Objective: Parkinsons disease (PD) pathogenesis may involve the gastrointestinal tract, with recent evidence implicating the human vermiform appendix. The appendix is a lymphoid tissue involved in the storage and regulation of the gut microbiome. We sought to determine whether the appendix microbiome is altered in PD and the biological consequences of the microbial alterations. Design: We investigated changes in the functional microbiome in the appendix of PD patients relative to controls by metatranscriptomic analysis. PD microbiome abnormalities were compared to those induced by synucleinopathy and gut inflammation in mice. The microbiome changes identified in the PD appendix led to an analysis of bile acids. We also investigated blood markers of biliary abnormalities at various stages of PD progression. Results: In the PD appendix, we found microbial dysbiosis affecting lipid metabolism, particularly an upregulation of bacteria responsible for bile acid synthesis. Bile acid analysis in the PD appendix revealed an increase in the microbially-derived, toxic bile acids deoxycholic acid (DCA) and lithocholic acid (LCA). Synucleinopathy in mice induced similar microbiome alterations to those of PD patients and amplified microbial changes to gut inflammation. The mouse model of synucleinopathy also had elevated DCA and LCA. Raised levels of DCA and LCA can lead to liver injury, and an analysis of blood markers showed evidence of biliary abnormalities early in PD, including elevated alkaline phosphatase and bilirubin. In at-risk individuals, bilirubin levels were increased before PD diagnosis. Conclusion: Microbially-derived toxic bile acids are heightened in PD and biliary changes may even precede the onset of overt motor symptoms.
bioRxiv Subject Collection: Neuroscience