News & Views on Systemic Body Odor and Halitosis such as trimethylaminuria TMAU. If you have fecal odors or bowel odors it may be metabolic/systemic

2 January 2021

my (current) opinion on FMO3 MALODOR (imho Fecal Body Odor)

My CURRENT opinion (self-styled expert) on the cause of 'FECAL BODY ODOR' (it's actually worse than that, as it can be fart smells, rotten egg, burnt rubber .... it's sulfide smells from the colon) 

It's all to do with FMO3 ENZYME (weakness, overload etc)

(my view hasn't changed much, but my opinion is more fixed and precise)

Type 1 genetic : SEVERE RARE (the fish smellers)

The FISH SMELL is the SEVERE TYPE.
Only severe's will tend to have a fish smell.
This is because most have enough FMO3 to keep the fish smell down, but severe's (and perhaps some overloaders) don't.
Fish Smellers may smell to a Dr as they are severe (and so smell more often)

This is RARE.
Its a tiny part of the community.
It will be people with RARE SEVERE VARIANTS (e.g. 153)
It ties in with previous estimates by any expert/health professional who has taken a look at TMAU. 

TYPE 2 genetic : the (quite) common FECAL BODY ODOR type

This group is quite large.
Estimates could be like 1%-4% or more ???  AT RISK
Its based on haplotypes / compound mixes of the common FMO3 SNP's 
(e.g. 158 (40% Whites ?) 308 (20% Whites ?) 257 (9% Whites ?)

There are 7 variants where at least 1 ethnicity has +1% carriers.
Mixes of these 7 probably make up the bulk of the community.
The common 7 variants OFTEN vary by ethnicity, though 158 seems common among all (esp White and Black). 
308 is not so common in Blacks (3% compared to Whites 20%).

Variants, it depends how bad they are predicted/proven to be ?
Maybe 40% carry 158, but how bad is it ?
Geneticist will say harmless ? But is it ?
Maybe it will turn out an issue in CFS often ?
FMO3 is an ignored enzyme.

Variants, silents and introns :
Variants change an amino (158 308)
Silents are wrong nucleotide, but amino ends up correct (eg 147, 285)

Perhaps SILENTS can play a (bad) role when part of a mix ?? (i.e. with 158,308 etc)
Its all about little flaws adding up.

Introns :
this is non-coding part of a gene.
Perhaps if you have enough flaws they add up is 0.5 points etc ??
Introns play no part in code, but is seems variants there can have negative affect. 

TYPE 2 will also be prone to FMO3 GUT DYSBIOSIS

I suspect FMO3 plays a role in the colon (cells) as an on-site oxidizer.
Current thinking is FMO3 needs an oxygen environment and so cannot survive in colon, but who knows ?  
It will also mean it keeps the microbiome in a good state.
With lower FMO3 you will be prone to sulfide dysbiosis, and so bigger load for FMO3 to oxidize.

So type 2s have bigger gut sulfide load + lower FMO3 to oxidize it (lose lose)

So Type 2s are PRONE to this dysbiosis by default

TYPE 2 (genetic) Smells 
not fish (it seems). Seem to have enough FMO3 to deal with that
But perhaps TMA is the main load, causing the overload of sulfides etc (???)

Type 2 (genetic) smells are 
Fecal
Fart
Rotten egg
Burnt Rubber
endless list of horrible sulfides (maybe a few amines thrown in)

POINT 3
It might be LOW CHOLINE MALODOR ??

person eats lots of choline ... its turned into TMA in the gut = Low blood choline 
health professional puts them on low-choline diet = low blood choline

Choline status could be easily checked in a trial, but no-one interested.
Currently Health Systems don't seem to check choline (nor do known private labs).
Maybe ask your Dr/Metabolic clinician to annoy them.


POINT 4
Best current test for FMO3 Malodor ... FMO3 GENE TEST.
Result will say you carry a few common SNPs
Result will say this is NORMAL.
If done by a Health System, result will not include silents, some common SNPs, introns.

Health system : you do not have FMO3 problem
Probable Truth : if you carry 2 or more of the SNPs (haplotypes etc, 158 308 257 etc) ... FMO3 is probably the root cause, but you are not a SEVERE. (unless you maybe have 153 etc)  
 
SUMMARY ...
Main (new) point is imho the FISH SMELL is probably severe type (type 1), the person will have a rare severe variant (at least 1, plus also maybe some of the common 7)     
Type 1 genetic will be rare, and maybe 1-5% of the community ?
Type 2 genetic will be many, and like 95% of cases

Type 2 genetic will probably pass any current TMAU URINE TEST
They will maybe have 2 or more of the common SNPs, plus maybe a silent.
Many introns are very common (e.g. 75%, 50%) but perhaps they tend to carry more of them too.

Perhaps there are no 'overload' TMAU cases that are not genetic.
Perhaps any who are the current TMAU2 have small flaws ?

CURES/THERAPIES :
Probably loads (for most) for decades but no-one interested 
1. Drug repurposing trial ?
2. Eat (protected) FMO3 ? (the load is in the gut)
3. Eat FMO3 rich probiotics ? 
4. Check choline status ? (it might be 'low choline malodor syndrome')  
5. TMA-blockers (P&G are creating one for consumer market)
6. Other things (like health companies wanting to stop poop smell for consumer market)
7. Need an ESENSOR (as most can't smell it ... imho the brain ignores blood smells)
   
TMAO is now associated with artery damage (Cleveland hypothesis 2011)

How Best to Help Yourself
1. Contact your Politician. Health System does not care.
2. Tell health professionals you smell of poop, not fish. This won't help really, but at least they will see a trend.
3. Tell health professional you identify with TMAU, you think its FMO3, but its probably sulfides.
4. Ask someone to conduct a choline status study (e.g. metabolic clinician).
5. Pressure Metabolic Clinicians especially.  

Do not think of health professionals having your best interest. Need to badger them.
But political pressure is best.

Bit of a ramble but meant for anyone seriously interested.
It is just an opinion (a hypothesis) to documenting the cause of what is known as 'FECAL BODY ODOR' (though its actually more smells than that !)
   

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23 June 2018

someday : 'fecal body odor' debate in Parliament ?

Someday politicians could be having a debate about 'fecal body odor' 'metabolic body odor' 'systemic body odor' 'TMAU' in their parliament / senate / congress etc.

Recently a 'M.E.' debate was held in the UK Parliament.

Here is the UK 'request for debate' stage (to show the interest of the MPs of all parties)


 
Someday they could be talking about (choose your label) :
FECAL BODY ODOR
METABOLIC / SYSTEMIC BODY ODOR
MET-BO
TMAU
etc

It shows that politicians are very aware of M.E. and realise it is ignored.
Perhaps the same politicians who have sympathy with ME would be sympathetic to FBO.

What can be done ?
One could write their local politician about FBO etc.
e.g. MP, Senator, Rep, UK, USA, Canada, anywhere.

Also could look for politicians sympathetic to M.E. etc and write them.

Health systems and researchers are not interested in FBO/TMAU etc.
They need to be forced by politicians to act.

In UK
MPs make All Party Parliamentary Groups.
M.E. seems to have a group (2016) ME APPG

Full video :
Recent UK Parliament M.E. debate (in backroom, not main chamber)


Other awareness ideas :
Bus ad
Write to high profile 'TV Dr's/naturopaths'


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12 June 2018

FMO3 survey to understand patterns in community

I would suggest its better to do the FMO3 DNA test first rather than the Urine test.
It's important we see a pattern of FMO3 variants to use as proof and to understand.

The FMO3 coding part is a 532 amino acid sequence (3 x 532 nucleotides)

Ways to FMO3 DNA test :
Full sequencing (hard to access)
23andme (23 of the 532 codons)
Geneology dna tests (raw data ... about 25 codons ?)

Ethnicities often have 'haplotypes', certain groups of variants.

Below is an 'ad-hoc' quick FMO3 survey.
The results will be made public.
Intention is to look for patterns.

Link for the survey (e.g. to share) https://tinyurl.com/y7kyxzpc



Problems with DNA testing :
If via a Health system lab, they don't give the 532 data, but rather mention variants they think important. They are likely very conservative.
If via 23andme : You need to look in the raw data. Not too hard. E.g. search FMO3. 

Why FMO3 ?
FMO3 oxidizes 1,000s of substrates, that are sulfides. amines, or phosphate containing.
It is my current opinion that FMO3 weakness is the cause of most cases of 'fecal body odor'.
Most enzymes have only maybe 1 to 10 substrates to alter.
But the oxidizer group, which includes FMO3, have 1,000s of substrates to alter. 



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23 April 2018

Paper : TMAO converts back to TMA by bacteria

New paper :
Metabolic retroconversion of trimethylamine N-oxide and the gut microbiota.
Reading Uni UK.

About :
How some gut bacteria can break down TMAO back to TMA.

Full paper : Link

Significance to TMAU :
Probably not that significant as most gut TMAO in humans would likely be from eating fish. Fresh fish contain a lot of TMAO.
Not unless the TMAO comes back from the blood into the bowel.
This would be known as TMAO reduction (to TMA).
Probably not the same as cleaving TMA from choline etc.

Main reason for posting the paper is bits and pieces of mild interest.
Not read the paper proper so the points below may be inaccurate.

Possible interesting points re TMAU

It says :
Enterobacteriaceae are the main TMAO reducers ?
Most of the TMA creation was around the lower small intestine and cecum, not the colon ?
Most of the TMA is absorbed, very little in feces ?

Not really much connection with TMAU but good to know research is going on about the gut flora and TMA metabolism.


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1 April 2018

Comment on the NEW UK TMAU Test (Sheffield)

NEW TEST

In early March the 'Sheffield TMAU Test Team' kindly gave a lecture at the UCL Adult Metabolic Unit in London to a group of TMAU patients.

Below is an abridged version of the lecture
Sheffield NEW TMAU Test lecture slides (hosted on SCH site)

The main 'changes' seems to be :
Almost no TMAU2 cases (this used to be a very large group).
A large amount that had no detectable TMA (this is a new category).
A big drop in TMAU1 cases (?)

Here's some thoughts on the old/new test.  The views may be inaccurate.
Maybe over time things will become clearer.

Interference :
A main reason given for the 'changes' is that the old test was prone to interference.
In effect saying there were many false 'positives'.
This may be true or not, but for some reason IMHO the old test was better at spotting the METBO smell disorder most people have.
Perhaps the incorrectly detected volatiles were a better measure of the disorder the person has.
Who knows ?

OLD TEST


Liberal (and fair) new ref range :
The new test has what could be termed a 'very liberal reference range' (TMAU1 = <94%).
The old test was very conservative. (TMAU1 = < 79%).
With the new test ref-range, old test results would maybe have been 70% positives ... which I think is likely in a group who identify with systemic body odor.
Instead, the new test gives 16% positives.

TMA and TMAO levels
New TMA levels are way lower than the old test levels :
TMAO seems slightly lower but not much,
but TMA levels in general seem way lower on average.

You'd think there would be many more TMAU1's but it's not the case.
Old test 'positive' rate : around 33%
New test : around 16%

I accept that the new test may be more 'precise' at detecting TMA, but have long guessed most metBO cases are not based around TMA anyway.
TMA should still be an excellent biomarker of FMO3 function, but I have doubts too.

For some reason I think the new test now misses the vast majority of FMO3 smellies, the 'mild genetic transients'.


New Sheffield ref ranges.

TMA:  < 7.7 µmol/mmol creatinine
TMANO: < 119µmol/mmol creatinine
% N-oxidation: > 90-94%


Old Sheffield ref ranges.

TMA:  2.5 - 10 µmol/mmol creatinine
TMANO: 17 - 147 µmol/mmol creatinine
% N-oxidation: > 79%


TMAU2
A new explanation for the lack of TMAU2's is that in fact most might be 'mild genetic TMAU1's'.
I tend to agree with this theory.
I don't think 'normals' ever fall into the 'zone'.

New big group of 'non-detectable TMA' cases
Of 722 tests, 147 had no detectable TMA level.
The old test thought that a normal human would have at least >2.5umol TMA.
I tend to agree with the old test. Humans probably have some TMA in them.

Old and New test can't be compared
It's been said the old and new test can't be compared.
Both use Gas Chromatography/Mass Spectrometry and have the same scale for ref range.
So to me they are directly comparable.


What can be done to change the UK system ?

TMAU / metBO people are poorly served by their societies.
It will be by miles the biggest 'rare disorder' (i.e. not rare).
Any Health Service test labs that offer the TMAU test regard it as very charitable and to question is an insult.
Their set-ups suit the department workers.

Any change to an acceptable minimum standard will have to come from politicians.
Examples :
People can write to their MPs
e.g.
Let people test direct and self-pay for the TMAU test.
If only one lab tests, it is the national lab, and has a  responsibility to do more ... e.g. have a website and contact point.

Perhaps if anyone lives in the Sheffield area they can contact their politician to insist of minimum levels of help.
Ultimately the test should be done at all NHS 'rare disorder' test labs.     

TMAU / MetBO people worldwide should always remember our current help is below a minimum standard.   

That said, thank you to Sheffield CH for the slides and lecture.




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31 March 2018

North Carolina Uni tests for TMAU

Update :
This lab will let a Dr order the test as long as :
1.the patient is DE-IDENTIFIED for the sample.
2. the patient name is not disclosed.
i.e. they do not find out the patient details.
This would be a special arrangement by your Dr.
Insurance will almost definitely not apply.
It seems the ZEISEL LAB in Uni of North Carolina has a TMAU urine test, but it's set up strictly for researchers.

Test (urine) :
Trimethylamine and its oxide TMAO,
and CHOLINE.
(tbc ... not clear of choline is just the blood test)

Where :
ZEISEL LAB at CHAPELLHILL site, Uni of North Carolina

Cost : 
currently $208

Access to test :
It's set up strictly for reserarch purposes, requiring e.g. ...
A researcher with an IRB and Uni proof etc.
Unidentified samples.
Not a CLIA test.

So sadly for the community, the test is there but currently beyond reach.

TMAU 'Profile' test
Choline would be added to the TMAU test, as TMAUers are probably naturally deficient in choline before and then extremely deficient after testing.
So TMA, TMAO and CHOLINE would make a natural TMAU PROFILE TEST.

This test is like 3 times cheaper than the Denver TMAU CLIA test.

Hopefully someday we can find a way to access this test.


Other ideas for tests for a TMAU PROFILE :
Maybe a sonar of the liver to check for NAFLD fatty liver. This can be caused by choline deficiency.

The lab also test Folic acid status and a few other choline metabolites including methionine.


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25 March 2018

Potential 2 year FMO3 Study

A Metabolic Consultant has offered to do a 2 year study on 2 ways to improve FMO3 function.

Part 2 (part 1 in the paper). would focus on NONSENSE mutations, which are rare but usually severe.
Part 1 would focus on MISSENSE mutations, which will be the vast majority of TMAU1 cases.
Speculation suggests that TMAU2 cases could also possibly be mild missense cases.

I make MISSENSE part 1 as this will be the vast majority
e.g. E158K E308G etc

What's needed for the study to happen :
A TRUSTED PARTY to set up a CROWDFUNDING PAGE.
Youcaring is suggested as it's free and has few clauses : Youcaring
But any crowdfund site would do.

Study cost : about $US 100,000

Why ? 
Someone will be hired fulltime for 2 years.
Plus equipment etc

Study basics :
1. Using ATALUREN to see if it helps with NONSENSE mutations.
2. DRUG REPURPOSING : going through many drugs in FMO3 cells to see if any improve FMO3 function. This would help with MISSENSE mutations.

Drug Repurposing often happens in pharma-world.
Such as viagra originally being for heart disease.
Often multi-uses are found for drugs accidentally.

The study needs funding

A best option would seem to be crowdfunding.
possible scenarios :
A trusted individual or collective to take on the crowdfund.
e.g. A group of respected older women ?
or
Using the REACT Fund as a trusted proxy (if they let the consultant have the money)
RE(ACT) TMAU FUND
or
Any other ideas

Fuller outline of the potential study

 Time-lines for the project (at half-yearly milestones):


Study component
Year 1
Year 2
Generation of a range of FMO3 nonsense and missense mutations and the in vitro tools for their functional analysis in a cell culture system
X
X


Evaluation of the efficacy of read-through agents and other drugs in our in vitro cell culture system, including acquisition of structural and functional evidence


X
X

2.  Repurposing of existing drugs:

TMAU is caused by a functional deficiency of the FMO3 protein.  Many of the missense mutations of the FMO3 gene are hypomorphs, ie there is some residual activity of the enzyme, albeit not enough to prevent the accumulation of TMA.  Augmenting expression of the faulty gene through activation of the FMO3 promoter, could improve overall FMO3 enzyme expression, with significant amelioration of the disorder(19).  Libraries of known therapeutic agents are commercially available that can be used in high throughput screening assays to screen for possible opportunities to “repurpose” the drug, ie apply it in a therapeutic context for which it was not originally designed.

We propose to use the cell culture models developed by us in a high throughput screening approach to identify new potential therapeutic agents that could augment expression of the FMO3 gene.

If we demonstrate potential in vitro efficacy of specific well-established therapeutic agents, we will then potentially be in a position to move to clinical trials in patients with trimethylaminuria, particularly if the therapeutic agent identified has an existing therapeutic track record in other disorders.

1.  Read through of premature termination mutations: (Nonsense mutations)

Premature termination or nonsense mutations arise as a result of a single nucleotide change in a gene where the change leads to the conversion of an amino acid in the protein sequence to a premature stop codon.  Such mutations often result in the protein losing most if not all of its functional capacity.  It was recognised a number of years ago that aminoglycoside antibiotics can force the transcriptional machinery to read through the premature stop mutations, and allow the normal protein to be made, restoring activity of the protein(13).  However, aminoglycoside antibiotics have significant side effects and are not a viable therapeutic option.  More recently a new class of drugs has been developed that has the capacity to promote read through of premature termination mutations, and which appear to be totally non-toxic(14).  One in particular, PTC124, has been shown to result in the production of normal dystrophin in the mdx mouse model of Duchenne muscular dystrophy(14), and has been used in clinical trials in human subjects with cystic fibrosis, with clear benefits being found(15).  In addition, there are a number of other read-through agents currently being evaluated for potential in vitro and in vivo use. An inborn error of metabolism like TMAU would be an excellent candidate for this type of therapy, as an increase of enzyme activity to perhaps as little as 10% of normal should be enough to overcome the biochemical block.


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15 March 2018

Sulfide and Methane production in humans : FBO connection ?

This is a very speculative post.
It is said that in the HUMAN MICROBIOME, that people tend to be either :
Sulfate reducers (so, sulfide producers)
or
Methane producers

It's not clear how much is known about the microbiome but the word seems to be the population is split 50/50 being either dominant in Methane or Sulfide producer.

It would be interesting to see if those who identify with FECAL BODY ODOR and the spectrum including fart, raw cabbage etc tend to be in the SULFATE REDUCER group.
Nothing has shown up in Ubiome results yet, or at least what I have seen.

Methane in humans would tend to be produced by Archaea microbes, which funnily have been suggested as a potential TMAU therapy (they would break down TMA).

Sulfide producers would probably be mostly due to DESULFIBRIVIO bacteria, but possibly other sources.

It seems odd that in 2018 humanity still doesn't seem to have documented what cause stool smells exactly. Good guesses can be made but there seems to be no consensus and few papers.   


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TMAU Stories

systemic BO/halitosis important links

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Do you have systemic body odor ?

FMO3 Survey Form

FMO3 DNA test result survey
for those who have FMO3 DNA tested
survey still OPEN

TMA blocker pill (links)

P&G - Cleveland press release aug 2015
1st mention of 'DMB pill' dec 2015
FMO3 DNA testing
Update Aug 17 :
Genos is back with it's EXOME test
link

Note :
Exome/Genome testing may be better option than single gene testing.

See this post : link

Note : Genos Exome Testing.

Exome testing is almost the same price now as single gene testing. Also Genos is consumer friendly, which standard DNA labs are not.

So the blog offer to test solely for FMO3 is almost obsolete, and so no longer offered.


Does Genos fully sequence FMO3 gene ?

At the moment it is not clear, but hoped this will become clear over the next few months

Note : possible 'wild west' way of testing FMO3
Use an ancestry dna site and rummage through the raw data

TMAU Webinar #5 : Preti et al