Parkinson’s Disease and the Metal–Microbiome–Gut–Brain Axis: A Systems Toxicology Approach

Abstract

Parkinson’s Disease (PD) is a neurodegenerative disease, leading to motor and non-motor 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.

The different trends in the burden of neurological and mental disorders following dietary transition in China, the USA, and the world: An extension analysis for the Global Burden of Disease Study 2019

“…It is well known that environment POPs, pesticides, heavy metal, and some antimicrobics would increase the risks of cancer and cardiovascular diseases ( 166 , 167 ). Among the neurological and mental disorders, neurodegenerative diseases such as Parkinson’s disease and neurodevelopmental disorders such as autism spectrum disorders are more sensitive to the above harmful residues in foods ( 92 – 94 , 104 , 168 ). It is not surprising that the disease burden of Parkinson’s disease is positively correlated with the usage of pesticides and fertilizers and the farming density of major livestock and pigs.…”

“…Residues of pesticides, heavy metals, and antibiotics in foods are also important diet-related factors interfering with gut 10.3389/fnut.2022.957688 microbiota and brain function (43,(91)(92)(93)(94)(95)(96). Tremendous use of fertilizers and pesticides have been used in China's agriculture in the past decades, reducing the diversity of soil microbiota and soil fertility (97-99), leaving high and probably growing persistent organic pollutions (POPs) and heavy metals in soil and water (100,101).…”

“…Then, livestock and fish accumulate more toxic substances in the body from these grains, grass, and environment. These toxic substances will probably pass to humans through food chains, disrupt human gut microbiota, and induce neurotoxicity and brain impairment through microbiota-gut-brain axis (43,92,94,(102)(103)(104).…”

ATP13A2 (PARK9) and basal ganglia function

“…Mn is transported by a variety of metal transporters, including but not limited to DMT1, dopamine transporter (DAT), L-type calcium channels, transferrin, and transferrin receptor (81)(82)(83). Mn enters the brain primarily through DMT1 and transferrin/transferrin receptors [transferrin-dependent pathway; (81,84)].…”

Impact of Environmental Pollutants on Gut Microbiome and Mental Health via the Gut–Brain Axis

“…Heavy metal ion interaction or accumulation inside the GI epithelium causes oxidative stress, microbial dysbiosis, cellular damage and an increased abundance of facultative anaerobes including Proteobacteria and Bacilli [ 121 ]. As a result, the amount of oxygen available to epithelial cells increases, depleting anaerobic SCFA-producing bacteria and lowering the production of anti-inflammatory and antioxidant metabolites that may further disrupt the integrity of the BBB and reduce neurogenesis, leading to disturbance in brain functions.…”