Microbial Metallomics Theory of Parkinson’s Disease: A Unified Framework Original paper
Researched by:
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Karen Pendergrass
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Karen Pendergrass
Read MoreKaren 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.
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Parkinson’s Disease
Parkinson’s Disease
Parkinson’s disease is increasingly recognized as a systemic disorder involving coordinated disturbances across the gut–brain axis, rather than a condition confined to dopaminergic neurodegeneration alone. Converging evidence implicates gut dysbiosis, altered microbial metabolites, impaired intestinal barrier integrity, and metal dyshomeostasis as upstream drivers of neuroinflammation and alpha-synuclein pathology. These interconnected microbiome, metabolomic, and metallomic signals provide a mechanistic framework for understanding disease initiation, progression, and therapeutic targeting beyond the central nervous system.
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Karen Pendergrass
Read More
Researched by:
-
Karen Pendergrass
ID
Karen Pendergrass
Read More
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
What was reviewed?
This review proposes the Microbial Metallomics Theory of Parkinson’s Disease, a unified explanatory framework that links environmental metal exposure, gut microbiome dysbiosis, ferroptosis, and α-synuclein aggregation. Instead of treating gut dysbiosis, neuroinflammation, and protein misfolding as disconnected phenomena, the paper frames them as downstream consequences of a shared initiating event: heavy metal dyshomeostasis. Environmental toxins, such as paraquat and transition metals like iron, copper, and manganese, initiate NCOA4-mediated ferritinophagy, leading to intracellular iron release and ferroptosis in dopaminergic neurons. Simultaneously, transferrin depletion in the substantia nigra disables iron export, reinforcing this neurodegenerative process. These metallomic disruptions propagate systemic effects that shape the gut microbiome, selecting for metal-tolerant, pro-inflammatory pathobionts with virulence mechanisms dependent on nickel and zinc.
Who was reviewed?
This review integrates data from in vivo and in vitro studies, systematic reviews, and human case–control studies involving Parkinson’s disease (PD) patients and relevant microbial taxa. Particularly emphasized are studies documenting microbial shifts in the gut microbiota of PD patients—such as enrichment of Desulfovibrionaceae, Enterobacteriaceae, and Proteobacteria—as well as evidence from animal models exposed to heavy metals like lead, arsenic, and manganese. Key microbial mechanisms are extrapolated from microbiological and metallomic studies examining the role of nickel- and zinc-dependent enzymes in virulence and immune evasion.
Most important findings
The microbial metallomics model of Parkinson’s disease (PD) outlines a cascading pathophysiological sequence initiated by environmental metal exposure. This model proposes that dysregulated metal homeostasis—particularly iron, nickel, and manganese—triggers ferroptosis, shapes a dysbiotic gut environment, and facilitates α-synuclein pathology. These interconnected mechanisms offer a mechanistic narrative linking toxicant exposure to the onset and progression of neurodegeneration in PD.
| Mechanistic Domain | Description of Events and Relevance to PD |
|---|---|
| Ferritinophagy and Iron Overload | Environmental toxins such as paraquat activate NCOA4-mediated ferritinophagy, releasing intracellular iron in dopaminergic neurons. This promotes ferroptosis via iron-induced lipid peroxidation. |
| Transferrin Deficiency | Transferrin levels are markedly decreased in the substantia nigra of PD brains, disrupting iron export and causing regional iron accumulation that exacerbates oxidative stress. |
| Mismetallation and Protein Aggregation | Metals including Mn, Cu, and Pb displace native cofactors in enzymes, destabilizing proteins like α-synuclein and SOD1. This promotes pathological misfolding and fibrillar aggregation. |
| Microbial Selection via Metal Pressure | Chronic metal exposure favors Gram-negative, metal-tolerant bacteria such as Desulfovibrio, E. coli, and Burkholderiales, altering gut ecology in PD patients. |
| Nickel-Dependent Microbial Virulence | Surviving pathobionts utilize nickel-dependent virulence enzymes such as urease, [NiFe]-hydrogenases, Ni-SOD, and Ni-glyoxalase I to resist immunity and intensify inflammation. |
| Zinc Metalloprotease Activity | Zinc-dependent proteases (e.g., fragilysin from Bacteroides fragilis) degrade host tight junctions and cleave transferrin/lactoferrin, releasing iron and disrupting epithelial barriers. |
| Desulfovibrio and α-Synuclein Seeding | Desulfovibrio produces magnetite and H₂S, increasing intracellular iron and oxidative stress in enteric neurons, which promotes α-synuclein misfolding and aggregation. |
| Gut-Brain Axis Propagation | Misfolded α-synuclein travels via the vagus nerve from the enteric nervous system to the brain. Systemic inflammation and exosome-mediated transport further accelerate CNS involvement. |
Key implications
The Microbial Metallomics Theory of Parkinson’s Disease reframes PD as a metal-initiated, microbiome-mediated neurodegenerative condition. This has profound clinical implications. If validated, it positions environmental metal detoxification and microbial modulation as upstream therapeutic targets rather than focusing solely on symptomatic management of neurodegeneration. Intervention strategies may include dietary reduction of metal exposure, use of metal chelators (e.g., lactoferrin, transferrin supplementation), microbiome-targeted therapies to suppress metal-tolerant pathobionts, and inhibition of microbial virulence systems (e.g., urease or metalloprotease inhibitors). The theory also emphasizes the importance of early detection via gut microbiome and metallomic profiling before CNS symptoms manifest. Finally, the theory offers a mechanistic scaffold for future clinical trials, which can use microbial and metallomic biomarkers as endpoints for evaluating therapeutic efficacy.
Citation
Pendergrass, K. (2025). Microbial Metallomics and Parkinson’s Disease: A Unified Metal-Driven Framework Linking Ferroptosis, Dysbiosis, and α-Synuclein Pathology. Microbiome Medicine Roundtable, Limassol, Cyprus. https://doi.org/10.5281/zenodo.17830083
Parkinson’s Disease
Parkinson’s disease is increasingly recognized as a systemic disorder involving coordinated disturbances across the gut–brain axis, rather than a condition confined to dopaminergic neurodegeneration alone. Converging evidence implicates gut dysbiosis, altered microbial metabolites, impaired intestinal barrier integrity, and metal dyshomeostasis as upstream drivers of neuroinflammation and alpha-synuclein pathology. These interconnected microbiome, metabolomic, and metallomic signals provide a mechanistic framework for understanding disease initiation, progression, and therapeutic targeting beyond the central nervous system.
Nickel
Bacteria regulate transition metal levels through complex mechanisms to ensure survival and adaptability, influencing both their physiology and the development of antimicrobial strategies.