Microbiote, Immunity, and NeuroDevelopment

Présentation

MINDev team: Microbiota, Immunity, and Neurodevelopment

Research in the Developmental Origins of Health and Disease (DOHaD) has clearly demonstrated that the gestational period and the first 2 years of life are critical for individuals’ future health, and in particular mental health. Several mental disorders have a clear neurodevelopmental origin, including the so-called neurodevelopmental disorders (NDD) diagnosed in early childhood (e.g. autism spectrum disorders (ASD) or attention deficits/hyperactivity), but also psychiatric disorders diagnosed later in life (e.g. depression, bipolarity, schizophrenia (SCZ)). All these diseases lead to lifelong impairments in everyday life and have heavy socio-economic costs and there is an urgent need to develop biomarkers and identify new therapeutic targets for these diseases.

NDD result from interactions between individual genetic predisposition and exposure to environmental risk factors, which may explain the great inter-individual heterogeneity in NDD clinical presentation. Aside from atypical or maladaptive behaviours, patients with NDD often exhibit gastrointestinal (GI) dysfunction, intestinal microbiota dysbiosis, and immune abnormalities such as abnormal serum cytokine levels. Preclinical studies have shown that both the gut microbiota and the immune system regulate neurodevelopmental processes, synaptic plasticity and brain functions, with long-term impact social and adaptive behaviors, cognition, stress response, and anxiety. While these data suggest that NDD behavioural alterations could result from an altered microbiota and/or immune alterations, the underlying molecular mechanisms remain to be elucidated. Also, biomarkers predictive of NDD risk or defining subtypes of NDD patients are generally lacking. Finally, identifying novel therapeutic targets to alleviate NDD behavioural deficits is critical.

Microbial metabolites produced by the microbiota have described pharmacological activities on host receptors or enzymes, and cytokines produced by immune cells and glial cells act on their cognate brain receptors. Our working hypothesis is that the effects of the microbiota and the immune system on neurodevelopment and behaviour are mediated by microbial metabolites and cytokines. To test this hypothesis, our translational and multidisciplinary research program is organized along two main research axes entitled “Gut microbiota, microbial metabolites and ASD” and “Immunity, cytokines and NDD”. Relevant to this hypothesis, our objectives are:

• To assess the utility of microbial metabolites and cytokines as biomarkers for the diagnosis, prognosis, or stratification of psychiatric disorders with neurodevelopmental origin (ASD, SCZ, depression). To achieve this, we will perform association and prediction studies based on clinical data and biomarker measures (cytokines, metabolites) in biological samples from cohorts of psychiatric patients and children from the two French birth cohorts EDEN and ELFE.
• To elucidate the pharmacological properties of endogenous microbial metabolites on host receptors and enzymes to understand how they can interfere with brain function to induce NDD. To achieve this, we will analyse the systemic, neurobiological and behavioural consequences of manipulating metabolite levels in mice and identify their molecular targets (enzyme, receptor);
• To elucidate how dysregulation of cytokine signalling during neurodevelopment leads to NDD. To achieve this, we will analyse the neurodevelopmental consequences of candidate cytokines gain/loss-of-function in human brain organoids;
• To propose novel therapeutic strategies for NDD targeting microbial metabolites (in mice) and the immune system (in human brain organoids and in a prospective clinical study).