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Parkinson’s disease (PD) is a devastating neurodegenerative disease affecting nearly one million people in the United States. Around 90,000 people are diagnosed with PD each year in the U.S. alone, which is a 50% increase from the previously estimated rate of 60,000 diagnoses annually, making PD part of the chronic non-contagious disease epidemic.

“…evidence supports the concept of PD…as a disorder of altered brain gut microbiome interactions, starting in the gut’s enteric nervous system and propagating along the vagus nerve to the brainstem and brain…”

Converging preclinical and clinical evidence supports the concept of PD (Braak’s hypothesis) as a disorder of altered brain gut microbiome interactions, starting in the gut’s enteric nervous system (resulting in new onset constipation), propagating along the vagus nerve to the brainstem (causing REM sleep abnormalities) and brain causing the characteristic neurological symptoms. Braak’s hypothesis, proposed in 2003, states that PD can be caused by an unknown pathogen in the gut that enters the body through the nose or mouth spreading from the peripheral to the central nervous system. A key disease mechanism is the abnormal accumulation of α-synuclein fibrils in the form of Lewy bodies in various parts of the nervous system, starting in the gut.

“…gut dysbiosis (imbalance in gut microbiota) has been suggested as one of the earliest events in PD pathogenesis.”

Based on a number of mechanistic preclinical studies and correlational human studies, gut dysbiosis (imbalance in gut microbiota) has been suggested as one of the earliest events in PD pathogenesis. However, due to the correlational nature of all human studies, and the fact that disease-related changes in bowel habits can alter the gut microbiome, a causal role of the dysbiosis in PD has not been established.

The meta-analysis, titled “Meta-analysis of Shotgun Sequencing of Gut Microbiota in Parkinson’s Disease,” published in the Nature Partner Journal Parkinson’s Disease, by Hiroshi Nishiwaki and colleagues from the Nagoya University, Japan focuses on identifying gut microbial features associated with PD through a comprehensive international meta-analysis, e.g. the combined analysis of several studies performed by different research groups around the world.

The study analyzed data from six different countries (Japan, USA, Germany, China1, China2, and Taiwan) to compare gut microbiota between PD patients and healthy controls, using shotgun sequencing of fecal samples. Fecal shotgun metagenomic sequencing is a state of the art technique that analyzes the total genomic DNA (metagenome) of all organisms in a fecal sample allowing researchers to identify both species and genes present in the sample.

The results showed that across all datasets, α-diversity (a measure of species diversity within a sample) was found to be higher in PD patients compared to controls. This suggests a greater variety of bacterial species in the guts of PD patients.

“…the mucus degrading bacterial species Akkermansia muciniphila was significantly increased, while butyrate-producing bacteria …were significantly decreased in PD patients.”

The taxonomic analysis indicated that the mucus degrading bacterial species Akkermansia muciniphila was significantly increased, while butyrate-producing bacteria Roseburia intestinalis and Faecalibacterium prausnitzii were significantly decreased in PD patients.

When the investigators performed analyses of the functional microbiome changes, they found that genes involved in the biosynthesis of riboflavin (vitamin B2) and biotin (vitamin B7) were markedly reduced in PD patients. At the same time, these genes were positively correlated with fecal concentrations of short-chain fatty acids (SCFAs) such as butyrate and polyamines, which were also found to be significantly decreased in PD patients.

“…indicating extensive reductions in bacterial metabolism of complex carbohydrates.”

Five out of six categories of carbohydrate-active enzymes were reduced in PD patients, indicating extensive reductions in bacterial metabolism of complex carbohydrates. Complex carbohydrate metabolism by gut microbes is the major source of anti-inflammatory and gut health promoting SCFAs. The study also highlighted significant decreases in the genes for SCFAs and polyamines.

Interestingly, the bacteria responsible for the decreased biosynthesis of riboflavin and biotin varied between country groups. For instance, different bacterial species accounted for the decreased biosynthesis of these vitamins in Japan, the USA, and Germany compared to China1, China2, and Taiwan.

“…the authors postulated that the reduction in SCFAs and Vitamin B polyamines may lead to a thinner intestinal mucus layer, resulting in increased intestinal permeability…”

Based on their findings, the authors postulated that the reduction in SCFAs and Vitamin B polyamines may lead to a thinner intestinal mucus layer, resulting in increased intestinal permeability (“leakiness”) and facilitate the translocation of neurotoxic substances from the gut, thus promoting neuroinflammation and α-synuclein aggregation.

The study’s results underscore the potential of targeting gut microbiota and related metabolic pathways for therapeutic interventions in PD. The authors imply that by identifying specific bacterial species and metabolic functions that are altered in PD, this research might open avenues for developing probiotics or dietary supplements aimed at restoring healthy gut microbiota balance and improving gut-derived metabolic deficiencies. However, despite their significant methodological improvement over the majority of previous studies showing gut microbial compositional and functional changes, their analysis is correlational and does not allow to implicate the observed microbiome changes as a cause for PD. Furthermore, their hypothesis that a reduction in Akkermansia species leads to a compromised mucus layer and intestinal permeability does not take into consideration that the same bacteria can stimulate compensatory mucus production in intestinal goblet cells.

In summary, the meta-analysis of gut microbiota in PD patients across different countries highlights consistent alterations in bacterial diversity, specific bacterial species, and metabolic pathways related to riboflavin and biotin biosynthesis. These findings suggest a crucial link between gut dysbiosis and PD, providing insights that could eventually lead to novel therapeutic strategies aimed at modulating the gut microbiome long before the development of neurological symptoms to potentially mitigate PD progression and symptoms.