Parkinson's Disease Medication Alters Small Intestinal Motility and Microbiota Composition in Healthy Rats

From BugSigDB
Reviewed Marked as Reviewed by Svetlana up on 2024-7-15
study design
Citation
PMID PubMed identifier for scientific articles.
DOI Digital object identifier for electronic documents.
URI
Authors
van Kessel SP, Bullock A, van Dijk G, El Aidy S
Journal
mSystems
Year
2022
Keywords:
Parkinson’s disease treatment, dopamine, drug side effects, gut motility, levodopa, microbiota, pramipexole, ropinirole, small intestinal bacterial overgrowth
Parkinson's disease (PD) is known to be associated with altered gastrointestinal function and microbiota composition. To date, the effect of PD medication on the gastrointestinal function and microbiota, at the site of drug absorption, the small intestine, has not been studied, although it may represent an important confounder in reported microbiota alterations observed in PD patients. To this end, healthy (non-PD) wild-type Groningen rats were employed and treated with dopamine, pramipexole (in combination with levodopa-carbidopa), or ropinirole (in combination with levodopa-carbidopa) for 14 sequential days. Rats treated with dopamine agonists showed a significant reduction in small intestinal motility and an increase in bacterial overgrowth in the distal small intestine. Notably, significant alterations in microbial taxa were observed between the treated and vehicle groups; analogous to the changes previously reported in human PD versus healthy control microbiota studies. These microbial changes included an increase in Lactobacillus and Bifidobacterium and a decrease in Lachnospiraceae and Prevotellaceae. Markedly, certain Lactobacillus species correlated negatively with levodopa levels in the systemic circulation, potentially affecting the bioavailability of levodopa. Overall, the study highlights a significant effect of PD medication intrinsically on disease-associated comorbidities, including gastrointestinal dysfunction and small intestinal bacterial overgrowth, as well as the gut microbiota composition. The results urge future studies to take into account the influence of PD medication per se when seeking to identify microbiota-related biomarkers for PD. IMPORTANCE Parkinson's disease (PD) is the second most common neurodegenerative disorder and is known to be associated with altered gastrointestinal function and microbiota composition. We previously showed that the gut bacteria harboring tyrosine decarboxylase enzymes interfere with levodopa, the main treatment for PD (S. P. van Kessel, A. K. Frye, A. O. El-Gendy, M. Castejon, A. Keshavarzian, G. van Dijk, and S. El Aidy, Nat Commun 10:310, 2019). Although PD medication could be an important confounder in the reported alterations, its effect, apart from the disease itself, on the microbiota composition or the gastrointestinal function at the site of drug absorption, the small intestine, has not been studied. The findings presented here show a significant impact of commonly prescribed PD medication on the small intestinal motility, small intestinal bacterial overgrowth, and microbiota composition, irrespective of the PD. Remarkably, we observed negative associations between bacterial species harboring tyrosine decarboxylase activity and levodopa levels in the systemic circulation, potentially affecting the bioavailability of levodopa. Overall, this study shows that PD medication is an important factor in determining gastrointestinal motility and, in turn, microbiota composition and may, partly, explain the differential abundant taxa previously reported in the cross-sectional PD microbiota human studies. The results urge future studies to take into account the influence of PD medication on gut motility and microbiota composition when seeking to identify microbiota-related biomarkers for PD.

Experiment 1


Reviewed Marked as Reviewed by Svetlana up on 2024-7-15

Curated date: 2024/03/08

Curator: Adeitan

Revision editor(s): Adeitan, Scholastica

Subjects

Location of subjects
Netherlands
Host species Species from which microbiome was sampled. Contact us to have more species added.
Rattus norvegicus
Body site Anatomical site where microbial samples were extracted from according to the Uber Anatomy Ontology
Jejunum Intestinum jejunum,Mid-intestine,Middle intestine,Jejunum,jejunum
Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology
Treatment Treatment,treatment
Group 0 name Corresponds to the control (unexposed) group for case-control studies
Vehicle group (VH)
Group 1 name Corresponds to the case (exposed) group for case-control studies
Dopamine treatment group (D)
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Jejunal samples from rats treated for 14 sequential days with dopamine (D)
Group 0 sample size Number of subjects in the control (unexposed) group
6
Group 1 sample size Number of subjects in the case (exposed) group
10
Antibiotics exclusion Number of days without antibiotics usage (if applicable) and other antibiotics-related criteria used to exclude participants (if any)
None

Lab analysis

Sequencing type
16S
16S variable region One or more hypervariable region(s) of the bacterial 16S gene
V3-V4
Sequencing platform Manufacturer and experimental platform used for quantifying microbial abundance
Illumina

Statistical Analysis

Data transformation Data transformation applied to microbial abundance measurements prior to differential abundance testing (if any).
relative abundances
Statistical test
LEfSe
Significance threshold p-value or FDR threshold used for differential abundance testing (if any)
0.01
MHT correction Have statistical tests be corrected for multiple hypothesis testing (MHT)?
Yes
LDA Score above Threshold for the linear discriminant analysis (LDA) score for studies using the popular LEfSe tool
2

Alpha Diversity

Chao1 Abundance-based estimator of species richness
unchanged

Signature 1

Reviewed Marked as Reviewed by Svetlana up on 2024-7-15

Curated date: 2024/03/09

Curator: Adeitan

Revision editor(s): Adeitan, Scholastica

Source: Supplementary Table S1

Description: Differential abundance analysis performed with LDA effect size (LEfSe) showing only significant taxa in the vehicle group (VH) versus dopamine treatment group (D)

Abundance in Group 1: increased abundance in Dopamine treatment group (D)

NCBI Quality ControlLinks
Enterococcus
Pantoea agglomerans

Revision editor(s): Adeitan, Scholastica

Signature 2

Reviewed Marked as Reviewed by Svetlana up on 2024-7-15

Curated date: 2024/03/09

Curator: Adeitan

Revision editor(s): Adeitan, Welile, Scholastica

Source: Supplementary Table S1

Description: Differential abundance analysis performed with LDA effect size (LEfSe) showing only significant taxa in the vehicle group (VH) versus dopamine treatment group (D)

Abundance in Group 1: decreased abundance in Dopamine treatment group (D)

NCBI Quality ControlLinks
Blautia
Erysipelotrichaceae
Helicobacter
Helicobacter cholecystus
Ileibacterium
Lachnospiraceae
Lachnospiraceae bacterium NK4A136
Muribaculaceae
Phocaeicola vulgatus
Prevotellaceae
uncultured Bacteroidales bacterium
uncultured Coriobacteriales bacterium
Prevotellaceae UCG-001Prevotellaceae UCG-001

Revision editor(s): Adeitan, Welile, Scholastica

Experiment 2


Reviewed Marked as Reviewed by Svetlana up on 2024-7-15

Curated date: 2024/04/07

Curator: Scholastica

Revision editor(s): Scholastica

Differences from previous experiment shown

Subjects

Group 1 name Corresponds to the case (exposed) group for case-control studies
Pramipexole treatment group (P)
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Jejunal samples from rats treated for 14 sequential days with pramipexole (P, in combination with levodopa-carbidopa)

Lab analysis

Statistical Analysis

Alpha Diversity

Chao1 Abundance-based estimator of species richness
increased

Signature 1

Reviewed Marked as Reviewed by Svetlana up on 2024-7-15

Curated date: 2024/04/07

Curator: Scholastica

Revision editor(s): Scholastica

Source: Supplementary Table S1

Description: Differential abundance analysis performed with LDA effect size (LEfSe) showing only significant taxa in the vehicle group (VH) versus pramipexole (P, in combination with levodopa-carbidopa) treatment group

Abundance in Group 1: increased abundance in Pramipexole treatment group (P)

NCBI Quality ControlLinks
Bradyrhizobium elkanii
Ectobacillus funiculus
Intrasporangium
Lysinibacillus
Microbacterium
Micrococcaceae
Mycobacterium
Neobacillus drentensis
Pantoea agglomerans
Priestia aryabhattai
Pseudoduganella
Rummeliibacillus
Solirubrobacter
Streptomyces
Tumebacillus
uncultured Alphaproteobacteria bacterium
uncultured Frankiales bacterium

Revision editor(s): Scholastica

Signature 2

Reviewed Marked as Reviewed by Svetlana up on 2024-7-15

Curated date: 2024/04/08

Curator: Scholastica

Revision editor(s): Scholastica

Source: Supplementary Table S1

Description: Differential abundance analysis performed with LDA effect size (LEfSe) showing only significant taxa in the vehicle group (VH) versus pramipexole (P, in combination with levodopa-carbidopa) treatment group

Abundance in Group 1: decreased abundance in Pramipexole treatment group (P)

NCBI Quality ControlLinks
Alistipes
Alloprevotella
Dielma
Erysipelotrichaceae
Helicobacter
Helicobacter cholecystus
Lachnospiraceae
Lachnospiraceae bacterium NK4A136
Lactobacillales
Muribaculaceae
Phocaeicola vulgatus
Prevotellaceae
Romboutsia
Sphingomonas paucimobilis
Turicibacter sp. LA61
gut metagenome
uncultured Bacteroidales bacterium
uncultured Desulfovibrionaceae bacterium
uncultured Lachnospiraceae bacterium
uncultured Oscillospiraceae bacterium
uncultured Rhizobiaceae bacterium
Prevotellaceae UCG-001Prevotellaceae UCG-001
DNF00809DNF00809
Lachnospiraceae UCG-006Lachnospiraceae UCG-006

Revision editor(s): Scholastica

Experiment 3


Reviewed Marked as Reviewed by Svetlana up on 2024-7-15

Curated date: 2024/04/07

Curator: Scholastica

Revision editor(s): Scholastica

Differences from previous experiment shown

Subjects

Group 1 name Corresponds to the case (exposed) group for case-control studies
Ropinirole treatment group (R)
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Jejunal samples from rats treated for 14 sequential days with ropinirole (R, in combination with levodopa-carbidopa)

Lab analysis

Statistical Analysis

Alpha Diversity

Chao1 Abundance-based estimator of species richness
increased

Signature 1

Reviewed Marked as Reviewed by Svetlana up on 2024-7-15

Curated date: 2024/04/08

Curator: Scholastica

Revision editor(s): Scholastica

Source: Supplementary Table S1

Description: Differential abundance analysis performed with LDA effect size (LEfSe) showing only significant taxa in the vehicle group (VH) versus ropinirole (R, in combination with levodopa-carbidopa) treatment group

Abundance in Group 1: decreased abundance in Ropinirole treatment group (R)

NCBI Quality ControlLinks
Alistipes
Bacteroides acidifaciens
Enterorhabdus
Erysipelotrichaceae
Helicobacter
Muribaculaceae
Phocaeicola vulgatus
uncultured Bacteroidales bacterium
uncultured Erysipelotrichaceae bacterium
Lachnospiraceae UCG-006Lachnospiraceae UCG-006

Revision editor(s): Scholastica

Experiment 4


Reviewed Marked as Reviewed by Svetlana up on 2024-7-15

Curated date: 2024/04/07

Curator: Scholastica

Revision editor(s): Scholastica

Differences from previous experiment shown

Subjects

Body site Anatomical site where microbial samples were extracted from according to the Uber Anatomy Ontology
Ileum Distal intestine,Intestinum ileum,Lower intestine,Posterior intestine,Ileum,ileum
Group 1 name Corresponds to the case (exposed) group for case-control studies
Dopamine treatment group (D)
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Ileal samples from rats treated for 14 sequential days with dopamine (D)

Lab analysis

Statistical Analysis

Alpha Diversity

Chao1 Abundance-based estimator of species richness
unchanged

Signature 1

Reviewed Marked as Reviewed by Svetlana up on 2024-7-15

Curated date: 2024/04/08

Curator: Scholastica

Revision editor(s): Scholastica

Source: Supplementary Table S1

Description: Differential abundance analysis performed with LDA effect size (LEfSe) showing only significant taxa in the vehicle group (VH) versus dopamine treatment group (D)

Abundance in Group 1: increased abundance in Dopamine treatment group (D)

NCBI Quality ControlLinks
Allobaculum
Firmicutes bacterium CAG_194_44_15
Lachnospiraceae
Lachnospiraceae bacterium NK4A136
Lactobacillus
Oscillibacter
Oscillospiraceae
uncultured prokaryote

Revision editor(s): Scholastica

Signature 2

Reviewed Marked as Reviewed by Svetlana up on 2024-7-15

Curated date: 2024/04/08

Curator: Scholastica

Revision editor(s): Scholastica

Source: Supplementary Table S1

Description: Differential abundance analysis performed with LDA effect size (LEfSe) showing only significant taxa in the vehicle group (VH) versus dopamine treatment group (D)

Abundance in Group 1: decreased abundance in Dopamine treatment group (D)

NCBI Quality ControlLinks
Acetitomaculum
Akkermansia
Alistipes
Bacteroides
Desulfovibrio
Dubosiella newyorkensis
Enterorhabdus
Lachnospiraceae
Lachnospiraceae bacterium 615
Lachnospiraceae bacterium A2
Lachnospiraceae bacterium MD335
Lachnospiraceae bacterium NK4A136
Muribaculaceae
Muribaculum
Oscillibacter
Parasutterella
Phocaeicola sartorii dnLKV3
Rikenellaceae
Roseburia
uncultured Bacteroidales bacterium
uncultured Desulfovibrionales bacterium
uncultured Lachnospiraceae bacterium
uncultured Oscillospiraceae bacterium
Prevotellaceae UCG-001Prevotellaceae UCG-001
Ruminococcaceae UCG-013Ruminococcaceae UCG-013
Ruminiclostridium_9Ruminiclostridium_9
Ruminiclostridium_5Ruminiclostridium_5
Clostridiales vadinBB60_groupClostridiales vadinBB60_group

Revision editor(s): Scholastica

Experiment 5


Reviewed Marked as Reviewed by Svetlana up on 2024-7-15

Curated date: 2024/04/07

Curator: Scholastica

Revision editor(s): Scholastica

Differences from previous experiment shown

Subjects

Group 1 name Corresponds to the case (exposed) group for case-control studies
Pramipexole treatment group (P)
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Ileal samples from rats treated for 14 sequential days with pramipexole (P, in combination with levodopa-carbidopa)

Lab analysis

Statistical Analysis

Alpha Diversity

Chao1 Abundance-based estimator of species richness
unchanged

Signature 1

Reviewed Marked as Reviewed by Svetlana up on 2024-7-15

Curated date: 2024/04/09

Curator: Scholastica

Revision editor(s): Scholastica

Source: Supplementary Table S1

Description: Differential abundance analysis performed with LDA effect size (LEfSe) showing only significant taxa in the vehicle group (VH) versus pramipexole (P, in combination with levodopa-carbidopa) treatment group

Abundance in Group 1: increased abundance in Pramipexole treatment group (P)

NCBI Quality ControlLinks
Allobaculum
Bifidobacterium
Firmicutes bacterium CAG_194_44_15
Ileibacterium
Lachnospiraceae
Lactobacillus
Oscillibacter
Ruminococcaceae bacterium UCG-005
Tyzzerella
gut metagenome
uncultured Desulfovibrionaceae bacterium
Coriobacteriaceae UCG-002Coriobacteriaceae UCG-002

Revision editor(s): Scholastica

Signature 2

Reviewed Marked as Reviewed by Svetlana up on 2024-7-15

Curated date: 2024/04/09

Curator: Scholastica

Revision editor(s): Scholastica

Source: Supplementary Table S1

Description: Differential abundance analysis performed with LDA effect size (LEfSe) showing only significant taxa in the vehicle group (VH) versus pramipexole (P, in combination with levodopa-carbidopa) treatment group

Abundance in Group 1: decreased abundance in Pramipexole treatment group (P)

NCBI Quality ControlLinks
Acetitomaculum
Akkermansia
Alistipes
Cardiobacterium sp. canine oral taxon 238
Desulfovibrio
Dubosiella newyorkensis
Enterorhabdus
Lachnospiraceae
Lachnospiraceae bacterium 615
Lachnospiraceae bacterium A2
Lachnospiraceae bacterium MD335
Lachnospiraceae bacterium NK4A136
Muribaculaceae
Oscillibacter
Parasutterella
Phocaeicola sartorii dnLKV3
Rikenella
Rikenellaceae
uncultured Bacteroidales bacterium
uncultured Desulfovibrionales bacterium
uncultured Lachnospiraceae bacterium
uncultured Peptococcaceae bacterium
Prevotellaceae UCG-001Prevotellaceae UCG-001
Lachnospiraceae UCG-006Lachnospiraceae UCG-006
GCA-900066575GCA-900066575
Ruminococcaceae UCG-014Ruminococcaceae UCG-014
Ruminococcaceae UCG-013Ruminococcaceae UCG-013
Ruminiclostridium_5Ruminiclostridium_5
Clostridiales vadinBB60_groupClostridiales vadinBB60_group

Revision editor(s): Scholastica

Experiment 6


Reviewed Marked as Reviewed by Svetlana up on 2024-7-15

Curated date: 2024/04/07

Curator: Scholastica

Revision editor(s): Scholastica

Differences from previous experiment shown

Subjects

Group 1 name Corresponds to the case (exposed) group for case-control studies
Ropinirole treatment group (R)
Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group
Ileal samples from rats treated for 14 sequential days with ropinirole (R, in combination with levodopa-carbidopa)

Lab analysis

Statistical Analysis

Alpha Diversity

Chao1 Abundance-based estimator of species richness
unchanged

Signature 1

Reviewed Marked as Reviewed by Svetlana up on 2024-7-15

Curated date: 2024/04/08

Curator: Scholastica

Revision editor(s): Scholastica

Source: Supplementary Table S1

Description: Differential abundance analysis performed with LDA effect size (LEfSe) showing only significant taxa in the vehicle group (VH) versus ropinirole (R, in combination with levodopa-carbidopa) treatment group

Abundance in Group 1: increased abundance in Ropinirole treatment group (R)

NCBI Quality ControlLinks
Allobaculum
Ileibacterium
Lactobacillus
uncultured Erysipelotrichia bacterium

Revision editor(s): Scholastica

Signature 2

Reviewed Marked as Reviewed by Svetlana up on 2024-7-15

Curated date: 2024/04/08

Curator: Scholastica

Revision editor(s): Scholastica

Source: Supplementary Table S1

Description: Differential abundance analysis performed with LDA effect size (LEfSe) showing only significant taxa in the vehicle group (VH) versus ropinirole (R, in combination with levodopa-carbidopa) treatment group

Abundance in Group 1: decreased abundance in Ropinirole treatment group (R)

NCBI Quality ControlLinks
Lachnospiraceae bacterium NK4A136
Muribaculaceae
Roseburia
uncultured Lachnospiraceae bacterium
Ruminiclostridium_5Ruminiclostridium_5

Revision editor(s): Scholastica