Candidatus Methanomethylophilus alvus
Overview
Candidatus Methanomethylophilus alvus is a methanogenic archaeon belonging to the order Methanomassiliicoccales, a relatively recently described order of methanogens found in the human gut microbiome and various animal digestive tracts. First characterized in 2012, this archaeon represents one of the predominant members of the "host-associated clade" or "intestinal clade" of Methanomassiliicoccales, which is primarily found in gut environments. Ca. M. alvus has garnered significant scientific interest due to its unique metabolic capabilities, particularly its ability to utilize trimethylamine (TMA) as a substrate for methanogenesis. This metabolic trait has important implications for human health, as TMA is a bacterial metabolite that, when oxidized in the liver, forms trimethylamine-N-oxide (TMAO), a compound associated with cardiovascular disease and chronic kidney disease. By consuming TMA in the gut before it can be absorbed into the bloodstream, Ca. M. alvus may play a beneficial role in human health. The archaeon has a circular genome of approximately 1.7 Mb, which contains genes necessary for methylotrophic methanogenesis from methanol and various methylamines. Unlike traditional methanogens, Ca. M. alvus lacks the methyl branch of the Wood-Ljungdahl pathway, reflecting its specialized metabolism. Its prevalence in the human gut varies across populations and appears to be influenced by factors such as age, diet, and health status. The potential health benefits associated with Ca. M. alvus have led to proposals for its use as an "Archaebiotic" (archaeal probiotic) for conditions like trimethylaminuria and potentially for reducing cardiovascular disease risk, highlighting the emerging recognition of archaea as important components of the human microbiome with direct implications for health.
Characteristics
Candidatus Methanomethylophilus alvus exhibits several distinctive characteristics that define its biological identity:
Taxonomic classification: Domain Archaea, Phylum Euryarchaeota, Class Thermoplasmata, Order Methanomassiliicoccales, Family Methanomethylophilaceae (proposed)
Morphology: Non-motile cocci (spherical cells) with a diameter ranging from 0.4 to 0.7 μm
Cell wall structure: Contains archaeal-specific cell membrane lipids with ether-linked isoprenoid chains, distinct from bacterial fatty acid-based membranes
Oxygen requirements: Strictly anaerobic, requiring an oxygen-free environment for growth and survival
Temperature preference: Mesophilic, growing optimally at human body temperature (37°C), with a growth range between 30°C and 40°C
pH preference: Grows optimally at pH 7.5, with a growth range of pH 6.9 to 8.3
Salinity tolerance: Optimal growth at 0.12 mol/L NaCl, with a tolerance range of 0.02 to 0.34 mol/L NaCl
Genome features:
- Circular genome of approximately 1.7 Mb
- G+C content of 55.6%
- Contains 44 tRNA genes
- Single copy of 23S and 16S rRNA genes
- Two non-contiguous copies of 5S rRNA genes distant from the 23S and 16S rRNA genes
- Approximately 1,785 protein-coding sequences
Metabolic uniqueness:
- Hydrogenotrophic methyl-reducing methanogen
- Utilizes methanol and methylamines (mono-, di-, and trimethylamine) as electron acceptors
- Requires hydrogen as an electron donor
- Cannot use H2/CO2, formate, ethanol, or acetate as energy sources
- Lacks the methyl branch of the H4MPT Wood-Ljungdahl pathway
Growth requirements:
- Requires unknown medium factors provided by certain bacteria (e.g., Eggerthella lenta) or present in rumen fluid
- Difficult to isolate and culture in pure form
Genetic features:
- Contains CRISPR regions and associated cas genes
- Possesses genes for pyrrolysine (Pyl) biosynthesis, the 22nd amino acid
- Contains amber codon in methyltransferase genes (mtmB, mtbB, and mttB)
Phylogenetic relationships:
- Distantly related to Methanomassiliicoccus luminyensis (86.9% 16S rRNA gene sequence identity)
- More closely related to uncultured archaea from animal digestive tracts
- Part of the previously described "rumen cluster C"
Adaptations to gut environment:
- Presence of specific adhesins for attachment to gut surfaces
- Contains genes for bile acid resistance
- Genomic adaptations specific to the intestinal environment
Cultivation challenges:
- Initially obtained only in enrichment cultures
- Recently isolated as strain Mx-05T, proposed as Methanomethylophilus alvi
- Requires specific growth conditions and medium supplements
These characteristics reflect Ca. M. alvus's specialized adaptation to the human and animal gut environment. Its restricted metabolism focused on methylotrophic methanogenesis using hydrogen as an electron donor, along with its specific growth requirements, highlight its niche specialization within the gut microbiome. The recent isolation of a representative strain (Mx-05T) has allowed for more detailed characterization of its physiological properties, confirming many of the genomic predictions made from the initial metagenomic analyses.
Role in Human Microbiome
Candidatus Methanomethylophilus alvus occupies a specialized niche within the human microbiome:
Distribution and prevalence:
- Present in human gut microbiome data sets from multiple countries
- Represented by several operational taxonomic units (OTUs) across different cohorts
- Prevalence varies across populations and age groups
- Generally more abundant in older adults
- Forms part of the "host-associated clade" of Methanomassiliicoccales primarily found in gut environments
Ecological significance:
- Functions as a hydrogenotrophic methyl-reducing methanogen
- Contributes to the removal of hydrogen from the gut ecosystem
- Specifically utilizes methylated compounds, particularly trimethylamine (TMA)
- Helps maintain the redox balance in the gut environment
- May influence the efficiency of bacterial fermentation processes
Population dynamics:
- Distribution appears to be influenced by factors such as age, diet, and health status
- More prevalent in certain dietary patterns
- May be affected by lifestyle changes, as observed in elderly populations
- Forms part of two distinct clades that show different correlations with host health status
Microbial interactions:
- Functional links with TMA-producing bacteria
- Abundance correlates positively with bacterial gene count for TMA production
- Depends on bacteria that produce methylated compounds as substrates
- May form syntrophic relationships with specific bacterial groups
- Competes with other hydrogen-consuming microorganisms
Host-microbe interface:
- Genomic adaptations for gut colonization, including adhesins and bile acid resistance genes
- Potential beneficial interactions through TMA depletion
- Abundance negatively correlates with fecal TMA concentrations
- May influence host metabolic pathways through removal of bacterial metabolites
Developmental aspects:
- Increased occurrence and diversity among older adults
- Acquisition pathway in humans not fully understood
- May be influenced by early-life exposures and diet
- Persistence patterns across the human lifespan remain to be fully characterized
Geographical and ethnic variations:
- Present in microbiome data sets from at least eight countries
- Phylogenetically distributed into distinct clades
- Prevalence may vary with regional dietary patterns
- Influenced by cultural and dietary habits
Habitat specificity:
- Primarily associated with the gut environment
- Part of a clade specifically adapted to host-associated environments
- Genomic features suggest specific adaptation to the intestinal habitat
- Distinguished from soil and sediment-associated Methanomassiliicoccales
Ca. M. alvus's role in the human microbiome extends beyond simple colonization. Its specialized metabolism targeting methylated compounds, particularly TMA, suggests it may have important functional contributions to gut ecology and potentially host health. The observed correlations between its abundance, bacterial TMA production capacity, and fecal TMA concentrations indicate a functional interaction with the bacterial community that may have implications for host metabolism. The presence of distinct clades with different correlations to host health status suggests that different strains or species within this group may have varying impacts on the host. As research continues to elucidate the complex interactions within the gut microbiome, Ca. M. alvus represents an important example of how archaeal members can have specific and potentially beneficial roles in human health through their metabolic activities.
Health Implications
Candidatus Methanomethylophilus alvus has several significant implications for human health:
Trimethylamine (TMA) metabolism:
- Consumes TMA as a substrate for methanogenesis
- TMA is a bacterial metabolite produced from dietary compounds like choline and carnitine
- By depleting TMA in the gut, prevents its absorption into the bloodstream
- Abundance negatively correlates with fecal TMA concentrations
- Subjects with higher abundance of Methanomassiliicoccales have lower TMA levels in feces
Cardiovascular disease prevention:
- TMA is oxidized in the liver to trimethylamine-N-oxide (TMAO)
- TMAO is increasingly recognized as an important factor in cardiovascular disease development
- By reducing TMA levels, may indirectly lower TMAO production
- Potential protective effect against atherosclerosis and related conditions
- Could represent a novel approach to cardiovascular risk reduction
Chronic kidney disease mitigation:
- TMAO has been associated with chronic kidney diseases
- TMA reduction may help prevent kidney damage
- Potential role in maintaining renal function
- May be particularly relevant in aging populations with increased kidney disease risk
Trimethylaminuria management:
- Trimethylaminuria (fish odor syndrome) affects 0.5-11% of people across different ethnic populations
- Caused by deficiency in liver FMO3 monooxygenase that normally converts TMA to TMAO
- Results in accumulation of TMA, which has a characteristic fishy odor
- By consuming TMA in the gut, may reduce symptoms of this condition
- Proposed as a potential "Archaebiotic" (archaeal probiotic) for trimethylaminuria
Aging-related health:
- More prevalent in older adults
- Different clades show opposite correlations with health status in elderly populations
- May be affected by lifestyle changes, such as entering long-term residential care
- Potential role in healthy aging through metabolic interactions
Inflammatory conditions:
- Unlike some other gut archaea (e.g., Methanosphaera stadtmanae), not known to have pro-inflammatory effects
- No evidence of pathogenic potential
- May contribute to gut homeostasis through metabolic activities
- Potential indirect anti-inflammatory effects through metabolite regulation
Metabolic health:
- Influences gut metabolic environment through hydrogen consumption
- May affect bacterial fermentation patterns
- Potential impact on production of short-chain fatty acids and other metabolites
- Complex interactions with diet and host metabolism
Therapeutic potential:
- Proposed as an "Archaebiotic" for conditions related to TMA/TMAO
- tRNAPyl-PylRS pair has attracted interest in synthetic biology
- Applications being developed for human in vivo studies and cancer therapeutics
- Genetic engineering of bacteria to express Methanomassiliicoccales genes for TMA reduction
- Potential dietary approaches to modulate its abundance
The health implications of Ca. M. alvus are primarily related to its ability to consume TMA, a bacterial metabolite with indirect negative effects on human health when converted to TMAO. This metabolic capability positions Ca. M. alvus as a potentially beneficial member of the gut microbiome, particularly in the context of cardiovascular disease, chronic kidney disease, and trimethylaminuria. The proposed use of Ca. M. alvus or its genetic elements as therapeutic agents represents an innovative approach to microbiome-based interventions for health. However, the complex ecology of the gut microbiome and the variable prevalence of Ca. M. alvus across populations suggest that its health effects may be context-dependent and influenced by factors such as diet, age, and overall microbiome composition. Further research is needed to fully understand the conditions under which Ca. M. alvus provides optimal health benefits and how its presence might be effectively promoted in therapeutic contexts.
Metabolic Activities
Candidatus Methanomethylophilus alvus exhibits highly specialized metabolic capabilities that distinguish it from other methanogens:
Core methanogenesis pathway:
- Hydrogenotrophic methyl-reducing methanogen
- Reduces methyl compounds to methane using H2 as an electron donor
- Primary substrates include methanol, monomethylamine, dimethylamine, and trimethylamine
- Cannot use H2/CO2, formate, ethanol, or acetate as energy sources
- Energy conservation through this pathway coupled to ATP synthesis
Unique metabolic architecture:
- Lacks the methyl branch of the H4MPT Wood-Ljungdahl pathway
- This absence is characteristic of all Methanomassiliicoccales
- Distinguishes it from other orders of methanogens
- Reflects evolutionary adaptation to a specialized metabolic niche
- Relies on alternative pathways for certain biosynthetic functions
Trimethylamine utilization:
- Contains genes needed for methylotrophic methanogenesis from trimethylamine
- Encodes specific methyltransferases for TMA utilization
- Methyltransferase genes (mtmB, mtbB, mttB) contain amber codons
- These amber codons encode pyrrolysine, the 22nd amino acid
- Pyrrolysine is essential for methylamine methyltransferase activity
Pyrrolysine system:
- Contains a complete pyl gene cluster for pyrrolysine biosynthesis
- Encodes tRNAPyl with a CUA anticodon for amber codon recognition
- The tRNAPyl-PylRS pair has applications in synthetic biology
- Can incorporate non-canonical amino acids with high specificity
- This system is being developed for applications in human studies and cancer therapeutics
Energy conservation:
- Employs a homologue of respiratory complex I
- Unlike typical complex I, does not transfer electrons to membrane-soluble carriers
- Represents a novel mode of energy conservation
- Coupled to the generation of a proton motive force
- ATP synthesis occurs via a membrane-bound ATP synthase
Hydrogen dependency:
- Absolute requirement for hydrogen as an electron donor
- Competes with other hydrogen-consuming microorganisms
- Hydrogen threshold likely influences its ecological distribution
- Contributes to hydrogen removal from the gut environment
- May influence bacterial fermentation through hydrogen consumption
Growth requirements:
- Requires unknown medium factors provided by certain bacteria
- Growth enhanced by factors from Eggerthella lenta or present in rumen fluid
- These requirements reflect its adaptation to the gut environment
- May indicate metabolic dependencies on other microorganisms
- Suggests potential syntrophic relationships in vivo
Adaptations to gut environment:
- Metabolic specialization allows exploitation of a specific niche
- Utilizes methylated compounds produced by bacterial fermentation
- Genomic adaptations for gut colonization complement metabolic specialization
- Bile acid resistance genes support survival in the intestinal environment
- Specific adhesins may facilitate attachment to gut surfaces
The metabolic activities of Ca. M. alvus reflect its specialized adaptation to the human gut ecosystem. Its restricted metabolism, focused exclusively on the reduction of methyl compounds with hydrogen, allows it to exploit a specific metabolic niche while avoiding competition with more versatile methanogens. The ability to utilize trimethylamine is particularly significant from a human health perspective, as this metabolic activity may help reduce levels of a compound that, when processed by the host, contributes to cardiovascular and kidney disease risk. The unique aspects of its energy conservation system and the presence of the pyrrolysine biosynthesis pathway further highlight the distinctive metabolic features of this archaeon. These metabolic specializations likely contribute to its ecological distribution and abundance patterns in the human gut, as well as its potential health effects through the modulation of gut metabolites.
Clinical Relevance
Candidatus Methanomethylophilus alvus has several aspects of clinical significance:
Cardiovascular disease prevention:
- Reduces trimethylamine (TMA), a precursor to trimethylamine-N-oxide (TMAO)
- TMAO is an established risk factor for atherosclerosis and cardiovascular disease
- Higher abundance correlates with lower fecal TMA concentrations
- Potential biomarker for reduced cardiovascular risk
- Could represent a novel target for cardiovascular disease prevention strategies
Chronic kidney disease management:
- TMAO has been associated with chronic kidney diseases
- By reducing TMA levels, may help prevent kidney damage
- Potential relevance for patients with existing kidney conditions
- May be particularly important in aging populations with increased kidney disease risk
- Could complement existing approaches to kidney disease management
Trimethylaminuria treatment:
- Trimethylaminuria (fish odor syndrome) affects 0.5-11% of people across different ethnic populations
- Results from deficiency in liver FMO3 monooxygenase that normally converts TMA to TMAO
- By consuming TMA in the gut, may reduce symptoms of this condition
- Proposed as a potential "Archaebiotic" (archaeal probiotic) for trimethylaminuria
- Could offer a novel approach to a condition with limited treatment options
Diagnostic considerations:
- Detection methods include PCR-based molecular techniques targeting 16S rRNA genes
- Metagenomic sequencing can identify and quantify its presence
- Not routinely included in standard microbiome testing panels
- Specialized assays required for detection
- Potential biomarker for gut microbiome health in certain contexts
Therapeutic development:
- Proposed as an "Archaebiotic" for conditions related to TMA/TMAO
- Challenges in cultivation may limit direct probiotic applications
- Alternative approach: genetic engineering of bacteria to express Methanomassiliicoccales genes
- tRNAPyl-PylRS pair being developed for applications in human studies and cancer therapeutics
- Potential dietary approaches to modulate its abundance
Aging-related health:
- More prevalent in older adults
- Different clades show opposite correlations with health status in elderly populations
- May be affected by lifestyle changes, such as entering long-term residential care
- Potential relevance for geriatric medicine and healthy aging
- Could inform microbiome-based interventions for elderly populations
Dietary interventions:
- Abundance may be influenced by dietary patterns
- Potential for dietary modulation to enhance its presence
- Interactions with TMA-producing bacteria suggest complex dietary effects
- Could inform personalized nutrition approaches
- Relevant for dietary management of conditions related to TMA/TMAO
Research challenges:
- Recently isolated as strain Mx-05T (proposed as Methanomethylophilus alvi)
- Requires specialized growth conditions and medium supplements
- Limited availability of reference strains
- Challenges in standardization of detection and quantification methods
- Need for further clinical studies to establish health benefits
The clinical relevance of Ca. M. alvus stems primarily from its ability to consume TMA, a bacterial metabolite with indirect negative effects on human health when converted to TMAO. This metabolic capability positions it as a potentially beneficial member of the gut microbiome, particularly in the context of cardiovascular disease, chronic kidney disease, and trimethylaminuria. The proposed use of Ca. M. alvus or its genetic elements as therapeutic agents represents an innovative approach to microbiome-based interventions for health. However, the complex ecology of the gut microbiome and the variable prevalence of Ca. M. alvus across populations suggest that its clinical applications may require personalized approaches that consider individual microbiome composition, diet, and health status. The recent isolation of a representative strain (Mx-05T) may facilitate further research into its potential clinical applications, though challenges in cultivation and standardization remain to be addressed.
Interactions with Other Microorganisms
Candidatus Methanomethylophilus alvus engages in complex interactions with other members of the human microbiome:
Functional links with TMA-producing bacteria:
- Abundance correlates positively with bacterial gene count for TMA production
- Utilizes TMA produced by bacterial fermentation of dietary compounds
- Key bacterial TMA sources include choline and carnitine metabolism
- Bacterial genera involved include Clostridium, Escherichia, and others
- These correlations suggest potential metabolic cross-feeding relationships
Dependence on bacterial partners:
- Requires unknown medium factors provided by certain bacteria
- Growth enhanced by factors from Eggerthella lenta or present in rumen fluid
- These requirements reflect potential syntrophic relationships
- May depend on specific bacterial species for optimal growth in vivo
- Suggests co-evolution with certain bacterial groups
Hydrogen economy interactions:
- Competes with other hydrogen-consuming microorganisms
- Alternative hydrogen consumers include acetogenic bacteria and sulfate-reducing bacteria
- Competition for hydrogen may influence community structure
- Hydrogen utilization affects the thermodynamics of bacterial fermentation
- May indirectly influence bacterial metabolism through hydrogen removal
Impact on bacterial metabolism:
- Consumption of hydrogen can shift bacterial fermentation toward more oxidized end products
- May enhance the efficiency of bacterial energy harvest
- Could influence the production of short-chain fatty acids
- Potential effects on bacterial gene expression and metabolic regulation
- These interactions contribute to overall ecosystem function
Co-occurrence patterns:
- Forms part of distinct clades that show different correlations with host health status
- May co-occur with specific bacterial taxa
- These patterns could reflect complementary metabolic capabilities
- Understanding these patterns helps elucidate community assembly rules
- May indicate metabolic networks or functional guilds within the microbiome
Ecological distribution:
- Part of the "host-associated clade" of Methanomassiliicoccales
- Primarily found in gut environments across various animal species
- Distinct from soil and sediment-associated Methanomassiliicoccales
- Suggests specialized adaptation to the gut environment
- May occupy different microenvironments within the gut ecosystem
Adaptation to specific host factors:
- Genomic adaptations for gut colonization, including adhesins and bile acid resistance genes
- These adaptations may influence interactions with other microorganisms
- Potential influence of host genetics, diet, and immune status on these interactions
- Temporal dynamics could vary in response to changing conditions
- These adaptations contribute to the complexity of the gut microbiome
Relationship with other archaea:
- Distinct ecological niche from other gut methanogens like Methanobrevibacter smithii
- Different substrate utilization patterns compared to other archaeal species
- May compete or coexist with other archaea depending on available substrates
- Part of the broader archaeal component of the gut microbiome
- Contributes to archaeal diversity in this environment
The interactions between Ca. M. alvus and other microorganisms in the human gut represent a fascinating aspect of microbiome ecology. The functional links with TMA-producing bacteria are particularly significant, suggesting a potential metabolic network where bacterial production of TMA is balanced by archaeal consumption. This relationship could have important implications for host health, particularly in the context of TMA-related conditions. The dependence of Ca. M. alvus on growth factors provided by specific bacteria highlights the interconnected nature of the gut ecosystem, where archaeal metabolism is intimately linked to bacterial activities. These interactions contribute to the overall function of the microbiome and may have important implications for host health, particularly in the context of metabolic conditions where gut microbiome composition plays a role. Understanding these complex ecological relationships is essential for developing effective microbiome-based interventions that consider the full diversity of microorganisms present in the gut, including both bacterial and archaeal components.
Research Significance
Candidatus Methanomethylophilus alvus has substantial significance across multiple research domains:
Archaeal biology and evolution:
- Represents a recently described order of methanogens (Methanomassiliicoccales)
- Provides insights into archaeal adaptation to the mammalian gut environment
- Illustrates specialized metabolic evolution with restricted energy metabolism
- Demonstrates how archaea can occupy specific niches within complex microbial communities
- Contributes to understanding the evolutionary history of host-associated archaea
Microbiome science:
- Highlights the importance of considering archaea in human microbiome studies
- Demonstrates functional interactions between archaeal and bacterial components
- Provides evidence for niche specialization among human gut methanogens
- Contributes to understanding the "hydrogen economy" of the gut ecosystem
- Illustrates how less abundant members can have significant functional impacts
Metabolic research:
- Exemplifies specialized metabolism (methyl compound reduction with hydrogen)
- Illustrates the importance of methylated compounds in gut metabolism
- Provides a model for studying hydrogen utilization in the gut
- Contributes to understanding methanogenesis in human-associated environments
- May inform research on microbial contributions to host metabolism
Cardiovascular disease research:
- Connects gut microbiome function to cardiovascular health
- Provides a potential mechanism for reducing TMAO, a cardiovascular risk factor
- Suggests novel approaches to cardiovascular disease prevention
- Contributes to understanding the gut-heart axis
- May inform development of microbiome-based interventions for heart health
Kidney disease research:
- TMAO has been associated with chronic kidney diseases
- TMA reduction may help prevent kidney damage
- Provides insights into gut-kidney connections
- May inform novel approaches to kidney disease management
- Contributes to understanding how gut microbiome affects renal function
Synthetic biology applications:
- tRNAPyl-PylRS pair has attracted growing interest in synthetic biology
- Can incorporate non-canonical amino acids with high specificity and efficiency
- Being developed for applications in human in vivo studies and cancer therapeutics
- Represents a valuable tool for protein engineering
- Illustrates how archaeal systems can have biotechnological applications
Probiotic development:
- Proposed as an "Archaebiotic" for conditions related to TMA/TMAO
- Represents a novel approach to probiotic development focusing on archaea
- Challenges in cultivation driving innovative approaches
- Alternative: genetic engineering of bacteria to express Methanomassiliicoccales genes
- May lead to new therapeutic modalities for microbiome modulation
Methodological advances:
- Drives development of techniques for studying archaea in complex microbiomes
- Recent isolation of representative strain (Mx-05T) advances cultivation methods
- Encourages inclusion of archaeal-specific methods in microbiome analysis
- Highlights the importance of multi-omics approaches in microbiome research
- Advances in studying Ca. M. alvus have broader applications in archaeal biology
Aging and geriatric research:
- More prevalent in older adults
- Different clades show opposite correlations with health status in elderly populations
- May be affected by lifestyle changes, such as entering long-term residential care
- Contributes to understanding microbiome changes in aging
- May inform interventions for healthy aging
The research significance of Ca. M. alvus extends far beyond its specific role in the human gut, touching on fundamental questions in microbiology, metabolism, and human health. As one of the key archaeal species in the human gut microbiome, it serves as an important model organism for understanding the contributions of this often-overlooked domain of life to human health and disease. The discovery of its TMA-utilizing capabilities and the potential health implications of this metabolic activity represent major advances in our understanding of microbiome-host interactions. The recent isolation of a representative strain (proposed as Methanomethylophilus alvi) opens new avenues for research into its biology and potential applications. Continued research on this organism promises to yield insights with broad applications in both basic science and clinical medicine, particularly in the context of cardiovascular and kidney health where its unique properties may offer new therapeutic opportunities.