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. 

Vaccine to cure body odor?

There could be a vaccine for everything. Scientists are working on personal vaccines, vaccines reducing body weight or narcotic dependence, vaccines for just about anything.  Can there be a vaccine improving body odor? Certainly, and it could target not only bacteria (in body crevices) worsening odor, but also molecules responsible for odor. This would be a very complex task, however, as there is still a lot we don't understand.  For example, if metabolism and microbiomes leading to body odor cause similar reactions to already existing vaccines. 

Several vaccines to prevent COVID-19 were authorized for emergency use and hundreds of millions doses have been administered. 2 millions of vaccinated individuals in the US completed a health survey in the 7 days following their vaccination via the v-safe app.

This table shows top adverse reactions reported to the first two vaccines authorized in the US. Hundreds of social media groups on Facebook, reddit and WhatsApp are also flooded by descriptions of adverse reactions and immunity related events. What is missing? The ability to systematically analyze all these reactions in different health and neighborhood communities.

We started such a study in one neighborhood community and would like to also conduct it in the MEBO/PATM communities. We are also opening it to MEBO friends and family - asking them to indicate their relationship with MEBO/PATM in the comment section of the survey.

We are also collecting COVID-19 experiences in different groups of people, analyzing infectious disease susceptibility risks. 

in English: https://bit.ly/BTN-eng

en Español: https:/bit.ly/BTN-esp

Thank you for your help!

REFERENCES

ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2021 April 6 - . Identifier NCT04832932, The COVID-19 Back-to-Normal Study [cited 2021 April 7]; Available from: https://clinicaltrials.gov/ct2/show/NCT04832932

Chapin-Bardales J, Gee J, Myers T. Reactogenicity Following Receipt of mRNA-Based COVID-19 Vaccines. JAMA. 2021 Apr 5. doi: 10.1001/jama.2021.5374. Epub ahead of print. PMID: 33818592. 

Zimmermann P, Curtis N. Factors that influence the immune response to vaccination. Clinical microbiology reviews. 2019 Mar 20;32(2). 

Mosquera MJ, Kim S, Zhou H, Jing TT, Luna M, Guss JD, Reddy P, Lai K, Leifer CA, Brito IL, Hernandez CJ. Immunomodulatory nanogels overcome restricted immunity in a murine model of gut microbiome–mediated metabolic syndrome. Science advances. 2019 Mar 1;5(3):eaav9788.

Bandaru P, Rajkumar H, Nappanveettil G. The impact of obesity on immune response to infection and vaccine: an insight into plausible mechanisms. Endocrinol Metab Synd. 2013;2(2):1000113-22. 

Kim YH, Kim JK, Kim DJ, Nam JH, Shim SM, Choi YK, Lee CH, Poo H. Diet-induced obesity dramatically reduces the efficacy of a 2009 pandemic H1N1 vaccine in a mouse model. Journal of Infectious Diseases. 2012 Jan 15;205(2):244-51. 

 Monteiro MP. Obesity vaccines. Hum Vaccin Immunother. 2014;10(4):887-95. doi: 10.4161/hv.27537. Epub 2013 Dec 23. PMID: 24365968; PMCID: PMC4896563. 

Ozgen MH, Blume S. The continuing search for an addiction vaccine. Vaccine. 2019 Aug 23;37(36):5485-90. 

Daniel W, Nivet M, Warner J, Podolsky DK. Early evidence of the effect of SARS-CoV-2 vaccine at one medical center. New England Journal of Medicine. 2021 Mar 23.