Nutritional immunity restricts metal access to pathogens, leveraging sequestration, transport, and toxicity to control infections and immunity.
Nutritional Immunity
Researched by:
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Karen Pendergrass
ID
Karen Pendergrass
Karen Pendergrass is a microbiome researcher specializing in microbiome-targeted interventions (MBTIs). She systematically analyzes scientific literature to identify microbial patterns, develop hypotheses, and validate interventions. As the founder of the Microbiome Signatures Database, she bridges microbiome research with clinical practice. In 2012, based on her own investigative research, she became the first documented case of FMT for Celiac Disease—four years before the first published case study.
Nutritional immunity restricts metal access to pathogens, leveraging sequestration, transport, and toxicity to control infections and immunity.
-
Karen Pendergrass
Researched by:
-
Karen Pendergrass
ID
Karen Pendergrass
Microbiome Signatures identifies and validates condition-specific microbiome shifts and interventions to accelerate clinical translation. Our multidisciplinary team supports clinicians, researchers, and innovators in turning microbiome science into actionable medicine.
Karen Pendergrass
Overview Overview
Nutritional immunity is a host-driven immunological strategy that regulates the bioavailability of essential and toxic metals to shape microbial survival, pathogenicity, and immune system dynamics. This defense mechanism operates through a highly coordinated network of metal-binding proteins, transporters, cellular sequestration systems, and oxidative stress pathways to control microbial access to metals such as iron (Fe), zinc (Zn), manganese (Mn), copper (Cu), and nickel (Ni)—which are indispensable for microbial enzymatic activity, metabolic function, and replication. Simultaneously, toxic metals such as lead (Pb) and cadmium (Cd) are sequestered or mobilized to disrupt microbial physiology. At its core, nutritional immunity exploits the metallomic dependencies of microbes by imposing metal starvation, metal intoxication, or dynamic metal redistribution within distinct immune and tissue compartments. These processes are mediated by both innate and adaptive immune responses, particularly at sites of infection, inflammation, and tissue damage.
Host Strategies in Nutritional Immunity
The host employs several overlapping mechanisms to control microbial access to metals. These strategies operate across cellular, tissue, and systemic levels to starve pathogens, poison them with toxic metals, and regulate metal movement to support immune functions.
| Strategy | Mechanism |
|---|---|
| Metal Starvation | The host limits microbial proliferation by reducing the availability of essential metals through high-affinity binding proteins (e.g., transferrin, lactoferrin, ferritin, calprotectin). |
| Metal Intoxication | Toxic metals such as copper (Cu) and zinc (Zn) are concentrated in phagosomes to disrupt microbial metabolism via oxidative damage, protein misfolding, and redox imbalance. |
| Transport Modulation | Metal transporters sequester, compartmentalize, or mobilize metals to deprive pathogens while ensuring immune cell functionality. |
| Microbiome-Metallome Interactions | Commensal microbes regulate host metal absorption, metabolism, and immune signaling, influencing nutritional immunity dynamics. |
Metal Starvation (Sequestration & Chelation)
The host employs a metal-withholding strategy to deprive pathogens of essential metals. High-affinity metal-binding proteins sequester metals, reducing their free concentrations to levels insufficient for microbial survival. Specialized immune cells, such as neutrophils and macrophages, further enforce this starvation by deploying chelating proteins at infection sites. By creating metal-deficient microenvironments, the host effectively inhibits microbial enzyme function, DNA replication, and energy metabolism, stifling pathogen proliferation.
| Metal | Host Mechanism of Starvation |
|---|---|
| Iron (Fe) | Sequestered by transferrin (bloodstream), lactoferrin (mucosal surfaces), and ferritin (intracellular storage). Hepcidin regulates iron export, further restricting access. |
| Zinc (Zn) | Neutrophils release calprotectin, binding zinc at infection sites. ZnT and ZIP transporters regulate zinc movement to prevent microbial uptake. |
| Manganese (Mn) | Similar to zinc, calprotectin chelates manganese, and SPCA1 (Secretory Pathway Ca²⁺-ATPase 1) redistributes manganese within immune compartments. |
| Nickel (Ni) | Lactoferrin binds nickel via histidine and tyrosine ligands, limiting its availability to nickel-dependent pathogens like Helicobacter pylori. |
Metal Intoxication (Toxic Metal Overload)
In contrast to starvation strategies, the host also leverages toxic metals as antimicrobial agents. Certain metals, particularly copper (Cu) and zinc (Zn), are actively concentrated within phagosomes to disrupt microbial physiology. These metals induce oxidative stress, protein misfolding, and enzyme inhibition, leading to pathogen death. This selective metal redistribution enhances immune cell antimicrobial activity and reinforces innate immune defense mechanisms against bacterial and fungal pathogens.
| Toxic Metal | Host Mechanism of Intoxication |
|---|---|
| Copper (Cu) | Ceruloplasmin binds Cu in serum, limiting microbial access. In phagosomes, ATP7A pumps excess Cu into compartments to induce oxidative stress. |
| Zinc (Zn) | ZIP8 mobilizes Zn into phagosomes, interfering with microbial metal-dependent enzymes and structural proteins. |
| Lead (Pb) & Cadmium (Cd) | Though primarily sequestered for host protection, some pathogens are susceptible to Pb and Cd accumulation, which disrupts their metabolic balance. |
Transport Modulation & Dynamic Redistribution
Beyond metal withholding and intoxication, the host dynamically redistributes metals to optimize immune function while denying them to pathogens. Specialized metal transporters and compartmentalization mechanisms tightly regulate this process. This strategic compartmentalization of metals allows the host to balance immune activation, metal homeostasis, and pathogen restriction.
| Transport Mechanism | Function in Nutritional Immunity |
|---|---|
| Efflux & Sequestration | The host removes excess metals from circulation or stores them intracellularly (e.g., ferritin for Fe) to limit microbial acquisition. |
| Localized Metal Mobilization | Certain metals are mobilized within immune compartments (e.g., zinc and copper in phagosomes) to reinforce antimicrobial activity. |
| Neutrophil Extracellular Traps (NETs) | Neutrophils release calprotectin and other metal-binding factors, trapping and starving microbes in metal-deficient microenvironments. |
Host-Microbiome-Metallome Interactions
The microbiome plays a critical role in regulating metal metabolism and shaping nutritional immunity outcomes. Commensal bacteria contribute to metal absorption, detoxification, and immune signaling, influencing host-pathogen dynamics. The interplay between host metal homeostasis and microbiome dynamics is an emerging field with implications for infectious disease management, microbiome-targeted therapies, and immune system modulation.
| Microbiome Influence | Effect on Nutritional Immunity |
|---|---|
| Metal Absorption & Metabolism | Gut microbes influence iron, zinc, and manganese absorption, modulating systemic metal availability. |
| Siderophore & Chelator Production | Some commensals produce siderophores to scavenge metals, altering the host’s metal-microbe interactions. |
| Immune Modulation | Microbial metabolites regulate host inflammatory responses, influencing metal sequestration during infection. |
Clinical & Therapeutic Implications
The dysregulation of nutritional immunity contributes to various disease states, including chronic infections, autoimmune disorders, microbiome dysbiosis, and anemia of inflammation. Conversely, pathogens such as Mycobacterium tuberculosis, Salmonella enterica, and Staphylococcus aureus have evolved counter-strategies such as siderophores, efflux pumps, and metal-responsive regulatory networks, highlighting the evolutionary arms race between microbial metallomics and host defenses. Therapeutically, modulating metal availability presents novel intervention strategies:
Metal-Based Antibiotics: Exploiting bacterial metal dependencies to design targeted antimicrobial therapies.
Immunomodulatory Therapies: Enhancing host metal sequestration strategies to suppress infections.
Microbiome-Driven Interventions: Engineering probiotics or dietary strategies to restore metal homeostasis in disease contexts.