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

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.

母亲孕前肥胖使后代易患认知功能障碍，然而，关于母亲肥胖对后代大脑功能和行为的跨代影响的机制却知之甚少。这一传统上被忽视的认知健康问题由于健康的社会决定因素而加剧，因为处于不利社会经济地位的女性受到肥胖的影响不成比例。目前，对于孕前肥胖妇女或其婴儿的产前护理还没有达成共识，需要新的治疗方法来预防受影响儿童的慢性病负担。遗传和非遗传因素导致肥胖；然而，流行病学研究表明，饮食是病理性体重增加和高体重指数的主要驱动因素，与遗传无关。重要的是，宿主饮食调节肠道微生物群的组成，肠道微生物区系正在成为哺乳动物大脑功能和行为的强大调节器。鉴于母亲的肠道微生物区系影响出生前和出生后的后代大脑发育，有助于神经发育编程，并从母亲垂直传播给后代，阐明饮食诱导的母亲肠道微生物群失调与后代认知健康不良结果之间的关系可能会导致创新的预防性治疗。在我们最近发表的工作和令人兴奋的初步数据的基础上，我们提出了一项结合元基因组学、代谢组学和神经科学的跨学科研究，以检验我们的假设，即母体西方饮食(MWD)诱导的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，我们旨在解决关键但尚未回答的问题：(1)WD引起的母体肠道微生物群失调是否会导致后代的不良认知结果？(2A)MWD增加的机会性致病菌是否会损害后代的认知功能？(2B)哪些MWD相关的微生物衍生代谢物会影响宿主认知功能？(2C)以及通过什么机制？(3)产前通过药理、益生菌或其组合治疗母体肠道微生物群是否可以拯救MWD相关的认知功能障碍？这些目标的成功完成将揭示WD如何在怀孕期间改变母亲肠道中的微生物群落结构，识别MWD消费改变的微生物衍生的生物活性代谢物，以及WD导致母亲肠道微生物群失调损害后代认知功能的潜在机制。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，从而改变对妊娠前肥胖妇女的产前护理。