Metabolomic Profiling of Bile Acids in an Experimental Model of Prodromal Parkinson’s Disease

Graham, Stewart F.; Rey, Nolwen L.; Ugur, Zafer; Yılmaz, Ali; Sherman, Eric; Maddens, Michael; Bahado‐Singh, Ray O.; Becker, Katelyn; Schulz, Emily; Meyerdirk, Lindsay; Steiner, Jennifer A.; Ma, Jiyan; Brundin, Patrik

doi:10.3390/metabo8040071

Cited by 42 publications

(32 citation statements)

References 43 publications

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“…Alterations in sulphur metabolism have been already described when using computational modelling of microbiomes from a cohort of early diagnosed and levodopa naive PD patients (Bedarf et al 2017; Hertel et al in revision) as well as an increased concentration of methionine and derived metabolites in blood samples (Hertel et al in revision). Furthermore, we and others have reported alterations in bile acids and taurine-conjugated bile acids in PD patients (Graham et al 2018; Hertel et al in revision). Our present study suggests again a key role of Bilophila in host-microbiome sulphur co-metabolism, which may link with bile acid metabolism.…”

Section: Discussionmentioning

confidence: 50%

Parkinson’s disease-associated alterations of the gut microbiome can invoke disease-relevant metabolic changes

Baldini

Hertel

Sandt

et al. 2019

Preprint

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25 26 Parkinson's disease (PD) is a systemic disease clinically defined by the degeneration of 27 dopaminergic neurons in the brain. While alterations in the gut microbiome composition have 28 been reported in PD, their functional consequences remain unclear. Herein, we first analysed 29 the gut microbiome of patients and healthy controls by 16S rRNA gene sequencing of stool 30 samples from the Luxembourg Parkinson's study (n=147 typical PD cases, n=162 controls). 31All individuals underwent detailed clinical assessment, including neurological examinations 32 and neuropsychological tests followed by self-reporting questionnaires. Second, we predicted 33 the potential secretion for 129 microbial metabolites through personalised metabolic modelling 34 using the microbiome data and genome-scale metabolic reconstructions of human gut 35 microbes. Our key results include: 1. eight genera and nine species changed significantly in 36 their relative abundances between PD patients and healthy controls. 2. PD-associated microbial 37 patterns statistically depended on sex, age, BMI, and constipation. The relative abundances of 38Bilophila and Paraprevotella were significantly associated with the Hoehn and Yahr staging 39 after controlling for the disease duration. In contrast, dopaminergic medication had no 40 detectable effect on the PD microbiome composition. 3. Personalised metabolic modelling of 41 the gut microbiomes revealed PD-associated metabolic patterns in secretion potential of nine 42 microbial metabolites in PD, including increased methionine and cysteinylglycine. The 43 microbial pantothenic acid production potential was linked to the presence of specific non-44 motor symptoms and attributed to individual bacteria, such as Akkermansia muciniphila and 45 Bilophila wardswarthia. Our results suggest that PD-associated alterations of gut microbiome 46 could translate into functional differences affecting host metabolism and disease phenotype. 47

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Section: Discussionmentioning

confidence: 50%

Parkinson’s disease-associated alterations of the gut microbiome can invoke disease-relevant metabolic changes

Baldini

Hertel

Sandt

et al. 2019

Preprint

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“…In humans, defective protein folding is thought to be connected with many neurodegenerative diseases [12,122]. In this respect, TUDCA not only has been shown to inhibit apoptosis induced by several stimuli in neuronal cells in vitro, but also to play a cytoprotective role in animal models of neurological disorders, such as Alzheimer's disease (AD) [6,35,[123][124][125], Parkinson's disease (PD) [3,6,[126][127][128][129][130], Huntington's disease (HD) [24,131], amyloid latheral sclerosis (ALS) [132][133][134], and Prion diseases [135]. Furthermore, pretreatment with TUDCA significantly reduced glutamate-induced apoptosis of rat cortical neurons [38] and improved synaptic plasticity as well as cognitive and motor impairment in the hippocampus of microcystin-leucine-arginine-treated rats [136,137].…”

Section: Tudca In Neurodegenerative Diseasesmentioning

confidence: 99%

“…The second most common neurodegenerative disorder worldwide is Parkinson's disease [127]. PD is characterized by the loss of dopaminergic neurons in the substantia nigra of the brain, which results in severe motor symptoms such as dyskinesia, tremor, and speech impairment [3,[127][128][129][130]. Dopamine cell death in PD may result from either genetic or environmental factors.…”

Section: Tudca In Neurodegenerative Diseasesmentioning

confidence: 99%

“…Currently, a novel approach towards the utilization of bile acids in PD is being considered. Since, to date, no reliable biomarkers of PD exist, Graham et al investigated alterations in bile acid profiles as potential biomarkers used in early diagnosis of PD [129,148]. In this respect, prodromal mouse model of PD was used to measure serum concentrations of 18 bile acids.…”

Section: Tudca In Neurodegenerative Diseasesmentioning

confidence: 99%

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Tauroursodeoxycholate—Bile Acid with Chaperoning Activity: Molecular and Cellular Effects and Therapeutic Perspectives

Kusaczuk

2019

Cells

140

125

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Tauroursodeoxycholic acid (TUDCA) is a naturally occurring hydrophilic bile acid that has been used for centuries in Chinese medicine. Chemically, TUDCA is a taurine conjugate of ursodeoxycholic acid (UDCA), which in contemporary pharmacology is approved by Food and Drug Administration (FDA) for treatment of primary biliary cholangitis. Interestingly, numerous recent studies demonstrate that mechanisms of TUDCA functioning extend beyond hepatobiliary disorders. Thus, TUDCA has been demonstrated to display potential therapeutic benefits in various models of many diseases such as diabetes, obesity, and neurodegenerative diseases, mostly due to its cytoprotective effect. The mechanisms underlying this cytoprotective activity have been mainly attributed to alleviation of endoplasmic reticulum (ER) stress and stabilization of the unfolded protein response (UPR), which contributed to naming TUDCA as a chemical chaperone. Apart from that, TUDCA has also been found to reduce oxidative stress, suppress apoptosis, and decrease inflammation in many in-vitro and in-vivo models of various diseases. The latest research suggests that TUDCA can also play a role as an epigenetic modulator and act as therapeutic agent in certain types of cancer. Nevertheless, despite the massive amount of evidence demonstrating positive effects of TUDCA in pre-clinical studies, there are certain limitations restraining its wide use in patients. Here, molecular and cellular modes of action of TUDCA are described and therapeutic opportunities and limitations of this bile acid are discussed.

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“…Parkinson's Disease (PD) is a progressive, adult-onset neurodegenerative disorder associated with the degeneration of dopaminergic (DAergic) neurons and the presence of proteinaceous inclusions such as αsynuclein (1). PD is the second most common neurodegenerative disorder after Alzheimer's Disease with a prevalence rate of 1% in people over 60 years of age (2).…”

Section: Introductionmentioning

confidence: 99%

Metabolic profiling of CSF from people suffering from Sporadic and LRRK2 Parkinson’s disease: a pilot study.

Yılmaz

Ugur

Ustun

et al. 2020

Preprint

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Background: CSF from unique groups of Parkinson’s disease (PD) patients were biochemically profiled to identify previously unreported metabolic pathways linked to PD pathogenesis and novel biochemical biomarkers of the disease were characterized. Methods: Utilizing both 1H NMR and DI-LC-MS/MS we quantitatively profiled CSF from patients with sporadic PD (n=20), those who are genetically predisposed (LRRK2) to the disease (n=20) and compared them with age,- and gender-matched controls (n=20). Further, we systematically evaluated the utility of several machine learning techniques for the diagnosis of PD.Results: 1H NMR and mass spectrometry-based metabolomics, in combination with bioinformatic analyses, provided useful information highlighting previously unreported biochemical pathways and CSF based biomarkers associated with both sporadic PD (sPD) and LRRK2 PD. Results of this metabolomics study further support our group’s previous findings identifying Bile Acid metabolism as one of the major aberrant biochemical pathways in PD patients.Conclusion: This study demonstrates that a combination of two complimentary techniques can provide a much more holistic view of the CSF metabolome and by association, the brain metabolome. Future studies for the prediction of those at risk of developing PD should investigate the clinical utility of these CSF based biomarkers in more accessible biomatrices. Further, it is essential that we determine if the biochemical pathways highlighted here are recapitulated in the brain of PD patients with the aim of identifying potential therapeutic targets.

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Metabolomic Profiling of Bile Acids in an Experimental Model of Prodromal Parkinson’s Disease

Cited by 42 publications

References 43 publications

Parkinson’s disease-associated alterations of the gut microbiome can invoke disease-relevant metabolic changes

Parkinson’s disease-associated alterations of the gut microbiome can invoke disease-relevant metabolic changes

Tauroursodeoxycholate—Bile Acid with Chaperoning Activity: Molecular and Cellular Effects and Therapeutic Perspectives

Metabolic profiling of CSF from people suffering from Sporadic and LRRK2 Parkinson’s disease: a pilot study.

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