Modulation of inflammation by toll-like receptor 4/nuclear factor-kappa B in diarrhea-predominant irritable bowel syndrome.

Xing He,Ying Wang,Yan Zheng,Xiao-Hui Wang,Zhi-Hui Yan,Li-Hong Cui,Zhe Luo,San-Dong Gong,Chao Li

doi:10.18632/oncotarget.23045

Abstract

In order to investigate the function of toll-like receptor 4/nuclear factor-kappa B (TLR4/NF-κB) signal pathways in the pathogenesis of diarrhea-predominant irritable bowel syndrome (IBS-D), IBS-D animal models were established in wistar rats challenged with acute and chronic stresses (29 days). Wistar rats without stress-challenged were used as controls. IBS-D models were randomly divided into two groups: one was treated with normal saline, another group was treated with TLR4/NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC) (50mg/kg/week) for continuous four times. Our results demonstrate that continuous stresses can induce the characteristic symptoms of IBS-D, including high wet stool rate and intestinal flora imbalance. Further examinations of colon tissues show that the protein expression levels of TLR4 and NF-κB in IBS-D groups are higher than that in control group. The secretory levels of interleukin (IL-8), tumor necrosis factor α (TNFα), and myeloid differentiation factor 88 (MyD88) are significantly increased in IBS-D group. Administration with PDTC effectively downregulates levels of these inflammatory factors. In contrast, interleukin-10 (IL-10) is in an opposite alteration with lower levels in IBS-D groups and the PDTC treatment increases it to the levels as in control group. Moreover, inhibition of the TLR4/NF-κB by PDTC improves the microstructure of intestinal mucosa mainly by increasing the height of villi. Our results suggest that TLR4/NF-κB signal pathway plays an important role in the modulation of inflammatory responses in IBS-D, which might be a therapeutic target for the IBS-D. All of these findings also provide the evidence concerning an inherent linkage between the axis of stress/NF-κB/inflammation and IBS-D.

Highlights

Irritable bowel syndrome (IBS), a heterogeneous gastrointestinal disorder, is a kind of digestive diseases characterized by chronic recurrent abdominal pain or discomfort associated with abnormal bowel habits and changes of defecation traits
Our results suggest that TLR4/NF-κB signal pathway plays an important role in the modulation of inflammatory responses in irritable bowel syndrome (IBS-D), which might be a therapeutic target for the IBS-D
The pyrrolidine dithiocarbamate (PDTC) administration was able to reduce the levels of myeloid differentiation factor 88 (MyD88) (Figure 3D). These results suggest that TLR4/NF-κB pathway can modulate inflammatory factors to affect the progress of IBS-D

Summary

Introduction

Irritable bowel syndrome (IBS), a heterogeneous gastrointestinal disorder, is a kind of digestive diseases characterized by chronic recurrent abdominal pain or discomfort associated with abnormal bowel habits and (or) changes of defecation traits. A variety of factors including diet, psychology, gene, environment, stress, and inflammation have been reported to be related with IBS [5,6,7,8]. These factors may alter gut-brain axis, induce abnormal gastrointestinal motility, or impair the intestinal mucosal barrier function, subsequently leading to relevant IBS-D symptoms [5,6,7,8]. Compelling evidence suggests a possible role for inflammation in the pathogenesis of IBS [9,10,11] Inflammatory cytokines, such as IL-1β, IL-8, and TNF-α can affect gastrointestinal motility, secretion, and reabsorption. TLR4 can activate a critical inflammatory mediator, NFκB to modulate inflammatory responses [14, 15]

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