Diet-dependent trimethylamine/trimethylamine N-oxide metabolism (WP5219)

Homo sapiens

The host-microbiome pathway trimethylamine/trimethylamine N-oxide (TMA/TMAO) pathway which exists along the gut-heart axis. The precursors choline, l-carnitine and betaine are first microbially transformed to TMA. This metabolite is subsequently converted to TMAO by the flavin-containing monooxygenase 3.


Nina Valenbreder , Kristina Hanspers , Eric Weitz , Egon Willighagen , and Denise Slenter


last edited

Discuss this pathway

Check for ongoing discussions or start your own.

Cited In

Are you planning to include this pathway in your next publication? See How to Cite and add a link here to your paper once it's online.


Homo sapiens



Pathway Ontology

classic metabolic pathway


Label Type Compact URI Comment
γBB Metabolite chembl.compound:CHEMBL2074645
Dimethylglycine Metabolite kegg.compound:C01026
Choline Metabolite kegg.compound:C00114
BETALD Metabolite kegg.compound:C00576
BET Metabolite kegg.compound:C00719
FAD Metabolite kegg.compound:C00016
Choline Metabolite kegg.compound:C00114
FAD Metabolite kegg.compound:C00016
FADH2 Metabolite wikidata:Q26998317
NADH Metabolite kegg.compound:C00003
H20 Metabolite chebi:15377
BET Metabolite kegg.compound:C00719
Carnitine Metabolite kegg.compound:C00318
TMA Metabolite kegg.compound:C00565
Acetate Metabolite kegg.compound:C00033
TMAO Metabolite kegg.compound:C01104
Transmethylase GeneProduct kegg.genes:EC
FMO3 Protein ensembl:ENSG00000007933
ALDH7A1 Protein ensembl:ENSG00000164904
TMAO aldolase Protein kegg.genes:
Tmm Protein kegg.genes:
SLC44A1 Protein ensembl:ENSG00000070214
CHDH Protein ensembl:ENSG00000016391
CntA/B Protein uniprot:D0C9N6


  1. Methylotrophic Bacteria in Trimethylaminuria and Bacterial Vaginosis. Wood AP, Warren FJ, Kelly DP. In: Handbook of Hydrocarbon and Lipid Microbiology [Internet]. Springer Berlin Heidelberg; 2010. p. 3227–40. Available from: DOI Scholia
  2. Betaine: New Oxidant in the Stickland Reaction and Methanogenesis from Betaine and l-Alanine by a Clostridium sporogenes-Methanosarcina barkeri Coculture. Naumann E, Hippe H, Gottschalk G. Appl Environ Microbiol. 1983 Feb;45(2):474–83. PubMed Europe PMC Scholia
  3. Microbial conversion of choline to trimethylamine requires a glycyl radical enzyme. Craciun S, Balskus EP. Proc Natl Acad Sci U S A. 2012 Dec 26;109(52):21307–12. PubMed Europe PMC Scholia
  4. Trimethylamine and Trimethylamine N-Oxide, a Flavin-Containing Monooxygenase 3 (FMO3)-Mediated Host-Microbiome Metabolic Axis Implicated in Health and Disease. Fennema D, Phillips IR, Shephard EA. Drug Metab Dispos. 2016 Nov;44(11):1839–50. PubMed Europe PMC Scholia
  5. Betaine in Inflammation: Mechanistic Aspects and Applications. Zhao G, He F, Wu C, Li P, Li N, Deng J, et al. Front Immunol. 2018 May 24;9:1070. PubMed Europe PMC Scholia
  6. Purification and Characterization of the Choline Trimethylamine-Lyase (CutC)-Activating Protein CutD. Bodea S, Balskus EP. Methods Enzymol. 2018;606:73–94. PubMed Europe PMC Scholia
  7. Choline oxidases. Gadda G. Enzymes. 2020;47:137–66. PubMed Europe PMC Scholia
  8. Structural basis of carnitine monooxygenase CntA substrate specificity, inhibition, and intersubunit electron transfer. Quareshy M, Shanmugam M, Townsend E, Jameson E, Bugg TDH, Cameron AD, et al. J Biol Chem. 2021;296:100038. PubMed Europe PMC Scholia
  9. Elucidation of an anaerobic pathway for metabolism of l-carnitine-derived γ-butyrobetaine to trimethylamine in human gut bacteria. Rajakovich LJ, Fu B, Bollenbach M, Balskus EP. Proc Natl Acad Sci U S A. 2021 Aug 10;118(32):e2101498118. PubMed Europe PMC Scholia
  10. The microbial gbu gene cluster links cardiovascular disease risk associated with red meat consumption to microbiota L-carnitine catabolism. Buffa JA, Romano KA, Copeland MF, Cody DB, Zhu W, Galvez R, et al. Nat Microbiol. 2022 Jan;7(1):73–86. PubMed Europe PMC Scholia