Characterizing dysbiosis of gut microbiome in PD: Evidence for overabundance of opportunistic pathogens

In Parkinson9s 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 represented 3 clusters of co-occurring microorganisms. Cluster 1 was composed of opportunistic pathogens; all were elevated in PD. Cluster 2 were short-chain-fatty-acid producing bacteria; all were reduced in PD. Cluster 3 were carbohydrate-metabolizing probiotics; elevated in PD. Depletion of anti-inflammatory short-chain-fatty-acid producing bacteria and elevated levels of probiotics are confirmatory. Overabundance of opportunistic pathogens is a novel finding and their identity provides a lead to experimentally test their role in PD.