Fecal microbiome alterations in treatment-naive de novo Parkinson’s disease

Boertien, Jeffrey M.; Murtomäki, Kirsi; Pereira, Pedro AB; Zee, Sygrid van der; Mertsalmi, Tuomas; Levo, Reeta; Nojonen, Tanja; Mäkinen, Elina; Jaakkola, Elina; Laine, Pia; Paulín, Lars; Pekkonen, Eero; Kaasinen, Valtteri; Auvinen, Petri; Scheperjans, Filip; Verwey, N. A.; Harten, B. van; Portman, A. T.; Langedijk, M. J. H.; Oomes, P. G.; Jansen, B. J. A. M.; Wieren, T. van; Bogaard, Simon J.A. van den; Steenbergen, W. van; Duyff, R.; Amerongen, J. P. van; Fransen, P. S. S.; Polman, S. K. L.; Zwartbol, R. T.; Kesteren, M. E. van; Braakhekke, J. P.; Trip, J.; Koops, L.; Langen, C. J. de; Jong, G. de; Hartono, J. E. S.; Ybema, H.; Bartels, Arthur; Reesink, Fransje E.; Postma, A. G.; Vonk, G. J. H.; Oen, J. M. T. H.; Brinkman, M. J.; Mondria, T.; Holscher, R. S.; Meulen, A. A. E. van der; Rutgers, A.W.F.; Boekestein, W. A.; Teune, Laura K.; Orsel, P. J. L.; Hoogendijk, Jessica E.; Laar, Teus van

doi:10.1038/s41531-022-00395-8

Cited by 19 publications

(17 citation statements)

References 65 publications

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“…Despite the strong association between Lachnospiraceae and levodopa in the current and previous studies, reduced levels of Lachnospiraceae and other SCFA producing taxa were already found in treatment-naïve de novo PD subjects independently of PD medication. 17,18 PD medication might therefore initiate reductions in certain Lachnospiraceae taxa or aggravate already existing deficits.…”

Section: Discussionmentioning

confidence: 99%

“…Stool sample collection and clinical assessments were performed as previously described. 17 Briefly, stool samples were immediately frozen upon collection and kept frozen until DNA…”

Section: Methodsmentioning

confidence: 99%

“…Wet lab work was performed at the University of Helsinki, Institute of Biotechnology, as previously described. 17 Additional nucleotides (depicted in non-capitalized letters) were introduced for mixing in sequencing. Two-step PCR amplification was done as previously described.…”

Section: Laboratory Proceduresmentioning

confidence: 99%

“…The bioinformatics pipeline was performed as previously described. 17 Briefly, primers were removed with cutadapt (v2.10). 43 DADA2 (v1.18) was used for further bioinformatics.…”

Section: Bioinformaticsmentioning

confidence: 99%

“…Recently, we published the results of two independent case-control cohorts of treatmentnaïve de novo PD subjects, with taxonomic differences mainly limited to reduced SCFA-producing bacteria, in particular including taxa belonging to the family of Lachnospiraceae. 17 Similarly, a study with a subpopulation of untreated PD subjects concluded that most differences in gut microbiome composition between PD and HC disappeared after statistical adjustment for treatment and disease duration. 18 The untreated subpopulation was still characterized by lower levels of the family Lachnospiraceae and two of its genera.…”

Section: Introductionmentioning

confidence: 99%

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

Boertien

Pereira

Laine

et al. 2022

Preprint

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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.

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Section: Discussionmentioning

confidence: 99%

“…Stool sample collection and clinical assessments were performed as previously described. 17 Briefly, stool samples were immediately frozen upon collection and kept frozen until DNA…”

Section: Methodsmentioning

confidence: 99%

Section: Laboratory Proceduresmentioning

confidence: 99%

“…The bioinformatics pipeline was performed as previously described. 17 Briefly, primers were removed with cutadapt (v2.10). 43 DADA2 (v1.18) was used for further bioinformatics.…”

Section: Bioinformaticsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Boertien

Pereira

Laine

et al. 2022

Preprint

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Fecal Microbiota Transplantation for Treatment of Parkinson Disease

Scheperjans,

Levo,

Bosch

et al. 2024

JAMA Neurol

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ImportanceDysbiosis has been robustly demonstrated in Parkinson disease (PD), and fecal microbiota transplantation (FMT) has shown promising effects in preclinical PD models.ObjectiveTo assess the safety and symptomatic efficacy of colonic single-dose anaerobically prepared FMT.Design, Setting, and ParticipantsThis was a double-blind, placebo-controlled, randomized clinical trial conducted between November 2020 and June 2023 with a follow-up period of 12 months at 4 hospitals in Finland. Patients with PD aged 35 to 75 years in Hoehn &amp; Yahr stage 1-3 with a mild to moderate symptom burden and dysbiosis of fecal microbiota were included. Of 229 patients screened, 48 were randomized and 47 received the intervention. One patient discontinued due to worsening of PD symptoms. Two further patients were excluded before analysis and 45 were included in the intention-to-treat analysis.InterventionParticipants were randomized in a 2:1 ratio to receive FMT or placebo via colonoscopy.Main Outcomes and MeasuresThe primary end point was the change of Movement Disorder Society Unified Parkinson’s Disease Rating Scale parts I-III (part III off medication) at 6 months. Safety was assessed by recording adverse events (AEs).ResultsThe median (IQR) age was 65 (52.5-70.0) years in the placebo group and 66 (59.25-69.75) years in the FMT group; 9 (60.0%) and 16 (53.3%) patients were male in the placebo group and the FMT group, respectively. The primary outcome did not differ between the groups (0.97 points, 95% CI, −5.10 to 7.03, P = .75). Gastrointestinal AEs were more frequent in the FMT group (16 [53%] vs 1 [7%]; P = .003). Secondary outcomes and post hoc analyses showed stronger increase of dopaminergic medication and improvement of certain motor and nonmotor outcomes in the placebo group. Microbiota changes were more pronounced after FMT but differed by donor. Nevertheless, dysbiosis status was reversed more frequently in the placebo group.Conclusions and RelevanceFMT was safe but did not offer clinically meaningful improvements. Further studies—for example, through modified FMT approaches or bowel cleansing—are warranted regarding the specific impact of donor microbiota composition and dysbiosis conversion on motor and nonmotor outcomes as well as medication needs in PD.Trial RegistrationClinicalTrials.gov Identifier: NCT04854291

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Metagenomics of the Gut Microbiome in Parkinson's Disease: Prodromal Changes

Palacios

Wilkinson²,

Bjørnevik

et al. 2023

Annals of Neurology

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ObjectivePrior studies on the gut microbiome in Parkinson's disease (PD) have yielded conflicting results, and few studies have focused on prodromal (premotor) PD or used shotgun metagenomic profiling to assess microbial functional potential. We conducted a nested case–control study within 2 large epidemiological cohorts to examine the role of the gut microbiome in PD.MethodsWe profiled the fecal metagenomes of 420 participants in the Nurses' Health Study and the Health Professionals Follow‐up Study with recent onset PD (N = 75), with features of prodromal PD (N = 101), controls with constipation (N = 113), and healthy controls (N = 131) to identify microbial taxonomic and functional features associated with PD and features suggestive of prodromal PD. Omnibus and feature‐wise analyses identified bacterial species and pathways associated with prodromal and recently onset PD.ResultsWe observed depletion of several strict anaerobes associated with reduced inflammation among participants with PD or features of prodromal PD. A microbiome‐based classifier had moderate accuracy (area under the curve [AUC] = 0.76 for species and 0.74 for pathways) to discriminate between recently onset PD cases and controls. These taxonomic shifts corresponded with functional shifts indicative of carbohydrate source preference. Similar, but less marked, changes were observed in participants with features of prodromal PD, in both microbial features and functions.InterpretationPD and features of prodromal PD were associated with similar changes in the gut microbiome. These findings suggest that changes in the microbiome could represent novel biomarkers for the earliest phases of PD. ANN NEUROL 2023

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Fecal microbiome alterations in treatment-naive de novo Parkinson’s disease

Cited by 19 publications

References 65 publications

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

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

Fecal Microbiota Transplantation for Treatment of Parkinson Disease

Metagenomics of the Gut Microbiome in Parkinson's Disease: Prodromal Changes

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