Menstruation and Trimethylaminuria link in females with one FMO3 variant

This is an interesting 2007 paper by Dr John Cashman et al showing a possible link between menstruation and trimethylaminuria if the female had one or more mutants or polymorphs/variants of the FMO3 enzyme. It looks like the research was carried out in Japan, with Dr Cashman acting in a secondary role, probably including doing the DNA testing.

Transient trimethylaminuria related to menstruation

Background

Trimethylaminuria, or fish odor syndrome, includes a transient or mild malodor caused by an excessive amount of malodorous trimethylamine as a result of body secretions. Herein, we describe data to support the proposal that menses can be an additional factor causing transient trimethylaminuria in self-reported subjects suffering from malodor and even in healthy women harboring functionally active flavin-containing monooxygenase 3 (FMO3).
Methods

FMO3 metabolic capacity (conversion of trimethylamine to trimethylamine N-oxide) was defined as the urinary ratio of trimethylamine N-oxide to total trimethylamine.
Results

Self-reported Case (A) that was homozygous for inactive Arg500stop FMO3, showed decreased metabolic capacity of FMO3 (i.e., ~10% the unaffected metabolic capacity) during 120 days of observation. For Case (B) that was homozygous for common [Glu158Lys; Glu308Gly] FMO3 polymorphisms, metabolic capacity of FMO3 was almost ~90%, except for a few days surrounding menstruation showing <> 90%) metabolic capacity, however, on days around menstruation the FMO3 metabolic capacity was decreased to ~60–70%.
Conclusion

Together, these results indicate that abnormal FMO3 capacity is caused by menstruation particularly in the presence, in homozygous form, of mild genetic variants such as [Glu158Lys; Glu308Gly] that cause a reduced FMO3 function.

Full paper:Transient trimethylaminuria related to menstruation

The paper raises more questions than answers. It also goes to show how the textbook definition of TMAu (homozygous with FMO mutants) doesn't seem satisfactory. In the end, if someone says they smell of abnormal systemic smells at times (and they do), that would be the diagnosis and starting point. Usually the first step towards a TMAu diagnosis is the urine test, but it seems sensible to have the FMO3 DNA tested also, to see if there is at least a polymorph or wild type present, although even that may not be final since they may not know all polymorphs yet. FMO3 does seem to be a primary suspect in anyone who feels they have systemic body odor and maybe halitosis. However the tests cannot be deemed as 'final status' at the moment, sicne they may not know every FMO3 mutant/variant or be sure about the urine % for 'normal' etc (the % cut-off point has increased from about 50% to around 90% now). It's also unclear if there is an international agreed list of FMO3 variants, or if anyone is keeping an updated list. Also testers worldwide may use a different equation for the test, or not bother with the TMA-oxide part.

It also shows what can be achieved when real case studies are well constructed and close monitoring is used. It's unlikely in the near future that any expert would voluntarily do such an insightful TMAU test over 120 days. Sadly the medical system does not realise systemic body odor is possibly a common problem. It seems sensible to have the FMO3 DNA tested to see if there is at least a polymorph or wild type present if you have a longterm systemic body odor problem, although even that may not be final since they may not know all polymorphs yet. FMO3 does seem to be a primary suspect in anyone who feels they have systemic body odor and maybe halitosis.

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keywords :
FMO3 mutant : a gene that has changed so that the normal transmission and expression of a trait is affected. Usually a bad thing. Usually 'severe'
FMO3 polymorphism : Difference in DNA sequence among individuals. Genetic variations occurring in more than 1% of a population would be considered useful polymorphisms for genetic linkage analysis.
FMO3 variant : A variant gene is usually a common very mild slightly different gene. Probably the same as a polymorphism.
homozygous : Possessing two identical forms of a particular gene, one inherited from each parent
heterozygous : Possessing two different forms of a particular gene, one inherited from each parent

how do you find out if you smell ?

With systemic body odor, the general pattern seems to be that close genetic relatives and partners can't seem to smell the suffererThere can't be a problem as uniquely frustrating as body odor or halitosis in that it is others that suffer the symptom (the smell) whereas the sufferer normally can't smell anything. This seems to be the overwhelming pattern both with the well-known types of body odor and halitosis, but also metabolic body odors, with the most common one seeming to be fecal body odor. This means the patient is dealing with an 'invisible' problem that they can't monitor, which is an impossible situation.

With systemic body odor, the general pattern seems to be that close genetic relatives and partners can't seem to smell the sufferer. It is still unknown why this should be. One theory is that they themselves may be carriers and there is not a distinct enough 'sensitivity gap' for them to detect the smell (having the same toxins in their bloodstream at much lower levels). Others feel it is to do with desensitisation (geting too used to the smell).

Most people may know someone who has 'typical' washable external body odor or halitosis that is married, and may wonder why doesn't his/her wife/husband or children tell him so they can wash it off ? The main assumption again must be that for some reason they can't smell them. The same seems true for people walking about with chronic permanent halitosis of the 'bad tooth' kind. Perhaps with foot body odor, usually genetic family and parntners can usually smell it. Perhaps it depends if a family generally has the same body or gut flora composition, with foot odor being an exception. At the moment we cannot be sure about anything

The remaining part of the article will focus on systemic body odor, but may be the same principle for those who feel they have other untreatable odor problems. It's an attempt to come up with a strategy to help you understand your problem as best you can.

1: Ask people you trust if you smell and when: This would seem a good idea. However, because of the general pattern of family/partners not detecting a smell as mentioned above, there's a good chance family/partners will be of no use in this sense. There's a chance with their wish to help you, they may focus on 'unimportant' smells, which is not much use or even makes the situation worse. Probably the best chance of finding a 'smell helper' is an outsider 'friend' or professional person or someone that you feel you can trust. Ask them every aspect about your smell problem. If you are at school, you could ask the school nurse or a teacher. A teacher would be ideal since they should have smelt you sometime.

2: Always ask medical 'helpers': In a perfect world no extra info would need to be added to this point, but we live in such an imperfect world that it must be said to be careful if you think you are going to be locked up for olfactory reference syndrome. Also, the general trend seems to be that nobody smells all the time (even though it feels like it), and so medical helpers probably genuinely can't smell you if they say so.If you go to medical helper about your problem, make sure you tell them about it. Many people understandably go and then don't mention it, because of shame and also the lack of feedback from possible 'helpers'.

3: Ask a non-genetic relative: This is a risky option, but there must be a chance a non-genetic relation has smelt you, although it cannot be assumed. For instance, if the 'carrier' theory was correct, they may be carriers too. Perhaps carriers tend to marry. Also it is unlikely you smell all the time. Perhaps an aunt would make a good confidante

These are just a few examples of trying to understand your body odor problem. Possibly a general rule could be, don't expect a genetic relative to say they have smelt you (at least in the way others have described), and you may well smell really bad at times, but not as often as you think (unless it's a washable or treatable surface problem).

Deficiency and Excess of vitamins and minerals

Mark Howard, Manager
Biolab Medical Unit
The STone House
9 Wymouth Street
London W1W 6DB, UK
info@biolab.co.uk

Excerpts from the interview with Mark Howard
February 2009

Are there vitamins or minerals you find are often surprisingly deficient in general ?

MH: It never ceases to amaze all of us at Biolab just how frequently we find micronutrient deficiencies, and the situation is deteriorating rather than improving. B12, folate, zinc, magnesium, selenium and B1, B2 and B6 deficiencies are regularly identified, essential fatty acid deficiencies and abnormal omega-3:omega-6 ratios are also very frequently observed. Vitamin D is definitely a problem, particularly, but not exclusively, at this time of the year. Of course the majority of patients being tested at Biolab are already unwell and are suspected of having sub-optimal micronutrient status, hence the referral.

We are also seeing an increasing number of raised levels of minerals and vitamins as a result of inappropriate supplementation and this is a growing area of concern. Nutrients in excess can be just as harmful as deficiencies.

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Vitamin and mineral supplements
Sorting fact from fiction

Vitamin deficiencies

Minerals the body needs

How much vitamins do I need?

Unfounded health claims.When vitamin supply is adequate your body automatically regulates circulating vitamin levels. Excess water-soluble vitamins are excreted in urine. Surplus fat-soluble vitamins are stored in body tissue. Because they're stored, excess fat-soluble vitamins can accumulate in your body and become toxic. Your body is especially sensitive to too much vitamin A and vitamin D...

http://your-doctor.com/patient_info/nutrition_supplements/vitamins.html

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Related posts in this blog: Summary Blog posts on vitamins/minerals

Resources
*Dr Ardith Brundt: "HEC 131 - Introduction to Nutrition " Chapters 7 & 8 @: http://iweb.tntech.edu/abrunt/homework.htm

*Mosbey's Medical & Nursing Dictionary, 1983:pp1140-1145.

*"Vitamin and nutritional supplements- Sorting out fact from fiction amid a storm of controversy." From Mayo Clinic Health Letter @ http://www.mayohealth.org/mayo/9707/htm/me_jun97.htm

FMO3 paper hints at 25% possibly with FMO3 issues in a trial

The xenobiotic metabolizing enzymes, or biotransformation enzymes (or probably other various names) are a very important group of enzymes in humans that are the main enzymes dealing with 'external' ('exogenous') chemicals, whether they be through food/drink, through the skin, breath etc. In effect, the frontline 'translators', translating the compounds into something the body knows what to do with. These enzymes can either detox something, or activate something (for instance the active compound in a medicine). They can be found in various places in the body, but are very concentrated in the liver, since this deals with blood purification etc. This group of enzymes can also detoxify internal ('endogenous') systemic chemicals, such as hormones/neurotransmitters etc; since, in the end, these sort of things are chemicals too.

If you tend to handle a drug/medicine badly, a doctor will suggest an allergy is to blame. However, it is probably more likely to be a 'weakness' in one or more of the biotransformation enzymes. Drugs/medicines rely on these enzymes so heavily for activation or detoxication, that any weakness is thoroughly tested.

Pharmacogenomics is the branch of pharmacology which deals with the influence of genetic variation on drug response in patients by correlating gene expression or single-nucleotide polymorphisms with a drug's efficacy or toxicity. By doing so, pharmacogenomics aims to develop rational means to optimise drug therapy, with respect to the patients' genotype, to ensure maximum efficacy with minimal adverse effects. Such approaches promise the advent of "personalized medicine"; in which drugs and drug combinations are optimized for each individual's unique genetic makeup.[1]

Pharmacogenomics is the whole genome application of pharmacogenetics, which examines the single gene interactions with drugs.

http://en.wikipedia.org/wiki/Pharmacogenomics

In the case of FMO3, it is already known that some drugs tend to be heavy users (at least partly) of FMO3 enzyme. Ranitidine being an example. This would mean that anyone with a FMO3 weakness would likely handle ranitidine badly. Because FMO3 is so unresearched, it's probably early stages as to knowing what drugs use FMO3 enzyme heavily.

Another point is that it is probably early days as to knowing how many will have one or more FMO3 enzyme that is sub-optimal. Whereas mutant copies likely mean the % efficiency will be greatly reduced, variant copies may mean a slightly less efficient enzyme. However when the end product is that you smell out a room, its not much comfort even if you only have one or more variant copies. With Trimethylaminuria, patients are regarded as 'severe' or 'mild'. Probably as a rule, 'severe' means mutant copies and 'mild' means variants. At the moment the estimates of sub-optimal FMO3 function are probably grossly underestimated.

In the paper by Williams and Krueger recently posted, there was mention of a paper on a group of people taking a drug that involves FMO3. They suggest the FMO role in the detox of that drug was the likely 'weak link', and that 25% had to cease use of the drug due to side effects likely due to poor FMO3 function. At the moment we have crumbs to go on regarding this type of research, but if researchers were to look into this they may find 25% or more of the population could have an FMO3 weakness.

Ethionamide (2-ethyl-4-thiocarbamoylpyridine) is structurally related to thiobenzamide and is being utilized in the treatment of tuberculosis. Recently, the laboratory of Dr. Paul Ortiz de Montellano demonstrated that ethionamide is a prodrug that must be S-oxygenated by an FMO in the target organism, Mycobacterium tuberculosis, to exert its effect (Vannelli et al., 2002). The metabolic activation of ethionamide by the bacterial FMO is the same as the mammalian FMO activation of thiobenzamide to produce hepatotoxic sulfinic and sulfinic acid metabolites. Not surprisingly, Dr. Ortiz de Montellano’s laboratory and our own have found ethionamide to be a substrate for human FMO1, FMO2, and FMO3 (unpublished observations). Approximately 25% of individuals have to discontinue ethionamide due to toxicity, primarily in liver, thought to be due to FMO3-dependent S-oxygenation. It would be of interest to determine if particular FMO3 allelic variants correlated to susceptibility to ethionamide hepatotoxicity.

http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=15922018

There's a lot of 'ifs' and 'buts' involved in this post, but the main point was to highlight how reactions to medicines may be a sign of a biotransformation enzyme weakness (many of the population probably have one weakness of some sort), and also how because of lack of research, the incidence of FMO3 weakness (in practice) may be greatly underestimated.

Update : With hindsight, the researchers may in fact be suggesting an active FMO2 enzyme is to blame for the 25%. In most humans, FMO2 is naturally 'disabled' due to a nonsense mutation. But it is known now that a proportion may in fact have functioning FMO2. However the principle of the post is the same, in that those with FMO3 issues may be greatly underestimated.

Shewanella baltica and other TMA producing bacteria in the gut

Nigel Manning
Principal Clinical Scientist
Dept. Clinical Chemistry
Sheffield Children's Hospital
Sheffield
email : Nigel.Manning@sch.nhs.uk

Excerpts from Part 2 of Interview with Nigel Manning
March 2009

The bacteria possibly responsible for the production of trimethylamine in the gut

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

NM: 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.

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[Shewanella baltica]...is also known to generate hydrogen sulphide - or 'rotten egg' gas.Shewanella baltica: Shewanella baltica (baltica of the Baltic Sea) is both an aerobic and anaerobic bacterium. Shewanella is the sole genus in the Shewanellaceae family of marine bacteria. Shewanella baltica are H2S-producing [hydrogen sulphide-producing] bacterial isolated from marine fish (mainly cod, plaice, and flounder) caught from the Baltic Sea. In aerobic conditions, the Black Sea strains of S. baltica absorbed significant quantities of Fe(III) from its medium, then reducing it to Fe (II) in anaerobic conditions. Under anaerobic conditions, S. baltica also oxidizes organic matter from the reduction of nitrate and sulfur compounds as well. S. baltica also has putrefaciens capable of high-rate azoreduction and humus reduction under anaerobic conditions. S. baltica produces a black precipitate of FeS when grown on TSI agar medium...(1)

Vibrio harveyi: Vibrio harveyi is a species of Gram-negative, bioluminescent, marine bacteria in the genus Vibrio. V. harveyi are rod-shaped, motile (via polar flagella), facultatively anaerobic, halophilic, and competent for both fermentative and respiratory metabolism. The do not grow at 4°C or above 35°C. V. harveyi can be found free-swimming in tropical marine waters, commensally in the gut microflora of marine animals, and as both a primary and opportunistic pathogen of marine animals, including Gorgonian corals, oysters, prawns, lobsters, the common snook, barramundi, turbot, milkfish, and seahorses[1]. V. harveyi is responsible for luminous vibriosis, a disease that affects commercially-farmed penaeid prawns[2]. Additionally, based on samples taken by ocean-going ships, V. harveyi is thought to be the cause of the milky seas effect, in which, during the night, a uniform blue glow is emitted from the seawater. Some glows can cover nearly 6,000 square miles. (2)

Vibrio fischeri: Vibrio fischeri is a gram-negative rod-shaped bacterium found globally in the marine environments. V. fischeri has bioluminescent properties, and is found predominantly in symbiosis with various marine animals, such as the bobtail squid. It is heterotrophic and moves by means of flagella. Free living V. fischeri survive on decaying organic matter (see saprotroph). The bacterium is a key research organism for examination of microbial bioluminescence, quorum sensing, and bacterial-animal symbiosis.(3)
See image results for Vibrio Fischeri (4)

Photobacterium leiognathi: Since ancient times mariners have reported seeing glowing seas as their ships sailed through the night. More recently, satellites have recorded pictures of glowing seas off the eastern coast of Africa. The bioluminescent microbes responsible for such phenomena require specific conditions and high concentrations to achieve this effect, but it is similar to the algae blooms that cause red tide. There are many varieties of bacterium that can emit light, and some of them have developed symbiotic relationships with animals. Photobacterium leiognathi is one such species...(5)

References:
(1) http://microbewiki.kenyon.edu/index.php/Shewanella_baltica
(2) http://en.wikipedia.org/wiki/Vibrio_harveyi
(3) http://en.wikipedia.org/wiki/Vibrio_fischeri
(4) http://images.google.com
(5) http://web.mst.edu/~microbio/BIO221_2006/P_leiognathi.htm

Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism

This 2005 review is an excellent reference paper on the human flavin-mono-oxygenase enzyme family, particularly the most active form of FMO in humans, FMO3. It can probably be regarded as the current defining article on FMO (especially FMO3), or at least the defining free version. It was written by Williams and Krueger of the Linus Pauling institute, who can probably be regarded as 2 of the few FMO experts in the world. FMO3 is the enzyme regarded as being at fault in cases of Primary Trimethylaminuria. The full paper can be read via the link.

Abstract:

Flavin-containing monooxygenase (FMO) oxygenates drugs and xenobiotics containing a “soft-nucleophile”, usually nitrogen or sulfur. FMO, like cytochrome P450 (CYP), is a monooxygenase, utilizing the reducing equivalents of NADPH to reduce 1 atom of molecular oxygen to water, while the other atom is used to oxidize the substrate. FMO and CYP also exhibit similar tissue and cellular location, molecular weight, substrate specificity, and exist as multiple enzymes under developmental control. The human FMO functional gene family is much smaller (5 families each with a single member) than CYP. FMO does not require a reductase to transfer electrons from NADPH and the catalytic cycle of the 2 monooxygenases is strikingly different. Another distinction is the lack of induction of FMOs by xenobiotics.

In general, CYP is the major contributor to oxidative xenobiotic metabolism. However, FMO activity may be of significance in a number of cases and should not be overlooked. FMO and CYP have overlapping substrate specificities, but often yield distinct metabolites with potentially significant toxicological/pharmacological consequences.

The physiological function(s) of FMO are poorly understood. Three of the 5 expressed human FMO genes, FMO1, FMO2 and FMO3, exhibit genetic polymorphisms. The most studied of these is FMO3 (adult human liver) in which mutant alleles contribute to the disease known as trimethylaminuria. The consequences of these FMO genetic polymorphisms in drug metabolism and human health are areas of research requiring further exploration.

Full paper (2005): Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism

Pediatrician 'checklist' for a patient with an odor

This is a typical 'procedure checklist' for pediatricians investigating a patient with a body odor or halitosis problem of some sort. Obviously fecal body odor or fecal breath aren't on the list, but it is good to see trimethylaminuria make it.

Point-of-Care Quick Reference: Odor (Unusual Urine and Body)

Electronic Noses Hold Out the Promise of Sniffing Out Criminals

Often new lines of hope come from the strangest places and for very different motives. The USA Dept of Home Security plans to research whether human body odor can be used as a 'lie detector', or whether every person has a unique 'body odor signature'. Ironically, a spin-off from this could be the discovery and recognition by the authorities of conditions like 'fecal body odor'. They would basically be using the same equipment and testing methods often mentioned in this blog.

It is of interest that they are researching if humans may emit certain odors or have odor changes when lying. People with metabolic body odor, especially fecal body odor, have mentioned they feel that emotions may be a symptomatic factor.

Scientific research shows that so-called volatile organic compounds present in human sweat, saliva and urine can be analyzed using a technique known as gas chromatograph-mass spectrometry.

Research published by the Royal Society in London in 2006 found "a substantial number of marker compounds [in human sweat] that can potentially differentiate individuals or groups."

Researchers took five samples each from 179 people over a 10-week period and analyzed them, finding hundreds of chemical markers that remained more or less constant for each person over time. An analysis of these compounds "found strong evidence for individual [odor] fingerprints" the researchers concluded.

They warned, however, that some people appear to have less distinctive odors than others.

"The reason for the variation in distinctiveness is unclear," the researchers said. More importantly, the odors of some people changed during the course of the study. "Not all subjects had consistent marker compounds over time, which might be due to physiological, dietary, or other changes," they concluded.

From Washington Times article about human body odor signatures (March 2009)

Australian Trimethylaminuria Foundation Fund : You can now donate online

Australian Trimethylaminuria Foundation Fund : You can now donate online

Regular readers will be aware that the Australian Trimethylaminuria Foundation are co-ordinating in a Trimethylaminuria research proposal led by Dr John Christodoulou. It is now possible to help donate to the fund online, as can be seen on this page : donate to the Trimethylaminuria research proposal .

Rob Brown, the chairman of the Australia TMAU Foundation, will no doubt keep us updated. Their website plans to host it's own forum, but in the meantime Rob can usually be found on his TMAUcure Yahoo Forum.

As Rob says

The Australian Trimethylaminuria Foundation (ATF) serves people with trimethylaminuria (TMAU) and other as yet undiagnosed or undescribed genetically mediated malodour disorders, and their friends, families and supporters.

The ATF’s primary aims are:
1. to facilitate scientific research into better treatments and a cure for TMAU.
2. to provide support for sufferers of TMAU and
3. to promote awareness of TMAU within the medical profession and within the wider community.

The ATF receives no financial support from government agencies but functions by way of donations and the voluntary work of its members.

TMAU is the only accepted 'bloodborne smell' disorder (if a Dr has ever heard of it), but the enzyme bearing the burden of that problem, FMO3, oxidizes many sulfides and amines. So it could be a case that FMO3 is responsible for a lot of various smells, in which case any FMO3 research would be of benefit if this turned out to be a factor. Since both the treatment proposals in this research are to do with FMO3, it would likely be of benefit for any FMO3 smell issues.

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Related links:
Australian TMAU Foundation Fund : You can now donate online
Australian Trimethylaminuria Foundation
Trimethylaminuria research proposal led by Dr John Christodoulou
TMAUcure Yahoo Forum
Blog post on the Trimethylainuria research proposal

TMA and hydrogen sulfide odor-producing bacteria in the gut and or vagina

In her interview posted in this blog of March 24, 2009, Cass Nelson-Dooley, M.S, Clinical Consultant at Metametrix Clinical Laboratory, with contributions by Mr. Tony Hoffman, tells us of the very important role of anaerobic bacteria that dwell in the colon or the vagina that produces smelly compounds like trimethylamine (TMA) and hydrogen sulfide, as opposed to them being products of human metabolism.

The first thing to do is lower protein intake and improve protein digestion to reduce undigested nitrogenous substrates (amino acids) that must be present to form ammonia.A very small percentage of the human population is diagnosed with Primary Trimethylaminuria, which is caused by a genetic disorder. Yet, many people who test negative for TMAU have the same or similar odor as a person with TMAU. Moreover, persons who test positive for Primary TMAU don't smell only of fish but also of other odors as well. This is because bacteria is the culprit that produces multiple types of volatile organic compounds (VOCs). As Cass Nelson-Dooley points out in her interview,

...The more smelly compounds like trimethylamine and hydrogen sulfide are not products of human metabolism, but they are produced by several bacteria under certain conditions. They tend to be strict anaerobes that could dwell in the colon or the vagina.

Question:

Some feel that trimethylamine can produce a wide range of odors. Do you think trimethylamine could cause the wide range of gut smells on its own

Answer:

No. However it can be a component in complex mixtures of products that are responsible for the varying odors among individuals.

It is for this reason that the National Institutes of Health recommends an odor-reducing management protocol for TMAU in their websites,

Genetests.org page on Trimethylaminuria
Rarediseases.info.nih.gov: What treatment is available for trimethylaminuria?

which in addition to a low choline diet and vitamin supplements, they also recommend the following:

Sequestering of trimethylamine produced in the gut:
• Activated Charcoal: 750mg twice daily for 10 days
• Copper Chlorophyllin: 60mg three times/day after meals for 3 weeks

Suppression of intestinal production of trimethylamine: A short course of antibiotics to modulate or reduce the activity of gut microflora, and thus suppress the production of trimethylamine.

Cass goes on to say in her interview that,

Question:

There is a 'diagnosis' of 'Secondary TMAU', where the enzyme involved is deemed fine, but the person has too much trimethylamine. Do you have any suggestion as to how to kill off the TMA-producing bacteria in particular?

Answer:

The first thing to do is lower protein intake and improve protein digestion to reduce undigested nitrogenous substrates (amino acids) that must be present to form ammonia. Perhaps water or juice fasting could be beneficial in these instances as it can change the microbial content of the gut. If you don’t feed the colonic bacteria, they can’t grow and produce strange products.

Question:

Some feel that trimethylamine can produce a wide range of odors. Do you think trimethylamine could cause the wide range of gut smells on its own?

Answer:

No. However it can be a component in complex mixtures of products that are responsible for the varying odors among individuals.

Ground Beef Calculator

Ground Beef Calculator - User select fat/lean percentage

Not only does this calculator give the choline and other nutrient and vitamins content of red meat, but it is a more refined analysis based on the fat content of the meat and the cooking method.

http://www.nal.usda.gov/fnic/foodcomp/cgi-bin/measure.pl?MSRE_NO=23999

2008 Dr Cashman paper: Role of flavin-containing monooxygenase in drug development

Dr John Cashman is a leading (probably THE leading) expert in flavin mono-oxygenase enzyme genetics. He is based at the HBRI in San Diego, that allows anyone to test for trimethylaminuria, both the DNA test (HBRI will do this) and the urine test (presumably sent elsewhere ?). Either test can be done for around $400 each. Although the standard procedure for someone testing for TMAU is to do the urine test first, and if it is negative to not test further, it probably makes sense for the group (and person) to do the DNA test, because the group can then see if this is truly an autosomal recessive problem or not. TMAU is such a new and neglected problem to the medical system that it may turn out their TMAU DNA assumptions are wrong. The main problem being, if not everyone does the DNA test, we don't know what their FMO3 DNA would be. A recent one-off dissertation paper hinted at the notion that TMAU may not be only a recessive problem



Whilst very few papers are written about FMO enzyme currently, Dr Cashman recently wrote a paper on the FMO family of enzymes. FMO are regarded as part of the 'phase 1' group of xenobiotic-metabolizing/biotransformation enzymes.

FMO3 (the main human isoform) seems to be a very versatile enzyme, neutralizing 1000's of external substrates (for instance through the skin and lungs and from the gut), and internal substrates (neurotransmitters, hormones etc), as well as activating other substrates (such as the active compound in medicines). It deals mostly with soft-nucleophilic heteroatom compounds that include a sulfide, amine, or phospohorous molecule. Since so many sulfides and amines are smelly in various ways, it could be a theory the various smells people suffer from, although currently no smell is accepted as a problem with FMO3 except trimethylamine. Perhaps FMO3 could be suspected as a 'multiple smelly enzyme'.

Unfortunately the paper is not available for free, and so the abstract can only be shown

This review summarizes some recent observations and information related to the role of the flavin-containing monooxygenase (FMO) in preclinical drug development. Flavin-containing monooxygenase is a complimentary enzyme system to the cytochrome P450 (CYP) family of enzymes and oxygenates several soft, highly polarizable nucleophilic heteroatom-containing chemicals and drugs. The products of FMO-mediated metabolism are generally benign and highly polar, readily excreted materials. There may be some advantages in designing drugs that are metabolized in part by FMO and not exclusively by CYP. In this review, I describe the practical aspects for the participation of FMO in drug and chemical metabolism including: i) the study of FMO using in vitro preparations; ii) some observations about metabolism of drugs and chemicals by FMO in vivo; and iii) the consequences of studying FMO-related metabolism in various small animal models. Some of the preclinical research and development areas related to FMO are not fully mature areas and there are certain gaps in our knowledge. However, I include discussion of these areas to stimulate further work and invite further discussion.

http://www.ncbi.nlm.nih.gov/pubmed/19040327

Antimicrobial Protein Produced by Vaginal Lactobacillus acidophilus that inhibits Gardnerella vaginalis

Alla A. Aroutcheva, Jose A. Simoes, and Sebastian Faro
Department of Obstetrics and Gynecology, Rush-Presbyterian-St. Luke's Medical Center, 1653W. Congress Pkwy, 720 Pav., Chicago, IL, 60612, USA,
Infect Dis Obstet Gynecol 2001;9:33–39

Objective: The objective of this study was to develop a simple method for recovery and purification of the antimicrobial protein produced by endogenous vaginal L. acidophilus. Obtaining a pure bacteriocin will permit investigations leading to a better understanding of the interaction between the endogenous bacteria of the vagina..

All nine isolates of Gardnerella were inhibited by the bacteriocin isolated from L. acidophilus 160.
Methods: L. acidophilus 160 was grown on two media. The first was MRS broth for 18 hours; the cells were harvested, washed, and placed into a chemically defined medium. The second medium resembled vaginal fluid minus protein. Bacteriocin was precipitated from both media using ammonium sulfate. The growth-inhibiting activity of bacteriocin was determined by a bioassay using nine different isolates of Gardnerella vaginalis.

Results: MRS broth is not a suitable medium for extracting bacteriocin, because it binds with Tween 80. Bacteriocin was isolated, without contaminating constituents, from chemically defined medium and identified as a single band by electrophoresis. Bacteriocin has a molecular weight of 3.8 kDa. All nine isolates of Gardnerella were inhibited by the bacteriocin isolated from L. acidophilus 160.

Lactobacilli, through the antagonistic interaction
with pathogenic bacteria, maintain the vaginal ecosystem in a healthy state.Conclusions: Bacteriocin produced by L. acidophilus 160 was isolated from the chemically defined medium (starvation medium) in a partially pure form. L. acidophilus 160 bacteriocin inhibited growth of all nine isolates of Gardnerella vaginalis

Lactobacilli, through the antagonistic interaction with pathogenic bacteria, maintain the vaginal ecosystem in a healthy state. Regulatory processes are carried out by species of Lactobacillus that produce antibacterial compounds, such as lactic and other organic acids, H2O2, and bacteriocins. Bacteriocins are biologically active, lowmolecular-weight proteins or peptides that inhibit the growth of a variety of bacteria.

The bacteriocin activity includes other species of lactobacilli, as well as a variety of Gram-positive and Gram-negative aerobic, facultative, and obligate anaerobic bacteria. It is significant that one species of Lactobacillus will produce a bacteriocin that inhibits the growth of other lactobacilli. This may be one mechanism that allows Lactobacillus to dominate the ecosystem by suppressing not only other bacteria but also other lactobacilli. This in turn reduces competition within an ecosystem.

Abstract: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1784632

Full text: http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1784632&blobtype=pdf

---

Related Posts:

Part 2 of interview with Cass Nelson-Dooley of Metametrix [keyword: lactobacillus]

Probiotics - Lactobacillus acidophilus

The 4 "R" Protocol for suspected dysbiosis

One of the Q & As in Part 2 of our interview with Cass Nelson-Dooley of Metametrix deals with the condition known as dysbiosis. Cass places a great deal of emphasis on the importance of the treatment provided by a physician for dysbiosis to be tailored to the patient's particular condition. Testing for this condition should be the first step before beginning any type of protocol to ensure that the proper treatment is being applied as opposed to further aggravating the condition.

I think the “4R Protocol” is the most general treatment advice and it’s comprehensive, but every doctor has a different approach and dysbiosis treatment should be tailored to the patient.

Question:
Is there general treatment advice for 'suspected' dysbiosis or does it vary too much ? For instance, take nystatin and metronidazole in a 'scorched earth' policy ?


Answer:

I think the “4R Protocol” is the most general treatment advice and it’s comprehensive, but every doctor has a different approach and dysbiosis treatment should be tailored to the patient.

Treatment using 4 “R” Protocol for Intestinal Health from the GI Effects Interpretive Guide

Remove offending foods, medications, gluten (if sensitive) and reduce poor quality fats, refined carbohydrates, sugars, and fermented foods (if yeast is present). Consider antimicrobial, antifungal, and/or antiparasitic therapies in the case of opportunistic/pathogenic bacterial, yeast, and/or parasite overgrowth (see below for specific recommendations).

Replace what is needed for normal digestion and absorption such as betaine HCl, pancreatic enzymes, herbs that aid in digestion such as deglycyrrhizinated licorice and marshmallow root, dietary fiber, and water.

Reinoculate with favorable microbes (probiotics such as Lactobacillus sp., Bifidobacter sp., and Saccharomyces boulardii). To enhance the growth of the favorable bacteria, supplement with prebiotics such as inulin, xylooligosaccharides, larch arabinogalactans, beta glucan, and fiber.

Repair mucosal lining by giving support to healthy intestinal mucosal cells, goblet cells, and to the immune system. Consider L-glutamine, essential fatty acids, zinc, pantothenic acid and vitamin C.

---

Additional Reading:

Gastrointestinal Dysregulation: Connections to Chronic Disease, a monograph, 2008, available from the Institute for Functional Medicine, www.functionalmedicine.org
authors: Leo Galland, M.D. with Helen Lafferty

Adapted from Lukaczer D. The “4R Program” in Jones DS, ed. Textbook of Functional Medicine, Gig Harbor, WA: The Institute for Functional Medicine

http://www.healthy.net/scr/Article.asp?Id=425&xcntr=1

Visiting a Dr about metabolic body odor and/or halitosis (especially 'fecal body odor')

Doctors are there to serve you, but they should be seen as gatekeepers. If you have fecal body odor or another metabolic body odor issue, referral to specialists would be the aim ... in a perfect world.

If you suffer from metabolic smells, particularly fecal or gas smells (or other 'bowel' smells), you are obviously not 'well' (in the 'normal' sense), and have a right to expect treatment (at least) from your medical system. The medical system's priority (those who work in it) is self-preservation of finance, conditions and status etc, as well as being highly motivated towards obvious defined health problems that have (supposed) answers. When visiting a Dr about a problem such as 'fecal body odor', at worst the Dr could be rude and/or arrogantly dismissive. However, it has to be understood they are there to serve you (not the other way around). The ordinary Dr should be seen as the obstacle to 'experts' (who will likely be of little use) and tests available via the system (probably of little use also, in this case). But if you could get a Dr on your side, it would be possibly helpful. So with that in mind, this post is an attempt at trying to get the most from a Dr's visit :

Notify them in advance what you will be visiting about: You can tell them by email or letter what you will be visiting about. Perhaps inform them of TMAU with a link to a couple of sites. For example, the genome.gov page on trimethylaminuria . This at least prepares them and makes them aware of metabolic body odor. TMAU is the only 'accepted' metabolic odor problem, so that makes the best (and only) example of the concept. It should be also assumed the Dr doesn't keep up to date with most health issues, and will not have heard of TMAU. You will be teaching them.

Try different doctors. Doctors (probably the toughest union there is) have for decades relied upon the common courtesy that patients regard Drs as royalty, and stay with the Dr even if they seem no good and are rude. Patients should remember the system is there for patients, not for doctors. You could try going around every Dr in the surgery to see what they are like, or move elsewhere. Keep in mind, surgery Drs are only generally gatekeepers (at a minimum), who have the power to send you to local 'experts'. This would be a minimum goal. It would be better if the Dr was at least sympathetic though.

Have clear aims : If you think you may have TMAU, it would be best to find out the nearest tester and ask the Dr to send a sample there. Or be referred to a sympathetic 'expert' etc. Probably anyone who feels they have a metabolic odor problem is best to get their FMO3 DNA checked (since it deals with many sulfides and amines), but if a TMAU test is offered, it will likely be the TMAU urine test instead. Ideally, it would be best to do both, but many stop at the urine test. Or you can ask to be referred to other 'local experts', such as a gastroenterologist or metabolism unit. If you were in or near London (for example), you could ask to be referred to Dr Robin Lachmann at the Charles Dent Metabolic Unit.

Try and make yourself smell : In Dr Preti's paper in which many TMAU cases who had visited him at Monell Chemical Senses Center were discussed, even the 2 who had very little FMO3 function ( less than 30% FMO3 function) did not smell until they took the choline challenge. So it seems very possible that most cases (including 'severe') only smell transiently. Obviously if you smell in the Drs office, it will be hard for them to diagnose you as 'olfactory reference syndrome '. If you think your FMO3 enzyme is suspect, you could try 'bulking up' on fatty fish meals the previous 2 days (fatty fish are high in TMA (technically, they are high in TMA-n-oxide, but get reduced to TMA in the gut), and so it would be a straight TMA challenge test) and/or choline (this would be a TMA-bacteria test, relying on bacteria to feed off the choline and produce TMA). It would seem very important to ask a Dr if you smell. With this condition, many often assume they smell, rather than asking. Because of this, it is hard to get a true overall picture of the problem. If the Dr says you don't smell, it's very likely at that moment that you don't. But it doesn't mean you don't have a problem. Smelling 10% of the time when you don't know when you smell is not much use. It is important to understand your 'smell' as much as possible.

What tests can a Dr commonly do ? (and could be made aware of ?): If you smell fecal/gas etc, you would think at least you were worthy of a good 'gut' checkout, and liver/metabolic tests. All Medical systems are usually very conservative and resistant to new ideas (it's a wonder anything is discovered) and often learn new concepts from adverts on TV same as small children (such as yogurt ads about probiotics). They will at least be aware of some basic tests you should have a right to, but keep in mind these tests are likely to not be of much use and may only be a factor in your smelling, or not even a factor at all. These are only a brief list to get your mind thinking about the concept :

Tests normally available from a standard medical system

h pylori	Unlikely to be a factor but worth ruling out
small intestine bacterial overgrowth	It's unknown how common this will be in fecal body odor syndrome
celiac	Unlikely to be a factor but worth ruling out
gastroenterologist (endoscopy etc)	Get your gut checked out as best you can. Pillcam would be useful but not commonly available and expensive.
metabolism unit (VOCs, TMAU)	Would be the best choice in a perfect world. In this world, don't expect much

There are other niche labs who believe the tests offered by medical systems are not enough to get a full picture. These are labs such as Genova, Metametrix, Biolab, and many others. An example of a subset who would use these labs would be film stars and athletes looking for 'real answers'. Medical systems are usually very conservative and very slow to take up on obvious answers. Sometimes these specialist tests can be done via medical systems if the Dr is sympathetic enough. BlueCross/BlueShield allows some Genova tests. With regards testing, a problem is that as a group we do not have a profile of the syndrome (apart for those who believe that TMAU is their only issue), and so we do not know exactly what to test for. At the moment as a group, we are looking for clues, rather than doing a few tests and being confident in a diagnosis.

These are just a few ideas as to what attitude to be in when visiting a Dr about body odor and/or halitosis (they are there to serve you, but also be aware of their limitations), and to try and get the most out of the medical system. But it should be kept in mind it is the system mainly at fault, with the Dr playing a lesser role.

Anthology update #5

I apologize for the lateness of posting the final draft of the anthology, because of computer problems. It will be posted no later than Saturday May 23, 2009 and submitted to our first publishing company no later than Saturday May 30.

To the new members joining the group since January and who have not read this and the following 2 paragraphs I posted on the General Board, welcome to the group! My name is Rich (or Richard). I am the editor of an anthology book that the group is currently working on. I’ve been away from the board since January. The book consists ff essays, poems, short fiction, certain posted messages that had been chosen from the board, etc. I might be contacting some of you soon to ask for your permission to place any of your posted messages into the anthology.

Please don’t feel intimidated and think that your writing is not good enough to put into our book. Any mistakes will be corrected. We are all amateurs here; none of us have been published yet.

If you want to find out whether this is something you’d be interested in participating in, please contact me at richardrcook2@aol.com. Also, send your work that you wish to be included in the anthology to that email address. New deadline: Friday May, 22, 2009. Let me know if you think you might be a little late.

The following paragraph was taken from the last update posted in January; I want to remind everyone of how we plan to get our book published.

I’ll submit our manuscript to several regular publishing companies first: the ones that don’t require a fee to publish our book. I should hear from our first publishing company 2-4 weeks after they receive our work. If we are rejected by them, I will send our book to the next one until we have exhausted all of our efforts to get it published for free. At that time, we would have to submit the manuscript to a vanity publishing company: one that requires a fee for publication. In this case, we would have to raise anywhere from $500.00 to $800.00 to get our book published. Details on how we can all donate whatever we can will be included in a future update, if necessary. Again, all of this will take place only if we are rejected by all of the free publishing companies we can contact. One way or another, our book will be published.

If you have any questions, please post them on this board. I will answer them as best I can and post the answers. If you prefer, you can also email me your questions.

I need for everyone to keep your fingers and eyes crossed that we won’t have to pay to get our book published. It wouldn’t hurt to cross your toes, too. Or would it?

Rich

Poll: TMAU urine test : % of tma-n-oxide

If your TMAU urine sample was positive for PRIMARY TMAU, What was your % for tma-n-oxide ?

Australian Trimethylaminuria Foundation website

As regular readers know, Robert Brown of the Yahoo TMAUcure forum has been busy setting up The Australian Trimethylaminuria Foundation, and he announced yesterday that the website is almost near completion and can be found at this address

http://www.tmaufoundation.org.au/

The organisation is closely associated with the exciting trimethylaminuria research proposal by Dr Christodoulou et al, which looks to be the most promising research into TMAU yet, and has been well documented here recently. Soon the body odor and halitosis community will be able to exercise the right to donate online to something promising in a few clicks.

Here is Robs full post on the latest update, from his TMAUcure Yahoo forum
TMAUcure Yahoo Forum Post can be seen here: post about Australian TMAU Foundation

I’d like to let everyone know that a receipt will be forwarded from the ATF for every donation and donors will be kept up to date on the progress of the research fund.

A very big thank you to those who have already donated.

Unlike the fund at NORD the ATF fund will not be absorbed into a general fund if it fails to reach a certain level within a certain time. Moreover, there will be no long process of bidding for the fund. What we are offering through the ATF is a fund that will go to a definite research project that people can read about in the files section at TMAUcure@yahoogroups.com and on the ATF website at www.tmaufoundation.org.au. It is a brilliant proposal whose results will be readily transferable to humans from the mouse model. The research proposal has been written by Dr John Christodoulou and his team and he will not have to wait goodness knows how many years to compete for a fund at NORD that may never reach it's target and may never go to TMAU research which we’ve seen happen before with NORD funds.

The research will be carried out through:

Western Sydney Genetics Program, The Children's Hospital at Westmead,

Sydney, Disciplines of Paediatrics and Child Health & Genetic Medicine,

University of Sydney, Sydney, New South Wales 2006, Australia.

And

Children’s Medical Research Institute, University of Sydney, Westmead, New

South Wales 2145, Australia.

The money required for Dr C's research is a lot. However, we can begin the research as soon as we raise the money to fund the first year's research as it is designed to be carried out in stages. Clear costings are provided by Dr C. in the proposal document. Also, the money that is donated to the research project goes into a trust account that can be accessed by absolutely nobody except at the direction of the board of directors and then only after a vote by all members of the Foundation. That is why I encourage donors to also become members of the ATF. The ATF is prevented by law from making payments to directors or distributions to members. The money raised can only be applied to the aims of the foundation which, as stated in the foundation's constitution, are directed at scientific research into TMAU. The ATF is independently audited and those audits as well as a copy of the ATF constitution will be available on the ATF website at http://www.tmaufoundation.org.au/ once construction is complete.

The ATF is a registered not for profit charity endorsed by the Commissioner for Taxation as a tax free and tax deductible entity. (See registration certificate in newsletter Vol. 1 Issue 2, also available on our website and on the various online forums) If anyone has any questions about the ATF and the research fund or the project itself I am happy to respond.

In the end, it wouldn't matter where the science got done. It could be done in Timbuktu for all I care - as long as it gets done and gets done yesterday. But research into a cure or better treatments is stalled everywhere it seems. That is the reason for this research fund. There are TMAUers all over the world. They belong to every race in every country. If we are going to fix this thing we need to think globally so that we can speak with one voice and make the biggest noise possible to attract funding. The ATF is trying to orchestrate that voice. We may be sufferers of a rare condition but count us up among the worlds 6 billion people and there are hundreds of thousands of us and probably an order of magnitude greater than that. With numbers like that we can do this!

As mentioned in a post at TMAUcure@yahoogroups.com, as well as smaller donations from TMAUers themselves, the ATF is now contacting philanthropic organisations and large pharmaceutical companies requesting funding. We will also be making requests to federal and state Health Departments here in Australia. I will post more about these efforts when successes occur - I don't want to shoot my mouth of just yet before the fish is in the bag (pardon the pun). Moreover, our website will be using the Google pay per click facility so that the ATF site will come up when people key in certain phrases calculated to attract potential donors. There is also our benefactor in Melbourne with whom negotiations are still afoot.

Please email if you have any questions.

Thanks and best wishes to all.

Rob

Australian Trimethylaminuria Foundation

Summary Blog posts on prebiotics and probiotics

One of the most important ways in which a probiotic organism may exert a beneficial effect on its host is to modify metabolic processes, particularly those occurring in the gut.1. Post title: The different types of probiotics

• Summary
  
• probiotics that are natural inhabitants
  
• probiotics that are not normal-inhabitants and so are transient, but they may have some advantageous benefit in the short-term…
  

2. Aruns opinion on body odor and halitosis,

Unfortunately, these types of rare strong odour conditions are difficult to treat but some people have had some success by following unusual diets e.g. vegan diet, low choline diet etc combined with excluding indole-producing vegetables from the diet. They have combined such diets with the use of supplements such as probiotics, chlorophyll, and used low PH body washes etc. It is my belief that for the systemic variety (means passed round the body via the blood) of breath/ body odour, if you do not get the diet right then no amount of supplement or body wash will help since you are still getting high levels of smell-forming metabolites being produced from the diet...

3. The Barron Report: The Probiotic Miracle

Then there's the question of how many live microorganisms are left in your formula when you actually use it. Pick up any probiotic formula, look at the label, and you'll see something like: "Contains 13 billion live organisms per capsule at time of manufacture." And that's the problem: "at time of manufacture."The die-off rate for probiotics can be astounding. Most formulas will experience a die-off approaching log 3 within just 60 days of manufacture. That means that the 13 billion you see on the label may be down to 13 million, or less, by the time you use it. Heat and moisture accelerate the process, which is why most manufacturers recommend keeping your probiotic supply refrigerated...

4. Prebiotics also discussed in video, Healing Quest TV article on probiotics (in general)

While probiotics are the actual friendly bacteria (hopefully, depending on what the manufacturer put in the capsules), prebiotics are regarded as the food for the desirable bacteria. They usually discriminately favor desirable bacteria (to different degrees of specifity), such as bifidogenic meaning they are good food specifically for bifidobacteria. As well as being naturally in certain foods, prebiotics can also be bought as a separate supplement and often are added to probiotics…

5. What are probiotics? This book, Probiotics, The scientific basis, presents the notion of probiotics since 1989.

6. Probiotics: Metabolic interactions in the gut
One of the most important ways in which a probiotic organism may exert a beneficial effect on its host is to modify metabolic processes, particularly those occurring in the gut. Such a beneficial effect could be achieved in theory by a variety of mechanisms:

• By suppressing reactions which result in the generation of toxic or carcinogenic metabolites.
  
• By stimulating enzymic reactions involved in detoxification of potentially toxic substances, either ingested or formed endogenously.
  
• By stimulating mammalian enzymes involved in the digestion of complex nutrients, or when such enzymes are absent (due to genetics or disease) providing a bacterial source of these enzymes.
  
• By synthesizing vitamins and other essential nutrients not provided in sufficient quantities in the diet...
  

7. videos : introduction to probiotics and Healing Quest TV article on probiotics (in general)

8. Part 2 of interview with Cass Nelson-Dooley of Metametrix

What do you think of the quality of probiotics on the market and are there any brands of probiotics you recommend ?

We are impressed with Klaire Labs probiotic and prebiotic formulas. I also like Custom Probiotics and a high dose probiotic called VSL#3. Designs for Health has a good probiotic product as well.

Is taking prebiotics on its own a good idea ? And which type of prebiotic do you feel is best ?

Fruits and vegetables are a great source of fiber (prebiotics). Other ideas are inulin, xylooligosaccharides, larch arabinogalactans, and beta glucan.

Is there general treatment advice for 'suspected' dysbiosis or does it vary too much ? For instance, take nystatin and metronidazole in a 'scorched earth' policy ?

I think the “4R Protocol” is the most general treatment advice and it’s comprehensive, but every doctor has a different approach and dysbiosis treatment should be tailored to the patient.

Treatment using 4 “R” Protocol for Intestinal Health from the GI Effects Interpretive Guide

Remove offending foods, medications, gluten (if sensitive) and reduce poor quality fats, refined carbohydrates, sugars, and fermented foods (if yeast is present). Consider antimicrobial, antifungal, and/or antiparasitic therapies in the case of opportunistic/pathogenic bacterial, yeast, and/or parasite overgrowth (see below for specific recommendations).

Replace what is needed for normal digestion and absorption such as betaine HCl, pancreatic enzymes, herbs that aid in digestion such as deglycyrrhizinated licorice and marshmallow root, dietary fiber, and water.

Reinoculate with favorable microbes (probiotics such as Lactobacillus sp., Bifidobacter sp., and Saccharomyces boulardii). To enhance the growth of the favorable bacteria, supplement with prebiotics such as inulin, xylooligosaccharides, larch arabinogalactans, beta glucan, and fiber.

Repair mucosal lining by giving support to healthy intestinal mucosal cells, goblet cells, and to the immune system. Consider L-glutamine, essential fatty acids, zinc, pantothenic acid and vitamin C.

Why does the intake of probiotics sometimes produce bloating and gas in some people and not in others?

Not all people react the same to probiotics because it depends on their microbial populations. When a person has a poor diet (high simple sugars, low fiber), taking probiotics can produce gas. However, this usually goes away with time. If the patient increases complex carbs and decreases simple sugars that often decreases any gas and bloating brought on by the probiotic. When there are unexplained reactions to probiotics or prebiotics, it is a good idea to run an Organix test, a GI Effects test, or food antibody test to identify underlying imbalances.

Conference Call Topic: Being Social

In today’s conference call, we dealt mainly with the emotional consequences and coping mechanism of daily living with a body odor condition. Some of the emotional responses frequently expressed by body odor sufferers are the following:

1. A strong sense of pessimism;

2. Develop a perception that others are attempting to take away our humanity, our sense of self-worth through social rejection, sometimes in a very hateful manner;

3. Our capacity to love people and to establish relationships is diminished to a certain degree;

4. Social powers decrease at work, school, friendships, and even with family members who are non-sufferers

5. Our awry social development may very well manifest itself while we attempt to establish relationships with each other in this community, however being more aware of the impact of our common social experiences with this condition we can help each other other grow to become better social beings in spite of our past experiences.

We can’t focus on everything that surrounds us in life, so we have to choose what we want to focus on...Recommended coping mechanism within the community and outside:

1. Improve communication skills in our community by seeking to become involved in as many social opportunities as possible. This may be participating in "multi-dimensional" communications involving hearing and seeing each others' voice tonality and body language, as opposed to our customary one-dimensional communication tool of posting in a forum. The most ideal situation would be to participate in meet-ups, the seconds best situation would be participating in conference calls, and of course, continue to participate in the forums.

2. Change our focus to what’s really going on with people around us as opposed to self-centeredness in which we become the focus of our attention. Realize that people may be talking, laughing, and thinking about their own issues as opposed to about us at any given moment in time.

3. Eye contact: When we feel shame, we tend to avoid eye contact, thus sending a message that, “I don’t want to connect with you.” We need to change our social approach to having eye contact in an inviting manner, so that others may see our humanity.

4. Think positively: Avoid thinking in negative terms:

a. Negative: I hope I don’t stink today.
b. Positive: Today I will be stress-free and I will smell good as a result.

5. Strive to be independent of needing praise: Change from being an insecure person to a more independent one; and acquiring an ‘I don’t care’ attitude regarding the odor while in a social setting.

6. Strive to be a group of selfless people – focusing less on our individual selves and more on the big picture of where we would like our community to take us – toward physical and emotional healing

7. We chose what to focus on: We can’t focus on everything that surrounds us in life at all times, so we have to choose what we want to focus on, either on the negative or the positive. Which will it be?

Christodoulou TMAU research proposal : Methylophilus methylotrophus as a TMAU probiotic

In the trimethylaminuria research proposal by Dr Christodoulou et al, he proposes trying 2 methods of treatments (albeit, on mice). The first is using PCT124/Ataluren to see if it can negate a nonsense mutation in primary trimethylaminuria. This would only be of benefit (if it works) to the subset of sufferers who have primary TMAU due to nonsense mutations.

The other method would potentially be of benefit to all sufferers. It has long been mentioned that if a bacteria/probiotic could detoxify trimethylamine in the gut, then it could do the (gut) detoxifying for the person. The long-speculated suggestion was for a bacteria engineered to be rich in FMO3. Dr Christodoulou is proposing to use a known harmless bacteria (Methylophilus methylotrophus) that, instead, detoxifies trimethylamine by an alternative pathway. Rather than FMO3 (which changes it to trimethylamine-n-oxide, the trimethylamine will be altered to dimethylamine and formaldehyde by an enzyme in the bacteria (trimethylamine dehydrogenase).

Not knowing anything of the metabolic differences, a first impression is that an FMO3 enriched bacteria would seem preferable, since the by-products of the other pathway don't seem too nice-sounding (dimethylamine and formaldehyde). Also, FMO3 is a commonly used enzyme, dealing with probably 1000s of substrates that are amines, sulfides, or phosphorous containing. Most of these substrates can go a slower more complicated alternative route if necessary, but in humans, TMA cannot (hence possibly the reason researchers feel TMA is the only smell issue with FMO3). Since most seem to say they can smell of all sorts of smells, you have to wonder if the whole xenobiotic-metabolizing-enzyme system is becoming 'backed up' with other typical FMO3 substrates, with TMA being a baseline problem? Or perhaps TMA is an inhibitor of these enzymes? For these types of reasons, it would seem preferable to have an FMO3-rich bacteria, but maybe this is not currently possible, or for logistical reasons. So Dr Christodoulou has gone for a bacteria known to have trimethylamine-dehydrogenase enzyme, an enzyme which humans don't possess.

However this may be unimportant and we are grateful for any research. It would be interesting to know if this bacteria is available. It is possibly used in the agricultural industry as a source of food for pigs. But nobody likely knows the potential averse reactions in humans. At this stage, we can only wait to see how the mice get on, although these 2 treatment stages aren't planned until year 3.

Other strategies for metabolising TMA in the small intestine:

Anaerobic gut bacteria can contribute to the trimethylamine load in patients with TMAU by enhancing the metabolism of choline in food to trimethylamine in the gut¹. As stated above, one form of therapy of TMAU, albeit in more extreme cases, is to treat patients with antibiotics aiming to reduce the intestinal load of these bacteria. However, the antibiotics that need to be used have potentially serious side effects, and so can only be used for short periods of time.

An alternative strategy for reducing the gut trimethylamine load would be to colonise the gut with harmless bacteria that are capable of metabolising trimethylamine. One such micro-organism is Methylophilus methylotrophus. This is an aerobic monoflagellate bacterium that uses methanol as the sole source of carbon and energy¹⁶. It was initially thought to be of potential commercial value in the single-cell protein production industry, but it proved to be a nonfinancial venture. When cultured in trimethylamine, the enzyme trimethylamine dehydrogenase is induced, which converts trimethylamine to dimethylamine and formaldehyde¹⁷. Extensive studies have shown that this micro-organism is non-pathogenic and non-toxic in animals^{18, 19}. Therefore colonisation of the gut with Methylophilus methylotrophus in individuals with TMAU could be of potential therapeutic utility.

Summary Blog posts on vitamins/minerals

...vitamins and minerals to optimize genetic enzyme weaknesses
1. Post title: Want to build muscle and need extra protein with your choline diet? It is safer to just go with the egg whites, since 1/4 cup/60g weight of liquid egg whites contain 1.410mg of choline and 0.250mg of betaine. I think it would be safe to say that you can have this a number of times a day as you keep track of your choline intake to your personal non-odor producing level.

Recommends a multivitamin that contains 100% of the DRI for vitamins and minerals, particularly folate [FOLIC ACID] and riboflavin [VITAMIN B2].

2. Post title: Vitamin & mineral deficiencies : An unknown quantity in bloodborne odors The status of the B Vitamins is probably a good starting point, since they are often co-factors in the drug metabolizing enzymes (the xenobiotic enzymes, of which the FMO family of enzymes are a part of). B Vitamins are also often produced by good gut bacteria [ so probiotics helps]. Biotin in particular.

3. Post title: Probiotics: Metabolic interactions in the gut One of the most important ways in which a probiotic organism may exert a beneficial effect on its host is to modify metabolic processes, particularly those occurring in the gut. Such a beneficial effect could be achieved in theory by a variety of mechanisms:

• By suppressing reactions which result in the generation of toxic or carcinogenic metabolites.
  
• By stimulating enzymic reactions involved in detoxification of potentially toxic substances, either ingested or formed endogenously.
  
• By stimulating mammalian enzymes involved in the digestion of complex nutrients, or when such enzymes are absent (due to genetics or disease) providing a bacterial source of these enzymes.
  
• By synthesizing vitamins and other essential nutrients not provided in sufficient quantities in the diet...
  

4. Post title: Comments posted in this blog "It might be dangerous to use charcoal in the long term because 'In addition to adsorption of toxins, activated charcoal also adsorbs food nutrients, vitamins, and minerals.' "

5. Post title: Berkeley press release on the theory of using vitamins and minerals to optimize genetic enzyme weaknesses This is the same as the recent article in a recent post about the potential of vitamins and minerals being used to optimize in-born genetic weaknesses in certain enzymes, but also includes a short video of one of the researchers. It is a Berkeley press release. Many enzymes need a 'co-factor' to function, such as a vitamin or mineral.

6. Post title: Dietary Reference Intakes Tables: Vitamins The table in this article shows the food source, function, and adverse effects of excessive consumption of vitamins. It recommends dosage for life stage groups, and advises of special considerations.

7. Post title: DRI Reprot-Thiamin, Riboflavin, Niacin, Vit B6, Folate, Vit B12, Pantothenic Acid, Biotin, & Choline This DRI [Dietary Reference Intake] report includes the eight water-soluble B complex vitamins — thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline, involved with energy metabolism and single-carbon unit transfer processes. View or download the entire 591 page document or just selected sections below, or find information for obtaining the book version...

8. Post title: Niacin, Vitamin B3, Nicotinic Acid "Niacin (also known as vitamin B3) is found in dairy products, poultry, fish, lean meats, nuts, and eggs. Legumes and enriched breads and cereals also supply some niacin." Many of these are foods high in choline that TMAU sufferers need to stay away from to prevent body odor. Therefore, it's important to review the recommended dose noted in this encyclopedic article to meet the known nutrient needs.

9. Post title: What should be done with the personal donations to MeBO ? One [of mebo’s] idea is to do small anecdotal studies to try to identify a pattern into systemic body odors. An example would be a leaky gut study, where members of the forum are offered the leaky gut test funded by MeBO. This study would not tell us anything conclusive, but if those that participate have leaky gut, it may tell us it could be a factor. Another example is B vitamin status. Many B vitamins are produced by a good gut flora. B vitamins are involved in many enzyme functions (often being a cofactor). If there was a vitamin deficiency involved, it would likely be a B vitamin. These amateur studies are far from ideal, but may tell us something, and are probably more enlightening than where we currently are. These small studies may also act as a focus and a template as to what the group can achieve in the future as well.

Possible areas of speculative testing with personal donation money:

genetics : DNA tests. FMO3 testing. Detoxigenomic test
vitamin status : probably B vitamins mostly
mineral status : Magnesium ?
dysbiosis tests : candida, parasites, etc.
leaky gut testing
Trimethylaminuria testing
Malodorous Volatile Organic Compound testing

10. Post title: Interview : Mark Howard of Biolab Medical Unit, London Biolab is a medical laboratory specialising in nutritional and environmental Medicine. We measure mineral and vitamin levels, toxic metals, other biochemical levels that are related to the availability of vitamins, minerals and other nutrients, and we also have an extensive range of profiles for assessing the effects of Twenty-First century lifestyles on our bodies (Tests).