Causes of Elevated TMAO Levels
Elevated TMAO levels result from three primary mechanisms: dietary intake of TMAO precursors (L-carnitine and phosphatidylcholine from red meat, eggs, and full-fat dairy), direct consumption of TMAO-rich foods (certain fish and seafood), and reduced renal clearance in kidney disease. 1
Primary Dietary Sources
Animal-Based Foods Rich in TMAO Precursors
- Red meat and processed meats contain high levels of L-carnitine and phosphatidylcholine, which gut microbes convert to trimethylamine (TMA), subsequently oxidized by hepatic flavin-containing monooxygenases (FMOs) to TMAO 1
- Eggs (particularly yolk) and full-fat dairy products are abundant sources of phosphatidylcholine that undergo microbial conversion to TMA and then TMAO 2
- Proteolytic fermentation by gut bacteria of these animal proteins produces TMA as an intermediate metabolite 1
Direct TMAO-Containing Foods
- Fish and seafood naturally contain TMAO, with content varying widely by species and depth of water where caught 2, 3
- Fish sticks, cod, and salmon consumption can lead to significant transient increases in circulating TMAO levels 3
- TMAO accumulates in fish muscle as protection against pressure and cold in deep-sea environments 3
- Shrimp and tuna also contain variable amounts of preformed TMAO 3
Supplementation-Related Sources
- Betaine supplementation may be converted by gut microflora into methylamine-N-oxide and subsequently metabolized into TMAO, potentially having negative long-term cardiovascular impact 4, 5
- Choline supplementation can be converted to TMAO by gut bacteria, with an upper limit of 3.5 g/day recommended to minimize this risk 4, 6
Metabolic and Physiological Factors
Gut Microbiome Composition
- Specific gut bacterial species convert dietary choline and L-carnitine into TMA through microbial choline TMA-lyase enzymes 7
- Uremic dysbiosis in chronic kidney disease results in overgrowth of microorganisms that increase TMA production 8, 2
- The profile of gut microbiota varies according to host genetics, dietary patterns, disease state, and environmental factors 2
Hepatic Metabolism
- Hepatic flavin-containing monooxygenases (FMOs), particularly FMO3, oxidize gut-derived TMA to TMAO 1
- Cruciferous vegetables can inhibit FMO3 activity, potentially reducing TMAO production from precursors 1, 4
- Elevated hepatic enzymatic activity in uremic states increases TMAO generation 2
Renal Function Impairment
- Reduced kidney function leads to decreased TMAO excretion, causing accumulation in circulation 8, 2
- TMAO is normally efficiently excreted by the kidneys, and plasma TMAO concentration is significantly increased in chronic kidney disease patients 1, 8
- TMAO levels in humans are often confounded by reduced kidney function rather than solely reflecting dietary intake 1
Important Clinical Caveats
The Fish Paradox
- Despite fish being rich in TMAO and its precursors, epidemiological findings consistently link fatty fish consumption with beneficial cardiometabolic outcomes 1, 4
- The American Heart Association recommends consuming nonfried seafood 1-2 times per week for cardiovascular benefits, acknowledging that concerns about TMAO from fish are not supported by evidence showing cardiovascular benefits from seafood 4
- Circulating TMAO levels return to baseline within 1 day after fish consumption in individuals with normal renal function 3
Modifiable Risk Factors
- Limiting red meat and processed meats reduces not only TMAO but also other detrimental metabolites including ammonia, p-cresol, and hydrogen sulfide 4
- Plant-based diets show promise for reducing gut-derived TMAO production by decreasing intake of animal-based precursors 9
- Selection of low TMAO content fish is prudent for subjects with elevated TMAO, cardiovascular disease, or impaired renal function 3