Calcitonin gene-related peptide (CGRP), a neuropeptide with α and β isoforms, is a pivotal regulator connecting the neural, immune, and gastrointestinal systems. This comprehensive analysis delineates the evidence-based mechanistic roles of CGRP within the microbiome–gut–brain axis, focusing on its bidirectional modulation of enteric and central nervous system pathways. Both α- and β-CGRP are widely expressed in sensory and enteric neurons, where they govern vasodilation, intestinal motility, secretion, and mucosal homeostasis. CGRP-mediated signaling integrates gut microbiota-derived cues with central neurocircuitry, influencing visceral sensitivity, immune activation, and behavioral states such as anxiety and satiety. Furthermore, CGRP interacts with major neurotransmitter systems-including serotonin (5-HT), histamine, dopamine, and glutamatethereby linking peripheral microbial activity to central pain and emotional processing. We discuss isoform-specific and receptor-level mechanisms (e.g., CLR/RAMP1) as evidence permits and highlight gaps in translating preclinical findings to human physiology. Although CGRP has significant roles in other systems, such as in metabolism and pancreatic function, these are beyond the scope of this review, which focuses specifically on the neuro-immune-gastrointestinal interface. Collectively, CGRP emerges as a critical neuroendocrine mediator in coordinating communication across the microbiota-gut-brain axis. A deeper understanding of its spatiotemporal dynamics and isoformspecific functions will be crucial for the development of targeted therapeutic strategies for CGRPrelated disorders affecting both neurological and gastrointestinal systems.
Qiu et al. (Tue,) studied this question.