Clinical Pharmacist and Master’s student in Clinical Pharmacy with research interests in pharmacovigilance, behavioral interventions in mental health, and AI applications in clinical decision support. Experience includes digital health research with Bloomsbury Health (London) and pharmacovigilance practice in patient support programs. Published work covers drug awareness among healthcare providers, postpartum depression management, and patient safety reporting. 
Clinical Pharmacist and Master’s student in Clinical Pharmacy with research interests in pharmacovigilance, behavioral interventions in mental health, and AI applications in clinical decision support. Experience includes digital health research with Bloomsbury Health (London) and pharmacovigilance practice in patient support programs. Published work covers drug awareness among healthcare providers, postpartum depression management, and patient safety reporting. What was reviewed?
This review article comprehensively examined the complex interplay between essential heavy metals—specifically iron, manganese, and copper and their interactions with neuroglia and gut microbiota in the context of Huntington’s disease. The authors systematically synthesized recent findings on how these metals, vital at low concentrations but potentially neurotoxic at elevated levels, can exacerbate Huntington’s disease pathology. Central to the review is the exploration of how heavy metals disrupt glial-neuronal communication and induce gut dysbiosis, both of which can trigger neuroinflammation and further neurodegeneration. The review also delves into the mechanisms by which heavy metals influence ferroptosis, oxidative stress, mitochondrial dysfunction, and blood-brain barrier integrity, all of which are relevant to the progression of neurodegenerative diseases. Additionally, the article highlights the bidirectional gut-brain axis, emphasizing how gut microbiota dysregulation may modulate the absorption and toxic potential of heavy metals in Huntington’s disease.
Who was reviewed?
The reviewed literature encompassed a broad range of experimental and clinical studies, including in vitro cellular models, animal models (notably murine and Drosophila models of Huntington’s disease), and human epidemiological and clinical investigations. Studies referenced in the review included reports on patients with Huntington’s disease, population-based assessments of metal exposure, and clinical trials of potential therapeutic strategies such as metal chelators and microbiome-targeted interventions. The reviewed entities also included research on neuroglial cell types, microglia, astrocytes, oligodendrocytes, and synantocytes—as well as studies on gut microbiota composition and its modulation by environmental factors, including heavy metal exposure.
Most important findings
| Heavy Metal | Principal Mechanisms & Findings |
|---|---|
| Iron (Fe) | Manganese is essential for enzymatic functions but at high levels, it accumulates in the basal ganglia, causing neurotoxicity and Parkinsonian symptoms. In HD, manganese dysregulation exacerbates oxidative stress and mitochondrial dysfunction, partly mediated via altered gut microbiota. Early-life manganese exposure impairs neurodevelopment. Some evidence suggests manganese can interact with insulin/IGF signaling, potentially modulating HD pathology, while deficiency may worsen disease progression. |
| Manganese (Mn) | Manganese is essential for enzymatic functions, but at high levels, it accumulates in the basal ganglia, causing neurotoxicity and Parkinsonian symptoms. Early-life manganese exposure impairs neurodevelopment. Some evidence suggests that manganese can interact with insulin/IGF signaling, potentially modulating HD pathology, while deficiency may worsen disease progression. |
| Copper (Cu) | Manganese is essential for enzymatic functions but at high levels, it accumulates in the basal ganglia, causing neurotoxicity and Parkinsonian symptoms. In HD, manganese dysregulation exacerbates oxidative stress and mitochondrial dysfunction, partly mediated via altered gut microbiota. Early-life manganese exposure impairs neurodevelopment. Some evidence suggests that manganese can interact with insulin/IGF signaling, potentially modulating HD pathology, while deficiency may worsen disease progression. |
Key implications
The review highlights that rigorous heavy metal monitoring is essential in both clinical and environmental contexts to mitigate risks for Huntington’s disease. For heavy metal certification programs, the findings underscore the crucial need to set strict, evidence-based exposure limits for iron, manganese, and copper. These metals, even at slightly elevated concentrations, can significantly worsen neurodegenerative processes via glial dysfunction and gut microbiota disruption. Certification should not only assess total metal content but also consider bioavailability, potential for gut absorption, and the impact on vulnerable populations. Programs should integrate current research on metal-microbiome-neuroglia interactions, supporting proactive risk management and the adoption of targeted interventions such as chelation therapy and microbiome modulation.
Citation
Tizabi Y, Bennani S, El Kouhen N, Getachew B, Aschner M. Heavy Metal Interactions with Neuroglia and Gut Microbiota: Implications for Huntington’s Disease. Cells. 2024;13(13):1144. https://doi.org/10.3390/cells13131144
Heavy metals are high-density elements that accumulate in the body and environment, disrupting biological processes. Lead, cadmium, arsenic, mercury, nickel, tin, aluminum, and chromium are of greatest concern due to persistence, bioaccumulation, and health risks, making them central to the HMTC program’s safety standards.
