Dopaminergic Medication Accentuates Fecal Gut Microbiome Changes in Parkinson’s Disease

Fecal gut microbiota changes are associated with Parkinson’s disease (PD). However, disease related changes cannot readily be discerned from medication effects, as almost all participants in previous studies were using PD medication, and conclusive longitudinal data related to treatment initiation is lacking. Here, fecal gut microbiota composition was assessed in 62 de novo PD participants who were untreated at baseline and used PD medication at one-year follow-up, by means of 16S-sequencing. In addition, participants were stratified for the type of dopaminergic medication. Overall gut microbiota composition did not differ between baseline and one-year follow-up, but was associated with levodopa dose and levodopa equivalent daily dose (LEDD). Several differentially abundant taxa are in line with previously described changes in PD. These included reduced levels of amplicon sequence variants (ASVs) belonging to Faecalibacterium prausnitzii and Lachnospiraceae in all participants at follow-up, and increased levels of an ASV belonging to Bifidobacterium in dopamine agonist users. The family Bifidobacteriaceae was increased in dopamine agonist users who only used pramipexole. Levodopa dose was inversely related to the abundance of the families Ruminococcaceae and Lachnospiraceae, and the genus Lachnospiraceae ND3007 group . PD medications exert a measurable and dose-dependent effect on gut microbiota composition and accentuate several previously described gut microbiota changes in PD. Detailed knowledge of medication effects should be part of future trial designs of gut microbiome studies in PD and are necessary to interpret previously published data. ### Competing Interest Statement JMB received an honorarium for writing an article for the magazine "Kinetic" by Britannia Pharmaceuticals and owns exchange traded funds that might include stocks in medically-related fields, SvdZ none, PL none, FS has received grants from The Academy of Finland, The Hospital District of Helsinki and Uusimaa, OLVI-Foundation, Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, The Wilhelm and Else Stockmann Foundation, The Emil Aaltonen Foundation, The Yrjoe Jahnsson Foundation, Renishaw, and honoraria from AbbVie, Orion, GE Healthcare, Merck, Teva, Bristol Myers Squibb, Sanofi, Biocodex, and Biogen. FS is founder and CEO of NeuroInnovation Oy and NeuroBiome Ltd., is a member of the scientific advisory board and has received consulting fees and stock options from Axial Biotherapeutics. TvL has received grant support from the MJFF, the UMCG, Menzis, Weston Brain Institute and the Dutch Brain Foundation. Consultancy fees were received from AbbVie, Britannia Pharm., Centrapharm and Neuroderm. Speaker fees were received from AbbVie, Britannia Pharm. and Eurocept. PABP, LP, PA, and FS have patents issued (FI127671B, US10,139,408, US11,499,971) and pending (US16/186,663, US17/116,045, US17/933,952, EP3789501, EP3149205) that are assigned to NeuroBiome Ltd. All authors declare to have no non-financial conflicts of interest. ### Clinical Protocols ### Funding Statement The DUPARC study was funded by the Weston Brain Institute and personal grants for JMB to cover personnel costs. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the ethics committee of the University Medical Center Groningen, was conducted in concordance with the declaration of Helsinki and all participants provided written informed consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Sequencing data of the V4 region of the 16S rRNA gene will be made available via the European Nucleotide Archive upon publication. Sample metadata can be requested from the principal investigator of the DUPARC cohort study upon reasonable request via duparc{at}neuro.umcg.nl.