Exploring Trimethylaminuria: Genetics and Molecular Mechanisms, Epidemiology, and Emerging Therapeutic Strategies

Overview

Journal Biology (Basel)

Publisher MDPI

Specialty Biology

Date 2025 Jan 8

PMID 39765628

Authors

Antonina Sidoti

Rosalia DAngelo

Andrea Castagnetti

Elisa Viciani

Concetta Scimone

Simona Alibrandi

Giuseppe Giannini

Affiliations

Soon will be listed here.

Abstract

Trimethylaminuria (TMAU) is a rare metabolic syndrome caused by the accumulation of trimethylamine in the body, causing odor emissions similar to rotten fish in affected patients. This condition is determined by both genetic and environmental factors, especially gut dysbiosis. The multifactorial nature of this syndrome makes for a complex and multi-level diagnosis. To date, many aspects of this disease are still unclear. Recent research revealed the haplotypes' role on the enzyme's catalytic activity. This could explain why patients showing only combined polymorphisms or heterozygous causative variants also manifest the TMAU phenotype. In addition, another research hypothesized that the behavioral disturbances showed by patients may be linked to gut microbiota alterations. Our review considers current knowledge about TMAU, clarifying its molecular aspects, the therapeutic approaches used to limit this condition, and the new therapies that are under study.

References

Cruciani G, Valeri A, Goracci L, Pellegrino R, Buonerba F, Baroni M . Flavin monooxygenase metabolism: why medicinal chemists should matter. J Med Chem. 2014; 57(14):6183-96. DOI: 10.1021/jm5007098. View

Descombe J, Dubourg D, Picard M, Palazzini E . Pharmacokinetic study of rifaximin after oral administration in healthy volunteers. Int J Clin Pharmacol Res. 1994; 14(2):51-6. View

Jameson E, Fu T, Brown I, Paszkiewicz K, Purdy K, Frank S . Anaerobic choline metabolism in microcompartments promotes growth and swarming of Proteus mirabilis. Environ Microbiol. 2015; 18(9):2886-98. PMC: 5026066. DOI: 10.1111/1462-2920.13059. View

Craciun S, Balskus E . Microbial conversion of choline to trimethylamine requires a glycyl radical enzyme. Proc Natl Acad Sci U S A. 2012; 109(52):21307-12. PMC: 3535645. DOI: 10.1073/pnas.1215689109. View

Williams D, Ziegler D, Nordin D, Hale S, Masters B . Rabbit lung flavin-containing monooxygenase is immunochemically and catalytically distinct from the liver enzyme. Biochem Biophys Res Commun. 1984; 125(1):116-22. DOI: 10.1016/s0006-291x(84)80342-3. View

Zhou P, Zhao X, Ma Y, Tang T, Wang S, Wang L . Virtual screening analysis of natural flavonoids as trimethylamine (TMA)-lyase inhibitors for coronary heart disease. J Food Biochem. 2022; 46(12):e14376. DOI: 10.1111/jfbc.14376. View

Simo C, Garcia-Canas V . Dietary bioactive ingredients to modulate the gut microbiota-derived metabolite TMAO. New opportunities for functional food development. Food Funct. 2020; 11(8):6745-6776. DOI: 10.1039/d0fo01237h. View

Shephard E, Chandan P, Stevanovic-Walker M, Edwards M, Phillips I . Alternative promoters and repetitive DNA elements define the species-dependent tissue-specific expression of the FMO1 genes of human and mouse. Biochem J. 2007; 406(3):491-9. PMC: 2049042. DOI: 10.1042/BJ20070523. View

Mitchell S, Smith R . Trimethylaminuria: the fish malodor syndrome. Drug Metab Dispos. 2001; 29(4 Pt 2):517-21. View

10.

Mayatepek E, Kohlmuller D . Transient trimethylaminuria in childhood. Acta Paediatr. 1998; 87(11):1205-7. DOI: 10.1080/080352598750031257. View

11.

Al-Waiz M, Ayesh R, Mitchell S, Idle J, Smith R . A genetic polymorphism of the N-oxidation of trimethylamine in humans. Clin Pharmacol Ther. 1987; 42(5):588-94. DOI: 10.1038/clpt.1987.201. View

12.

DAngelo R, Esposito T, Calabro M, Rinaldi C, Robledo R, Varriale B . FMO3 allelic variants in Sicilian and Sardinian populations: trimethylaminuria and absence of fish-like body odor. Gene. 2012; 515(2):410-5. DOI: 10.1016/j.gene.2012.12.047. View

13.

Martinez-Del Campo A, Bodea S, Hamer H, Marks J, Haiser H, Turnbaugh P . Characterization and detection of a widely distributed gene cluster that predicts anaerobic choline utilization by human gut bacteria. mBio. 2015; 6(2). PMC: 4453576. DOI: 10.1128/mBio.00042-15. View

14.

Maksymiuk K, Szudzik M, Gawrys-Kopczynska M, Onyszkiewicz M, Samborowska E, Mogilnicka I . Trimethylamine, a gut bacteria metabolite and air pollutant, increases blood pressure and markers of kidney damage including proteinuria and KIM-1 in rats. J Transl Med. 2022; 20(1):470. PMC: 9571686. DOI: 10.1186/s12967-022-03687-y. View

15.

Kalnins G, Sevostjanovs E, Hartmane D, Grinberga S, Tars K . CntA oxygenase substrate profile comparison and oxygen dependency of TMA production in Providencia rettgeri. J Basic Microbiol. 2017; 58(1):52-59. DOI: 10.1002/jobm.201700428. View

16.

Alibrandi S, Nicita F, Donato L, Scimone C, Rinaldi C, DAngelo R . Adaptive Modelling of Mutated FMO3 Enzyme Could Unveil Unexplored Scenarios Linking Variant Haplotypes to TMAU Phenotypes. Molecules. 2021; 26(22). PMC: 8618768. DOI: 10.3390/molecules26227045. View

17.

Li J, Huang P, Cheng W, Niu Q . Stilbene-based derivatives as potential inhibitors of trimethylamine (TMA)-lyase affect gut microbiota in coronary heart disease. Food Sci Nutr. 2023; 11(1):93-100. PMC: 9834892. DOI: 10.1002/fsn3.3046. View

18.

Shimizu M, Cashman J, Yamazaki H . Transient trimethylaminuria related to menstruation. BMC Med Genet. 2007; 8:2. PMC: 1790885. DOI: 10.1186/1471-2350-8-2. View

19.

Treacy E, Akerman B, CHOW L, Youil R, Bibeau C, Lin J . Mutations of the flavin-containing monooxygenase gene (FMO3) cause trimethylaminuria, a defect in detoxication. Hum Mol Genet. 1998; 7(5):839-45. DOI: 10.1093/hmg/7.5.839. View

20.

Hernandez D, Janmohamed A, Chandan P, Phillips I, Shephard E . Organization and evolution of the flavin-containing monooxygenase genes of human and mouse: identification of novel gene and pseudogene clusters. Pharmacogenetics. 2004; 14(2):117-30. DOI: 10.1097/00008571-200402000-00006. View