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ZJUS-B
Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology)  2016, Vol. 17 Issue (1): 1-9    DOI: 10.1631/jzus.B1500181
Review     
Nerve growth factor and diarrhea-predominant irritable bowel syndrome (IBS-D): a potential therapeutic target?
Xiao-juan Xu1,2,Liang Liu3,Shu-kun Yao1,2,?()
1 Gastroenterology Department, China-Japan Friendship Hospital, Beijing 100029, China
2 Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100073, China
3 Jinan Central Hospital Affiliated to Shandong University, Jinan 250014, China
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Abstract  

Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder characterized by recurrent abdominal pain or discomfort associated with abnormal bowel habits. Diarrhea-predominant IBS (IBS-D) is a major subtype of IBS, the predominant manifestations of which are abdominal pain and diarrhea. The pathogenesis of IBS-D remained unknown until recently. The effects of psychosocial stress, central hypervigilance, neuroendocrine abnormality, disturbed gastrointestinal motility, mucosal immune activation, intestinal barrier dysfunction, visceral hypersensitivity (VH), altered gut flora, and genetic susceptibility may be involved in its development. Recently, increased attention has been placed on the neural-immune-endocrine network mechanism in IBS-D, especially the role of various neuroendocrine mediators. As a member of the neurotrophin family, nerve growth factor (NGF) has diverse biological effects, and participates in the pathogenesis of many diseases. Basic studies have demonstrated that NGF is associated with inflammatory- and stress-related VH, as well as stress-related intestinal barrier dysfunction. The aim of this study is to summarize recent literature and discuss the role of NGF in the pathophysiology of IBS-D, especially in VH and intestinal barrier dysfunction, as well as its potential as a therapeutic target in IBS-D.

Key words： Nerve growth factor      Diarrhea-predominant irritable bowel syndrome      Pathophysiology      Intestinal barrier dysfunction      Visceral hypersensitivity     
Received: 27 June 2015      Published: 01 January 2016
Fund:  Project supported by the National Ministry of Science and Technology “Twelfth Five-Year“ Supporting Project, China(No. 2014BAI08B02)
Corresponding Authors: Shu-kun Yao     E-mail: Ysk12329@126.com
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Xiao-juan Xu,Liang Liu,Shu-kun Yao. Nerve growth factor and diarrhea-predominant irritable bowel syndrome (IBS-D): a potential therapeutic target?. Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology), 2016, 17(1): 1-9.

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http://www.zjujournals.com/xueshu/zjus-b/10.1631/jzus.B1500181     OR     http://www.zjujournals.com/xueshu/zjus-b/Y2016/V17/I1/1

Fig. 1 Flow diagram of the study selection and exclusion process
Reference Country Study type Employed techniques Key findings
Willot et al., 2012 Canada Human Immunohistochemistry, enzyme-linked immuno sorbent assay (ELISA) Rectal mucosal NGF content was higher in IBS-D children than in control and correlated with mast cell (MC) number
Dothel et al., 2015 Italy Human Immunohistochemistry, ELISA, primary cell culture, qRT-PCR Higher nerve fiber density, neuronal sprouting, and mucosal NGF and TrkA levels in IBS patients; NGF antibodies inhibited the neurotrophic effect of mucosal supernatants from IBS patients
Barreau et al., 2004 France Animal Immunohistochemistry, RT-PCR, gut permeability (GP) by 51Cr-EDTA Maternal deprivation (MD) increased visceral sensitivity, GP, and colonic NGF expression in rats; NGF antibodies abolished these effects
van den Wijngaard, 2009 The Netherlands Animal Immunohistochemistry, qRT-PCR, Western blotting Acute stress induced colonic hypersensitivity and elevated colonic MC numbers in adult MD rats; MC stabilizer, NGF antibodies, or TRPV1 antagonist prevented the hypersensitivity
Yu et al., 2008 China Animal Intraperitoneal NGF injection NGF enhanced water avoidance (WA)-induced visceral hypersensitivity
Delafoy et al., 2003 France Animal Intraperitoneal NGF injection Both NGF and trinitrobenzene sulfonic acid (TNBS) induced colonic hypersensitivity via capsaicin-sensitive afferent fibers; NGF antibodies could reverse the effects of NGF and TNBS
Delafoy et al., 2006 France Animal Drug intervention, colonic sensitivity assessment via barostat Calcitonin gene-related peptide (CGRP) antagonist alleviated TNBS or NGF-induced colonic hypersensitivity; NGF antibodies failed to reverse CGRP-induced hypersensitivity
Barreau et al., 2007 France Animal Drug intervention, GP by 51Cr-EDTA, immunohistochemistry, ELISA MD rats showed increased GP and colonic NGF content; CRF acts on mast cells to stimulate NGF release and participates in the elevated GP observed in MD adult rats
Barreau et al., 2008 France Animal Immunohistochemistry, ELISA, drug intervention MD induced increased nerve fiber density and synaptogenesis, as well as mast cell hyperplasia and hypertrophy; NGF antibodies prevented these effects
Table 1 Key data from the various studies exploring the role of NGF in IBS pathophysiology
Fig. 2 NGF-MC-nerve interaction in IBS-D pathophysiology
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