Abstract
Grape seed extract (GSE) is rich in polyphenols composed mainly of proanthocyanidins, which are known to attenuate proinflammatory cytokine production. Repeated water avoidance stress (WAS) induces visceral allodynia and colonic hyperpermeability via toll-like receptor 4 (TLR4) and proinflammatory cytokine pathways, which is a rat irritable bowel syndrome (IBS) model. Thus, we explored the effects of GSE on repeated WAS (1 h for 3 days)-induced visceral allodynia and colonic hyperpermeability in Sprague-Dawley rats. Paracellular permeability, as evaluated by transepithelial electrical resistance and flux of carboxyfluorescein, was analyzed in Caco-2 cell monolayers treated with interleukin-6 (IL-6) and IL-1β. WAS caused visceral allodynia and colonic hyperpermeability, and intragastric administration of GSE (100 mg/kg, once daily for 11 days) inhibited these changes. Furthermore, GSE also suppressed the elevated colonic levels of IL-6, TLR4, and claudin-2 caused by WAS. Paracellular permeability was increased in Caco-2 cell monolayers in the presence of IL-6 and IL-1β, which was inhibited by GSE. Additionally, GSE suppressed the claudin-2 expression elevated by cytokine stimulation. The effects of GSE on visceral changes appear to be evoked by suppressing colonic TLR4-cytokine signaling and maintaining tight junction integrity. GSE may be useful for treating IBS.
Highlights
Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by chronic abdominal pain with altered bowel habits [1]
We have recently demonstrated that IL-6, IL-1β, and toll-like receptor 4 (TLR4) pathways mediated these visceral changes induced by repeated water avoidance stress (WAS) [4,12], which is similar to the LPS-induced IBS model
The current study showed that repeated WAS increased the colonic levels of IL-6, IL-1β and TLR4, and altered colonic tight junction (TJ) protein expression, which could impair gut barrier integrity
Summary
Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by chronic abdominal pain with altered bowel habits [1]. Stress alters the visceral sensory function and has a significant impact on the development and exacerbation of IBS symptoms [3]. There have been several reports showing that compromised gut barrier function manifested by gut hyperpermeability is observed in some patients with IBS, and stress enhances gut permeability [3,4]. Impaired gut barrier leads to bacterial translocation causing increased lipopolysaccharide (LPS) and proinflammatory cytokines, which is considered to be a pivotal. It was reported that circulating pro-inflammatory cytokines and LPS are increased in IBS patients [5,8,9,10]. We previously showed that LPS induced visceral hypersensitivity and gut barrier disruption via interleukin-6 (IL-6), IL-1 [7], and toll-like receptor
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