Divergent effects of exendin‐4 and interleukin‐6 on rat colonic secretory and contractile activity are associated with changes in regional vagal afferent signaling

• Published in: Neurogastroenterology and motility Vol. 33; no. 10; pp. e14160 - n/a
• Main Authors: O'Brien, Rebecca, Buckley, Maria M., O'Malley, Dervla
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.10.2021
• Subjects: Animals; Colon; Cytokines; Electrophysiology; enteric nervous system; Exenatide - pharmacology; Glucagon; glucagon‐like peptide‐1; Inflammation; Interleukin-6 - pharmacology; interleukin‐6; Intestine; Irritable bowel syndrome; Motor activity; Muscle contraction; Rats; Rats, Sprague-Dawley; Sensory neurons; smooth muscle; vagus; Vagus Nerve; smooth muscle; enteric nervous system; vagus; interleukin-6; glucagon-like peptide-1
• ISSN: 1350-1925; 1365-2982
• DOI: 10.1111/nmo.14160

Background The pro‐inflammatory cytokine, interleukin (IL)‐6 is elevated in individuals with the functional bowel disorder, irritable bowel syndrome (IBS). IL‐6 can independently modify intestinal secreto‐motor function, thereby contributing to IBS pathophysiology. Additionally, hormonal changes may underlie symptom flares. Post‐prandial exacerbation of IBS symptoms has been linked to secretion of the incretin hormone, glucagon‐like peptide‐1 (GLP‐1), which can also influence colonic secreto‐motor activity. This study aimed to ascertain if the effects of GLP‐1 on colonic secretory and contractile activity was impacted by elevated IL‐6 levels and if sensory signals regarding such changes were reflected in altered vagal afferent activity. Methods Colonic secretory currents and circular muscle contractile activity was investigated in Sprague Dawley rats using Ussing chamber and organ bath electrophysiology. Regional afferent signaling was assessed using extracellular electrophysiological recordings from colonic vagal afferents. Key Results Application of the GLP‐1 receptor agonist, exendin‐4 (Ex‐4) in the presence of IL‐6 potentiated colonic secretory currents and transepithelial resistance. Vagal afferent fibers originating in the submucosal layer exhibited larger responses to Ex‐4 when IL‐6 was also present. In contrast, co‐application of Ex‐4 and IL‐6 to gut‐bath chambers suppressed circular muscle contractile activity. The activity in extrinsic afferents originating in the colonic myenteric layer was similarly suppressed. Conclusions & Inferences Application of Ex‐4 in the presence of IL‐6 had divergent modulatory effects on colonic secretion and contractile activity. Similar patterns were observed in vagal afferent signaling originating in the submucosal and myenteric neuronal layers, indicating regional afferent activity reflected immune‐ and endocrine‐mediated changes in colonic function. In the context of elevated levels of interleukin‐6, symptoms of irritable bowel syndrome are exacerbated by meal ingestion, which triggers secretion of the incretin hormone, glucagon‐like peptide‐1. Exposure to a glucagon‐like peptide‐1 agonist in the presence of interleukin‐6 had an additive effect on colonic secretory currents but a reduced effect on smooth muscle contractile activity.