ENTEROENDOCRINE CELLS REGULATE BARRIER INTEGRITY AND PROTECT AGAINST DSS-INDUCED OUTCOMES

Enteroendocrine cells (EECs) are often dysregulated in metabolic and gastrointestinal diseases, such as inflammatory bowel disease, although their roles in disease pathogenesis remain unknown. EECs are rare sensory cells scattered throughout the gastrointestinal epithelium that respond to environmental stimuli like nutrients and microbes by secreting over 20 distinct hormones, neurotransmitters, and metabolites. EECs are well-known for their systemic effects in regulating endocrine and exocrine pancreas function and appetite, but the roles they play within their local environment of the intestine remain obscure. Many metabolic and gastrointestinal diseases are associated with impaired function of the intestinal epithelial barrier, allowing undigested food, microbes, metabolites, and toxins to cross the epithelium and enter the submucosa which triggers local and systemic inflammation. We found that EEC-deficient human intestinal organoids have increased barrier permeability and upregulate an inflammatory signature compared to healthy control organoids, which can be rescued by the administration of exogenous EEC-derived products in vitro. Moreover, EEC-deficient mice exhibit worse outcomes when exposed to dextran sulfate sodium (DSS) in the drinking water. These experiments define a new role for EECs in maintaining gastrointestinal homeostasis, uncover a novel mechanism regulating barrier integrity in health and disease, and provide a basis for future therapies aimed at repairing a leaky gut.