Targeting opportunistic pathogens to improve maternal obesity-associated health outcomes in offspring

针对机会性病原体，改善与母亲肥胖相关的后代健康结果

• 批准号: 10895023
• 负责人: Shelly A Buffington
• 金额: $ 51.12万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-25 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10895023
• 关键词: Address; Adverse effects; Affect; Amino Acids; Amygdaloid structure; Animal Model; Antibiotics; Attenuated; Bacteroides; Behavior; Behavioral; Biological Assay; Brain; Branched-Chain Amino Acids; Catabolism; Cephalosporins; Child; Chronic Disease; Cognition Disorders; Cognitive; Cognitive deficits; Combined Modality Therapy; Consensus; Consumption; Data; Development; Diet; Electrophysiology (science); Environment; Exhibits; Exposure to; FDA approved; Fatty acid glycerol esters; Functional disorder; Genetic; Germ-Free; Growth; Health; Hippocampus; Homeostasis; Human; Human Milk; Impaired cognition; Impairment; Infant; Interdisciplinary Study; Intervention; Lactation; Light; Measures; Memory; Metagenomics; Metformin; Molecular; Mothers; Mus; Mutation; Neurocognitive; Neurosciences; Obesity; Outcome; Pathologic; Pathway interactions; Penicillins; Pharmacologic Substance; Phenotype; Postpartum Period; Pregnancy; Prevalence; Preventive treatment; Probiotics; Protein Biosynthesis; Publishing; Serum; Socioeconomic Status; Structure; Synaptic plasticity; Testing; Transplant Recipients; Up-Regulation; Weight Gain; Whole-Genome Shotgun Sequencing; Woman; Work; antenatal; antenatal care; burden of illness; cognitive function; diet-induced obesity; disadvantaged women; disorder risk; dysbiosis; early life exposure; epidemiology study; fecal transplantation; fetal; gut dysbiosis; gut microbiome; gut microbiota; high body mass index; ileum; improved; in utero; innovation; maternal obesity; metabolome; metabolomics; microbial; microbial community; microbiota; mouse model; multiple omics; nervous system development; neurophysiology; non-genetic; novel therapeutics; offspring; opportunistic pathogen; pathogen; pathogenic bacteria; permissiveness; personalized approach; pharmacologic; postnatal; pre-clinical; prenatal; prepregnancy; prepregnancy obesity; prevent; probiotic therapy; social health determinants; soluble fiber; transmission process; western diet

Maternal prepregnancy obesity predisposes offspring to cognitive dysfunction, yet little is known about the mechanisms underlying the transgenerational effects of maternal obesity on offspring brain function and behavior. This traditionally overlooked cognitive health problem is exacerbated by social determinants of health, given that women of disadvantaged socioeconomic status are disproportionately affected by obesity. Currently, there is no consensus on antenatal care for women with prepregnancy obesity or their infants, and new therapies are needed to prevent chronic disease burden in affected children. Genetic and nongenetic factors contribute to obesity; yet, epidemiological studies suggest that diet, independent of genetics, is the primary driver of pathological weight gain and high body mass index. Importantly, host diet regulates the composition of the gut microbiome, and gut microbiota are emerging as powerful regulators of mammalian brain function and behavior. Given that maternal gut microbiota affect pre- and postnatal offspring brain development, contribute to neurodevelopmental programming, and are vertically transmitted from the mother to her offspring, elucidating the relationship between diet-induced dysbiosis of the maternal gut microbiome and adverse cognitive health outcomes in offspring could lead to innovative preventative treatments. Building on our recently published work and exciting preliminary data, we propose an interdisciplinary study combining metagenomics, metabolomics, and neuroscience to test our hypothesis that maternal Western diet (mWD)-induced upregulation of opportunistic pathogenic bacteria and associated changes in the microbially-derived metabolome are causally related to cognitive dysfunction in mWD offspring. With the proposed work, we aim to address key, yet unanswered questions: (1) Is WD-induced dysbiosis of the maternal gut microbiome causal in adverse cognitive outcomes in offspring? (2a) Can opportunistic pathogenic bacteria increased by mWD impair cognitive function in offspring? (2b) Which mWD-associated microbially-derived metabolites affect host cognitive function? (2c) And by what mechanism? (3) Could antenatal targeting of the maternal gut microbiome via pharmacological, probiotic, or combination therapies thereof rescue mWD-associated cognitive dysfunction in offspring? Successful completion of the aims will reveal how WD alters microbial community structure in the maternal gut during pregnancy, identify microbially-derived, bioactive metabolites altered by mWD consumption, and the underlying mechanism by which WD-induced dysbiosis of the maternal gut microbiome impairs cognitive function in offspring. Most importantly, our findings have the potential to transform antenatal care for women with prepregnancy obesity by identifying a new class of preventative antenatal interventions to improve neurocognitive health outcomes in affected children.

母亲孕前肥胖会使后代容易出现认知功能障碍，但人们对母亲肥胖对后代大脑功能和行为产生跨代影响的机制知之甚少。鉴于社会经济地位处于不利地位的女性尤其容易受到肥胖的影响，健康的社会决定因素加剧了这一传统上被忽视的认知健康问题。目前，对于孕前肥胖妇女或其婴儿的产前护理尚未达成共识，需要新的疗法来预防受影响儿童的慢性疾病负担。遗传和非遗传因素导致肥胖；然而，流行病学研究表明，与遗传无关的饮食是病理性体重增加和高体重指数的主要驱动因素。重要的是，宿主饮食调节肠道微生物群的组成，而肠道微生物群正在成为哺乳动物大脑功能和行为的强大调节剂。鉴于母体肠道微生物群影响产前和产后后代大脑发育，有助于神经发育编程，并从母亲垂直传播给后代，阐明了饮食引起的母体肠道微生物群失调与后代不良认知健康结果之间的关系可能会带来创新的预防性治疗。基于我们最近发表的工作和令人兴奋的初步数据，我们提出了一项结合宏基因组学、代谢组学和神经科学的跨学科研究，以检验我们的假设，即母亲西方饮食（mWD）诱导机会性致病菌上调以及微生物衍生代谢组的相关变化与 mWD 后代的认知功能障碍有因果关系。通过拟议的工作，我们的目标是解决关键但尚未解答的问题：（1）WD 引起的母体肠道微生物群失调是否会导致后代不良认知结果？ (2a) mWD 增加的机会致病菌是否会损害后代的认知功能？ (2b) 哪些 mWD 相关微生物代谢物影响宿主认知功能？ (2c) 通过什么机制？ (3) 通过药理学、益生菌或其组合疗法在产前针对母体肠道微生物组是否可以挽救后代与 mWD 相关的认知功能障碍？成功完成这些目标将揭示 WD 如何改变怀孕期间母体肠道的微生物群落结构，识别因食用 mWD 而改变的微生物来源的生物活性代谢物，以及 WD 引起的母体肠道微生物菌群失调损害认知功能的潜在机制在后代中。最重要的是，我们的研究结果有可能通过确定一类新的预防性产前干预措施来改善受影响儿童的神经认知健康结果，从而改变孕前肥胖妇女的产前护理。