FMO3 and COVID-19

Flavin-containing monooxygenase 3 (FMO3) enzyme is a seemingly insignificant enzyme that normally converts fishy-smelling trimethylamine (TMA) into a neutral trimethylamine-N-oxide (TMAO). The amounts of this highly specialized detoxifying enzyme are highly variable. It depends on the age, sex hormones, infections (estradiol and testosterone, hepatitis virus have been found to reduce FMO3 capacity), obesity traits and diseases such as diabetes. The difference can be up to 20-fold between individuals. Mutations in the FMO3 gene cause low metabolic capacity associated with the disorder trimethylaminuria (TMAU) that attracts little biomedical interest.  This condition, however, might matter more than it seems.

Could there be a link between FMO3 and SARS-CoV-2 infection and vaccination? 

Individuals differ in their susceptibility to viral infections and genes contribute to the risk score. Less than 10% of humans infected with Mycobacterium tuberculosis develop TB, partially because of polymorphism in Tyrosine kinase (TYK2, P1104A) also responsible for severe COVID-19. Early in the pandemic, it was discovered that SARS-CoV-2 infection is dependent on the ACE2 receptor for cell entry and the serine protease TMPRSS2 for spike protein priming. ACE2 expression, indeed, influences COVID-19 risk and a rare variant located close to this gene was found to confer protection against COVID-19, possibly by decreasing ACE2 expression. Interestingly, FMO3 is one of the few genes with expression correlated to ACE2 [Sungnak et al, 2020] along with genes associated with immune functions. 

One of the characteristics of COVID-19 is the appearance of inflammatory processes, which could be leading to increased levels of TMAO. It could contribute to the hypercoagulative state in COVID-19-associated coagulopathy (CAC). SARS-Cov2 was shown to enhance TMAO-induced inflammation.  

Coronavirus disease is associated with increased risk of thrombotic events. According to recent research, low levels of FMO3 protect against thrombosis [Shih et al, 2019] while some FMO3 mutations confer higher risk [Oliveira-Filho et al, 2021]. FMO3 rs1736557 might increase the anti‐platelet efficacy of clopidogrel [Zhu et al, 2021]. Genetic risk can be mediated by gut microbiota [Gabashvili, 2020]. There are also associations with salt tolerance, wound healing, and diseases such as diabetes, renal and cardiovascular conditions increasing risk of severe COVID-19. 

Studying trimethylaminuria-like conditions might help in developing strategies for prevention and therapy of other diseases, including COVID-19.

Our COVID-19 disease and vaccines study [NCT04832932, Gabashvili, 2021] compares side-effects of vaccines and clinical course of infections (including vaccine breakthroughs) in several cohorts including MEBO and TMAU. You can help by enrolling and participating in this online survey in English or Spanish.

REFERENCES

Andreakos E, Abel L, Vinh DC, Kaja E, Drolet BA, Zhang Q, O’Farrelly C, Novelli G, Rodríguez-Gallego C, Haerynck F, Prando C. A global effort to dissect the human genetic basis of resistance to SARS-CoV-2 infection. Nature immunology. 2021 Oct 18:1-6. 

Gabashvili IS. Cutaneous Bacteria in the Gut Microbiome as Biomarkers of Systemic Malodor and People Are Allergic to Me (PATM) Conditions: Insights from a Virtually Conducted Clinical Trial. JMIR Dermatology. 2020 Nov 4;3(1):e10508.  

Gabashvili IS. Community-Based Phenotypic Study of Safety, Tolerability, Reactogenicity and Immunogenicity of Emergency-Use-Authorized Vaccines Against COVID-19 and Viral Shedding Potential of Post-Vaccination Infections: Protocol for an Ambispective study. medRxiv 2021.06.28.21256779; doi: https://doi.org/10.1101/2021.06.28.21256779

Liu W, Wang C, Xia Y, Xia W, Liu G, Ren C, Gu Y, Li X, Lu P. Elevated plasma trimethylamine-N-oxide levels are associated with diabetic retinopathy. Acta Diabetologica. 2021 Feb;58(2):221-9.

Janmohamed A, Dolphin CT, Phillips IR, Shephard EA. Quantification and cellular localization of expression in human skin of genes encoding flavin-containing monooxygenases and cytochromes P450. Biochemical pharmacology. 2001 Sep 15;62(6):777-86.

Oliveira-Filho AF, Medeiros PF, Velloso RN, Lima EC, Aquino IM, Nunes AB. Trimethylaminuria and Vascular Complications. Journal of the Endocrine Society. 2021 Apr;5(Supplement_1):A313-4. 

Zhu KX, Song PY, Li MP, Du YX, Ma QL, Peng LM, Chen XP. Association of FMO3 rs1736557 polymorphism with clopidogrel response in Chinese patients with coronary artery disease. European Journal of Clinical Pharmacology. 2021 Mar;77(3):359-68.

Sungnak W, Huang N, Bécavin C, Berg M, Queen R, Litvinukova M, Talavera-López C, Maatz H, Reichart D, Sampaziotis F, Worlock KB. SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nature medicine. 2020 May;26(5):681-7.

Shih, D.M., Zhu, W., Schugar, R.C., Meng, Y., Jia, X., Miikeda, A., Wang, Z., Zieger, M., Lee, R., Graham, M. and Allayee, H., 2019. Genetic deficiency of Flavin-containing monooxygenase 3 (Fmo3) protects against thrombosis but has only a minor effect on plasma lipid levels—brief report. Arteriosclerosis, thrombosis, and vascular biology, 39(6), pp.1045-1054. 

The Messina Lab Paper on FMO3 Haplotypes: A Different Way of Looking at TMAU

Alibrandi S, Nicita F, Donato L, Scimone C, Rinaldi C, D'Angelo R, Sidoti A. Adaptive Modelling of Mutated FMO3 Enzyme Could Unveil Unexplored Scenarios Linking Variant Haplotypes to TMAU Phenotypes. Molecules. 2021 Nov 22;26(22):7045. doi: 10.3390/molecules26227045. PMID: 34834137; PMCID: PMC8618768. 

For many years, trimethylaminuria (TMAU) has often been presented in fairly simple terms.

The traditional teaching is that someone either has "true genetic TMAU" or they do not. In this model, severe inherited TMAU is usually associated with two rare disease-causing mutations in the FMO3 gene (one inherited from each parent), resulting in a greatly reduced ability to convert trimethylamine (TMA) into the odourless trimethylamine N-oxide (TMAO).

This has influenced the typical clinical pathway.

• If the urine test is positive, FMO3 genetic testing may be offered.

• If the urine test is negative, investigation often stops, with no further genetic analysis.

While this approach identifies patients with classic severe TMAU, it may overlook a much larger group of people whose symptoms are intermittent, milder, or influenced by combinations of genetic and environmental factors.

The Missing Middle

In clinical practice, many patients who undergo FMO3 sequencing do not fit the textbook picture of carrying two rare pathogenic mutations.

Instead, they often carry combinations of common FMO3 variants that have traditionally been labelled as "benign" or "polymorphisms."

These combinations have generally attracted little attention because each individual variant appears to have only a small effect.

The important question is:

Can several mild variants together reduce FMO3 activity enough to contribute to TMAU symptoms?

This is exactly the question investigated by researchers at the University of Messina in Italy.

The Messina Study

Adaptive Modelling of Mutated FMO3 Enzyme Could Unveil Unexplored Scenarios Linking Variant Haplotypes to TMAU Phenotypes (2021)

The researchers analysed 26 patients with TMAU and found:

• 17 different FMO3 variants

• 26 different genetic haplotypes

• many patients whose genetics did not fit the classic "two rare severe mutations" model

Using computational protein modelling, molecular docking and urine metabolite analysis, they proposed that combinations of variants (haplotypes) may alter how the FMO3 enzyme binds and processes trimethylamine.

Rather than viewing common variants individually, the paper suggests they should sometimes be considered together as functional genetic combinations.

The authors wrote:

"Variants classified as benign... have a high frequency in TMAU patients, frequently without the contemporary presence of causative mutations."

They therefore hypothesised that these variant combinations could reduce FMO3 activity sufficiently to contribute to disease.

Why Haplotypes Matter

A haplotype is simply a combination of genetic variants inherited together.

Each individual variant may have only a modest effect.

However, several small effects combined may reduce enzyme efficiency more than expected from considering each variant separately.

This idea is well recognised in many areas of genetics, where multiple low-impact variants together influence disease severity or susceptibility.

The Messina paper suggests that TMAU may follow a similar pattern in at least some patients.

Moving Beyond "Normal" or "Severe"

One way of thinking about this is to compare walking ability.

Traditional teaching effectively assumes there are only two categories:

• walks normally

• cannot walk

In reality, there is a broad spectrum.

Many people can walk but with limitations caused by arthritis, injuries, muscle weakness or neurological problems.

Likewise, FMO3 activity may exist on a spectrum rather than as a simple "working" versus "not working" enzyme.

Some people may have almost complete enzyme function.

Others may have very little.

Many may fall somewhere in between.

Those in this middle group might only develop symptoms during periods of illness, hormonal changes, dietary excess, stress, altered gut microbiota, or other metabolic challenges.

Why This Could Matter Clinically

The current diagnostic pathway often depends heavily on urine testing.

However, urinary TMA measurements can vary considerably depending on:

• recent diet

• timing of sample collection

• symptom fluctuation

• gut microbiome activity

• liver enzyme activity

If a patient's urine test is normal on the day of testing, genetic analysis may never be performed.

If mild FMO3 haplotypes contribute to symptoms, this group could easily be under-recognised.

This remains a hypothesis rather than an established clinical fact, but it is one that deserves further investigation.

An Important Shift in Thinking

The significance of the Messina paper is not that it proves common variants cause TMAU.

Rather, it challenges the assumption that they are always clinically irrelevant.

Instead of asking:

"Does this patient have two rare pathogenic mutations?"

the question becomes:

"Could this particular combination of variants reduce FMO3 function enough to contribute to symptoms?"

That is a much more nuanced—and potentially more useful—way of approaching patients who do not fit the classic textbook description.

Since 2021

The Messina group's work has continued.

In 2024 they published a comprehensive review of TMAU covering genetics, molecular mechanisms, epidemiology and emerging treatments. The review again discusses the potential importance of variant combinations and the need to better understand how different FMO3 genotypes translate into clinical symptoms.

Research into treatments has also expanded.

A 2025 study investigated a mixture of postbiotics and tyndallized probiotics that reduced trimethylamine production in laboratory and animal models, highlighting growing interest in targeting the gut microbiome as part of TMAU management.

At the same time, other researchers continue to report newly identified pathogenic FMO3 mutations in different populations, demonstrating that classic severe genetic TMAU certainly exists while broadening our understanding of the condition worldwide.

If larger patient studies demonstrate that combinations of common FMO3 variants significantly reduce enzyme activity, it could eventually change how clinicians investigate patients whose symptoms are compatible with TMAU but who do not fit the traditional diagnostic model.

That would represent an important step toward recognising that TMAU may encompass a broader spectrum of FMO3 dysfunction than has historically been appreciated.

References

Alibrandi S, Nicita F, Donato L, Scimone C, Rinaldi C, D'Angelo R, Sidoti A. Adaptive Modelling of Mutated FMO3 Enzyme Could Unveil Unexplored Scenarios Linking Variant Haplotypes to TMAU Phenotypes. Molecules. 2021 Nov 22;26(22):7045. doi: 10.3390/molecules26227045. PMID: 34834137; PMCID: PMC8618768.

Alibrandi S, Nicita F, Donato L, et al. (2021). Adaptive Modelling of Mutated FMO3 Enzyme Could Unveil Unexplored Scenarios Linking Variant Haplotypes to TMAU Phenotypes.

Sidoti A, D'Angelo R, Castagnetti A, et al. (2024). Exploring Trimethylaminuria: Genetics and Molecular Mechanisms, Epidemiology, and Emerging Therapeutic Strategies.

Giannini G, Soldi S, Elli M, et al. (2025). A Mixture of Postbiotics/Tyndallized Probiotics Reduces Trimethylamine (TMA) in Trimethylaminuria Models.

Alghanem B, Alamri HS, Barhoumi T, et al. (2024). First Report from Saudi Arabia of Trimethylaminuria Caused by a Premature Stop Codon Mutation in the FMO3 Gene.