Lipopolysaccharide accelerates peristalsis by stimulating glucagon-like peptide-1 release from L cells in the rat proximal colon.

Abstract

Upon epithelial barrier dysfunction, lipopolysaccharide (LPS) stimulates glucagon-like peptide-1 (GLP-1) secretion from enteroendocrine L cells by activating Toll-like receptor 4 (TLR4). Because GLP-1 accelerates peristalsis in the proximal colon, the present study aimed to explore whether LPS facilitates colonic peristalsis by stimulating L cell-derived GLP-1 release. In isolated segments of rat proximal colon that were serosally perfused with physiological salt solution and luminally perfused with 0.9% saline, peristaltic wall motion was video recorded and converted into spatio-temporal maps. Fluorescence immunohistochemistry was also carried out. Intraluminal administration of LPS (100 or 1 µg mL-1 but not 100 ng mL-1) increased the frequency of oro-aboral propagating peristaltic contractions. The LPS-induced acceleration of colonic peristalsis was blocked by TAK-242 (the TLR4 antagonist), exendin-3 (the GLP-1 receptor antagonist) or BIBN4096 (the calcitonin gene-related peptide receptor antagonist). GLP-1-positive epithelial cells co-expressed TLR4 immunoreactivity. In aspirin-pretreated preparations where epithelial barrier function had been impaired, a lower dose of LPS (100 ng mL-1) became capable of accelerating peristalsis. By contrast, luminally applied dimethyl sulphoxide, a reactive oxygen species scavenger that protects epithelial integrity, attenuated the prokinetic effects of a higher dose of LPS (100 µg mL-1). In colonic segments of a stress rat model leading to a leaky gut, LPS induced more pronounced prokinetic effects. Colonic L cells may well sense luminal LPS via TLR4 triggering the release of GLP-1 that stimulates calcitonin gene-related peptide-containing neurons. The resultant acceleration of peristalsis would facilitate excretion of Gram-negative bacteria from the intestine, and thus L cells may have a protective role against intestinal bacterial infections. KEY POINTS: Colonic epithelial cells form a barrier against bacterial invasion but also may contribute more actively to the exclusion of luminal pathogen by stimulating colonic motility. Luminal lipopolysaccharide (LPS) accelerated colonic peristalsis by stimulating calcitonin gene-related peptide-containing neurons. The prokinetic effect of LPS was mediated by the secretion of glucagon-like peptide-1 from enteroendocrine L cells in which Toll-like receptor 4 was expressed. The LPS-mediated acceleration of peristalsis depended on epithelial barrier integrity. L cells have a defensive role against Gram-negative bacterial infections by facilitating faecal excretion, and could be a potential therapeutic target for gastrointestinal infections.