Scientists are increasingly recognizing how interactions between the gut and brain shape the disease and developing therapeutic techniques that target α-synuclein, the hallmark ‘abhorrent protein’ of PD.
Research has shown that inhibiting α-synuclein is a key strategy for disease modification. In their review, the authors explored how polyphenols influence gut microbiota and how this may potentially enhance the modulation of α-synuclein aggregation.
“Understanding the interaction between polyphenols and gut microbiota and identifying which specific microbes may enhance the efficacy of polyphenols is crucial for developing therapeutic strategies and precision nutrition based on the microbiome,” they wrote in the journal Nutrients.
New focus on the gut
An estimated 1.5 million people in the United States live with PD, with 60,000 Americans diagnosed each year. PD is a progressive neurological disorder that mainly affects motor function, leading to symptoms including tremors, stiffness and slowness.
One of PD’s hallmark pathologies is accumulation of alpha-synuclein (α-synuclein). This is a presynaptic neuronal protein that aggregates into insoluble fibrils, forming Lewy bodies (LBs) and Lewy neurites in the brain. So far its exact function is not fully understood. However, abnormal accumulation contributes to neurone death and the symptoms of PD.
Previous PD studies tended to focus on the brain, but now the gastrointestinal (GI) system is recognized as pivotal in PD pathogenesis. Recent research has increasingly focused on the gut–brain axis: a complex bidirectional communication system connecting the whole enteric nervous system (ENS) of the GI tract with the central nervous system (CNS).
Emerging evidence suggests that α-synuclein pathology may start in the gut and then spread to the brain through the vagus nerve. This idea has been supported by observations of GI abnormalities in PD patients years before the start of motor symptoms. Plus, alterations in gut microbiota composition have been observed in PD patients, showing the potential role of gut dysbiosis in the disease’s progression.
Polyphenols are known for their antioxidant and anti-inflammatory properties. They also influence the composition and function of gut microbiota. By modulating the gut microbial community, dietary polyphenols may reduce intestinal inflammation, enhance gut barrier function and produce metabolites that could potentially inhibit the aggregation of α-synuclein.
This means understanding the mechanisms behind interactions between dietary polyphenols, the gut–brain axis and α-synuclein pathology could open new avenues for preventing or slowing the progression of PD.
Exploring ‘a new frontier’
The researchers described the gut–brain axis as a “new frontier in PD”. They found evidence that PD pathogenesis may be influenced by the interplay between the imbalance of gut microbes and altered bacterial metabolites. Findings in both PD patient studies and experimental animal studies have revealed gut bacteria help regulate anti-inflammatory and pro-inflammatory profiles. This suggests that alterations in the gut microbiome can influence the risk of developing PD.
The authors found some PD patients have shown elevated lipopolysaccharide serum levels—which could correlate to increased intestinal permeability. In addition, the guts of PD patients are often colonized by lipopolysaccharide-producing bacteria which causes chronic inflammation and degradation of gut mucosal lining.
Biopsies of GI tissues from PD patients have shown α-synuclein accumulation in the lower parts of the esophagus, stomach, duodenum, colon and rectum. Finding α-synuclein outside the CNS supports the hypothesis that the presence of α-synuclein in both the brain and the gut may result from a common pathological aggregation pathway involving the vagus nerve.
EGCG, quercetin, polyphenolic acids, curcumin and their derivatives are some of the most well-known and effective polyphenolic inhibitors of α-synuclein.
Polyphenols as promising agents
The authors concluded that dietary polyphenols make promising agents for PD prevention because of their abundance and relatively low toxicity.
Polyphenols showed benefits in animal models of PD—with evidence from epidemiological studies demonstrating the association between polyphenols and a reduced risk of developing PD. However, data from randomized controlled trials in patients with pre-existing PD are currently limited. The researchers said this means future clinical studies are necessary to evaluate the effectiveness of dietary polyphenols in slowing PD progression.
“More focused research is needed to fully understand the mechanisms between polyphenols, the gut microbiota and α-synuclein in order to establish the therapeutic viability of polyphenols in clinical settings,” they wrote.
Source: Nutrients 2024, 16(13), 2041
doi: 10.3390/nu16132041
“Gut–Brain Axis in Focus: Polyphenols, Microbiota, and Their Influence on α-Synuclein in Parkinson’s Disease.”
Authors: Elizabeth Riegelman and Jia-Sheng Wang