Excretion Of Trimethylamine Research Articles

Le « Fish odor syndrome » : une maladie socialement invalidante

IntroductionFish odor syndrome (FOS) is a rare metabolic disorder that manifests as “rotten fish” body odor and is caused by the excretion of trimethylamine (TMA) in body fluids. This disease can have a negative impact on the social life of affected patients. Case reportsWe report the case of two female patients complaining about unpleasant body odor. The diagnosis of FOS was confirmed by the demonstration of trimethylaminuria by NMR spectroscopy and by molecular analysis of the FMO3 gene. A restrictive choline diet combined with digestive decontamination reduced odor symptoms and improved the social life of these 2 patients. ConclusionsFish odor syndrome is a rare and unrecognized disease that can affect the quality of life of affected persons. Following laboratory diagnosis, treatment is often effective.

Gut-Brain Axis Cross-Talk and Limbic Disorders as Biological Basis of Secondary TMAU.

Background: Trimethylaminuria (TMAU) is a rare metabolic syndrome characterized by the accumulation and the excretion of trimethylamine (TMA), a volatile diet compound produced by gut microbiota. Gut microbiota alterations are mainly involved in the secondary TMAU, whose patients show also different psychiatric conditions. We hypothesized that the biological activity of several molecules acting as intermediate in TMA metabolic reaction might be at the basis of TMAU psychiatric comorbidities. Methods: To corroborate this hypothesis, we performed the analysis of microbiota of both psychiatric suffering secondary TMAU patients and TMAU “mentally ill” controls, comparing the alteration of metabolites produced by their gut bacteria possibly involved in neurotransmission and, in the same time, belonging to biochemical pathways leading to TMA accumulation. Results: 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. Conclusions: Knowledge of microbiota-gut-brain axis may become a potential new strategy for improving metabolic diseases and to treat linked psychiatric disorders.

Archaea, specific genetic traits, and development of improved bacterial live biotherapeutic products: another face of next-generation probiotics.

Trimethylamine (TMA) and its oxide TMAO are important biomolecules involved in disease-associated processes in humans (e.g., trimethylaminuria and cardiovascular diseases). TMAO in plasma (pTMAO) stems from intestinal TMA, which is formed from various components of the diet in a complex interplay between diet, gut microbiota, and the human host. Most approaches to prevent the occurrence of such deleterious molecules focus on actions to interfere with gut microbiota metabolism to limit the synthesis of TMA. Some human gut archaea however use TMA as terminal electron acceptor for producing methane, thus indicating that intestinal TMA does not accumulate in some human subjects. Therefore, a rational alternative approach is to eliminate neo-synthesized intestinal TMA. This can be achieved through bioremediation of TMA by these peculiar methanogenic archaea, either by stimulating or providing them, leading to a novel kind of next-generation probiotics referred to as archaebiotics. Finally, specific components which are involved in this archaeal metabolism could also be used as intestinal TMA sequesters, facilitating TMA excretion along with stool. Referring to a standard pharmacological approach, these TMA traps could be synthesized ex vivo and then delivered into the human gut. Another approach is the engineering of known probiotic strain in order to metabolize TMA, i.e., live engineered biotherapeutic products. These alternatives would require, however, to take into account the necessity of synthesizing the 22nd amino acid pyrrolysine, i.e., some specificities of the genetics of TMA-consuming archaea. Here, we present an overview of these different strategies and recent advances in the field that will sustain such biotechnological developments. KEY POINTS: • Some autochthonous human archaea can use TMA for their essential metabolism, a methyl-dependent hydrogenotrophic methanogenesis. • They could therefore be used as next-generation probiotics for preventing some human diseases, especially cardiovascular diseases and trimethylaminuria. • Their genetic capacities can also be used to design live recombinant biotherapeutic products. • Encoding of the 22nd amino acid pyrrolysine is necessary for such alternative developments.

Diagnosis and phenotypic assessment of trimethylaminuria, and its treatment with riboflavin: 1H NMR spectroscopy and genetic testing

BackgroundTrimethylaminuria (TMAU) is a metabolic disorder characterized by the excessive excretion of the malodorous compound trimethylamine (TMA). The diagnosis of TMAU is challenging because this disorder is situated at the boundary between biochemistry and psychiatry. Here, we used nuclear magnetic resonance spectroscopy to assess TMAU in 13 patients. We also sequenced the FMO3 gene in 11 of these patients. Treatment with vitamin B2 was prescribed.ResultsTwo patients (aged 3 and 9 years at the initial consultation) had a particularly unpleasant body odor, as assessed by their parents and the attending physicians. The presence of high urine TMA levels confirmed the presence of a metabolic disorder. The two (unrelated) children carried compound heterozygous variants in the FMO3 gene. In both cases, vitamin B2 administration decreased TMA excretion and reduced body odor. The 11 adults complained of an unpleasant body odor, but the physicians did not confirm this. In all adult patients, the urine TMA level was within the normal range reported for control (non-affected) subjects, although two of the patients displayed an abnormally high proportion of oxidized TMA. Seven of the 9 tested adult patients had a hypomorphic variant of the FMO3 gene; the variant was found in the homozygous state, in the heterozygous state or combined with another hypomorphic variant. All 11 adults presented a particular psychological or psychiatric phenotype, with a subjective perception of unpleasant odor.ConclusionsThe results present the clinical and biochemical data of patients complaining of unpleasant body odor. Contrary to adult patients, the two children exhibited all criteria of recessively inherited trimethylaminuria, suspected by parents in infancy. B2 vitamin treatment dramatically improved the unpleasant body odor and the ratio of TMA/Cr vs TMAO/Cr in the urine in the children. Other patients presented a particular psychological or psychiatric phenotype.

A compound heterozygous mutation in the FMO3 gene: the first pediatric case causes fish odor syndrome in Korea.

Trimethylaminuria (TMAuria), known as “fish odor syndrome,” is a congenital metabolic disorder characterized by an odor resembling that of rotting fish. This odor is caused by the secretion of trimethylamine (TMA) in the breath, sweat, and body secretions and the excretion of TMA along with urine. TMAuria is an autosomal recessive disorder caused by mutations in flavin-containing monooxygenase 3 (FMO3). Most TMAuria cases are caused by missense mutations, but nonsense mutations have also been reported in these cases. Here, we describe the identification of a novel FMO3 gene mutation in a patient with TMAuria and her family. A 3-year-old girl presented with a strong corporal odor after ingesting fish. Genomic DNA sequence analysis revealed that she had compound heterozygous FMO3 mutations; One mutation was the missense mutation p.Val158Ile in exon 3, and the other was a novel nonsense mutation, p.Ser364X, in exon 7 of the FMO3 gene. Familial genetic analyses showed that the p.Val158Ile mutation was derived from the same allele in the father, and the p.Ser364X mutation was derived from the mother. This is the first description of the p.Ser364X mutation, and the first report of a Korean patient with TMAuria caused by novel compound heterozygous mutations.

The complex metabolism of trimethylamine in humans: endogenous and exogenous sources.

Trimethylamine (TMA) is a tertiary amine with a characteristic fishy odour. It is synthesised from dietary constituents, including choline, L-carnitine, betaine and lecithin by the action of microbial enzymes during both healthy and diseased conditions in humans. Trimethylaminuria (TMAU) is a disease typified by its association with the characteristic fishy odour because of decreased TMA metabolism and excessive TMA excretion. Besides TMAU, a number of other diseases are associated with abnormal levels of TMA, including renal disorders, cancer, obesity, diabetes, cardiovascular diseases and neuropsychiatric disorders. Aside from its role in pathobiology, TMA is a precursor of trimethylamine-N-oxide that has been associated with an increased risk of athero-thrombogenesis. Additionally, TMA is a major air pollutant originating from vehicular exhaust, food waste and animal husbandry industry. The adverse effects of TMA need to be monitored given its ubiquitous presence in air and easy absorption through human skin. In this review, we highlight multifaceted attributes of TMA with an emphasis on its physiological, pathological and environmental impacts. We propose a clinical surveillance of human TMA levels that can fully assess its role as a potential marker of microbial dysbiosis-based diseases.

Revealing the impact of 17 mutations of human FMO3 protein associated with trimethylaminuria on its local spatial properties: a bioinformatic approach

Background Trimethylaminuria (TMAU) is a rare metabolic disorder manifesting in enormous excretion of trimethylamine (TMA) with urea, sweat and breath that leads to unpleasant body odour similar to rotting fish. TMAU has a strong genetic basis: 18 mutations (associated with 17 amino acid substitutions or chain truncation) of flavincontaining monooxygenase 3 (FMO3) are now recognized as a causative factor of TMAU. Surprisingly, only few of them are related with active site structure, while the molecular basis of other mutations impact on the protein structure is unknown. Moreover, there are no FMO3 models solved experimentally. So, the aim of study was to reveal the effects of 17 known mutations on human FMO3 structure by means of structural bioinformatics techniques.

The Enhanced Daily Excretion of Urinary Methylamine in Rats Treated with Semicarbazide or Hydralazine May Be Related to the Inhibition of Semicarbazide-sensitive Amine Oxidase Activities

The effects of amine oxidase inhibitors upon the daily urinary excretion of monomethylamine (MMA), dimethylamine (DMA), trimethylamine (TMA) and ammonia in the rat have been examined. Administration of hydralazine (5 mg kg-1) or semicarbazide (100 mg kg-1), drugs which irreversibly inhibit semicarbazide-sensitive amine oxidases (SSAO) but not monoamine oxidase (MAO), enhanced MMA excretion by around three- to six-fold above pretreatment levels, whereas no effect of pargyline (25 mg kg-1), a selective irreversible inhibitor of MAO was found. No apparent changes in DMA or TMA excretion in response to drug-treatment were observed. Ammonia excretion also was generally unchanged except for an apparent marked increase (approximately four-fold) over the 24 h following semicarbazide, a result which might be explained if ammonia is a degradation product of semicarbazide metabolism in the rat. With recent evidence that MMA is a substrate in-vitro for SSAO activities, results here may indicate that SSAO or related enzymes are involved in endogenous MMA turnover.

Diagnosis of suspected trimethylaminuria by NMR spectroscopy

Background Trimethylamine (TMA) is a volatile substance produced in the gut, absorbed into the blood and further metabolized by healthy individuals into trimethylamine- N-oxide (TMAO) by TMA-oxidase and then excreted in urine. Patients suffering from trimethylaminuria (TMAU) show an impaired enzymatic oxidation of TMA, excreting this amine in breath, urine and other body secretions which confers an unpleasant body odor. Methods We diagnosed a Brazilian adult male patient suspected of trimethylaminuria with a burden of choline bitartarate by monitoring the urinary excretion of TMA and TMAO by proton nuclear magnetic resonance spectroscopy ( 1H-NMR). Results The patient's urinalyses showed an augmented TMA (12.64±0.95 mg/l) and TMAO (88.42±0.82 mg/l) excretion 6 h after the overload test representing an oxidation capacity of 84.6%, consistent with a heterozygosis condition. Diets containing tuna fish or eggs resulted in an excretion of TMA and TMAO similar to that of the control diet. Only the diet based on dogfish, rich in TMAO, enhanced the excretion of TMA and TMAO reaching 24.65 and 1055.55 mg/l, respectively, in the 0–24 h urine sample. Conclusions It was concluded first, that the patient was not able to metabolize the dietary overload of TMA and second, that more studies are needed to substantiate foods that should be avoided, especially regarding fish, due to their high TMA precursor contents.

439 The effect of oral L-tyrosine, vitamin E and vitamin C administration on perphenazine - induced catatonia in rat

Experiments were performed with rats to examine the sources and disposition of dimethylamine (DMA), trimethylamine (TMA), and trimethylamine N-oxide (TMAO), all potential substrates for in vivo nitrosation to form N-nitrosodimethylamine (NDMA), a potent carcinogen. When bolus doses of [14C]DMA or [14C]TMA were given ip, recovery of radioactivity in the urine was essentially complete, and respiratory excretion, fecal excretion, and accumulation in tissues of these amines or their metabolites were negligible. Urine analysis following doses of stable isotopes showed that DMA was not converted to TMA or TMAO. Varying amounts of TMA were oxidized to TMAO, the fraction oxidized decreasing at higher doses of TMA. Ingestion and excretion of naturally occurring methylamines were monitored over a 5-day period in separate groups of normal and germ-free rats. The results of these metabolic balance studies indicate that there is net synthesis of DMA by gut bacteria and net consumption of TMAO by endogenous processes. The net intake or excretion of TMA and TMAO observed in normal and germ-free rats is consistent with bacterial synthesis of TMA followed by its almost complete oxidation to TMAO. Blood concentrations of DMA and TMA were measured in rats for 8 hr following <5, 100, or 1000 μmol bolus iv or ip doses of radioisotopes or stable isotopes. At any given dose of DMA or TMA, the decay in blood concentration was approximately monoexponential. At the lowest (most physiologic) dose the apparent volume of distribution (VD) for DMA was larger than that for TMA. Both values of VD greatly exceeded the size of the animals, suggesting that DMA and TMA are highly concentrated at one or more locations in the body. This was confirmed by measurements in tissue homogenates sampled 1 hr after a dose. The overall handling of methylamines by rats is generally consistent with observations in humans. The presence of high local concentrations of DMA and TMA at various extragastric sites merits further investigation in connection with the potential for endogenous nitrosation of these methylamines to form NDMA.

Effect of dietary intake of trimethylamine on human metabolism of the industrial catalyst dimethylethylamine.

The aim was to study the effect of trimethylamine (TMA) on the metabolism of the industrial catalyst dimethylethylamine (DMEA) to ascertain whether biological monitoring of industrial exposure to DMEA is compromised and excretion of the malodorous DMEA in sweat and urine is increased by dietary intake of TMA. DMEA (0/25 mg) and TMA (0/300/600 mg) were given simultaneously once weekly for six weeks to five healthy volunteers. Plasma was collected before and one hour after the doses, and urine 0-2, 2-4, 4-6, 6-8, and 8-24 hours after the doses. Specimens were analysed by gas chromatography with a nitrogen sensitive detector. Both amines were readily absorbed from the gastrointestinal tract and excreted in urine within 24 hours (DMEA 80%; TMA 86%). Oral intake of TMA increased the DMEA content of plasma and urine dose dependently, although there were large individual differences. Plasma and urinary TMA concentrations also increased, but not dose dependently. Moreover, the findings suggested the formation of endogenous TMA, little dealkylation of DMEA and TMA, and considerable first-pass metabolism. Although intake of TMA reduced N-oxygenation of DMEA and TMA, total urinary DMEA values (aggregate of DMEA and its oxide DMEAO excretion) were unaffected. Thus, monitoring occupational exposure to DMEA by analysis of biological specimens is not confounded by dietary intake of TMA, provided that total urinary DMEA is monitored. Although the increased urinary and hidrotic excretion of DMEA may contribute to body odour problems, they were primarily due to TMA excretion, which is much the greater.

The N-oxidation of trimethylamine in a Jordanian population.

The ability to oxidise trimethylamine (TMA) to trimethylamine N-oxide (TMAO) is distributed polymorphically within a British white population with the majority of individuals excreting greater than 90% of total urinary TMA as TMAO. The opposite extreme is characterised by a rare inborn error of TMA N-oxidation known as the fish-odour syndrome. However there is a lack of information regarding inter-individual variability in the N-oxidation of TMA in other ethnic groups. In this study the urinary excretion of TMA and TMAO was determined over a period of 24 h in 82 Jordanian subjects. A frequency distribution histogram of % of total urinary TMA excreted as TMAO revealed that the majority of subjects excreted greater than 80% of the total urinary TMA as TMAO, however eight subjects (9.7%) excreted less than 80% of the total TMA as TMAO. In a previous study of 169 white British subjects only one (0.6%) excreted less than 80% of the total TMA as TMAO. The results suggest that the prevalence of compromised ability to N-oxidise TMA may be higher in a Jordanian population than in a British population.

Metabolism and Excretion of Methylamines in Rats

Experiments were performed with rats to examine the sources and disposition of dimethylamine (DMA), trimethylamine (TMA), and trimethylamine N-oxide (TMAO), all potential substrates for in vivo nitrosation to form N-nitrosodimethylamine (NDMA), a potent carcinogen. When bolus doses of [14C]DMA or [14C]TMA were given ip, recovery of radioactivity in the urine was essentially complete, and respiratory excretion, fecal excretion, and accumulation in tissues of these amines or their metabolites were negligible. Urine analysis following doses of stable isotopes showed that DMA was not converted to TMA or TMAO. Varying amounts of TMA were oxidized to TMAO, the fraction oxidized decreasing at higher doses of TMA. Ingestion and excretion of naturally occurring methylamines were monitored over a 5-day period in separate groups of normal and germ-free rats. The results of these metabolic balance studies indicate that there is net synthesis of DMA by gut bacteria and net consumption of TMAO by endogenous processes. The net intake or excretion of TMA and TMAO observed in normal and germ-free rats is consistent with bacterial synthesis of TMA followed by its almost complete oxidation to TMAO. Blood concentrations of DMA and TMA were measured in rats for 8 hr following <5, 100, or 1000 μmol bolus iv or ip doses of radioisotopes or stable isotopes. At any given dose of DMA or TMA, the decay in blood concentration was approximately monoexponential. At the lowest (most physiologic) dose the apparent volume of distribution (VD) for DMA was larger than that for TMA. Both values of VD greatly exceeded the size of the animals, suggesting that DMA and TMA are highly concentrated at one or more locations in the body. This was confirmed by measurements in tissue homogenates sampled 1 hr after a dose. The overall handling of methylamines by rats is generally consistent with observations in humans. The presence of high local concentrations of DMA and TMA at various extragastric sites merits further investigation in connection with the potential for endogenous nitrosation of these methylamines to form NDMA.

The identification of trimethylamine excess in man: Quantitative analysis and biochemical origins

The underlying biochemical causes of chronic odor problems in humans have attracted only a few investigators. This may be due, in part, to intermittent odor complaints, to the psychological problems often associated with these patients, or to the low incidence of a true metabolic disorder. One cause of intense odor is an excessive excretion of trimethylamine (TMA) in sweat, breath, and urine and was reported to be due to a defect in the liver enzyme that converts this volatile amine to its N-oxide. Other investigators have reported TMA excess as a result of liver, kidney, and/or gastrointestinal dysfunction. We report on the development of an analytical technique for urine that can be used to identify those individuals whose chronic odor is caused by a defect in their TMA pathway. A simple extension of the basic TMA analysis can be used to measure the concentration of TMA N-oxide in the affected patients. These data can, in turn, be used to demonstrate the level of activity of the N-oxide-forming enzyme in these subjects. The results obtained from using this test on more than 50 subjects indicate, in addition to a normal population, at least two types of patients with TMA excess. One group has excess TMA excretion with low activity of the N-oxide and another group shows excess TMA excretion with normal N-oxide activity.

Conversion of Dietary Choline to Trimethylamine and Dimethylamine in Rats: Dose-Response Relationship

Trimethylamine (TMA) and dimethylamine (DMA) are normal components of human urine and are precursors of dimethylnitrosamine, a potent carcinogen. In part, DMA and TMA are products of the metabolism of dietary choline by intestinal bacteria. Most TMA formed in the intestinal tract is later oxidized and excreted as trimethylamine oxide (TMAO). Humans treated with large doses of choline smell "fishy" (the odor of TMA). Humans ingest choline as part of foods, and yet rarely smell fishy, suggesting that TMA formation must depend upon the dose of choline ingested. We found that, in adult rats, at low doses of choline (1.5 mmol/kg body wt) only 9 mumol choline (6% of the dose) reached the part of the intestine which is colonized by bacteria (the cecum and colon). After administration of 15 mmol choline/kg body wt, 237 mumol (16% of the dose) reached the cecum and colon. At both doses, 64-65% of the administered choline was absorbed from the intestine by 3 h after the dose. We found that orally administered choline slightly increased TMA and TMAO excretion at doses of choline smaller than 7 mmol/kg body wt, but that there was a disproportionately large increase in TMA excretion per 24 h when larger doses were administered (from 11 mumol TMA and 100 mumol TMAO per kg body wt in controls to 226 mumol TMA and 3617 mumol TMAO per kg body wt in rats treated with 15 mmol choline/kg body wt).(ABSTRACT TRUNCATED AT 250 WORDS)

Trimethylaminuria: The detection of carriers using a trimethylamine load test

A method potentially of value for investigating putative heterozygotes or carriers of trimethylaminuria by using a single oral dose of trimethylamine (TMA) is described. For healthy volunteers under normal dietary condition and following oral challenge with 300 mg and 600 mg TMA-base, over 90% of the urinary TMA was excreted in the form of TMA (93.6 +/- 1.6%). However, at a dose level of 900 mg TMA-base, there was clear evidence of saturation of the N-oxidation reaction as urinary TMA excretion declined to 77.2% (range 74.8-78.9) of the total dose of TMA. By contrast, in pedigree studies based upon propositi with trimethylaminuria, several parents were identified who showed clear evidence of saturation of the N-oxidation of TMA at the 600 mg TMA-base dose level, but not at 300 mg TMA-base or under normal dietary condition. In these individuals, the proportion of urinary TMA as trimethylamine N-oxide (TMAO) declined to (77.3 +/- 1.7%). Accordingly we propose that the oral administration of 600 mg TMA-base and the analysis of the following 0-8-h urine collection may be useful for the investigation of possible carriers of trimethylaminuria.

Renal ammoniagenesis and acid excretion in the dogfish, Squalus acanthias.

Renal ammoniagenesis and acid excretion were investigated in normal dogfish (Squalus acanthias) and dogfish made acidotic by HCl injection (0.65 meq X kg-1). After acid loading, renal ammonia excretion doubled, rising from 0.11 to 0.25 mueq X h-1, and titratable acid output increased from 28.6 to 44.9 mueq X h-1. Trimethylamine excretion averaged 23.2 mueq X h-1 and did not change in response to the acidosis. During the first 24 h postinjection, the increase in renal acid excretion accounted for the elimination of 15% of the acid load. In vitro studies with kidney slices demonstrated that the dogfish kidney has the capacity to synthesize ammonia from a number of amino acids including glutamine, glutamate, alanine, aspartate, and glycine, with the greatest ammonia production resulting from glutamine. The relatively high glutamine concentration in the kidney, compared with the blood, suggested a high renal capacity for glutamine synthesis. In renal homogenates, enzymatic activities for both the deamidation (glutaminase) and synthesis (glutamine synthetase) of glutamine were investigated. The Michaelis constant (Km) values for the two enzymes were found to be almost equal (4.48 mM glutamine and 4.33 mM glutamate) and at the same levels as the substrate concentrations in the kidney (3.69 mM glutamine and 3.36 mM glutamate). Subcellular localization revealed that both enzymes occur predominantly in the mitochondria. The activities of glutaminase and glutamine synthetase in the renal mitochondria suggest the presence of a substrate cycle that could be modulated to increase ammonia production during acidosis.