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MEBO - UBIOME study 2018

NCT03582826
ClinicalTrials.gov
MEBO Gut Microbiome Study
Funded by uBiome Research Grant

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

Dynamics of the Gut Microbiota in
Idiopathic Malodor Production
& PATM

Started May 2018 - Ongoing

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

NO LONGER RECRUITING

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Metabolomic Profiling Study
NCT02683876

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


Note : Stage 1 is Canada only.
Return cut-off date : passed
Analysis can take 6/8 weeks
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Sunday, May 3, 2009

Christodoulou TMAU research proposal : Methylophilus methylotrophus as a TMAU probiotic

In the trimethylaminuria research proposal by Dr Christodoulou et al, he proposes trying 2 methods of treatments (albeit, on mice). The first is using PCT124/Ataluren to see if it can negate a nonsense mutation in primary trimethylaminuria. This would only be of benefit (if it works) to the subset of sufferers who have primary TMAU due to nonsense mutations.

The other method would potentially be of benefit to all sufferers. It has long been mentioned that if a bacteria/probiotic could detoxify trimethylamine in the gut, then it could do the (gut) detoxifying for the person. The long-speculated suggestion was for a bacteria engineered to be rich in FMO3. Dr Christodoulou is proposing to use a known harmless bacteria (Methylophilus methylotrophus) that, instead, detoxifies trimethylamine by an alternative pathway. Rather than FMO3 (which changes it to trimethylamine-n-oxide, the trimethylamine will be altered to dimethylamine and formaldehyde by an enzyme in the bacteria (trimethylamine dehydrogenase).

Not knowing anything of the metabolic differences, a first impression is that an FMO3 enriched bacteria would seem preferable, since the by-products of the other pathway don't seem too nice-sounding (dimethylamine and formaldehyde). Also, FMO3 is a commonly used enzyme, dealing with probably 1000s of substrates that are amines, sulfides, or phosphorous containing. Most of these substrates can go a slower more complicated alternative route if necessary, but in humans, TMA cannot (hence possibly the reason researchers feel TMA is the only smell issue with FMO3). Since most seem to say they can smell of all sorts of smells, you have to wonder if the whole xenobiotic-metabolizing-enzyme system is becoming 'backed up' with other typical FMO3 substrates, with TMA being a baseline problem? Or perhaps TMA is an inhibitor of these enzymes? For these types of reasons, it would seem preferable to have an FMO3-rich bacteria, but maybe this is not currently possible, or for logistical reasons. So Dr Christodoulou has gone for a bacteria known to have trimethylamine-dehydrogenase enzyme, an enzyme which humans don't possess.

However this may be unimportant and we are grateful for any research. It would be interesting to know if this bacteria is available. It is possibly used in the agricultural industry as a source of food for pigs. But nobody likely knows the potential averse reactions in humans. At this stage, we can only wait to see how the mice get on, although these 2 treatment stages aren't planned until year 3.

Other strategies for metabolising TMA in the small intestine:

Anaerobic gut bacteria can contribute to the trimethylamine load in patients with TMAU by enhancing the metabolism of choline in food to trimethylamine in the gut1. As stated above, one form of therapy of TMAU, albeit in more extreme cases, is to treat patients with antibiotics aiming to reduce the intestinal load of these bacteria. However, the antibiotics that need to be used have potentially serious side effects, and so can only be used for short periods of time.

An alternative strategy for reducing the gut trimethylamine load would be to colonise the gut with harmless bacteria that are capable of metabolising trimethylamine. One such micro-organism is Methylophilus methylotrophus. This is an aerobic monoflagellate bacterium that uses methanol as the sole source of carbon and energy16. It was initially thought to be of potential commercial value in the single-cell protein production industry, but it proved to be a nonfinancial venture. When cultured in trimethylamine, the enzyme trimethylamine dehydrogenase is induced, which converts trimethylamine to dimethylamine and formaldehyde17. Extensive studies have shown that this micro-organism is non-pathogenic and non-toxic in animals18, 19. Therefore colonisation of the gut with Methylophilus methylotrophus in individuals with TMAU could be of potential therapeutic utility.


2 comments:

Anonymous said...

Is there a cure then?

Jan 26, 2013, 7:27:00 PM
blogcontributor2 said...

Hi

If you mean this,the funding was never raised so it was never tried.

In theory there are probably similar things that could be tried to reduce or metabolise TMA production, although currently it is not known if anyone is trying to do this.

Jan 26, 2013, 11:31:00 PM
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