Mast Cell-Dependent Excitation of Visceral-Nociceptive Sensory Neurons in Irritable Bowel Syndrome

Abstract

Background & Aims:Intestinal mast cell infiltration may participate to abdominal pain in irritable bowel syndrome (IBS) patients. However, the underlying mechanisms remain unknown. We assessed the effect of mast cell mediators released from the colonic mucosa of IBS patients on the activation of rat sensory neurons in vitro. Methods: Colonic mast cell infiltration and mediator release were assessed with quantitative immunoflorescence and immunoenzymatic assays. The effect of mucosal mediators was tested on mesenteric sensory nerve firing and Ca 2؉ mobilization in dorsal root ganglia in rats. Results: Mediators from IBS patients, but not controls, markedly enhanced the firing of mesenteric nerves (14.7 ؎ 3.2 imp/sec vs 2.8 ؎ 1.5 imp/sec; P < .05) and stimulated mobilization of Ca 2؉ in dorsal root ganglia neurons (29% ؎ 4% vs 11% ؎ 4%; P < .05). On average, 64% of dorsal root ganglia responsive to mediators were capsaicin-sensitive, known to mediate nociception. Histamine and tryptase were mainly localized to mucosal mast cells. IBS-dependent nerve firing and Ca 2؉ mobilization were correlated with the area of the colonic lamina propria occupied by mast cells (r ‫؍‬ 0.74; P < .01, and r ‫؍‬ 0.78; P < .01, respectively). IBS-dependent excitation of dorsal root ganglia was inhibited by histamine H 1 receptor blockade and serine protease inactivation (inhibition of 51.7%; P < .05 and 74.5%; P < .05; respectively). Conclusions: Mucosal mast cell mediators from IBS patients excite rat nociceptive visceral sensory nerves. These results provide new insights into the mechanism underlying visceral hypersensitivity in IBS.

Fecal Assays Detect Hypersensitivity to Cow's Milk Protein and Gluten in Adults With Irritable Bowel Syndrome

“…Further studies should clarify whether the elimination diet can improve the previously demonstrated mast cell mucosal inflammation and the neural damage which has been reported in IBS. 3,4,[7][8][9] In fact, the relationship between FH and dismotility in pediatric patients has been clearly demonstrated. 20,[33][34][35] ECP might be as useful in FH patients as it is in patients with respiratory allergic diseases.…”

“…3 In fact, several studies have shown an increased number of immunocytes both in the lamina propria and in the epithelium of mucosal biopsy specimens from IBS patients. 4 -10 Lamina propria and intraepithelial lymphocytes, 5,10 mast cells, 4,7,9 and macrophages 11 are among the immunocytes involved in mucosal inflammation in IBS, and a role for a previous infectious enteritis in determining this inflammation has been established. 11,12 However, it is also known that dietary factors might be important in the pathogenesis of IBS 3 and the same inflammatory cells, together with eosinophils, are the immunologic effectors of food hypersensitivity (FH).…”

Mast Cells and Irritable Bowel Syndrome: From the Bench to the Bedside

“…10,14 Supernatants from mucosal biopsies from IBS patients are more likely to activate intestinal nerves than those from healthy subjects. 31,33 Histamine and proteases are the main sensitizing mediators to nerves, which increased in spontaneous release in IBS patients without consideration of different subtypes. 33 Histamine H1 and H2 receptors (H 1 R and H 2 R) may mediate the activation of visceral afferents and enteric neurons, while H 3 R mediate suppression of fast synaptic transmission.…”

“…31,33 Histamine and proteases are the main sensitizing mediators to nerves, which increased in spontaneous release in IBS patients without consideration of different subtypes. 33 Histamine H1 and H2 receptors (H 1 R and H 2 R) may mediate the activation of visceral afferents and enteric neurons, while H 3 R mediate suppression of fast synaptic transmission. 9,24 Tryptase causes long-lasting neuronal hyperexcitability through cleaving and activating proteaseactivated receptor 2 (PAR2) located on enteric nerves and visceral afferents.…”

Immune Activation in Irritable Bowel Syndrome: Can Neuroimmune Interactions Explain Symptoms?

“…At least two subsets of macrophages have been described, M1 and M2, based on functional diff erences, but much remains to be learned regarding appropriate closer proximity to colonic nerve endings in IBS patients, a fi nding that correlated strongly with severity and frequency of pain ( 55 ). Further, supernatants from mucosal biopsies from IBS patients are more likely to activate intestinal nerves than those from healthy subjects ( 52,54,56,66,68 ). Th is nerve activation is dependent on mast cell-derived mediators, including serine proteases acting on protease-activated receptor-2, histamine acting on its H 1 receptor, and serotonin acting on its 5-HT 3 receptor ( Figure 2 ), and occurs regardless of whether changes in absolute mast cell numbers are observed or not.…”