Sulfurous, fecal or pungent (other) nasal bb? Read on.

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Do you have sulfurous, fecal, metallic, smoky or otherwise pungent nasal (extraoral) bb or musty bo? Then READ ON.

It is now known from research that TMAU can manifest as ISOLATED HALITOSIS without body odour, with the breath smelling in different ways, such as SULFUROUS, FECAL or PUNGENT (unclear), but NOT FISHY. In this post I’ll include both genetic & secondary (non-genetic) causes, available treatments, diet, the metabolic pathways to TMA formation, FMO3 function, etc.
To start off: in different research studies it was mentioned several times that false negative results for TMAU are very common. They can differ significantly throughout the day and throughout the menstrual cycle (hormones affect it), so a once in a month/year test is not reliable even if it’s negative. Moreover, FMO3 is not the only gene responsible for the malodor and TMAU-like malodour can manifest when the FMO3 gene alone seems functional.
New genes are found to cause TMAU:
https://bmcmedgenet.biomedcentral.com/a ... 017-0369-8

The characteristics of the people studied:
(I couldn’t insert a picture of the table, so read it as a table listing the characteristics of the subjects studied; the ones on top have worst TMA oxidising capacity as indicated by low tmao/tma ratio)

1)Tmao:tma ratio 2) Common body odour 3) Common oral odours
1) 0.13 2) None 3) Pungent,sulfurous
1) 0.37 2) None 3) Sulfurous/fecal
1) 0.47 2) None 3) Fecal,pungent
1) 0.54 2) None 3) Mild sulfurous
1) 0.58 2) None 3) Mild metallic, smoky
1) 0.61 2) None 3) Mild
1) 0.79 2) None 3) Sulfurous
1) 0.79 2) None 3) Strong sulfurous
1) 0.86 2) Musty 3) Unremarkable
1) 0.87 2) None 3) Unremarkable

I speculate that the differences of the odours are likely attributable to the fact that other oxidoreductase genes were affected, which might mean that on top of TMA other compounds couldn’t be oxidised and can explain strong bb in people with subnormal TMA oxidation threshold. Maybe other compounds affected the odours not typically associated with TMAU because FMO3 oxidises sulfur-containing substances too! (included in “detailed notes”).Thus, it is a more broad and diverse metabolic issue of dysfunctional oxidoreductase genes. Have you done or considered doing genetic testing? The research paper is in open access, so you can have a look at the new identified genes yourself. It is very informative, the best one I have found on the topic and covers specific SNPs (alleles) that are first identified as contributors to this metabolic issues.

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Smell:
“In small quantities a build up of TMA can cause halitosis (bad breath) a fishy or garbage like odour but a greater build up of TMA can cause a smell of rotting fish as well as being sulphurous. Symptoms can be present from birth, but most people seem to develop symptoms around puberty and through the teens, however, TMAU can develop much later in life. In women symptoms can be more severe just before and during menstruation, after taking oral contraceptives and around the time of menopause.”
“TMA has been described as smelling like rotting fish, rotting eggs, garbage, or urine. “
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Interesting random fact: “Indoles in cruciferous vegetables – cabbage, broccoli, cauliflower and Brussel sprouts - naturally inhibit the FMO3 enzyme.”
Do cruciferous vegetables worsen your bb?

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There is a new drug in development that is patented for the cardiovascular disease but works for TMAU as well. It is not launched yet, but probably will in future. It works by preventing the formation of TMA in the gut, so there’s hope for those affected.

Drug:
https://pubmed.ncbi.nlm.nih.gov/24247281/

https://www.google.ru/amp/s/newsroom.cl ... robes/amp/

iodomethylcholine (IMC): small molecule inhibitors of the major bacterial trimethylamine (TMA) lyase enzymes have been developed:

https://pubmed.ncbi.nlm.nih.gov/32330092/

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Not only genes, but gut microbiota are a pivotal contributor!

Sulfate reducing bacteria convert choline into tma:
https://bmcmedgenet.biomedcentral.com/a ... 017-0369-8

https://www.pnas.org/content/109/52/21307

Archaebiotics: proposed therapeutic use of archaea to prevent trimethylaminuria and cardiovascular disease:
https://pubmed.ncbi.nlm.nih.gov/24247281/

Microbiota analyses showed that Clostridiaceae, Lachnospiraceae and Coriobacteriaceae alterations represented the bacterial families with highest variations. This results in an excessive release of serotonin and an hyperactivation of the vagus nerve that might determine the widest spectrum of psychiatric disorders shown by affected patients. These metabolites, as short chain fatty acids, lactate and neurotransmitter precursors, are also related to TMA accumulation.
https://pubmed.ncbi.nlm.nih.gov/33572540/

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Trials in US and UK for ANOTHER (novel) approach for treating TMAU:

https://www.healtheuropa.eu/fish-odour- ... air/96357/

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Tmau diet - reducing food high in choline, nitrogen, sulfur:
https://www.nutritionhouse.com/Library/ ... x?ID=65271

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SECONDARY TMAU:
Secondary trimethylaminuria occurs when the liver FMO3 enzyme is either overwhelmed or underactive for some reason. The enzyme may be overwhelmed by an excessive dietary intake of trimethylamine precursors or when there is bacterial overgrowth in the bowel resulting in increased production of trimethylamine.

The enzyme may be underactive in liver and kidney disease, during menstruation or in the presence of inhibitors such as those derived from eating Brussel sprouts, oral thiourea or topical hydroquinone. It is likely that in many instances, secondary trimethylaminuria occurs in cases with an inherent reduction in enzyme activity such as in a carrier for the defective gene (a heterozygote).

A transient form has been described in childhood. Investigations confirm the elevated level of trimethylamine in the urine, but the actual conversion of trimethylamine to trimethylamine N-oxide is borderline normal. It resolves spontaneously after months or years and the levels and conversion are then normal. It is thought to be due to overproduction of trimethylamine in the bowel, although no abnormality could be demonstrated. It is important to distinguish this form from primary trimethylaminuria by measuring both the trimethylamine and trimethylamine N-oxide levels in urine.
Trimethylamine is also the cause of the fishy smell associated with bacterial vaginosis.

The smell may fluctuate and triggers for an increase in odour include:
* menstruation, with a worsening just before and during a menstrual period. Studies of normal subjects show a reduced enzyme activity of 60-70% at this time. Thus it appears sex hormones affect the ability to metabolise trimethylamine.
* use of the oral contraceptive pill
* excessive stress or emotional upset exercise
* infection, especially with fever
* dietary intake of high choline or trimethylamine N-oxide-containing foods.

The diagnosis is confirmed on 24-hour urine collection while on a normal diet, and an 8-hour urine collection after either a marine fish meal (for children) or 600mg oral trimethylamine load (adults). Both trimethylamine and trimethylamine N-oxide should be measured. The trimethylamine challenge will detect both carriers and sufferers, as both will have a reduced conversion to trimethylamine N-oxide. Normal subjects will convert more than 80% of the trimethylamine to the N-oxide form, carriers convert less than 80% and sufferers less than 25% after the oral challenge. In menstruating females, the timing of the test is important as it may be a transient problem.

Some sufferers respond well to courses of neomycin, amoxicillin or metronidazole as these alter the bowel bacteria, reducing the production of trimethylamine. This will be particularly helpful in secondary trimethylaminuria due to bacterial overload and can be used in primary trimethylaminuria for important social situations or when dietary restriction cannot be maintained. To reduce the risk of antibiotic-resistance, antibiotics should only be used intermittently or alternated every 2 weeks.

Oral copper-chlorophyllin may also give temporary improvement by altering the bowel bacteria. low metabolic capacity to convert TMA to its odorless metabolite, TMAO. The metabolic capacity, as defined by the concentration of TMAO excreted in the urine divided by TMA concentration plus TMAO concentration, in these seven individuals ranged from 70 to 90%. In contrast, there were no healthy controls examined with less than 95% of the metabolic capacity to convert TMA to TMAO.

intake of dietary charcoal (total 1.5 g charcoal per day for 10 days) reduced the urinary free TMA concentration and increased the concentration of TMAO to normal values during charcoal administration. Copper chlorophyllin (total 180 mg per day for 3 weeks) was also effective at reducing free urinary TMA concentration and increasing TMAO to those of concentrations present in normal individuals. In the TMAU subjects examined, the effects of copper chlorophyllin appeared to last longer (i.e., several weeks) than those observed for activated charcoal.

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DETAILED NOTES

TREATMENTS:
1)3,3‐dimethyl‐1‐butanol (DMB), the structural analog of choline, which serves as a tool drug to lower TMA formation through inhibition of microbial choline TMA lyse (94). It was showed to significantly reduce the circulating levels of TMAO non‐lethally in ApoE−/− mice fed a high choline diet (94).
2) Fluoromethylcholine (FMC) and iodomethylcholine (IMC) are second‐generation TMA lyase inhibitors and choline analogues. In contrast to DMB, both FMC and IMC promoted the irreversible inhibition of microbial TMA lyase via generating a reactive species, which had the greatly tight interaction with active site residue of TMA lyase after C‐N bond cleavage (93). Remarkably, they displayed enhanced inhibitory potency, including suppressing TMA and TMAO levels and reducing the rate of thrombus formation without observed toxicity in vivo compared with DMB (93).
3) supervised exercise combined with caloric restricted diets effectively lowered the TMAO levels (105)
4) antibiotics are regarded as a promising approach to target microbiota‐derived TMAO production. In a clinical study, healthy participants were required to administrate ciprofloxacin plus metronidazole for one month, which are broad‐spectrum antibiotics. It was found that administration of antibiotics could effectively decrease plasma levels of TMAO. However, after the withdrawal of antibiotics, the plasma TMAO levels returned to the initial levels with recovery of intestinal microbiota (20). Long‐term antibiotic exposure can lead to the resistance of intestinal microbial colonization in the hosts, and the TMAO levels gradually rebounded to the initial levels (13). More notably, antibiotics can not only target harmful bacteria, but also some beneficial species.
5) Both prebiotics and probiotics are good candidates for the modulating the gut microbiota and conferring favorable effects to the host. An example of prebiotics is as follows: Resveratrol is a natural phenolic phytochemical with poor bioavailability in the intestinal, and it can modulate intestinal bacteria effectively. Intake of Resveratrol promotes the growth of beneficial bacteria including Bacteroides, Lactobacillus and Bifidobacterium with the decline in the TMAO levels (112, 113). Preclinical data have showed that Resveratrol decreased TMAO levels and inhibited development of atherosclerosis in vivo (114). As with prebiotics, the consumption of various probiotics such as Lactobacillus plantarum could decrease TMAO production and attenuate atherosclerotic lesion formation in ApoE−/− mice (111). Another example of probiotics is E. aerogenes, the serum TMAO and fecal TMA levels in mice fed choline‐rich diet with E. aerogenes were lower compared with those of control group. The study showed that treatment with E. aerogenes significantly decreased serum TMAO levels with altered microbial composition, which might be an alternative approach for atherosclerosis treatment (115). Besides that, there is a group of methanogens colonized in the gastrointestinal tract that can only utilize TMA as a substrate. A recent research has found that the Methanomassiliicoccus luminyensis strain B10 was able to deplete TMA and TMAO by combining H2 for methanogenesis (116).

GUT MICROBIOTA:
choline can be decomposed by an array of biological reactions involving the splitting of the carbon–nitrogen bond of choline. These processes are regulated by gut microbiota, particularly by the phylum Firmicutes, phylum Proteobacteria and six microbial genera, such as Anaerococcus hydrogenalis, Clostridium asparagiforme, Clostridium hathewayi, Clostridium sporogenes, Escherichia fergusonii, Proteus penneri, Providencia rettgeri and Edwardsiella tarda (37, 38). Also, gut microbiota plays a crucial role in the metabolism of L‐carnitine by cleaving the 3‐hydroperoxybutyryl moiety. The main microbial species responsible for the degradation of L‐carnitine are proteobacteria and Bacteroidetes at phyla level and Prevotellaceae at family level (15, 33, 39). More notably, in line with the obligatory role of gut microbiota played in TMAO production, studies have shown that the use of broad‐spectrum antibiotics altered gut microbiota composition and reduced TMAO levels, which indicated the importance of gut microbiota in the metabolism of TMAO
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Patent
WO/2018/236899

Treating disease & promoting weight loss by inhibiting the TMA/FMO3/TMAO pathway

Inventors: Hazen SL, Brown JM

Assignee: The Cleveland Clinic Foundation, Cleveland, Ohio (USA)
Trimethylamine N-oxide is generated from trimethylamine (produced from dietary nutrients such as choline, lecithin and carnitine by gut microbial lyases) by hepatic flavin-containing monooxygenases (primarily FMO3) [26]; this is the TMA/FMO3/TMAO pathway. TMAO is associated with microbial dysbiosis and its dysregulation is being studied for its linkage with cardiovascular and neurological disorders, renal diseases and cancer [27]. TMAO being a potent atherogen, the link of FMO3 with cholesterol is particularly strong [28,29]. Applications to achieve weight loss in obesity, as claimed here, do not seem to have been reported so far. Plasma TMAO levels in mice and FMO3 mRNA expression in men demonstrated positive correlations with obesity. The complex therapy can consist of elements including: 3,3-dimethyl-l-butanol or a derivative; acetylsalicylic acid or a derivative, optionally delivered directly to the colon or cecum; an FMO3 inhibitor (tenofovir, methimazole or an antibody); a gut TMA lyase inhibitor (e.g., iodomethyl choline); fecal microbiota transplantation; a probiotic, prebiotic or broad-spectrum antibiotic that reduces TMA production in the gut; an antiplatelet agent; a TMA and/or TMAO sequestering agent; a compound comprising at least one of: ethanol amines, trimethylsilylethanol, phosphocholine and P,P,P-trimethyl ethanolphosphine; and an inhibitor of TMA-induced trace amine-associated receptor 5 activation. In 6-week-old male C57BL6/J mice maintained on either 60% high-fat diet with 0.06% (w/w) TMA lyase inhibitor iodomethyl choline for 20 weeks, weight gain was significantly reduced versus high-fat controls; this was replicated in leptin-deficient ob/ob mice on standard chow with or without iodomethyl choline. For closely related work from the inventors concerning platelet responsiveness, see Zhu et al. [30].
Published: 27 December 2018
MeSH keywords: flavin-containing monooxygenase/methylamines/obesity

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FMO3 function
Human flavin-containing monooxygenase 3 (FMO3) in the liver catalyzes a variety of oxygenations of nitrogen- and sulfur-containing medicines and xenobiotic substances. Because of growing interest in drug interactions mediated by polymorphic FMO3, benzydamine N-oxygenation by human FMO3 was investigated as a model reaction. Among the 41 compounds tested, trimethylamine, methimazole, itopride, and tozasertib (50 μM) suppressed benzydamine N-oxygenation at a substrate concentration of 50 μM by approximately 50% after co-incubation. Suppression of N-oxygenation of benzydamine, trimethylamine, itopride, and tozasertib and S-oxygenation of methimazole and sulindac sulfide after co-incubation with the other five of these six substrates was compared using FMO3 proteins recombinantly expressed in bacterial membranes. Apparent competitive inhibition by methimazole (0-50 μM) of sulindac sulfide S-oxygenation was observed with FMO3 proteins. Sulindac sulfide S-oxygenation activity of Arg205Cys variant FMO3 protein was likely to be suppressed more by methimazole than wild-type or Val257Met variant FMO3 protein was. These results suggest that genetic polymorphism in the human FMO3 gene may lead to changes of drug interactions for N- or S-oxygenations of xenobiotics and endogenous substances and that a probe battery system of benzydamine N-oxygenation and sulindac sulfide S-oxygenation activities is recommended to clarify the drug interactions mediated by FMO3.
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Both human FMO1 and FMO3 S-oxygenate a number of nucleophilic sulfur-containing substrates and in some cases, does so with great stereoselectivity. Human FMO3 is sensitive to steric features of the substrate and aliphatic amines with linkages between the nitrogen atom and a large aromatic group such as a phenothiazine of at least five carbons are N-oxygenated significantly more efficiently than those substrates with two or three carbons. For amines with smaller aromatic substituents such as phenethylamines, often these compounds are efficiently N-oxygenated by human FMO3. Currently, the most promising non-invasive probe of in vivo human FMO3 functional activity is the formation of trimethylamine N-oxide from trimethylamine that comes from dietary choline. (S)-Nicotine N-1'-oxide formation can also be used as a highly stereoselective probe of human FMO3 function for adult humans that smoke cigarettes. Finally, cimetidine S-oxygenation or ranitidine N-oxidation can also be used as a functional probe of human FMO3. With the recent observation of human FMO3 genetic polymorphism and poor metabolism phenotype in certain human populations, variant human FMO3 may contribute to adverse drug reactions or exaggerated clinical response to certain medications. Knowledge of the substrate specificity for human FMO3 may aid in the future design of more efficacious and less toxic drugs.

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As others have pointed out and as I have observed myself some people react very strongly, whereas some seem not to notice/know at all. Some people are even able to maintain relationships.

In the case of TMA, for example, research estimated 7% of participants have TMA-specific anosmia: they can’t feel TMA at all.

https://link.springer.com/article/10.1007/BF00988023

This is the case with various Volatile Organic Compounds. If you take some genetic tests, they can tell if you’re able to smell certain compounds based on your genes (not bb related, common compounds).

This can explain partially (the other factor is politeness) the differences in reactions you get - the sensitivity to smells and even the subjective perception of the smells differs (yes, it does differ for even the most common smells). Even if you don’t have TMAU.

I don’t have TMAU, but I have seen few people, who didn’t feel my smell no matter how bad it was. It wasn’t due to politeness, I always notice when someone tries to be polite and doesn’t give reactions, but still is aware of it.