Optimal DX FYI: Gut Microbes Increase TMAO

Trimethylamine N-Oxide (TMAO) is directly associated with systemic inflammation and significantly increased cardiovascular risk. Elevated TMAO in the blood can contribute to insulin resistance by interfering with hepatic gluconeogenesis and glucose transport. TMAO is unreliable as a standalone biomarker due to the significant influence and variability of liver function, diet, gut microbiota diversity, and genetic factors.

TMAO is formed in the liver from trimethylamine (TMA), a substance produced by gut bacteria from food-based compounds such as choline, carnitine, lecithin, betaine, gamma-butyrobetaine, and ergothioneine. These compounds are found in animal protein foods, processed and unprocessed meats, egg yolks, dairy foods, fatty fish, and some plant-based foods.

If TMA to TMAO conversion is inhibited, trimethylaminuria, or “fish odor syndrome,” can occur due to TMA accumulation and excretion in the urine, sweat, and breath.

Various factors influence TMAO blood levels, including diet, GI microbial composition, and liver enzyme activity. Genetic polymorphisms, low-grade inflammation, poor diet, dysbiosis, and chronic disease, including diabetes and cardiovascular disease, may increase the conversion of TMA to TMAO.

• High-fat, high-protein, and Western diets are associated with higher levels of TMAO.
• A vegetarian diet or including plant-based foods such as pistachios and foods high in indigestible fiber may reduce TMAO production.
• A diet low in carbohydrates and fiber, e.g., a ketogenic diet, contributes to an unfavorable increase in Firmicutes:Bacteroidetes ratio and an acute increase in postprandial TMAO production.

TMA's action in pathological conditions. The dietary intake of choline isoforms, carnitine, and gamma-butyrobetaine contributes to increased plasma levels of TMA. TMA is converted into TMAO in the liver. TMAO is involved in and correlated with kidney and liver disease, gastrointestinal cancers, diabetes type II, atherosclerosis, and cardiac muscle damage.

The microorganisms most likely to promote TMAO production include some of those in the Firmicutes phylum, Clostridia class (e.g., Clostridium, Ruminococcaceae and Lachnospiraceae). Also, Escherichia coli, Citrobacter, Klebsiella pneaumoniae, and Shigella, Achromobacter from the strain of Betaproteobacteria, Sporosarcina from Firmicutes, and Actinobacteria have enzymes that can lead to the conversion of all food compounds including choline, betaine, lecithin, gamma-butyrobetaine, ergothioneine and L-carnitine into TMA.

Therapeutic approaches

• Limiting TMA precursors in individuals with elevated TMAO would be prudent.
• Maintaining a healthy, balanced gut microbiota is vital.
• Researchers are exploring the therapeutic approach of using bacterial strains that can use TMAO as a substrate.
• Prebiotic and probiotic use may help reduce TMAO production:
• Administration of probiotic Lacticaseibacillus paracasei, but not Lacticaseibacillus casei, or Lactiplantibacillus plantarum, may reduce circulating TMA and TMAO levels
• Enterobacter aerogenes ZDY01 increased Bacteroidales (Bacterodetes phylum) and decreased Prevotellaceae and Helicobacteraceae families
• Supplementing with Archeobacteria phylum, may reduce TMA and TMAO
• The prebiotic Arabinoxylan oligosaccharide plus vitamins B and D showed a small reduction in serum TMAO
• Prebiotics such as resveratrol increased the Bacterodetes phylum, while Firmicutes, aside from Lactobacillus and Bifidobacterium genus, decreased along with TMAO plasma levels
• Physical activity has a favorable effect on gut microbiota composition
• Some natural products, including 3,3-dimethyldimetyl-1-butanol (DMB) from vinegar, olive oil, and grapeseed oil, may inhibit the conversion of choline, betaine, and carnitine to TMA.

TMA Precursors

Betaine

• Also called trimethyl-glycine due to its three methyl groups
• Found in abundance in beets, spinach, cashews, mushrooms, whole grains, all-bran cereal, wheat flour, pasta, oat bran, liver, soy sauce, shrimp, Atlantic cod, tilapia, and soy sauce
• Required for methylation of homocysteine to methionine

Carnitine

• Found in abundance in red meat ham, chicken liver, turkey, lamb, and goat cheese
• Current intake of 2 to 12 mol/kg/day or 22.7 to 136.1 mg/day for a 70 kg person should be adequate without further supplementation
• Produced endogenously from lysine and methionine
• Supplementation is not recommended unless indicated
• Required for the transport of long-chain fatty acids into the cell for mitochondrial energy generation
• Is easily converted to TMA by gut microbiota

Choline

• Found in abundance in egg yolks (contains mainly the more favorable phosphatidylcholine), liver, whole milk, chicken meat and skin, sausage, Atlantic cod, tilapia, broccoli, tomato paste, cashews, hazelnuts, macadamias, pistachios, kidney beans, peanut butter, wheat bread, all-bran cereal, soy milk, and soy sauce
• Choline bitartrate seems to raise TMAO levels and urinary excretion, but not phosphatidylcholine
• Recommended intake is 7 mg/kg/day for most adults
• Can be produced endogenously
• Essential to cell membranes
• Vital to neurological health
• Required for acetylcholine production

Ergothioneine

• Found in meats, liver, kidney, mushrooms, and beans

Gamma-butyrobetaine

• Found in red meat

Reference

Tacconi, Edoardo et al. “Microbiota Effect on Trimethylamine N-Oxide Production: From Cancer to Fitness-A Practical Preventing Recommendation and Therapies.” Nutrients vol. 15,3 563. 21 Jan. 2023, doi:10.3390/nu15030563 This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).