Evidence linking PD to the gut precedes our recent appreciation of the microbiome. Gastrointestinal (GI) symptoms, including constipation, often precede the motor signs of PD. Lewy bodies and α-synuclein, which are the neuropathological hallmarks of PD, may appear in the gut before they appear in the brain. Colonic inflammation has also been documented in PD. These observations have led to the hypothesis that PD starts in the gut and spreads to the brain. Increased intestinal permeability in conjunction with presence of α-synuclein in the gut at early stages of disease suggests that a leaky gut membrane may contribute to the spread of the disease. Decreased incidence of PD among individuals who underwent vagotomy adds to the evidence that PD might start in the gut and spread to the brain via the enteric nervous system. The human gut hosts tens of trillions of microorganisms, including more than 1000 species of bacteria.[6, 7] The collective genomes of the microorganisms in the gut (the microbiome) is more than 100 times larger than the number of genes in the human genome. A well-balanced gut microbiota is critical for maintaining general health. Alterations in the composition of gut microbiota have been linked to a range of disorders including inflammatory, metabolic, neurologic, and oncologic (reviewed in ref. ). Research on human disease and the gut microbiota is a relatively new field, and so far most studies have treated the disease as a single predictor, disregarding the wide range of variables that could also affect the microbiome and obscure the disease signature. The need to disentangle the gut microbiota signature of disease from that of medication and other confounders is becoming increasingly evident.
Studies linking the gut microbiome to PD include 1 conducted in mice that showed colonization with microbiota from PD patients enhanced neuroinflammation and motor symptoms in animals overexpressing α-synuclein and 4 conducted in humans that reached divergent conclusions.[11-14] A direct comparison of the results is difficult because they had relatively small sample sizes (68 to 144 cases and controls combined) and differed in subject inclusion/exclusion criteria, sequencing techniques, statistical methods, and the treatment of confounders. Here we report a case-control study that included 327 participants and a systematic analysis of 39 variables as potential confounders. We applied different techniques when available to assure results were robust to methodological differences and examined the gut microbiome at the global, taxonomic, and functional levels. The results help coalesce the seemingly inconsistent literature.
Conclusion: PD is accompanied by dysbiosis of gut microbiome. Results coalesce divergent findings of prior studies, reveal altered abundance of several taxa, nominate functional pathways, and demonstrate independent effects of PD medications on the microbiome. The findings provide new leads and testable hypotheses on the pathophysiology and treatment of PD.