Gut Health
It's All About the Microbiome
How your microbiome influences choline metabolism, TMAO levels, and your cardiovascular health.
Gut Health
How your microbiome influences choline metabolism, TMAO levels, and your cardiovascular health.
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In ancient Ayurvedic wisdom, "You are what you digest," there is actually much truth. For beyond the question of what we eat, it also matters how we metabolize what we've eaten. And in the case of the crucially important nutrient choline, this depends less on us personally and more on our gut inhabitants.
The composition of your gut flora is crucial in determining how much of the ingested choline becomes available to your body and how much of the troublesome TMAO is produced from it.
What Exactly Is TMAO?
To understand TMAO, we must start with choline. Choline is abundant in eggs, liver, and wheat germ, and a choline deficiency can lead to serious problems in the brain, muscles, and liver.
Certain gut bacteria produce the intermediate compound trimethylamine (TMA) from choline and similar compounds like betaine and L-carnitine, which is then converted in the liver to trimethylamine N-oxide (TMAO).
TMAO is now considered a new risk marker for cardiovascular disease.
After all: TMAO correlates with cardiovascular disease in many studies and is suspected of promoting atherosclerosis and heart attacks through various mechanisms, such as inhibiting reverse cholesterol transport and increasing oxidative stress in blood vessels (1–4).
However, there are also studies showing that TMAO in low doses might even be beneficial (5). Whether TMAO is a cause or consequence of cardiovascular disease remains unclear.
Metabolic Dysfunction from the Wrong Bacteria
Choline-rich eggs and red meat, which contains lots of carnitine, have become suspect partly because of the presumed increase in TMAO levels.
But two key points have been overlooked:
Some members of Firmicutes, Proteobacteria, and Actinobacteria such as Desulfovibrio desulfuricans, Escherichia coli, Citrobacter, Klebsiella pneumoniae, and Shigella readily consume the choline that arrives in the gut.
Bacteroidetes, on the other hand, which include the genera Prevotella and Bacteroides, cannot metabolize choline.
A fascinating study in mice shows what happens when the wrong bacteria take over (6).
Mice with a choline-consuming E. coli strain in their gut had massively elevated TMAO levels under a choline-rich diet compared to control mice whose bacteria cannot metabolize choline.
But that's not all: They had only one-third of the choline in their blood, which according to researchers led to epigenetic changes and expected metabolic disorders.
The mice were literally rendered metabolically dysfunctional by colonization with the choline-loving E. coli strain, evident in elevated body fat and high levels of free fatty acids, leptin, and triglycerides.
In humans too, different increases in TMAO were observed depending on microbiome composition. Subjects who produced more TMAO after a meal had a higher Firmicutes to Bacteroidetes ratio and lower bacterial diversity (7).
You Are What Your Microbiome Eats
Let's be clear: The microbiome has an enormous influence on nutrient metabolism and availability.
A gut dysbiosis could, for example, rob valuable choline and generate TMAO from it, now established as a risk factor.
Meat and eggs can continue to be exonerated, because they don't inherently raise TMAO levels (8–10). Instead, the microbiome is responsible: When vegans are given a dose of carnitine, they produce almost no TMAO from it, in contrast to omnivores (11).
So how can we reprogram our microbiome to produce less TMAO? There are some simple approaches:
The Mediterranean diet provides substances that can directly inhibit the formation of TMA by gut bacteria.
These include di-methyl-butanol, or DMB, from olive oil and grape seed oil (13), resveratrol from grapes and balsamic vinegar (14), and allicin from garlic (15).
So if you cook your eggs in olive oil and garlic, you should be on the safe side when it comes to TMAO ;)
Sources
Qi J, You T, Li J, Pan T, Xiang L, Han Y, et al. Circulating trimethylamine N‐oxide and the risk of cardiovascular diseases: a systematic review and meta‐analysis of 11 prospective cohort studies. J Cell Mol Med. January 2018;22(1):185–94.
Heianza Y, Ma W, Manson JE, Rexrode KM, Qi L. Gut Microbiota Metabolites and Risk of Major Adverse Cardiovascular Disease Events and Death: A Systematic Review and Meta‐Analysis of Prospective Studies. J Am Heart Assoc Cardiovasc Cerebrovasc Dis. June 29, 2017;6(7):e004947.
Sanchez-Gimenez R, Ahmed-Khodja W, Molina Y, Peiró OM, Bonet G, Carrasquer A, et al. Gut Microbiota-Derived Metabolites and Cardiovascular Disease Risk: A Systematic Review of Prospective Cohort Studies. Nutrients. June 27, 2022;14(13):2654.
Zheng Y, He JQ. Pathogenic Mechanisms of Trimethylamine N-Oxide-induced Atherosclerosis and Cardiomyopathy. Curr Vasc Pharmacol. 2022;20(1):29–36.
Huc T, Drapala A, Gawrys M, Konop M, Bielinska K, Zaorska E, et al. Chronic, low-dose TMAO treatment reduces diastolic dysfunction and heart fibrosis in hypertensive rats. Am J Physiol-Heart Circ Physiol. December 2018;315(6):H1805–20.
Romano KA, Campo AM del, Kasahara K, Chittim CL, Vivas EI, Amador-Noguez D, et al. Metabolic, Epigenetic, and Transgenerational Effects of Gut Bacterial Choline Consumption. Cell Host Microbe. September 13, 2017;22(3):279-290.e7.
Cho CE, Taesuwan S, Malysheva OV, Bender E, Tulchinsky NF, Yan J, et al. Trimethylamine-N-oxide (TMAO) response to animal source foods varies among healthy young men and is influenced by their gut microbiota composition: A randomized controlled trial. Mol Nutr Food Res. January 2017;61(1).
Zhu C, Sawrey-Kubicek L, Bardagjy AS, Houts H, Tang X, Sacchi R, et al. Whole egg consumption increases plasma choline and betaine without affecting TMAO levels or gut microbiome in overweight postmenopausal women. Nutr Res N Y N. June 2020;78:36–41.
Wilcox J, Skye SM, Graham B, Zabell A, Li XS, Li L, 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. September 2021;134(9):1160-1169.e3.
Lemos BS, Medina-Vera I, Malysheva OV, Caudill MA, Fernandez ML. 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):716–23.
Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med. May 2013;19(5):576–85.
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Wang Z, Roberts AB, Buffa JA, Levison BS, Zhu W, Org E, et al. Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell. December 17, 2015;163(7):1585–95.
Chen M liang, Yi L, Zhang Y, Zhou X, Ran L, Yang J, et al. Resveratrol Attenuates Trimethylamine-N-Oxide (TMAO)-Induced Atherosclerosis by Regulating TMAO Synthesis and Bile Acid Metabolism via Remodeling of the Gut Microbiota. mBio. April 5, 2016;7(2):e02210-15.
Wu WK, Panyod S, Ho CT, Kuo CH, Wu MS, Sheen LY. Dietary allicin reduces transformation of L-carnitine to TMAO through impact on gut microbiota. J Funct Foods. May 1, 2015;15:408–17.
