Parkinson’s Disease (PD) is a neurodegenerative disease, leading to motor and nonmotor complications. Autonomic alterations, including gastrointestinal symptoms, precede motor
defects and act as early warning signs. Chronic exposure to dietary, environmental heavy metals
impacts the gastrointestinal system and host-associated microbiome, eventually affecting the central
nervous system. The correlation between dysbiosis and PD suggests a functional and bidirectional
communication between the gut and the brain. The bioaccumulation of metals promotes stress
mechanisms by increasing reactive oxygen species, likely altering the bidirectional gut–brain link.
To better understand the differing molecular mechanisms underlying PD, integrative modeling
approaches are necessary to connect multifactorial perturbations in this heterogeneous disorder. By
exploring the effects of gut microbiota modulation on dietary heavy metal exposure in relation to
PD onset, the modification of the host-associated microbiome to mitigate neurological stress may
be a future treatment option against neurodegeneration through bioremediation. The progressive
movement towards a systems toxicology framework for precision medicine can uncover molecular
mechanisms underlying PD onset such as metal regulation and microbial community interactions
by developing predictive models to better understand PD etiology to identify options for novel
treatments and beyond. Several methodologies recently addressed the complexity of this interaction
from different perspectives; however, to date, a comprehensive review of these approaches is still
lacking. Therefore, our main aim through this manuscript is to fill this gap in the scientific literature by
reviewing recently published papers to address the surrounding questions regarding the underlying
molecular mechanisms between metals, microbiota, and the gut–brain-axis, as well as the regulation
of this system to prevent neurodegeneration. CLICK TO REVIEW
Keywords: heavy metals; neurotoxicity; Parkinson’s disease; ROS; human microbiome; systems
toxicology