Articles

Safety and efficacy of faecal microbiota transplantation in

patients with mild to moderate Parkinson’s disease
(GUT-PARFECT): a double-blind, placebo-controlled,
randomised, phase 2 trial
Arnout Bruggeman,a,b,c,d Charysse Vandendriessche,c,d Hannelore Hamerlinck,b,e Danny De Looze,b,f David J. Tate,b,f Marnik Vuylsteke,c,g
Lindsey De Commer,h,i Lindsay Devolder,h,i Jeroen Raes,h,i Bruno Verhasselt,b,e Debby Laukens,b,j Roosmarijn E. Vandenbroucke,c,d,j and
Patrick Santensa,b,j,∗
a
Department of Neurology, University Hospital Ghent, Ghent, Belgium
b
Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
c
VIB-UGent Center for Inflammation Research, VIB, Ghent, Belgium
d
Faculty of Sciences, Ghent University, Ghent, Belgium
e
Department of Laboratory Medicine, Ghent University Hospital, Ghent, Belgium
f
Department of Gastroenterology, University Hospital Ghent, Ghent, Belgium
g
Statistics for Biosciences, Gnomixx, Melle, Belgium
h
Department of Microbiology and Immunology, Rega Institute for Medical Research, Leuven, Belgium
i
VIB-KU Leuven Center for Microbiology, VIB, Leuven, Belgium

Summary eClinicalMedicine
2024;71: 102563
Background Dysregulation of the gut microbiome has been implicated in Parkinson’s disease (PD). This study aimed
to evaluate the clinical effects and safety of a single faecal microbiota transplantation (FMT) in patients with early- Published Online 27 March
2024
stage PD. https://doi.org/10.
1016/j.eclinm.2024.
Methods The GUT-PARFECT trial, a single-centre randomised, double-blind, placebo-controlled trial was conducted 102563
at Ghent University Hospital between December 01, 2020 and December 12, 2022. Participants (aged 50–65 years,
Hoehn and Yahr stage 2) were randomly assigned to receive nasojejunal FMT with either healthy donor stool or
their own stool. Computer-generated randomisation was done in a 1:1 ratio through permutated-block scheduling.
Treatment allocation was concealed for participants and investigators. The primary outcome measure at 12
months was the change in the Movement Disorders Society-Unified Parkinson’s Disease Rating Scale (MDS-
UPDRS) motor score obtained during off-medication evaluations. Intention-to-treat analysis was performed using
a mixed model for repeated measures analysis. This completed trial is registered on ClinicalTrials.gov
(NCT03808389).

Findings Between December 2020 and December 2021, FMT procedures were conducted on 46 patients with PD: 22
in the healthy donor group and 24 in the placebo group. Clinical evaluations were performed at baseline, 3, 6, and 12
months post-FMT. Full data analysis was possible for 21 participants in the healthy donor group and 22 in the placebo
group. After 12 months, the MDS-UPDRS motor score significantly improved by a mean of 5.8 points (95% CI −11.4
to −0.2) in the healthy donor group and by 2.7 points (−8.3 to 2.9) in the placebo group (p = 0.0235). Adverse events
were limited to temporary abdominal discomfort.

Interpretation Our findings suggested a single FMT induced mild, but long-lasting beneficial effects on motor
symptoms in patients with early-stage PD. These findings highlight the potential of modulating the gut
microbiome as a therapeutic approach and warrant a further exploration of FMT in larger cohorts of patients with
PD in various disease stages.

Funding Flemish PD patient organizations (VPL and Parkili), Research Foundation Flanders (FWO), Biocodex
Microbiota Foundation.

*Corresponding author. Ghent University Hospital, Ghent, Belgium.

E-mail address: [email protected] (P. Santens).
j
Shared senior authorship.
Translation: For the Dutch translation of the abstract see Supplementary Materials section.

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Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Keywords: Parkinson’s disease; Gut-brain axis; Faecal microbiota transplantation; Clinical trial; Gut microbiota

Research in context

Evidence before this study these studies, adverse events associated with FMT were mild
A comprehensive search was conducted on PubMed from and restricted to transient gastro-intestinal discomfort and
database inception till September 1st, 2023, using the search diarrhoea.
terms “Parkinson” and “gut microbiota” or “gut microbiome”,
Added value of this study
without any language or date restrictions. The existing
We present the results of a one-year, randomized, double-
literature supports an early involvement of the
blind, placebo-controlled study of nasojejunal FMT in patients
gastrointestinal system in the aetiology and progression of
with early-stage PD. This study is the first of its kind with
Parkinson’s disease (PD) for a sub-group of patients,
larger sample sizes compared to previously reported trials. The
supporting the gut-first versus brain-first hypothesis. During
healthy donor FMT group demonstrated significantly greater
the prodromal phase of the disease, evidence suggests the
improvements in motor symptom severity compared to the
presence of alpha-synuclein in the enteric nervous system,
control group, with the effect becoming more pronounced
subclinical gut inflammation, compromised intestinal barrier
starting from the 6 to 12 months interval. Objective
integrity, and gastrointestinal symptoms like constipation.
measurements of gastrointestinal transit indicated
Several recent meta-analyses comparing the gut microbiota of
improvements in the healthy donor group, starting from the
patients with PD to healthy controls have shown differential
3 to 6 months interval. No severe adverse events were
abundances of taxa associated with reduced mucosal barrier
reported in either group, further supporting the safety profile
and increased intestinal inflammation. An additional search
of FMT.
was performed on PubMed using the terms “Parkinson” and
“microbiota transplantation” which yielded 82 reports Implications of all the available evidence
predominantly focusing on faecal microbiota transplantation The findings of this study, combined with earlier smaller and
(FMT) as a potential treatment for PD. Four open-label open studies, highlight the potential of FMT as a treatment
studies with small number of patients have demonstrated option for patients with PD. However, larger multicentre trials
beneficial effects on symptoms, mainly constipation. with extended follow-up periods are necessary to validate
Although technically not a FMT study, a recently conducted these results. Furthermore, the correlation between beneficial
pilot study with a randomized and placebo-controlled design outcomes, alterations in microbiota composition and
(n = 11), using an orally lyophilised donor stool product or inflammatory markers needs to be further investigated and
matching placebo, was well tolerated and reported reduced validated from a pathophysiological perspective.
constipation, however objective UPDRS motor improvements
were transient and not statistically different from placebo. In

Introduction of the disease.6 This aggregated alpha-synuclein can reach

Parkinson’s disease (PD) is a rapidly growing neurolog- the brain via the vagal nerve, which has been shown
ical disorder characterized by progressive degeneration of directly in animal models7 and indirectly by an apparent
dopaminergic neurons in the substantia nigra, resulting reduced risk of developing PD after vagotomy.8 These
in bradykinesia, rigidity, resting tremor, and postural findings led to the dual-hit Braak hypothesis which states
instability.1 Additionally, patients experience non-motor that alpha-synuclein aggregation is triggered by micro-
symptoms that significantly impact their quality of life biota at the level of the gut and/or the olfactory nerves.9
and often precede the motor symptoms.2 Prodromal Recently, this hypothesis has been expanded to a body-
gastrointestinal dysfunction is highly prevalent with first or brain-first onset of PD.10 In the body-first
approximately 80% of de novo untreated patients exhib- phenotype, pathology is believed to start in the gut and
iting prolonged colon transit time as a marker for con- emerging evidence suggests that the gut microbiome
stipation.3 Several other findings emphasise the may play this pivotal role in PD pathogenesis and pro-
important role of the gut in PD. Patients with newly gression.11 Meta-analyses comparing the gut microbiota
diagnosed, untreated PD exhibit evidence of increased of patients with PD and healthy controls have revealed
intestinal inflammation and disturbed permeability of the differentially abundant taxa associated with reduced
intestinal epithelial barrier.4,5 The pathological hallmark mucosal barrier and increased intestinal inflammation.12
of PD, alpha-synuclein aggregates, has been observed in In preclinical studies, modulating the gut microbiota had
the gastrointestinal system during the prodromal phase neuroprotective effects.13,14

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Faecal microbiota transplantation (FMT) represents Participants

the most effective method for achieving comprehensive The inclusion criteria were a clinical PD diagnosis ac-
and long-lasting changes in gut microbiota composition. cording to the Movement Disorder Society criteria, age
FMT has been safely and successfully used for Clos- limit of 65 years old, age of motor symptoms onset older
tridioides difficile infections, for which it is an approved than 50 years old, and Hoehn & Yahr stage II or III in an
indication.15 However, evidence supporting the use of off-medication state. We excluded patients with a first
FMT in patients with PD is limited to case reports and degree relative or more than one relative with PD, pa-
open-label studies involving a small number of tients with a diagnosis of dementia or Mini-Mental State
patients.16–20 These studies have reported subjective and Examination Score <25, patients with a diagnosis of
objective improvement in motor and non-motor symp- depression or psychosis (DSM-V criteria), patients with
toms, particularly constipation. Nevertheless, variations gastrointestinal dysfunction unrelated to PD (primary
in inclusion criteria, FMT procedures and administra- disease or surgery leading to structural abnormalities of
tion routes, clinical assessment, and follow-up periods, the intestines), patients with an immune disorder or
as well as the absence of placebo controls, have hindered under clinical immunosuppression. In addition, drug
the interpretation of results and the estimation of po- abuse, malignancy, or any severe comorbidity that
tential placebo effects. might interfere with the study course were considered
Here, we present the results of the first randomised, exclusion criteria. The FMT procedure was only per-
double-blind, and placebo-controlled trial designed to formed if there was no use of probiotics or antibiotics in
evaluate the safety and efficacy of a single FMT pro- the three months prior to the FMT, and no gastroin-
cedure via nasojejunal administration of healthy donor testinal or respiratory tract infection in the two months
stool (active treatment group) compared to own stool prior to the FMT. Eligibility was established through in-
(placebo group) in patients with mild to moderate PD. person assessments following pre-screening over the
This study aimed to provide robust evidence regarding phone or via e-mail. After inclusion via written informed
the therapeutic potential of FMT in PD and address the consent, a formal baseline study visit was organised to
limitations of previous investigations. minimize the time between baseline visit and date of
FMT, and to allow for assessment in off-medication
state.
Methods
Study design Randomisation and masking
A single-centre randomised, double-blind and placebo- Eligible patients were randomly assigned to receive
controlled phase 2 trial was performed at Ghent Uni- nasojejunal FMT with either healthy donor stool (active
versity Hospital (GUT-PARFECT trial) between treatment group) or their own stool (placebo group).
December 01, 2020 and December 12, 2022. Treatment Computer-generated randomisation was done by an
groups included a healthy donor FMT and a placebo independent person involved in FMT preparation in a
FMT (own stool). The study included a baseline visit, a 1:1 ratio through a permutated-block schedule with a
colonoscopy before and 3 months after FMT, the FMT block size of 4. Treatment allocation was masked for
procedure itself, and study visits at 3, 6, and 12 months participants, personnel involved in FMT administration
after FMT. All clinical assessments were done at Ghent and clinical investigators. Consequently, all patients had
University Hospital by the same clinical investigator to to deliver a stool sample to prepare a potential placebo
avoid inter-investigator variability. The double-blind FMT solution.
treatment period started at randomisation and lasted
until the final study visit of the last participant. Changes Procedures
in pharmacotherapy during the trial period were left at Healthy donors were recruited via the Ghent Stool Bank
the discretion of the treating neurologist. The study did following a strict inclusion protocol according to na-
not use an independent data safety monitoring board, in tional (Superior Health Council of Belgium nr. 9202)
view of the experience with FMT gained in various in- and international guidelines (European FMT working
dications. The full trial protocol is available in the group).21 The selection process involves a meticulous
appendix. review of the donor’s clinical and personal information
(collected through a questionnaire) as well as serology
Ethics and stool testing. Faecal donations were collected over a
The trial protocol was approved by the ethical committee period of 1 month and were released from quarantine
of Ghent University Hospital. Prospective written after serological testing 3 months after the last faecal
informed consent forms were obtained from every donation. This procedure helps to ensure safety, cost-
candidate prior to the start of the study. The study was efficiency, and availability. For each FMT preparation,
performed in accordance with the ethical principles of 50 g of faecal product was used. The faecal product was
the Declaration of Helsinki, Good Clinical Practice diluted with sterile saline and subsequently homoge-
(GCP) and applicable regulatory requirements. nized anaerobically and filtered using a stomacher

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(BagMixer, Interscience). Glycerol (10%) was added as a Wexner Constipation Scale, Bristol Stool Chart, Geri-
cryoprotectant to the filtered product resulting in a total atric Depression Scale, Parkinson Anxiety Scale, Lille
volume of 200 ml. The faecal suspension was stored Apathy Rating Scale, Parkinson’s Disease Sleep Scale,
at −80 ◦ C. Maximum 4 h before the FMT, the faecal and Parkinson’s Fatigue Scale.
suspension was thawed for 30 min in a water bath at The MDS-UPDRS (all 4 parts) and the Montreal
37 ◦ C. Importantly, only healthy donor stools that were Cognitive Assessment was performed at the beginning
collected before the COVID-19 pandemic were used to of the study visit. During the study visit, the other filled-
avoid any potential confounder related to COVID-19. in questionnaires were briefly checked by the study
FMT solutions of 17 different healthy donors were investigator to minimize omissions. At the baseline
used in the study. Due to the double-blind set-up of the visit, a 16-item Sniffin’ Sticks identification test was
study, each participant delivered a fresh stool sample to performed (Burghart, Wedel, Germany), a result <11
the lab 10–14 days preceding the FMT, and potential points was defined as hyposmia. In addition, the REM
placebo FMT solutions were prepared from each Sleep Behavior Disorder Screening Questionnaire
participant. Participants collected this sample at home (RBDSQ) was administered and considered positive
using a sampling kit containing a plastic collection box, with a cut-off of >5 points. Furthermore, we performed
cooler blocks, a sealable container, and an AnaeroGen™ an orthostatic hypotension test by measuring blood
Compact pouch to create an anaerobic environment in pressure in prone position, as well as upright 1 and
the sealable container. Participants delivered the stool 3 min later. A drop in systolic blood pressure of
sample to the Laboratory of Medical Microbiology of 20 mmHg or diastolic blood pressure drop of 10 mmHg
Ghent University Hospital within 2 h. The stool samples was defined as orthostatic hypotension. Finally, to
were aliquoted and the correct dilution for the faecal determine a more objective estimation of the colon
transplant solution was based on faecal weight as transit time, we performed a radiopaque pellets test at
described above. baseline, 3, 6, and 12 months post-FMT. Ten radiopaque
Seven days before the FMT, patients underwent a markers (3.5 mm x 3.5 mm; SAPA6210; Sapi Med,
colonoscopy to screen for contra-indications. This colo- Allesandria, Italy) had to be ingested every morning
noscopy was preceded by a bowel preparation according starting from the sixth day before the study visit until
to the standard procedures of our centre, including low- the last day before the study visit. The study visit ended
fiber diet three days beforehand and solely clear liquid with an abdominal x-ray to determine the amount and
intake the day beforehand. Polyethylene glycol location of radiopaque markers. Colon transit time was
(Plenvu®, Norgine) preparations were taken the evening calculated using the following equation (total number of
and the morning preceding the colonoscopy, according pellets on day 7 + 5)/10.22 Safety assessments were
to the manufacturer’s instructions. For FMT, candidates performed at every study visit, as well as by telephone
underwent this bowel preparation again. The FMT so- and/or e-mail one week after FMT, and included general
lution was thawed at 37 ◦ C prior to the FMT procedure. questions concerning the presence of fever, gastroin-
The transplantation itself was performed through testinal changes, or other self-reported symptoms.
nasojejunal administration. The correct placement of
the tube was confirmed through the Cortrak Enteral Outcomes
Access System,15 followed by release of the FMT solu- The primary endpoint was the change of the motor
tion (200 ml). Afterwards, candidates lied still for 1 h section score of MDS-UPDRS, measured in an off-
before leaving the hospital again. medication state (as defined above), from baseline to
The study visits at baseline, 3, 6, and 12 months post- 12 months post-FMT for the healthy donor group
FMT were always performed in the morning in a fasting compared to the placebo group. Other prespecified
state. The off-medication state was defined as a period of secondary endpoints at 12 months post-FMT were the
withdrawal of levodopa for at least 8 h (i.e., overnight) or levodopa-equivalent daily dose (LEDD), the radiopaque
36 h in the case of long-acting drugs such as ropinirole, pellets test to determine colon transit time, and the
pramipexole, rasagiline, and safinamide. Dopamine scores of the MDS-UPDRS total score and scores of the
agonist doses were reduced to 50% of the initial dose other subdivisions (1, 2 and 4), Parkinson’s Disease
three days before the study visit, and no dose was taken Questionnaire, Non-motor Symptoms Scale, Wexner
on the day before the study visit. In addition, we also Constipation Scale, Geriatric Depression Scale, Parkin-
included an overnight withdrawal of amantadine, and son Anxiety Scale, Lille Apathy Rating Scale, Parkin-
anticholinergic agents when prescribed for a resting son’s Disease Sleep Scale, Parkinson’s Fatigue Scale,
tremor. and Montreal Cognitive Assessment.
Prior to the study visit, the participants received
questionnaires and instructions to achieve an off- Statistical analysis
medication state based on their individual medication Our study was powered to show an effect of FMT on
list. The questionnaires included the Parkinson’s Dis- MDS-UPDRS part 3 (motor score) in one year that was
ease Questionnaire, Non-motor Symptoms Scale, large enough to suggest a disease modifying effect of

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gut microbiota alteration in PD. The Prospective Par- placebo FMT effects across time windows, were
kinson’s Progression Markers Initiative (PPMI) cohort assessed using an approximate F-test as implemented in
showed a mean MDS-UPDRS motor score progression Genstat version 22. All data reported, including tables
over 12 months of 6.35 (SD 6.6) for patients with early and figures, are results from this MMRM adjusted for
PD.23 A total sample size of 46 patients was calculated to covariates.
provide 90% power to detect a MDS-UPDRS motor For safety data, the incidence of adverse events were
score difference of 6.35 (SD 6.6) between the two summarized. This completed trial is registered on
treatment groups with a two-sides significance level of ClinicalTrials.gov (NCT03808389).
0.05.
A linear mixed model for repeated measurements Role of the funding source
(MMRM) was fitted to all the data combined, using the The sponsors had no role in study design, data collec-
method of residual maximum likelihood, as imple- tion, data analysis, data interpretation or in manuscript
mented in Genstat version 22 (VSN International, writing. All authors had full access to all the data in the
Hemel Hempstead, UK). This procedure has the study and the senior authors had final responsibility for
advantage of reducing the influence of missing data on the decision to submit for publication.
the analysis because of LMM’s benefit to model corre-
lations between data. Briefly, the linear mixed model
(random terms underlined) of the form y = μ + Results
gender + treatment + time + treatment.time + Due to COVID-19-related restrictions, recruitment and
covariates + patient + patient.time was fitted to the treatment allocation were delayed from October 2019 to
repeated measurements. Two kinds of analyses were December 2020. During this period, a total of 289 pa-
performed: 1) either having the baseline measurements tients were assessed for eligibility, with 47 patients ul-
(T0) as covariate (MDS-UPDRS motor score was slightly timately enrolled (Fig. 1). The FMT procedures took
higher at baseline compared to the placebo group, place between December 2020 and December 2021,
therefore we decided to correct for this in the model), or with one patient discontinuing the procedure upon
2) having T0 as first level of the time factor. The con- request. Among the enrolled patients, 46 were randomly
stant μ represents an overall mean across all observa- assigned to receive either healthy donor FMT (n = 22) or
tions. The factor gender represents the effect of male placebo FMT with their own stool (n = 24). Of these
and female averaged across all time points. The factor patients, 43 completed all study visits, with 21 in the
treatment represents the effect of either healthy donor healthy donor and 22 in the placebo FMT group. There
FMT or placebo FMT averaged across all time points. was a limited amount of missing data, mainly caused by
The factor time indicates the effect at each time point, three participants that did not complete all study visits
averaged across healthy donor FMT and placebo FMT. (as depicted in Fig. 1).
The interaction term treatment. time represents the Baseline demographic variables were well-balanced
differences between the two treatment levels as a func- between the treatment groups, although the healthy
tion of time. We decided to include several covariates in donor group had a higher baseline MDS-UPDRS motor
the model to correct for disease duration, as well as score. There were no notable differences between the
factors that could indicate either a gut-first or brain-first groups in terms of LEDD, Hoehn and Yahr stage, and
PD phenotype. Covariates other than T0 included in the duration since PD diagnosis, which are all markers of
model are age, BMI, LEDD, duration of illness, amount disease progression (Table 1). Both groups had a male/
of radiopaque pellets, Sniffin’ Sticks test score, and female ratio reflecting the usual pattern in PD (roughly
constipation according to Rome IV criteria. The term 2/3 ratio) and were quite representative of the PD pop-
patient time represents the residual error term with ulation in this stage of the disorder. Comorbidities and
dependent errors because the repeated measurements prescribed non-dopaminergic medication is listed for
are taken in the same individual, causing possible cor- every participant in Supplementary Table S1.
relations among observations. Several covariance At the 12-month mark, the primary outcome mea-
models were fitted to the data to account for the corre- sure, namely the MDS-UPDRS motor scores in an off-
lation present in the data. The power (city-block metric) medication state, showed improvement in the healthy
correlation model was selected as best fitted model donor FMT group with a decrease of 5.8 points (95%
based on the Akaike’s information criterion coefficient. CI −11.4 to −0.2) compared to 2.7 points (−8.3 to 2.9) in
Additional options selected to get a best fitting model the placebo group (Table 2; Fig. 2). The change in MDS-
included a common correlation between any pair of UPDRS motor score from baseline to 12 months post-
measurement points, done through the random term FMT was significantly different between treatment
patient in the model, and allowance of unequal vari- groups (p = 0.0235; Table 2; Fig. 2), with the most
ances across time (heteroscedasticity). The significance important between-group deviation in the 6-to-12-
of the fixed terms in the model and significance of months interval. The placebo FMT group experienced
changes in difference between healthy donor FMT and an increase in the number of radiopaque pellets by 6.9

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289 patients assessed

for eligibility

242 screening failure

143 ineligible
91 refused inclusion
47 enrolled 8 withdrew consent

1 technical failure of transplantation

22 randomly assigned to 24 randomly assigned to

donor stool own stool (placebo)

1 discontinued follow-up 2 discontinued follow-up

1 missed final visit because 1 refused post-treatment
of choice to undergo deep study visits
brain stimulation 1 missed final visit because
of choice to undergo deep
brain stimulation

21 completed all 22 completed all

study visits study visits

22 included in 24 included in
intention-to-treat intention-to-treat
analysis analysis

Fig. 1: Trial profile.

Donor FMT Placebo FMT

(n = 22) (n = 24)
Sex
Men 15 (68.2%) 14 (58.3%)
Women 7 (31.8%) 10 (41.7%)
Age (years) 61 (1.1) 60.5 (0.7)
Duration since Parkinson’s disease diagnosis (years) 4.2 (0.7) 4.4 (0.7)
MDS-UPDRS part 3 off medication 40.3 (2.7) 37.1 (2.5)
Hoehn and Yahr stage 2 off medication 22 (100%) 24 (100%)
Levodopa-equivalent daily dose (mg) 383 (53) 431 (51)
Body mass index (kg/m3) 24.6 (0.8) 24.3 (0.8)
MoCA score 27.6 (0.3) 28.2 (0.3)
Constipation
Constipation (ROME-IV criteria) 14 (63.3%) 15 (62.5%)
Number of radiopaque pellets on day 7 20.6 (2.0) 18.6 (2.1)
Bristol stool chart score 3.4 (1.1) 3.0 (0.9)
16-item sniffing sticks identification test 7.9 (0.6) 7.1 (0.5)
RBDSQ >5 points 6 (27.3%) 5 (20.8%)
Orthostatic hypotension 9 (40.9%) 7 (29.2%)
Data are n (%) or mean (SEM). MDS-UPDRS, Movement Disorders Society Unified Parkinson’s Disease Rating Scale. MoCA, Montreal Cognitive Assessment. RBDSQ, REM
Sleep Behavior Disorder Screening Questionnaire.

Table 1: Patient characteristics at baseline.

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Baseline 3 months 6 months 12 months Change p value

(0–12 months)
MDS-UPDRS part 3 (off-medication)
Donor FMT 40.3 (2.7) 38.3 (2.7) 38.8 (2.6) 34.6 (3.0) −5.8 (2.0) 0.0235
Placebo FMT 37.1 (2.5) 32.6 (2.6) 31.5 (2.5) 34.5 (2.9) −2.7 (1.9)
MDS-UPDRS part 1
Donor FMT 11.0 (1.3) 11.1 (1.4) 10.6 (1.4) 11.0 (1.3) 0.1 (0.9) 0.7875
Placebo FMT 10.6 (1.3) 9.9 (1.4) 8.4 (1.4) 9.3 (1.2) −1.3 (0.9)
MDS-UPDRS part 2
Donor FMT 10.7 (1.3) 11.2 (1.3) 12.0 (1.4) 12.1 (1.3) 1.4 (0.8) 0.7059
Placebo FMT 8.0 (1.2) 8.3 (1.3) 8.8 (1.3) 8.5 (1.3) 0.6 (0.8)
MDS-UPDRS part 4
Donor FMT 2.2 (0.6) 2.3 (0.5) 2.1 (0.6) 2.4 (0.6) 0.2 (0.4) 0.6308
Placebo FMT 2.6 (0.5) 2.5 (0.5) 2.8 (0.6) 2.5 (0.6) −0.1 (0.4)
MDS-UPDRS total
Donor FMT 63.9 (4.2) 62.7 (4.3) 62.7 (4.4) 60.1 (4.6) −3.7 (2.8) 0.2884
Placebo FMT 58.2 (4.0) 53.3 (4.1) 51.2 (4.2) 54.9 (4.5) −3.3 (2.8)

Data are mean (SEM). MDS-UPDRS, Movement Disorders Society Unified Parkinson’s Disease Rating Scale. Significant differences (p < 0.05) are indicated in bold.

Table 2: MDS-UPDRS scores between baseline and 12 months.

pellets (2.0–11.8) corresponding to an increased colon Wexner Constipation Scale, Geriatric Depression Scale,
transit time, whereas the active treatment group had a Parkinson Anxiety Scale, Lille Apathy Rating Scale,
small decrease of 1.2 pellets (−6.1 to 3.7) (p = 0.0252; Parkinson’s Disease Sleep Scale, and Montreal Cogni-
Table 3; Fig. 3). Additionally, the healthy donor FMT tive Assessment (Table 3).
group demonstrated worse performance on the Par- No severe adverse events associated with treatment
kinson’s Fatigue Scale (p = 0.0418; Table 3). There were were observed during the study. Mild transient gastro-
no significant differences between the treatment groups intestinal adverse events, such as abdominal cramps and
in other scores of the MDS-UPDRS (part 1, part 2, part nausea, were reported in the first week after treatment
4, and part 1–4 total score; Table 2), the LEDD, the Non- in 13 (59%) patients in the healthy donor FMT group
Motor Symptoms Scale for Parkinson’s Disease, the and 6 (25%) patients in the placebo FMT group.
Parkinson’s Disease Quality of Life Questionnaire, Non-treatment-related hospital admissions occurred in

A 45
Placebo Healthy donor
B 1
Change in MDS-UPDRS part 3 score

40
MDS-UPDRS part 3 score

35

-5
30

25

0 -10
0 3 6 12 0 3 6 12
Months Months

Fig. 2: MDS-UPDRS part 3 motor scores (A) and changes in MDS-UPDRS part 3 motor scores (B), by study visit. Data are means for the
off-medication state. Error bars represent standard error of the mean. MDS-UPDRS, Movement Disorders Society Unified Parkinson’s
Disease Rating Scale.

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Baseline 3 months 6 months 12 months p value

Radiopaque pellets test (number of radiopaque pellets on day 7)
Donor FMT 20.6 (2.0) 22.1 (2.1) 19.2 (2.1) 19.4 (2.1) 0.0252
Placebo FMT 18.6 (2.1) 19.4 (2.1) 23.7 (2.1) 25.5 (2.2)
Levodopa-equivalent daily dose (mg)
Donor FMT 383.0 (53.3) 398.8 (57.2) 399.5 (57.0) 429.1 (59.0) 0.8350
Placebo FMT 431.1 (50.8) 429.7 (54.7) 442.1 (54.5) 455.9 (56.5)
Non-Motor Symptoms Scale for Parkinson’s Disease (NMSS)
Donor FMT 45.8 (9.1) 50.1 (8.9) 48.2 (8.6) 54.7 (8.3) 0.1443
Placebo FMT 44.4 (8.6) 31.6 (8.5) 35.9 (8.3) 33.4 (8.0)
Parkinson’s Disease Quality of Life Questionnaire (PDQ-39)
Donor FMT 34.4 (4.7) 32.8 (4.5) 35.4 (4.8) 36.5 (4.6) 0.5439
Placebo FMT 26.2 (4.4) 24.3 (4.3) 26.8 (4.6) 25.0 (4.5)
Wexner Constipation Scale
Donor FMT 6.7 (1.3) 6.8 (1.0) 6.7 (1.0) 6.7 (1.1) 0.7696
Placebo FMT 5.8 (1.2) 5.5 (1.0) 4.7 (1.0) 5.1 (1.0)
Geriatric Depression Scale (GDS)
Donor FMT 17.5 (0.7) 17.2 (0.6) 17.4 (0.6) 16.8 (0.6) 0.1674
Placebo FMT 17.3 (0.6) 17.3 (0.6) 17.7 (0.5) 18.3 (0.6)
Parkinson Anxiety Scale (PAS)
Donor FMT 8.7 (1.8) 9.7 (1.7) 8.1 (1.7) 9.6 (1.7) 0.1519
Placebo FMT 8.8 (1.7) 8.0 (1.6) 8.2 (1.6) 8.2 (1.6)
Lille Apathy Rating Scale (LARS)
Donor FMT −19.4 (1.5) −19.8 (1.6) −19.0 (1.5) −19.3 (1.4) 0.4253
Placebo FMT −20.7 (1.4) −21.2 (1.5) −21.9 (1.5) −22.4 (1.3)
Parkinson’s Disease Sleep Scale (PDSS)
Donor FMT 101.1 (5.7) 104.5 (5.5) 101.3 (5.4) 102.7 (5.3) 0.7290
Placebo FMT 109.7 (5.4) 109.7 (5.3) 108.8 (5.3) 110.5 (5.1)
Parkinson’s Fatigue Scale (PFS)
Donor FMT 37.3 (3.2) 39.6 (2.9) 40.0 (3.1) 43.4 (3.2) 0.0418
Placebo FMT 34.7 (3.0) 35.7 (2.8) 34.7 (3.0) 33.4 (3.2)
Montreal Cognitive Assessment (MoCA)
Donor FMT 27.6 (0.3) – 28.4 (0.3) 28.2 (0.2) 0.4828
Placebo FMT 28.2 (0.3) – 28.7 (0.3) 28.9 (0.2)

Data are mean (SEM). MDS-UPDRS, Movement Disorders Society Unified Parkinson’s Disease Rating Scale. Significant differences (p < 0.05) are indicated in bold.

Table 3: Secondary outcomes between baseline and 12 months.

three healthy donor FMT patients, including recurring compared to 2.7 points (−8.3 to 2.9) after placebo FMT
paroxysmal atrial fibrillation, lower back pain, and an with autologous stool. Of note, this difference is
accidental fall resulting in a humerus fracture. One considered clinically meaningful for patients with PD,
placebo FMT patient had a hospital admission for elec- as a within-group change of 3.25 indicates relevant
tive knee surgery. improvement.24
Non-motor symptoms were assessed through ques-
tionnaires, except for the more objective testing of
Discussion constipation through the radiopaque pellets test. Treat-
This study represents the first randomised, double- ment group differences in the radiopaque pellets test
blind, placebo-controlled clinical trial demonstrating were noticeable as early as 3–6 months after FMT, while
the improvement of motor symptoms in patients with the greatest improvement in motor symptoms (MDS-
mild to moderate PD through FMT via nasojejunal UPDRS part 3 in off-medication state) was observed in
administration. the 6-to-12-months interval, suggesting a primary
In GUT-PARFECT, a significant improvement of 5.8 beneficial effect of FMT at the gastrointestinal level,
points (95% CI −11.4 to −0.2) on the MDS-UPDRS before neurological effects become apparent. No sig-
motor score in an off-medication state was observed nificant differences were observed between the treat-
twelve months following FMT with healthy donor stool ment groups for LEDD and MDS-UPDRS parts 1, 2, 4,

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A B
30 10
Placebo Healthy donor

Change in number of radiopaque pellets

Number of radiopaque pellets

25
5

20

15

0 -5
0 3 6 12 0 3 6 12
Months Months

C 3.5 D 1.0
Change in colon transit time (days)
Colon transit time (days)

3.0
0.5

2.5

0
2.0

0 -0.5
0 3 6 12 0 3 6 12
Months Months

Fig. 3: Number of radiopaque pellets on day 7 (A) and changes in number of radiopaque pellets (B), by study visit. Higher number of
radiopaque pellets correlates to slower colon transit as a marker for constipation (C, D). Data are means. Error bars represent standard
error of the mean.

and total score, as well as for the other questionnaires, from the patients’ perspective. This could explain why
except for the Parkinson’s Fatigue Scale where patients there is no significant difference in the patient-reported
in the healthy donor group performed slightly worse. scores on the Wexner Constipation Scale.
The positive effect that we report on constipation has FMT was well-tolerated and safe, consistent with its
also been reported in clinical trials investigating FMT established use as a treatment for recurrent C. difficile
for idiopathic slow transit constipation, as well as in the infection. Mild gastrointestinal symptoms were more
open-label studies of FMT in PD16–19 and in probiotic frequently observed in the healthy donor FMT group,
trials in PD.25 The results of the radiopaque pellets test but these were transient and resolved within one week
indicate a slower progression of constipation in the after the intervention. We observed no severe adverse
treated group compared to the placebo group, with the events associated to FMT. A systematic review exam-
latter exhibiting an increase in colon transit time of ining potential adverse events associated with FMT over
more than 12 h. The observed difference, although the last 20 years revealed that serious adverse events,
statistically significant, might still be too minimal after such as infections and deaths, were observed in 1.4% of
one year to result in a noticeable clinical improvement FMT procedures.26 However, it is important to note that

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all these reported severe adverse events were only nerve, as supported by potential protective effects of
observed in patients with mucosal barrier injury. Con- vagotomy.8 The colon is only innervated by the vagal
cerning long-term safety data (>1 year post-FMT), FMT nerve for two-thirds of its length, making colonic FMT
does not appear to be linked to specific safety issues or administration less suitable.30 Furthermore, colonic
adverse events.26 FMT is less likely to alter gut microbiota composition in
An important unresolved issue of this study is the the small intestine compared to nasojejunal FMT. A
large and relatively long-lasting response in the placebo disadvantage of nasojejunal administration is that it is
FMT group. Indeed, up to 6 months after FMT, the technically challenging which might lead to failure or
response in the placebo group was not significantly intolerability of the procedure, as was the case in one of
different from that in the group receiving healthy donor our study candidates.
FMT. Only after 12 months a significant difference in Our study also has several limitations. Based on the
the evolution of MDS-UPRDS motor score could be brain-first versus body-first hypothesis, certain PD
demonstrated. While we can only speculate, it’s plau- phenotypes may be more likely to benefit from FMT. In
sible to hypothesize that the clinical differences light of this, inclusion criteria could have been adapted
observed might be aligned with the effects on gut to increase likelihood of including patients with the
motility, as evidenced by the radiopaque pellet test re- body-first hypothesis. This group of patients would be
sults at the 6-month evaluation. Another critical aspect expected to have a higher prevalence of prodromal
to consider is the recent findings indicating significant autonomic symptoms such as constipation and ortho-
alterations in the gut microbiome following autologous static hypotension, as well as REM-sleep behaviour
FMT.27 These findings could play a crucial role in future disorder. Pre-screening could also entail objective
evaluations of placebo-controlled FMT studies, high- transit time testing (such as the radiopaque pellets tests)
lighting the potential impact of microbiome changes on and MIBG scintigraphies.10 The fact that we only chose
clinical outcomes. Finally, it remains to be recognized to perform a single FMT could also be considered a
that studies of this kind dramatically raise expectations limitation of the study. The debate continues regarding
among participants, potentially leading to a considerable whether multiple consecutive FMTs produce superior
placebo response. results in altering the gut microbiome compared to a
The study’s strengths include its randomised single FMT. At present, there is insufficient evidence to
placebo-controlled design and single-centre setting with support the higher cost and burden of multiple FMTs
one designated clinical investigator, which prevented over a single FMT.21 In addition, only a limited number
both inter-site and inter-investigator variability in data of studies have investigated the gut microbiome one
collection, potentially facilitating the detection of sig- year after FMT, however these studies still indicate
nificant effects, and possibly also limiting the drop-out similarity to the healthy donor’s composition, thus
rate. Previous literature has quantified the intra-rater indicating a repeat FMT was not necessary within a
and inter-rater variability of the (MDS-)UPDRS, with year.31 Finally, our sample size was small, nonetheless
inter-rater variability showing good but not excellent still sufficient to show a significant difference in the
Intraclass Correlation Coefficient (ICC) scores between primary outcome. One specific remark at this point is
0.65 and 0.91. Intra-rater variability shows excellent that the number of included patients was slightly below
reliability with ICCs between 0.90 and 0.91.28 Changes that calculated in the power analysis (43 versus 46). A
in medication were left to the treating neurologist’s simulation study based on the current data indicated a
discretion, ensuring the FMT intervention did not power of 74%, which is a strong indicator of a signifi-
interfere with the routine clinical follow-up. During the cant effect. In contrast with motor symptoms, the
trial there were no significant differences between analysis non-motor symptoms might be more affected
treatment groups for medication changes as exemplified by this small sample size.
by the LEDD. The FMT solutions utilized 17 different As this study represents the first randomised,
healthy donors due to the absence of defined criteria for double-blind, placebo-controlled trial of FMT in PD, it is
selecting suitable healthy donors for PD, while this is crucial to independently reproduce these results. Ideally,
somewhat clearer for other indications such as inflam- a multicentre study with a larger sample size and the
matory bowel diseases.29 The inclusion of a diverse same primary outcome, e.g. MDS-UPDRS motor score,
range of healthy donors aimed to avoid ambiguous should be initiated. The pronounced difference in MDS-
results due to selecting an ‘inadequate donor’. In GUT- UPDRS motor score between treatment groups starting
PARFECT, we chose to perform FMT through nasoje- from the 6 to 12 months timepoint and not earlier
junal administration. While both nasojejunal and suggests a potential disease-modifying effect rather than
colonic FMT routes are equally effective for treating solely symptomatic improvement. This finding un-
C. difficile infections, different considerations are war- derscores the necessity for long-term follow-up for PD
ranted when trying to impact gut-brain communica- interventions to evaluate potential beneficial effects. The
tion.21 Indeed, nasojejunal administration might be need for a one-year follow-up to observe the full treat-
preferred for PD due to the significant role for the vagal ment difference between placebo and treatment groups

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in Parkinson’s disease was explicitly shown in a recent consulting and/or speaking fees from Aphea, Biofortis, DSM, Ferring,
meta-analysis.32 However, clinical trials with a longer GSK, Janssen Pharmaceuticals, Metagenics, MSD, MRM/Prodigest,
Nutricia, Sanofi, Takeda, Tsumura.
duration also entail increased patient burden and higher
RV has received grants from MRM Health, Prodigest, CellCarta,
costs. The same holds true for the inclusion of neuro- Evox Therapeutics and Sanofi.
imaging outcome parameters such as DaT-SPECT or All other authors declare no competing interests.
F-DOPA PET, which could yield additional measures of
longitudinal evolution, although the correlation between Acknowledgements
We thank the patients and their families who participated in the trial.
imaging parameters and clinical findings is not always This study was funded by general funds of the research groups of RV
straightforward. and BV, support from the Flemish PD patient organizations (VPL and
If the benefits of FMT are confirmed, further in- Parkili) and a grant from the Biocodex Microbiota Foundation (2019
vestigations are warranted to elucidate the precise National Research Grant). AB and CV were supported by the Research
Foundation Flanders (FWO) (1S47418N & 1295223N). BV was sup-
mechanisms through which the microbiota exert their
ported by the Research Foundation Flanders (FWO) (T000819N). BV
effects. A crucial next step is the sequential analysis of and HH were supported by the Fonds voor Innovatie en Klinisch
the microbiome before and after the FMT, which will Onderzoek UZ Gent. We thank Hilde Devlies and Jonas Castelein for
allow an evaluation of the extent and duration of alter- technical lab support. We thank the nursing staff from the Gastroen-
ations and eventually of the correlations with clinical terology department of University Hospital Ghent for their excellent
care during colonoscopy and FMT procedures.
outcomes. As mentioned above this analysis will also
explore the effects of autologous FMT as a potential Appendix A. Supplementary data
explanation of the placebo response in this study. Supplementary data related to this article can be found at https://doi.
Another future aim is the development of less invasive org/10.1016/j.eclinm.2024.102563.
microbiome-altering therapies such as increasing the
abundance of beneficial microbiota by supplementing
live organisms directly (i.e., probiotics), dietary in- References
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JR has received grants from Beneo, Cargill, Colruyt group, Danone, transplantation in Parkinson’s disease patients with constipation.
DSM, J&J, MRM/Prodigest, Nestle, Pfizer, and Takeda; and has received Microb Cell Fact. 2021;20(1):e98.

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