The enteric nervous system is a complex network that includes, in the digestive mucosa, neuronal bodies and fibers interacting with the immune system and mucosal mast cells (MC). These interactions involve the secretion of messengers, such as the neurotrophin nerve growth factor (NGF), which influence colonic motility and sensitivity, both affected in irritable bowel syndrome (IBS). This study was designed to test the hypothesis that, in children with IBS, colonic mucosal innervation, NGF content, and MC infiltration are altered. We aimed to measure MC infiltration, number of neuronal bodies, distance from MC to nerve fibers, inflammation, and NGF content in rectal mucosa of pediatric patients with IBS as compared with controls.
Rectal biopsies from children (median age: 14 years) with diarrhea-predominant IBS (n = 11) and controls (n = 14) were studied. MC and neuronal mucosal structures were identified by tryptase, CD117 and PGP9.5 immunoreactivity. Inflammatory cells (neutrophils, eosinophils, and lymphocytes) were counted. NGF was quantified in situ by ELISA. Key
No mucosal inflammation was detected in IBS. MC infiltration and number of neuronal bodies were not significantly different between IBS and controls. The distance between MC and nerve fibers was not different in IBS compared with controls (5.2 ± 0.3 vs 5.0 ± 0.3 μm). Number of MC in close proximity to nerve fibers (<5 μm) was not different in the two groups. However, in IBS, NGF content was higher than controls (0.93 ± 0.3 vs 0.62 ± 0.3 pg mg(-1) protein, P < 0.05) and significantly correlated with MC number.
Regardless of inflammation, NGF content is increased in rectal mucosa of diarrhea-predominant IBS children.
[Show abstract][Hide abstract] ABSTRACT: Neural plasticity is not only the adaptive response of the central nervous system to learning, structural damage or sensory deprivation, but also an increasingly recognized common feature of the gastrointestinal (GI) nervous system during pathological states. Indeed, nearly all chronic GI disorders exhibit a disease-stage-dependent, structural and functional neuroplasticity. At structural level, GI neuroplasticity usually comprises local tissue hyperinnervation (neural sprouting, neural, and ganglionic hypertrophy) next to hypoinnervated areas, a switch in the neurochemical (neurotransmitter/neuropeptide) code toward preferential expression of neuropeptides which are frequently present in nociceptive neurons (e.g., substance P/SP, calcitonin-gene-related-peptide/CGRP) and of ion channels (TRPV1, TRPA1, PAR2), and concomitant activation of peripheral neural glia. The functional counterpart of these structural alterations is altered neuronal electric activity, leading to organ dysfunction (e.g., impaired motility and secretion), together with reduced sensory thresholds, resulting in hypersensitivity and pain. The present review underlines that neural plasticity in all GI organs, starting from esophagus, stomach, small and large intestine to liver, gallbladder, and pancreas, actually exhibits common phenotypes and mechanisms. Careful appraisal of these GI neuroplastic alterations reveals that-no matter which etiology, i.e., inflammatory, infectious, neoplastic/malignant, or degenerative-neural plasticity in the GI tract primarily occurs in the presence of chronic tissue- and neuro-inflammation. It seems that studying the abundant trophic and activating signals which are generated during this neuro-immune-crosstalk represents the key to understand the remarkable neuroplasticity of the GI tract.
[Show abstract][Hide abstract] ABSTRACT: Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder associated with idiopathic colonic hypersensitivity (CHS). However, recent studies suggest that low-grade inflammation could underlie CHS in IBS. The pro-inflammatory mediator nerve growth factor (NGF) plays a key role in the sensitization of peripheral pain pathways and several studies have reported its contribution to visceral pain development. NGF modulates the expression of Acid-Sensing Ion Channels (ASICs), which are proton sensors involved in sensory neurons sensitization. This study examined the peripheral contribution of NGF and ASICs to IBS-like CHS induced by butyrate enemas in the rat colon.
Colorectal distension and immunohistochemical staining of sensory neurons were used to evaluate NGF and ASICs contribution to the development of butyrate-induced CHS.
Systemic injection of anti-NGF antibodies or the ASICs inhibitor amiloride prevented the development of butyrate-induced CHS. A significant increase in NGF and ASIC1a protein expression levels was observed in sensory neurons of rats displaying butyrate-induced CHS. This increase was specific of small- and medium-diameter L1 + S1 sensory neurons, where ASIC1a was co-expressed with NGF or trkA in CGRP-immunoreactive somas. ASIC1a was also overexpressed in retrogradely labeled colon sensory neurons. Interestingly, anti-NGF antibody administration prevented ASIC1a overexpression in sensory neurons of butyrate-treated rats.
Our data suggest that peripheral NGF and ASIC1a concomitantly contribute to the development of butyrate-induced CHS NGF-ASIC1a interplay may have a pivotal role in the sensitization of colonic sensory neurons and as such, could be considered as a potential new therapeutic target for IBS treatment.
Neurogastroenterology and Motility 07/2013; 25(11). DOI:10.1111/nmo.12199 · 3.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Neuroimmune interactions and inflammation have been proposed as factors involved in sensory-motor dysfunction and symptom generation in adult irritable bowel syndrome (IBS) patients. In children with IBS and healthy controls, we measured ileocolonic mast cell infiltration and fecal calprotectin and evaluated the relationships between these parameters and abdominal pain symptoms and stooling pattern.
Irritable bowel syndrome patients diagnosed according to Pediatric Rome III criteria and healthy controls kept a 2-week pain/stooling diary. Ileocolonic mucosal mast cells (MC) and MC in close proximity to nerve fibers (MC-NF) were identified immunohistochemically and quantified. Fecal calprotectin concentration was measured.
21 IBS patients and 10 controls were enrolled. The MC-NF count was significantly higher in the ileum (p = 0.01), right colon (p = 0.04), and left colon (p < 0.001) of IBS patients compared with controls. No differences in fecal calprotectin concentration were noted. Abdominal pain intensity score correlated with ileal MC count (rs = 0.47, p = 0.030) and right colon MC-NF count (rs = 0.52, p = 0.015). In addition, children with IBS with >3 abdominal pain episodes/week had greater ileal (p = 0.002) and right colonic (p = 0.01) MC counts and greater ileal (p = 0.05) and right colonic (p = 0.016) MC-NF counts than children with less frequent pain. No relationship was found between MC and MC-NF and fecal calprotectin or stooling pattern.
Mast cells-nerve fibers counts are increased in the ileocolonic mucosa of children with IBS. Mast cells and MC-NF counts are related to the intensity and frequency of abdominal pain.
Neurogastroenterology and Motility 11/2013; 26(2). DOI:10.1111/nmo.12250 · 3.59 Impact Factor
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