We evaluate the role of disordered gut-brain interactions in the pathophysiology of several diseases (Table 1) and explain how the GLP-1 receptor agonists (e.g., semaglutide) for obesity and guanylyl cyclase C agonists (e.g., linaclotide) for irritable bowel syndrome (IBS) work through a gut-brain mechanism. Here, GUCY2C is linked to obesity due to melanocortin 4 receptor deficiency.