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Here is a super interesting study, showing another method of bypassing the TMAO problem:


Abstract 13412: 24-Hour Water-Only Fasting Acutely Reduces Trimethylamine N-Oxide: the FEELGOOD Trial

Benjamin D Horne, James E Cox, Joseph B Muhlestein, Viet T Le, Amy R Butler, Heidi T May, John F Carlquist and Jeffrey L Anderson

Originally published27 Mar 2018Circulation. 2014;130:A13412


Background: Routine, periodic fasting is associated with lower risk of diabetes and coronary artery disease (CAD), and may reduce weight and improve metabolic parameters. Multiple related biological pathways are acutely affected by water-only fasting, potentially leading to long-term health improvements including lower CAD. Trimethylamine N-oxide (TMAO) is produced by intestinal bacteria and may increase CAD risk. This study evaluated the change in TMAO due to fasting in apparently healthy people.

Methods: The FEELGOOD Trial (clinicaltrials.gov NCT01059760) included subjects free of cardiovascular disease who had never fasted for more than 12 hours (N=24). All individuals participated in a randomized cross-over trial of 24-hour water-only fasting and 24 hours of ad libitum eating. In this secondary analysis of stored samples, TMAO was measured by liquid chromatography-mass spectrometry.

Results: Age averaged 43.6±13.5 years, 66.7% were female, and baseline TMAO averaged 27.1 ng. TMAO was reduced at the end of the 24-hour fasting intervention compared to the eating day (14.3 ng vs. 28.2 ng, p=0.034). The change in TMAO during the fasting day averaged -10.8 ng compared to an average increase of +2.6 ng during the eating day (p=0.23). For those randomized to fast the first day, the difference in TMAO change on the fast day vs. eating day (-12.1 ng, n=12) was similar to the TMAO change of those randomized to eat on the first day (-14.6 ng, n=12). For those who fasted the first day, TMAO levels were found to have returned to baseline after the full 48 hours of the study (baseline: 22.5 ng, 48 hours: 28.8 ng, p=0.55).

Conclusion: Water-only 24-hour fasting reduced plasma levels of TMAO, a potential risk factor for CAD. The rapid resumption of TMAO production after renewed caloric intake suggests that fasting-reduced TMAO likely resulted from elimination of the substrate for TMAO production. Elimination of TMAO-producing bacteria may also account for this, but recolonization likely would take more time than it was observed to take for resumption of TMAO production. These findings suggest that routine, periodic fasting (multiple episodes over time on a regular basis) may have long-term impact on TMAO levels and related CAD risk, but this requires further investigation."

I'm on a combination of 5:2 and 16:8 diet - I attempt to leave at have 16 hours of fasting every single day, usually closer to 18 hours, so I skip breakfast and eat lunch and dinner within 6-8 hour span; additionally on two days a week (Monday and Thursday), I only eat lunch and skip dinner altogether, i.e. very low calorie days 400 cal. more or less (which also then results in a 22 hour fast). I was already thinking about transitioning from eating anything on those two days - i.e. fasting for a total of 40-42 hours on those days. That gives me two water only fasting periods a week. Now it seems might even be useful wrt. TMAO. YMMV. 

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I’m also doing the 16-8 five days per week and 1 meal on two non-consecutive days (500 cals).

Combining that with optimal nutrition and resistance training 3 days per week.



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Tom,  thanks for pointing out this study.   I found a more recent full text article elaborating on the same study.

Pilot Study of Novel Intermittent Fasting Effects on Metabolomic and Trimethylamine N-oxide Changes During 24-hour Water-Only Fasting in the FEELGOOD Trial (2019)

Apparently the study shows that if you eliminate the substrate for TMAO production,  TMAO production ceases,  which would seem to be quite predictable.  There appears to be no effect on the TMA-producing bacteria themselves, since upon resumption of food intake, there is a rapid resumption of TMAO production.



During the fasting period of the study, TMAO levels were substantially decreased during the fasting day compared to the fed day. However, during the fed period, TMAO production rapidly returned back to concentrations similar to baseline levels. The change score for the fasting day compared to the fed day was not statistically significant, but the improvement in TMAO was tightly controlled, with substantially less variation when fasting than at the fed or baseline measurement.

This TMAO reduction followed by a resumption of baseline levels is likely a result of elimination from the body of the substrate needed to produce TMAO [11].


The possibility that the TMA-producing bacteria are eliminated during fasting is seen as highly improbable:


Alternatively, the bacteria that produce TMAO may have been eliminated from the gastrointestinal tract during fasting. While more difficult to conceive of how this may occur in a 24-h period, this also would not explain the rapid resumption of TMAO produced within the day of feeding. Likely, recolonization of the bacteria within the intestine should take lontger than the one day observed for TMAO production to resume [10].


While fasting does give the cardiovascular system a short break from TMAO production,  it would be entirely  speculative to infer a long-term positive effect via that mechanism.


This lack of substrate  [during fasting] may be as simple as the elimination of matter from the gastrointestinal tract during fasting and could lead to a period of physiological rest from the cardiovascular risk associated with TMAO.

*  *  *  *  *

[...] The long-term effects of fasting on TMAO should be researched in future studies to determine the full implications for human health.


In summary,  intermittent fasting would produce intermittent breaks from TMAO production but would not reduce the total amount of TMAO production in a given extended period. Those intermittent TMAO breaks may or may not have positive effects.  

In order to reduce total TMAO production over a longer period,   it seems one would have to:  1) reduce substrate (choline, carnitine etc.) and/or 2) reduce TMA-producing gut bacteria (through diet,  cruciferous vegetables,  garlic etc. intake,  etc.), and/or 3) reduce the conversion of TMA to TMAO in the liver (as discussed previously.)

Intermittent fasting no doubt has positive effects through various mechanisms apart from TMAO reduction.  And there is still no compelling evidence that TMAO production is a problem for healthy folks on a low-calorie plant based diet who aren't supplementing with substantial amounts of choline/PC or carnitine.

Edited by Sibiriak

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11 hours ago, Sibiriak said:


11 hours ago, Sibiriak said:

In order to reduce total TMAO production over a longer period,   it seems one would have to:  1) reduce substrate (choline, carnitine etc.) and/or 2) reduce TMA-producing gut bacteria (through diet,  cruciferous vegetables,  garlic etc. intake,  etc.)


Yes.  The bottom line:  Have a good CRONnie diet, mostly plants, possibly a small amount of fish, no red or white meat,  HAVE a lot of TMAO.  The takeaway:  Dietary TMAO (as in fish) can be ignored.

Sort of similar to shrimp and LDL cholesterol:  Shrimp have cholesterol; but eating them won't raise your LDL cholesterol.

  --  Saul

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On 10/15/2019 at 2:43 AM, Sibiriak said:

... In order to reduce total TMAO production over a longer period,   it seems one would have to:  1) reduce substrate (choline, carnitine etc.) and/or 2) reduce TMA-producing gut bacteria (through diet,  cruciferous vegetables,  garlic etc. intake,  etc.),...

The Effects of Vegetarian and Vegan Diets on Gut Microbiota

"Vegetarians have a different gut microbiota composition than omnivores with a diminished capacity to produce trimethylamine (TMA), the precursor to TMAO. The plasma concentrations of TMAO appear to be similar in vegans and lacto-ovo-vegetarians (99, 100).

Lowering TMAO levels may be achieved through greater adherence to the Mediterranean diet, particularly a vegetarian one rich in fruits and vegetables (77, 100). Increased vegetable consumption reduces TMAO levels by reducing the enzymes responsible for converting TMA to TMAO and by remodeling the gut microbiota. The studies have shown TMAO production to decrease in vegetarians, which decreases their cardiovascular risk. To be objective, we have to mention a recent study, leaving a room for further analyses. Vegan fecal microbiota transplantation in metabolic syndrome patients resulted in significant changes in intestinal microbiota composition but failed to show changes in TMAO production. Authors explained that the 2-week follow-up was not a sufficient length of time to observe changes in TMAO production (101).

On average, twenty five percent of plasma metabolites are different between omnivores and vegans, suggesting a significant direct effect of diet on the host metabolome. No unique bacterial taxa have been significantly associated with individual metabolite levels after adjustment for multiple comparisons (102). These findings suggest that while inter-individual variability exists, dietary patterns significantly influence the microbial composition."

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Al Pater posted (thanks Al!) a new prospective study [1] of 760 healthy women followed for almost 30 years as part of the the Nurses Health Study. It found a strong correlation between TMAO level and CHD, with a 58% higher risk of heart disease in those in the highest tertile of serum TMAO compared to the lowest tertile.

In addition, regardless of a subject's initial TMAO level, an increase in serum TMAO level over a 10 year period was also highly correlated with increased risk of CHD. Eating a diet low in vegetables and high in meat amplified the correlation between TMAO change and heart disease.

The authors suggest that the gut's production of TMAO may be one of the reasons that meat intake results in greater heart disease. Here is a passage on the topic from the discussion section:

On the other hand, our stratifed analysis by dietary patterns also showed that the TMAO-CHD association was signifcantly strengthened by unhealthy dietary patterns, and was attenuated by healthy dietary patterns characterized by higher intake of vegetables and lower intake of animal foods. Previous studies show that omnivorous people produced more TMAO than did vegans or vegetarians following dietary L-carnitine intake through a microbiota-dependent mechanism (10,11). A more recent study reported similar associations that intake of red meat increased TMAO levels, and discontinuation of red meat intake reduced plasma TMAO levels within 4 weeks (29). Diet is one of the most important modifable factors to modulate circulating TMAO levels and gut microbiome (3,10,11,25–29,46), and our study emphasizes the importance of better dietary quality and healthier eating patterns, as recommended by current dietary guidelines, to reduce the adverse effects of TMAO changes on the development of CHD.



[1] Is Our Diet Turning Our Gut Microbiome Against Us?
Heidenreich PA, Mamic P.
J Am Coll Cardiol. 2020 Feb 25;75(7):773-775. doi: 10.1016/j.jacc.2019.12.023. No abstract available.
PMID: 32081287
Long-Term Changes in Gut Microbial Metabolite Trimethylamine N-Oxide and Coronary Heart Disease Risk.
Heianza Y, Ma W, DiDonato JA, Sun Q, Rimm EB, Hu FB, Rexrode KM, Manson JE, Qi L.
J Am Coll Cardiol. 2020 Feb 25;75(7):763-772. doi: 10.1016/j.jacc.2019.11.060.
PMID: 32081286
A gut-microbial metabolite, trimethylamine N-oxide (TMAO), has been associated with coronary atherosclerotic burden. No previous prospective study has addressed associations of long-term changes in TMAO with coronary heart disease (CHD) incidence.
The purpose of this study was to investigate whether 10-year changes in plasma TMAO levels were significantly associated with CHD incidence.
This prospective nested case-control study included 760 healthy women at baseline. Plasma TMAO levels were measured both at the first (1989 to 1990) and the second (2000 to 2002) blood collections; 10-year changes (Δ) in TMAO were calculated. Incident cases of CHD (n = 380) were identified after the second blood collection through 2016 and were matched to controls (n = 380).
Regardless of the initial TMAO levels, 10-year increases in TMAO from the first to second blood collection were significantly associated with an increased risk of CHD (relative risk [RR] in the top tertile: 1.58 [95% confidence interval (CI): 1.05 to 2.38]; RR per 1-SD increment: 1.33 [95% CI: 1.06 to 1.67]). Participants with elevated TMAO levels (the top tertile) at both time points showed the highest RR of 1.79 (95% CI: 1.08 to 2.96) for CHD as compared with those with consistently low TMAO levels. Further, we found that the ΔTMAO-CHD relationship was strengthened by unhealthy dietary patterns (assessed by the Alternate Healthy Eating Index) and was attenuated by healthy dietary patterns (p interaction = 0.008).
Long-term increases in TMAO were associated with higher CHD risk, and repeated assessment of TMAO over 10 years improved the identification of people with a higher risk of CHD. Diet may modify the associations of ΔTMAO with CHD risk.
coronary heart disease; diet; gut-microbial metabolites; prospective cohort study; risk factors

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From a study posted by Al today:

Dietary intake of choline and phosphatidylcholine and risk of type 2 diabetes in men: The Kuopio Ischaemic Heart Disease Risk Factor Study.
Virtanen JK, Tuomainen TP, Voutilainen S.
Eur J Nutr. 2020 Mar 20. doi: 10.1007/s00394-020-02223-2. [Epub ahead of print]
PMID: 32198672
To investigate associations of total dietary choline intake and its major dietary form, phosphatidylcholine, with type 2 diabetes risk.
We included 2332 men aged 42-60 years at baseline in 1984-1989 from the Kuopio Ischaemic Heart Disease Risk Factor Study in eastern Finland. Dietary intakes were assessed with 4-d food recording at baseline. Type 2 diabetes diagnosis was based on self-administered questionnaires, fasting and 2-h oral glucose tolerance test blood glucose measurements, or by record linkage to national health registries. Multivariable-adjusted Cox proportional hazards regression models were used for statistical analysis.
During the mean 19.3-year follow-up, 432 men had type 2 diabetes diagnosis. After multivariable adjustments, those in the highest vs. lowest choline intake quartile had 25% (95% CI 2-43%) lower relative risk (P trend across quartiles = 0.02) and those in the highest vs. lowest phosphatidylcholine quartile had 41% (95% CI 22-55%) lower relative risk (P trend < 0.001) of type 2 diabetes.
Higher choline intake, especially phosphatidylcholine, was associated with lower type 2 diabetes risk among men.
Choline; Diet; Phosphatidylcholine; Population study; Prospective study; Type 2 diabetes

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 A recent comprehensive review:

Trimethylamine N-Oxide in Relation to Cardiometabolic Health—Cause or Effect? (May 2020)

Christopher Papandreou,1Margret Moré,2 and Aouatef Bellamine3,*

PMCID: PMC7284902
PMID: 32392758




Trimethylamine-N-oxide (TMAO) is generated in a microbial-mammalian co-metabolic pathway mainly from the digestion of meat-containing food and dietary quaternary amines such as phosphatidylcholine, choline, betaine, or L-carnitine. Fish intake provides a direct significant source of TMAO.

Human observational studies previously reported a positive relationship between plasma TMAO concentrations and cardiometabolic diseases. Discrepancies and inconsistencies of recent investigations and previous studies questioned the role of TMAO in these diseases.

Several animal studies reported neutral or even beneficial effects of TMAO or its precursors in cardiovascular disease model systems, supporting the clinically proven beneficial effects of its precursor, L-carnitine, or a sea-food rich diet (naturally containing TMAO) on cardiometabolic health.

In this review, we summarize recent preclinical and epidemiological evidence on the effects of TMAO, in order to shed some light on the role of TMAO in cardiometabolic diseases, particularly as related to the microbiome.




6. Summary and Conclusions

Given the complexity of cardiometabolic diseases and based on (1) the fact that observational trials cannot resolve the cause from the effects, (2) the recent PREDIMED data [58,74] measuring TMAO at baseline, and (3) the recent bi-directional Mendelian randomization analysis [180] examining the causal direction between TMAO and its precursors and the diseases, it can be concluded that TMAO increases in patients are the result (rather than the cause) of disease.

The apparent contradictions and the results from animal studies have to be interpreted in light of several factors. Animal studies, which apply excess amounts of TMAO or its precursors in distress-suffering animal models (e.g., coronary ligation models), are far from the normal situation and cannot explain a causal relationship between TMAO and disease development.

On the other hand, several animal experiments using lower doses of TMAO and its precursors did show protective effects.

The most convincing data in humans are derived from studies on fish consumption or intake of the dietary supplement L-carnitine. Indeed, the increased plasma TMAO levels observed in CVD/T2D may be a compensatory mechanism. Furthermore, the type of precursor for TMAO generation may also be important.

Increases in TMAO levels during CVD/T2D progression (beyond the observed wide natural intraindividual variability in TMAO levels) could be the result of disease-related dysbiosis.

Another factor in such variability is related to the methodology itself. Indeed, most studies reported plasma TMAO only without considering TMA or urinary secretion. Perhaps it would be more relevant to consider the plasma TMA/TMAO ratio as a marker.

It is also possible that TMAO elevation is a result of injuries caused by disease (e.g., atheroma lesions), which will induce TMAO up-regulation to promote the healing process. TMAO has been shown to be up-regulated in ischemic-injury models, as discussed above. These up-regulations may be mediated by FMO gene regulation, which in turn is modulated by many factors.

In conclusion, increased TMAO levels may be a compensatory mechanism in response to disease. Further research and intervention studies with relatively low levels of TMAO may be needed to confirm this theory.



Dysbiosis is part of the disease network including cardiometabolic diseases (Figure 1). Dysbiosis in turn may alter TMAO levels, by either decreasing or increasing TMA producing strains within the microbiome. In some cases, TMA-producing bacteria are somehow reduced by dysbiosis [140,141,142]. In other cases, it has been shown that increased TMAO correlates with a dysbiotic microbiome [143,144].

Dysbiosis is known to be triggered by factors like an unhealthy diet, especially a high-animal fat diet [12]. However, several different factors can contribute to dysbiosis including the cardiometabolic disease network (Figure 1).

Furthermore, dysbiosis contributes to the progression of CVDs by promoting major CVD risk factors: atherosclerosis and hypertension [12]. Dysbiosis has been shown to promote kidney disease, since the intestinal barrier becomes more permeable for microbially generated metabolites [145,146,147]. Relative abundance of Akkermansiamucinophilia in colon biopsies was shown to be inversely correlated with TMAO levels [131]. A. mucinophilia is a mucotroph bacterium and an indicator of a functioning intestinal mucus layer [126,148].

Altogether, the amount of microbial TMA formation largely depends on the composition of the intestinal flora as well as the state of the mucus layer, both of which can be influenced by several factors, including but not limited to diet and disease status (Figure 1).

Increases in TMAO levels resulting from TMA increases are plausible but provide no statement regarding any effects on health or disease by TMAO.





See also (cited above):


Assessment of Causal Direction Between Gut Microbiota-Dependent Metabolites and Cardiometabolic Health: A Bidirectional Mendelian Randomization Analysis (2019)


Our Mendelian randomization findings support that T2DM and kidney disease increase TMAO levels and that observational evidence for cardiovascular diseases may be due to confounding or reverse causality.


Edited by Sibiriak

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Thank you Sibiriak for sharing.  Prospective randomized designs do not eliminate the potential for confounding but help.

You may be interested in this randomized crossover RCT (1) just published in the American Journal of Clinical Nutrition.  I am not sure what to make of the order effect ( nor necessarily the authors ), but with the solid methodology this strong effect size is compelling:

Mean ± SEM TMAO concentrations were significantly lower overall for Plant (2.7 ± 0.3) than for Animal (4.7 ± 0.9) (P = 0.012)”

Open questions as I see it are the relative dietary quality of the two interventions, and ongoing research needed to assess the clinical impact of the differences in TMAO level.

Regardless of the apparent quality of the study, consistent replicability of the findings is also imperative.


Anthony Crimarco, Sparkle Springfield, Christina Petlura, Taylor Streaty, Kristen Cunanan, Justin Lee, Priya Fielding-Singh, Matthew M Carter, Madeline A Topf, Hannah C Wastyk, Erica D Sonnenburg, Justin L Sonnenburg, Christopher D Gardner, A randomized crossover trial on the effect of plant-based compared with animal-based meat on trimethylamine-N-oxide and cardiovascular disease risk factors in generally healthy adults: Study With Appetizing Plantfood—Meat Eating Alternative Trial (SWAP-MEAT), The American Journal of Clinical Nutrition, , nqaa203, https://doi.org/10.1093/ajcn/nqaa203

(https://academic.oup.com/ajcn/advance-article-abstract/doi/10.1093/ajcn/nqaa203/5890315?redirectedFrom=fulltext )


Edited by Mechanism

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