Development of a gut-on-a-chip platform to monitor dynamic GLP-1 secretion from primary intestinal tissue

Secreted by enteroendocrine L-cells along the intestinal epithelium, glucagon-like peptide-1 (GLP-1) is a key regulator of glucose and energy homeostasis in health, obesity and type 2 diabetes. Understanding the stimuli and mechanisms governing GLP-1 secretion is fundamental to the development of novel therapies for metabolic disorders. Mechanistic studies have, hitherto, relied largely on well-based static incubation of immortalised cell lines or primary intestinal tissues, approaches that have limited physiological relevance and lack the capacity to monitor dynamic hormone release under biomimetic conditions. This study aimed to develop a microfluidic 'gut-on-a-chip' (GOC) platform to enable assessment of dynamic GLP-1 secretion from primary mouse intestinal tissue in a biomimetic environment. We initially characterised regional GLP-1 secretion capacity along the mouse small intestine to inform device design. A polymethyl methacrylate microchip was then micromachined to accommodate a segment of intestinal tissue and support parallel luminal and serosal perfusion via peristaltic microfluidic pumps. In proof-of-concept experiments, physiological GLP-1 secretagogues (taurocholic acid and glucose) were subsequently delivered to the luminal or serosal surface of duodenal and colonic tissue under continuous or intermittent perfusion. The GOC platform demonstrated superiority over static incubation for studying GLP-1 secretion in primary intestinal tissue, capturing dynamic serosal concentration changes over 2 h while better preserving tissue viability and morphology. This novel system provides a powerful tool to elucidate the mechanisms underlying gut hormone release and to screen candidate GLP-1 secretagogues for potential therapeutic development.