Ulcerative Colitis and phosphatidylcholine (and FBO)

There's a theory going around that PHOSPHATIDYLCHOLINE (PPC) may be a therapy for Ulcerative Colitis.
It seems that PPC plays an important role in protecting the intestine lining.

Why would this be of interest for Systemic Body Odor ?

1. A lot of people with 'fecal body odor' / TMAU report of suspecting they have  LEAKY GUT (where the gut lining is not acting as a fine sieve as it should, instead the sieve having holes and letting through bigger things to the bloodstream). 
Whether there is a connection between 'leaky gut' and 'FBO' is not known, though it seems very possible.
However, it seems most people with leaky gut do not have FBO (i.e. FBO people will be a small % of total leaky gut people),
so perhaps it is part of a FBO syndrome symptom for people prone to FBO (i.e. probably a FMO3 fault being the main reason for ending up in the syndrome).

2. PPC is a form of choline.
A speculation is that TMAU-prone people are naturally deficient in choline. 

The 2 scenarios would be :
1 eats lots of choline ... choline is altered to tma by gut microbes ....
result : lack of choline for the gut lining and for the bloodstream.
2 diagnosed and avoids choline .... not enough choline.

How much consensus does the Ulcer Colitis - PPC theory have ?
There's not many papers on it, and it seems it may be just one of those theories that has been suggested but not made it to mainstream. So in effect nobody knows.


Links of interest about the theory

Nestle have patented a PPC product in 2016 
(the big pharmas patenting 'natural' things is often a sign where the advertising for the industry will go) : Nestle PPC product.
note : when pharmas patent a natural product, they seem to have to do something to it to make it not just the natural product ... i.e. bundle it with a combo of things to make it 'unique'. 

Dr Myhill has mentioned the UC-PPC theory on her site.
Dr Myhill link
Dr Myhill is an open-minded UK GP who the GMC tried to strike off. She is aware of gut candidiasis, leaky gut etc.

Random pubmed paper on the UC-PPC theory : link

Final comment
It's interesting a theoretical connection to UC-PPC has been made, and perhaps there is a connection for FBO people too.
But for now, we don't know but can follow up.

Acronyms :
FBO : Fecal Body Odor
UC : Ulcerative Colitis
PPC : Phosphatidylcholine

Reason for posting (FBO connection) :
If people with FBO tend to have 'leaky gut', perhaps it's due to the gut microbes eating the choline and creating a lack of PPC for the gut lining (probably mostly the colon).
Example : gut microbes in the small intestine ... get first go at diet choline ... lack of PPC reaches the colon. 

Best ways to get PPC :
1. Pure(?) PPC (expensive).
2. Lecithin. About 1/3 PPC ? But also contains normal choline ?

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fecal body odor, possible future therapy

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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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Putting FMO3 through the 'drug repurpose' checklist

FMO3 has been taught that it cannot be induced as most other redox enzymes can (e.g. the CYPs).
Perhaps this thinking is because so few have investigated FMO3.
A recent paper suggested a Korean herbal mushroom may induce FMO3.

DRUG REPURPOSING :
A (new ?) method of (relatively) 'inexpensive' enzyme research is to check how drugs past their patent period to see if they may be of any use in other health conditions.

Drug Repurposing for enzyme disorders (e.g. FMO3)
For enzyme disorders this probably involves checking the reaction of  the enzyme to a list of unpatented drugs in a lab (e..g FMO3). In this case a priority would probably to be to see if it can INDUCE FMO3 (i.e. make it work harder) so you maybe get another 10-20% output.

Main benefits of Drug Repurposing (?) :
It's RELATIVELY inexpensive.
It should be reasonably quick and easy to do (? a year ?)
A lot will be known of the drugs already.  
May learn more about enzyme (e.g. a group of compounds induce/inhibit)

RESEARCHER INTERESTED IN FMO3 DRUG REPURPOSING
A researcher has shown an interest in putting FMO3 through the 'drug repurposing' check.
As usual funding would be the issue.
A opening estimate is that it may cost around $US 74,000 (probably mostly to hire someone to run the checks.)
An opening estimate is that it would take around a year.
They are looking at possible ways of getting funding but it's difficult.

It's something the community can think about.

Links about Drug Repurposing :
NIH USA website
wikipedia
101 website
findacure UK 

FMO3 and Systemic Malodor
My own interest in FMO3 is because I currently suspect it is my main suspect enzyme for most cases of 'systemic/metabolic malodor' (i.e. caused by an enzyme deficiency or overload, not hygiene etc).
FMO3 oxidizes many sulfides and amines in humans. But other enzymes cannot be ruled out.

Current possible therapies for TMAU or FMO3 'smells' :
TMA inhibition/reduction in the gut (e.g. Cleveleand Clinic working on a reducer to be marketed as a supplement by P&G. Not known when it will be available).
TMA metabolization in the gut (e.g. 'probiotic' that metabolizes TMA. Probably a 'methanogen' which will take it the methane route.)
'Gene Therapy' (probably ideal option)

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announcement, crowdfunding, fecal body odor, fmo3, FMO3 research, metabolic/systemic malodor research, possible future therapy, research, systemic body odor, systemic malodor syndrome, TMAU research

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Can FMO3 be induced by Korean mushroom ?

FMO3 experts teach that (in general ?) FMO3 cannot be induced or inhibited.
This is despite 'redox' enzymes often being induced/inhibited by foods/drugs/compounds.
A good example is a grapefruit compound greatly inhibiting enzyme CYP3A4 (discovered by accident).
FMO3 is known to be inhibited by certain indoles mainly in cruciferous veg (Cashman et al).
Also menstruation hormones have been shown to inhibit FMO3 (Cashman et al).
But still, the teaching seems to be that FMO3 cannot be induced/inhibited.

One view could be that so little is known of FMO3 (and perhaps other redox enzymes, but perhaps FMO3 is less important) that perhaps FMO3 can be induced/inhibited by compounds in food/drink/drugs. We don't know.

Paper : Korean herbal mushroom induces FMO3 
In a research paper last week, the authors seem to think they have shown that FMO3 can be induced by a Asian mushroom commonly used by Korean Herbalists.

Korean paper (University of Seoul, Seoul, Korea):
Korean herbal mushroom induces FMO3 in mice in research paper.
mushroom : Phellinus baumii

Quote :
"PBE was responsible for the induction of Fmo2, Fmo3, and Fmo4 expression. PBE also accelerated the metabolic clearance of carbendazim in vivo and so could be applied to the detoxification of xenobiotics such as drugs, pesticides, and nicotine."

pubmed link to abstract

My own view of this :
It's a one-off paper, perhaps biased to Korean herbal compounds.
I won't be looking to buy the mushroom.
The more I try herbal compounds, the worse I feel.
I think FMO3 was thought to develop in the animal/plant warfare fight, as plants developed poisons, FMO3 was developed to metabolize these (could be wrong),

But, it raises the question again about FMO3 INDUCTION as a possible therapy.

My main thought on this paper :
The notion that FMO3 INDUCTION may be worth exploring as a possible FMO3/TMAU therapy. This would be to say boost function by say 10-20%.
FMO3 induction would probably only be any use to those with FMO3 weakness/deficiency.

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fmo3, FMO3 research, metabolic malodor, metabolic/systemic malodor, metabolic/systemic malodor research, possible future therapy, systemic body odor, systemic malodor syndrome, tmau, TMAU research

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marine trimethylamine : a big source of greenhouse gas methane

It seems that trimethylamine produced in marine environments is often broken down to methane.
Methane is a main gas that cause the 'greenhouse effect' (Global warming).
Perhaps this is another reason for scientists to look at ways to block TMA formation.
Which in turn could lead to a therapy for human gut TMA formation.

TMA produced in marine environments : 
I only heard of this TMA connection. Probably marine microbes produce TMA. Apparently the TMA is broken down to methane, which is a major part of the gases that cause global warming.

I have tried to look for the % stats for sources of greenhouse gases, but not been too successful.
One site said

% methane makes up greenhouse gases : 16% (2nd after CO2).
% of NATURAL methane sources are marine : 88% (78% wetlands, 10% sea).
This does not include HUMAN sources (e.g. petrol, coal, farming).

I would guess the marine TMA is a by product of microbe fermentation, which then is broken down to methane. Ironically this has been suggested as a possible therapy for TMAU, in that some microbes would break down the TMA in the gut. I guess so few are thought to have TMAU it would not add much to the total world methane output.

But ... this means it's in the world's interest to find TMA blockers, so that TMA does not produce methane. This would probably mean interfering with the enzyme that produces TMA. Antibiotics are often 'microbe enzyme inhibitors', so it's much the same thing as antibiotics.

So maybe there is research going on to prevent methane formation from TMA to save the planet.

3 main ways TMA could be inhibited or broken down (I know of) :

1. Interfering/inhibiting the microbe enzyme that produces TMA (antibiotics often work this way).
2. 'Drugging the relevant microbes'. This seems to be the Cleveland method. They are tricking the microbes into working on a compound that is like choline but much more dificult for them to breakdown.
3. Use microbes to break TMA down via the methane pathway. Some microbes have enzymes that can break TMA down.

My thoughts on TMAU and systemic body odor
Any therapy that inhibited TMA formation or broke down TMA (e.g. to methane) would be good for anyone who thought their smell(s) were solely created by TMA. I am a bit sceptical that TMA is the only source of smells for most, so a bit worried such a therapy would not have the expected benefits. But I may be wrong.

Acronynms :
TMA : trimethylamine
TMAU : trimethylaminuria

Note :
graph and stats may be incorrect.
    

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By sysbodyodor

gut dysbiosis, metabolic malodor, metabolic/systemic malodor, possible future therapy, systemic body odor, TMAU research

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Bacteroidetes don't produce trimethylamine from choline

 2012 paper suggests bacteroidetes phyla are poor at degrading choline to trimethylamine.
Firmicutes, Actinobacteria, and Proteobacteria can produce TMA.
Ubiome suggest Firmicutes make up 60% of normal flora, Bacteroidetes 30%.
My own Ubiome results average (of 4) were Firmicutes 70%, Bacteroidetes 26%.
My own opinion, not enough known of the gut flora for me to have an opinion.
This post more a 'for your information' post, rather than any 'breakthrough'.
Perhaps others should try stool DNA testing.

The new Phillips/Shephard TMAU-FMO3 overview paper mentioned a 2012 paper which they seemed to have great credence for. The research in the paper proved TMA could be produced from choline by certain gut bacteria flora phyla (Firmicutes, Actinobacteria, and Proteobacteria) but not from Bacteroidetes.

Quote from Phillips/Shephard/Fennema paper

Free choline is absorbed throughout the small intestine and is subsequently integrated into cell membranes or actively taken up by the liver, where it can be converted to betaine, phosphocholine, or lecithin (Zeisel, 1990). High amounts of choline may exceed the absorptive capacity and pass through to the large intestine, however, where it is metabolized to methylamines by microbial action (Zeisel et al., 1983). Choline is a quaternary ammonium compound containing a trimethylammonium moiety. Thus, it can act as a precursor for TMA (Zeisel et al., 1989; Chalmers et al., 2006). The bacterial conversion of choline to TMA involves the cleavage of the carbon-nitrogen bond of choline, producing TMA and acetaldehyde (Hayward and Stadtman, 1959). Craciun and Balskus (2012) proposed that a glycyl radical enzyme CutC (EC 4.3.99.4), encoded by the bacterial choline utilization gene cluster (cut), might act as a choline TMA-lyase to catalyze this initial step in choline degradation (Fig. 1). This was confirmed by demonstrating that deletion of cutC in Desulfovibrio desulfuricans abolished the ability of the organism to produce TMA from choline. Bioinformatics analysis revealed cutC homologs in 89 bacterial genomes. The homologs are not distributed evenly among the major bacterial phyla of the human gut, being present in Firmicutes, Actinobacteria, and Proteobacteria spp. but absent from Bacteroidetes (Craciun and Balskus, 2012). Table 1 shows bacteria known to be associated with formation of TMA via choline degradation.

This is the paper they refer to :
Microbial conversion of choline to trimethylamine requires a glycyl radical enzyme

Firmicutes and Bacteroidetes seem to make up the bulk of the gut flora. There seems to be different opinions on what that % make-up should be for a healthy gut.

Ubiome suggest the healthy gut should have about 70% Firmicutes and 30% Bacteroidetes.

My own Firmicute/Bacteroidetes ratio :
I have tested with Ubiome 4 times.
In 3 samples my Firmicute was slightly higher than normal. Bacteroidetes was slightly lower.

My view on the knowledge of the human gut flora :
I would suggest if you compare it to the history of USA, it may be around the year 1620. Perhaps I'm wrong, but my impression is so little is understood of the gut flora (Oct 16). I'm hoping technology has caught up and we will be at around year 1900 in the next few years.

My view on my own results :
I will not be excitedly trying to alter my firmicute/bacteriodetes ratio, though may look around for info. It seems that bacteroidetes are not the type usually put in 'probiotics'. Possibly partly as they are so 'sensitive' (and die easy in oxygen). Possibly there is no 'bacteroidetes' probiotic on the market. The general view seems to be taking 'prebiotics' is the best hope of feeding bacteroidetes.

Perhaps others can do the stool DNA test :
Since the stool  DNA test is relatively cheap, and sometimes they do special offers (e.g. 3 for 1), perhaps others with systemic body odor/halitosis can do the test and mention anything they want about the results in the comment section of this post.

Stool DNA test suppliers :
Ubiome (choose citizen science)
American Gut (also 'UK Gut')

These are the 2 best known suppliers. Thankfully, they are consumer health friendly, and not health learning obstacles as is the case with normal DNA tests, urine tests etc. The spirit of the testing would be that it may be not very useful, but perhaps will be in hindsight.    

What's this to do with systemic body odor ?
My own view is that most cases of SBO are probably due to enzyme weaknesses, probably the bulk of which are due to sub-par FMO3 enzyme function. But I also think gut dysbiosis will be a common factor in 'FMO3 body odor', probably as part of the syndrome, and perhaps often the 'tipping point'.

Currently TMAU is the only acccepted form of systemic body odor. My own view is that 'FMO3 body odor' can mean smelling of any FMO3 substrate rather than just TMA, and many of the volatiles produced in the gut are probably FMO substrates. Although this paper was about TMA, perhaps bacteroidetes can't produce other FMO3 substrates, but who knows.

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fecal body odor, gut dysbiosis, metabolic/systemic malodor, my results, possible future therapy, stool dna, systemic body odor, systemic malodor syndrome, TMAO-CVD, tmau, TMAU research

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

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How much DMB for TMAU ?

What daily dosage of DMB should a TMAU patient take to block TMA formation in the gut each day ?

Answer (estimate, in theory) : about 10-20g DMB a day (divided into doses) 

About this answer :
This is an estimate by a very respected CVD expert in a recent overview paper of the TMA-oxide - atherosclerosis connection proposed by Hazen et al in 2011.

Answer is based on Mouse studies for atherosclerosis :
The answer is not based on humans taking DMB as trials have not reached that stage. It is an estimate based on extrapolating the dosage given in mice studies. So you could say it is a 'expert estimate based on mouse studies' given the current info.

The estimate is generally from this overview paper : link

Acronyms

DMB :  3, 3 dimethyl-1-butanol
TMAO : trimethylamine-n-oxide
TMA : trimethylamine
CVD : cardiovascular disease
FMO3 : flavin mono-oxygenase enzyme (isoform 3)

About DMB :
DMB in this case refers to 3, 3 dimethyl-1-butanol.

Atherosclerosis and TMA-oxide theory :
Put forward by Hazen et al of Cleveland Clinic in 2011. My impression is that the theory is that TMA-oxide may be the main factor in the development of atherosclerosis.

Connection with TMAU :
Since TMAU is proposed as being a malodor caused by TMA, any research that may block TMA formation in the gut would be a potential therapy. This is an obvious target for the 'atherosclerosis researchers' to aim for. So TMAU patients should be incidental benefactors of this approach.

Where do you humans get TMA from ?
TMA is smelly so is not normally consumed by humans. Nor is it a metabolite from human metabolism. It's only real source in humans is gut flora altering certain compounds in the diet (e.g. choline, carnitine, lecithin, TMA-oxide in fish).

The 'TMA blocker' story so far :
Hazen et al lead research into the TMAO - CVD theory. In Nov 2015 they published a paper showing DMB blocks TMA formation in mice (gut).

How long until a 'TMA blocker' drug is available ?
Cleveland Heartlab have already signed a deal with Proctor & Gamble to market an 'over the counter' TMA-blocker drug. It is not known when this will be available. I am currently presuming it may be DMB based, but perhaps they will find an even better 'TMA-blocker'.  

How can you get DMB now ?
DMB is a natural compound in things like balsamic vinegar, olive oil, red wine etc. I do not know how much you would need to take to get 10-20g daily of DMB. My own view is that these foods are probably bad for people with FMO3 issues, as they will likely contain many other FMO3 substrates that may end up causing smells (probably indirectly after being altered by gut flora).          

My own view :
I am very optimistic about a 'TMA-blocker'. But my own belief is that people with an FMO3 issue probably smell of all FMO3 substrates and not just TMA. So that concerns me but I am still optimistic. Also FMO3/TMAU was a very neglected disorder, but now TMA metabolism in humans is on the center of radars for atherosclerosis researchers. I will certainly buy DMB when available. If I thought TMA was the only malodor problem I would be ecstatic.

It also shows how TMAU/FMO3 has been a neglected disorder, as this therapy is an obvious concept which was never looked at for TMAU. Now that it is proposed to be connected with CVD we can expect lots of research into TMA metabolism.

My feelings on this (in tags) in relation to metabolic/systemic malodor :
optimistic, excited, cautious, research leads could appear from anywhere now, TMA metabolism is on the radar bigtime.

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By sysbodyodor

DMB pill, gut dysbiosis, Hazen TMAO research, metabolic/systemic malodor research, possible future therapy, research, systemic body odor, systemic malodor syndrome, TMAO Research, TMAO-CVD, tmau

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Popular Science article on TMAO / CVD theory

A good article for the public on the timeline of the trimethylamine-oxide and cardiovascular disease connection theory, posted on the website Popular Science.

The first paper on the TMAO - CVD theory was published in 2011.
The notion being that TMAO may be a major factor in causing CVD.
Published by Dr Stan Hazen et al at the Cleveland Clinic.
Research still ongoing, including finding that DMB inhibits TMA production in the gut.
This would be very good for those with Trimethylaminuria.
A deal is signed with Proctor & Gamble to market a DMB product which hopefully will also be beneficial for TMAU.

Link : Popular Science article on TMAO  

The team went as far as to define particular bacterial genera responsible for the condition.
.....
The authors themselves suggest there may be a route forward by trying to target the TMAO pathway in microbes.

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Hazen TMAO research, possible future therapy, TMAO-CVD

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DMB food products for TMAU : bad ?

Future 'DMB pill' is exciting development for TMAU
But I am not keen on takings foods with DMB in them
Foods rich in DMB probably are high in choline and other FMO3 sulfides/amines

It seems likely that Cleveland Heartlab and Proctor & Gamble have agreed to make and sell a 'DMB pill' as a protective heart disease supplement. It's unknown when this will be available. This is being sold as a 'TMAO management' supplement. It will likely reduce TMA levels in the human gut, which is great news for those who feel TMA is the sole source of their systemic malodor.

DMB is an alcohol naturally present in certain types of foods, such as 'extra virgin olive oil' and 'balsamic vinegar'. I have a feeling these foods will be bad for people with FMO3 issues.

Reasons :
1 : They are probably high in choline ? If you think TMA is the only source of your odor, then I presume taking high choline foods may be contra-indicative.

2 : They are probably full of FMO3 substrates (sulfides and amines) which might also cause malodor or feed malodor causing bacteria.

3 : Other vague reasons such as concern about acidity.

I tend to find I have a natural aversion to these type of foods, which I suspect is due to them being full of FMO3 sulfide/amines and maybe feeding bacteria that produce sulfide/amines. I had a go with the balsamic vinegar but after a week or 2 started getting migraines.

DMB pill :
Presumably the DMB pill will not have choline or the other FMO3 sulfides/amines, so I will certainly be trying that when it arrives.

FMO3 malodor :
As I always say, I do not think those with FMO3 issues have a problem solely with TMA, so I am always sceptical about something that may help only with TMA.

Links :
P&G announce TMAO management deal Aug 2015
Buffalo news : A DMB pill ?         

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By sysbodyodor

DMB pill, fmo3, Hazen TMAO research, possible future therapy, TMAO Research

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new paper : Meldonium and TMAU ?

New paper on how drug meldonium might help with CVD.
The question is does it stop trimethylamine formation ?
This new paper is probably due to all the interest in TMA-oxide and CVD

This is a new one-off paper by Latvian researchers : Feb 2016
Pharmacological effects of meldonium: Biochemical mechanisms and biomarkers of cardiometabolic activity.

Link : meldonium TMAO abstract
Quote from paper :  Here, we briefly reviewed the pharmacological effects and mechanisms of meldoniumin treatment of heart failure, myocardial infarction, arrhythmia, atherosclerosis and diabetes.

Note : I only have access to the abstract, not the full paper

What has this to do with TMAU ?
It looks like meldonium somehow interferes with TMA-oxide formation. I don't know if this means it also blocks trimethylamine formation. If it did, then I guess it would be similar to the hoped the Cleveland Clinic have for the natural compound DMB.

My current opinion :
I guess it's worth checking up further but I'm not overly interested. Partly because I suspect people with 'FMO3 body/breath malodor' probably have issues with many sulfides and amines, not just TMA. Plus with DMB hopefully being available sometime in the future and being OTC, I'm hoping this will do the same job.

wikipedia : meldonium

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By sysbodyodor

possible future therapy, TMAO Research, TMAO-CVD

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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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Prof Colin Dolphin post about potential TMAU therapies

Prof Colin Dolphin is an English academic who has had a long-term interest in FMO3 enzyme and TMAU. I believe he was one of the team who documented the FMO3 gene coding sequence in the late 1990's

Occasionally Dr Dolphin writes posts on the tmau.org.uk forum for TMAU people. Indeed he has been given his own thread there : Questions for Dr Dolphin

Recently he posted an in-depth post about potential therapies for TMAU and the obstacles.

Dr Dolphin's tmau.org.uk post about potential TMAU therapies : link

My non-expert interpretation of  the post :

The post suggests 3 potential TMAU therapies and their obstacles :

1. Using bacteria that can oxidize TMA in the gut to TMA-oxide
Obstacle : these bacteria tend to be aerobic (need oxygen) and do not tend to survive well in oxygen-deprived areas (such as the gut)

2. Genetically modifying gut-friendly bacteria with enzymes that oxidize TMA to TMA-oxide
This would seem more possible, but the TMA-oxide may be quickly 'reduced' back to TMA by other gut bacteria enzymes. So it would be a cycle of TMA-TMAO-back to TMA.

3. A drug that blocks the production of TMA from choline/carnitine etc.      
Again seems possible but may involve taking many drugs and not really practical ?

Dr Dolphin mentions a final idea where the aim would be to eliminate TMA-producing bacteria in the gut (?). He also mentions how he applied for a grant to check the gut flora of TMAU population against normal people but the application was unsuccessful.

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By sysbodyodor

possible future therapy, tmau

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Herbal Hill deodorant range : A project to raise funding

Herbal Hill

Regular readers may be aware that a small research company known to the metabolic malodor community, Trinzyme, is looking to develop a therapeutic that may be helpful to the metabolic malodor community.

However, much funding will be needed to do the research. For that reason they are looking at various ways to raise funding for the research. For that reason they have developed a range of deodorizing products that are aimed at helping with malodors. The brand is called 'Herbal Hill'. The founder is in touch with us about this project.

Herbal Hill products are in their very early stages of development.
link : Herbal Hill website   

Perhaps one way of looking at this project is that it is in it's 'alpha stage' and of course it is a means to an end in that it is hoped to be a source of funding for a therapy in the long-term.

Secrecy :
It is the standard practice for research companies to be very coy about making information public, especially in early stages, due to concerns such as patent theft etc. So it is is difficult to make much information public, hence the secrecy. It is frustrating for everyone but pretty standard for the industry. This explains the lack of public info. For instance, quite often those with info are asked to sign confidentiality agreements before discussion.

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By sysbodyodor

announcement, fecal body odor, Herbal Hill, metabolic malodor, personal treatment, possible future therapy, systemic body odor, tmau, TMAU research, Trinzyme

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TMAU webinar about the potential therapy 'FMO cream'

TMAU webinar June 2015
Hosted by : Rob at rareconnect.org
Guest speaker : Jake Wintermute PhD
Webinar title :  Synthetic Biology and Microbiome Engineering approaches for Trimethylaminuria



My understanding of this subject :
It could leads to a 'FMO cream' that is currently theorized as being based on genetically modified harmless skin organism rich in FMO that would oxidize TMA and other FMO substrates on touch.

The end product could be cheap and easy to manufacture but it may take millions to develop

A funder would need to be found for such a project (probably a pharma company)

As FMO needs oxygen to thrive, currently it is thought it could only realistically be a skin cream and not a 'probiotic' that could be taken orally as the gut is mostly a very 'oxygen deprived' area.

Other speculative thoughts :
Perhaps it would not need to be a 'probiotic' cream but rather just a FMO rich cream or some other oxidizer that is capable of oxidizing FMO3 substrates. FMO3 substrates can be oxidized by other metabolic pathways (not usually in humans).

It would probably not have to be specifically FMO3 enzyme, but merely a FMO enzyme (there are are 6 types of FMO enzymes known : FMO1 - FMO6). FMO's hopefully have a broad overlap in function in this situation.  

The perfect scenario would be some sort of pill that oxidizes FMO3 substrates in the gut.  

It is a very exciting potential therapy. Lets hope we can get the project going.

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By sysbodyodor

crowdfunding, fecal body odor, fmo3, FMO3 research, possible future therapy, systemic body odor, tmau, TMAU research, TMAU skin cream project, video, videos, webinar

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TMAU webinar : Monday 8 June 6pm Paris time

rareconnect.org webinar

Monday 8 June

6pm Paris time

Webinar title :

Synthetic Biology and Microbiome Engineering approaches for Trimethylaminuria (TMAU)

Guest Speaker :

Jake Wintermute, Ph.D.

Postdoctoral Researcher

Paris Descartes University

in the rareconnect.org Webinar Room : click here
to check your local time : google '6pm Paris time'

Jake is a biologist at the Centre de Recherches Interdisciplinaires in Paris. In the summer of 2014, Jake challenged a team of undergraduates to use genetic engineering to improve human health and well being. The result was "The Smell of Us," a collection of new biotechnologies to control body odors by engineering the bacteria that live on human skin. The team's work was awarded prizes for "Best New Application" and "Best Art and Design" in an international genetic engineering competition can be seen online (http://2014.igem.org/Team:Paris_Bettencourt).

In this webinar, Jake will discuss his group's work-in-progress on TMAU. The primary pathology of TMAU is the appearance of trimethylamine (TMA) in the sweat. Many microbes are capable of metabolically neutralizing TMA, including some that occur naturally on human skin. Genetic modification may enhance this ability, creating microbial products to attenuate the symptoms of TMAU. Jake will discuss his scientific progress and the specific challenges of developing a genetically modified organism for human use.

Link : TMAU project for IGEM 2014 

Webinar will be free and recorded

rareconnect.org Webinar Room

My own comment :

This is a realistic potential therapy for 'FMO3 malodor' on the skin. It would be better if it could result in 'internal solutions' such as a probiotic that would oxidize FMO3 substrates before being absorbed into the bloodstream, but because the microbe need an oxygen rich environment they would not survive in the gut. But who knows, maybe one day. So skin products with these microbes is a decent 'bandaid' and supposedly cheap and easy to make. Unfortunately it needs lots of funding to create such a product, as no doubt Jake will explain. It should be a great webinar. Don't miss it (but it will be recorded and put on youtube).

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By sysbodyodor

announcement, join in, media, possible future therapy, tmau, TMAU research, webinar, webinar announcement

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IGEM 2014 TMAU project : French Team neutralise trimethylamine with GM microbe.

Click to visit link

A group of French graduates based at Paris Descartes University genetically engineered a skin bacteria to make it rich in an enzyme (trimethylamine mono-oxygenase) that oxidizes (neutralizes) trimethylamine to TMA-oxide. The experiment was for an annual international genetic engineering contest for undergraduate teams (IGEM 2014) and was proven to work in a lab (i.e. the concept of proven 'in a test tube').

Link : Something Fishy (IGEM 2014)

The undergraduate team are based at
Centre for Research and Interdisciplinarity (CRI)

Faculty of Medicine Cochin Port-Royal,

South wing, 2nd floor
Paris Descartes University

The team seem to be called 'Paris Bettencourt' for the annual IGEM competition. Perhaps most of their funding is by the Bettencourt Foundation (Bettencourt being the founding family of L'oreal).

The experiment :

The experiment was to take an enzyme that oxidizes trimethylamine to TMA-O from a microbe and put the enzyme in a 'human-friendly' micro-organism. It was one of 4 projects they did in relation to body odor and how genetic engineering may help. In this project, they took a TMA oxidizing enzyme (trimethylamine mono-oxygenase) from a non-human bacteria (Ruegeria pomeroyi) and put it in  E.coli and Corynebacterium striatum, a skin-native bacterium.

Results :

It seems that they were able to put the TMA oxidizing enzyme into E Coli and the Corynebacterium striatum which is a skin-native bacterium 

They put the genetically modified TMM rich E Coli in a TMA liquid and it did oxidize much of the TMA to TMAO.

Possible applications :

They mention the possibility of a TMM-rich bacteria added to a spray or cream to put on the skin and eliminate TMA on the skin.

Presumably another possibility is to make a GM  skin-native bacteria rich in TMM enzyme that could be nurtured to live on humans (?)

Possibly an internal therapy answer could be formulated , such as a TMM rich probiotic.

Final comment :

The big question is whether these types of answers are only possible now or could have been found earlier but have not due to no interest in TMAU/FMO3 by the research community overall. It is also not known if the above project is being followed up on. 

The project says TMM is not just TMA specific, so perhaps it will work on other/all smelly substrates which may be the same as FMO3 substrates.

Desulfovibrio desulfuricans :

The project also seems to 'blame'  Desulfovibrio desulfuricans bacteria as the cause of degradation of choline to TMA. This is the first time I have heard of this connection. It is interesting because it has been a bacteria of suspicion and is mostly known for producing hydrogen sulfide (H2S) from sulfates. Many people with metabolic malodor and TMAU report of smelling of 'rotten egg' which H2S is one known possible source of this smell.           

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By sysbodyodor

experiment, FMO3 research, possible future therapy, research, TMAU research

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Rich investors needed for Trimethylaminuria research project

MEBO Research is in touch with a biotech start-up that is researching a therapy for genetic trimethyaminuria (TMAU) and 'overload' TMAU (secondary TMAU).

It is normal in the medical research sector and invention sector for companies to be very secretive about their projects (due to patent concerns etc), so very little can be said about the project at this stage. The only info that can be given is that the research is now at a stage where it needs £/$ millions, so realistically any investors would need to be very rich. As is normal with this type of arrangement, any rich investor could find our more about the project by signing a confidentiality agreement.

A press release was written by Karen of MEBO Research which can be seen on the MEBO blog. Below is an abridged version of the release :

Are there any affluent philanthropists or serious investors out there willing to back a promising therapy for Trimethylaminuria?

Wealthy individuals are sought for investment discussions with a trusted, UK-based, biotech company looking to raise capital for continued research into a very promising TMAU therapeutic. This treatment could potentially handle both primary and secondary versions of TMAU. It is also a great opportunity for investors to have a stake in a company actively looking at therapeutics for other disorders and diseases.

Confidentiality would be assured, and any interested parties would be invited to sign a confidentiality agreement before being shown data about the project.

Please e-mail MEBO ( maria.delatorre@meboresearch.org or karen.james@meboresearch.org ) who will put you into contact immediately with the relevant company.         

links :
Full press release on MEBO Research website
MEBO Research blog
MEBO Research website

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By sysbodyodor

announcement, FMO3 research, possible future therapy, research, TMAU research

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New Hazen paper : Fecal transplant mice get TMAO artherosclerosis

A recent theory suggests TMA-oxide may cause atherosclerosis. TMA-oxide is oxidized trimethylamine. Hence a therapy is likely to try and reduce or neutralize TMA levels produced in the gut

New paper from Dr Stan Hazen et al re TMA-oxide and CVD  :  Fecal transplants in mice

Dr Stan Hazen research has often been reported here as since around 2011 his lab has suggested a strong connection between TMA-oxide plasma levels in humans and risk of atherosclerosis (CVD). This research may have an added benefit to metabolic malodor sufferers who feel trimethylamine is the sole cause of their malodor, as any resulting therapy may mean neutralizing or blocking TMA production in the gut, thus the person will absorb no TMA into their bloodstream.

Fecal transplant in mice to give them atherosclerosis
In this paper they seemed to use 2 strains of lab mice and gave their fecal transplant microbes to a strain of mouse that was microbe free in the gut. One strain of mouse seems to have a high TMAO 'flora', whereas the other does not. It seems that the transfer of the feces from the high-TMAO producing mouse caused the donor mouse to develop CVD. So they seem to be saying risk of CVD is highly likely to be due to a TMA rich gut flora and when they transfered this flora to a mouse with no gut flora, the mouse then developed CVD.

This seems to be more evidence for the TMAO-CVD connection theory, though I guess it is still a theory to be given a consensus in the CVD research community.

The paper says at the end :
Gut microbes may thus represent a novel therapeutic target for modulating atherosclerosis susceptibility.

So they are suggesting that altering a TMA rich gut flora should reduce the chance of CVD, but also for the TMAU community it should mean reducing or negating or blocking TMA in the gut, possibly by altering the gut flora. This may lead to anti-TMA probiotics, for example. It is also very likely that research will be done to see which microbes generate TMA in the gut.    

     

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By sysbodyodor

fecal body odor, gut dysbiosis, Hazen TMAO research, metabolic malodor, possible future therapy, research, systemic body odor, systemic malodor syndrome, TMAO-CVD, TMAU research

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