The Role of Short-Chain Fatty Acids on Intestinal Epithelial Cell Migration

Inflammatory Bowel Disease (IBD) is a chronic remitting and relapsing autoimmune disorder of the gastrointestinal tract that affects millions of people worldwide with incidence and prevalence on the rise. Increases in the rates of IBD have been partly attributed to shifts toward a western diet, which emphasizes calorie dense, nutrient poor foods high in saturated fats, sugars, and artificial sweeteners. Importantly, dietary fiber intake is low in the United States and abroad. Dietary fiber is fermented into short-chain fatty acids (SCFAs) by the gut microbiota and is vital to proper gut function. Previous studies have found that diets lacking fiber, SCFAs, or receptors for SCFAs predispose both animals and humans to IBD and colorectal cancer. However, in order to utilize SCFAs for clinical management of IBD, we must further understand their functions and mechanisms of action. This work describes the effects of SCFAs, specifically propionate, on intestinal epithelial cell migration and wound healing. Intestinal epithelial cell migration is critical for epithelial restitution, the first phase in wound healing in the intestine. The studies in this dissertation demonstrated the effectiveness of SCFAs to trigger epithelial cell migration independent of proliferation up the crypt-villus axis and reduce ulceration in mice in a model of colitis. Notably, the effects of SCFAs on epithelial migration in a histone deacetylase inhibition (HDACi) and GPR43 dependent manner allows for further targeting of these pathways to circumvent some of the current pitfalls of SCFAs, mainly their ability to inhibit epithelial proliferation, which could be detrimental to ulcer healing.