Feixue Chen

Brain-derived neurotrophic factor contributes to abdominal pain in irritable bowel syndrome

Objective Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, may play a critical role in many chronic pain conditions. The possible involvement of BDNF in the altered gut sensation in patients with irritable bowel syndrome (IBS) was investigated in the present study. Methods Rectosigmoid biopsies were collected from 40 patients with IBS fulfilling the Rome II criteria and 21 healthy controls. Abdominal pain was quantified by a validated questionnaire. The presence of BDNF and nerve fibres in the mucosa was assessed by immunohistochemistry. The structure of mucosal nerve fibres was assessed by transmission electron microscopy. Mucosal BDNF release was measured by ELISA and correlated with abdominal pain scores. Animal studies using BDNF+/− mice were carried out to evaluate visceral sensitivity, mucosal nerve fibre density and ultrastructural changes. Alterations of visceral sensitivity and TrkB expression in dorsal root ganglia were examined in BDNF+/+ mice following different doses of BDNF administration. Results Biopsies from patients with IBS revealed a significant upregulation of BDNF (p=0.003), as compared with controls. Total nerve fibres were also substantially increased in patients with IBS. Electron microscopy showed ultrastructural damage on the mucosal nerve fibres (eg, swollen mitochondria and nerve axons). Elevated BDNF release was significantly correlated with the abdominal pain scores. Meanwhile, abdominal withdrawal reflex scores to colorectal distension and mucosal protein gene product 9.5 immunoreactivity were significantly lowered in BDNF+/− than in BDNF+/+ mice. Electron microscopy showed degenerative changes on the mucosal nerve fibres in BDNF+/− mice. Exogenous BDNF induced an obvious dose-dependent increase in TrkB expression in dorsal root ganglia and dose-dependent decrease in threshold pressure in BDNF+/+ mice. Conclusions The increased expression of BDNF in colonic mucosa, together with the structural alterations of mucosal innervation, may contribute to the visceral hyperalgesia in IBS.

A school-based study with Rome III criteria on the prevalence of functional gastrointestinal disorders in Chinese college and university students.

Background Functional gastrointestinal disorders, including functional dyspepsia, irritable bowel syndrome and functional constipation are very common worldwide. Objective This research aims to estimate the prevalence and associated factors involved in functional gastrointestinal disorders in Chinese college and university students using the Rome III criteria. Methods A total of 5000 students from Shandong University in China were asked in January-May 2012 to complete questionnaires, including the Rome III questionnaire, hospital anxiety and depression scale, and negative life events scale. Results Based on the 4638 students who completed the questionnaire, the prevalence of functional dyspepsia, irritable bowel syndrome and functional constipation in college and university students of North China worked out to be 9.25%, 8.34% and 5.45% respectively. They were more frequent in female students. The factors of anxiety (OR 1.07; 95% CI 0.99 to 1.16, P = 0.002<0.05) and depression (OR 0.55; 95% CI 0.15 to 1.05, P = 0.045<0.05) indicated a high risk of causing irritable bowel syndrome. Conclusion Functional dyspepsia, irritable bowel syndrome and functional constipation were common in college and university students of North China. Psychological disorders such as anxiety and depression provide significant risk factors for irritable bowel syndrome patients.

Gadolinium chloride improves the course of TNBS and DSS-induced colitis through protecting against colonic mucosal inflammation

Inflammatory macrophages in colonic mucosa are the leading drivers of the pathology associated with inflammatory bowel disease (IBD). Here we examined whether gadolinium chloride (GdCl3), a macrophage selective inhibitor, would improve the course of 2,4,6-trinitro benzene sulfonic acid (TNBS) and dextran sodium sulfate (DSS)-induced colitis in mice and the potential mechanisms were investigated. By giving GdCl3 to colitis mice through intravenous or intrarectal route, we found that GdCl3 markedly ameliorated the colitis severity, including less weight loss, decreased disease activity index scores, and improved mucosal damage. To investigate the potential mechanisms, flow-cytometric analysis was performed to detect the proportion of mucosal macrophages in colon. The results showed that GdCl3 had no macrophage depletion effect in colonic mucosa, but significantly suppressed TNBS and DSS-induced TNFα, IL-1β and IL-6 secretions. Also, Western blotting analysis indicated that NF-κB p65 expression was significantly attenuated in the mucosa in colitis mice with GdCl3 treatment. Then, the anti-inflammatory activity of GdCl3 was confirmed in LPS-stimulated RAW 264.7 cells that GdCl3 might down-regulate the production of proinflammatory cytokines by macrophages through inhibition of the NF-κB signaling pathway. Therefore, intervention with mucosal inflammatory macrophages may be a promising therapeutic target in IBD.

Increased production of BDNF in colonic epithelial cells induced by fecal supernatants from diarrheic IBS patients

Colonic brain-derived neurotrophic factor (BDNF) plays an essential role in pathogenesis of abdominal pain in diarrhea-predominant irritable bowel syndrome (IBS-D), but regulation on its expression remains unclear. We investigated the role of fecal supernatants (FSN) from IBS-D patients on regulating BDNF expression in colonic epithelial cells of human and mice. Using human Caco-2 cells, we found that IBS-D FSN significantly increased BDNF mRNA and protein levels compared to control FSN, which were remarkably suppressed by the serine protease inhibitor. To further explore the potential mechanisms, we investigated the impact of protease-activated receptor-2 (PAR-2) on BDNF expression. We found a significant increase in PAR-2 expression in Caco-2 after IBS-D FSN stimulation. Knockdown of PAR-2 significantly inhibited IBS-D FSN-induced upregulation of BDNF. Moreover, we found that phosphorylation of p38 MAPK, not NF-κB p65, contributed to PAR-2-mediated BDNF overexpression. To confirm these results, we intracolonically infused IBS-D or control FSN in mice and found that IBS-D FSN significantly elevated colonic BDNF and visceral hypersensitivity in mice, which were both suppressed by the inhibitor of serine protease or antagonist of PAR-2. Together, our data indicate that activation of PAR-2 signaling by IBS-D FSN promotes expression of colonic BDNF, thereby contributing to IBS-like visceral hypersensitivity.

Brain-derived neurotrophic factor accelerates gut motility in slow-transit constipation

Brain‐derived neurotrophic factor (BDNF) may play a critical role in gut motility. We aimed to investigate BDNFs physiologic effects on gut motility in slow‐transit constipation (STC) and to explore the underlying molecular mechanisms.

BDNF modulates intestinal barrier integrity through regulating the expression of tight junction proteins

Brain‐derived neurotrophic factor (BDNF) may play a vital role in the homeostatic regulation of intestinal barrier integrity. We aimed to investigate the physiological role of BDNF in maintaining the intestinal epithelial barrier using postinflammatory irritable bowel syndrome (PI‐IBS) mice and explore the underlying molecular mechanisms using intestinal epithelial cells in vitro.

Increased Gap Density Predicts Weakness of the Epithelial Barrier In Vivo by Confocal Laser Endomicroscopy in Indomethacin-Induced Enteropathy

Background and AimsThe intestinal epithelial barrier plays an important role in the pathogenesis of non-steroidal anti-inflammatory drug-induced enteropathy, and its disruption is often associated with increased cell shedding. The purpose of this report is to observe the gap density in indomethacin-induced small intestinal damage by confocal laser endomicroscopy (CLE) and to investigate the mechanisms involved in this process and how mucosal protectants improve intestinal epithelial barrier dysfunction. CLE is expected to provide a new way for evaluating non-steroidal anti-inflammatory drugs-induced enteropathy in humans and assessing drug efficacy.MethodsUsing the new technique of CLE, we established a method to evaluate, in real time, intestinal damage after the administration of indomethacin in Wistar rats by investigating the gap density in the small intestine. The mucosal protectant teprenone and acid-suppressant rabeprazole were then given by gavage before and after the administration of indomethacin, and the mechanisms affecting the intestinal epithelial barrier were investigated.ResultsUsing CLE, gaps could be clearly observed and easily distinguished from goblet cells. Gap density was increased after the administration of indomethacin. During this process, the expression of tumor necrosis factor-α, nuclear factor-κB, and caspase-3 was up-regulated and the expression of tight junctions was down-regulated, which led to the damage of the epithelial barrier. Teprenone and rabeprazole could intervene in this pathway and protect the integrity of the epithelial barrier.ConclusionsCLE can be objective, accurate, and real time in investigating gap density. Teprenone and rabeprazole can prevent indomethacin-induced intestinal lesions and protect the epithelial barrier by intervening in the tumor necrosis factor-α pathway. Gap density was expected to be an indicator of evaluating intestinal inflammation and drug efficacy.

Colonic N-methyl-D-aspartate receptor contributes to visceral hypersensitivity in irritable bowel syndrome.

N‐methyl‐d‐aspartate receptor (NMDAR) in brain, spinal cord, and enteric nervous system is involved in visceral hypersensitivity. This study aimed to reveal the functional expression of NMDAR on mucosal cells in colon and to investigate the downstream signal pathway from colonic NMDAR activation to visceral hypersensitivity in irritable bowel syndrome (IBS).

Probe-Based Confocal Laser Endomicroscopy for Imaging TRAIL-Expressing Mesenchymal Stem Cells to Monitor Colon Xenograft Tumors In Vivo

Introduction Mesenchymal stem cells (MSCs) can serve as vehicles for therapeutic genes. However, little is known about MSC behavior in vivo. Here, we demonstrated that probe-based confocal laser endomicroscopy (pCLE) can be used to track MSCs in vivo and individually monitor tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) gene expression within carcinomas. Methods Isolated BALB/c nu/nu mice MSCs (MSCs) were characterized and engineered to co-express the TRAIL and enhanced green fluorescent protein (EGFP) genes. The number of MSCs co-expressing EGFP and TRAIL (TRAIL-MSCs) at tumor sites was quantified with pCLE in vivo, while their presence was confirmed using immunofluorescence (IF) and quantitative polymerase chain reaction (qPCR). The therapeutic effects of TRAIL-MSCs were evaluated by measuring the volumes and weights of subcutaneous HT29-derived xenograft tumors. Results Intravital imaging of the subcutaneous xenograft tumors revealed that BALB/c mice treated with TRAIL-MSCs exhibited specific cellular signals, whereas no specific signals were observed in the control mice. The findings from the pCLE images were consistent with the IF and qPCR results. Conclusion The pCLE results indicated that endomicroscopy could effectively quantify injected MSCs that homed to subcutaneous xenograft tumor sites in vivo and correlated well with the therapeutic effects of the TRAIL gene. By applying pCLE for the in vivo monitoring of cellular trafficking, stem cell-based anticancer gene therapeutic approaches might be feasible and attractive options for individualized clinical treatments.

Ramosetron for the treatment of irritable bowel syndrome with diarrhea: a systematic review and meta-analysis of randomized controlled trials

BackgroundRamosetron is a potent and selective serotonin type 3 receptor antagonist. This meta-analysis aimed to analyze the efficacy and safety of ramosetron for irritable bowel syndrome with diarrhea (IBS-D).MethodsPubmed, MEDLINE, EMBASE and the Cochrane Library were searched for randomized controlled trials investigating the efficacy and safety of ramosetron for IBS-D. Risk of bias was assessed as described in the Cochrane handbook. A random effects model was used to calculate the effects of ramosetron vs placebo on symptomatic improvements, including relief of overall IBS symptoms, relief of abdominal discomfort/pain, improvement in abnormal bowel habits, and improvement in stool consistency, expressed as pooled relative risks (RRs) with 95% confidence interval (CI). Adverse events data were also summarized with RRs.ResultsFour randomized controlled trials involving 1623 participants were included. Compared with placebo, ramosetron could lead to relief of overall IBS symptoms (RR 1.70; 95%CI 1.48, 1.95), relief of abdominal discomfort/pain (RR 1.41; 95%CI, 1.24, 1.59), improvement in abnormal bowel habits (RR 1.72; 95%CI, 1.50, 1.98) and improvement in stool consistency (RR 1.71; 95%CI 1.40, 2.08). Ramosetron could lead to relief of overall IBS symptoms in both male and female patients (RR; 95%CI: 1.94; 1.58, 2.38 and 1.49; 1.25, 1.79). The RR (95%CI) for reported adverse events of ramosetron vs placebo was 1.10 (0.97, 1.26) across all studies. No serious adverse events (e.g., ischemic colitis) were reported. The incidences of hard stool and constipation were higher in ramosetron group compared with placebo group (RR; 95%CI: 4.74; 3.00, 7.51 and 2.53; 1.57, 4.10, respectively).ConclusionsRamosetron had beneficial effects to both male and female IBS-D patients. Treatment with ramosetron could cause more hard stool and constipation, without severe adverse events.