Abstract
In Parkinson’s disease (PD), gastrointestinal features are common and often precede the motor signs. Braak and colleagues proposed that PD may start in the gut, triggered by a pathogen, and spread to the brain. Numerous studies have examined the gut microbiome in PD; all found it to be altered, but found inconsistent results on associated microorganisms. Studies to date have been small (N = 20 to 306) and are difficult to compare or combine due to varied methodology. We conducted a microbiome-wide association study (MWAS) with two large datasets for internal replication (N = 333 and 507). We used uniform methodology when possible, interrogated confounders, and applied two statistical tests for concordance, followed by correlation network analysis to infer interactions. Fifteen genera were associated with PD at a microbiome-wide significance level, in both datasets, with both methods, with or without covariate adjustment. The associations were not independent, rather they represented three clusters of co-occurring microorganisms. Cluster 1 was composed of opportunistic pathogens and all were elevated in PD. Cluster 2 was short-chain fatty acid (SCFA)-producing bacteria and all were reduced in PD. Cluster 3 was carbohydrate-metabolizing probiotics and were elevated in PD. Depletion of anti-inflammatory SCFA-producing bacteria and elevated levels of probiotics are confirmatory. Overabundance of opportunistic pathogens is an original finding and their identity provides a lead to experimentally test their role in PD.
Highlights
Parkinson’s disease (PD) is a common, progressive, and debilitating disease, which currently cannot be prevented or cured
In PD patients, we found that 80% of Corynebacterium_1 was composed of one unique ASV with 100% identity to Corynebacterium amycolatum and Corynebacterium lactis; 96% of Porphyromonas was composed of ASVs that matched Porphyromonas asaccharolytica, Porphyromonas bennonis, Porphyromonas somerae, or Porphyromonas uenonis with >99–100% identity, and 98% of Prevotella was composed of ASVs that matched Prevotella bivia, Prevotella buccalis, Prevotella disiens, or Prevotella timonensis with >99–100% identity (83% of Prevotella matched P. bivia, P. buccalis, P. disiens, or P. timonensis at 100% identity)
We first confirmed that the gut microbiome is altered in PD and showed that the PD effect on the global composition of the gut microbiome is independent of the effects of sex, age, body mass index (BMI), constipation, gastrointestinal discomfort, geography, and diet
Summary
Parkinson’s disease (PD) is a common, progressive, and debilitating disease, which currently cannot be prevented or cured. Many susceptibility loci[1] and environmental risk factors[2] have been identified, but each has a modest effect on risk and none is sufficient to cause disease. Every study that has compared the global composition of the gut microbiome in PD vs controls found it to be significantly altered; in contrast, attempts to identify PD-associated microorganisms have produced inconsistent results[31,32]. A myriad of factors can affect the microbiome ranging from diet, health, and medication to cultural habits, lifestyles, race, and geography[33,34]
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