Unraveling the role of calcitonin gene-related peptide b in gastrointestinal disorders: Implications for migraine

ABSTRACT

Introduction: Calcitonin gene-related peptide (CGRP) a is well-known to be implicated in migraine pathophysiology. Its b isoform, released mainly in the enteric nervous system, has not been as extensively studied. Previous research prompt CGRP has a role in gastrointestinal motility, as well as immune and intestinal blood flow regulation. It is postulated to help peptic ulcer healing, and immune cell migration and regulation in acute gastrointestinal infections. In COVID-19 between 2% and 50% of patients develop diarrhea, and its prevalence increases with the severity of the disease. The pathophysiology of the diarrhea in this infection is not completely clear but CGRP has been proposed to play a role in different aspects of the symptomatology. Inflammatory bowel disease (IBD), known to be associated with migraine, is a chronic gastrointestinal autoimmune disease. Neuropeptides like CGRP might play a role in the complex pathophysiology of the disease, but this has not been well established yet. On the other hand, the most frequent adverse event of new monoclonal antibodies against CGRP for migraine is constipation, which points out that the blockage may affect CGRPbeta release. Objective(s) To assess the role of CGRPbeta in two gastrointestinal disorders COVID-19 with acute diarrhea;and IBD. Method(s) CGRPbeta were measured by ELISA (CUSABIO, China) in early morning serum samples in patients with IBD at diagnosis, as well as in COVID-19 inpatients experiencing diarrhea. We compared each group with a cohort of healthy controls matched by age and sex. Image Results: Twenty-six COVID-19 inpatients with diarrhea were included (mean age=62+/-16 years, range 31-91 years;69.2% females) who were matched with 30 healthy controls (mean age=61+/-15 years, range 29-89 years, 66.6% women). Fifty-nine patients with early IBD (mean age 48.9+/-16.4 years, range 21-79 years;62,7% females were matched with 59 healthy controls (mean age 49.0+/-14.9 years, range 23-77 years;62,7% females). While CGRPbeta levels were significantly elevated in COVID-19 patients (6,3+/-2.6 pg/mL) vs controls (4.2+/-2.4 pg/mL) (+26.2%;p<0.01), CGRPbeta levels in patients with IBD were significantly decreased (3.1+/-1.8 pg/mL) as compared to controls (4.8+/-2.6 pg/mL) (-35.4%, p<0.001). Conclusion(s) CGRPbeta seems to exert different actions depending on the underlying conditions. While its increase with diarrhea in COVID-19 patients fits very well with the known acute effects of increase gastrointestinal motility in CGRP infusion in volunteers, the decrease in CGRPbeta levels in IBD confirm a protective role of this peptide in the homeostasis of the intestinal mucosa. These findings may help to explain the role of CGRPbeta in digestive manifestations of migraine and in the constipation seen in migraine patients on CGRP antibodies as well.