The maternal microbiome in childhood growth and immunity during undernutrition

在全球范围内，营养不良占五岁以下儿童死亡的44%1。发育迟缓或直线生长减慢是营养不良的主要并发症，与新陈代谢和传染病风险增加、教育程度降低和晚年认知功能低下有关3。发育迟缓的母亲在分娩过程中更有可能出现并发症，生下发育迟缓的孩子5。反过来，许多出生时发育迟缓的儿童尽管进行了现有的治疗措施，但仍无法康复4。因此，发育迟缓通常被称为代际综合征，迫切需要新的方法来改善弱势群体的童年发育。母体免疫系统在塑造后代的身体、认知和免疫发育方面发挥着重要作用。肠道微生物群同样影响局部和系统免疫，增加了母亲微生物群可能影响胎儿和儿童发育的可能性。我们假设，在营养不良期间，母体肠道微生物组成塑造了胎儿免疫环境，以控制后代的生长和免疫发育。我们建议使用代际营养不良的小鼠模型来确定特定的免疫和微生物靶点进行治疗干预。我们的初步数据表明，与来自健康或严重发育迟缓捐赠者的微生物群定居的繁殖小鼠产生的后代具有不同的体重、骨骼和免疫发育表型，这些表型持续到成熟。我们将使用这个模型来分离母亲肠道微生物组和新生儿微生物组的作用，为潜在干预的窗口提供关键的洞察力。我们还将确定能够影响后代生长和免疫发育的特定微生物亚群，并表征与这些变化相关的微生物代谢产物。最后，我们将确定对这些微生物群落做出反应的母体免疫细胞和信号通路，以控制后代的健康生长和免疫发育。这些实验将确定特定的微生物物种以及宿主免疫途径，以治疗为靶点，并确定适当的发育阶段进行干预。考瓦丁实验室位于弗吉尼亚大学儿童健康研究中心内，作为跨大学微型生物群倡议的成员，它是唯一适合进行这些研究的机构。该实验室拥有成功完成这些目标所需的基础设施和专业知识。最终，这一提议将导致潜在的益生菌和免疫治疗方法，以阻断发育迟缓从母亲到孩子的传播。

Globally, undernutrition contributes to 44% of childhood deaths under the age of five 1. Stunting, or reduced linear growth, is a major complication of undernutrition that is associated with increased risk of metabolic and infectious disease, reduced educational attainment and poor cognitive function later in life 3. Stunted mothers are more likely to experience complications during childbirth, and to give birth to stunted children 5. In turn, many children that are born stunted do not recover despite current therapeutic interventions 4. Therefore, stunting is often referred to as an intergenerational syndrome, and new approaches are desperately needed to improve childhood growth in vulnerable populations. The maternal immune system plays a major role in shaping offspring physical, cognitive and immune development. The gut microbiota likewise influences both local and systemic immunity, raising the possibility that the maternal microbiome could influence fetal and childhood development. We hypothesize that maternal gut microbial composition shapes the fetal immune environment to control offspring growth and immune development during undernutrition. We propose to use a mouse model of intergenerational undernutrition to identify specific immune and microbial targets for therapeutic intervention. Our preliminary data demonstrate that breeding mice colonized with microbiota from healthy or severely stunted donors produce offspring with divergent weight, bone, and immune developmental phenotypes that persist into maturity. We will use this model to isolate the role of the maternal gut microbiome from the neonatal microbiome, giving critical insight into the window of potential intervention. We will also identify specific subsets of microbes that are capable of influencing offspring growth and immune development and characterize microbial metabolic products associated with these changes. Finally, we will identify maternal immune cells and signaling pathways that respond to these microbial communities to control healthy growth and immune development in offspring. These experiments will identify specific microbial species as well as host immune pathways to target therapeutically and define the appropriate developmental stage in which to intervene. The Cowardin lab is located within the Child Health Research Center at the University of Virginia, and as a member of the Trans- University Miocrobiome Initiative, is uniquely suited to pursuing these studies. The lab has both the infrastructure and expertise required for successful completion of these goals. Ultimately, this proposal will lead to potential probiotic and immunotherapeutic treatments to disrupt the transmission of stunting from mother to child.