Inflammatory bowel disease (IBD) is a sizable health challenge that has emerged in the 21st century, affecting millions of people worldwide with incidence rates on the rise. Current therapies are insufficient to induce long- term remission in many patients, leading to high rates of surgical intervention and increased risk of colorectal cancer (CRC). Thus, new therapies are needed to decrease morbidity and mortality from IBD. Many patients with IBD are deficient in the microbial metabolites of dietary fibers, short chain fatty acids (SCFAs), and thus SCFAs represent a potential target for therapeutic development. SCFAs play complex roles in gut homeostasis including epithelial turnover, proliferation, apoptosis, and immune regulation. SCFAs have a profound impact on human health and disease, and a diet high in dietary fibers has been linked to decreased risk of CRC and IBD. To date, the evidence for use of SCFAs as a treatment for IBD has been inconsistent. These inconsistencies are most likely driven by SCFAs ability to regulate gene expression by inhibition of histone deacetylases; however, which genes are differentially regulated is largely dependent on the type of SCFA, its concentration relative to other SCFAs, and the cell type, all of which further complicate treatment. To date, the identity of the specific genes that are differentially regulated by SCFAs to induce wound healing and modulate inflammation are unknown. Recently, we identified a secreted glycoprotein, milk fat globule-EGF factor 8 (MFGE8), which is significantly upregulated by SCFAs. MFGE8 is deficient in IBD patients, and plays roles in cellular migration and T cell differentiation. Thus, the long-term goal of this project is to understand the role of SCFAs in the promotion of migration and suppression of inflammation, key processes in wound healing and protection against colitis. Our hypothesis is that SCFAs differentially regulate intestinal epithelial cell (IEC) expression of MFGE8 to induce wound healing and suppress inflammation in IBD. Using MFGE8 deficient cell lines and KO mice, we will employ several molecular biology techniques including wound healing assays, immunohistochemistry, confocal microscopy, kinase assays, ex. vivo enteroid cultures, flow cytometry, and acute and transfer models of experimental colitis to address our hypothesis through two specific aims: 1) Define the role of MFGE8 in SCFA-induced wound healing; 2) Determine SCFA conditioning of IEC to induce Treg development through induction of MFGE8. Elucidating the roles of MFGE8 in SCFA induction of wound healing and suppression of inflammation in IBD will help deepen our understanding of the potential of SCFAs as a therapeutic. This information will be utilized to inform future therapeutic development involving SCFAs, and ultimately remove a critical barrier that is preventing long-term sustained remission in a large percentage of IBD patients. !
PUBLIC RELEVANCE Inflammatory bowel disease (IBD) is a major public health problem with many patients being unable to enter long-term sustained remission with current therapies. This preclinical research project will explore how microbiota metabolites of dietary fibers, short chain fatty acids (SCFAs), which are deficient in many IBD patients, function in wound healing and suppression of inflammation. The results of this project have the potential to lead to the development of new therapeutics containing SCFAs that would be able to help more patients with IBD achieve long-term sustained remission.