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

大脑是一个极其复杂的器官，在胚胎时期就开始发育了。神经发育是表观遗传和遗传程序执行的结果，并受到环境因素的强烈影响。一个精确的事件序列被启动，而被遗传缺陷或感染等环境损害打乱，引发不可恢复的发育改变，导致精神疾病。除了与神经发育障碍相关的突触和/或连通性功能障碍外，大脑炎症（也称为神经炎症）是不同神经发育障碍（如唐氏综合症、脆性X综合征和自闭症谱系障碍）共有的特征之一。事实上，神经炎症会严重影响大脑活动和行为。最近的研究表明，存在一个肠脑轴，通过它肠道微生物群能够调节炎症和影响行为。µNeuroINF项目将探索肠道细菌可能引发神经炎症的假设，这反过来影响代谢和行为，并最终促进神经发育疾病的进展。利用唐氏综合症、脆性x综合征和自闭症谱系障碍的小鼠模型，我们将研究肠道细菌、它们的基因、蛋白质和代谢物，以确定哪些与这些疾病共同的微生物代谢物被肠道吸收并扩散到血液中到达大脑。这些代谢物的潜在促炎作用将在体外通过筛选其在宿主体内的药理学靶点和在体内的疾病动物模型中进行研究。这将最终导致由肠道微生物组驱动的NDD的新治疗策略。µNeuroINF计划是一项针对肠道细菌在神经炎症中的作用的创新多学科项目。我们独特的研究策略使用尖端技术来探索肠道微生物如何调节神经发育障碍中的脑炎症。该项目不仅将展示肠道细菌影响我们行为的最基本机制之一，而且还将确定可用于更好地监测脑部炎症（“生物标志物”）或用于治疗神经炎症的新药（“先导化合物”）的微生物代谢物

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, neuroinflammationdrastically 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 impactbehaviour. The µNeuroINF project will explore the hypothesis that our gut bacteria may triggerneuroinflammation, which in turn impacts metabolism and behaviour, and ultimately contributes toneurodevelopmental disease progression. Using mouse models of Down syndrome, Fragile Xsyndrome and autism spectrum disorders, we will study the gut bacteria, their genes, proteins andmetabolites 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 projecttargeting the role of the gut bacteria in neuroinflammation. Our unique research strategy uses cuttingedge technologies to explore how gut microbes modulate brain inflammation in neurodevelopmentaldisorders. Not only the project will demonstrate one of the most fundamental mechanisms by whichour 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