Showing posts with label FMO3. Show all posts
Showing posts with label FMO3. Show all posts

Tuesday, December 20, 2022

Current Trends in Deodorization

In the Victorian era, people would wash off with a sponge soaked in cool water and vinegar, use sweat-absorbing pads in armpit areas and overwhelm unpleasant smells with perfume. The most popular scent was ambergris known for its marine, sweat and earthy scent with a fecal note (if not properly aged). Since energy was obtained from burning of fuels, large amounts of sulfur were always present in the air, covering odors of animal and human waste released into river and streams. 

Engineers eventually designed centralized closed water sewage treatment systems and modern plumbing, enabling rigorous personal hygiene. But in the early 1900s, fear-based marketing convinced people that they smelled bad, and this turned niche deodorant trades into a $22 billion industry. Odorono (from "Odor? Oh No!") was one of the first antiperspirants at the forefront of this transformation. 

The use of antiperspirant deodorants has been declining in recent years due to their potential effect on health and environment, and the availability of more natural and organic alternatives. COVID-19 pandemics has also negatively affected the deodorant market. As a result, the demand for deodorization has decreased during these times. But innovation continues.

Across North America, the deodorants market witnessed growth of few brands creating antiperspirants intended for alternative body parts, such as hands, face, and feet. For example, Gamer Grip Hand Antiperspirant, designed for athletes to improve their grip, has a lasting fragrance for 4 to 6 hours. Neat 3B Face Saver is an antiperspirant gel for the face that can be applied before makeup. Carpe No-Sweat Face is a natural, sweat absorbing gelled lotion created with sweat absorbing ingredients like jojoba esters, vitamin B3, silica microspheres, aloe vera, and colloidal oatmeal.

In the early 2000s, new types of deodorants appeared on the market. Deo Perfume Candy, Swallowable Parfum, and Otoko Kaoru were designed as edibles, and the fragrance was supposed to be released from the user's mouth and nose. However, these products were eventually discontinued due to safety concerns, as well as their lack of popularity. 

Beginning in the mid-2000s, many clothing companies started incorporating silver nanoparticles into their products including nano-engineered anti-odor textiles. While the technology was initially developed for use in the medical industry (antimicrobial wound dressings), nano-porous materials in clothing presented another way to manage body odor. These materials offered the potential to make traditional deodorants old-fashioned or even obsolete. 

Ag nanoparticles, for example, are effective at slowing the growth of bacteria that cause body odor and itchiness. Nano-silver socks help in preventing bacterial and fungal growth. Haojey creates textiles comprising a TiO2 particle core to provide UV resistance, silver nanoparticles for antibacterial textiles, and nanobamboo for odor adsorption. Cotton treated with pomegranate and galnut extract showed excellent deodorizing performance against trimethylamine. Odor-free medical masks are fabricated using Polyvinyl Butyral and Eucalyptus Anti Odor Agent. Aloe Vera and Polyvinyl Alcohol (AV/PVA) electrospun nanofibers show excellent results suppressing growth of S. aureus bacteria (by ~25%) although not E. coli. A team from UC Berkeley introduced a way to reduce underarm sweating and odor by using a cross-linked microporous copolymer containing methacrylate and acrylate units. 

Unfortunately, many of nano-infused textile products are investigated as skin irritants. Besides, considerable amounts of Ag nanoparticles were found to be released on washing Ag nanoparticle integrated fabrics, which is highly toxic to aquatic life. 

Another trend in the world of skincare that started in the late 2000s was topically applied probiotics. 

Although the idea is not new, as research into the human microbiome began to uncover the role that probiotics could play in improving health, the use of probiotics, prebiotics and postbiotics to help combat odor-causing bacteria began to gain traction. Oral deodorizers with probiotics are already commonly found in the market in the form of chewing tablets, lozenges, and capsules. Topical probiotic formulations could exert anti-inflammatory effects by stimulating regulatory T-cells and release of anti-inflammatory cytokines such as IL-10, within the immune system, competing with odor-causing microbes for nutrients, and aggregating and displacing them. When applied to the skin, Lactobacilli, for example, exhibits antimicrobial activity against Escherichia coli, Pseudomonas aeruginosa, and Cutibacterium (formerly Propionibacterium) acnes. Topical microbiome transplantation (Roseomonas mucosa lysate cultured from healthy volunteers) is believed to improve atopic dermatitis by restoring epithelial barrier function and innate/adaptive immune balance as well as via inhibition of S. aureus growth. Nitrosomonas eutropha improves appearance of skin. Transplantation of microbiome enriched in S. epidermidis helped to reduce axillary malodor in siblings or other matching individuals. Bacteria responsible for odor emitted from the skin is known and is common for individuals suffering from a variety of odor disorders, including those with genetic variations in ABCC11, FMO3 and those with idiopathic malodor. The presence of these bacteria in the gut microbiome correlates with the intensity of malodor. Balancing composition of gut microbes will definitely help to improve the odor but may take a long time and require tailor-made diets. And it is not clear if "suicide substrate inhibitors" such as iodomethylcholine are sufficiently safe to use.

More than a dozen topical probiotic species have been found to have a unique spectrum of characteristics, including keratin adhesion, inhibitory action, organic acid production, and inhibition of biofilm formation, skin whitening, moisturizing, anti-aging, anti-wrinkle and removing body odor. A new bilayer vaginal tablet of Lactococcus lactis has been designed for the treatment of vaginal bacterial infections and could also help to combat unpleasant odors. And so could Nitrosomonas eutropha, although so far it was only proven to help with acne. Genetically modified bacteria are also being investigated as topical therapeutics. Candidate genes are Fillaggrin, LEKTI, IL-10, genes encoding growth factors and hormones. Studies of safety and efficiency are still, however, in very early stages. The application of high amounts of bacteria, could, for example, lead to a skin immune reaction with irritation and side effects as a result. It could also lead to infection. 

The skin microbiome is relatively stable and quickly restores after washing and skincare product application, even if they contain antimicrobials. The reason is, skin microbiome is actually derived from within the skin, the deeper stratum corneum layers, skin hair follicles and is connected to the gut microbiome. Skin microbiome transplantation methods are currently being investigated and showed some promising results although many challenges remain that need to be overcome. 

Probiotic-infused products and skin transplants are gaining popularity due to their ability to promote healthy bacteria growth on the skin, which can, for example, help reduce body odor. However, there is still a lack of strong scientific evidence of effectiveness and a lack of thorough understanding of side effects.  Probiotics are living microorganisms, which means that they are sensitive to environmental conditions and can be difficult to work with. This can make it challenging to incorporate probiotics into skincare products in a way that preserves their effectiveness and stability. Finally, there are regulatory issues to consider when it comes to introducing new probiotic-based skincare products to the market. In order to be sold as a cosmetic product, a skincare product must be safe and effective, and the manufacturer must provide evidence to support these claims. This process can be time-consuming and costly and may discourage some companies from investing in the development of new probiotic-based skincare products. 

Overall, while there is a growing interest in the potential benefits of probiotics, prebiotics and postbiotics for the skin, the development of new probiotic-infused skincare products is likely to continue to be slow and incremental as researchers and manufacturers work to understand more about how probiotics work and how they can be effectively incorporated into skincare products. 

It is likely that skincare products developed in the future will be tailored to specific genetic profiles, as researchers continue to learn more about the role that genetics plays in skin health and the skincare concerns that people may have. 

One example is a urea-containing moisturizer that could be effective for people with a certain genetic variation in the filaggrin gene, Transient erythema (reddening of skin) is a potential side effect. A number of genes (such as MC1R, ASIP and BNC2) are related to skin conditions including sun sensitivity, skin moisturizing function, oxidative stress, stretch marks, and skin inflammation and are being investigated in personalized skincare R&D. 

Gene therapy and enzyme replacement therapies have achieved some notable successes in recent years. For instance, the US Food and Drug Administration (FDA) approved Luxturna for a rare form of inherited blindness, and Kymriah using genetically modified T cells to attack cancer cells, in 2017. However, the costs of research and development and the risk of side effects are extremely high. 
As a result, it can be difficult to obtain funding for non-fatal conditions like TMAU (trimethylaminuria). Trinzyme, a company focused on enzyme replacement therapies, was founded in 2011 with the goal of developing treatments for TMAU. While the company was able to secure initial funding, it has not yet been able to deliver on its promise of a treatment for this condition. Despite these challenges, the potential for gene therapy and enzyme replacement therapies to revolutionize the way we treat and prevent diseases remains significant, and research and development in these fields continues to advance.

In 2022, several companies started testing their deodorizing cosmetic products intended to block smelly chemical trimethylamine, emitted from the skin if the liver cannot completely break down this product of essential nutrients. Spain-based perfume manufacturer Eurofragance has recently teamed up with a Barcelona Children Hospital on a project to neutralize the strong odor of those who suffer from trimethylaminuria (caused by genetic mutations that affect the FMO3 function of the liver). The hospital's program initially focused on pediatric subjects with primary carnitine deficiency, manifesting as metabolic encephalopathy, lipid storage myopathy, or cardiomyopathy. Since the patients are not able to process long-chain fatty acids to convert them into energy, the accumulation of toxic fatty acyl derivatives impedes gluconeogenesis and urea cycle function which, in turn, causes hypoketotic hypoglycemia, transaminase elevations, and hyperammonemia - hence fishy odor. Eurofragance solution has citrus notes blocking the fish odor receptors in the nose. This way the fishy odor does not disappear, but it is not perceived. Eurofragance designed body cream lotion with 1% fragrance, an eau de toilette with 5% fragrance and a body serum with 2% fragrance. Other businesses designing their own solutions were Nannic "Skin care by science", and stealth-mode teams from British and US companies. 

While there is still a lot more research to be done, the development of these new deodorizing cosmetic products has provided hope for those who struggle with trimethylaminuria and similar conditions.

REFERENCES

Callewaert C, Knödlseder N, Karoglan A, Güell M, Paetzold B. Skin microbiome transplantation and manipulation: Current state of the art. Computational and Structural Biotechnology Journal. 2021 Jan 1;19:624-31.

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 Dermatol 2020;3(1):e10508 URL: https://derma.jmir.org/2020/1/e10508 DOI: 10.2196/10508

Gabashvili IS. Identifying subtypes of a stigmatized medical condition. medRxiv. 2019 Jan 1:19005223.

Habeebuddin M, Karnati RK, Shiroorkar PN, Nagaraja S, Asdaq SM, Khalid Anwer M, Fattepur S. Topical Probiotics: More Than a Skin Deep. Pharmaceutics. 2022 Mar 3;14(3):557.

Lee GR, Maarouf M, Hendricks AJ, Lee DE, Shi VY. Topical probiotics: the unknowns behind their rising popularity. Dermatology Online Journal. 2019;25(5).

Lee YH, Lee SG, Hwang EK, Baek YM, Cho S, Kim JS, Kim HD. Deodorizing performance and antibacterial properties of fabric treated with pomegranate and gallnut extracts compared with properties of commercial deodorizing and antibacterial agents. Textile Science and Engineering. 2016;53(1):45-54.

Myles IA, Earland NJ, Anderson ED, Moore IN, Kieh MD, Williams KW, Saleem A, Fontecilla NM, Welch PA, Darnell DA, Barnhart LA. First-in-human topical microbiome transplantation with Roseomonas mucosa for atopic dermatitis. JCI insight. 2018 May 5;3(9).

Qadir MB, Jalalah M, Shoukat MU, Ahmad A, Khaliq Z, Nazir A, Anjum MN, Rahman A, Khan MQ, Tahir R, Faisal M. Nonwoven/Nanomembrane Composite Functional Sweat Pads. Membranes. 2022 Dec 5;12(12):1230.

Yang J. Personalized Skin Care Service Based on Genomics. InInternational Conference on Health Information Science 2021 Oct 25 (pp. 104-111). Springer, Cham.

 

Thursday, November 17, 2022

Olfactory Signatures and COVID-19

Olfactory disorders have a significant impact on human lives - be it a lost/distorted sense of smell or unpleasant odors affecting the sense of smell of others. 

Odortypes can be influenced by human leukocyte antigen (HLAgenes of the major histocompatibility complex (MHC), genes associated with stronger response to COVID-19 vaccine as well as the severity of this disease. HLA may also be related to people's perception of the odor of other people. 

Of course, these are not the only variables involved, and there are more potentially overlapping risk factors for olfaction, metabolic body odor (MEBO), including trimethylaminuria (TMAU), and COVID-19: FMO3, SELENBP1HspA, UGT2A1/UGT2A2, etc. 

A new peer-reviewed paper reporting results of a decentralized observational study (NCT04832932) compared MEBO participants to general populations in respect to their response to COVID-19 vaccines and SARS-Co-V2 infections. 
Body odor flareups were observed in about 10% of malodor sufferers after vaccination, as preliminarily reported. This number was similar to flareups of other chronic symptoms in groups of participants with gastrointestinal and autoimmune disorders.  

Long-term worsening of body odor was observed by other researchers after COVID-19 vaccination in about ~1% of studied populations. Dry mouth leading to halitosis was 10 times more prevalent compared to flu vaccines. MEBO participants reported stronger reactions than general population pointing to genetic and microbiome influences beyond FMO3.  

A better understanding of systemic malodor conditions could offer leads for targeted therapies. Findings on genetic and microbiome overlaps between COVID-19 and MEBO could pave the way for precision medicine to address the unmet needs of odor sufferers.


REFERENCE

Gabashvili IS. The Incidence and Effect of Adverse Events Due to COVID-19 Vaccines on Breakthrough Infections: Decentralized Observational Study With Underrepresented Groups. JMIR Formative Research. 2022 Nov;6(11):e41914. DOI: 10.2196/41914. PMID: 36309347; PMCID: PMC9640199.

Wednesday, December 1, 2021

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 tolerancewound 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. 

Tuesday, January 26, 2021

Rebuild your Health

There is increasing evidence that intestinal microbial dysbiosis has a role in the pathogenesis of systemic malodor conditions and other metabolic disorders. The most studied non-syndromic malodor condition Trimethylaminuria is usually inherited in an autosomal recessive fashion, which means that two mutations from both parents, both affecting abilities of FMO3 enzyme to catalyze the N-oxidation of trimethylamine into trimethylamine (eg, [Glu158Lys (rs2266782) and Glu308Gly (rs2266780)]), may be needed for a person to have symptoms. Yet genotype is not always predictive of phenotype, not even in this case.

Illustration by Monica Garwood

Studies have shown that the symptoms of metabolic inefficiencies, food intolerance and even allergies can be relieved by changing the composition of intestinal microbes and adjusting dietary components feeding these microbes - to encourage growth of microorganisms properly digesting problem ingredients. Lactose-digesting bacteria Lactobacillus acidophilus, Lactobacillus bulgaricus and Streptococcus thermophilus, for example, can help to digest lactose into useful compounds, instead of offensive gas. On the other hand, the low-FODMAP diet reduces gastrointestinal symptoms by reducing the food that bacteria ferment. For lactose-intolerance, however,  the "O" in FODMAPs - oligosacharides - can be beneficial as Galacto-oligosaccharides (GOS) are useful prebiotics promoting the growth of the right microorganisms. 

Rebuilding the network of microorganisms on and inside our bodies can help to improve the volatiles in the surrounding air, aka body and breath odor. Microbes associated with unpleasant odors include Anaerococcus, Corynebacterium, Campylobacter, and Propionibacterium [1], Gardnerella, Alloprevotella, Sutterella, and species of Candida. Microbes associated with improvements in odors include archaebiotic Methanomassiliicoccus luminyensis, Lactobacillus pentosus KCA1, and Lactobacillus salivarius, but there are more, working together and relying on each other. Our studies (see protocols of microbiome [2] and volatilome [3] trials published on Medrxiv)  identified several microbial strains and volatile compounds associated with improvement of malodor symptoms. We are currently summarizing our results and plan to publish it. Development of personalized protocols and defining the right compositions of probiotics and prebiotics is a long-term research endeavor. Meanwhile, be your own best medical researcher and take control of your wellbeing: 

Step 1: Pull out your fitness journal and create an action plan

  • Analyze your diet, everyday activities, exercise and sleep patterns to make initial guesses about things that could be triggering your flareups or making you feel better. Write out a list of these things. 
  • Break your goal into small steps and milestones. For example: if you have fructose as a potential trigger on your list, go fructose free for a week. An earlier survey of about 100 body odor and halitosis sufferers indicated stress (34%), food (25%) and environment, including the weather and perfumed products (15%) as main triggers of odors or PATM. Make sure you are not missing something in your diet - like Zinc, Vitamin C, or Vitamin D - insufficient amounts of these vitamins and minerals could also contribute to PATM. 
  • Develop metrics for evaluating progress. Some people can't objectively evaluate their malodor or PATM condition. Try to find a trust buddy or take note of how the people around you react when you’re in close proximity. For example, pay attention to the space people leave between you and themselves (assuming COVID-19 is behind us and the 6-feet rule no longer applies!)
Step 2: Change your diet, physical activity and behavior
  • Intestinal lining is regenerating every five to seven days, so you need to stick to your diet for at least a week to notice improvements in your symptoms. Most elimination diets are actually recommended for about 3–6 weeks, to allow the antibodies (negatively reacting to problem food components) dissipate. So if your diet seems to be helping, extend it to 3 or 6 weeks. 
  • If it is not helping, try the next thing on your list. It should not be just diet - one study showed that bad breath was associated with abnormal sleep patterns. Perhaps you need to reevaluate your clothing material, temperature an humidity or mycotoxins in the environment? Are you getting enough sunlight ? Does your home have a healthy microbiome? Try to eliminate the triggers one at a time. No need to reduce your overall food intake, many people observe malodor or PATM flareups when they are hungry & undernourished. Try to train your body to digest more fiber - but start adding them to your diet little at a time, on weekends when you can safely experiment.   

Step 3: Let go of past hurts

  • Stop dwelling on the past. You have the power to change your future. Learn how to express confidence with your body language. Pretend you are comfortable in presence of other people and they will learn to be comfortable in yours. 


RFRERENCES

1. 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.

2. Gabashvili I.S. Dynamics of the Gut Microbiota in MEBO and PATM conditions: Protocol of a fully remote clinical study. medRxiv. 2020 Aug.24. medRxiv 2020.08.21.20179242; doi: https://doi.org/10.1101/2020.08.21.20179242

3. Gabashvili I.S. Effects of diet, activities, environmental exposures and trimethylamine metabolism on alveolar breath compounds: protocol for a retrospective case-cohort observational study medRxiv 2021, Jan. 26 2021.01.25.21250101; doi: https://doi.org/10.1101/2021.01.25.21250101

Friday, October 23, 2020

The Many Genes of TMAU

Twenty years ago Trimethylaminuria was linked to mutations in the FMO3 gene. It turns out there are many more genes that can lead to this condition. 

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