Primary & Secondary Secondary TMAU, updates on treatment & research 2020

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PUBLICATION:

"Treatments of trimethylaminuria: where we are and where we might be heading", Aaron C. Schmidt and Jean-Christophe Leroux, of the Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, Zurich, Switzerland,

• Presents a good description of Primary and Secondary TMAU,
• Discussion on the pros and cons of TMAU treatment options and ongoing research directly or indirectly related to TMAU,
• Discussion on ongoing research directly and indirectly related to TMAU.

Definition of Secondary TMAU:

Secondary TMAU
Often referred to as acquired or sometimes transient TMAU, people becoming afflicted with secondary TMAU might show prolonged symptoms. This form of the disorder can occur in a variety of different scenarios. Treatment with choline in Huntington’s and Alzheimer’s diseases has been associated with the development of a strong fishy body odor [26,27], and is a classic example of precursor overload where the enzyme is unable to completely oxidize the TMA burden. Liver failure and portosystemic shunting of the blood can also result in increased TMA levels, owing to interference with first-pass metabolism [28,29]. Other factors that have been reported to cause or exacerbate the condition (including primary TMAU) encompass menstruation [30,31], asymptomatic viral hepatitis [32] and testosterone treatment [33], and have been reviewed elsewhere [4].
Treatments of trimethylaminuria: where we are and where we might be heading

Treatment options discussed:

1. Limiting precursor intake
2. Protonation of TMA
3. Targeting gut metabolism
4. Antibiotics
5. Probiotics, including Methanogenic archaebiotics, Fecal microbial Transplantation (FMT).

Some ongoing research studies:

Fecal Microbial Transplantation

In the Fecal microbial transplantation (FMT) discussion, the authors present findings reported by Dr. Stanley Hazen, MD, et al. while studying FMT in the context of CVD [105]. Since Dr. Hazen's focus is on on the results of TMAO levels in the blood, as opposed to TMA levels, even though TMAO levels in serum leveled out after 16-20 weeks of FMT, it does not necessarily translate into reduction in TMA. Therefore, further research with TMA being the focus, as opposed to TMAO, is needed.
Gregory, J.C. et al. (2015) Transmission of atherosclerosis susceptibility with gut microbial transplantation. J. Biol. Chem. 20, 5647-5660
http://refhub.elsevier.com/S1359-6446(20)30254-3/sbref0525http://refhub.elsevier.com/S1359-6446(20)30254-3/sbref0525

 DMB and Aspirin

Dr. Hazen's research on DMB and aspirin (2012, 2013, 2015):

In 2012, Hazen et al. patented the small molecule 3,3-dimethyl-1-butanol (DMB) and similar compounds for their ability to lower intestinal TMA in the treatment of CVD [108]. After observing decreased TMA production from choline in mouse cecum in vitro, DMB was administered to C57BL/6J mice in drinking water, resulting in a reduction of urinary and plasma TMA levels. The proposed mechanism of action was the inhibition of several TMA lyases, including choline TMA lyase, as determined in vitro [109]. The patent was further extended to acetylsalicylic acid (ASA) and its derivatives, because ASA showed inhibition of TMA lyase activity of Proteus mirabilis – a microbe with abundant TMA lyase activity in an in vitro setup [110].

[108] Hazen, S.L. et al. (2013) Treatment and prevention of cardiovascular disease and thrombosis. US9168233B2.
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[109] Z. Wang, et al.
Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis
Cell, 163 (2015), pp. 1585-1595
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[110] Hazen, S.L. (2015) Treating and preventing disease with tma and tmao lowering agents US20160089386A1.
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