Hungatella

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title: Hungatella type: entity subtype: microbe created: 2026-04-10 updated: 2026-04-16 last_substantive_update: 2026-04-16 sources: [altinok-dindar-2023-gut-microbiota-breast-cancer-diet, qin-2024-consistent-microbiome-signatures-old-young-onset-crc, zhang-2025-gut-virome-premalignant-colorectal-adenoma, rahman-2022-gut-microbiota-cvd-therapeutic-regulation, yadav-2022-ms-gut-mycobiome-fungal-bacterial, yin-2022-pcos-bacteriome-mycobiome-metabolome-bmi, zhou-2024-gut-microbiome-schizophrenia-mendelian-randomization] source_count: 7 metal_dependencies: [iron, selenium, cobalt] key_enzymes: [TMA lyase (choline TMA-lyase), carnitine oxygenase, betaine reductase, beta-glucuronidase, cobalt-dependent methionine synthase] tags: [pathobiont, CRC-enriched, breast-cancer-enriched, TMA-producer, TMAO-precursor, estrobolome, pcos-enriched, schizophrenia-risk, recently-described] platform: wikibiome seo_target: "Hungatella hathewayi TMA TMAO colorectal cancer breast cancer gut microbiome" wikipedia_differentiation: "Iron and selenium dependency with TMA/TMAO-estrobolome dual mechanism linking cancer-associated pathobiont to cardiovascular, cancer, and neuropsychiatric axes; beta-glucuronidase activity connecting Hungatella to estrogen recirculation in PCOS and breast cancer; schizophrenia MR data; PCOS BMI-independent enrichment — all absent from Wikipedia which does not have a Hungatella entry" conditions_enriched_in: [colorectal-cancer, breast-cancer, cardiovascular-disease, polycystic-ovary-syndrome, multiple-sclerosis, schizophrenia] conditions_depleted_in: [] pathogenic_potential: commensal-turned-pathogen gram_stain: "positive" oxygen_requirement: "obligate anaerobe"—-

Hungatella hathewayi is a Gram-positive, obligate anaerobic bacterium within the Firmicutes phylum (family Clostridiaceae) that has rapidly emerged as a multi-disease cancer-associated pathobiont. A recently reclassified genus (from Clostridium hathewayi), it is now recognized as one of the most consistently enriched taxa across colorectal cancer, breast cancer, polycystic-ovary-syndrome, and multiple sclerosis — united by its capacity to produce trimethylamine (TMA) and operate as a beta-glucuronidase producer in the estrobolome.

Taxonomy

• Hungatella hathewayi — type species; named after R.E. Hungate, pioneer of anaerobic microbiology.
• Reclassified from Clostridium hathewayi (Kaur et al., 2014) based on phylogenetic separation from core Clostridium sensu stricto.
• Family Clostridiaceae, order Clostridiales, class Clostridia.
• A second species, H. effluvii, has been described from anaerobic digesters, further distinguishing the genus from Clostridium.

Metal Dependencies

Iron:

• Central to Hungatella's anaerobic respiration. Iron-sulfur cluster enzymes (ferredoxins, NADH oxidoreductases) support the electron flow required for TMA production from choline, carnitine, and betaine.
• Iron availability in cancer and inflammatory environments — where hemorrhage and neovascularization release hemoglobin-derived iron — provides a selective growth advantage for iron-dependent anaerobes like Hungatella.
• The iron-dependent carnitine oxygenase step in carnitine-to-TMA conversion requires non-heme iron as cofactor.

Selenium:

• Selenocysteine-containing proteins in the formate dehydrogenase family are widespread in Clostridiales; Hungatella likely encodes selenium-dependent oxidoreductases supporting its anaerobic metabolism.
• Selenium status in the host influences the activity of selenium-dependent microbial enzymes, linking dietary selenium intake to the metabolic output of TMA-producing gut bacteria.

Cobalt:

• Corrinoid (B12-like) enzymes are required for the methyl-transfer reactions in betaine degradation: betaine → dimethylglycine → sarcosine, ultimately contributing to TMA production via the betaine-TMA lyase pathway.
• Cobalt-dependent methionine synthase also supports one-carbon metabolism generating SAM — relevant to the epigenetic implications of Hungatella metabolite production.

TMA/TMAO Production: The Cardiovascular-Cancer Bridge

H. hathewayi produces trimethylamine (TMA) from dietary choline, L-carnitine, and betaine through three distinct enzymatic pathways:

1. Choline TMA-lyase (CutC/CutD system): Cleaves choline directly to TMA + acetaldehyde; this is the highest-flux pathway in a choline-rich dietary environment (eggs, meat).
2. Carnitine oxygenase pathway: L-carnitine → γ-butyrobetaine → TMA (via iron-dependent oxidation).
3. Betaine reductase: Betaine (glycine betaine, found in beets, spinach, quinoa) → TMA via cobalt-dependent demethylation.

TMA is absorbed in the colon, transported to the liver, and oxidized to trimethylamine N-oxide (TMAO) by flavin monooxygenase 3 (FMO3). TMAO:

• Promotes macrophage foam cell formation and atherosclerosis via altered cholesterol reverse transport
• Enhances platelet hyperreactivity and thrombotic risk
• Correlates with major adverse cardiovascular events in prospective cohort studies
• May also promote tumor growth via FMO3-TMAO-driven hepatic lipid metabolism

This TMA/TMAO pathway is the mechanistic bridge connecting cancer-associated gut dysbiosis to cardiovascular risk — explaining why CRC patients have elevated cardiovascular mortality beyond what tumor burden alone would predict.

Beta-Glucuronidase and the Estrobolome

Beyond TMA, Hungatella expresses beta-glucuronidase — the enzyme that deconjugates glucuronide-bound estrogens in the gut, releasing free estrogens that can be reabsorbed and recirculated ^[1].

This positions Hungatella within the estrobolome: the subset of gut microbiota whose beta-glucuronidase activity drives estrogen recirculation. In estrogen-dependent conditions:

• Breast cancer: Hungatella enrichment elevates circulating estrogen, potentially fueling ER+ tumor growth.
• PCOS: Hungatella enrichment is present regardless of BMI (BMI-independent finding) alongside Lachnospira, E. coli-Shigella, and Erysipelotrichaceae_UCG-003 ^[1], linking it to the hyperandrogenism/estrogen imbalance of PCOS through beta-glucuronidase-driven hormone recirculation.

The TMA and beta-glucuronidase activities are independent pathways that may act synergistically in cancer and metabolic disease: TMA fuels cardiovascular co-morbidity while beta-glucuronidase fuels hormonal dysregulation.

Disease Associations

Colorectal Cancer

H. hathewayi is a core member of the CRC-associated microbiome signature:

• Enriched in both old-onset and young-onset CRC alongside parvimonas micra, Clostridium symbiosum, and Peptostreptococcus stomatis ^[2].
• Correlated with sessile serrated adenoma-associated viral OTUs in virome-bacteria network analyses, suggesting involvement from premalignant stages before frank carcinoma ^[3].
• Enrichment across geographically diverse CRC cohorts supports a biologically meaningful role.
• TMAO production provides a mechanistic hypothesis: local TMAO promotes tumor cell growth via FMO3-driven lipid metabolism and may suppress anti-tumor immune responses through macrophage polarization.

Breast Cancer

• Enriched in newly diagnosed, treatment-naive breast cancer patients (38% prevalence vs. 9% in controls) ^[4].
• Hungatella-positive participants had distinct dietary patterns: lower dairy and higher total vegetable intake — suggesting that plant-derived betaine (beets, spinach) rather than meat-derived carnitine may be the predominant TMA substrate in this population.
• Co-enriched with Acidaminococcus and Tyzzerella as part of the breast cancer gut microbiome signature.
• Both TMA/TMAO production and beta-glucuronidase-driven estrogen recirculation provide mechanistic links to breast cancer biology.

Polycystic Ovary Syndrome

• BMI-independent enrichment in PCOS: present in both normal-weight and overweight PCOS patients ^[1].
• The PCOS-Hungatella connection links to estrobolome biology (beta-glucuronidase → estrogen recirculation) and cardiometabolic risk (TMA/TMAO production in the context of PCOS insulin resistance).
• Targeting Hungatella TMA production has been proposed as a potential intervention for reducing cardiometabolic risk in PCOS.

Cardiovascular Disease

• Enriched in some heart failure cohorts alongside Prevotella and Succinclasticum ^[5].
• TMA/TMAO production provides a direct mechanistic link to atherosclerotic cardiovascular disease — Hungatella is among the most TMA-productive human gut anaerobes.
• Dietary choline and L-carnitine intake (red meat, eggs) modulates the TMA substrate pool available to Hungatella.

Multiple Sclerosis

• Increased in MS patients alongside Blautia and Eggerthella in the context of altered bacterial-fungal interaction networks ^[6].
• MS-Hungatella enrichment adds to a pattern of metabolically active cancer-associated taxa also appearing in neuroinflammatory conditions — a cross-condition pattern likely reflecting shared dysbiosis mechanisms.

Schizophrenia

• Hungatella appears as a risk-associated taxon in Mendelian randomization analysis of gut microbiome effects on schizophrenia ^[7], adding a neuropsychiatric dimension to its multi-disease profile.
• The pathway may involve TMAO-driven neuroinflammation or TMA's known effects on brain mitochondrial function.

Ecological Role in Dysbiosis

In the healthy gut, Hungatella is a minor member of the Clostridiaceae community held in check by SCFA producers and fiber-fermenting bacteria. In dysbiotic states:

1. Selective advantage in iron-rich environments: Tumor, inflammatory, and high-red-meat dietary contexts all elevate available iron, fueling Hungatella's iron-dependent metabolism.
2. Substrate abundance: High-choline, high-carnitine, high-betaine diets (typical of Western patterns) provide abundant TMA substrates.
3. Community vacuums: Loss of Bifidobacterium, Lactobacillus, and Roseburia in dysbiosis removes competitors that occupy overlapping metabolic niches.

Dietary Modulation

Hungatella abundance responds to dietary substrate availability:

• Red meat, eggs: provide L-carnitine and choline for TMA production via CutC/carnitine pathways.
• Beets, spinach, quinoa: provide betaine as alternative TMA substrate — explaining why "healthy" plant-based diets paradoxically support Hungatella in PCOS patients ^[1].
• Dietary modulation of TMA production (not of Hungatella abundance per se) may be achievable through 3,3-dimethyl-1-butanol (DMB) — a natural TMA lyase inhibitor found in cold-pressed oils.

Cross-References

• colorectal cancer — core member of the cross-cohort CRC microbiome signature
• breast cancer — enriched in treatment-naive BCa patients; TMA + estrobolome dual mechanism
• polycystic-ovary-syndrome — BMI-independent enrichment; beta-glucuronidase links to PCOS hyperandrogenism
• cardiovascular disease — TMA/TMAO production links gut metabolism to atherosclerosis and thrombosis
• multiple sclerosis — enriched in MS alongside altered mycobiome interactions
• schizophrenia — MR-identified risk association
• parvimonas — co-enriched CRC pathobiont in oral-gut translocation consortium
• iron — required for iron-sulfur cluster enzymes and carnitine oxygenase
• selenium — formate dehydrogenase-family selenoprotein cofactor
• cobalt — corrinoid enzyme cofactor for betaine TMA-lyase pathway
• estrobolome — beta-glucuronidase activity drives estrogen recirculation
• dysbiosis — enrichment reflects disease-associated community restructuring across multiple conditions