Journal Article

Glucagon-like peptide 1 receptor (GLP-1R) expression by nerve fibres in inflammatory bowel disease and functional effects in cultured neurons

MacQuillan, Anthony, Akbar, Ayesha, Korchev, Yuri E., Bloom, Steve R., Sinisi, Marco, Yiangou, Yiangos, Anand, Uma, Jones, Ben, Fox, Mike, Anand, Praveen, Quick, Tom

2018

Overview

Glucagon like-peptide 1 receptor (GLP-1R) agonists diminish appetite and may contribute to the weight loss in inflammatory bowel disease (IBD). The aim of this study was to determine, for the first time, the expression of GLP-1R by colon nerve fibres in patients with IBD, and functional effects of its agonists in cultured rat and human sensory neurons. GLP-1R and other nerve markers were studied by immunohistochemistry in colon biopsies from patients with IBD (n = 16) and controls (n = 8), human dorsal root ganglia (DRG) tissue, and in GLP-1R transfected HEK293 cells. The morphological effects of incretin hormones oxyntomodulin, exendin-4 and glucagon were studied on neurite extension in cultured DRG neurons, and their functional effects on capsaicin and ATP signalling, using calcium imaging. Significantly increased numbers of colonic mucosal nerve fibres were observed in IBD biopsies expressing GLP-1R (p = 0.0013), the pan-neuronal marker PGP9.5 (p = 0.0008), and sensory neuropeptide CGRP (p = 0.0014). An increase of GLP-1R positive nerve fibres in IBD colon was confirmed with a different antibody to GLP-1R (p = 0.016). GLP-1R immunostaining was intensely positive in small and medium-sized neurons in human DRG, and in human and rat DRG cultured neurons. Co-localization of GLP-1R expression with neuronal markers in colon and DRG confirmed the neural expression of GLP-1R, and antibody specificity was confirmed in HEK293 cells transfected with the GLP-1R. Treatment with oxyntomodulin, exendin-4 and GLP-1 increased neurite length in cultured neurons compared with controls, but did not stimulate calcium influx directly, or affect capsaicin responses. However, exendin-4 significantly enhanced ATP responses in human DRG neurons. Our results show that increased GLP-1R innervation in IBD bowel could mediate enhanced visceral afferent signalling, and provide a peripheral target for therapeutic intervention. The differential effect of GLP-1R agonists on capsaicin and ATP responses in neurons suggest they may not affect pain mechanisms mediated by the capsaicin receptor TRPV1, but may enhance the effects of purinergic agonists.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adult / Aged / Animals / Appetite / ATP / Biology and Life Sciences / Biomarkers / Calcitonin gene-related peptide / Calcium / Calcium imaging / Calcium influx / Calcium signalling / Capsaicin / Capsaicin receptors / Cell receptors / Cells, Cultured / Colon / Colon - metabolism / Colon - pathology / Development and progression / Diabetes / Dorsal root ganglia / Endocrinology / Female / Fibers / Ganglia / Ganglia, Spinal - pathology / Gene Expression Regulation / Genetic aspects / Glucagon / Glucagon-like peptide 1 / Glucagon-Like Peptide-1 Receptor - metabolism / Health aspects / HEK293 Cells / Hormones / Human behavior / Humans / Immunohistochemistry / Inflammatory bowel disease / Inflammatory bowel diseases / Inflammatory Bowel Diseases - metabolism / Inflammatory Bowel Diseases - pathology / Innervation / Insulin / Intestine / Irritable bowel syndrome / Kinases / Localization / Medicine / Medicine and Health Sciences / Metabolism / Middle Aged / Mucosa / Nerve Fibers - metabolism / Nerve Fibers - pathology / Neurons / Pain / Patients / Peptides / Peripheral neuropathy / Physiological aspects / Rats / Research and Analysis Methods / Sensory neurons / Signal transduction