Metagenomics of Parkinson’s disease implicates the gut microbiome in multiple disease mechanisms

Wallen, Zachary D.; Demirkan, Ayşe; Twa, Guy; Cohen, Gwendolyn; Dean, Marissa; Standaert, David G.; Sampson, Timothy R.; Payami, Haydeh

doi:10.1101/2022.06.08.495316

Cited by 2 publications

(2 citation statements)

References 83 publications

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“…This is a crucial question that needs to be addressed, since most current therapies are aimed at targeting FUS in the central nervous system, without considering the systemic alterations caused by FUS mutation. Of note, investigation of pleiotropic phenotypes in Parkinson's disease has proven illuminating, with a role for the gut-brain axis proposed as a major early pathomechanism (Wallen et al 2022).…”

Section: Discussionmentioning

confidence: 99%

Mutation in the FUS nuclear localisation signal domain causes neurodevelopmental and systemic metabolic alterations

Ali,

Godoy-Corchuelo,

Martins-Bach

et al. 2023

Disease Models &Amp; Mechanisms

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Mutations in the ubiquitously expressed DNA/RNA binding protein FUS cause aggressive juvenile forms of amyotrophic lateral sclerosis (ALS). While most FUS mutation studies have focused on motor neuron degeneration, little is known about wider systemic or developmental effects. We studied pleiotropic phenotypes in a physiological knock-in mouse model carrying the pathogenic FUSDelta14 mutation in homozygosity. RNA sequencing of multiple organs aimed to identify pathways altered by the mutant protein in the systemic transcriptome, including metabolic tissues given the link between ALS-FTD and altered metabolism. Few genes were commonly altered across all tissues, and most genes and pathways affected were generally tissue-specific. Phenotypic assessment of mice revealed systemic metabolic alterations related to the pathway changes identified. MRI brain scans and histological characterisation revealed that homozygous FUSDelta14 brains were smaller and displayed significant morphological alterations including a thinner cortex, reduced neuronal number and increased gliosis, which correlated with early cognitive impairment and fatal seizures. We show that the disease aetiology of FUS mutations can include both neurodevelopmental and systemic alterations.

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Section: Discussionmentioning

confidence: 99%

Mutation in the FUS nuclear localisation signal domain causes neurodevelopmental and systemic metabolic alterations

Ali,

Godoy-Corchuelo,

Martins-Bach

et al. 2023

Disease Models &Amp; Mechanisms

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“…To test the effect of medication usage we applied two independent strategies. First, we selected all metadata related to medication usage available from Wallen et al 15,103 We then retained only medications used in at least 20% of the participants (11 medications in total) and used them to perform a variable selection using the regsubsets function in the leaps v_3.1 R package 104 . This was done for the regressions modelling the abundance of the features as a function of medications and disease status, allowing models with a maximum of 12 variables (including all medications and the disease status).…”

Section: Methodsmentioning

confidence: 99%

Machine learning-based meta-analysis reveals gut microbiome alterations associated with Parkinson’s disease

Romano,

Wirbel,

Ansorge

et al. 2023

Preprint

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There is strong interest in exploring the potential of the gut microbiome for Parkinson’s disease (PD) diagnosis and treatment. However, a consensus on the microbiome features associated with PD and a multi-study assessment of their diagnostic value is lacking. Here, we present a machine learning meta-analysis of PD microbiome studies of unprecedented scale (including 4,490 samples). Within most studies, microbiome-based machine learning models could accurately classify PD patients. However, models were study-specific and did not generalise well across other studies. By training models on multiple datasets, we could improve their general applicability and disease specificity as assessed against microbiomes from other neurodegenerative diseases. Meta-analysis of shotgun metagenomes moreover delineated PD-associated microbial pathways potentially contributing to the deterioration of gut health and favouring the translocation of pathogenic molecules along the gut-brain axis. Strikingly, diverse microbial pathways for the biotransformation of solvents and pesticides were enriched in PD. These results align with the epidemiological evidence that exposure to these molecules increases PD risk and raise the question of whether gut microbial metabolism modulates their toxicity. Taken together, we offer the most comprehensive overview to date about the PD gut microbiome and provide future reference for its diagnostic and functional potential.

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Metagenomics of Parkinson’s disease implicates the gut microbiome in multiple disease mechanisms

Cited by 2 publications

References 83 publications

Mutation in the FUS nuclear localisation signal domain causes neurodevelopmental and systemic metabolic alterations

Mutation in the FUS nuclear localisation signal domain causes neurodevelopmental and systemic metabolic alterations

Machine learning-based meta-analysis reveals gut microbiome alterations associated with Parkinson’s disease

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