Choline seems to be tagged as the new folate in the pregnancy world. Indeed, the evidence is accumulating and strongly suggesting that being Choline replete (like folate and B12) is important for preventing neural tube defects . Further to this, adequate maternal choline status appears to support healthy brain development and may even have positive effects on offspring temperament [1, 2]. The requirements during preconception, pregnancy and lactation can be hard to achieve with most parents and potential parents falling short of these [3-5]. Most health bodies are recommending 450mg during pregnancy and 550mg during lactation, while some authors are suggesting these targets should be higher [3, 6]. So, we find ourselves scrambling to include this in our already bulging pregnancy nutrition support recommendations. If you don’t have time to read the full blog cut to the last paragraph for our bottom line on this topic!
With this news it’s not surprising to see choline starting to be included in prenatal multivitamins and several brands have taken this a step further and brought out higher potency choline supplements, often combining choline with important prenatal nutrients like DHA and iodine. That’s a good thing right? Well, yes it probably is – although there is a catch. The form that is being included in supplements is typically Choline Bitartrate and it seems it may lead to an increase in serum trimethylamine-N-Oxide (TMAO for short) according to three human clinical intervention studies [7-9].
TMAO is gaining recognition as an important risk factor for metabolic and cardiovascular disease with dose response associations  [11-13] , which is of course, a pretty on the nose status to have. It is proposed that TMAO plays a role in vascular inflammation and calcification as well as plaque instability . Furthermore, and of particular interest here, there is preliminary evidence from cohort studies suggesting higher plasma levels of TMAO are associated with gestational diabetes, pre-eclampsia, and potentially poorer fertility [16-19], although not all study findings corroborate .
What has this got to do with the microbiome? Well, Trimethylamine-N is formed by the gut microbiota from precursors such as L-carnitine, principally from red meat and potentially from choline and betaine. [21, 22] Trimethylamine-N is further oxidized in the liver to form trimethylamine-N-oxide TMAO.  The good news is that overall dietary choline does not appear to raise TMAO for the most part, or be associated with cardiovascular disease . Further, the majority of human intervention studies looking at supplementing with eggs or choline as phosphatidylcholine do not observe a rise in TMAO associated with these interventions [8, 9, 25-27]. However, there may be some populations that are susceptible to a rise in TMAO following any choline intake and this may be in part related to microbiome and genetic features. [27, 28] An important comment to make is that not all studies investigating choline bitrate supplementation have observed an associated TMAO rise [28, 29]. However, we feel the three studies that have suggested this give us good cause for caution and a bit of a re-think on how we support optimal choline status during preconception and pregnancy, especially with the growing awareness of TMAO being associated with poor pregnancy outcomes discussed earlier.
Of interest most of what we know about the health effects of choline during the perinatal period relate to dietary intake of this nutrient, which would commonly be found in the form of phosphatidylcholine in foods like eggs. So, the other consideration to pose is whether supplementing with Choline bitartrate would afford the same protections and health benefits clinically as dietary intake of this nutrient?
So now… with this in mind how do we get those choline levels up in a health promoting way? One possibility is recommending lecithin as a rich source of choline, and it would seem that sunflower lecithin is a particularly good source with 10g providing approximately 330mg of choline . Eggs are of course a fantastic source with the average egg providing 125mg of choline.
What about the microbiome? Well, yes this may be a target for us to work on to reduce an individual’s tendency to make TMAO in the first place. This is an area to watch as the research comes together. But the themes coming through are probably unsurprising. Diets high in plant foods, polyphenols, prebiotics and low in red meat, animal foods and saturated fat all seem to be helpful [21, 31-34]. Somewhat comforting to see is the preliminary evidence to suggest one of our favourite probiotic strains Lactobacillus rhamnoses GG could also help lower TMAO .
What’s the bottom line here? Choline is an important nutrient to take care of during preconception, pregnancy and lactation. The form we give may matter and there seems to be a potential for Choline bitartrate to be more likely to promote higher plasma TMAO which could be harmful. Balancing the risks, it is easy to argue that it is more important to have adequate choline then not, but where possible it makes sense to support optimal choline status using dietary source or supplements containing phosphatidylcholine. And finally, we may be able to prevent TMAO rises through promoting wholefood, plant-based diets and optimising microbiome health.
1. Obeid, R., E. Derbyshire, and C. Schön, Association between Maternal Choline, Fetal Brain Development, and Child Neurocognition: Systematic Review and Meta-Analysis of Human Studies. Adv Nutr, 2022. 13(6): p. 2445-2457.
2. Nicholas, D., et al., Infant Temperament: Exploring The Potential Role of Maternal Dietary Choline and Folate Consumption During Pregnancy in a Michigan Pregnancy Cohort. Curr Dev Nutr. 2022 Jun 14;6(Suppl 1):697. doi: 10.1093/cdn/nzac061.081. eCollection 2022 Jun.
3. Korsmo, H.W., X. Jiang, and M.A. Caudill, Choline: Exploring the Growing Science on Its Benefits for Moms and Babies. Nutrients, 2019. 11(8): p. 1823.
4. Wiedeman, A.M., et al., Dietary Choline Intake: Current State of Knowledge Across the Life Cycle. Nutrients, 2018. 10(10): p. 1513.
5. Probst, Y., et al., Estimated Choline Intakes and Dietary Sources of Choline in Pregnant Australian Women. Nutrients, 2022. 14(18).
6. Adams, J.B., et al., Evidence based recommendations for an optimal prenatal supplement for women in the US: vitamins and related nutrients. Matern Health Neonatol Perinatol, 2022. 8(1): p. 4.
7. Cho, C., et al., Free Choline, but Not Phosphatidylcholine, Elevates Circulating Trimethylamine-N-oxide and This Response Is Modified by the Gut Microbiota Composition in Healthy Men. Current Developments in Nutrition, 2020. 4(Supplement_2): p. 379-379.
8. Wilcox, J., et al., Dietary Choline Supplements, but Not Eggs, Raise Fasting TMAO Levels in Participants with Normal Renal Function: A Randomized Clinical Trial. Am J Med, 2021. 134(9): p. 1160-1169.e3.
9. Böckmann, K.A., et al., Differential metabolism of choline supplements in adult volunteers. Eur J Nutr, 2022. 61(1): p. 219-230.
10. Dehghan, P., et al., Gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) potentially increases the risk of obesity in adults: An exploratory systematic review and dose-response meta- analysis. Obesity Reviews, 2020. 21(5): p. e12993.
11. Abbasalizad Farhangi, M. and M. Vajdi, Gut microbiota-associated trimethylamine N-oxide and increased cardiometabolic risk in adults: a systematic review and dose-response meta-analysis. Nutr Rev, 2021. 79(9): p. 1022-1042.
12. Farhangi, M.A., M. Vajdi, and M. Asghari-Jafarabadi, Gut microbiota-associated metabolite trimethylamine N-Oxide and the risk of stroke: a systematic review and dose-response meta-analysis. Nutr J, 2020. 19(1): p. 76.
13. Zhuang, R., et al., Gut microbe-generated metabolite trimethylamine N-oxide and the risk of diabetes: A systematic review and dose-response meta-analysis. Obes Rev, 2019. 20(6): p. 883-894.
14. Qi, J., et al., Circulating trimethylamine N-oxide and the risk of cardiovascular diseases: a systematic review and meta-analysis of 11 prospective cohort studies. Journal of Cellular and Molecular Medicine, 2018. 22(1): p. 185-194.
15. Wang, B., et al., Gut Metabolite Trimethylamine-N-Oxide in Atherosclerosis: From Mechanism to Therapy. Frontiers in Cardiovascular Medicine, 2021. 8.
16. McArthur, K.L., et al., Trimethylamine N-Oxide and Its Precursors Are Associated with Gestational Diabetes Mellitus and Pre-Eclampsia in the Boston Birth Cohort. Curr Dev Nutr, 2022. 6(7): p. nzac108.
17. Huo, X., et al., Trimethylamine N-Oxide Metabolites in Early Pregnancy and Risk of Gestational Diabetes: A Nested Case-Control Study. J Clin Endocrinol Metab, 2019. 104(11): p. 5529-5539.
18. Huang, X., et al., Association between risk of preeclampsia and maternal plasma trimethylamine-N-oxide in second trimester and at the time of delivery. BMC Pregnancy Childbirth, 2020. 20(1): p. 302.
19. Wen, Y., et al., Maternal serum trimethylamine-N-oxide is significantly increased in cases with established preeclampsia. Pregnancy Hypertens, 2019. 15: p. 114-117.
20. Jääskeläinen, T., et al., No association in maternal serum levels of TMAO and its precursors in pre-eclampsia and in non-complicated pregnancies. Pregnancy Hypertension, 2022. 28: p. 74-80.
21. Mei, Z., et al., Dietary factors, gut microbiota, and serum trimethylamine-N-oxide associated with cardiovascular disease in the Hispanic Community Health Study/Study of Latinos. Am J Clin Nutr, 2021. 113(6): p. 1503-1514.
22. Wang, Z., et al., Impact of chronic dietary red meat, white meat, or non-meat protein on trimethylamine N-oxide metabolism and renal excretion in healthy men and women. Eur Heart J, 2019. 40(7): p. 583-594.
23. Yang, S., et al., Gut Microbiota-Dependent Marker TMAO in Promoting Cardiovascular Disease: Inflammation Mechanism, Clinical Prognostic, and Potential as a Therapeutic Target. Frontiers in Pharmacology, 2019. 10.
24. Meyer, K.A. and J.W. Shea, Dietary Choline and Betaine and Risk of CVD: A Systematic Review and Meta-Analysis of Prospective Studies. Nutrients, 2017. 9(7).
25. Liu, X., et al., Egg consumption improves vascular and gut microbiota function without increasing inflammatory, metabolic, and oxidative stress markers. Food Sci Nutr, 2022. 10(1): p. 295-304.
26. Zhu, C., et al., Whole egg consumption increases plasma choline and betaine without affecting TMAO levels or gut microbiome in overweight postmenopausal women. Nutr Res, 2020. 78: p. 36-41.
27. Missimer, A., et al., Compared to an Oatmeal Breakfast, Two Eggs/Day Increased Plasma Carotenoids and Choline without Increasing Trimethyl Amine N-Oxide Concentrations. J Am Coll Nutr, 2018. 37(2): p. 140-148.
28. Thomas, M.S., et al., Comparison between Egg Intake versus Choline Supplementation on Gut Microbiota and Plasma Carotenoids in Subjects with Metabolic Syndrome. Nutrients, 2022. 14(6).
29. Lemos, B.S., et al., Effects of Egg Consumption and Choline Supplementation on Plasma Choline and Trimethylamine-N-Oxide in a Young Population. J Am Coll Nutr, 2018. 37(8): p. 716-723.
30. Mortensen, A., et al., Re-evaluation of lecithins (E 322) as a food additive. Efsa j, 2017. 15(4): p. e04742.
31. Palombaro, M., et al., Impact of Diet on Gut Microbiota Composition and Microbiota-Associated Functions in Heart Failure: A Systematic Review of In Vivo Animal Studies. Metabolites, 2022. 12(12).
32. Rehman, A., et al., A water-soluble tomato extract rich in secondary plant metabolites lowers trimethylamine-n-oxide and modulates gut microbiota: a randomized, double-blind, placebo-controlled cross-over study in overweight and obese adults. J Nutr, 2023. 153(1): p. 96-105.
33. García-Cordero, J., et al., Regular Consumption of Cocoa and Red Berries as a Strategy to Improve Cardiovascular Biomarkers via Modulation of Microbiota Metabolism in Healthy Aging Adults. Nutrients, 2023. 15(10).
34. Lombardo, M., et al., The Influence of Animal- or Plant-Based Diets on Blood and Urine Trimethylamine-N-Oxide (TMAO) Levels in Humans. Curr Nutr Rep, 2022. 11(1): p. 56-68.
35. Cantero, M.A., et al., Trimethylamine N-oxide reduction is related to probiotic strain specificity: A systematic review. Nutr Res, 2022. 104: p. 29-35.