Neurobiological and neurocognitive consequences of diverse microbiome functional trajectories

不同微生物组功能轨迹的神经生物学和神经认知后果

• 批准号: 10443912
• 负责人: STEVEN R. GILL
• 金额: $ 72.32万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10443912
• 关键词: 4 year old; Age; Anabolism; Anxiety; Area; Bacteria; Behavior; Biochemical; Biological; Birth; Blood specimen; Brain; Chemicals; Child; Clinical; Clinical Research; Cognition; Collection; Communication; Data; Development; Enteric Nervous System; Event; Exposure to; First Pregnancy Trimester; Future; Goals; Human Milk; Immune; Individual Differences; Infant; Intervention; Intestines; Life; Link; Maternal Exposure; Measures; Metagenomics; Modeling; Molecular; Mothers; Neurobiology; Neurocognitive; Neurotransmitters; Newborn Infant; Outcome; Participant; Pathway interactions; Peripheral; Phase; Placenta; Play; Pregnancy; Prevention strategy; Production; Reporting; Risk Factors; Role; Sampling; Shapes; Signal Transduction; Source; Taxonomy; Testing; Third Pregnancy Trimester; Umbilical Cord Blood; base; cohort; design; early onset; endophenotype; feeding; gut bacteria; gut colonization; gut microbiome; gut microbiota; gut-brain axis; imprint; improved; indexing; infant gut microbiome; maternal anxiety; maternal imprint; maternal microbiome; maternal microbiota; maternal risk; metabolomics; metagenome; microbiome; microbiome composition; microbiota; mother nutrition; neglect; neurodevelopment; neuroimaging; nutrition; offspring; parent grant; postnatal; postnatal development; postnatal period; pre-clinical; prenatal; prenatal exposure; prenatal influence; prospective; vaginal fluid; vaginal microbiome

There is compelling evidence for a critical role of the maternal and infant gut microbiome in early infant brain neurodevelopment. Temporal milestones in postnatal infant gut microbiome development align with changes in early infant brain development, suggesting functional relationships between these two pivotal events. The premise of our proposal is based on a wealth of studies and new preliminary analyses reported below linking maternal prenatal anxiety (PNA), a prominent prenatal maternal risk factor, and child neurodevelopment. We hypothesize that the prenatal maternal microbiome and its influence on newborn neurodevelopment is shaped by PNA, and that early infant cognition is determined by mother-to-infant microbiome transfer, postnatal development and biosynthesis of microbiota-derived neuroactive metabolites (NAMs). Our study is framed by a proposed developmental model that includes two major components; prenatal anxiety and developmental phase trajectories of the infant gut microbiome. The proposed model has scientific as well as practical strengths, as it leverages a wealth of existing data collected as part of a large, prospective longitudinal and diverse pregnancy cohort that has been followed from the first trimester through the child’s 4th year, with extensive longitudinal characterization of prenatal exposures, child microbiome and other key biological samples, and child neurodevelopment assessed longitudinally that will enable important and previously neglected incorporation of potential confounds. We use these components to test the central hypothesis that neurodevelopment is dependent on age-driven biosynthesis of NAMs through the postnatal period of infant gut-microbiome (IGM) development. In Aim 1, we use metagenomic analysis of the prenatal maternal vaginal microbiome (MVM) to identify species and functional biosynthetic pathways for NAMs associated with PNA. We also assess the potential transfer of maternal anxiety through the initial colonization of the infant gut microbiome by an anxiety “imprinted” MVM. In Aim 2, we use metagenomic and metabolomic analyses to determine the association between key stages of IGM development and differential synthesis of NAMs over the first year, attending to confounds and competing exposures, most notably, maternal diet and infant feeding. In Aim 3, we apply this rich data to predict neurocognitive assessments from age 1 to 4 years to formally test the temporal relationship between microbiome phase and neurodevelopment in the first year of life and durability of the microbiota- neurodevelopment relationship through 4 years of age. The scientific impact of the study will be on advanced understanding of the role of prenatal exposures; documenting sources of between- and within-individual differences in the IGM through the first years of life; identifying NAMs with a possible mechanistic role in the MGB axis; documenting a potentially broad and persistent impact on neurodevelopment.

有令人信服的证据表明，母婴肠道微生物组在婴儿早期大脑中起着关键作用