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Maternal gut microbiota in fetal programming of neurodevelopment and related disorders

母体肠道微生物群在胎儿神经发育和相关疾病编程中的作用

基本信息

批准号：
10668634
负责人：
Shelly A Buffington
金额：
$ 56.66万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-15 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10668634
关键词：
ATAC-seq Adoptive Transfer Adverse effects Affect Behavior Behavior assessment Behavioral Behavioral Symptoms Brain Brain region Businesses CD4 Positive T Lymphocytes Cell Maturation Cell Separation Chronic Disease Consensus Coupled Data Development Diet Disease Disease susceptibility Embryo Environmental Risk Factor Epigenetic Process Exposure to Family Female Fetal Development Functional disorder Generations Genetic Predisposition to Disease Germ-Free Goals Health High Fat Diet Human Hypothalamic structure Immune Impairment Individual Industrialization Inflammation Inflammatory Inflammatory Bowel Diseases Interdisciplinary Study Intervention Life Mediating Metabolic syndrome Metagenomics Mus Neurodevelopmental Deficit Neurodevelopmental Disorder Outcome Pathologic Pathology Pathway interactions Peptide Initiation Factors Personal Satisfaction Phenotype Physiology Population Predisposition Pregnancy Probiotics Process Rag1 Mouse Recovery Reporting Rewards Schizophrenia Serum Social Behavior Social Interaction Synaptic plasticity Testing Therapeutic Volatile Fatty Acids Whole-Genome Shotgun Sequencing Work antenatal care associated symptom autism spectrum disorder cell type critical period cytokine discrete time dysbiosis experience fecal transplantation fetal fetal programming gastrointestinal symptom gut dysbiosis gut microbiome gut microbiota immune activation immune function imprint improved in utero insight male maternal microbiome metabolome metabolomics microbial microbiome microbiome composition microbiota transplantation neural circuit neurobehavioral neurodevelopment neuroinflammation neuropathology neuropsychiatric disorder neuropsychiatry offspring patient population prenatal exposure prevent sex sexual dimorphism social social deficits therapeutic target transcriptome sequencing

项目摘要

Project Summary Social interaction is fundamental to the most universal of human experiences, such as family life, business, and romance; however, social dysfunction is a debilitating hallmark of major neurodevelopmental disorders, including autism and schizophrenia. Despite significant advances, the mechanisms underlying social dysfunction and other core behavioral symptoms associated with neurodevelopmental disorders remain elusive and interventions limited. There is growing consensus in support of a ‘two hit’ hypothesis for neurodevelopmental disorders, in which a secondary environmental factor initiates abnormal developmental programming that contributes to behavioral dysfunction in genetically predisposed individuals. Among environmental factors, diet is a leading factor contributing to host disease susceptibility. Notably, diet is the chief determinant of host gut microbiome composition. Through modulation of host immune function, and even the brain and behavior, the gut microbiome is emerging as a major influence on host health and well-being. Disruption, or ‘dysbiosis,’ of the gut microbiome is, in turn, associated with several common inflammatory disorders, including inflammatory bowel disease and metabolic syndrome. Dysbiosis is also observed in neuropsychiatric patient populations, who have a high rate of gastrointestinal symptom comorbidity; yet, the relationship between dysbiosis of the gut microbiome and neurodevelopmental or other neuropsychiatric disorders is poorly understood. In this project, we will determine if maternal high-fat diet (MHFD)-induced dysbiosis of the gut microbiome during pregnancy contributes to descendant neurobehavioral dysfunction and the underlying mechanisms. Previously, we reported that MHFD induces dysbiosis of the male offspring gut microbiome as well as social dysfunction and underlying deficits in synaptic plasticity in the social reward circuit. Recently, we identified a sexually dimorphic effect of MHFD on offspring behavior–stronger social deficits are evident in males versus females–however, we observed dysbiosis of both the male and female MHFD offspring gut. We reasoned that if the maternal gut microbiome is causally related to offspring social dysfunction, then enduring dysbiosis of the female MHFD offspring gut microbiome in the F1 generation may be sufficient to impair neurodevelopment and behavior in F2 males. Indeed, we observed robust social dysfunction in male, but not female, F2 offspring. Here, we will test the hypothesis that HFD-induced dysbiosis of the maternal gut microbiome drives abnormal fetal programming in F1 offspring that underlies social dysfunction in both F1 and F2 males. In Aim 1, we will ask how HFD/MHFD affects remodeling of the P/F1 maternal gut microbiome during pregnancy. In Aim 2, we will determine the effects of HFD/MHFD on maternal immune function, fetal immune imprinting, and the embryonic brain. In Aim 3, we will determine if modulation of the maternal gut microbiome during pregnancy can rescue descendant social dysfunction. This study will yield key insight into the mechanisms by which MHFD modulates fetal development and the potential for therapeutic targeting of the maternal microbiome to prevent adverse neurobehavioral outcomes in descendant generations.