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March20 podcast Dr Hazen
anti-TMA pill in a year or 2 ? (scroll 12 mins)

Additional info: https://youtu.be/811v7RLXP9M
MEBO Karen
at UK Findacure conf 2020

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MEBO TMAU TESTING DISCONTINUED
(2012-2017)

MEBO Map Testing & Meetups


Full details : https://goo.gl/TMw8xu
want listed ? contact info@meboresearch.org

MEBO - UBIOME study 2018

'PRESS RELEASE'

NCT03582826
ClinicalTrials.gov

MEBO Gut Microbiome Study
"Microbial Basis of Systemic Malodor and PATM Conditions (PATM)"
Funded by uBiome Research Grant

"Microbial Basis of Systemic Malodor and PATM Conditions (PATM)"

Dynamics of the Gut Microbiota in
Idiopathic Malodor Production
& PATM

Started May 2018 - Ongoing

Current people sent kits : 100/100
3 kits per person

NO LONGER RECRUITING

Participation info : LINK English

MEBO Private Facebook Group
to join : go to
or contact
Join/Watch the weekly
BO Sufferers Podcasts

MEBO TMAU Videos

Petitions

TMAU Petition world
TMAU UK end total:262
TMAU UK ends 23/01/20
TMAU Petition USA end total 204
USA : Moveon open
TMAU (Dominican)
Metabolomic Profiling Study
NCT02683876

Start : Aug 2016
Stage 1 : 27 Canadian volunteers to test
Latest click here (26 oct) :
17 samples returned


Note : Stage 1 is Canada only.
Return cut-off date : passed
Analysis can take 6/8 weeks
Analysis start in/before Nov
MEBO Research is a
EURORDIS and
NORD Member Organization
See RareConnect
rareconnect.org TMAU

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Blog Archive

MEBO Metabolic Malodor Survey (international) for Dr Hazen click here
click to Read more/less

survey for ANYONE who identifies with METABOLIC MALODOR

begun : Oct20
end : no ending for now

Regular readers will know that Dr Stan Hazen et al at Cleveland Clinic are developing a TMA-blocker pill, as they proposed in a 2011 paper that TMAO is a factor in CVD. Recently Dr Hazen and colleagues contacted MEBO as they have always thought they could also help with TMAU. This survey is to give them an idea of the 'state of the community'. It is a "version 1". They may not even look (though they have access permission), but it could be useful to give them an overview of the community

MEBO had a zoom call with Dr Hazen and his team in October. Another zoom call is planned when they have time

This is a GOOGLE FORMS survey

short url for survey :
https://forms.gle/vem2TjepKobYZPBu8

current participants : 113 (update 18dec20)

Monday, December 6, 2021

Messina lab paper on FMO3 'haplotypes'

TMAU is taught as : person is normal or severe.

Severe is 2 very rare mutations as  a couple ... homozygous.

The Dr/patient approach to TMAU is ... do urine test. If negative, take no further action. 
If positive, do FMO3 gene test.

Re urine test :   
positive ... then test FMO3 gene. 'severe and rare' will show, but also many FMO3 results will not match concept of homozygous/coupled rare mutations. Most will be a patchwork of common variants taught as harmless etc. Dr not too bothered. 
negative ... and so do not test FMO3 gene (so all the 'FMO3 patchwork' cases in this group aren't spotted.)

a clinical lab in Messina Italy seems to be doing very relevant clinical TMAU/FMO3 that may help sufferers, especially those who are negative in the urine test (probably 95% cases).

They seem to be looking in to the theory that most cases of TMAU are not 'rare severe homozygous' cases as is taught, but rather combinations of mild common (or common taught as harmless) variants (heterozygous), which are known as Haplotypes. Or Compound Heterozygotes.

The blog opinion is that this theory is correct and will make up 95%+ of the cases, most of which will currently pass the urine test.

An analogy would be can someone walk or not.
Currently TMAU diagnosis and teaching is : 1 or other.
But we know many can't walk well or very far etc. Crutches, sprained ankles, whatever.
This gray-area is probably where most TMAU cases lie. Transient.

So for a clinical lab to put this theory forward in a paper would be very beneficial to the TMAU community in the sense it may change the attitude of the clinical health professionals for a diagnosis.

Probably they are still being conservative, in that they are likely trying to match positive urine cases to FMO3 results that don't fit the 'rare severe variant' teaching. This is already obvious, but nice for a lab to make a paper of it. 

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

Simona Alibrandi, Fabiana Nicita, Luigi Donato, Concetta Scimone, Carmela Rinaldi, Rosalia D'Angelo, Antonina Sidoti
Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Division of Medical Biotechnologies and Preventive Medicine, University of Messina, 98125 Messina, Italy.

Background: Trimethylaminuria (TMAU) is a rare genetic disease characterized by the accumulation of trimethylamine (TMA) and its subsequent excretion trough main body fluids, determining the characteristic fish odour in affected patients. We realized an experimental study to investigate the role of several coding variants in the causative gene FMO3, that were only considered as polymorphic or benign, even if the available literature on them did not functionally explain their ineffectiveness on the encoded enzyme. Methods: Mutational analysis of 26 TMAU patients was realized by Sanger sequencing. Detected variants were, subsequently, deeply statistically and in silico characterized to determine their possible effects on the enzyme activity. To achieve this goal, a docking prediction for TMA/FMO3 and an unbinding pathway study were performed. Finally, a TMAO/TMA urine quantification by 1H-NMR spectroscopy was performed to support modelling results. Results: The FMO3 screening of all patients highlighted the presence of 17 variants distributed in 26 different haplotypes. Both non-sense and missense considered variants might impair the enzymatic kinetics of FMO3, probably reducing the interaction time between the protein catalytic site and TMA, or losing the wild-type binding site. Conclusions: Even if further functional assays will confirm our predictive results, considering the possible role of FMO3 variants with still uncertain effects, might be a relevant step towards the detection of novel scenarios in TMAU etiopathogenesis.

Quotes:

"To date, 91 FMO3 variants were identified, and more than half of them are responsible for the TMAU phenotype (http://www.hgmd.cf.ac.uk/ac/index.php, accessed on 19 October 2021). Among the remaining variants, some are of uncertain clinical significance, while others are classified as “benign” and, therefore, should not affect the FMO3 enzyme activity

However, as such variants have a high frequency in TMAU patients, frequently without the contemporary presence of causative mutations, we hypothesized that their haplotypes could play a significant role in FMO3 activity reduction or alteration. To confirm this hypothesis, we performed a proteomic in silico analysis, using different platforms and software, with the final aim of revealing how these variant combinations could influence the enzyme folding, also simulating its dynamic behaviour with the TMA substrate."

Messina TMAU lab ask for DNA results !!!
In a previous post we mentioned Messina TMAU lab are always looking for FMO3 results from people who identify with TMAU. Although a small lab, it looks like their TMAU/FMO3 clinical research will continue. They are possibly 1 of only 2 labs (both small) who do direct TMAU/FMO3 research. The other lab in Argentina was only recently noticed, and will be a new post.   

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Thursday, December 2, 2021

What We Might Learn from COVID-19

The COVID-19 pandemic has had a profound effect on communities and MEBO community is not an exception. Planned diagnostic and therapeutic studies were put on hold or transitioned from collecting new data to just analyzing the data. Any disadvantage, however, can be turned into an advantage. COVID-19 can help us to learn more about FMO3, distorted sense of smell, gut dysbiosis and other conditions contributing to malodor syndromes. Observations about COVID-19/vaccine reactogenicity in the MEBO community could help to attract researchers' interest and design better interventions against malodor conditions. 


The COVID-back-to-normal study (registered as NCT04832932) follows about 1000 participants from different online and offline communities and compares their susceptibility to SARS-CoV-2 infection, reactions to vaccines, COVID- and post-COVID symptoms. 

Preliminary results suggest there are interesting differences between the MEBO community and others. 

It is not unexpected. This figure from a recent article in Nature Medicine shows that FMO3 is one of the genes whose expression correlates with ACE2, the gene employed by  SARS-CoV-2 for cellular entry. A few other potential links between TMAU and COVID-19 are discussed in the latest Aurametrix blog


Your observations, hypotheses and comments are most welcome.


Short URLs for the survey : 
https://bit.ly/BTN-eng  (in English) 



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Sunday, November 28, 2021

TMA the inflammation baddie ? TMAO a goodie ??

2 big FMO3-smell related stories recently :

1 : new study : TMA is the inflammation baddie and not TMAO ???
2. small Messina Italy lab looking at whether FMO3 common haplotypes with ma currently regarded harmless etc may affect FMO3 function in combination (readers say yes ??)

This post will look at the 'TMA-bad' recent study by Quadram Institute, Norwich, England

Note : paper details not fully absorbed. post may have errors.

Theory of paper :  in mice models, TMA caused blood-brain barrier inflammation, whereas TMAO was protective !!
This seems to contradict the TMAO-CVD theory put forward by Cleveland Clinic scientists in 2011.

That said, they are looking at at the blood-brain barrier, whereas Cleveland's theory is about blood vessel internal damage (blood vessels to heart etc). So both could be right (???). 
This paper seems to have been funded by an Alzheimers charity.

Group behind the study :
Quadram Institute UK is based around microbiome research etc. Seems to be quite well funded, probably by Government.
Microbiome research seems to have given us little useful info up until now. Possibly this is still the way their research is going.

Tweets same to suggest it was a 'eureka' wild research guess from a scientist based there.
The online fecal body odor forums are probably decades ahead of them in this type of study thinking. 
The idea for the study seems to be of Profs Lesley Hoyles and Simon McArthur.

How will this affect FMO3-smelly people ?
Probably win-win either way. Whether its TMA or TMAO they try to block, doesn't matter as they will both likely block TMA. For TMA to be the baddie would be preferable, as it means it's the main target for big pharmas, but TMAO as a target likely means blocking TMA anyway.
In theory it means TMA people are meant to be more prone to CVD etc, but 1 opinion is neither TMA or TMAO are much important re CVD but pharma-fanaticism about TMA/TMAO is very welcome. Perhaps TMA makes more sense, but who knows about either. Maybe TMA is just a sign of dysbiosis.

Details on the paper :

Regulation of blood–brain barrier integrity by microbiome-associated methylamines and cognition by trimethylamine N-oxide
Lesley Hoyles, Matthew G. Pontifex, Ildefonso Rodriguez-Ramiro, M. Areeb Anis-Alavi, Khadija S. Jelane, Tom Snelling, Egle Solito, Sonia Fonseca, Ana L. Carvalho, Simon R. Carding, Michael Müller, Robert C. Glen, David Vauzour & Simon McArthur 

 
"Here, we use an integrated in vitro/in vivo approach to show that physiologically relevant concentrations of the dietary methylamine trimethylamine N-oxide (TMAO) enhanced blood-brain barrier (BBB) integrity and protected it from inflammatory insult, acting through the tight junction regulator annexin A1. In contrast, the TMAO precursor trimethylamine (TMA) impaired BBB function and disrupted tight junction integrity. Moreover, we show that long-term exposure to TMAO protects murine cognitive function from inflammatory challenge, acting to limit astrocyte and microglial reactivity in a brain region-specific manner."


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