Becoming Vegan: Comprehensive Edition: The Complete Reference to Plant-Base Nutrition  who see no problem meeting choline requirements with a reasonable vegan diet.

I also pointed out that the the European Food Safety Authority (EFSA), after an exhaustive study of the issue,  set a conservative Adequate Intake (AI) level for choline  at 400 mg/day  for all adults--substantially lower than the  550mg/day requirement Michael Rae insists must be met.  

 

And according to Jack Norris:

Quote

There is reason to think that choline in large amounts might contribute to heart disease. Keeping levels not much higher than the AI is a prudent choice at this time. It might even be better to keep levels closer to 300 mg/day.

Research on choline and cancer indicates that a moderate amount of choline (about 300 mg/day) could reduce breast cancer compared to lower amounts, but too much could increase the risk of colon and prostate cancer. 

 

Finally,  there is the issue of fish consumption.   While meat, eggs etc., all types of choline supplements, and carnitine supplements increase plasma TMAO  by feeding TMA-producing gut bacteria and having that TMA converted to TMAO in the liver,  a  fish meal, in contrast,  "skips all that and simply dumps a big load of TMAO directly into the bloodstream. "   And yet " 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 explanation for this contradiction  is probably that the correlation between TMAO and atherosclerosis  an indirect one and likely to be the result of dysbiotic gut microbiota  and/or excess FMO3 enzyme activity in the liver,  both of which can be avoided simply by eating a  healthy plant-based diet (putting aside  unusual individual cases).     Still,  out of caution it would probably be wise to keep fish intake moderate as, for example, recommended by Valter Longo  (limit to two portions a week)(fish is also high in methionine), or avoid it entirely for ethical and/or ecological reasons on top of any health concerns.

Edited by Sibiriak

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There might be other pretty serious reasons to avoid fish in the future, in addition to heavy metals and PCBs...

 

Fukushima: Japan will have to dump radioactive water into Pacific, minister says

More than a million tonnes of contaminated water lies in storage but power company says it will run out of space by 2022

Justin McCurry in Tokyo

Tue 10 Sep 2019 08.02 BSTFirst published on Tue 10 Sep 2019 06.32 BSTSh

Storage tanks for radioactive water at the Fukushima Daiichi nuclear power plant.  Storage tanks for radioactive water at the Fukushima Daiichi nuclear power plant. Photograph: Issei Kato/Reuters

Edited by mccoy

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...a converging line of evidence indicates that even the current RDI may not be optimal for a proper aging process (Blusztajn, Slack, & Mellott, 2017; Caudill, Strupp, Muscalu, Nevins, & Canfield, 2018; Wallace et al., 2018)

https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13037

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Excerpts dealing with familiar themes from two articles referenced above:

Neuroprotective Actions of Dietary Choline ( 2017)
 

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Although the studies summarized in the preceding paragraphs underscore the potential benefits of adequate dietary choline intake, less is known about the potential harms of excess choline supplementation [227]. The addition of methylation pathway components such as folate, choline, and B vitamins to certain food products as well as dietary supplements has coincided with an increased incidence of diseases related to altered DNA methylation including cancer, autism spectrum disorders, and some neurological disorders (reviewed in [228]). A prospective study of male health professionals reported an increased risk of lethal prostate cancer in subjects in the highest quintile of choline consumption, even after adjusting for the presence of other nutrients that could increase cancer risk [229]. In contrast, several studies reported that high choline intake was associated with reduced incidence of breast [9], colorectal [230] and liver [13] cancer. It is clear that more studies in humans will be necessary to refine our understanding of what constitutes optimal choline intake at various stages of life, and how this may be affected by polymorphisms in the genes responsible for choline metabolism.

4. Conclusions

High choline intake during gestation and the early postnatal period has been shown to enhance cognitive performance in childhood, adulthood and into old age in multiple animal models and in some human studies. Moreover, choline is neuroprotective in a variety of experimental models of neuronal damage. Choline intake in adulthood may also be critical for normal cognitive function in people. The maternal choline supply during pregnancy modifies fetal DNA [78,231] and histone methylation [232], implicating an epigenomic mechanism in these long-term effects. While these epigenomic mechanisms may also operate in the adult, the effects of dietary choline both during development and in the adult brain may also be mediated, at least in part, by an influence on the peripheral and central metabolism of polyunsaturated species of PC. Taken together, the available evidence strongly supports the notion that adequate choline intake during pregnancy, and throughout life, is an important determinant of brain development, cognitive performance in the adult, and resistance to cognitive decline associated with aging and neurodegenerative disease. 

 

Choline  The Underconsumed and Underappreciated Essential Nutrient (2018)

(co-authored by prominent choline researcher Steven H. Zeisel,  referred to in posts earlier in this thread here and here, as well as in Michael Rae's "Nutrition and Supplementation for Veg(etari)ans" thread here.)

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The Adequate Intake (AI) for choline was established by the Food and Nutrition Board of the National Academy of Medicine (NAM) (formerly the Institute of Medicine) in 1998, at a time when dietary intakes across the population were unknown for the nutrient. Traditionally, the AI reflects an observed or experimentally determined approximation or estimate of intake by a group (or groups) of healthy individuals.1,5 Adequate Intakes have been used when data to calculate an estimated average requirement (EAR) and recommended dietary allowance (RDA) are not available. Unlike this typical NAM approach, the development of the AI for choline was informed by the previously mentioned depletion-repletion study in adult men, in which deficiency resulted in liver damage.1,5

The AI for adults was calculated as 7 mg/kg times the reference weight of a man (76 kg) or woman (61 kg), with rounding based on prevention of liver damage. Upward adjustments during pregnancy and lactation were made based on the amount of choline accretion by the fetus and placenta and the amount secreted in human breast milk. For infants aged 0 to 6 months, the AI was set to reflect the observed mean intake of choline from consuming human breast milk (note: this value does not take into consideration the higher content of the colostrum) (Table (Table11).1 The dietary requirement for choline has not been revisited by NAM since 1998, despite a growing body of scientific literature.

There is a need for dose-response studies across various populations to inform revision of the current Dietary Reference Intakes (DRIs) to include an EAR and RDA, so that accurate assessment of the amounts of individuals who are inadequate can be determined.

 

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Consumption of choline has been shown to increase the production of trimethylamine N-oxide (TMAO), a gut-derived metabolite, which has recently emerged as a candidate risk factor for cardiovascular diseases (CVDs).35,36 The choline-TMAO connection is not yet established. Microbes metabolize choline, betaine, and carnitine to trimethylamine (TMA), which is oxidized to TMAO in the host liver by the insulin-regulated enzyme flavin-containing monooxygenase 3. Significant preclinical evidence has been generated suggesting that high levels of TMAO exhibit proatherogenic and prothrombotic effects. Supporting this is a growing body of observational evidence associating high fasting TMAO levels with CVD.37

This evolving body of literature has suggested that dietary choline, betaine, and carnitine may increase the risk of CVDs. However, randomized clinical trial evidence to assess the relationship of TMAO to CVD in humans is limited, and ethical considerations preclude the likelihood of such studies. Current epidemiological studies do not show a link between dietary choline intakes and CVD.38 Of note, not all animal models have supported the relationship between TMAO and atherogenesis,39 and the evidence amassed from epidemiological cohorts has not adequately addressed the potential for reverse causality and/or confounding (ie, high TMAO levels could result from the impact of disease on kidney function and the microbiome).

The available evidence at present leaves substantial uncertainty regarding the impact of efforts to reduce dietary choline to reduce TMAO levels and cardiovascular outcomes. Efforts to modify circulating TMAO concentrations with diet may additionally have unintended consequences, as choline exhibits pleiotropic effects beyond its impact on circulating TMAO levels (such as choline’s role in supporting hepatic function), and foods that contain additional cardioprotective nutrition, such as omega-3 fatty acid-rich fish, contain substantial quantities of preformed TMAs that can be converted to TMAO in the liver.

A recent crossover feeding trial in healthy young men consuming meals containing TMAO (fish, cod), its dietary precursors, choline (eggs), and carnitine (beef) versus a fruit control showed that fish consumption yielded higher blood and urinary concentrations of TMAO (42–62 times) than did eggs, beef, or the fruit control.40

High TMAO producers were found to have a higher ratio of the microbial phyla Firmicutes to Bacteroidetes and a less diverse gut microbiome40; this is consistent with previous reports that suggest that TMAO is produced by Firmicutes but not Bacteroidetes.41 Notably, a greater ratio of Firmicutes to Bacteroidetes has previously been associated with an increased risk of obesity and metabolic syndrome.42

This research highlights the important role of gut microbial composition in determining TMAO production and bolsters the notion that higher circulating concentrations of TMAO in a diseased versus nondiseased state may reflect differences in gut microbe composition owing to the disease itself or other lifestyle factors, rather than indicating a causative role of TMAO itself in the disease process.40,43

 

Edited by Sibiriak

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