A novel protein regulator of host-bacterial interactions in the gut in health and disease

The healthy intestine maintains a homeostatic equilibrium between epithelial integrity, a resident immune system and a symbiotic microbiome. Intestinal infections temporarily disrupt this balance, and inflammatory bowel disease (IBD) can be defined as permanent disruption of this homeostasis. Enteric infections are a significant cause of childhood mortality worldwide, and remain a major cause of GP and hospital presentations in Australia. IBD affects 1/200 young Australians, with increasing worldwide incidence. IBD is a life-long disease that often presents in childhood. Treatments are expensive, have serious side effects and lose efficacy over time. There is an urgent need for new therapies for IBD that are effective without systemic immunosuppression. Type I interferons (T1IFN) are a family of cytokines with a single receptor and pleiotropic functions. Constitutive T1IFN is critical in maintaining intestinal homeostasis and limiting inflammation after infection or injury. We have recently identified IFNε, a novel T1IFN, in mouse and human intestinal epithelium. We propose it plays a crucial role in regulating intestinal immune responses to the microbiome. We have compelling preliminary data to support this idea, as IFNε was protective in a mouse model of IBD and limited an in vitro infection model. Other T1IFNs have been used in both IBD patients and models of infection with conflicting results about their protective effects. We now hypothesise that IFNε, expressed in the human intestinal epithelium, is an important regulator of responses to the microbiome.To move these findings from murine models to the clinic, we have recently developed a creative technique to simultaneously analyse both host immune responses from patient intestinal biopsies and the bacteria from the same sample. This allows concurrent host-microbiome analysis to tease apart their interactions. From our paediatric (P)IBD cohort (n=150), we have shown a dysregulated T1IFN response in IBD. By using cutting edge bioinformatic analysis of this extremely large dataset (>3000 bacterial isolates), we have identified a candidate Lactobacillus species associated with this T1IFN response. From this same cohort we have grown small intestinal organoids (mini-guts). These will allow us to analyse ex vivo epithelial-microbe interactions in health and IBD with both pathogens and putative commensal organisms. This patient cohort, combined with unique access to in-house IFNε reagents, will allow us to understand the role of this critical cytokine in human intestinal health and disease. We are seeking enthusiast students to student this novel protein-microbiome interaction with the aim of developing new therapies for gut diseases in children and adults around the world.