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Do eggs raise TMAO? A trial
Dietary Choline Supplements, but Not Eggs, Raise Fasting TMAO Levels in Participants with Normal Renal Function: A Randomized Clinical Trial.
Overview
Wilcox J et al.. Am J Med 2021 · PMID 33872583 · DOI 10.1016/j.amjmed.2021.03.016
Eating four eggs a day for four weeks did not raise fasting TMAO; choline pills did.
Does the study support the specific claim? No · Methodological quality: moderate
Plain-language summary
Study explained simply
- What did the researchers want to find out?
Do eggs raise TMAO and platelet reactivity?
- How was the study done?
Randomised intervention study with 5 arms, 4 weeks
- How many people, animals or samples were studied?
82 (18+20+16+18+10); Healthy volunteers with normal renal function (median age 28; 41% male; 81% Caucasian)
- What was actually found?
Fasting plasma TMAO did not rise significantly with 4 eggs/day (median 2.0 to 2.3 uM; P=0.20) or with phosphatidylcholine capsules (P=0.27), but rose strongly in all three arms with choline bitartrate tablets (e.g. 1.9 to 11.1 uM; P<0.0001). Platelet reactivity rose only in the choline-tablet arms; eggs P=0.10.
- How large was the observed effect?
Within-arm comparisons
- What do the results mean in everyday life?
Eggs do not appear to raise this heart-risk marker in healthy people.
- What are the study's limitations?
Small arms (10-20); fifth arm added later (not randomised concurrently); no placebo arm; diet not controlled; only fasting samples; 4 weeks; healthy young adults with normal kidneys
- What does it say about Elawady's specific claim?
Contradicts.
- Do the results apply to Germany and Europe?
Not region-specific.
- What can explicitly not be concluded from this study?
Cannot exclude a small or postprandial TMAO rise, nor effects in people with kidney disease, and says nothing about heart attacks or strokes.
Scientific in-depth review
1. Full reference
- Authors
- Wilcox J et al.
- Journal
- Am J Med
- Year
- 2021
- Identifier
- PMID 33872583 DOI 10.1016/j.amjmed.2021.03.016
- Verification
- verified – PubMed efetch 2026-10-25
- Retracted
- no
- Corrections
- none
- Extent checked
- full text
- Conflicts of interest and funding
Funding: NIH and Office of Dietary Supplements (R01HL103866, R01HL126827, P01 HL147823); Shimadzu Center of Excellence award (instrumentation); SLH partial support from Leonard Krieger Fund and Foundation Leducq. COI: SLH co-inventor on Cleveland Clinic patents on cardiovascular diagnostics/therapeutics, paid consultant for and research funds from Procter & Gamble, research funds from Roche Diagnostics, eligible for royalties from Cleveland Heart Lab and Procter & Gamble; WT consultant for Sequana Medical AG (unrelated); others none.
2. Research question
Do eggs raise TMAO and platelet reactivity?
3. Study design and population
- Study design
- Randomised controlled trial – Randomised, open-label (participants unblinded; laboratory analyses blinded to arm) parallel-arm intervention study, 4 arms randomised plus a fifth phosphatidylcholine arm enrolled later; 28 days; registered NCT03039023
- Population
Healthy volunteers from the Cleveland, Ohio area with normal renal function (median age 28.0 [IQR 24.0-38.8]; 41.5% male; 81.7% Caucasian; median BMI 26.9)
- Country
USA
- Period
Not stated in full text
- Sample size
89 consented; 82 (92%) completed and analysed (arm 1 eggs 18; arm 2 choline bitartrate 20; arm 3 eggs + choline 16; arm 4 egg whites + choline 18; arm 5 phosphatidylcholine 10); platelet aggregometry subset N=50 (correlations N=49)
- Inclusion and exclusion criteria
Age >=18, eGFR >60, normal serum creatinine, no microalbuminuria; excluded: known chronic illness, inflammatory bowel disease, bariatric surgery, antibiotics or probiotics in the month before enrolment
4. Methods and endpoints
- Exposure / intervention
Daily for 28 days, on top of habitual diet: 4 large hardboiled eggs (467 mg total choline, virtually all esterified); 2 x 500 mg choline bitartrate (411 mg free choline); eggs + choline bitartrate (about double choline dose); whites of 4 eggs (2.80 mg choline) + choline bitartrate; 6 x 420 mg phosphatidylcholine capsules (410 mg total choline)
- Comparator
Within-arm baseline vs day 28; between-arm comparisons (Kruskal-Wallis). No placebo/no-intervention control arm
- Endpoints
Fasting plasma TMAO (primary focus), 24-h and spot urine TMAO, plasma choline/betaine/carnitine, ADP-induced platelet aggregation, lipid panel
- Statistical methods
Non-parametric: Wilcoxon signed-rank (within arm), Kruskal-Wallis (between arms), Spearman correlation; p<0.05; completers only; no sample-size calculation or multiplicity adjustment reported
5. Actual results
- Results
Plasma TMAO median [IQR] baseline vs day 28: eggs 2.0 [1.4-3.5] vs 2.3 [1.9-3.7] uM, P=0.20; choline tablets 1.9 [1.4-3.4] vs 11.1 [7.1-25.4] uM, P<0.0001; eggs + choline 2.3 [1.5-2.8] vs 12.3 [5.1-26.5] uM, P<0.0001; egg whites + choline 2.6 [1.8-5.3] vs 28.1 [9.2-44.1] uM, P<0.0001; phosphatidylcholine 2.8 [2.0-5.1] vs 3.4 [2.6-7.1] uM, P=0.27. 24-h urine TMAO: increased in choline-tablet arms (P<0.001 each), not with eggs (P=0.28) or PC (P=0.11). Platelet reactivity increased in choline-tablet arms (all P<0.01), not with eggs (P=0.10) or PC (P=0.79). Platelet aggregation correlated with plasma TMAO (r=0.51, P<0.0001, N=49). Plasma choline rose in all arms (eggs P=0.005), indicating compliance. No lipid-panel changes in any arm. No confidence intervals for between-arm differences reported.
- Absolute risks
not applicable (biomarker study; no clinical events)
- Authors' conclusion
Four eggs daily for four weeks did not substantially raise fasting TMAO or platelet reactivity in healthy participants with normal renal function; phosphatidylcholine capsules gave similar results; an equivalent amount of choline as choline bitartrate substantially raised TMAO and platelet aggregation; the form of choline matters. Authors caution against choline supplements and transfer to renal disease.
6. Strengths
- Randomised allocation of the first four arms; trial registered
- Laboratory analyses blinded to group assignment
- Verified choline content of each intervention by LC/MS/MS
- Plasma, 24-h urine and spot urine concordant
- Compliance supported by rise in plasma choline in all arms
- 92% completion
7. Weaknesses
- Small arms (10-20); no power calculation; non-significance for eggs (P=0.20) does not exclude a small rise
- Fifth (PC) arm enrolled later, i.e. not concurrently randomised
- No placebo/no-egg control arm; inference relies on within-arm change
- Baseline imbalance acknowledged by authors (arm 3 94% female; differences in age, BMI)
- Background diet not controlled
- Only fasting samples; postprandial TMAO not measured (Miller et al. reported rises 24 h after eggs)
- Only 4 weeks; healthy young adults with normal kidney function (authors: most important limitation)
- Completer analysis; reasons for 7 dropouts in a figure not available in text
- Senior author has TMAO-related patents/royalty interests (would, if anything, favour finding TMAO effects)
8. Risk of bias
- Orienting tool
- RoB 2
- Type of assessment
- structured assessment based on the full text by a single reviewer (no formal double review)
- Full formal assessment
- no
- Overall risk of bias
- some concerns
- Rationale
Single-reviewer structured RoB 2 based on the full text (supplement with randomisation details not available). Not a formal assessment: that requires two independent reviewers and the trial protocol.
| Domain | Judgement | Rationale |
|---|---|---|
| D1 randomisation process | some concerns | Arms 1-4 randomised (details only in online supplement, not available); arm 5 enrolled later and not concurrently randomised; small arms produced baseline imbalance (arm 3 94% female). |
| D2 deviations from intended interventions | some concerns | Open-label food/supplement interventions on top of an uncontrolled habitual diet; compliance supported by plasma choline rise but not otherwise quantified. |
| D3 missing outcome data | low | 82/89 (92%) completed; small loss, unlikely to change results materially. |
| D4 measurement of the outcome | low | Objective LC/MS/MS biomarkers and aggregometry by investigators blinded to group assignment. |
| D5 selection of the reported result | some concerns | Registered (NCT03039023) but registered outcomes not compared here; multiple matrices and time points with within-arm testing only; consistent pattern across matrices reduces concern. |
Full-text review (25 October 2026): Corrected egg-arm plasma TMAO P value to 0.20 (0.28 was 24-h urine); added medians/IQRs, funding and COI details, registration, inclusion/exclusion, completion 82/89, platelet subset N=50; noted fifth arm enrolled later and absence of a placebo arm; full RoB 2 domains (overall unchanged: some concerns).
9. Assessment of the statistical interpretation
Within-arm tests only for the egg question; P=0.20 for plasma TMAO with eggs (n=18) is a non-significant change with small sample, not proof of no effect, but medians (2.0 to 2.3 uM) are far below the roughly 5- to 10-fold rises with free choline. No effect sizes with CIs for between-arm differences.
10. Relevance to the specific claim
11. Independent contrary findings
Small; A-EGG-13 shows acute rise after challenge.
12. Transferability to Germany and Europe
Not region-specific.
13. Overall methodological judgement
Direct, reasonably well-conducted small trial: whole eggs (4/day, 4 weeks) did not raise fasting TMAO or platelet reactivity in healthy adults, whereas free choline did. Contradicts the archive derivation that egg phosphatidylcholine raises TMAO, for fasting levels in healthy people; does not address postprandial levels, kidney disease or clinical events.
| Multidimensional assessment | |
|---|---|
| Authenticity of the source | verified |
| Methodological quality | moderate |
| Risk of bias | some concerns |
| Precision of results | low |
| Directness | direct |
| Reproducibility | partly replicated |
| Consistency with the overall evidence | mixed |
| Regional transferability | high |
| Adequacy of the interpretation (by the archive) | not applicable |
14. Open questions
Postprandial TMAO after eggs; effects in chronic kidney disease or existing cardiovascular disease; longer exposure; adequately powered between-arm comparison with a no-egg control.
15. Linked fact checks
- Egg-yolk phosphatidylcholine is converted by gut bacteria into TMAO, and therefore eggs raise the risk of major cardiovascular events (about 2.5-fold). – Studies contradicting or limiting the claim