Nerve fiber outgrowth is increased in the intestinal mucosa of patients with irritable bowel syndrome.

BACKGROUND & AIMS: Mediators released by the intestinal mucosa of patients with irritable bowel syndrome (IBS) affect the function of enteric and extrinsic sensory nerves, which can contribute to the development of symptoms. Little is known about the effects of mucosal mediators on intestinal neuroplasticity. We investigated how these mediators affect the phenotypes of colonic mucosa nerve fibers, neuron differentiation, and fiber outgrowth. METHODS: We analyzed mucosal biopsy samples collected from 101 patients with IBS and 23 asymptomatic healthy individuals (controls). We measured levels of neuronal-specific enolase, growth-associated protein 43, nerve growth factor (NGF), and tyrosine kinase receptor A (NTRK1) by immunohistochemistry and enzyme-linked immunosorbent assay. Primary rat enteric neurons and human SH-SY5Y cells were incubated with supernatants from the mucosal biopsies and analyzed by morphometric and polymerase chain reaction analyses. RESULTS: Compared with mucosal tissues of controls, mucosa from patients with IBS had a significant increase in the area of lamina propria occupied by neuronal-specific enolase-positive (57.7% increase) and growth-associated protein 43-positive fibers (56.1% increase) and staining density of NGF (89.3% increase) (P < .05 for all). Levels of NGF protein were also increased in tissues from patients with IBS vs controls (18% increase; P = .16) along with levels of NTRK1 (64% increase; P < .05). Mucosal supernatants from tissues of patients with IBS induced higher levels of neuritogenesis in primary culture of enteric neurons, compared with controls, and more NGF-dependent neuronal sprouting in SH-SY5Y cells. CONCLUSIONS: Nerve fiber density and sprouting, as well as expression of NGF and NTRK1, are significantly increased in mucosal tissues of patients with IBS. Mucosal mediators participate to these neuroplastic changes.

Mucosal immune activation in irritable bowel syndrome: gender-dependence and association with digestive symptoms.

OBJECTIVES: Immune activation may be involved in the pathogenesis of irritable bowel syndrome (IBS). However, the relative magnitude of this immune component and its correlation with gender and gastrointestinal complaints in IBS patients remains poorly elucidated. METHODS: We enrolled 48 IBS patients, with either diarrhea or constipation, 12 patients with microscopic colitis, 20 patients with ulcerative colitis, and 24 healthy controls. Colonic immunocytes were identified with quantitative immunohistochemistry on mucosal biopsies. Gastrointestinal symptoms were assessed using a validated questionnaire. RESULTS: IBS patients showed a significant 72% increase in mucosal immune cells compared to controls (P<0.001). Further analyses showed that increased immune cells were present in 50% of the IBS patients. The magnitude of the immune infiltrate in IBS was significantly lower than that of microscopic colitis or ulcerative colitis (42% and 124% increases vs. IBS, respectively; P<0.001). Compared with controls, IBS patients had increased numbers of CD3+, CD4+, and CD8+ T cells and mast cells (P<0.001). Compared to male IBS patients, female IBS patients had greater numbers of mast cells (P=0.066), but lower numbers of CD3+ and CD8+ T cells (P=0.002 and <0.001, respectively). Mucosal mast cell infiltration of IBS patients was significantly associated with abdominal bloating frequency (P=0.022) and with symptoms of dysmotility-like dyspepsia (P=0.001), but not ulcer-like dyspepsia. CONCLUSIONS: A large subset of IBS patients shows gender-dependent mucosal infiltration of immunocytes that correlates with abdominal bloating and dysmotility-like dyspepsia. These results provide the rationale for considering immune mechanisms as a pathophysiological component in a subset of IBS patients.

Probiotics and irritable bowel syndrome: rationale and clinical evidence for their use.

Growing evidence suggests a potential role of intestinal microbiota in irritable bowel syndrome (IBS) pathophysiology and symptom generation. Earlier studies based on classic microbiologic techniques hypothesized the presence of qualitative changes in intestinal microbiota in IBS patients. Recently, studies with molecular techniques have provided evidence of significant changes in microbial profiles in IBS and that the composition may be correlated with certain symptoms reported by patients. Although these studies are far from being exhaustive and conclusive they provide promising results that deserve further investigation. In addition, initial evidence indicated the presence of increased amounts of bacteria in the upper small intestine of IBS patients, a condition know as small intestinal bacterial overgrowth. However, the results of these studies have provided contradictory results suggesting that this area requires further work. These qualitative and quantitative changes in intestinal microbiota may induce different effects on the intestinal mucosa including mucosal barrier defects and immune activation which may contribute to symptom generation. Studies in IBS patients have attempted to target changes in intestinal microflora with different therapeutic approaches, such as the use of prebiotics, probiotics, synbiotics, and nonabsorbable and systemic antibiotics. Overall, the results obtained in probiotic clinical trials suggest some beneficial effect over placebo in the relief of IBS symptoms. However, these results, although encouraging, should be confirmed in larger well-designed, placebo-controlled studies. A number of open questions remain to be addressed, including the dose, type, and time of administration of probiotics.