The gut endocrine system comprises a collection of enteroendocrine cells scattered throughout the intestinal epithelium, producing hormones that signal locally within the gut and distantly at tissues such as the brain and pancreas. In the field of diabetes and obesity, therapies based on GLP-1 are now in widespread clinical use, and dual/triple agonists such as GLP1/GIP and GLP1/GIP/glucagon are showing even greater efficacy.

The study of GLP-1 secretion can now be performed using human intestinal organoids, engineered by CRISPR-Cas9 to label specific enteroendocrine cell populations or to knock out genes of interest. Application of live cell imaging, electrophysiology and transcriptomics to these organoid model has identified signalling pathways of particular interest including those activated by glucose, bile acids and free fatty acids. Whereas glucose stimulates enteroendocrine cells as a consequence of its electrogenic uptake via SGLT1, bile acids and free fatty acids target specific G-protein coupled receptors on the cell membrane, most notably GPBAR1 and FFAR1.

Understanding signalling in the gut brain axis provides a foundation for identifying new drugs for type 2 diabetes and obesity that act by targeting gut endocrine cells, thus mimicking the gut endocrine consequences of bariatric surgery.