ECCO Grant Investigating regenerative pathways in salivary glands to mitigate oral manifestations of inflammatory bowel diseases

Abstract Background and Aims Inflammatory bowel diseases (IBD) impact 4-16% of patients with extraintestinal manifestations in the upper gastrointestinal (GI) tract, including stomach and esophageal ulcers, dry mouth, taste alterations, halitosis, ulcers, and periodontitis. The underlying mechanisms remain unclear. This study hypothesizes that intestinal inflammation disrupts upper GI tract homeostasis by impairing salivary gland functions and aims to: Aim 1: Elucidate cellular and molecular mechanisms of intestinal inflammation on upper GI tract mucosa and salivary glands. Aim 2: Evaluate therapeutic potential of liver X receptor (LXR) activation in restoring salivary gland function in colitis-induced oral pathology. Methods I will use a novel mounting method for spatial proteogenomic analysis of upper GI tract mucosa to identify colitis-induced perturbations. Salivary glands will be studied separately, employing bulk and single-cell transcriptomic profiling to identify mechanisms driving colitis-induced atrophy, dysfunction, and candidate regenerative pathways. Additionally, salivary gland organoids will be used to study regeneration mechanisms in vitro, such as LXR activation, and the therapeutic potential of successful candidate pathways will be tested in vivo using pre-clinical models of colitis and salivary gland damage/repair (irradiation). Anticipated Impact This research will provide insights into mechanisms by which intestinal inflammation disrupts upper GI tract homeostasis through salivary gland impairment and assess the role of candidate pathways in salivary gland regeneration. In the short to medium term, findings may contribute to developing novel therapeutic strategies for managing colitis-induced oral pathology, benefiting the IBD community by improving patients' quality of life.