Eggerthella lenta

Eggerthella lenta is a gram-positive, non-spore-forming, obligately anaerobic rod-shaped bacterium belonging to the phylum Actinobacteria, class Coriobacteriia, family Eggerthellaceae. It is a prevalent member of the human gut microbiome, found in approximately 80% of individuals, and has gained significant attention due to its unique metabolic capabilities and associations with human health and disease.

Key Characteristics

E. lenta is characterized by its slow growth, strict anaerobic requirements, and distinctive metabolic capabilities. Cells are typically rod-shaped, sometimes slightly curved, and may appear singly, in pairs, or in short chains. The bacterium lacks motility and does not form spores. It has a relatively small genome (approximately 3.6 Mb) that encodes specialized enzymes for various metabolic functions, particularly those involved in the transformation of host-derived and dietary compounds.

E. lenta possesses several unique biochemical features, including the ability to reduce nitrate, produce indole, and metabolize a wide range of substrates. It is catalase-negative and bile-resistant, which enables it to survive in the intestinal environment. The cell wall contains meso-diaminopimelic acid, a characteristic feature of many Actinobacteria.

Role in the Human Microbiome

E. lenta is primarily found in the human intestinal tract, where it typically constitutes a small but significant portion of the gut microbiome. Its abundance varies between individuals and can be influenced by factors such as:

1. Diet: Dietary components, particularly protein and specific phytochemicals, may influence E. lenta populations
2. Host genetics: Certain host genetic factors may affect colonization and abundance
3. Age: Generally more prevalent in adults than in children
4. Health status: Abundance may change in various disease states

Within the gut ecosystem, E. lenta occupies a specialized metabolic niche, interacting with host-derived compounds, dietary components, and potentially with other members of the microbiota through metabolic cross-feeding relationships. It is particularly notable for its ability to transform bile acids, steroid hormones, and various plant-derived compounds, which may have significant implications for host physiology.

Metabolic Activities

E. lenta possesses several distinctive metabolic capabilities that have attracted scientific interest:

Drug Metabolism

One of the most well-studied aspects of E. lenta metabolism is its ability to transform various drugs, with profound implications for therapeutic efficacy and toxicity. E. lenta impacts the bioavailability, activity, and toxicity of over fifty pharmaceutical compounds.^[1][1]

Digoxin Inactivation

The most clinically significant drug metabolism involves the cardiac glycoside digoxin:

• Mechanism: E. lenta inactivates digoxin by reducing the α,β-unsaturated γ-butyrolactone ring to form inactive dihydrodigoxin
• Genetic Basis: The cardiac glycoside reductase (cgr) operon consists of two genes (cgr1 and cgr2)
• Key Enzyme: Cgr2 is a novel oxygen-sensitive [4Fe-4S]-containing radical SAM enzyme requiring FAD cofactor
• Strain Variation: Only 20-30% of E. lenta strains carry the cgr operon, but 74.7% of humans harbor cgr2+ bacteria
• Regulation: The cgr operon is upregulated >165-fold in response to digoxin and transcriptionally repressed by dietary arginine
• Clinical Significance: Digoxin has a narrow therapeutic index, making inter-individual microbiome variation highly clinically relevant^[2][1]

L-Dopa Metabolism (Parkinson's Disease Relevance)

E. lenta participates in an interspecies pathway that reduces L-dopa bioavailability in Parkinson's disease patients:^[3][2]

• Pathway: Enterococcus faecalis converts L-dopa to dopamine → E. lenta transforms dopamine to m-tyramine
• Enzyme: Dopamine dehydroxylase (Dadh), a molybdenum-dependent enzyme
• Activity Determinant: Single nucleotide polymorphism at position 506 (R506 = active, S506 = inactive)
• Clinical Impact: As little as 1-5% of oral L-dopa reaches the brain; gut bacterial metabolism causes gastrointestinal distress, orthostatic hypotension, and cardiac arrhythmias
• Therapeutic Note: Host-targeted carbidopa does NOT prevent microbial L-dopa metabolism; AFMT [(S)-α-fluoromethyltyrosine] is an effective inhibitor

Resveratrol Metabolism

E. lenta metabolizes the polyphenol resveratrol, with important implications for its therapeutic effects:^[4][8]

• Enzyme: Novel resveratrol reductase (RER), an FAD-dependent ene-reductase
• Product: Dihydroresveratrol (DHR), which shows >30% stronger anti-colitis activity than resveratrol itself
• Metabolism Rate: E. lenta converts resveratrol nearly 100× faster than other gut bacteria
• Gene Prevalence: RER+ bacteria in 59.85% of healthy individuals vs 46.41% of colitis patients
• Clinical Implication: Resveratrol efficacy depends on RER-mediated conversion to the more active DHR metabolite

Catechol Metabolism

E. lenta possesses specialized enzymes for the metabolism of catechols (compounds containing a 1,2-dihydroxylated aromatic ring):

1. Dopamine Dehydroxylase (Dadh): Metabolizes the catecholamine neurotransmitters dopamine and norepinephrine
2. Hydrocaffeic Acid Dehydroxylase (Hcdh): Acts on hydrocaffeic acid, a dietary compound
3. Catechin Dehydroxylase (Cadh): Transforms catechin, a flavonoid found in various plant foods

These dehydroxylation reactions may alter the bioactivity and bioavailability of these compounds, with potential implications for host physiology.

Bile Acid Metabolism

E. lenta can transform primary bile acids through various reactions, including dehydroxylation. This activity may influence:

1. Bile acid pool composition: Affecting lipid absorption and metabolism
2. Signaling through bile acid receptors: Potentially modulating metabolic and inflammatory pathways
3. Interactions with other gut microbes: As bile acids can influence microbial community structure

Other Metabolic Activities

1. Steroid Hormone Metabolism: Can transform steroid hormones, potentially affecting their bioactivity
2. Dietary Phytochemical Transformation: Metabolizes various plant-derived compounds, including lignans and flavonoids
3. Production of Bioactive Metabolites: Generates metabolites such as imidazole propionate, which may influence host physiology

Health Implications

E. lenta has been associated with both beneficial and detrimental effects on human health:

Pathogenic Potential

E. lenta is considered an opportunistic pathogen and has been implicated in various infections:

1. Bloodstream Infections: E. lenta bacteremia is associated with significant mortality (up to 30-40% in some studies) and is often linked to gastrointestinal sources, such as intestinal perforation or colorectal cancer
2. Intra-abdominal Abscesses: Can be isolated from abdominal abscesses, often as part of polymicrobial infections
3. Wound Infections: Occasionally reported in wound infections, particularly those with anaerobic components

Risk factors for E. lenta infections include immunosuppression, recent abdominal surgery, malignancy, and advanced age.

Associations with Chronic Diseases

E. lenta has been causally implicated in several chronic conditions through mechanistic studies:

Rheumatoid Arthritis^[5][5]

• Causal Evidence: E. lenta expansion initiates preclinical autoreactive response; produces rheumatoid factor in naïve mice
• Immune Effects: Increases CXCL5, CD4 T cells, IL-17-producing B cells, and IFN-γ-producing B cells
• Metabolic Effects: Causes gut dysbiosis, decline in amino acids and NAD+, increases bile acids (DCA, LCA)
• Sex Bias: Women have higher E. lenta load with earlier onset and more severe arthritis
• Gene Association: cgr2 gene detected in 83% of RA patients vs 54% of healthy controls

Inflammatory Bowel Disease^[6][4]

• Mechanism: cgr2+ E. lenta induces Th17 cells via Rorγt pathway; worsens DSS-induced colitis
• Correlation: E. lenta levels significantly correlated with disease scores when cgr2 detected
• Causation: Causal role in Th17-dependent colitis demonstrated in gnotobiotic mice
• Dietary Intervention: Dietary arginine blocks E. lenta-induced intestinal inflammation and Th17 activation

Bronchiectasis (Gut-Lung Axis)^[7][7]

• Mechanism: E. lenta produces TUDCA (taurine ursodeoxycholic acid) which circulates from gut to lung
• Effect: TUDCA binds AMPK in neutrophils, reducing ATP production and impairing Pseudomonas aeruginosa clearance
• Therapeutic Target: Metformin (AMPK activator) improved disease severity in mouse models

Metabolic Disorders

• Type 2 Diabetes: Higher relative abundance linked to imidazole propionate production, which impairs insulin signaling
• Cardiovascular: Metabolizes N,N-dimethylarginine; high plasma levels associated with atherosclerosis and hypertension

Potential Beneficial Roles

Despite its pathogenic potential, E. lenta may also contribute positively to host health:

1. Xenobiotic Metabolism: Transformation of potentially harmful compounds
2. Immune System Modulation: May influence immune development and function
3. Metabolic Regulation: Potential role in metabolic homeostasis through bile acid and hormone metabolism

Genetic Tools and Research Advances

Recent advances have significantly expanded our ability to study E. lenta:

1. Genetic Manipulation: Development of shuttle vectors, transformation methods, and genome editing tools using the endogenous CRISPR-Cas system
2. Reporter Systems: Creation of tools to study gene expression and regulation
3. Inducible Expression Systems: Development of systems for controlled gene expression

These tools have enabled detailed studies of E. lenta biology, including the characterization of a previously unappreciated family of membrane-spanning LuxR-type transcriptional regulators involved in catechol metabolism.

Clinical Relevance

The clinical significance of E. lenta extends beyond its role as an opportunistic pathogen:

1. Antibiotic Susceptibility: Generally susceptible to metronidazole, carbapenems, and beta-lactam/beta-lactamase inhibitor combinations, which are important for treating infections
2. Drug-Microbiome Interactions: E. lenta's drug-metabolizing capabilities may influence the efficacy of certain medications, suggesting potential for personalized medicine approaches
3. Biomarker Potential: Altered E. lenta abundance or activity may serve as biomarkers for certain conditions
4. Therapeutic Target: Modulating E. lenta populations or activities might represent a therapeutic strategy for certain conditions

Research Directions

Current and future research on E. lenta focuses on several key areas:

1. Metabolic Interactions: Further characterization of E. lenta's role in transforming host and dietary compounds
2. Host-Microbe Interactions: Elucidating mechanisms by which E. lenta influences host physiology and disease
3. Strain Diversity: Understanding functional differences between E. lenta strains and their health implications
4. Therapeutic Applications: Exploring potential for targeted modulation of E. lenta activities
5. Ecological Interactions: Investigating E. lenta's interactions with other members of the gut microbiota

As research continues to advance, our understanding of E. lenta's complex roles in human health and disease will likely expand, potentially opening new avenues for microbiome-based diagnostics and therapeutics.