Noncanonical NF-KB is an alternative NF-KB pathway that is critically involved in the development and maturation of the adaptive immune system. As such, it has typically been studied in B and T cell biology without application to complex organ systems such as the gut. The following work explores the contribution of noncanonical NF-KB to inflammatory and neoplastic disease in the gastrointestinal (GI) system, as well as the effects of its loss on GI health. Chapter 1 opens with an overview of gastrointestinal homeostasis and inflammation, with emphasis on the particular diseases studied in this body of work. Chapter 2 focuses on a review of noncanonical NF-KB function and components, as well as its applications in inflammatory bowel disease (IBD), a quintessential example of disruption of intestinal homeostasis. In Chapter 3 we determine the role of noncanonical NF-KB in allergic disease of the upper gastrointestinal tract, namely a novel model of the disease eosinophilic esophagitis. Our studies revealed that loss of NF-KB-inducing kinase (NIK), the bottleneck molecule in noncanonical NF-KB signaling, results in targeted esophageal inflammation, remodeling, and gene expression changes that are comparable to the human disease. In Chapter 4, we examine the role of noncanonical NF-KB in inflammatory bowel disease using biopsy samples from human IBD patients, and compare the expression of various components of the pathway to inflammation status and treatment response. Noncanonical NF-KB is upregulated in IBD patients, and also appears to be specifically upregulated in patients that have lost response to anti-TNF inhibitors, which are potent drugs that are widely used to treat IBD. In Chapter 5 we focus on NIK and its effects on stem cell function, growth, and inflammation-induced cancer in the gut. Loss of NIK in mice results in alterations in colonic stem cell function and changes in colonic microbiome, which predisposes them to the development of inflammation-induced carcinogenesis. Indeed, in human patients with colorectal cancer, noncanonical NF-KB is also suppressed. Overall, we have discovered multiple novel roles of noncanonical NF-KB signaling at multiple levels in the gut and in the context of a variety of diseases, and have greatly expanded the current body of knowledge as to the functions and effects of this pathway.Ph. D.The gastrointestinal system has a complex set of checks and balances to maintain overall health. If factors involved in the promotion or suppression of inflammation, the regulation of growth, or the prevention of tumor formation become dysregulated, there can be catastrophic consequences for the human body. The aim of this work is to investigate a pathway called noncanonical NF-κB in the development of various diseases in the GI tract. Noncanonical NF-κB is not a well understood pathway and to date has mostly been studied in the context of white blood cell development. However, we discovered that noncanonical NF-κB has several very important functions in the GI tract that have implications in conditions such as inflammatory bowel disease and colorectal cancer. First we explored the role of noncanonical NF-κB in the upper GI tract, namely the esophagus, and found that this signaling pathway is critically involved in the movement of white blood cells called eosinophils to the esophagus, resulting in throat inflammation in both mouse models and human patients. Secondly, we determined that this same pathway also has effects in the lower GI tract. Human patients with inflammatory bowel disease, especially those who develop resistance to popular medications, see an upregulation of this pathway in their colon tissue. Loss of this pathway in the colons of mice also causes changes in growth of the colonic epithelium, and predisposes them to the formation of colon cancer. Interestingly, in human colon cancer patients, we also see similar changes in expression of genes associated with this pathway. Overall, we have found many new and exciting roles for this underappreciated pathway in the gut.