Part 2 of interview with Nigel Manning

This is part 2 of an email interview with:

Mr Nigel Manning, Principal Clinical Scientist
Dept. Clinical Chemistry
Sheffield Children's Hospital
Sheffield

email : Nigel.Manning@sch.nhs.uk

Almost every patient TMAU urine sample in the UK will have been tested by Mr Manning.

Part 1 can be read here

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Do we know what bacteria is responsible for gut Trimethylamine (TMA) production ?

There are more than 400 species of bacteria in the colon but only a few described as TMA-producing. The fishing industry’s research microbiologists have published many papers on TMA and ‘fish-spoiling’ and cite species such as Vibrio harveyi, Vibrio fischeri, Photobacterium leiognathi and Shewanella baltica. The last of these is also know to generate hydrogen sulphide – or ‘ rotten egg’ gas. Whether these microbes are those responsible for human TMA production is a good question, but they may represent a small portion of the total.

Is the bacteria in the colon or small intestine ?

The distal part of the colon is responsible for protein and amino acid breakdown and I suspect the area for TMA production. Although there are hundreds of intestinal bacterial species there may be just 30 or 40 species which represent more than 90% of the microbes in number. If a TMA-producing species becomes predominant, eradication with antibiotics may prove to be very difficult. Apparently there are ten times as many bacterial cells in the human gut as cells making up the entire human body – making the gut flora a powerful metabolic force. Attempts at eradication with antibiotics such as metronidazole have been successful for TMAU2 sufferers – leaving them odour-free after a single course in some instances (as I mentioned earlier). Other antibiotics include neomycin and amoxicillin. Without specific identification of bacterial species involved (and their severity of overgrowth) the choice of an effective antibiotic for TMAU2 is often a question of trial and error. TMAU1 sufferers can also benefit from periodic antibiotic therapy as well as dietary choline restriction. Both TMAU1 and 2 can be controlled in similar ways, although the secondary (acquired) form has the possibility of a complete cure. TMAU1 may be controlled to some degree by antibiotics, restriction of choline (eggs, liver, beans) carnitine (meat) and TMA-oxide (seafood). The odour effects of TMA may also be reduced by activated charcoal or copper chlorophyllin tablets to adsorb TMA in the gut and the use of pH5 skin creams to neutralize TMA in sweat.

Do you think if someone has excess TMA, it could indicate that their gut flora is abnormal ? For instance small intestine bacteria overgrowth ?

[see previous answers]

Is there a particular antibiotic/treatment you think may be best to control excess bacteria in Secondary TMAU ?

[see previous answers]

Do you have any advice to Primary TMAU sufferers ?
Any advice to Secondary TMAU sufferers ?

To both of these questions I would recommend seeking the advice and guidance of a metabolic physician who specialises in TMAU – such as Robin Lachmann at The National Hospital for Neurology and Neurosurgery in London. There are several other metabolic specialists across the UK with increasing experience of TMAU, supported by dieticians, who can help TMAU sufferers with a variety of treatments from antibiotics and dietary regimens to odour-reducing tablets and low pH skin creams.

Do you think a Secondary TMAU diagnosis means in theory they should be able to be 'cured' ?

Yes, with the correct antibiotic therapy a patient with normal FMO3 activity but an overproduction of TMA by gut flora may be effectively cured.

Do you expect Primary TMAU positives to have problems with other FMO3 substrates ?

FMO3 may have up to 1000 substrates ie compounds that can be oxidized by this enzyme in the liver. With deficient oxidation these compounds may stay in the body longer and have unwanted consequences. Many drugs may be included in this list and are currently know to include codeine, tamoxifen, ketoconazole, nicotine, cimetidine, ranitidine and phenothiazine. High blood pressure is also a known complication due to foods which contain large amounts of the neurotransmitter tyramine (cheese, red wine and chocolate are examples). FMO3 deficiency should be taken into account whenever drugs are prescribed in case of an adverse reaction.

Do you think with Primary TMAU, the person may have other health weaknesses, such as chronic fatigue ?

It’s not possible to speculate about this – TMAU1 sufferers are individuals prone to conditions that all of us may encounter. Adverse reactions to FMO3 substrates may add complications under certain circumstances, such as hypertension (high blood pressure).

Many people, including people with primary or secondary TMAU diagnosis, as well as those who are negative, have wide ranging odors. From gas/fecal to rotten egg and all sorts. Do you have a theory on this ?

Body odour is caused by the release of volatile compounds from the skin in sweat. Just as TMA is produced in the gut by bacteria, there are probably many other volatile compounds which are naturally produced – like skatole which has a faecal odour. Only when the production of these compounds are produced in excess that the odour can become a problem. There may be other conditions like TMAU which are caused by an unusual gut flora as well as a lack of a detoxifying enzyme. Unfortunately we only have the ability to test for TMA at the moment.

Do you think with a TMAU diagnosis, they will only smell of 'fish body odor' ?

It may be possible to be afflicted with overproduction of more than one volatile compound if conditions in the gut are such that excesses of different species of odour-causing bacteria are pre-dominant. Other bacteria may be responsible for a mixture of volatiles. Some species of Shewanella are known to produce both TMA and hydrogen sulphide (rotten egg gas).

Are there any recent advances in TMAU ?

I’m not aware of any major breakthroughs in the treatment of TMAU, although as with many areas of medicine change is gradual and new therapies may be some time in development. Riboflavin treatment to boost the activity of FMO3 was mentioned a few years ago, although I’ve yet to see the results of any trial published.
Our advances in diagnostics have been in establishing a DNA service here at Sheffield Children’s Hospital. Recent increased awareness of the condition can certainly count as an advance – with it comes the prospect of increased chances to diagnose and treat TMAU sufferers.

What do you think sufferers could do to get research going ?

Perhaps by joining organisations such as the TMA Foundation (based in New York and ably run by Sandy) TMAU sufferers could channel efforts into fundraising to support researchers in the field of FMO3 function or antibiotic therapy trials.

Do you think it may be feasible for a manufacturer to develop a 'home
maintenance' TMAU test like they have for diabetes ? whether its TMAU test strip papers or a breathalyzer etc ?

There have been attempts at measuring TMA in sweat, although this is a long way from a commercial kit as a mass spectrometer was still required to detect the TMA.
When it comes to future developments – ‘never say never’ may be the best answer I can give.

Are there any ideas you have of possible 'money no object' lines of
research, such as genetic engineering ?

There are many hundreds of genetic conditions for which genetic engineering still remains the ultimate goal. Stem cell therapy with the correction of an abnormal gene, its re-introduction to the body and then normal function of the previously deficient enzyme may be possible in the future for many of these disorders….maybe even FMO3 deficiency.

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