Lead (Pb)

Overview and clinical relevance

Lead is a non-essential, cumulative toxicant that partitions predominantly into red blood cells (99%), where it binds and inhibits δ-aminolevulinic acid dehydratase (ALAD), disrupting heme synthesis and serving as a sensitive functional biomarker of exposure.^[1] Bone is the major long-term reservoir (>90% of the body burden in adults), enabling chronic recirculation years after exposure ceases.^[2] At the population level, public-health benchmarks have tightened: the U.S. CDC’s pediatric blood lead reference value is 3.5 µg/dL, and EPA’s 2024 Lead and Copper Rule Improvements lowered the drinking-water action level to 10 µg/L, underscoring that there is no known safe level.^[3] Microbiome-relevant evidence spans humans and models, showing that prenatal and chronic low-dose exposures are associated with decreased gut alpha-diversity, shifts in taxa, and functional alterations in children and adults, with plausible links to barrier injury and immune modulation.^[4] These host–metal–microbe interactions create selection pressures that can favor metal-resistance determinants and, in some settings, co-selection of antimicrobial resistance (AMR).

Chemical speciation across host niches

Lead, a toxic heavy metal, exists in several chemical forms in the human body, with its speciation significantly affecting its bioavailability, toxicity, and distribution across various tissues.^[5] Upon exposure, lead primarily enters the bloodstream as an inorganic ion (Pb²⁺), but it can also bind to proteins, lipids, and other biomolecules, forming complexes that enhance its retention in tissues.^[6] A significant fraction of lead is deposited in bones, where it mimics calcium, binding to hydroxyapatite and remaining stored for years.^[7] Bone lead serves as a reservoir, releasing the metal into the bloodstream during periods of bone turnover, such as pregnancy or osteoporosis.^[8] In the kidneys, lead interferes with sulfhydryl groups in enzymes, leading to renal dysfunction, while in the brain, it crosses the blood-brain barrier, where it disrupts synaptic function and neurotransmission by interfering with calcium signaling pathways, contributing to neurotoxicity.^[9][10] Lead can form organic compounds such as tetraethyl lead, which are absorbed more rapidly and present higher acute toxicity.^[11] The speciation of lead in various body compartments determines its toxicological impact, influencing both acute and chronic health effects, including its potential to disrupt the gut microbiome.

Microbial acquisition and regulation

Bacteria do not intentionally absorb lead (Pb²⁺) for nutrition; instead, it enters the cell unintentionally via porins and ion transport pathways that typically carry essential metals like calcium and zinc.^[12] Lead mimics these ions, causing accidental uptake. Once inside, lead can be toxic, disrupting biological processes. To counteract this, bacteria have evolved resistance systems such as the pbr operon in Cupriavidus metallidurans CH34.^[13] This operon includes PbrR, which senses lead and activates the pbr promoter, leading to the production of proteins that help detoxify lead.^[14] PbrA, a P1B-type ATPase, actively pumps lead out of the cell, while PbrB helps precipitate lead on the bacterial surface. PbrC and PbrD further sequester lead. P-type ATPases like ZntA can efflux lead, illustrating widespread resistance mechanisms across bacteria in metal-contaminated environments.^[15] Lead exposure also triggers general stress responses, activating alternative σ factors that help bacteria adapt to stress. These responses can affect motility and changes in the bacterial envelope, which are essential for survival in metal-contaminated habitats.

Metal toolkit

Nutritional immunity and host sequestration

Nutritional immunity is a defense mechanism where the host limits the availability of lead (Pb) to pathogens and harmful organisms by sequestering it in less toxic forms. Lead, which competes with essential metals like calcium, zinc, and iron, is stored primarily in bones and teeth, where it mimics calcium and binds to hydroxyapatite, acting as a long-term reservoir. During periods of bone turnover, lead is released into the bloodstream, and metallothioneins, small proteins that bind metals, help sequester lead in non-toxic forms, reducing its bioavailability. The blood-brain barrier prevents lead from entering sensitive brain tissues, and the intestinal mucosa helps limit its absorption into circulation. Additionally, iron and calcium-binding proteins, such as ferritin, bind to lead in the bloodstream, further reducing its potential for toxicity. These mechanisms work together to reduce lead’s toxic effects on the body, protecting against its neurotoxic, renal, and cardiovascular impacts.

Host sequestration

Metallophores and community competition

Although evolved for Fe(III), several microbial chelators capture Pb(II) measurably and can alter local metal availability. The trihydroxamate siderophore desferrioxamine B (DFO-B) forms stable complexes with multiple divalent metals including Pb(II), and related siderophores such as desferricoprogen (DFC) can bind Pb even more strongly. In mixed communities, such off-target chelation can either buffer Pb toxicity (by lowering free ion activity) or mobilize particle-bound Pb. Beyond small molecules, extracellular polysaccharides and teichoate-rich Gram-positive surfaces provide abundant carboxylate/phosphate sites that sorb Pb and shift exposure toward cell-surface precipitation. These capture processes are ecologically relevant in biofilms, where sorption and precipitation at community interfaces set the gradient of bioavailable Pb(II) confronting sensitive taxa.

Metallophores and capture

Mismetallation and cross-metal crosstalk

Pb(II) is a soft, thiophilic cation that readily binds cysteine-rich sites and can displace native metals in proteins. In bacteria, Pb stress risks mismetallation of Zn-dependent enzymes and metal-sensing regulators (e.g., MerR-family), perturbing transcriptional programs and stress defenses. Pb can also mimic or compete with Ca²⁺ at binding sites, altering envelope processes and signaling; at community interfaces, sulfide-driven PbS precipitation competes with phosphate-driven mineralization, changing where Pb is sequestered and which taxa are exposed. Together these interactions re-wire metal homeostasis and can push communities toward exporters, phosphate liberation, and EPS-rich biofilm states that lower intracellular Pb but favor persistence.

Mismetallation map

Virulence pathway mapping

Pb exposure does not endow microbes with new virulence factors, but it reweights existing regulatory circuits. In C. metallidurans, Pb(II) induces the pbr system and broader stress regulons under alternative sigma control (σ²⁴/σ³²/σ²⁸), intersecting with motility and envelope remodeling—axes commonly tied to colonization, invasion, and biofilm formation in pathogens. Metal-sensor cross-talk (MerR family) can reshape promoter architecture for resistance island genes, while envelope stress and redox pressure select for EPS-rich biofilms that protect against both metals and host defenses. In polymicrobial settings, off-target siderophore binding of Pb can modulate competitive access to Fe and other cations, indirectly affecting pathogen fitness. These mechanisms yield testable predictions: Pb-rich niches favor strains with robust ATPase efflux (PbrA/ZntA), thick EPS matrices, and stress-tolerant motility programs, traits often correlated with persistence on mucosa and devices.

Virulence targets to MBTIs

Exposure to microbiome outcomes

Human cohort data indicate prenatal Pb exposure (maternal blood ~33–35 µg/L) associates with reduced α-diversity and compositional shifts in children at 9–11 years; cross-sectional studies in contaminated settings likewise show diversity and functional disruptions in adults. In animals, chronic low-dose Pb in drinking water alters communities and metabolites, with barrier perturbation.^[20] Translating to decision-use thresholds, microbiome selection is plausible at exposures below clinical toxicity cutoffs, especially where chloride/carboxylate ligands and sulfide gradients magnify local bioavailability or precipitation. The table pairs pragmatic exposure bands with expected selection pressure, acknowledging interindividual variability and co-exposures.

Exposure thresholds to selection

Antimicrobial resistance co-selection

Heavy metals and antibiotics often co-reside on mobile elements, and metal pressures can select for ARG-bearing lineages even without antibiotic exposure. Genome-scale surveys and environmental studies consistently show co-occurrence of metal resistance genes (MRGs) and ARGs, with mechanistic contributions from co-resistance (linked loci), cross-resistance (shared pumps), and stress-enhanced horizontal gene transfer. While lead-specific datasets are fewer than for Cu/Zn/Hg, metal-polluted habitats repeatedly show ARG–MRG coupling and mobility signatures, supporting conservative risk framing when Pb exposure is chronic.

AMR co-selection signals

Assays and decision use

For exposure, ICP-MS of capillary/venous blood remains the clinical workhorse; pediatric reference value is 3.5 µg/dL, but any detectable Pb merits source control. Bone Pb (K-XRF/portable XRF) estimates cumulative burden and recirculation risk. Functional biomarkers (ALAD activity; erythrocyte zinc protoporphyrin) reflect heme-pathway inhibition and can complement total Pb. In stools/urine, ICP-MS tracks excretion and therapy response (e.g., DMSA/EDTA chelation), though stool Pb primarily informs elimination rather than current absorption. For microbiome endpoints, 16S/shotgun profiling with metal/metabolite panels helps link exposures to barrier and inflammation markers.

Assays to decision use

Body-site biogeography

Lead’s microbiome interface is niche-specific. In the stomach, chloride complexes increase solubility, potentially enhancing proximal uptake. In the small intestine, citrate/albumin complexes and competition with essential metals shape epithelial transfer. Microbial H₂S drives PbS precipitation in the colon, reducing dissolved Pb while increasing surface-bound Pb in biofilms and fecal solids. In blood, erythrocyte sequestration minimizes plasma free Pb; in bone, slow turnover maintains chronic background exposure. These distributions determine which microbes “see” Pb as a dissolved ligand versus a sorbed particulate, and which countermeasures (efflux vs. sorption/precipitation) are most favored.

Site to interaction of interest

MBTIs and clinical strategies

Microbiome-based therapeutic ideas (MBTIs) for Pb aim to lower free luminal Pb, divert it to insoluble phases, and strengthen barrier function. High-fiber diets and ligands that favor distal complexation/precipitation (e.g., fermentable fibers raising sulfide in the colon within safe physiological ranges) can reduce bioavailability. Certain lactic-acid bacteria and enterococci exhibit strong biosorption of Pb on cell walls/EPS, suggesting probiotic consortia could immobilize Pb in lumenal solids; meanwhile, butyrate-producing commensals support mucosal defense. These are adjunctive to primary hazard control (remediation, water treatment) and clinical care.

Intervention to expected microbial effect

Knowledge gaps and priorities

Lead–microbiome studies need standardized exposure metrics linking free-ion activity to community outcomes across body sites. Pb-specific metallophore ecology remains underexplored, as does quantitative mapping of mismetallation in bacterial targets at environmental doses. Longitudinal human cohorts that integrate bone Pb (K-XRF), repeated blood Pb, metagenomes/transcriptomes, and metabolomics will clarify dose–response and recovery trajectories. Finally, interventional trials should test whether biosorption-focused probiotics, dietary fiber strategies, or combined approaches measurably lower luminal free Pb and mitigate selection for metal/antibiotic co-resistance—always alongside primary exposure abatement.

Update History

References

1. Lead and δ-Aminolevulinic Acid Dehydratase Polymorphism: Where Does It Lead? A Meta-Analysis.. Scinicariello, F., Murray, H. E., Moffett, D. B., Abadin, H. G., Sexton, M. J., & Fowler, B. A. (2006).. (Environmental Health Perspectives, 115(1), 35.)
2. Public and occupational health risks related to lead exposure updated according to present-day blood lead levels.. Yu, Y., Yang, W., Hara, A., Asayama, K., Roels, H. A., Nawrot, T. S., & Staessen, J. A. (2023).. (Hypertension Research, 46(2), 395-407.)
3. Update of the Blood Lead Reference Value — United States, 2021.. Ruckart, P. Z., Jones, R. L., Courtney, J. G., LeBlanc, T. T., Jackson, W., Karwowski, M. P., Cheng, Y., Allwood, P., Svendsen, E. R., & Breysse, P. N. (2021).. (Morbidity and Mortality Weekly Report, 70(43), 1509.)
4. Prenatal Lead Exposure is Negatively Associated with the Gut Microbiome in Childhood.. Eggers, S., Midya, V., Bixby, M., Gennings, C., Torres-Olascoaga, L. A., Walker, R. W., Wright, R. O., Arora, M., & Téllez-Rojo, M. M. (2023).. (MedRxiv, 2023.05.10.23289802.)
5. MOLECULAR MECHANISMS OF LEAD NEUROTOXICITY.. Virgolini, M. B., & Aschner, M. (2021).. (Advances in Neurotoxicology, 5, 159.)
6. MOLECULAR MECHANISMS OF LEAD NEUROTOXICITY.. Virgolini, M. B., & Aschner, M. (2021).. (Advances in Neurotoxicology, 5, 159.)
7. Metal toxicity and opportunistic binding of Pb2 + in proteins.. Kirberger, M., Wong, H. C., Jiang, J., & Yang, J. J. (2013).. (Journal of Inorganic Biochemistry, 125, 40-49.)
8. Lead as a Risk Factor for Osteoporosis in Post-menopausal Women.. Manocha, A., Srivastava, L. M., & Bhargava, S. (2016).. (Indian Journal of Clinical Biochemistry, 32(3), 261.)
9. MOLECULAR MECHANISMS OF LEAD NEUROTOXICITY.. Virgolini, M. B., & Aschner, M. (2021).. (Advances in Neurotoxicology, 5, 159.)
10. Neurotoxic Effects and Biomarkers of Lead Exposure: A Review.. Sanders, T., Liu, Y., Buchner, V., & Tchounwou, P. B. (2008).. (Reviews on Environmental Health, 24(1), 15.)
11. Organic Lead Toxicology.. Patocka, Jiri. (2008).. (Acta Medica (Hradec Kralove, Czech Republic). 51. 209-213.)
12. Lead: Natural Occurrence, Toxicity to Organisms and Bioremediation by Lead-degrading Bacteria: A Comprehensive Review.. Ashkan MF.. (J Pure Appl Microbiol. 2023;17(3):1298-1319.)
13. Cysteine coordination of Pb(II) is involved in the PbrR-dependent activation of the lead-resistance promoter, PpbrA, from Cupriavidus metallidurans CH34.. Hobman, J.L., Julian, D.J. & Brown, N.L.. (BMC Microbiol 12, 109 (2012).)
14. Lead(II) resistance in Cupriavidus metallidurans CH34: interplay between plasmid and chromosomally-located functions.. Taghavi S, Lesaulnier C, Monchy S, Wattiez R, Mergeay M, van der Lelie D.. (Antonie Van Leeuwenhoek. 2009 Aug;96(2):171-82.)
15. Multi-Omics Reveals that Lead Exposure Disturbs Gut Microbiome Development, Key Metabolites and Metabolic Pathways.. Gao, B., Chi, L., Mahbub, R., Bian, X., Tu, P., Ru, H., & Lu, K. (2017).. (Chemical Research in Toxicology, 30(4), 996.)
16. Lead: Natural Occurrence, Toxicity to Organisms and Bioremediation by Lead-degrading Bacteria: A Comprehensive Review.. Ashkan MF.. (J Pure Appl Microbiol. 2023;17(3):1298-1319.)
17. Cysteine coordination of Pb(II) is involved in the PbrR-dependent activation of the lead-resistance promoter, PpbrA, from Cupriavidus metallidurans CH34.. Hobman, J.L., Julian, D.J. & Brown, N.L.. (BMC Microbiol 12, 109 (2012).)
18. An efflux transporter PbrA and a phosphatase PbrB cooperate in a lead-resistance mechanism in bacteria.. Hynninen, A., Touzé, T., Pitkänen, L., Mengin-Lecreulx, D., & Virta, M. (2009).. (Molecular Microbiology, 74(2), 384-394.)
19. Multi-Omics Reveals that Lead Exposure Disturbs Gut Microbiome Development, Key Metabolites and Metabolic Pathways.. Gao, B., Chi, L., Mahbub, R., Bian, X., Tu, P., Ru, H., & Lu, K. (2017).. (Chemical Research in Toxicology, 30(4), 996.)
20. Multi-Omics Reveals that Lead Exposure Disturbs Gut Microbiome Development, Key Metabolites and Metabolic Pathways.. Gao, B., Chi, L., Mahbub, R., Bian, X., Tu, P., Ru, H., & Lu, K. (2017).. (Chemical Research in Toxicology, 30(4), 996.)