Abstract
Diarrhea-predominant irritable bowel syndrome (IBS-D) is a multifactorial chronic gastrointestinal disorder characterized by inflammation and immune response. In this context, NLRP3 over-activation is associated with a breakdown of enteric-immune balance related to IBS-D. The aim of this study was to evaluate the effect of the inflammasome inhibitor, BAY 11-7082, in a rat model of IBS-D. Syndrome was induced by intracolonic instillation of 1 mL 4% acetic acid at 8 cm proximal to the anus for 30 s and sacrificed 2 weeks after IBS-D induction. BAY 11-7082 (10 and 30 mg/kg) was administered daily by oral gavage. The results obtained showed that the treatment with BAY 11-7082 (30 mg/kg) significantly reduced tissue injury characterized by edema, neutrophil infiltration, and loss of colon structure. We demonstrated that BAY 11-7082 treatment inhibited NLRP3 inflammasome activation and NF-kB translocation, reducing inflammatory mediators. Moreover, treatment with BAY 11-7082 restored tight junction alteration following IBS-D induction and reduced the restraint stress. Taken together, our data demonstrate that IBS-D induced NLRP3 inflammasome pathway activation, accompanied by the production of proinflammatory response. The modulation of the inflammosome pathway with BAY 11-7082 inhibitor significantly reduced pathological signs of IBS-D, therefore, can be considered a valuable strategy to reduce the development of IBS-D.
Highlights
Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder characterized by recurrent abdominal pain [1]
Our results showed a basal expression of occludin and zonula occludens-1 (ZO-1) in the colon tissue of the sham group (Figure 2A,F); while the irritable bowel syndrome (IBS-D) group was characterized by a reduction of Tight junctions (TJs) expression (Figure 2B,G)
Previous studies have proven that inflammation and the immune system are important in the development of IBS-D [43]; it is believed that excessive inflammatory and immune responses in the intestine are due to an imbalance of the intestinal epithelial barrier causing deterioration of the colonic mucus layer which is recurrent in patients with intestinal disorders [44]
Summary
Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder characterized by recurrent abdominal pain [1]. Diarrhea-predominant irritable bowel syndrome (IBS-D) is generally reported as the most common subtype (28–46%) of IBS associated with abdominal bloating and watery stools [1,2]. The pathophysiology of IBS is unclear; several mechanisms have been proposed, including altered gastrointestinal (GI) microbiota, infectious gastroenteritis, visceral hypersensitivity, dysregulation of gut–brain axis, chronic stress, and genetic factors [3,4]. Recent studies revealed that inflammation plays a key role in IBS-D development, associated to intestinal dysfunction and increased intestinal epithelial cell (IEC) permeability [6,7]. The nucleotide-binding domain leucine-rich repeat-containing receptors (NLRs) are a family of intracellular innate immune receptors which play essential roles in the areas of intestinal mucosal
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