Metabolomic Profiling for Systemic Body Odor

This post is meant to be thought provoking.

Need to discover all volatiles/metabolites that cause systemic body odor.
Once discovered, these volatiles will be known as the biomarkers for the diagnostic test,

Trimethylaminuria (TMAU) was 'discovered' in 1970 by Denver Dr's. A patient's mother had said sometimes their child smelt of fish (they had another serious disorder) and the Drs decided to test the TMA level since they knew this volatile smells of fish.

So the only volatile currently tested for systemic/metabolic body odor came about in an anecdotal case and no-one has looked any further than this since (that's if they even look for TMA). It goes to show how much 'sufferers' need to further the understanding of systemic body odor themselves, as no-one is looking.

Personally I think maybe 1% population could be 'prone' to  transient systemic body odor, probably 'fecal body odor'. Maybe even more. I would guess it may well be the biggest 'undiscovered' metabolic disorder left.

Metabolome Testing
It's only about 18 years since the FMO3 enzyme DNA code was fully documented. So genetics is still at a fairly new stage. Along with genetics, the other science that compliments it is human metabolomics, the study of the metabolites in humans. Again this is a fairly new science, both in knowledge and the technology needed. It does seem to be maturing now.

Metabolomics for understanding systemic body odor
When a disorder is fully understood it will have a 'phenotype' test where they look for the known biomarkers in human fluid to see if the person has the disorder. Since the concept of systemic body odor has not been documented, it will currently need a test like an exploratory metabolome test to look for higher levels of metabolites (probably volatiles). Once they document the biomarkers for systemic body odor, you can then use these biomarkers as the 'disorder test'.

How to do a Metabolome test
First you need to make sure it will look for the 'suspect' metabolites. In the case of SBO, these will probably be sulfide volatiles, but I wouldn't rule anything out for now. I would guess most labs would do a very broad spectrum exploratory test.

examples of 'suspect' volatiles I would look for in systemic body odor :
dimethylsulfide
dimethyldisulfide
methanethiol

Personally I would be looking at FMO3 substrates, as I reckon this enzyme may be to blame for the biggest group of SBO sufferers.

Ease of testing
Since it's a new science, I am unsure of how many labs do metabolomic testing. It's probably not a regular in the mainstream medical health industry (e.g hospitals). Probably more a test done at University labs where trends for testing probably start off.

Also, as usual most labs will probably insist only a Dr can order the test. The usual obstacle to testing used in the medical health industry. Hopefully someday the law will change to allow people to self-pay any test.

Testing Centers :    
Looking around I am not aware of too many potential test centers. A quick google search came up with these possible leads :
Uni of Alberta
Baylor Clinic
Human Metabolome Technologies (Boston)  

The system :
I would say at the moment, expect the system to be against you.

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By sysbodyodor

Body Odor, fecal body odor, metabolic/systemic malodor, metabolic/systemic malodor research, systemic body odor, systemic malodor syndrome

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Paper : firmicutes produce more TMA than bacteroides

New paper :
The aim seems to be to see how trimethylamine precursors (choline in foods etc) affect TMA-oxide levels in a group of healthy young men. The conclusion seems to be that those with a higher ratio of Firmicutes / Bacteroide gut bacteria generate more trimethylamine from precursors.    

The paper was done with the 2011 Hazen et al TMA-oxide - Heart Disease theory in mind, which links TMA-oxide with blood vessel damage.

Research paper :
Trimethylamine-N-oxide (TMAO) response to animal source foods varies among healthy young men and is influenced by their gut microbiota composition: a randomized controlled trial

Cornell University

Link

What's this to do with systemic body odor ?

My own current opinion is that most cases of systemic/metabolic body odor are probably to do with FMO3 enzyme and it's substrates. Most cases are probably an FMO3 weakness that means overload of FMO3 substrates at any time. The volatiles produced by gut bacteria are probably often FMO3 substrates. Currently the only volatile accepted as causing systemic/metabolic body odor is trimethylamine. With the interest in TMA-oxide since 2011, it's likely a TMA blocker will be a therapy. 

My opinion :
My 2 main points are :

1. This seems to be a one-off research paper. From a lab with no previous history on TMA-oxide. Cornell is greatly respected but I don't know how significant or accepted the result will be.

2. I feel there is too little known about the gut flora overall. Both in knowledge and in testing. So for me I can take or leave the info. It may someday prove to be important, but for now I don't know.

My Ubiome stool DNA results :

Previously I wrote how my Ubiome Stool DNA result was lower than average in firmicutes. For now I wouldn't take this as my norm. As I say, I think not enough is known about the gut flora for me to think anything. So I won't be making any changes due to this result. I'm waiting for the Procter & Gamble TMA-blocker to come to market.

Summary :
It's too speculative for me to make any conclusions from this at the moment. I will keep a lookout though.

Other Links :
Cornell in-house article on TMAO (4Aug16)

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By sysbodyodor

stool dna, TMAO Research, TMAO-CVD

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FMO3 codon 285 'silent mutation' : N285N

The DNA code for FMO3 is a 1596 nucleotide sequence (532 x 3).
This 532 x 3 nucleotide sequence creates a 532 amino acid sequence which creates the FMO3 protein.

codon	3-nucleotide code	resulting amino acid
283	gta	valine
284	ttt	phenylalinine
285	aac	asparagine (N)
286	gat	aspartic acid

Silent codons
Often a wrong nucleotide inserted can mean an incorrect amino acid created in the codon sequence.
FMO3 example : the common substitution at codon 158 results in E158K. It should be an E but came out a K (E stands for glutamic acid, K for lysine). Many people have this common mutation (estimates : 20-40% caucasians). It is currently regarded as 'benign' on it's own, but this may in future turn out to be wrong.

However, there are also substitution mutations where the wrong nucleotide is inserted but the resulting amino acid is correct. They are known as 'silent' (presumably as they are presumed not to affect function).

FMO3 example : N285N  (N = asparagine)

N285N turns out to be a seemingly common 'silent mutation' in ethnicities.

The question is, can 'silent' mutations affect function ?

At the moment, who knows ? . We have to assume mainstream experts will currently say no (?)

Common 'silent mutations' in the FMO3 gene coding region:
codon 147
codon 285 (N285N)

My own FMO3 'coding faults'
You can have faults in the coding part of your FMO3 DNA, but also faults in the non-coding parts (introns, promoter region, exon parts that do not code).
Ignoring my non-coding parts (as I don't have the info), I know the most important part : my own 532 coding sequence.
Note : Your 'coding region' can be 'normal' but you can still have TMAU due to faults in the non-coding region.

I carry 3 common SNP's :
E158K
N285N
E308G

FMO3 is about efficiency :
Bad analogy : 100m runner. Say a runner has small handicaps, e.g. broken arm. This may not effect his run much (say 94% normal). Whereas a broken leg may make the run 20% normal. It's the same idea with most FMO3 faults. They may affect function minimally, or you may have a few compounded small gene faults which may drag you down to 85% sometimes. FMO3 should be working at say 95%+.

So at the moment I am presuming my 'small faults' combine to affect FMO3 function either to a small % or perhaps intermittently. Personally I always feel lousy (e.g. migraine) and suspect it may be to do with FMO3 function as FMO3 is regarded as one of the group of heavy-duty 'detoxifier' enzymes (in the case of FMO3, to detoxify abundant small sulfides and amines of a certain structure). It seems not that much is known of the 'detoxifier enzymes', with the main group (the CYP450's) being identified as the main players, and FMO3 regarded as lesser players ... but perhaps this will later prove to be incorrect,

The main reason for the post was to point out the notion of 'silent' SNP's.

Commonality of N285N :
This paper from 2006 mentions N285N and it's commonality in some ethnicities.
2007 FMO3 paper :
Identification and Functional Analysis of Common Human Flavin-Containing Monooxygenase 3 Genetic Variants

Summary :
N285N silent mutation is currently regarded as having no effect on the efficiency of FMO3 enzyme function, and is quite common. It will most likely not be listed in a clinical FMO3 gene test as they tend to list only mutations they feel may have an affect. To see if you have N285N, you would need a copy of your full 532 codon FMO3 code (or at least, any variations from 'normal' listed).

What has this to do with systemic body odor ?
My own current belief is that FMO3 enzyme may be implicated in most cases of systemic body odor. SBO is not currently a properly documented disorder, with only TMAU being given as a diagnosis of the SBO concept ... perhaps a gross underdiagnosis.

Other links :
2006 paper : silent mutations
2014 article : silent mutations
Stanford 2015 article
Codon amino acid abbreviation code list
The main different types of mutations in a gene
wikipedia : FMO enzyme family

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By sysbodyodor

fmo3, FMO3 reference, systemic body odor, systemic malodor syndrome

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P&G TMA-blocker will be stronger than DMB

In a magazine article in April about the gut flora, this statement was made

"Hazen says DMB, the olive-oil molecule from his study, is too weak to put into a pill. He’s working on creating stronger inhibitors."

So it looks like something stronger than DMB will be used by the Cleveland Clinic for their 'TMA-blocking supplement' which will be marketed as an over-the-counter product sometime in the future by Proctor & Gamble.

Full article : Statnews April 2016

DMB : 3,3 di-methyl-1-butanol (wikipedia)
DMB is of interest to the TMAU community as it's been shown to block the formation of trimethylamine in the gut (of mice) by gut flora. It's naturally present in olive oil, balsamic vinegar etc.

TMA-oxide and atherosclerosis theory (wikipedia)
In 2011 Dr Hazen et al at the Cleveland Clinic put forward a theory that tma-oxide may be a factor (perhaps main factor) in the development of atherosclerosis. Since then the lab has been researching this and putting many papers forward to enforce this. In 2015 they said that DMB was an inhibitor of TMA in the gut of mice.

Analogs
Quite often an approach in humans to damage is to find an 'inhibitor' which stops a damaging checmical reaction. in the 'TMA precursor (choline etc) -- TMA -- TMA-oxide' cycle of reactions, the aim is to block TMA formation. 'Inhibitors' or often refered to as Analogs, and in this case they found that DMB is an inhibitor of TMA formation (from choline etc).

Better inhibitor than DMB
So it seems they are looking at stronger inhibitors than DMB to put in the P&G 'supplement'. The final product will not be a 'DMB pill'. This is even better news I guess. A heart-disease expert recently reviewed the evidence on the 'TMAO- atherosclerosis' theory and estimated that perhaps 10-20g of DMB (in divided doses) would be needed to block TMA in the gut. But something better than DMB is even better.

Possible 'resistance' like antibiotics ?
One potential 'danger' pointed out is that the article seems to say that the DMB probably alters the gut flora composition, which might mean 'immune' bacteria then become dominant. Very much like antibiotic drug resistance. DMB is not lethal to gut flora like antibiotics, but nevertheless the same resistance may occur due to flora composition change.

Good news for Trimethylamiuria people
Obviously blocking TMA formation in the gut is great news for those with TMAU. First documented in 1970, up until this interest in 'TMAO-atherosclerosis' there has been almost no interest in TMA metabolism in humans. Now suddenly TMA metabolism in humans is of main interest in human health research.

My view (in terms of systemic body odor) :
A 'TMA-blocker' pill sold over-the-counter by Proctor & Gamble will definitely happen. Anyone who thinks trimethylamine is the sole cause of their systemic malodor should regard this as possible a very good therapy for 'TMAU'. But personally I feel TMA may not be the only volatile that causes what I call 'FMO3 smells', so I am a bit worried. But maybe TMA is a main factor (indirectly) and blocking TMA may relieve the pressure on FMO3 (for example). Anyhow, I will definitely be trying it and could be regarded a 'banker' hopeful therapy that will happen while we worry about other hopes.
 

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By sysbodyodor

DMB pill, gut dysbiosis, metabolic malodor, metabolic/systemic malodor research, possible future therapy, systemic body odor, TMAO Research

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