Impact of oral COMT-inhibitors on gut microbiota and short chain fatty acids in Parkinson's disease

Grúň, Daniel; Zimmer, Valerie C.; Kauffmann, J. M.; Spiegel, Jörg; Dillmann, Ulrich; Schwiertz, Andreas; Faßbender, Klaus; Fousse, Mathias; Unger, Marcus M.

doi:10.1016/j.parkreldis.2019.11.020

Cited by 15 publications

(11 citation statements)

References 6 publications

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“…In the latter experiments however, a trend ( p = 0.05) towards a positive association between COMT inhibitors and butyrate production was found. This is in contrast with findings of Unger et al (2016) 5 and a recent pilot study by Grün et al (2020), that found a negative association between entacapone, but not other COMT inhibitors, and Faecalibacterium prausnitzii (a butyrate-producer) and a trend towards reduced fecal butyrate 34 . It is not clear how COMT inhibitors are associated with SCFA production.…”

Section: Discussioncontrasting

confidence: 87%

Parkinson’s disease patients’ short chain fatty acids production capacity after in vitro fecal fiber fermentation

Baert

Matthys

Maselyne³

et al. 2021

npj Parkinsons Dis.

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Animal models indicate that butyrate might reduce motor symptoms in Parkinson’s disease. Some dietary fibers are butyrogenic, but in Parkinson’s disease patients their butyrate stimulating capacity is unknown. Therefore, we investigated different fiber supplements’ effects on short-chain fatty acid production, along with potential underlying mechanisms, in Parkinson’s patients and age-matched healthy controls. Finally, it was investigated if this butyrate production could be confirmed by using fiber-rich vegetables. Different fibers (n = 40) were evaluated by in vitro fermentation experiments with fecal samples of Parkinson’s patients (n = 24) and age-matched healthy volunteers (n = 39). Short-chain fatty acid production was analyzed by headspace solid-phase micro-extraction gas chromatography-mass spectrometry. Clostridium coccoides and C. leptum were quantified through 16S-rRNA gene-targeted group-specific qPCR. Factors influencing short-chain fatty acid production were investigated using linear mixed models. After fiber fermentation, butyrate concentration varied between 25.6 ± 16.5 µmol/g and 203.8 ± 91.9 µmol/g for Parkinson’s patients and between 52.7 ± 13.0 µmol/g and 229.5 ± 42.8 µmol/g for controls. Inulin had the largest effect, while xanthan gum had the lowest production. Similar to fiber supplements, inulin-rich vegetables, but also fungal β-glucans, stimulated butyrate production most of all vegetable fibers. Parkinson’s disease diagnosis limited short-chain fatty acid production and was negatively associated with butyrate producers. Butyrate kinetics during 48 h fermentation demonstrated a time lag effect in Parkinson’s patients, especially in fructo-oligosaccharide fermentation. Butyrate production can be stimulated in Parkinson’s patients, however, remains reduced compared to healthy controls. This is a first step in investigating dietary fiber’s potential to increase short-chain fatty acids in Parkinson’s disease.

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Section: Discussioncontrasting

confidence: 87%

Parkinson’s disease patients’ short chain fatty acids production capacity after in vitro fecal fiber fermentation

Baert

Matthys

Maselyne³

et al. 2021

npj Parkinsons Dis.

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“…At genus level, the relative abundance of Faecalibacterium decreased by 66.08% and Bifidobacterium doubled when comparing PD_LE to PD_L. These results corroborate with earlier reports ( Unger et al., 2016 ; Weis et al., 2019 ; Grün et al., 2020 ), suggesting that entacapone itself is able to redistribute bacterial community profile in PD patients. Studies done by real-time quantitative PCR showed that the abundance of Faecalibacterium prausnitzii significantly reduced in PD patients on entacapone when compared to controls or participants without COMT-inhibitors ( Unger et al., 2016 ; Grün et al., 2020 ).…”

Section: Discussionsupporting

confidence: 91%

“…Being a common medication used in combination with LD for the treatment of Parkinson’s disease, microbiologists have gained interests in the interactions between entacapone and gut microbiome, resulting in research that has been conducted in the related field ( Unger et al., 2016 ; Weis et al., 2019 ; Grün et al., 2020 ). Yet most of these in vivo studies overlooked the impact of LD on the microbial composition ( Weis et al., 2019 ; Cirstea et al., 2020 ), which led to findings that could possibly be associated with LD instead of entacapone.…”

Section: Discussionmentioning

confidence: 99%

A Pilot Study Exploring the Association of Entacapone, Gut Microbiota, and the Subsequent Side Effects in Patients With Parkinson’s Disease

Lee

Hsieh

et al. 2022

Front. Cell. Infect. Microbiol.

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Background and AimsEntacapone, one of the most common drugs distributed among patients with Parkinson’s disease, is a peripherally acting catechol-O-methyltransferase (COMT) inhibitor that is used in addition to levodopa to control symptoms. However, there have been negative effects reported against entacapone, namely, gastrointestinal (GI) problems and drowsiness. In this pilot study, we aim to examine the hypothesis that the discomfort induced by entacapone might be originated from the shift of microbial composition by adjusting the effect of levodopa.MethodsThe population in this pilot study consisted of 13 PD patients treated with levodopa only and 11 with both levodopa and entacapone. The 16S rRNA gene sequence data were processed, aligned, and categorized using the DADA2. Alpha diversity indices for Observed, Chao1, Shannon, and Simpson metrics were calculated with Phyloseq 1.32.0. Dissimilarities were calculated using unweighted unique fraction metrics (Unifrac), weighted Unifrac, and Canberra distance. Functional differences were calculated by PICRUSt2 based on the KEGG database.ResultsResults of 16S rRNA sequencing analysis showed that while entacapone did not influence the species richness, the composition of the microbial community shifted considerably. Relative abundances of bacteria related to constipation and other GI disorders also altered significantly. Functional enrichment analysis revealed changes in the metabolic activity of alanine, aspartate, and glutamate. These amino acids are related to common side effects of entacapone such as auditory hallucinations, fatigue, and nightmare.ConclusionOur findings provide testable hypothesis on the cause of unpleasant side effects of entacapone, which in the long run could possibly be reduced through gut microbiota manipulation.

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“…Therefore, a shift in the community of beneficial microbes decreases anti-inflammatory microbial mediators, thereby contributing to a persistent loss in gut barrier integrity and a constipation phenotype often noted in PD patients. Grun et al (2020) reported that commonly prescribed PD drugs such as COMT inhibitors can further lower the abundance of F. prausnitzii and SCFAs concentrations, thereby enhancing the drug's bioactivity and toxicity and further damaging the gut epithelial barrier leading to infiltration of other opportunistic pathogens (reviewed in Weersma et al, 2020).…”

Section: Chronic Gut-inflammation and Intestinal Barrier Dysfunction ...mentioning

confidence: 99%

Mechanistic Insights Into Gut Microbiome Dysbiosis-Mediated Neuroimmune Dysregulation and Protein Misfolding and Clearance in the Pathogenesis of Chronic Neurodegenerative Disorders

et al. 2022

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The human gut microbiota is a complex, dynamic, and highly diverse community of microorganisms. Beginning as early as in utero fetal development and continuing through birth to late-stage adulthood, the crosstalk between the gut microbiome and brain is essential for modulating various metabolic, neurodevelopmental, and immune-related pathways. Conversely, microbial dysbiosis – defined as alterations in richness and relative abundances – of the gut is implicated in the pathogenesis of several chronic neurological and neurodegenerative disorders. Evidence from large-population cohort studies suggests that individuals with neurodegenerative conditions have an altered gut microbial composition as well as microbial and serum metabolomic profiles distinct from those in the healthy population. Dysbiosis is also linked to psychiatric and gastrointestinal complications – comorbidities often associated with the prodromal phase of Parkinson’s disease (PD) and Alzheimer’s disease (AD). Studies have identified potential mediators that link gut dysbiosis and neurological disorders. Recent findings have also elucidated the potential mechanisms of disease pathology in the enteric nervous system prior to the onset of neurodegeneration. This review highlights the functional pathways and mechanisms, particularly gut microbe-induced chronic inflammation, protein misfolding, propagation of disease-specific pathology, defective protein clearance, and autoimmune dysregulation, linking gut microbial dysbiosis and neurodegeneration. In addition, we also discuss how pathogenic transformation of microbial composition leads to increased endotoxin production and fewer beneficial metabolites, both of which could trigger immune cell activation and enteric neuronal dysfunction. These can further disrupt intestinal barrier permeability, aggravate the systemic pro-inflammatory state, impair blood–brain barrier permeability and recruit immune mediators leading to neuroinflammation and neurodegeneration. Continued biomedical advances in understanding the microbiota-gut-brain axis will extend the frontier of neurodegenerative disorders and enable the utilization of novel diagnostic and therapeutic strategies to mitigate the pathological burden of these diseases.

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Impact of oral COMT-inhibitors on gut microbiota and short chain fatty acids in Parkinson's disease

Cited by 15 publications

References 6 publications

Parkinson’s disease patients’ short chain fatty acids production capacity after in vitro fecal fiber fermentation

Parkinson’s disease patients’ short chain fatty acids production capacity after in vitro fecal fiber fermentation

A Pilot Study Exploring the Association of Entacapone, Gut Microbiota, and the Subsequent Side Effects in Patients With Parkinson’s Disease

Mechanistic Insights Into Gut Microbiome Dysbiosis-Mediated Neuroimmune Dysregulation and Protein Misfolding and Clearance in the Pathogenesis of Chronic Neurodegenerative Disorders

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