RARE DISEASE
Severe primary trimethylaminuria
Severe primary trimethylaminuria
Severe primary trimethylaminuria
Synonyms: TMAU
Synonyms: TMAU
Synonyms: TMAU
Drug discovery
1
drug
With orphan designation
Overview
Severe primary trimethylaminuria is a rare autosomal recessive metabolic disorder caused by mutations in the FMO3 gene, resulting in deficient hepatic oxidation of trimethylamine (TMA). This leads to systemic accumulation of TMA, causing persistent body odor resembling rotting fish in sweat, breath, and urine. Diagnosis involves urinary TMA/TMAO quantification and genetic testing. Management focuses on dietary modification, odor-mitigation strategies, and psychosocial support [1][2][6][10].
Population
Prevalence estimates range from 1 in 40,000 to <1 in 1 million globally, with higher carrier frequencies in specific populations (e.g., ~1% in the UK, up to 11% in Papua New Guinea) [1][2][10].
Typically presents from birth or puberty, with both sexes affected but higher diagnostic rates in females due to hormonal exacerbations [1][10][14].
Burden
Profound psychosocial impact: 70–90% report depression, anxiety, or social isolation due to odor-related stigma [4][10][14].
Functional limitations: Avoidance of relationships, employment, and public activities; 30% experience suicidal ideation in severe cases [4][10].
Lifelong management challenges: Dietary adherence is complex, requiring nutritionist support to prevent deficiencies (e.g., choline) [2][7][14].
Therapies
Dietary restriction: Avoidance of TMA precursors (e.g., fish, eggs, legumes, choline-rich foods) [1][7][10].
Pharmacologic: Intermittent antibiotics (neomycin, metronidazole) to reduce gut TMA production, riboflavin supplements to enhance residual FMO3 activity, and activated charcoal/copper-chlorophyllin for TMA binding [1][9][10].
Adjunctive measures: Low-pH (5.5–6.5) hygiene products, antiperspirants, and stress management [1][7][12].
Categories: rare genetic diseases, rare inborn errors of metabolism
Research Papers
29 drug discovery papers about Severe primary trimethylaminuria, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
29 drug discovery papers about Severe primary trimethylaminuria, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-03-24 | Signed, sealed, delivered: a generalizable model for living biotherapeutic dosing and metabolism.
Living Biotherapeutic Products (LBPs) offer a promising therapeutic strategy for metabolic disorders rooted in gut microbiome dysfunction, yet quantitative frameworks for predicting their efficacy remain underdeveloped. We introduce the Bacterial Compartment Absorption and Transit (BCAT) model, a pharmacokinetic-pharmacodynamic framework that couples probiotic transit, endogenous microbiome metabolism, and enzymatic transformation within a unified dose-optimization setting. Building on the classical CAT model, BCAT incorporates mechanistically-derived colon compartments and treats dosing time as a control variable. We validate BCAT against clinical data for native choline metabolism and SYNB1618 probiotic trials, achieving 5% mean prediction error compared to ~30% for prior two-compartment models. Applying BCAT to trimethylaminuria (TMAU), we predict that ~109 CFU of engineered probiotic, administered 3-4 h before meals, achieves 95% reduction in systemic trimethylamine, matching healthy hepatic clearance. Global sensitivity analysis identifies enzyme expression level as the dominant design parameter, enforcing the broad applicability of this model. The BCAT framework generalizes to any gut microbiome-mediated metabolic disorder and provides quantitative dosing targets to guide live biotherapeutic development.
2025-10-08 | Table 1_A mixture of postbiotics/tyndallized probiotics reduces trimethylamine (TMA) in trimethylaminuria models: Evidence from in vitro and in vivo studies.docx
Introduction Trimethylaminuria (TMAU), also known as “fish-odor syndrome,” is a rare metabolic disorder characterized by a body malodor that smells like a decaying fish. This syndrome is caused by a FMO3 liver enzyme malfunction, leading to trimethylamine (TMA) accumulation. To date, there is no definitive therapeutic treatment but only palliative care for TMAU, such as a controlled diet, taking antibiotics, or using acidic soaps to capture sweat-released TMA. Methods Here, we describe an innovative approach for the treatment of this disorder, where the use of postbiotics/tyndallized probiotics is able to effectively inhibit the bacterial TMA lyase present, thus preventing the formation of TMA. We obtained a preparation (a mixture of tyndallized probiotics and their postbiotics) that was derived from the fermentation of Lacticaseibacillus paracasei in the presence of garlic extract and senna leaf. This preparation was used in in vitro assays on human fecal slurry while monitoring the levels of TMA released over time, and it was also tested in vivo in both Mus musculus C57BL/6 (FMO3+/+) strain WT and C57BL/6-Fmo3em1Smoc (KO) mouse models to measure the trimethylamine N-oxide (TMAO) and TMA levels in the blood and urine, along with gut microbiota analysis in feces via next-generation sequencing (NGS). Results L. paracasei fermentation yielded 4.1 × 1012 CFU/g lyophilized powder. In vitro assays involving fecal slurries supplemented with the fermentation product demonstrated a reduction in TMA levels, and the NGS analysis revealed that Collinsella, Clostridium, and Streptococcus were the most common bacterial genera that produced TMA. The in vivo study showed a significant reduction in TMAO levels in C57BL/6(FMO3+/+) strain WT mouse models and in TMA levels in C57BL/6-Fmo3em1Smoc (KO) mouse models. In addition, bacteria belonging to the TMA-producing genera were still present after treatment with the tested compounds, excluding their bactericidal action. The postbiotics obtained may find a useful therapeutic application both in the prevention of cardiovascular events and as valid supports to reduce TMA production in TMAU patients.
2025-10-08 | A mixture of postbiotics/tyndallized probiotics reduces trimethylamine (TMA) in trimethylaminuria models: Evidence from in vitro and in vivo studies
Introduction Trimethylaminuria (TMAU), also known as “fish-odor syndrome,” is a rare metabolic disorder characterized by a body malodor that smells like a decaying fish. This syndrome is caused by a FMO3 liver enzyme malfunction, leading to trimethylamine (TMA) accumulation. To date, there is no definitive therapeutic treatment but only palliative care for TMAU, such as a controlled diet, taking antibiotics, or using acidic soaps to capture sweat-released TMA. Methods Here, we describe an innovative approach for the treatment of this disorder, where the use of postbiotics/tyndallized probiotics is able to effectively inhibit the bacterial TMA lyase present, thus preventing the formation of TMA. We obtained a preparation (a mixture of tyndallized probiotics and their postbiotics) that was derived from the fermentation of Lacticaseibacillus paracasei in the presence of garlic extract and senna leaf. This preparation was used in in vitro assays on human fecal slurry while monitoring the levels of TMA released over time, and it was also tested in vivo in both Mus musculus C57BL/6 (FMO3 +/+ ) strain WT and C57BL/6 -Fmo3em1Smoc (KO) mouse models to measure the trimethylamine N-oxide (TMAO) and TMA levels in the blood and urine, along with gut microbiota analysis in feces via next-generation sequencing (NGS). Results L. paracasei fermentation yielded 4.1 × 10 12 CFU/g lyophilized powder. In vitro assays involving fecal slurries supplemented with the fermentation product demonstrated a reduction in TMA levels, and the NGS analysis revealed that Collinsella , Clostridium , and Streptococcus were the most common bacterial genera that produced TMA. The in vivo study showed a significant reduction in TMAO levels in C57BL/6(FMO3 +/+ ) strain WT mouse models and in TMA levels in C57BL/6 -Fmo3em1Smoc (KO) mouse models. In addition, bacteria belonging to the TMA-producing genera were still present after treatment with the tested compounds, excluding their bactericidal action. The postbiotics obtained may find a useful therapeutic application both in the prevention of cardiovascular events and as valid supports to reduce TMA production in TMAU patients.
2025-09-05 | Fluoromethylcarnitine, a novel inhibitor of trimethylamine levels in trimethylaminuria and trimethylamine N-oxide related disorders.
Excessive production of trimethylamine (TMA) by the gut microbiota leads to increased concentrations of TMA or trimethylamine N-oxide (TMAO) in the bloodstream, which is associated with health risks. High levels of TMAO have been linked to cardiovascular disease, inflammation and other health problems. In addition, people affected by a genetic deficiency of the liver enzyme FMO3, which oxidises TMA to TMAO, suffer from trimethylaminuria (TMAU), a rare disorder caused by mutations in the Fmo3 gene, in which the body odour resembles that of rotting fish, leading to significant discomfort and social isolation. We report here on (R)-N-fluoromethylcarnitine (FCAR), the first inhibitor of TMA production that acts without altering the microbiome and has favourable pharmacokinetic properties. We also tested FCAR in an animal model of trimethylaminuria (TMAU) using mice with a knock-out for the Fmo3 gene. We observed that FCAR reduced TMA levels in the blood and urine of these mice. No weight loss was observed in the animals, demonstrating the low toxicity of FCAR and making it a potential candidate for clinical development for the treatment of trimethylaminuria (TMAU) and other TMA-related disorders.
2025-06-26 | Signed, Sealed, Delivered: A Generalizable Model for Probiotic Delivery and Metabolism in the Gut
Abstract As genetic engineering advances, so does the need for quantitative models to inform biological engineering. This is particularly true for the nascent field of synthetic probiotic therapy of the gut microbiome. Gut microbiome health is linked to health of the host organism. Decline in microbiome health is correlated with severe metabolic disorders. However, as far as we know, there are no models that account for ingestion and transfer of a synthetic probiotic as well as its intended metabolic effect. We present here the first model that accounts for such effects. We call our model the bacterial compartment absorption and transit (BCAT) model. It is a generalization of the pharmacokinetic compartment absorption and transit (CAT) model As a specific example, we employ the BCAT model in the context of trimethylaminuria (TMAU), a metabolic disorder characterized by a persistent fishy odor emanating from affected individuals. The BCAT model predicts the dose of probiotic required for adequate medical treatment of TMAU. Moreover, our model is flexible to apply to any metabolic disorder pertaining to the gut microbiome.
cell therapies
2025-03-03 | A Spotlight on Archaea in Humans, Livestock and Poultry: A Review.
The microbiota includes prokaryotes (archaea and bacteria) and eukaryotes. Archaea are single-celled prokaryotes and essential part of gut microbiome. Researches on archaea in ruminants and humans are more than mono-gastric. The low abundance of archaea in the gut depends on the method used (metagenomics or meta-transcriptomic) and age of people or poultry. The lack of complete recognition of archaea is due to their small number and method of identifying them (16S rRNA gene primers). The uses of archaea include analytical kit, reduce oil pollution, archaeosomes or drugs production, vaccines agents, lipid carriers in the pharmaceutical industry and molybdenum extraction in the nuclear industry. The nutritional functions of methanogenic archaea including feed utilization (ruminants) and efficiency, hydrogen reducing (human), fat deposition and enhancement of energy harvesting in mice, CAZymes genes, cecal fermentation, syntrophic potential, carotenoid source and improved transit time and appetite and SCFAs production. Archaea acting as antibiotics (produce archaeocins, sulfolobicins and halocin KPS1) and as probiotics (archaeobiotics) can reduce TMAU (trimethylaminuria) disease, cardiovascular diseases (CVDs), and atherosclerosis, brain abscess, cancer, colorectal cancer, inflammatory bowel disease (IBD), constipation, obesity, food allergies, asthma and anti-inflammation which can be prevented by using archaea, and other functions include energy homeostasis, heat shock protein (HSP) production and reducing aging.
2020-04-12 | 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. • 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.
2014-01-01 | Archaea and the human gut: New beginning of an old story
Methanogenic archaea are known as human gut inhabitants since more than 30 years ago through the detection of methane in the breath and isolation of two methanogenic species belonging to the order Methanobacteriales, Methanobrevibacter smithii and Methanosphaera stadtmanae .During the last decade, diversity of archaea encountered in the human gastrointestinal tract (GIT) has been extended by sequence identification and culturing of new strains.Here we provide an updated census of the archaeal diversity associated with the human GIT and their possible role in the gut physiology and health.We particularly focus on the still poorly characterized 7 th order of methanogens, the Methanomassiliicoccales, associated to aged population.While also largely distributed in non-GIT environments, our actual knowledge on this novel order of methanogens has been mainly revealed through GIT inhabitants.They enlarge the number of final electron acceptors of the gut metabolites to mono-di-and trimethylamine.Trimethylamine is exclusively a microbiota-derived product of nutrients (lecithin, choline, TMAO, L-carnitine) from normal diet, from which seems originate two diseases, trimethylaminuria (or Fish-Odor Syndrome) and cardiovascular disease through the proatherogenic property of its oxidized liver-derived form.This therefore supports interest on these methanogenic species and its use as archaebiotics, a term coined from the notion of archaea-derived probiotics.
2013-10-31 | Archaebiotics: proposed therapeutic use of archaea to prevent trimethylaminuria and cardiovascular disease.
Trimethylamine (TMA) is produced by gut bacteria from dietary ingredients. In individuals with a hereditary defect in flavin-containing monooxygenase 3, bacterial TMA production is believed to contribute to the symptoms of trimethylaminuria (TMAU; fish-odor syndrome). Intestinal microbiota TMA metabolism may also modulate atherosclerosis risk by affecting trimethylamine oxide (TMAO) production levels. We propose that reducing TMA formation in the gut by converting it to an inert molecule could be used to prevent or limit these human diseases, while avoiding the major drawbacks of other clinical interventions. Reducing TMA levels by microbiological interventions could also be helpful in some vaginoses. Particular members of a recently discovered group of methanogens, that are variably present in the human gut, are unusual in being apparently restricted to utilizing only methyl compounds including TMA as substrates. We confirmed experimentally that one of these strains tested, Methanomassiliicoccus luminyensis B10, is able to deplete TMA, by reducing it with H2 for methanogenesis. We therefore suggest that members of this archaeal lineage could be used as treatments for metabolic disorders.
small molecules
2026-03-24 | Signed, sealed, delivered: a generalizable model for living biotherapeutic dosing and metabolism.
Living Biotherapeutic Products (LBPs) offer a promising therapeutic strategy for metabolic disorders rooted in gut microbiome dysfunction, yet quantitative frameworks for predicting their efficacy remain underdeveloped. We introduce the Bacterial Compartment Absorption and Transit (BCAT) model, a pharmacokinetic-pharmacodynamic framework that couples probiotic transit, endogenous microbiome metabolism, and enzymatic transformation within a unified dose-optimization setting. Building on the classical CAT model, BCAT incorporates mechanistically-derived colon compartments and treats dosing time as a control variable. We validate BCAT against clinical data for native choline metabolism and SYNB1618 probiotic trials, achieving 5% mean prediction error compared to ~30% for prior two-compartment models. Applying BCAT to trimethylaminuria (TMAU), we predict that ~109 CFU of engineered probiotic, administered 3-4 h before meals, achieves 95% reduction in systemic trimethylamine, matching healthy hepatic clearance. Global sensitivity analysis identifies enzyme expression level as the dominant design parameter, enforcing the broad applicability of this model. The BCAT framework generalizes to any gut microbiome-mediated metabolic disorder and provides quantitative dosing targets to guide live biotherapeutic development.
2025-10-08 | Table 1_A mixture of postbiotics/tyndallized probiotics reduces trimethylamine (TMA) in trimethylaminuria models: Evidence from in vitro and in vivo studies.docx
Introduction Trimethylaminuria (TMAU), also known as “fish-odor syndrome,” is a rare metabolic disorder characterized by a body malodor that smells like a decaying fish. This syndrome is caused by a FMO3 liver enzyme malfunction, leading to trimethylamine (TMA) accumulation. To date, there is no definitive therapeutic treatment but only palliative care for TMAU, such as a controlled diet, taking antibiotics, or using acidic soaps to capture sweat-released TMA. Methods Here, we describe an innovative approach for the treatment of this disorder, where the use of postbiotics/tyndallized probiotics is able to effectively inhibit the bacterial TMA lyase present, thus preventing the formation of TMA. We obtained a preparation (a mixture of tyndallized probiotics and their postbiotics) that was derived from the fermentation of Lacticaseibacillus paracasei in the presence of garlic extract and senna leaf. This preparation was used in in vitro assays on human fecal slurry while monitoring the levels of TMA released over time, and it was also tested in vivo in both Mus musculus C57BL/6 (FMO3+/+) strain WT and C57BL/6-Fmo3em1Smoc (KO) mouse models to measure the trimethylamine N-oxide (TMAO) and TMA levels in the blood and urine, along with gut microbiota analysis in feces via next-generation sequencing (NGS). Results L. paracasei fermentation yielded 4.1 × 1012 CFU/g lyophilized powder. In vitro assays involving fecal slurries supplemented with the fermentation product demonstrated a reduction in TMA levels, and the NGS analysis revealed that Collinsella, Clostridium, and Streptococcus were the most common bacterial genera that produced TMA. The in vivo study showed a significant reduction in TMAO levels in C57BL/6(FMO3+/+) strain WT mouse models and in TMA levels in C57BL/6-Fmo3em1Smoc (KO) mouse models. In addition, bacteria belonging to the TMA-producing genera were still present after treatment with the tested compounds, excluding their bactericidal action. The postbiotics obtained may find a useful therapeutic application both in the prevention of cardiovascular events and as valid supports to reduce TMA production in TMAU patients.
2025-10-08 | A mixture of postbiotics/tyndallized probiotics reduces trimethylamine (TMA) in trimethylaminuria models: Evidence from in vitro and in vivo studies
Introduction Trimethylaminuria (TMAU), also known as “fish-odor syndrome,” is a rare metabolic disorder characterized by a body malodor that smells like a decaying fish. This syndrome is caused by a FMO3 liver enzyme malfunction, leading to trimethylamine (TMA) accumulation. To date, there is no definitive therapeutic treatment but only palliative care for TMAU, such as a controlled diet, taking antibiotics, or using acidic soaps to capture sweat-released TMA. Methods Here, we describe an innovative approach for the treatment of this disorder, where the use of postbiotics/tyndallized probiotics is able to effectively inhibit the bacterial TMA lyase present, thus preventing the formation of TMA. We obtained a preparation (a mixture of tyndallized probiotics and their postbiotics) that was derived from the fermentation of Lacticaseibacillus paracasei in the presence of garlic extract and senna leaf. This preparation was used in in vitro assays on human fecal slurry while monitoring the levels of TMA released over time, and it was also tested in vivo in both Mus musculus C57BL/6 (FMO3 +/+ ) strain WT and C57BL/6 -Fmo3em1Smoc (KO) mouse models to measure the trimethylamine N-oxide (TMAO) and TMA levels in the blood and urine, along with gut microbiota analysis in feces via next-generation sequencing (NGS). Results L. paracasei fermentation yielded 4.1 × 10 12 CFU/g lyophilized powder. In vitro assays involving fecal slurries supplemented with the fermentation product demonstrated a reduction in TMA levels, and the NGS analysis revealed that Collinsella , Clostridium , and Streptococcus were the most common bacterial genera that produced TMA. The in vivo study showed a significant reduction in TMAO levels in C57BL/6(FMO3 +/+ ) strain WT mouse models and in TMA levels in C57BL/6 -Fmo3em1Smoc (KO) mouse models. In addition, bacteria belonging to the TMA-producing genera were still present after treatment with the tested compounds, excluding their bactericidal action. The postbiotics obtained may find a useful therapeutic application both in the prevention of cardiovascular events and as valid supports to reduce TMA production in TMAU patients.
2025-09-05 | Fluoromethylcarnitine, a novel inhibitor of trimethylamine levels in trimethylaminuria and trimethylamine N-oxide related disorders.
Excessive production of trimethylamine (TMA) by the gut microbiota leads to increased concentrations of TMA or trimethylamine N-oxide (TMAO) in the bloodstream, which is associated with health risks. High levels of TMAO have been linked to cardiovascular disease, inflammation and other health problems. In addition, people affected by a genetic deficiency of the liver enzyme FMO3, which oxidises TMA to TMAO, suffer from trimethylaminuria (TMAU), a rare disorder caused by mutations in the Fmo3 gene, in which the body odour resembles that of rotting fish, leading to significant discomfort and social isolation. We report here on (R)-N-fluoromethylcarnitine (FCAR), the first inhibitor of TMA production that acts without altering the microbiome and has favourable pharmacokinetic properties. We also tested FCAR in an animal model of trimethylaminuria (TMAU) using mice with a knock-out for the Fmo3 gene. We observed that FCAR reduced TMA levels in the blood and urine of these mice. No weight loss was observed in the animals, demonstrating the low toxicity of FCAR and making it a potential candidate for clinical development for the treatment of trimethylaminuria (TMAU) and other TMA-related disorders.
2025-06-26 | Signed, Sealed, Delivered: A Generalizable Model for Probiotic Delivery and Metabolism in the Gut
Abstract As genetic engineering advances, so does the need for quantitative models to inform biological engineering. This is particularly true for the nascent field of synthetic probiotic therapy of the gut microbiome. Gut microbiome health is linked to health of the host organism. Decline in microbiome health is correlated with severe metabolic disorders. However, as far as we know, there are no models that account for ingestion and transfer of a synthetic probiotic as well as its intended metabolic effect. We present here the first model that accounts for such effects. We call our model the bacterial compartment absorption and transit (BCAT) model. It is a generalization of the pharmacokinetic compartment absorption and transit (CAT) model As a specific example, we employ the BCAT model in the context of trimethylaminuria (TMAU), a metabolic disorder characterized by a persistent fishy odor emanating from affected individuals. The BCAT model predicts the dose of probiotic required for adequate medical treatment of TMAU. Moreover, our model is flexible to apply to any metabolic disorder pertaining to the gut microbiome.
cell therapies
2025-03-03 | A Spotlight on Archaea in Humans, Livestock and Poultry: A Review.
The microbiota includes prokaryotes (archaea and bacteria) and eukaryotes. Archaea are single-celled prokaryotes and essential part of gut microbiome. Researches on archaea in ruminants and humans are more than mono-gastric. The low abundance of archaea in the gut depends on the method used (metagenomics or meta-transcriptomic) and age of people or poultry. The lack of complete recognition of archaea is due to their small number and method of identifying them (16S rRNA gene primers). The uses of archaea include analytical kit, reduce oil pollution, archaeosomes or drugs production, vaccines agents, lipid carriers in the pharmaceutical industry and molybdenum extraction in the nuclear industry. The nutritional functions of methanogenic archaea including feed utilization (ruminants) and efficiency, hydrogen reducing (human), fat deposition and enhancement of energy harvesting in mice, CAZymes genes, cecal fermentation, syntrophic potential, carotenoid source and improved transit time and appetite and SCFAs production. Archaea acting as antibiotics (produce archaeocins, sulfolobicins and halocin KPS1) and as probiotics (archaeobiotics) can reduce TMAU (trimethylaminuria) disease, cardiovascular diseases (CVDs), and atherosclerosis, brain abscess, cancer, colorectal cancer, inflammatory bowel disease (IBD), constipation, obesity, food allergies, asthma and anti-inflammation which can be prevented by using archaea, and other functions include energy homeostasis, heat shock protein (HSP) production and reducing aging.
2020-04-12 | 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. • 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.
2014-01-01 | Archaea and the human gut: New beginning of an old story
Methanogenic archaea are known as human gut inhabitants since more than 30 years ago through the detection of methane in the breath and isolation of two methanogenic species belonging to the order Methanobacteriales, Methanobrevibacter smithii and Methanosphaera stadtmanae .During the last decade, diversity of archaea encountered in the human gastrointestinal tract (GIT) has been extended by sequence identification and culturing of new strains.Here we provide an updated census of the archaeal diversity associated with the human GIT and their possible role in the gut physiology and health.We particularly focus on the still poorly characterized 7 th order of methanogens, the Methanomassiliicoccales, associated to aged population.While also largely distributed in non-GIT environments, our actual knowledge on this novel order of methanogens has been mainly revealed through GIT inhabitants.They enlarge the number of final electron acceptors of the gut metabolites to mono-di-and trimethylamine.Trimethylamine is exclusively a microbiota-derived product of nutrients (lecithin, choline, TMAO, L-carnitine) from normal diet, from which seems originate two diseases, trimethylaminuria (or Fish-Odor Syndrome) and cardiovascular disease through the proatherogenic property of its oxidized liver-derived form.This therefore supports interest on these methanogenic species and its use as archaebiotics, a term coined from the notion of archaea-derived probiotics.
2013-10-31 | Archaebiotics: proposed therapeutic use of archaea to prevent trimethylaminuria and cardiovascular disease.
Trimethylamine (TMA) is produced by gut bacteria from dietary ingredients. In individuals with a hereditary defect in flavin-containing monooxygenase 3, bacterial TMA production is believed to contribute to the symptoms of trimethylaminuria (TMAU; fish-odor syndrome). Intestinal microbiota TMA metabolism may also modulate atherosclerosis risk by affecting trimethylamine oxide (TMAO) production levels. We propose that reducing TMA formation in the gut by converting it to an inert molecule could be used to prevent or limit these human diseases, while avoiding the major drawbacks of other clinical interventions. Reducing TMA levels by microbiological interventions could also be helpful in some vaginoses. Particular members of a recently discovered group of methanogens, that are variably present in the human gut, are unusual in being apparently restricted to utilizing only methyl compounds including TMA as substrates. We confirmed experimentally that one of these strains tested, Methanomassiliicoccus luminyensis B10, is able to deplete TMA, by reducing it with H2 for methanogenesis. We therefore suggest that members of this archaeal lineage could be used as treatments for metabolic disorders.
Access all drug discovery papers and probability of success in trials forecasts:
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Drug Discovery Landscape
1 orphan drug designation for Severe primary trimethylaminuria.
1 orphan drug designation for Severe primary trimethylaminuria.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
paracoccus aminovorans | other | FDA | 2025-05-15 | — | BioMe Inc. |
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