The early life environment and the growth-immune conflict. Does the gut-brain axis play a role?

早期生活环境与生长免疫冲突。

• 批准号: RGPIN-2018-05300
• 负责人: Connor, Kristin
• 金额: $ 1.75万
• 依托单位: Carleton University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=713582
• 关键词: early; life; environment; growth; immune

The biological mechanisms regulating growth and development are not fully understood. This may be due to our limited understanding of how an organism's development is shaped through its interactions with the environment and other living things, including microorganisms, in early life. We do know that exposures early in an animal's development set its growth trajectory, prioritising growth for immediate survival. However, this strategy has known adverse consequences, including compromising immune function, which can influence fitness, behaviour and survival long-term. Despite this knowledge, there is limited data on how early life exposures impact organ systems that are critical for regulating both growth and cellular/biological defence mechanisms. Studying how these systems coordinate to support appropriate growth and immune function, and how their function is shaped by early environmental and microbial exposures, will uncover new fundamental knowledge about development and provide insight into physiological adaptations to early life challenges. The long-term objective of my research programme is to understand the genomic and biological mechanisms that regulate growth and development and how these mechanisms may be in conflict with those that support an animal's immune defences. To do this, an innovative approach is required that considers the cross-talk that occurs in early life between organ systems important for both growth and immune function. We will use a mouse model of maternal nutritional programming to induce poor growth. Using 16S gene sequencing and mass spectrometry we will determine how this nutritional environment affects the community of microbes inhabiting the birth canal that colonise the offspring during delivery, and the composition of the maternal milk, critical for offspring growth and establishing its immune defences. We will use RNA sequencing, histological techniques and brain imaging to uncover how malnutrition and poor growth alter functional genes and cellular pathways in the offspring brain that regulate metabolism and communication with the gut. We will also evaluate how this model alters genes and cells in the gut required for growth and establishing appropriate immune defences and responses. Finally, we will test the impact of non-digestible fibres and specific microbes, delivered during key periods of growth and immune system development, on the interactions between the gut and brain and their ability to optimise development. This research takes a comparative approach and integrates environmental, host and microbial factors to identify gut-brain connections that mechanistically link growth with immune function. Defining these interactions has the potential to advance knowledge of the biology of stress resilience and compromised immune function, and impact efforts to optimise growth and establish superior immune defences in animals.

调控生长发育的生物学机制尚不完全清楚。这可能是因为我们对生物体在早期生命中如何通过与环境和其他生物(包括微生物)的相互作用而形成发育的了解有限。 我们知道，动物发育早期的暴露决定了它的生长轨迹，将增长放在第一位，以求立即生存。然而，这一策略也有已知的不利后果，包括损害免疫功能，这可能会影响健康、行为和长期生存。尽管有这些知识，但关于早期生命暴露如何影响器官系统的数据有限，这些器官系统对于调节生长和细胞/生物防御机制都是至关重要的。研究这些系统如何协调以支持适当的生长和免疫功能，以及它们的功能如何受到早期环境和微生物暴露的影响，将揭示有关发育的新基础知识，并为早期生命挑战的生理适应提供洞察力。 我的研究计划的长期目标是了解调节生长和发育的基因组和生物学机制，以及这些机制可能如何与支持动物免疫防御的机制冲突。要做到这一点，需要一种创新的方法，考虑到早期生命中器官系统之间的串扰对生长和免疫功能都很重要。 我们将使用母体营养编程的小鼠模型来诱导生长不良。使用16S基因测序和质谱分析，我们将确定这种营养环境如何影响分娩期间定居后代的产道微生物群落，以及对后代生长和建立免疫防御至关重要的母乳成分。我们将使用RNA测序、组织学技术和脑成像来揭示营养不良和生长不良如何改变后代大脑中调节新陈代谢和与肠道沟通的功能基因和细胞路径。我们还将评估该模型如何改变肠道中生长所需的基因和细胞，并建立适当的免疫防御和反应。最后，我们将测试在生长和免疫系统发育的关键时期提供的不可消化纤维和特定微生物对肠道和大脑之间的相互作用及其优化发育的能力的影响。 这项研究采用比较的方法，整合了环境、宿主和微生物因素，以确定将生长与免疫功能机械地联系在一起的肠道-大脑联系。定义这些相互作用有可能促进对应激适应能力和免疫功能受损生物学的了解，并影响优化动物生长和建立优越免疫防御系统的努力。