Aicardi-Goutières syndrome (AGS) is a cause of very severe brain disease in children. A lot of evidence exists to indicate that this brain damage is due to an inflammatory process involving the production of a chemical called interferon. Interferon is normally produced by cells in response to infection by a virus, and some children with AGS are initially misdiagnosed as having a viral-related disease because of the close clinical overlap of these states. In contrast to the production of interferon secondary to virus, in AGS an excess of interferon occurs due to a primary genetic defect. Because of the severity of the condition there is an urgent need to develop new treatments for AGS. We think this should be possible if we better understand how the responsible genetic changes drive interferon production. We intend to use the very latest genetic and cell technologies to understand how brain cells are damaged by inflammation in AGS. AGS is rare, and few parents feel able to agree to post-mortem if their affected child dies. However, a family with affected twin girls has generously donated the brain of one of their very recently deceased daughters. This almost unique resource will allow us to study human neurological tissue in more detail than ever before, and using new techniques which have not been available previously. Additionally, we are going to make use of state-of-the-art methods for producing ‘brain cells’ in a test-tube - derived from cells of patients with AGS, so that we can study brain tissue in the context of several different genetic sub-types of AGS. We also intend to analyse a strain of mouse which has changes in one of the AGS-related genes as another approach to trying to understand the human disease. Although AGS is rare, the study of the genes and the proteins related to the disease has become of very high scientific importance – partly because of the involvement of these genes / proteins in how the body reponds to infection by HIV-1 (the virus that causes AIDS), and also because of an overlap with diseases where the body attacks itself – so-called autoimmunity. Thus, not only will our work be relevant to the children and families affected by this dreadful condition, it may also have relevance for a much wider set of human medical disorders.

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, which, 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 gut microbes 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.