Cadmiun (Cd)

Overview and clinical relevance

Cadmium (Cd) is a non-essential heavy metal toxin that has become ubiquitous in the environment due to industrial emissions and tobacco smoke.^[1] Chronic low-level exposure (e.g., 30 μg Cd ingested per day via food) leads to bioaccumulation in the kidney, liver, and bone.^[2] Clinically, Cd is a known carcinogen and nephrotoxin, but it also perturbs the host–microbiome ecosystem. Even at sub-toxic concentrations, Cd²⁺ can disrupt gut microbiota composition and metabolic output, promoting dysbiosis and intestinal inflammation. In parallel, Cd exposure places co-selective pressure on bacteria, enriching for strains that harbor metal-resistance genes often linked with antibiotic resistance determinants. Principal host niches affected include the gut (dietary Cd), lungs (inhaled Cd in smokers), and circulation, where Cd-induced oxidative stress dampens immune functions.

Chemical speciation across host niches

Cadmium primarily exists as a soluble metal in biological fluids, and its speciation is influenced by pH and the presence of various ligands. In the saliva (pH: 7), cadmium from sources such as cigarette smoke or contaminated dust dissolves, forming complexes with thiol-containing molecules or proteins. In the gastric lumen (pH: 2), the acidic environment keeps cadmium soluble, primarily as chloride complexes (e.g., CdCl⁺), which enhances its absorption. Raising gastric pH can reduce cadmium solubility and its uptake into the body. As the metal moves into the duodenum (pH: 6), cadmium can form less soluble complexes with phosphate or food ligands, reducing its bioavailability. In the colon (neutral pH, anaerobic), microbial sulfides (H_2S) form insoluble cadmium sulfide (CdS), sequestering the metal in the lumen. Any remaining soluble cadmium can bind to bacterial cell walls or polysaccharides. In blood, cadmium is primarily bound to proteins such as transferrin (~50%) and albumin (~30-40%), which helps keep free cadmium concentrations low, limiting its microbial availability. Urine excretion is minimal, as most cadmium is retained in tissues, with only small amounts excreted in complex with cysteine or citrate. Wound exudates also contain cadmium, which binds to exudate proteins and extracellular DNA. Overall, cadmium’s bioavailability across host niches is highly regulated by local pH and ligand presence, where acidic, low-ligand environments favor absorption, while alkaline, high-sulfide environments reduce its microbial availability.

Microbial acquisition, regulation, and buffering

Bacteria lack a nutritive requirement for Cd, but they inadvertently uptake Cd²⁺ via broad-range metal transporters. Import: Cd^2+ hijacks high-affinity import systems for essential divalent cations. For example, the Mn²⁺ ABC transporter PsaBCA of Streptococcus pneumoniae can bind Cd²⁺ and import it when Cd is presentpmc.ncbi.nlm.nih.govpmc.ncbi.nlm.nih.gov. Similarly, E. coli’s promiscuous ZIP importer ZupT transports Cd alongside Zn/Fe/Coresearchgate.netresearchgate.net. Regulation: Bacteria sense Cd stress through metalloregulatory proteins. S. aureus carries a plasmid-encoded repressor CadC that detects Cd²⁺ and derepresses the cadA efflux pump. Likewise, Pseudomonas spp. use a transcriptional activator (CadR) to induce czcCBA heavy-metal efflux in response to Cd. Buffering and storage: Cytosolic thiols (glutathione, cysteine) and metallothionein-like proteins bind Cd²⁺ to mitigate its reactivity. For instance, Salmonella upregulates a metallothionein homolog under Cd exposure, and glutathione sequesters excess Cd²⁺ in S. pneumoniae until its buffering capacity is exceeded. Maturation factors: No enzyme specifically requires Cd, so there are no dedicated Cd metallochaperones; however, general Zn chaperones may inadvertently bind Cd. Efflux: Active export is the primary defense. P-type ATPases (e.g. ZntA in Vibrio parahaemolyticus) pump Cd²⁺ out of the cytosoltandfonline.com, and RND family proton antiporters (e.g. CzcCBA in Pseudomonas aeruginosa) expel Cd²⁺ into the periplasm or extracellular space.

Metal toolkit

Nutritional immunity and host sequestration

Hosts do not intentionally deploy cadmium in nutritional immunity (since Cd is not needed by microbes), but they sequester Cd^2+ passively as a protective measure. In blood, Cd^2+ binds strongly to circulating proteins – notably transferrin (~50% of plasma Cd) and albumin (30–40%)academic.oup.comjournals.sagepub.com. This binding limits freely diffusible Cd^2+, thereby reducing acute metal toxicity to both host and any blood-borne bacteria. The host’s major metal-binding proteins have varying affinity for Cd: transferrin, primarily an iron transporter, can aberrantly chelate Cd^2+academic.oup.com, and albumin provides additional thiolate coordination sites. Intracellularly, metallothionein (MT) is the key Cd buffer – MT is a cysteine-rich protein inducible in liver, kidneys, and intestinal mucosa that tightly sequesters Cd^2+ (as well as Zn^2+ and Cu^+). Cadmium exposure triggers MT expression in enterocytes and hepatocytes, which confines Cd in innocuous complexes but also hijacks Zn binding sites, potentially exacerbating Zn starvation for microbes. During inflammation, host calprotectin (S100A8/A9) avidly chelates Zn^2+ and Mn^2+; it has lower affinity for Cd^2+, meaning cadmium escapes nutritional immunity while essential metals are withheld. The consequence is a “double hit” to pathogens: they face Zn/Mn limitation by calprotectin, yet any available Cd^2+ can infiltrate their transporters, causing mismetallation (e.g. replacing Zn/Mn in enzymes)pmc.ncbi.nlm.nih.gov. This combination impairs bacterial growth and virulence in inflamed niches. Host phagocytes do not actively deploy Cd (unlike Cu or Zn used as antimicrobials); however, macrophages sequester Cd^2+ by MT and vesicular compartmentalization, reducing cytosolic spread. In sum, host factors inadvertently shield microbes from high Cd by binding the metal, but in doing so the host also intensifies microbes’ reliance on correct metals. Key host sequestration factors and microbial consequences are outlined below:

Host sequestration map

Update History

References

1. Dysregulation of transition metal ion homeostasis is the molecular basis for cadmium toxicity in Streptococcus pneumoniae.. Begg, S. L., Eijkelkamp, B. A., Luo, Z., Couñago, R. M., Morey, J. R., Maher, M. J., Ong, Y., McEwan, A. G., Kobe, B., Paton, J. C., & McDevitt, C. A. (2015).. (Nature Communications, 6, 6418.)
2. Effect of a controlled food-chain mediated exposure to cadmium and arsenic on oxidative enzymes in the tissues of rats.. Ezedom, T., & Asagba, S. O. (2016).. (Toxicology Reports, 3, 708.)