Search

The small intestine is a highly dynamic and complex cellular ecosystem, which serves as the primary interface between the host and its environment. A critical component of this ecosystem is the microbiota, which plays a pivotal role in shaping both immune and physiological homeostasis of the host from the moment of birth. However, interaction with the microbiota is a double-edged sword – and the inappropriate establishment of host-microbiota crosstalk could lead to detrimental consequences. Eosinophils are multi-functional granulocytes, recruited into the intestine in early life – but the relevance of this phenomenon has remained enigmatic, given the dogmatic view of these cells as drivers of pathophysiology in type-II immune mediated disorders. Understanding the functional significance of their residency in this tissue under homeostatic conditions warrants further investigation and may provide invaluable insight into their dysregulation in disease. In this thesis, I report our investigation of the contributions of eosinophils to small intestinal homeostasis through a broad characterization of changes in various intestinal functions consequent of eosinophil-deficiency. We approached this expansive question through a combination of histological, cellular and transcriptional analyses, which have afforded us unprecedented insight to eosinophil function in this tissue. Using Δdbl.GATA1 mice, a model of constitutive eosinophil deficiency, we provide evidence for a central role for eosinophils in tissue integrity maintenance in response to the microbiota. We report herein that eosinophil-mediated tissue protection is largely driven by epithelial-derived alarmins, released in response to barrier stress – which equips eosinophils with the capacity to maintain small intestinal integrity and homeostasis through the regulation of extracellular matrix remodelling. In summary, our work provides a functional rationale for the early life recruitment of eosinophils in the small intestine, implicating these cells as key facilitators in the establishment of appropriate host-microbiota crosstalk.

Eosinophils are granulocytes, typically implicated as end-stage effector cells in type-II immune responses. They are capable of producing a wide array of pre-formed molecules which render them with vast potential to influence a wide variety of processes. Nonetheless, eosinophil research has traditionally focused on their role in anti-helminthic responses and pathophysiological processes in type-II immune disorders, such as allergy and asthma, where eosinophilia is a hallmark phenotype. However, a number of key studies over the past decade have placed this restricted view of eosinophil function into question, presenting additional evidence for eosinophils as critical regulators of various homeostatic processes including immune maintenance, organ development, and tissue regeneration.