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Wednesday, January 18, 2012

Using an engineered probiotic for colitis : Possible use for FMO3 deficiency ?

An interesting concept to deal with FMO3 deficiency has been the idea of delivering amounts of FMO3 to the gut in a genetically engineered probiotic so that it can detoxify FMO3 substrates present in the gut, particularly in the colon (eg certain sulfides and amines). This would hopefully reduce the toxic load being absorbed into the bloodstream, reducing the need for such a load to reach the hepatic FMO3. It has also been speculated that perhaps FMO3 can be taken orally on it's own without having to be put into a probiotic, though this has never been tried and the consequences are unknown.

Going back to the notion of engineered probiotics, recently a paper was published that demonstrated this technique in mice to be used in gut inflammation disorders. With the engineered probiotic, the mice seemed to respond well.


BACKGROUND:
While cytokine therapy and the use of immunosuppressive cytokines such as transforming growth factor-β (TGF-β) offer great potential for the treatment of inflammatory bowel disease (IBD), issues concerning formulation, stability in vivo, delivery to target tissues, and potential toxicity need to be addressed. In consideration of these problems we engineered the human commensal bacterium Bacteroides ovatus for the controlled in situ delivery of TGF-β(1) and treatment of colitis...

...RESULTS:
BO-TGF secreted high levels of biologically active dimeric TGF-β in vitro and in vivo in a xylan-controlled manner. Administration of xylan in drinking water to BO-TGF-treated mice resulted in a significant clinical improvement of colitis, accelerating healing of damaged colonic epithelium, reducing inflammatory cell infiltration, reducing expression of proinflammatory cytokines, and promoting production of mucin-rich goblet cells in colonic crypts. These beneficial effects are comparable and in most cases superior to that achieved by conventional steroid therapy.

CONCLUSIONS:
This novel drug delivery system has potential for the targeted and controlled delivery of TGF-β(1) and other immunotherapeutic agents for the long-term management of various bowel disorders

http://www.ncbi.nlm.nih.gov/pubmed/21830271

The first mention of the notion of FMO3 enriched probiotics playing a role in FMO3 deficiency seems to have been in the excellent overview of TMAU by Smith and Mitchell in 2003

..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-odorousN-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...

Smith/Mitchell 2003 TMAU overview

Links:
flavin containing monooxygenase 3
genetically engineered probiotics

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