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Wednesday, April 1, 2009

hypothesis: genetically modified probiotic for trimethylaminuria

As mentioned in an earlier post, it seems probably already technically and probably financially very feasible to develop a probiotic enriched with FMO3 enzyme that could colonise the colon and neutralize trimethylamine on-site in the gut. It has been mentioned before, as a hypothetical treatment for TMAU:

As to the future, one may envisage some new approach to treating or managing the condition quite apart form the obvious one of gene therapy with replacement of the human gene for FMO3. Alternative approaches might embrace the following: use of gut absorbents, such as charcoal or ion-exchange resins; modify the gut flora to reduce the bacterial species responsible for the conversion of precursors to trimethylamine; incorporate micro-organisms "engineered" with human FMO3 into the gut flora, to oxidize any trimethylamine released to its non-odorous N-oxide; provide riboflavin supplements, a precursor of the FAD cofactor for flavin monooxygenase function, in an attempt to maximize any residual activity; and finally, from the cosmetic point of view, the development of "malodor suppressants" in hygiene products to disguise the offensive smell of trimethylamine.

Mitchell/Smith TMAU paper 2003
Probably the main reason it hasn't been acted upon is a perceived lack of a need and profit (from the hypothetical manufacturers point of view), of which neither are likely correct. Smell problems associated with FMO3 function are likely very underestimated (the opening paper for the 2002 TMAU workshop estimated maybe 1% could be 'at risk' of TMAU). While gene-therapy is in it's infancy and may have unforeseen downsides, genetically-engineered-bacteria therapy would not have the same possible systemic downsides, since it's the bacteria that has been altered instead. however there could be unknown side-effects (for instance, would it effect the gut flora composition compared to normal people ? The gut flora is likely a powerful metabolic factor, as mentioned by Dr Manning in his interview).

Scientists are currently researching the same principle (genetically engineered bacteria for the gut) for HIV. Presumably the bacteria in this case are stopping the virus from getting to the absorption surface. In the case of TMAU, it would only need to be present in the gut too, so as to neutralize trimethylamine, although it would in theory detoxify all FMO3 substrates present in the gut (such as other sulfides, amines, phosphorus compounds etc).

The HIV research seems to have begun around 2005.
Scientists have genetically modified bacteria living in the human body to produce chemicals that block HIV infection. Although the research is still at an early stage, they hope it could eventually lead to a practical and cost effective new way to combat the virus.

http://news.bbc.co.uk/2/hi/health/4692905.stm
There also seems to have been research with this concept in relation to other gut disorders such as Crohn's disease. There has been no feedback in our initial enquiries regarding this concept.

Note: this would not affect systemic FMO3 function other than reducing the amount of FMO3 substrates absorbed from the gut. It would be no good for internal FMO3 substrates detoxification (endogenous substrates), of which there are many. Normally most FMO3 substrates can be detoxified other slower routes. For systemic FMO3 function, either gene therapy would be a hypothetical answer, although there has been speculation that if a FMO3-bacteria could be absorbed (for instance through a nasal spray) it may produce enough FMO3 to circulate in the bloodstream and have a noticeable effect.


related links:
http://www.pnas.org/content/102/34/11993.full?ck=nck

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