ERA-NET NEURON: The Gut Microbiome in Neuroinflammation and Neurodevelopmental Disorders

Lead Research Organisation: Imperial College London
Department Name: Dept of Surgery and Cancer

Abstract

The brain is an extraordinarily complex organ that develops early on in embryonic life.
Neurodevelopment results from the execution of epigenetic and genetic programs, and is strongly influenced by environmental factors. A precise sequence of events is initiated, hich, while disrupted by genetic defects or environmental insults such as infections, provokes non-recoverable developmental alterations leading to mental diseases. In addition to the synaptic and/or connectivity dysfunctions associated to neurodevelopmental disorders, inflammation in the brain (otherwise called neuroinflammation) is one of the hallmarks shared by different neurodevelopmental disorders, such as Down syndrome, Fragile X syndrome and Autism Spectrum Disorders. In fact, neuroinflammation
drastically affects brain activity and behaviour. Recent studies demonstrate the existence of a gutbrain axis through which the intestinal microbiota is able to modulate inflammation and impact
behaviour. The µNeuroINF project will explore the hypothesis that our gut bacteria may trigger
neuroinflammation, which in turn impacts metabolism and behaviour, and ultimately contributes to
neurodevelopmental disease progression. Using mouse models of Down syndrome, Fragile X
syndrome and autism spectrum disorders, we will study the gut bacteria, their genes, proteins and
metabolites to identify which microbial metabolites common to these diseases are absorbed in the gut and diffuse into the bloodstream to reach the brain. The potential pro-inflammatory role of these metabolites will be investigated in vitro by screening their pharmacological targets in the host, and in vivo in the animal models of the disease. This will ultimately lead to novel therapeutic strategies for NDD driven by the gut microbiome. The µNeuroINF initiative is an innovative multidisciplinary project
targeting the role of the gut bacteria in neuroinflammation. Our unique research strategy uses cuttingedge technologies to explore how guticrobes modulate brain inflammation in neurodevelopmental
disorders. Not only the project will demonstrate one of the most fundamental mechanisms by which
our gut bacteria influence our behaviour, but it will also identify the microbial metabolites that can be used to better monitor brain inflammation ("biomarkers") or to lead to new drugs ("lead compounds") for the treatment of neuroinflammation

Technical Summary

Neurodevelopmental disorders (NDD) appear during nervous system development and maturation and originate from a variety of genetic and environmental causes or a combination of both. NDDs
result in lifelong intellectual disability and behavioural alterations (anxiety, hyperactivity, social
impairment, communication deficits) and have therefore extremely heavy socio-economical
consequences. Neuroinflammation is one of the hallmarks shared by NDD, including Down syndrome
(DS, 1:800), Fragile X syndrome (FXS, 1:6000) and Autism Spectrum Disorders (ASD, 1:100). Recent
studies demonstrate the existence of a gut-brain axis through which the intestinal microbiota is able to
modulate inflammation. The µNeuroINF project is driven by our hypothesis that the gut microbiome
modulates neuroinflammation impacting metabolism and behaviour and contributing to NDD
pathophysiology. By studying common effects across three mouse models of NDD: i) the Fmr1-KO
mouse model of FXS, ii) the Ts65Dn trisomic mouse model of DS, and iii) the Maternal Immune
Activation (MIA) ASD mouse model, we aim to unravel mechanisms by which gut microbial
metabolites modulate neuroinflammation and contribute to NDD-related behavioural phenotypes. Our
three specific objectives are: 1) to acquire complete metabolomic, metagenomic and metaproteomic
neuroinflammatory signatures in three NDD mouse models, 2) to identify microbial metabolites
modulating neuroinflammation in NDD, 3) to screen their pharmacological targets and test in vivo their effect on neuroinflammation and behaviour. Meta-"omics" will reveal microbial genes, proteins and
metabolites associated with variations in brain cytokines, immune cell populations and behavioural phenotypes in NDD. Microbial metabolites will be screened for pharmacological targets such as receptors and kinases, and mechanisms will be validated in vivo to explore the modulatory role of the gut microbiome on immunity and behaviour. This will ultimately lead to ovel personalised medicine
and therapeutic strategies for NDD and neuroinflammation, driven by the gut microbiome.

Publications

10 25 50
 
Description I was invited to participate in an event organised by the Microbiology Society to develop the society's Microbiome Policy, so that to inform the public and various stakeholders and to influence government policy on the subject.
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
URL http://www.microbiologysociety.org/policy/microbiome-policy-project.cfm
 
Description Joint-funding from MRC/ANR/BMBF/MINECO as part of ERANET Neuron II award 
Organisation Bellvitge Biomedical Research Institute
Country Spain 
Sector Charity/Non Profit 
PI Contribution The current MRC award was made as part of an ERANET joint funding initiative for the µNeuroInf collaborative project, investigating the role of the gut microbiome in neuroinflammation and neurodevelopment disorders. As part of this award our team at Imperial has profiled the metabolome of animal models of neurodevelopmental disorders and has implemented methods for metagenomic sample preparation and data analysis. Our group has also screened a selection of 10 microbial metabolites against a panel of >500 pharmacological targets that are clinically relevant. We have followed up and tested whether these microbial metabolites are pro-inflammatory or anti-inflammatory by cell-based assays using brain immune cells (microglia) and cells in charge of feeding neutrons (astrocytes) in order to reduce the number of animals used for validations.
Collaborator Contribution Partners involved in the consortium have generated animal models for Down Syndrome (IDIBELL, Barcelona, Spain), Fragile X Syndrome and Autism (CNRS, Nice, France) which have been studied by proteomics (University of Tuebingen, Germany).
Impact This collaboration has resulted in the publication of 3 reviews (listed in the publication output) during the first year of activity: - one review on metabolomics in neuroscience - one review on the pharmacology of microbial metabolites - one review on the use of microbiome data in personal nutrition
Start Year 2015
 
Description Joint-funding from MRC/ANR/BMBF/MINECO as part of ERANET Neuron II award 
Organisation Eberhard Karls University of Tubingen
Country Germany 
Sector Academic/University 
PI Contribution The current MRC award was made as part of an ERANET joint funding initiative for the µNeuroInf collaborative project, investigating the role of the gut microbiome in neuroinflammation and neurodevelopment disorders. As part of this award our team at Imperial has profiled the metabolome of animal models of neurodevelopmental disorders and has implemented methods for metagenomic sample preparation and data analysis. Our group has also screened a selection of 10 microbial metabolites against a panel of >500 pharmacological targets that are clinically relevant. We have followed up and tested whether these microbial metabolites are pro-inflammatory or anti-inflammatory by cell-based assays using brain immune cells (microglia) and cells in charge of feeding neutrons (astrocytes) in order to reduce the number of animals used for validations.
Collaborator Contribution Partners involved in the consortium have generated animal models for Down Syndrome (IDIBELL, Barcelona, Spain), Fragile X Syndrome and Autism (CNRS, Nice, France) which have been studied by proteomics (University of Tuebingen, Germany).
Impact This collaboration has resulted in the publication of 3 reviews (listed in the publication output) during the first year of activity: - one review on metabolomics in neuroscience - one review on the pharmacology of microbial metabolites - one review on the use of microbiome data in personal nutrition
Start Year 2015
 
Description Joint-funding from MRC/ANR/BMBF/MINECO as part of ERANET Neuron II award 
Organisation National Center for Scientific Research (Centre National de la Recherche Scientifique CNRS)
Department Institute of Molecular and Cellular Pharmacology
Country France 
Sector Public 
PI Contribution The current MRC award was made as part of an ERANET joint funding initiative for the µNeuroInf collaborative project, investigating the role of the gut microbiome in neuroinflammation and neurodevelopment disorders. As part of this award our team at Imperial has profiled the metabolome of animal models of neurodevelopmental disorders and has implemented methods for metagenomic sample preparation and data analysis. Our group has also screened a selection of 10 microbial metabolites against a panel of >500 pharmacological targets that are clinically relevant. We have followed up and tested whether these microbial metabolites are pro-inflammatory or anti-inflammatory by cell-based assays using brain immune cells (microglia) and cells in charge of feeding neutrons (astrocytes) in order to reduce the number of animals used for validations.
Collaborator Contribution Partners involved in the consortium have generated animal models for Down Syndrome (IDIBELL, Barcelona, Spain), Fragile X Syndrome and Autism (CNRS, Nice, France) which have been studied by proteomics (University of Tuebingen, Germany).
Impact This collaboration has resulted in the publication of 3 reviews (listed in the publication output) during the first year of activity: - one review on metabolomics in neuroscience - one review on the pharmacology of microbial metabolites - one review on the use of microbiome data in personal nutrition
Start Year 2015
 
Title MWASTools: an integrated pipeline to perform metabolome-wide association studies 
Description MWASTools provides a complete pipeline to perform metabolome-wide association studies. Key functionalities of the package include: quality control analysis of metabonomic data; MWAS using different association models (partial correlations; generalized linear models); model validation using non-parametric bootstrapping; visualization of MWAS results; NMR metabolite identification using STOCSY; and biological interpretation of MWAS results. 
Type Of Technology Software 
Year Produced 2017 
Open Source License? Yes  
Impact The MWASTools R package provides an integrated pipeline with efficient analysis and visualization tools for: (i) performing QC analysis; (ii) conducting robust MWAS analysis with efficient handling of epidemiological confounders; (iii) structural assignment of metabolic features of interest; (iv) biological interpretation of MWAS results. The MWASTools package can be applied to both targeted and untargeted metabonomic datasets, acquired with different analytical platforms. 
URL http://www.bioconductor.org/packages/release/bioc/html/MWASTools.html
 
Title MetaboSignal: a network-based approach to overlay and explore metabolic and signaling KEGG pathways 
Description MetaboSignal is an R package that allows merging, analyzing and customizing metabolic and signaling KEGG pathways. It is a network-based approach designed to explore the topological relationship between genes (signaling- or enzymatic-genes) and metabolites, representing a powerful tool to investigate the genetic landscape and regulatory networks of metabolic phenotypes. 
Type Of Technology Software 
Year Produced 2017 
Open Source License? Yes  
Impact 'MetaboSignal' is a versatile package integrating metabolic and signaling transduction pathways to build parsimonious visualizations of gene-metabolite associations based on the analysis of network topology. MetaboSignal is a biomolecular navigation system allowing the exploration of organism-specific, and even tissue-specific, relationships between any given gene and any given metabolite retrieved from KEGG. This approach is ideally suited to identify candidate genes in metabotype-QTL studies (e.g. trans-acting associations), or to identify biological pathways affected in transgenic models (e.g. knock-out, CRISPR-Cas9). 
URL http://bioconductor.org/packages/release/bioc/html/MetaboSignal.html
 
Description Imperial Fringe (science festival): Food of Tomorrow 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Animation of a stand on the microbiome entitled Meet your micro-lodgers. This was part of the wider Food of Tomorrow event. Over 1,200 people signed up for the event, and we estimate at least 800 attended over the course of the evening. Those who attended came from the sectors represented in the registration, which included representatives from over 30 food companies (including Sainsbury's, Unilever, Youngs, Innocent drinks, GÜ Puds, United Biscuits), 61 alumni, stakeholders from government and funding agencies, and students from 12 London schools.
Year(s) Of Engagement Activity 2016
URL http://www3.imperial.ac.uk/newsandeventspggrp/imperialcollege/eventssummary/event_8-12-2015-11-54-47
 
Description Participation in "Big Biology Week" public engagement event, Hills Road College, Cambridge, 15th October 2016. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact In this event, I chaired a session sponsored by the Microbiology Society to raise pupils, parents and general public's awareness of the gut microbiome. The event was held on Saturday 15th of October 2016 at Hills Road Sixth Form College in Cambridge to ensure maximum outreach.
The event was designed to be fun, engaging and informative for children and adults. This was one of more than a 100 events organised by the Royal Society of Biology: https://www.rsb.org.uk/get-involved/biologyweek
Year(s) Of Engagement Activity 2016
URL http://www.hillsroad.ac.uk/college-life/events/2016/10/15/default-calendar/big-biology-day