The paper, “Open Access Trimethylamine and Trimethylamine N-Oxide, a Flavin-Containing Monooxygenase 3 (FMO3)-Mediated Host-Microbiome Metabolic Axis Implicated in Health and Disease” (2016) by Prof Elizabeth Shephard, PhD., Ian R. Phillips, PhD., et al, discusses TMA, TMAO, and FMO3-mediated host-microbiome metabolic axis implicated in Health and Disease. Both Professors Shephard and Phillips have been long standing Consultants for MEBO, and Prof Shephard was the Principal Investigator of her research study on a therapeutic for TMAU, funded by the UK Medical Research Council (MRC) grant award of £358,000 GBP.
As noted in a post in this Blog (October 22, 2016), , ‘New Phillips/Shephard TMAU & FMO3 overview paper’, they give a relatively thorough overview of the function of the FMO3 metabolic enzyme and address the new controversial interest in TMAO adversely affecting health, including cardiovascular disease, reverse cholesterol transport, and glucose and lipid homeostasis. A summary of this paper is noted in this Blog post.
Since 2016, there has been significant research around the world into the effects of TMAO on cardiovascular disease (CVD), since CVD is a very common disease in humans, which tends to support the theory of excessive levels of TMAO causing CVD and other health issues noted in this paper. Based on this theory, Dr. Stanley Hazen, M.D., PhD, has designed a compound that inhibits TMA-producing bacteria from taking up TMAO, choline, carnitine, and lecithin and converting it to TMA.
It is currently widely accepted in the scientific community that TMAO primarily enters the body through 2 avenues:
- by eating foods rich in TMAO, like fish and seafood, and
- by TMA-producing gut bacteria. TMA is then taken through the hepatic portal system to the liver to be metabolized, thus converted into TMAO. (TMA has very strong odor. TMAO is odorless)
TMAO RICH FOODS:
Fish and seafood contain TMAO (yes the ODORLESS compound because it has an oxygen molecule). However, when fish die, bacteria convert this TMAO into the odorous compound, TMA. For this reason, the fish market has been measuring TMA levels in fish to determine the freshness of the fish, and thus its market value.GUT BACTERIA CONVERTS TMAO, choline, carnitine and lecithin into TMA
Like fish, the human gut also has TMA-producing bacteria, although possibly different species. This bacteria takes up the TMAO from the ingested fish and converts it into odorous TMA. This bacteria also takes up choline, carnitine, and lecithin and converts it to odorous TMA. Then this TMA passes through the tight junction of the intestinal semipermeable wall into the bloodstream to be metabolized by FMO3 enzymes in the liver. See more information below about the tight junction of intestinal semipermeable wall. This metabolic process involves adding an oxygen molecule to odorous TMA to convert it to its odorless state, TMAO.It would stand to reason to think that it's great that TMAO takes away the TMA odor, so why is it bad? Well the latest scientific research these past 5 to 10 years involves testing the theory that high levels of TMAO causes health issues, including cardiovascular disease (CVD), kidney disease, colorectal cancer, and in impaired glucose tolerance, as noted in this 2016 paper. These past 2 years, significant research has taken place on this, including the research carried out by Dr. Stanley Hazen, M.D., PhD, at the Cleveland Clinic, who has designed a compound to control TMA production by gut bacteria. The theory is that by controlling TMA levels, so is the TMAO level controlled to prevent these diseases.
ISN’T TMAU THE RESULT OF LOW TMAO LEVELS?
No matter what the TMAO levels are, choline in serum levels are also important indicators of health, particularly to TMAU sufferers.
It is most certainly so in the case of a faulty FMO3 metabolic enzyme, as in the case of Primary TMAU. However, it is not so if the problem stems from excessive production of TMA, even though the FMO3 enzymes may be working normally. Too much TMA in the blood can overwhelm a well-functioning FMO3 metabolism, leaving behind free TMA in the blood, resulting in TMAU odor condition. If there are low levels of TMAO with high levels of free TMA in the bloodstream, the odorous TMA will be eliminated from the body by the cleansing organs resulting in the odor condition called Trimethylaminuria (TMAU), whether caused by genetic faults, liver damage resulting in a deficient FMO3 enzyme, or simply too much free TMA in the blood. It is also theorized that high levels of the abundance of TMA-producing bacteria “steals” the essential nutrient, choline, from the diet. Consequently, when a TMAU sufferers goes on a low choline diet, an even lower amount of choline enters the body, since some of the choline ingested is taken up by TMA produced by bacteria. No matter what the TMAO levels are, choline in serum levels are also important indicators of health, particularly to TMAU sufferers.
As most everything in nature, too much of anything throws off the normal equilibrium nature intended for health and life. Too much TMA or too much TMAO is not something a human body is supposed to have. It will have adverse consequences to the sufferer’s health. The key is to determine normal levels and then how to control them through diet and supplements without the use of antibiotics, which then alters healthy gut microbiota. It is also believed that long-term use of antibiotics results in injury to the gut wall. Logic dictates that in order to determine whether TMA suppressing supplements is indicated, diagnostic tests should be used to identify abundance of TMA-producing bacteria and TMA/TMAO Ratio in serum.
Quotes from the 2016 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 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 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.
http://dmd.aspetjournals.org/content/44/11/1839.long
Clinical significance of the opening of intercellular tight junctions (increased intestinal permeability), any of which may result in opening of tight junction, resulting in the passing of electrolytes into the blood without transition through the intestinal cell metabolism.
Clinical significance [Wikipedia]
The opening of intercellular tight junctions (increased intestinal permeability) can allow passage of microbes, microbial products, and foreign antigens into the mucosa and the body proper. This can result in activation of the immune system and secretion of inflammatory mediators.[12]
Increased intestinal permeability is a factor in several diseases, such as Crohn's disease, celiac disease,[13] type 1 diabetes,[14]type 2 diabetes,[13] rheumatoid arthritis, spondyloarthropathies,[15] inflammatory bowel disease,[8][16] irritable bowel syndrome,[9]schizophrenia,[17][18] certain types of cancer,[8] obesity,[19] fatty liver,[20] atopy and allergic diseases,[14] among others. In the majority of cases, increased permeability develops prior to disease,[8] but the cause–effect relationship between increased intestinal permeability in most of these diseases is not clear.[16][21]
For a clearer understanding of the above used terms, see illustration below:
------------------------------ Transcellular route (pathway): The route through cells, as opposed to between the cells.
- Paracellular route: the route between cells
- Tight junction: A type of cell junction formed between epithelial cells of vertebrates wherein the outer layers of two adjacent cells fuse, thereby serving as a barrier to the passage of fluid between cells
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María de la TorreFounder and Executive Director
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