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

母亲孕前肥胖易使后代出现认知功能障碍，但对母亲肥胖对后代脑功能和行为的跨代影响机制知之甚少。这一传统上被忽视的认知健康问题因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妇女受到肥胖的影响尤为严重。目前，对孕前肥胖妇女及其婴儿的产前护理尚无共识，需要新的治疗方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，饮食，独立于遗传，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，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。考虑到母体肠道微生物群影响产前和产后后代的大脑发育，促进神经发育编程，并从母亲垂直传递给她的后代，阐明饮食诱导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导致创新的预防性治疗。基于我们最近发表的工作和令人兴奋的初步数据，我们提出了一项跨学科的研究，结合宏基因组学、代谢组学和神经科学来验证我们的假设，即母体西方饮食（mWD）诱导的机会致病菌上调和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。通过提出的工作，我们的目标是解决关键的，但尚未解决的问题：(1)wd诱导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增加的机会致病菌是否会损害后代的认知功能？（2b）哪些与mwd相关的微生物衍生代谢物影响宿主的认知功能？（2c）通过什么机制？(3)产前通过药物、益生菌或其联合治疗靶向母体肠道微生物组能否挽救与mwd相关的后代认知功能障碍？这些目标的成功完成将揭示妊娠期间孕妇肠道微生物群落结构的改变，鉴定食用孕妇肠道微生物衍生的生物活性代谢物，以及孕妇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。

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.