- •Colonic motility is known to be compromised in DD patients.
- •CGRP is important mediator of GI motility thus it was investigated in context of DD.
- •CGRP levels within the enteric plexuses are declined in symptomatic DD patients.
- •Longitudinal smooth muscles display elevated relaxant response to CGRP.
- •Alterations to CGRP might contribute to mobility impairment associated with DD.
Diverticular disease (DD) is one of the most prevalent diseases of the large bowel. Lately, imbalance of neuro-muscular transmission has been recognized as a major etiological factor for DD. Neuronal calcitonin gene-related peptide (CGRP) is a potent gastrointestinal smooth muscle relaxant shown to have a widespread effect within the alimentary tract. Nevertheless, CGRPergic innervation of the enteric ganglia has never been considered in the context of motility impairment observed in DD patients.
Changes in CGRP and calcitonin receptor-like receptor (CRLR) abundance within enteric ganglia were investigated in sigmoid samples from symptomatic and asymptomatic DD patients using quantitative fluorescence microscopy. CGRP effect on gastrointestinal smooth muscle was investigated using organ bath technique.
We found CGRP levels within the enteric ganglia to be declined by up to 52% in symptomatic DD patients. Conversely, CRLR within the enteric ganglia was upregulated by 41% in symptomatic DD. Longitudinal smooth muscle displayed an elevated (+10.5%) relaxant effect to the exogenous application of CGRP in colonic strips from symptomatic DD patients. Samples from asymptomatic DD patients consistently showed intermediate values across different experiments.
In conclusion, the present study demonstrates that CGRPergic signaling is subject to alteration in DD. Our results suggest that a hypersensitization mechanism to gradually decreasing levels of CGRP-IR nerve fibers takes place during DD progression. Alterations to CGRPergic signaling in DD disease may have implications for physiological abnormalities associated with colonic DD.
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- Calcitonin gene-related peptide (CGRP) and amylin and the endocrine pancreas.Int. J. Pancreatol. 1990; 6: 1-15
- Changes in the response to excitatory antagonists, agonists, and spasmolytic agents in circular colonic smooth muscle strips from patients with diverticulosis.Neurogastroenterol. Motil. 2015; 27: 1600-1612https://doi.org/10.1111/nmo.12659
- Pathogenesis of multiple diverticula of the sogmoid colon in diverticular disease.Acta Chir. Scand. Suppl. 1964; 63: 1-68
- Cross-talk between neural and immune receptors provides a potential mechanism of homeostatic regulation in the gut mucosa.Mucosal Immunol. 2014; 7: 1283-1289https://doi.org/10.1038/mi.2014.80
- Revised immunolocalization of the Na+‑d‑glucose cotransporter SGLT1 in rat organs with an improved antibody.Am. J. Phys. Cell Phys. 2008; 295: C475-C489https://doi.org/10.1152/ajpcell.00180.2008
- Calcitonin gene-related peptide regulates amino acid absorption across rat jejunum.Regul. Pept. 2000; 90: 39-45
- Twenty-four hour recordings of colonic motility in patients with diverticular disease.Dis. Colon Rectum. 2001; 44: 1814-1820
- Alterations in colonic motility and relationship to pain in colonic diverticulosis.Clin. Gastroenterol. Hepatol. 2005; 3: 248-253
- Myenteric plexitis: a frequent feature in patients undergoing surgery for colonic diverticular disease.United European Gastroenterol J. 2015; 3: 523-528https://doi.org/10.1177/2050640614563822
- The enteric serotonergic system is altered in patients with diverticular disease.Gut. 2013; 62: 1753-1762https://doi.org/10.1136/gutjnl-2012-302660
- Two submucosal nerve plexus in human intestines.Histochem. Cell Biol. 2010; : 149-161https://doi.org/10.1007/s00418-009-0657-2
- Localization of calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1) in human gastrointestinal tract.Peptides. 2012; 35: 202-211https://doi.org/10.1016/j.peptides.2012.03.020
- Human enteric neuropathies: morphology and molecular pathology.Neurogastroenterol. Motil. 2004; 16: 515-531https://doi.org/10.1111/j.1365-2982.2004.00538.x
- Review article: molecular, pathological and therapeutic features of human enteric neuropathies.Aliment. Pharmacol. Ther. 2008; 28: 25-42https://doi.org/10.1111/j.1365-2036.2008.03707.x
- A novel receptor for calcitonin gene-related peptide (CGRP) mediates secretion in the rat colon: implications for secretory function in colitis.FASEB J. 2000; 14: 1439-1446
- Nitrergic neuro-muscular transmission is up-regulated in patients with diverticulosis.Neurogastroenterol. Motil. 2014; 26: 1458-1468https://doi.org/10.1111/nmo.12407
- Intrinsic primary afferent neurons and nerve circuits within the intestine.Prog. Neurobiol. 2004; : 143-164https://doi.org/10.1016/j.pneurobio.2003.12.004
- In vitro motor patterns and electrophysiological changes in patients with colonic diverticular disease.Int. J. Color. Dis. 2013; 28: 1413-1422https://doi.org/10.1007/s00384-013-1716-7
- Mechanisms of disease smooth muscle cholinergic denervation hypersensitivity in diverticular disease.Lancet. 2003; 361: 1945-1951
- Longitudinal muscle shows abnormal relaxation responses to nitric oxide and contains altered levels of NOS1 and elastin in uncomplicated diverticular disease.Color. Dis. 2007; 9: 218-228https://doi.org/10.1111/j.1463-1318.2006.01160.x
- CGRP as a transmitter in the sensory pathway mediating peristaltic reflex.Am. J. Phys. 1994; 266: G1139-G1145
- Neurotransmitters mediating the intestinal peristaltic reflex in the mouse.J. Pharmacol. Exp. Ther. 2003; 307: 460-467https://doi.org/10.1124/jpet.103.053512
- The peristaltic reflex induced by short-chain fatty acids is mediated by sequential release of 5-HT and neuronal CGRP but not BDNF.Am. J. Physiol. Gastrointest. Liver Physiol. 2007; 292: G429-G437https://doi.org/10.1152/ajpgi.00376.2006
- Brain-derived neurotrophic factor augments peristalsis by augmenting 5-HT and calcitonin gene-related peptide release.Gastroenterology. 2006; 130: 771-780https://doi.org/10.1053/j.gastro.2005.12.026
- The enteric nervous system I: organisation and classification.Pharmacol. Toxicol. 2003; 92: 105-113
- Receptor activity-modifying proteins (RAMPs): new insights and roles.Annu. Rev. Pharmacol. Toxicol. 2016; 56: 469-487https://doi.org/10.1146/annurev-pharmtox-010715-103120
- Alterations of the enteric smooth musculature in diverticular disease.J. Gastroenterol. 2014; 49: 1241-1252https://doi.org/10.1007/s00535-013-0886-y
- Calcitonin gene-related peptide action on intestinal circular muscle.Am. J. Phys. 1989; 256: 546-552
- Neuronal populations in the submucous plexus of the human colon.J. Anat. 1989; 166: 7-22
- Visceral hypersensitivity in symptomatic diverticular disease and the role of neuropeptides and low grade inflammation.Neurogastroenterol. Motil. 2012; 24: 318-e163https://doi.org/10.1111/j.1365-2982.2011.01863.x
- Calcitonin gene-related peptides relax guinea pig and rat gastric smooth muscle.Eur. J. Pharmacol. 1989; 162: 129-134https://doi.org/10.1016/0014-2999(89)90612-2
- Diverticular disease: a fresh approach to a neglected disease.Dig. Dis. 2012; 30: 5https://doi.org/10.1159/000336866
- Calcitonin gene-related peptide (CGRP) in the circular muscle of guinea-pig colon: role as inhibitory transmitter and mechanisms of relaxation.Regul. Pept. 1996; 61: 27-36
- CGRP potentiates excitatory transmission to the circular muscle of guinea-pig colon.Regul. Pept. 1997; 69: 127-136
- The influence of inflammation and nerve damage on the neurochemical characterization of calcitonin gene-related peptide-like immunoreactive (CGRP-LI) neurons in the enteric nervous system of the porcine descending colon.Int. J. Mol. Sci. 2018; 19 (E548)https://doi.org/10.3390/ijms19020548
- The influence of low doses of zearalenone and t-2 toxin on calcitonin gene related peptide-like immunoreactive (CGRP-LI) neurons in the ENS of the porcine descending colon.Toxins (Basel). 2017; 9 (E98)https://doi.org/10.3390/toxins9030098
- A standard for calibration and shading correction of a fluorescence microscope.Cytometry. 2001; 44: 309-316https://doi.org/10.1002/1097-0320(20010801)44:4<309::AID-CYTO1122>3.0.CO;2-3
- Vasodilator effect of adrenomedullin and calcitonin gene-related peptide receptors in rat mesenteric vascular beds.Biochem. Biophys. Res. Commun. 1993; 196: 245-251https://doi.org/10.1006/bbrc.1993.2241
- The aetiology of diverticulosis of the colon with special reference to the action of certain drugs on the behaviour of the colon.Ann. R. Coll. Surg. Engl. 1964; 34: 98-119
- Calcitonin gene-related peptide excites myenteric neurons.Eur. J. Pharmacol. 1986; 132: 163-170
- Motility studies in diverticular disease of the colon.Gut. 1969; 10: 534-542
- The genetic epidemiology of diverticulosis and diverticular disease: emerging evidence.United European Gastroenterol J. 2015; 3: 409-418https://doi.org/10.1177/2050640615576676
- The involvement of nitric oxide synthase neurons in enteric neuropathies.Neurogastroenterol. Motil. 2011; 23: 980-988https://doi.org/10.1111/j.1365-2982.2011.01780.x
- Calcitonin gene-related peptide: physiology and pathophysiology.Physiol. Rev. 2014; 94: 1099-1142https://doi.org/10.1152/physrev.00034.2013
- Post inflammatory damage to the enteric nervous system in diverticular disease and its relationship to symptoms.Neurogastroenterol. Motil. 2009; 21: 847-e858https://doi.org/10.1111/j.1365-2982.2009.01308.x
- Calcitonin gene-related peptide neurons innervating the canine digestive system.Regul. Pept. 1992; 42: 15-26
- Possible involvement of calcitonin gene-related peptide (CGRP) in non-cholinergic non-adrenergic relaxation induced by mesenteric nerve stimulation in guinea pig ileum.Brain Res. 1989; 478: 199-203
- Calcitonin gene-related peptide-like Immunoreactivity in the human small intestine.Acta Anat. (Basel). 1992; 143: 48-53
- Outer submucous plexus: an intrinsic nerve network involved in both secretory and motility processes in the intestine of large.Anat. Rec. 2001; 262: 71-78
- A study on the peptidergic nerves (VIP, substance P) in the colon of patients with diverticular disease.Regul. Pept. 1993; 46: 244-246https://doi.org/10.1016/0167-0115(93)90048-D
- Role of nitric oxide in the left-sided colon of patients with diverticular disease.Hepato-Gastroenterology. 2000; 47: 692-696
- Diverticulosis today: unfashionable and still under-researched.Ther. Adv. Gastroenterol. 2016; 9: 213-228https://doi.org/10.1177/1756283X15621228
- Interaction of NO and VIP in gastrointestinal smooth muscle relaxation.Curr. Pharm. Des. 2004; 10: 2483-2497https://doi.org/10.2174/1381612043383890
- Pathogenesis of colonic diverticular disease.Langenbeck's Arch. Surg. 2012; 397: 1025-1033https://doi.org/10.1007/s00423-012-0961-5
- Accuracy and precision in quantitative fluorescence microscopy.J. Cell Biol. 2009; 185: 1135-1148https://doi.org/10.1083/jcb.200903097
- Diverticular disease is associated with an enteric neuropathy as revealed by morphometric analysis.Neurogastroenterol. Motil. 2010; 22 (e93-4): 407-414https://doi.org/10.1111/j.1365-2982.2009.01445.x
- Intraganglionic laminar endings are mechano-transduction sites of vagal tension receptors in the guinea-pig stomach.J. Physiol. 2001; 534: 255-268
asymptomatic diverticular diseaseCGRP
calcitonin gene-related peptideCRLR
calcitonin receptor-like receptorDD
enteric nervous systemFI
inner submucosal (Meissner's) plexusMP
myenteric (Auerbach's) plexusNO
neuronal nitric oxide synthaseOSP
outer submucosal (Schabadasch's) plexusPGP 9.5
protein gene-product 9.5 (pan-neuronal marker)RAMP1
receptor activity modifying protein 1SDD
symptomatic diverticular disease (diverticulitis)SNP
vasoactive intestinal peptide
Published online: September 18, 2018
Accepted: September 16, 2018
Received in revised form: August 4, 2018
Received: July 2, 2018
© 2018 Elsevier B.V. All rights reserved.