Understanding the Role of Innate Immunity, the Microbiome, and Host Factors in Colitis and Intestinal Fibrosis

Inflammatory Bowel Disease (IBD) affects millions of Americans and is steadily increasing in incidence globally every year. IBD is typically broken down into Crohn’s Disease (CD) and Ulcerative Colitis (UC), with an approximately even distribution of diagnoses. This disease is categorized by an uncontrolled, pathogenic inflammation in the gastrointestinal tract and is thought to be caused by a combination of genetic and environmental factors. There is currently no cure to IBD, but historically, treatments have been developed by targeting immune mechanisms. This thesis examines several models of IBD to contribute a better understanding of the interaction between the innate immune system, the gut microbiome, and host factors in the pathogenesis of IBD. The role of the innate immune system in IBD is poorly understood as it is typically overshadowed by the adaptive immune system. Suppression of T cells is commonly the target of IBD therapies, while the innate immune system remains understudied. This thesis examines a mouse model of colitis that is exclusively driven by the innate immune system through the knockout of RAG1 and transgenic expression of TNF Alpha Induced Protein 3 (TNFAIP3) under a villin promoter so that it is constitutively active in the epithelial cells of the GI tract. Through this model, this thesis demonstrates that the innate immune system can respond to a disrupted gut microbiome which leads to intestinal inflammation. This model was then expanded upon to uncover the role of innate lymphoid cells (ILCs) by knocking out retinoid orphan receptor gamma t (ROR?t) and it was shown that ROR?t is dispensable for the development of this colitis. The gut microbiome is the community of bacteria, archaea, fungi, and viruses that colonize the digestive tract. The composition of the gut microbiome is important for the maintenance of a variety of health functions including obvious functions nutrient acquisition and digestion, but increasing evidence shows that the gut microbiome may also influence the susceptibility to mental health conditions such as anxiety and depression, as well as diseases like Parkinson’s, Alzheimer’s, and IBD. This thesis demonstrates that the gut microbiome in fact drives the innate model of colitis developed and studied in this thesis. Host factors are an extremely important means for both how the human body interacts with itself as well as with external factors such as infections, tissue damage, and the gut microbiome. Host factors can influence homeostasis not only of our own cellular functions, but of the populations of microbes that colonize our guts. This thesis investigates the role of the host factor Gastrokine-1 (Gkn1) on both the microbiome and additional host proteins to protect against the induction of colitis. The work presented in this thesis is aimed at advancing our understanding of the GI tract and the molecular mechanisms that trigger IBD.