Shop
eStoreRx™
Online Supplement Dispensary
Easy direct-to-patient ordering & fulfilment for Lifelong Wellness, eStoreRx™ is offered as part of the WholePractice membership or as a stand-alone program.
A growing body of evidence suggests that gastrointestinal (GI) dysfunction, particularly in the enteric nervous system (ENS) which innervates the GI tract, may play an etiological role in the development of Parkinson’s disease (PD), at least in some cases, coined as the so-called “bottom’s up” vs. “top-down” progression/origin of the disease, and sometimes termed Braak's hypothesis. It is well-known that prodromal GI symptoms of PD, including constipation, dysphagia, and delayed gastric emptying, precede the onset of motor symptoms. Constipation specifically has been reported to be found in over 40% of people with prodromal PD, it is associated with a more than 6-fold increase in risk for PD, and may occur decades before classical motor symptoms begin.
Classically PD has been characterized as originating with the loss of dopaminergic neurons in the brain, specifically the substantia nigra pars compacta, an event primarily attributed to misfolding of the protein α-synuclein and its prion-like spread. Yet mucosal biopsies from the GI tract have provided evidence of misfolded α-synuclein in the ENS of untreated patients with PD, years before the onset of motor symptoms, suggested as a possible biomarker for early disease detection. Additionally, Braak’s hypothesis posits that α-synuclein pathology may travel up from the ENS to the CNS along the vagus nerve, pointing to spread via the gut-brain axis (as well as possible bidirectional communication).
Braak’s hypothesis also suggests that environmental pathogens/toxins may play a role in PD pathogenesis, potentially via exposure through either the ENS or the olfactory bulb (the structure that transmits smell information from the nose to the brain; misfolded α-synuclein has also been found there). The possibility that environmental toxins, such as pesticides and herbicides, may play a role in PD development and progression is supported by experimental models and epidemiological data. For example, use of the pesticide rotenone has been shown to cause mitochondrial dysfunction and induce PD-like effects in the brain in experimental models. Perhaps more importantly, at low doses, it decreases the number of neurons in the ENS, and promotes both the release of α-synuclein and its travel up the vagus nerve. Experimental models also show that vagotomy, severing of the vagus nerve, prevents the progression of the α-synuclein-induced damage to the brain, suggesting that halting the transmission of α-synuclein along the vagus nerve could prevent the common motor symptoms of PD.
Multiple case-control and cohort studies have found an association between pesticide exposure and late-onset PD. For example, in one systematic review of cohort studies, the better-designed among them observed over a 2.5-fold increased risk for PD with occupational exposure. Additionally, multiple gene-pesticide interactions have been identified in PD; reduced activity of paraoxonase 1 (PON1, an enzyme that metabolizes many pesticides), for example, appears to increase the risk for PD, especially when combined with ambient (non-agricultural) pesticide exposure.
More recent evidence suggests that the gut-related dysfunction associated with PD may be connected to changes in the microbiome, and that pesticides are one potential driver of this change. In 2020, an article published in the Journal of Neurology reported that 14 (mainly cross-sectional) studies from seven countries found alterations in the microbiome among people with PD, and in 2021 a review of 22 case-control studies found that every single study documented changes in the microbiome of people with PD, with evidence that the microbiota may be necessary for the transport of α-synuclein from the gut to the brain. A variety of mechanisms have been suggested, including increased intestinal permeability, LPS production, and a decrease in short-chain fatty acid production, all contributing to the formation of misfolded α-synuclein.
Dysbiosis of the microbiome appears to be a consequence of pesticide exposure, potentially providing a mechanism to explain the observational data. For example, the nearly ubiquitous pesticide glyphosate (a component of the weed-killer RoundUp®), in addition to being classified as a probable human carcinogen acts as a competitive inhibitor of 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase, needed in plants for survival. While animals do not have this enzyme, many bacteria present in the human GI tract certainly do; by one estimate, 54% of the “core human gut microbiome” is predicted to be sensitive to glyphosate.
There are multiple mechanisms by which glyphosate may disrupt neurotransmitter metabolism through its impact on gut microbiota (reviewed here); for example, because EPSP is the rate-limiting enzyme for aromatic amino acid synthesis, amino acids needed for neurotransmitter production, such as tryptophan, may be limited following glyphosate exposure. It’s worth noting that glyphosate has been associated with case reports of PD-like symptoms, and residential exposure to glyphosate in Washington state indicated a 33% higher premature mortality from PD. Authors of a recent review considered PD the neurological condition for which glyphosate represents the greatest concern. In an editorial recently published in the Journal of Parkinson’s Disease, the authors conclude that “there must be a continued push to expand the safety guidelines to include considerations of the potential effects of pesticides on the gut integrity and microbiome.” With a plausible mechanism of action, pesticide-induced dysbiosis as underlying Braak’s hypothesis cannot be easily dismissed.
Submit your comment