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

调控生长发育的生物学机制尚不完全清楚。这可能是由于我们对生物的发育是如何通过其与环境和其他生物（包括微生物）在生命早期的相互作用而形成的理解有限。******我们确实知道，在动物发育的早期，暴露在环境中决定了它的生长轨迹，优先考虑当前生存的生长。然而，这种策略有已知的不良后果，包括损害免疫功能，这可能影响健康、行为和长期生存。尽管有这些知识，关于生命早期暴露如何影响对调节生长和细胞/生物防御机制至关重要的器官系统的数据有限。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，将揭示关于发育的新基础知识，并为早期生活挑战的生理适应提供见解。******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，以及这些机制如何与支持动物免疫防御的机制相冲突。要做到这一点，需要一种创新的方法来考虑发生在生命早期对生长和免疫功能都很重要的器官系统之间的串扰。******我们将使用母体营养规划的小鼠模型来诱导生长不良。通过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产道内的微生物群落，以及母乳的成分，这对后代的生长和建立免疫防御至关重要。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通路。我们还将评估该模型如何改变肠道中生长和建立适当免疫防御和反应所需的基因和细胞。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能力的影响。******本研究采用比较方法，整合环境，宿主和微生物因素，以确定肠-脑连接，机械地将生长与免疫功能联系起来。定义这些相互作用有可能推进对应激恢复力和免疫功能受损的生物学知识，并影响优化动物生长和建立优越免疫防御的努力。

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.