Escherichia coli

[NiFe] Hydrogenases#

E. coli encodes multiple [NiFe] hydrogenases.^{[1]Role of Nickel in Microbial PathogenesisRobert J. Maier, Stéphane L. Benoit · 2019Open reference 1 ↓} Hyd-1 (HyaABC): membrane-bound, H2-uptake. Expressed under aerobic/microaerobic conditions.

Hyd-2 (HybOABC): membrane-bound, H2-uptake. Most active under anaerobic conditions with alternative electron acceptors. Hyd-3 (HycBCDEFG): cytoplasmic, H2-evolving.

Part of the formate hydrogenlyase (FHL) complex; produces H2 during mixed-acid fermentation.

Hyd-4 (HyfABCDEFGHIR): second FHL-associated complex.

In pathogenic E. coli, hydrogenases provide. Respiratory flexibility in the oxygen-variable gut environment. Acid resistance: Hyd-3/FHL consumes formate and produces H2 + CO2, removing acidic fermentation products.

Energy generation in nutrient-limited intracellular niches (for UPEC inside bladder epithelial cells).

Urease (in Shiga Toxin-Producing E. coli)#

STEC/EHEC strains use Urease for acid survival during gastric transit.^{[1]Role of Nickel in Microbial PathogenesisRobert J. Maier, Stéphane L. Benoit · 2019Open reference 1 ↓} Urease-mediated Ammonia production buffers pH, enabling survival through the stomach to reach the intestinal colonization site. Not all E. coli pathotypes carry urease—it is primarily found in STEC and some UPEC strains.

Ni-Acireductone Dioxygenase (ARD)#

Part of the methionine salvage pathway; the nickel (Ni)-bound form is present in E. coli and other gamma-proteobacteriaceae. Provides metabolic flexibility depending on available metal cofactors.

Fe-Dependent Virulence#

Enterobactin: the canonical high-affinity siderophore (Ka for iron(III) (Fe3+) = ~10^52). Aerobactin: found in many UPEC and invasive strains; functions at lower affinity but under a broader range of conditions. Yersiniabactin: see below—dual iron/nickel role.

ChuA/Chu system: heme uptake receptor in EHEC and UPEC. Shiga toxin expression is iron-regulated (repressed by Fur under high iron; induced under iron limitation).

NikABCDE—The Model Nickel Transporter#

First characterized nickel (Ni)-specific ABC transporter.^{[1]Role of Nickel in Microbial PathogenesisRobert J. Maier, Stéphane L. Benoit · 2019Open reference 1 ↓} NikA: periplasmic nickel-binding protein. NikB/NikC: integral membrane permease subunits.

NikD/NikE: ATP-binding cassette subunits providing energy. Regulated by NikR (nickel-responsive repressor)—under high nickel, NikR represses nikABCDE to prevent toxicity.

This system is the paradigm for understanding nickel import across all bacteria; homologs found in Salmonella enterica serovar Typhimurium, Helicobacter pylori (NiuBDE), and many other pathogens.

Yersiniabactin—A Dual Iron/Nickel Metallophore#

Originally characterized as an iron siderophore in Yersinia pestis, but the UPEC yersiniabactin also binds extracellular nickel.^{[1]Role of Nickel in Microbial PathogenesisRobert J. Maier, Stéphane L. Benoit · 2019Open reference 1 ↓} In uropathogenic E. coli, yersiniabactin serves a dual role. Iron acquisition for growth.

Nickel import for hydrogenase/urease metalation during UTI. Nickel transport via yersiniabactin is upregulated during urinary tract infection, suggesting active nickel scavenging in the urinary environment. This dual-specificity metallophore represents a metabolically efficient strategy: one molecule, two essential metals.

Hydrogenase Maturation#

HypABCDEF: accessory proteins for [NiFe] active site assembly, shared across all four hydrogenases. HypB is a GTPase/nickel metallochaperone; HypA delivers nickel to HypB.

Nutritional Immunity Evasion#

Lipocalin-2: host protein that sequesters enterobactin-iron (Fe) complexes. UPEC strains carrying yersiniabactin or salmochelin evade lipocalin-2. Calprotectin: sequesters zinc (Zn), manganese (Mn), and nickel (Ni) at infection sites.

Lactoferrin: sequesters iron in mucosal secretions and urine.

UPEC nickel transport upregulation during UTI suggests the pathogen senses host-mediated nickel restriction and responds with increased scavenging.

Disease Associations#

Urinary tract infections (UTI): UPEC is the #1 cause of community-acquired UTI; nickel transport upregulated during infection.^{[1]Role of Nickel in Microbial PathogenesisRobert J. Maier, Stéphane L. Benoit · 2019Open reference 1 ↓} Hemolytic uremic syndrome (HUS): STEC/EHEC (O157:H7); Shiga toxin is iron-regulated.^{[1]Role of Nickel in Microbial PathogenesisRobert J. Maier, Stéphane L. Benoit · 2019Open reference 1 ↓} Neonatal meningitis: K1 capsular strains.

Traveler's diarrhea: ETEC strains. Crohn's disease-associated: adherent-invasive E. coli (AIEC) in the ileum. Bacteremia/sepsis: from urinary or GI source; E. coli translocation from the gut is a major source of sepsis in severe COVID-19.^{[2]Bernard-Raichon et al. 2022 — Gut microbiome dysbiosis in antibiotic-treated COVID-19 patients is associated with microbial translocation and bacteremiaLucie Bernard-Raichon, Mericien Venzon, Jon Klein et al. · 2022Open reference 2 ↓}

Chronic kidney disease: Enterobacteriaceae including E. coli are enriched and LPS translocation contributes to uremic Metal-Driven Inflammation.^{[3]Alobaidi 2025 — The Gut-Kidney Axis in CKD: Mechanisms, Microbial Metabolites, and Microbiome-Targeted TherapeuticsSami Alobaidi · 2025Open reference 3 ↓[4]Protein-Bound Uremic Toxins from Gut Microbiota and Inflammatory Markers in CKDNatalia A. Borges, Amanda F. Barros, Lia S. Nakao et al. · 2016Open reference 4 ↓}

GERD / esophageal Dysbiosis: Enterobacteriaceae including E. coli are enriched in a Type II (LPS-driven) esophageal microbiome signature associated with erosive disease.^{[5]Esophageal microbial dysbiosis impairs mucosal barrier integrity via toll-like receptor 2 pathway in patients with gastroesophageal reflux symptomsChen S, Jiang D, Zhuang Q et al. · 2024Open reference 5 ↓[6]Alageel 2025 — Examining the Microbiome Composition in Patients with Gastroesophageal Reflux Disease: A Systematic ReviewAlageel AA, Alomran DA, Alharbi HB et al. · 2025Open reference 6 ↓}

Endometriosis: Gram-negative E. coli and related Enterobacteriaceae are enriched in cervical, vaginal, and gut compartments; nickel-sensitive IBS symptoms overlap with endometriosis dysbiosis.^{[7]Molecular detection of microbial colonization in cervical mucus of women with and without endometriosisAkiyama K, Nishioka K, Khan KN et al. · 2019Open reference 7 ↓[8]Irritable Bowel Syndrome-Like Disorders in Endometriosis: Prevalence of Nickel Sensitivity and Effects of a Low-Nickel Diet. An Open-Label Pilot StudyBorghini R, Porpora MG, Casale R et al. · 2020Open reference 8 ↓[9]Gut and Vaginal Microbiota in the Endometriosis: Systematic Review and Meta-AnalysisColonetti T, Saggioratto MC, Grande AJ et al. · 2023Open reference 9 ↓}

Colorectal cancer: colibactin-producing and mucosa-associated E. coli are enriched and drive genotoxic damage.^{[10]Comparison between 16S rRNA and Shotgun Sequencing in Colorectal Cancer, Advanced Colorectal Lesions, and Healthy Human Gut MicrobiotaBars-Cortina D, Ramon E, Rius-Sansalvador B et al. · 2024Open reference 10 ↓[11]Metabolic Interactions: How Gut Microbial Metabolites Influence Colorectal CancerCao Q, Yang M, Chen M · 2025Open reference 11 ↓}

Necrotizing enterocolitis: Enterobacteriaceae bloom (including E. coli) precedes NEC onset in preterm infants.^{[12]Torrazza 2013 — Intestinal Microbial Ecology and Environmental Factors Affecting NECTorrazza RM, Ukhanova M, Wang X et al. · 2013Open reference 12 ↓[13]Nickel as a Catalytic Driver of Necrotizing Enterocolitis: Dietary Nickel, Microbial Metallomics, and the Activation of Nickel-Dependent Virulence Pathways in the Preterm GutKaren Pendergrass · 2026Open reference 13 ↓}

Type 1 diabetes: Bacteroides dorei-like and E. coli populations with immunoinhibitory LPS structures alter early immune priming and are linked to T1D progression.^{[14]Davis-Richardson & Triplett 2015 — Bacteroides dorei as a Model for T1D Microbiome PathogenesisAustin G. Davis-Richardson, Eric W. Triplett · 2015Open reference 14 ↓[15]Vatanen et al. 2018 — The Human Gut Microbiome in Early-Onset Type 1 Diabetes from the TEDDY StudyTommi Vatanen, Eric A. Franzosa, Randall Schwager et al. · 2018Open reference 15 ↓}

Connection to Environmental Metal Exposure#

Dietary nickel excreted in urine provides substrate for UPEC nickel scavenging during UTI—higher dietary nickel may theoretically support UPEC virulence.^{[1]Role of Nickel in Microbial PathogenesisRobert J. Maier, Stéphane L. Benoit · 2019Open reference 1 ↓}

Gut E. coli populations are exposed to dietary metals; iron supplementation is known to promote pathogenic E. coli expansion in the gut.^{[16]Mechanism of Iron Ion Homeostasis in Intestinal Immunity and Gut Microbiota RemodelingHonghong Bao, Yi Wang, Hanlin Xiong et al. · 2024Open reference 16 ↓}

Yersiniabactin's dual iron/nickel specificity means environmental iron AND nickel both feed UPEC metal acquisition.^{[1]Role of Nickel in Microbial PathogenesisRobert J. Maier, Stéphane L. Benoit · 2019Open reference 1 ↓} Agricultural metal contamination selects for metal-tolerant E. coli in food-animal production.

Synergistic toxicity of copper, nickel, iron, and sulfur modulates E. coli stress and survival responses.^{[17]Darwiche 2025 — The Molecular Basis of the Synergistic Toxicity of Nickel and Copper, Common Environmental Co-ContaminantsLinda Darwiche, Carlos A Rodriguez-Bornot, Rebecca A Ingrassia et al. · 2025Open reference 17 ↓}