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Saturday, October 22, 2016

New Phillips/Shephard TMAU & FMO3 overview paper

Profs Ian Phillips & Elizabeth Shephard 
New TMAU-TMA-TMAO-FMO3 overview paper by Prof Phillips, Shephard (and Fennema).
Good overview for health professionals and the public.
Possibly no new info.

Prof Phillips and Shephard of London are probably at this time the most prominent all-round 'experts' on FMO3 and TMAU in humans. Whilst their knowledge is great, perhaps this is partly as there are so few FMO3 experts and so little interest in FMO3, especially it seems at this time (apart from the TMAO - cardiovascular disease theory).

Occasionally they tend to publish overviews of TMAU and FMO3. Perhaps with a student as a project ? (in this case Fennema ?)

Here is their latest TMAU-FMO3 overview in full :
TMAU and FMO3 overview 2016

Quotes from the paper :

On the FMO family of enzymes :
Flavin-containing monooxygenases (FMOs) catalyze the NADPH-dependent oxidative metabolism of a wide array of foreign chemicals, including drugs, dietary-derived compounds, and environmental pollutants. Humans possess five functional FMO genes: FMO1, 2, 3, 4, and 5. The main site of expression of FMO3 is the liver.

On FMO3 :
The importance of FMO3 in detoxification and bioactivation of xenobiotics has recently been reviewed. The FMO3 gene is highly polymorphic and genetic variants that are common in the general population are known to influence drug metabolism.

On FMO3 and TMA :
Of the five functional FMOs of humans (FMOs 1–5), only FMO3 effectively catalyzes the conversion of TMA to TMAO

On recent interest in TMAO :
Recently, there has been much interest in FMO3 and its catalytic product TMAO. This is because TMAO has been implicated in various conditions affecting health, including cardiovascular disease, reverse cholesterol transport, and glucose and lipid homeostasis.

Carnitine and TMA :
Gut bacteria are thought to cleave the 3-hydroperoxybutyryl moiety from L-carnitine to produce TMA 

Typical TMA diet levels in humans :
Individuals who consume a ‘typical’ Western diet will produce, via the action of gut bacteria, about 50 mg of TMA/day, most of which (∼95%) is converted to TMAO, which is excreted in the urine.

On DNA faults in FMO3 gene promoter region (not tested in DNA test) :
Polymorphic promoter-region variants of the FMO3 gene have been identified that severely reduce transcription in vitro, whereas others increase transcription but the impact of these variants on expression of FMO3 in vivo has not been validated.

On TMAO and proposed connection with diseases :
Recently, TMAO has been implicated in a number of disease states as a cause, consequence, or biomarker of the disease. It has been suggested that an increase in the plasma concentration of TMAO, as a consequence of production of TMA from dietary supplements of choline, carnitine, or TMAO by gut bacteria and its subsequent oxygenation by FMO3 in the liver, increases the risk of cardiovascular disease. TMAO has also been implicated in chronic kidney disease, colorectal cancer, and in impaired glucose tolerance in mice fed a high-fat diet and a TMAO supplement; however, lower plasma concentrations of TMAO have been associated with inflammatory bowel disease and with active versus inactive ulcerative colitis.

On TMAO causing CVD and other diseases :
The implication that TMAO itself is a causative factor for cardiovascular and other diseases is controversial.

On TMAO as a possible biomarker in diseases :
An alternative explanation for high levels of TMAO associated with cardiovascular disease is that the concentrations are indicative of dysfunction(s) elsewhere and that TMAO is not the mediator but is merely a marker of the disease.

On TMA-producing bacteria :
Although TMA-producing species are widely distributed across bacterial phyla, they are more common in Firmicutes and relatively scarce in Bacteriodetes (Table 1). Consequently, decreasing the ratio of Firmicutes to Bacteriodetes would be expected to reduce production of TMA from dietary precursors. A low ratio of Firmicutes to Bacteriodetes is associated with a healthy microbiome (Ley et al., 2006); thus, such alteration of the gut microbiome would promote general health as well as aiding in the management of TMAU.

On TMA in the gut flora, and blockers etc :
One approach to altering the composition of the gut microbiome is exogenous supplementation with beneficial species (probiotics); however, a recent study found that the multistrain probiotic VSL#3 had no effect on the increase in plasma concentration of TMAO in individuals fed a high-fat diet (Boutagy et al., 2015). Another proposal is the therapeutic use of methylotrophic strains of archaea (archaebiotics) that use TMA as an energy source (Brugère et al., 2014), although this has yet to be tried.

A further possibility is the selective inhibition of bacterial enzymes that catalyze reactions involved in the production of TMA. Candidates are TMA reductase, CutC, and CntAB, which respectively catalyze TMA production from TMAO, choline and carnitine (Fig. 1). For instance, 3,3-dimethyl-1-butanol, a structural analog of choline, inhibits microbial CutC and reduces the plasma concentration of TMAO in mice fed diets rich in choline or carnitine (Wang et al., 2015); however, most of the choline eaten by humans is in the form of lecithin, which is not a good dietary source of TMA (Zhang et al., 1999); thus, the efficacy of the inhibitor for reducing TMA production in human gut is unclear.

On TMA in gut flora :
Bacteria from several phyla produce TMA from dietary precursors but are more common in Firmicutes and scarce in Bacteriodetes.

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