Ghrelin acts in the brain to block colonic hyperpermeability in response to lipopolysaccharide through the vagus nerve （グレリンは脳に作用して迷走神経を介してLPSで誘導される腸管透過性亢進を抑制する）

Brain ghrelin plays a role in gastrointestinal functions. Among them, ghrelin acts centrally to stimulate gastrointestinal motility and induce visceral antinociception. Intestinal barrier function, one of important gastrointestinal functions, is also controlled by the central nervous system. Little is, however, known about a role of central ghrelin in regulation of intestinal permeability. The present study was performed to clarify whether brain ghrelin is also involved in regulation of intestinal barrier function and its mechanism. Colonic permeability was estimated in vivo by quantifying the absorbed Evans blue in colonic tissue in rats. Intracisternal injection of ghrelin dose-dependently abolished increased colonic permeability in response to LPS while intraperitoneal injection of ghrelin at the same dose or intracisternal injection of des-acyl-ghrelin failed to block it. Carbachol potently attenuated LPS-induced intestinal hyperpermeability, and atropine or bilateral subdiaphragmatic vagotomy prevented the improvement of intestinal hyperpermeability by central ghrelin. Intracisternal (D-Lys3)-GHRP-6, a selective ghrelin receptor antagonist, significantly blocked improvement of intestinal barrier function by intravenously administered 2-deoxy-d-glucose, central vagal stimulant. Intracisternal injection of orexin 1 receptor antagonist, SB-334867 blocked intracisternal ghrelin-induced improvement of colonic hyperpermeability. These results suggest that exogenously administered or endogenously released ghrelin acts centrally to improve a disturbed intestinal barrier function through orexinergic signaling and the vagal cholinergic pathway. Central ghrelin may be involved in the pathophysiology and be a novel therapeutic option in not only gastrointestinal diseases such as irritable bowel syndrome but also non-gastrointestinal diseases associated with the altered intestinal permeability.博士（医学）旭川医科大

Imeglimin prevents visceral hypersensitivity and colonic hyperpermeability in irritable bowel syndrome rat model

Visceral hypersensitivity and leaky gut, which are mediated via corticotropin-releasing factor (CRF) and Toll-like receptor 4 are key pathophysiology of irritable bowel syndrome (IBS). Metformin was reported to improve these gastrointestinal (GI) changes. In this study, we attempted to determine the effects of imeglimin, which was synthesized from metformin on GI function in IBS rat models. Imeglimin blocked lipopolysaccharide- or CRF-induced visceral hypersensitivity and colonic hyperpermeability. These effects were prevented by compound C or naloxone. These results suggest that imeglimin may be effective for the treatment of IBS by improved visceral sensation and colonic barrier via AMPK and opioid receptor