Irritable Bowel Syndrome: Methods, Mechanisms, and Pathophysiology. Neural and neuro-immune mechanisms of visceral hypersensitivity in irritable bowel syndrome

Abstract

Irritable bowel syndrome (IBS) is characterized as functional because a pathobiological cause is not readily apparent. Considerable evidence, however, documents that sensitizing proinflammatory and lipotoxic lipids, mast cells and their products, tryptases, enteroendocrine cells, and mononuclear phagocytes and their receptors are increased in tissues of IBS patients with colorectal hypersensitivity. It is also clear from recordings in animals of the colorectal afferent innervation that afferents exhibit long-term changes in models of persistent colorectal hypersensitivity. Such changes in afferent excitability and responses to mechanical stimuli are consistent with relief of discomfort and pain in IBS patients, including relief of referred abdominal hypersensitivity, upon intra-rectal instillation of local anesthetic. In the aggregate, these experimental outcomes establish the importance of afferent drive in IBS, consistent with a larger literature with respect to other chronic conditions in which pain is a principal complaint (e.g., neuropathic pain, painful bladder syndrome, fibromyalgia). Accordingly, colorectal afferents and the environment in which these receptive endings reside constitute the focus of this review. That environment includes understudied and incompletely understood contributions from immune-competent cells resident in and recruited into the colorectum. We close this review by highlighting deficiencies in existing knowledge and identifying several areas for further investigation, resolution of which we anticipate would significantly advance our understanding of neural and neuro-immune contributions to IBS pain and hypersensitivity.

Altered colorectal afferent function associated with TNBS-induced visceral hypersensitivity in mice

“…Stretch-sensitive muscular and muscular-mucosal afferents respond to circumferential colorectal stretch and subserve the sensory encoding of colorectal distension/tension in vivo (9,11). Here we report that responses of muscular afferents were significantly increased (i.e., sensitized) at day 14 post-TNBS, whereas responses of muscular-mucosal afferents were unchanged.…”

Impact of psychological stress on irritable bowel syndrome

“…These mast cells release neuropeptides, i.e., 5-HT, proteases and pro-inflammatory cytokines, known to be the mediators responsible for the altered intestinal sensation, motility, secretion and permeability characteristic of IBS [29] . As the majority of enteroendocrine cells, intestinal EC number and its product 5-HT content are elevated after early life stress (neonatal maternal separation) [30][31][32] , and the increased 5-HT has been confirmed to have close correlation with the symptom generation of IBS [33,34] .…”

A biomarker panel and psychological morbidity differentiates the irritable bowel syndrome from health and provides novel pathophysiological leads

“…8,9 While the aetiology of this disorder remains obscure, there is a body of evidence suggesting dysregulation of several pathophysiological pathways including serotonin biosynthesis and metabolism, [10][11][12] mast cell infiltration and degranulation, [13][14][15][16][17] visceral hypersensitivity, an exaggerated stress response, immune activation and bacterial infection (post-infectious IBS) or microbiota alterations. [18][19][20][21][22] Gene expression profiling in tissue samples taken from patients with IBS has been reported using sigmoid colonic mucosal tissue. 23 Although certain gene expression biomarkers have been recently reported in the literature, these markers were derived from data mining of a published inflammatory bowel disease study.…”