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: 10444554
• 负责人: Shelly A Buffington
• 金额: $ 50.63万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10444554
• 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 (Brain); Homeostasis; Human; Human Milk; Impaired cognition; Impairment; Infant; Interdisciplinary Study; Intervention; Lactation; Lead; Light; Measures; Memory; Metagenomics; Metformin; Molecular; Mothers; Mus; Mutation; Nervous system structure; Neurocognitive; Neurosciences; Obesity; Outcome; Pathologic; Pathway interactions; Penicillins; Pharmacologic Substance; Pharmacology; Phenotype; Postpartum Period; Pregnancy; Prevalence; Preventive treatment; Probiotics; Protein Biosynthesis; Publishing; Serum; Socioeconomic Status; Structure; Synapses; 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; 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; neurophysiology; non-genetic; novel therapeutics; offspring; opportunistic pathogen; pathogen; pathogenic bacteria; personalized approach; postnatal; pre-clinical; prepregnancy; prepregnancy obesity; prevent; probiotic therapy; social health determinants; soluble fiber; western diet; 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 (Brain); Homeostasis; Human; Human Milk; Impaired cognition; Impairment; Infant; Interdisciplinary Study; Intervention; Lactation; Lead; Light; Measures; Memory; Metagenomics; Metformin; Molecular; Mothers; Mus; Mutation; Nervous system structure; Neurocognitive; Neurosciences; Obesity; Outcome; Pathologic; Pathway interactions; Penicillins; Pharmacologic Substance; Pharmacology; Phenotype; Postpartum Period; Pregnancy; Prevalence; Preventive treatment; Probiotics; Protein Biosynthesis; Publishing; Serum; Socioeconomic Status; Structure; Synapses; 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; 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; neurophysiology; non-genetic; novel therapeutics; offspring; opportunistic pathogen; pathogen; pathogenic bacteria; personalized approach; postnatal; pre-clinical; prepregnancy; prepregnancy obesity; prevent; probiotic therapy; social health determinants; soluble fiber; 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.

孕产妇孕前肥胖使后代患有认知功能障碍，但对于产妇肥胖对后代脑功能和行为的转世代作用的机制知之甚少。鉴于弱势社会经济地位受到肥胖的影响不成比例的影响，这种传统上被忽视的认知健康问题受到了社会决定因素的加剧。目前，对于患有孕妇肥胖症或其婴儿的女性产前护理尚无共识，需要新的疗法来防止受影响儿童的慢性病负担。遗传和非遗传因素有助于肥胖。然而，流行病学研究表明，与遗传学无关的饮食是病理体重增加和高体重指数的主要驱动力。重要的是，宿主饮食调节肠道微生物组的组成，而肠道微生物群正在成为哺乳动物脑功能和行为的强大调节剂。鉴于产妇肠道菌群会影响出生前和产后后代的大脑发育，有助于神经发育的编程，并垂直从母亲传播到她的后代，从而阐明了饮食诱发的母体肠道肠道微生物组的营养不良与不良的认知健康健康状况的关系可能会导致治疗方面的治疗方案。 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.通过拟议的工作，我们旨在解决关键，但没有解决问题：（1）在后代的不良认知结果中，WD诱导的孕产妇肠道微生物组因果关系是否会发生？ （2a）机会性致病细菌可以通过MWD增加后代的认知功能增加吗？ （2b）哪种MWD相关的微生物代谢产生了宿主认知功能？ （2C）以及通过什么机制？ （3）在后代的药理学，益生菌或联合疗法中，产妇肠道微生物组是否可以通过药理学，益生菌或联合疗法靶向后代的认知功能障碍？成功完成目标将揭示WD在怀孕期间如何改变孕产妇肠道中的微生物群落结构，鉴定因MWD消耗而改变的微生物衍生的生物活性代谢产物以及WD诱导的母体肠guut微生物组障碍的基础机制，在后脱位中造成了障碍。最重要的是，我们的发现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，从而改变患有孕前肥胖的女性产前护理。