Calcitonin gene-related peptide (CGRP) in the pathophysiology of gastrointestinal disorders: a key mediator in the gut-brain axis

The concept "gut-brain axis" means a bidirectional communication between the central nervous system and the gastrointestinal (GI) tract. This axis is key in keeping the physiological homeostasis of the GI tract and its dysfunction has been implicated in a number of neuropsychiatric and gut conditions. A number of neurotransmitters are known to be involved in the performance of gut-brain axis. Our objective has been to review and critically analyze the contribution of the calcitonin gene-related peptide (CGRP) in the physiology and pathophysiology of the gut-brain axis, with emphasis in the fresh, basic, and clinical evidence supporting an outstanding role of this neuropeptide. CGRP is considered the pivotal molecule and the first biomarker of migraine, a debilitating disease combining digestive and neurological symptoms. A number of recent experimental and clinical data support a relevant protective role for CGRP, and in particular for beta-CGRP, the isoform located in the enteric nervous system, in the gut-brain axis proper functioning and in the pathophysiology of several gut diseases, including conditions such as diverticular disease, acute infectious diarrhea or inflammatory bowel disease. As examples of its adaptable behavior, circulating beta-CGRP levels are increased in patients with acute diarrhea in COVID-19 infection or reduced already in the early phases of inflammatory bowel disease. In addition, beta-CGRP antagonism could explain the constipation seen with the new CGRP antagonists used in the preventive treatment of frequent migraine. These evidences indicate a relevant role of CGRP in gut-brain axis functioning and call for analyzing a potential role of CGRP in other common diseases of the GI tract, comorbid with brain conditions, such as irritable bowel syndrome or chronic constipation.