Nerve growth factor and diarrhea-predominant irritable bowel syndrome (IBS-D): a potential therapeutic target?

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.

Expression of inducible nitric oxide synthase in mast cells contributes to the regulation of inflammatory cytokines in irritable bowel syndrome with diarrhea

“…This remarkable long‐term hyperexcitability also can be observed after degranulation of MCs . Previous report demonstrated that NGF was involved in the modulation of visceral hyperalgesia and hypersensitivity in IBS patients and rat model of IBS . In the present study, changes of NGF, tryptase, and some pro‐inflammatory cytokines in MCs or BMMCs provided a molecular mechanism for IBS in visceral hypersensitivity processes.…”

Increased expression of nerve growth factor correlates with visceral hypersensitivity and impaired gut barrier function in diarrhoea‐predominant irritable bowel syndrome: a preliminary explorative study

“…Impaired gut barrier exposes the mucosal and submucosal structures to intraluminal pathogens and noxious stimuli, causing low‐grade mucosal inflammation‐immune activation and sensitisation of visceral nociceptors such as TRPV1. Visceral hypersensitivity and impaired barrier function constitute the two important factors in IBS‐D pathogenesis, and also the main causes of symptoms such as abdominal pain, distension and diarrhoea …”

Effects of SCN9A gene modification on Na+ channel and the expression of nerve growth factor in a rat model of diarrhea‑predominant irritable bowel syndrome

“…In addition, disturbed gastrointestinal motility is a risk factor for D-IBS, and ion channels including Na v 1.8 and Na V 1.9 may influence the contractile ability of these organs, suggesting that the development of D-IBS may require the active participation of ion channels. Since expression of Na v 1.8 and Na v 1.9 channels, as well as NGF were enhanced by SCN9A gene modification, this may lead to a novel direction for D-IBS treatment (5). Designer genetic recombination tools and mammalian genetic modification technology are currently novel, reliable and efficient methods to target genomic sequences, which may result in further advances in understanding of gene expression and its associated influence (23).…”

“…The concrete pathogenesis of IBS is multifaceted and not completely understood, however several risk factors for IBS have been identified including genetic, epigenetic, environmental and behavioral factors (2). The development of D-IBS is correlated with psychosocial stress, altered gut flora, intestinal barrier dysfunction, disturbed gastrointestinal motility, mucosal immune activation, visceral hypersensitivity, euro-endocrine abnormality and genetic susceptibility (5). There is still no agreement over optimal pharmacological treatment for D-IBS and as ion channels are important in gastrointestinal function, disrupted ion channels may result in disease, therefore the present study aimed to investigate whether a gene associated with ion channels may act as a novel target to treat the disease (4,6).…”