Role of IL-25 in the maintenance of intestinal homeostasis and host-microbial interactions

Abstract

Within the gastrointestinal (GI) tract a rich, diverse microbiota exists, which provide a number of benefits to the host including nutrient acquisition and immune maturation. However, strict immunological control is required to maintain this mutually beneficial relationship between the host and the microbiota. Recent investigations have demonstrated immunological deficiencies can result in an imbalanced microbiota, resulting in microbial dysbiosis that is associated with inflammatory diseases such as inflammatory bowel disease. A single layer of intestinal epithelial cells forms a physical barrier to separate the host from intestinal microbes, and these cells are critically important in the regulation of intestinal immune responses and homeostasis. Interleukin-25 (IL-25) is an epithelial derived cytokine that is induced following microbial exposure. Yet, the role of IL-25 in barrier function and microbial handling that underpins optimal host-microbe interactions remains unknown. IL-25 expression is reduced in biopsies from inflammatory bowel disease (IBD) patients, and IL-25 production increases following disease remission. These data strongly suggest an important role for IL-25 in the regulation of intestinal inflammation. To delineate the IL-25 mediated cellular and molecular mechanisms predisposing to disease, I employed the DSS model of intestinal inflammation. I observed that IL-25 deficient (IL-25-/-) mice displayed markedly increased intestinal inflammation as compared to C57BL/6 mice. Further, the inflammatory response was dependent on intestinal microbes, as demonstrated by an amelioration of intestinal inflammation following broad-spectrum oral antibiotic treatment. Analysis of gut microbial communities revealed key differences in IL-25-/- mice, and this dysregulated microbial composition and exacerbated inflammatory response were transmissible to C57BL/6 mice. To investigate the mechanisms by which IL-25 controls host-microbial mutualism, I examined a role for IL-25 in the regulation of barrier and immune function in the intestine. I found altered intestinal epithelial cell homeostasis, characterised by reduced intestinal permeability and mucous production in IL-25-/- mice. I have also shown that IL-25 deficiency affects the number and function of intestinal eosinophils. In addition, IL-25-/- mice display multiple defects in intestinal immune pathways that regulate microbial handling including IgA and IL-22, and these perturbations likely contribute to the microbial dysbiosis that I have characterised in these mice. Moreover, the microbial dysbiosis present in IL-25-/- mice is sufficient to transmit many of these defects to C57BL/6 mice, demonstrating that intestinal microbial composition impacts intestinal homeostasis. Yet, the defects in intestinal homeostasis remain in IL-25-/- mice even in the absence of the inflammation-associated dysbiosis, supporting the role of IL-25 in the regulation of these pathways. To distinguish the relative contributions of IL-25 and intestinal microbes for intestinal homeostasis, I conducted inbreeding of cross-fostered C57BL/6 mice. Strikingly, the progeny of cross-fostered C57BL/6 mice have restored intestinal and microbial homeostasis, demonstrating that microbial dysbiosis can be rescued through IL-25-mediated maternal regulation of intestinal microbiota. In support of this, analysis of breast milk from IL-25-/- mice revealed a significant reduction in IgA levels. Taken together, these data demonstrate that IL-25 influences microbial colonisation through modulation of breast milk IgA production and intestinal immune responses, thus identifying IL-25 as a putative therapeutic target for long lasting immune health benefits.