Sheffield TMAU survey : Old and New Test

Quick update on anecdotal SHEFFIELD TMAU Test Survey.
Aim : To show differences in trends between OLD test (Nigel's pre-2017 test)
and the NEW post-2016 test.

Measurement is umol/mmol creatinine.

Conclusions :

1. TMA is 10-80 times lower for NEW test ??

TRIMETHYLAMINE levels seems to be 10  to nearly 100 times less than the old test, even though they both use GAS CHROMATOGRAPHY as the method.
The reason given so far is that the old test had 'false positives', which means many were told they were positive wrongly.

For whatever reason, the old test was more in line with numbers I would expect to be positive. My suspicion is the new test spots only GENETICALLY SEVERE TMAU cases now, whereas the bulk of us were GENETICALLY MILD or even borderline or 'carriers'.

Paper of concept 1999 : susceptibility of heterozygotes

2.

There's 5 NEW tests in the survey of 22 (viable answers). So apart from the TMA difference trend, it's hard to make other conclusions.
TMAO levels seem similar but slightly lower. Does not have the huge variance where the OLD test had TMAO levels in the 100's. It looks like none will be over 100 in NEW test.

The 2 above comments are to do with the MACHINE METHOD ; not the 2nd part, the reference range.

SHEFFIELD TMAU Survey :
Anyone can take part in the survey if their TMAU urine test was done at SHEFFIELD CHILDRENS HOSPITAL.
This would be anyone who has tested on the NHS.

AIM : To show difference in patterns of OLD and NEW TMAU test.

LINK TO SHEFFIELD/NHS TMAU SURVEY

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By sysbodyodor

announcement, campaign, important, join in, tmau, TMAU stats, trimethylaminuria

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the 'big 3' FMO3 variants : a cheap way to test

There are 3 common variants for FMO3, that perhaps most 'FMO3 smell people' carry. The easiest and cheapest way to find out is to do the 23andme.com test, or an ancestry test that lets you download the raw data.

FMO3 is a 532 amino acid sequence, and 23andme only test about 50 of the 532, but it does test the 3 main variants at codons 158, 257, 308.
It would be interesting to see if most of carry 2 or more of these.

Estimates of carriers of the 3 main variants :
E158K : 40% people ?
E308G : 20% ?
V257M : 10% ?

DIY STUDY
We should be aiming to flood PUBMED with papers about TMAU, SysBO/Hali etc.
PUBMED is where researchers look to see whats going on.

But for now, as beggars, we can try a DIY STUDY.

Question 
Do you carry E158K, V257M and/or E308G ?

Feel free to put your result in the COMMENT SECTION.
Anon if you want ?
e.g.
E158K : AG
V257M : AA
E308G : AG

HOW CAN I TEST FOR THIS ?
A cheap and easy way to test for the 3 most common FMO3 variants is :

1. Find and buy an ancestry test that lets you download the RAW DATA ...
or buy 23andme.com test.

2. Look for these 3 variants :

rs2266782

variant known as E158K

normal : GG

variant : A

rs1736557

variant known as V257M

normal : GG

variant : A

rs2266780

variant known as E308G

normal : AA

variant : G

FMO3 PROTEIN is a 532 amino acid sequence, but there are 3 most common variants. E158K V257M E308G . Many people carry these faults (Whites carry maximum for the 3 : 45%, 25% 10% ...  estimate from memory). No-one is bothered much to find out if they are 'pathogenic' or not, but it would be interesting to see if those who identify with metabolic malodor tend to carry them in a mix.

My own current view :
I suspect most cases of 'metabolic/systemic body odor' are due to weakness in the FMO3 enzyme, but there may be other enzyme disorders too.

COMMENT SECTION
Feel free to put your result in the comment section. Anon if you want.

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By sysbodyodor

fecal body odor, fmo3, genetics, important, systemic body odor, TMAU research

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Mice on high choline diet deficient in choline : Paper

This could be a very important paper for the following malodor problems :
TMAU (if you believe that TMA is the sole source of your malodor).
Possibly 'FMO3 malodors' (if you think many FMO3 substrates cause your smells).
Possibly (in theory), if low blood choline caused smells (this is an unknown).

2017 Paper :
Metabolic, Epigenetic, and Transgenerational Effects of Gut Bacterial Choline Consumption
Romano KA et al
Unis of Wisconsin and Harvard

link to paper : low blood choline in mice (2017)

in the news : link

Summary
Choline is an essential nutrient and methyl donor required for epigenetic regulation. Here, we assessed the impact of gut microbial choline metabolism on bacterial fitness and host biology by engineering a microbial community that lacks a single choline-utilizing enzyme. Our results indicate that choline-utilizing bacteria compete with the host for this nutrient, significantly impacting plasma and hepatic levels of methyl-donor metabolites and recapitulating biochemical signatures of choline deficiency. Mice harboring high levels of choline-consuming bacteria showed increased susceptibility to metabolic disease in the context of a high-fat diet. Furthermore, bacterially induced reduction of methyl-donor availability influenced global DNA methylation patterns in both adult mice and their offspring and engendered behavioral alterations. Our results reveal an underappreciated effect of bacterial choline metabolism on host metabolism, epigenetics, and behavior. This work suggests that interpersonal differences in microbial metabolism should be considered when determining optimal nutrient intake requirements.

link to paper : low blood choline in mice (2017)

in the news : link

My interp
It seems they wanted to see how mice differed between groups that had 1:abundant bacteria that turn choline into TMA ... and 2: mice that had a cloned enzyme that blocked microbes changing choline into TMA.

The results were
The TMA-microbe rich mice had low choline blood levels even on a normal choline rich diet.
This is because the gut microbes COMPETE with the host for choline (and microbes get first go).
This caused significantly lower METHYL DONOR metabolite levels in blood and liver, as choline is one of our main methyl donors.
The low blood methyl/choline levels in blood seemed to cause behavioral problems (e.g. anxiety).

Choline
Seems to be one of our main METHYL DONORS (in the blood).
Is an important fat decongestant for the liver.
As we can make some, it was regarded a non-essential nutrient, but now it is accepted that we cannot make anywhere near the amount we need, so is in effect an essential nutrient.

Behavior problems
It's interesting they report the 'low choline blood' mice as having behavior issues such as anxiety, as many with TMAU report of anxiety.

My thoughts
I have thought this before, that low choline blood may be an issue for anyone with 'TMAU' who eats a high choline diet, or even worse for someone following a low choline diet.
As said, choline is important for the liver and as a methyl donor.

NAFLD
I do wonder if perhaps those with TMAU are prone to non-alcoholic fatty liver disease. Perhaps in general or in a particular way. Very speculative.
Many Drs feel that most westerners will have some fatty liver say over 40+, due to diet and lifestyle. But perhaps low choline could be an issue.

Appropriate tests :
1. I guess a liver ultrasound to see how the liver is. (mainstream test)
2. Choline blood test. This is not mainstream and seems very hard to find. It should be mainstream but it's not.

What can a TMAU person do to raise choline blood levels ?
It would seem impossible as the choline will be altered to TMA before it is absorbed.
One choline expert suggested phosphatidylcholine was less easy for microbes to alter, and may be worth a try (unlikely ??).
My own view is that testing for choline blood level would be the best option, so we could see if there was a 'syndrome' common to us.

TMAU low choline predicament (my theory)
2 scenarios
1. High  choline diet (normal west diet) > TMA microbes eat the choline before they are absorbed > person has low blood choline.
2. Person goes on low choline diet > even lower in blood choline level.

They cloned an enzyme in the microbes that did not produce TMA
I note they mention they had an enzyme cloned and put into microbes that stopped production of TMA.
My guess is this approach would be an obvious therapy for TMAU.
Something we should certainly investigate.
My opinion : PROBIOTIC THERAPY with CLONED MICROBES that don't carry CHOLINE-TMA enzyme is one of our best hopes.

Could low choline blood levels cause the smells ?
I guess it's possible that LOW CHOLINE BLOOD levels could cause the smells for metabolic/systemic malodors to do with related enzymes (e.g. FMO3) , but for now it must be deemed an outside chance but definitely one worth following up.

My advice for now 
Try and find a test supplier to do the choline blood test (possibly very difficult).
And perhaps a liver ultrasound to see if you have some fatty liver.

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By sysbodyodor

Body Odor, fecal body odor, fmo3, FMO3 research, important, metabolic malodor, possible future therapy, systemic body odor, systemic malodor syndrome, TMAO Research, TMAU research, trimethylaminuria

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UK Campaign : Template letter to Politicians

UK Campaign to get Politicians involved with TMAU.

Here is an idea of a campaign that people can do if they want. Involves writing to your/a MP or member of House of Lords. A main aim would be to get a TMAU All Party Parliamentary Group (chance : 5%).

When writing to a politician, the rules are :
MP : MP's may say they can only reply to constituents.
But the website says you can contact any : Link .
1 strategy is : contact your own MP first.

House of Lords : you can contact anyone.

Some random ideas of aims for the politician :
To be a TMAU 'patron'.
To form/join a TMAU All Party Parliamentary Group.
To do general things that may promote awareness/research/ease of testing.

Of course, people can write their own emails.
Find your MP : link

Example email :
Can be altered or totally changed etc.
May be of inspiration for other countries.

Example Letter (can be used/altered if you wish)

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Dear

re Trimethylaminuria (TMAU)

TMAU is the only systemic/metabolic body/breath malodor currently documented.

While the severe form is rare, the 'mild' transient type could be fairly common. The 2 common polymorphs, about 10% Caucasians are estimated to carry. This does not mean 10% have 'smell issues, but among this group a fair amount may be 'prone' to transient smells.
It also appears to be across both genders and all ethnicities.

TMAU origins (1970)
TMAU was a 'guess' at a volatile to test for a 'fishy smell' back in 1970. Since then no other smelly volatile has been tested. Most TMAU people do not identify with a fishy smell, but rather a broad spectrum of 'bowel' smells.

While many sufferers don't think TMA alone is the sole volatile, or even a main player, it should be a good biomarker of FMO3 function, and for now is the only 'volatile' to rally round the concept of 'systemic body odor'.
So for now we will focus our aims on TMAU.

FMO3
FMO3 is the enzyme regarded as meant to neutralize TMA. It is an oxidizing enzyme that neutralizes/activates many smelly volatiles/compounds in humans.
You could say TMA oxidation is a good biomarker of FMO3 function.

TMAU ignorance
Probably about 20 researchers have ever taken an interest in TMAU. None are actively interested for maybe 10 years or more.
There were 2 conferences set up in 1999 and 2002, but these fizzled out.
Probably only a handful of health professionals know of TMAU.
About 99.999% will not.
For GPs it may be higher.

A consensus among the group is :
The understanding of TMAU is very basic and the 'treatment' does not work and may be bad for your health (choline being important for liver function).
Currently nothing is being done research-wise.

A few points about TMAU
1. the person usually cannot smell themselves.
2. most cases would seem to be transient.
3. Unlike probably all other 'rare disorders', the person will start seeking answers as an adult or teen. It is not a Dr-led diagnosis.
4. The group are pretty disorganised (partly to do with shame) and could use help to get organised.

UK Political Help
Here is a list of ways a UK politician may help the TMAU cause :
In reply, you may use this list with your answer if you want.

1. Become a TMAU UK group 'Patron' (or similar title. Could be from title-only to some extra duties).

2. Form/Join a TMAU All Party Parliamentary Group.
This could perhaps be for a few meetings only, or a trial basis. Mainly to have a thorough look at the subject in the House.

3. Attend a Charles Dent UCL 'TMAU Group'  quarterly meeting.
There have been 2 meetings so far (perhaps a new NHS law ?). Since it's near the House, perhaps you could attend. Or attend one at a regional metabolic unit (so far only Birrmingham known).

4. Help in finding a broker for the TMAU test to subvert the 'NHS professional-only' testing law.
HIV testing is now available via direct-testing. Since TMAU is an 'adult' disorder, and GPs won't know of it, people want to test direct and self-pay. If you could help us in source an agreed method of testing this would take away our greatest anxiety.

5. Ask a TMAU question in the House

6. Help with publicity, advice etc.

7. Help us organise.

Or any other ideas you care to mention.

There are 2 things regarding potential treatment :
1. What could be done now.
Possibly a lot could.
e.g. using enzymes to metabolize TMA in the gut. TMA can be put down the 'methane route' by enzymes in certain microbes. Also an 'FMO3 pill' has been suggested, as most of the load may be in the gut.

2. What could be done in the future (gene therapy etc)

So probably things could be done now, which are not of interest to researchers, pharma companies etc.

Thank you

Some links about TMAU
https://youtu.be/7IPV72B4-3c
https://youtu.be/qrW_QYk6zRI
https://youtu.be/U8RriLVkXdw (severe case)
https://youtu.be/FnETAQHepX8
https://youtu.be/SN-7KWLqjMw   
https://youtu.be/4Iqb42_pVk0

http://middleeast.thelancet.com/journals/lancet/article/PIIS0140-6736(05)77067-7/fulltext
https://www.ncbi.nlm.nih.gov/books/NBK1103/

TMAU testing among a random group from Imperial College.
https://www.ncbi.nlm.nih.gov/pubmed/8893042
Back then, <80% was the '+ve' ref. range. This is now  <94% for '+ve'.
This would make 3.8% of this 421 now 'TMAU +ve'.
  

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By sysbodyodor

announcement, campaign, community, important, join in, raising awareness

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1st mention of DMB pill to block TMA

Dr. Mike Roizen, is chief wellness officer and chairman of the Wellness Institute at the Cleveland Clinic and co-writes a regular health column for the Buffalo News. In the latest column he mentions a 'DMB pill' to block TMA formation in the gut from choline.

We know that the Cleveland Clinic Heart Lab has signed a deal with Proctor & Gamble to issue an OTC product for 'TMAO management'. Until this article we had to guess it would be a 'DMB pill', but this seems the first public mention by anyone close to the researchers that this would be the case.

They also give some guidelines as to how you can get DMB naturally in your diet.

Link : Buffalo News Article

Link : Research paper Dec 2015 : DMB hinders Choline to TMA process

Link : P&G announce 'tmao management' deal : Aug 2015

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By sysbodyodor

Hazen TMAO research, important, possible future therapy, TMAO Research, tmau, TMAU research

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new Chinese paper : FMO3 gene therapy in mouse

Chinese academic research
FMO3 mutation successfully replaced by a normal copy in a single cell mouse embryo
They think it will 'cure' the mouse and each future generation
This is stage 1 (proof of concept), so probably would take years to reach a clinical therapy if that were possible
Probably the 1st time this has been tried with FMO3
A commenter tells me this is unlikely to lead to a therapy for anyone other than embryos

Link (pubmed abstract) : FMO3 gene therapy in single cell mouse embryo : China

comment :
A group of Chinese academics seem to have for some reason tried to change a mutated FMO3 gene in a mouse embryo and change it to a 'correct' FMO3 gene using gene therapy. It seems they were successful. Why they chose FMO3 is not known.

Keep expectations in context :
While it's exciting to see the concept of gene therapy for FMO3 in a mammal proven, an expert has suggested to me it is not  likely to result in a therapy for humans other than those at the embryo stage.

Still, it's an interesting development. It would be interesting know why they chose FMO3 as the gene to try, and if they plan to continue this research using FMO3.

Why FMO3 is of interest to systemic body odor :
It is my belief that FMO3 gene is responsible for what is commonly referred to as 'Fecal Body Odor', which I think is due to the build up of FMO3 substrates. FMO3 oxidizes many sulfides and amines.

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By sysbodyodor

fmo3, FMO3 research, gene therapy, important, metabolic malodor, possible future therapy, systemic body odor, systemic malodor syndrome

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