V. Stanghellini

A role for inflammation in irritable bowel syndrome

Attention has been directed to the putative role of low grade mucosal inflammation in irritable bowel syndrome (IBS) on the basis of evidence showing that some patients with IBS have an increased number of inflammatory cells in the colonic and ileal mucosa. Previous episodes of infectious enteritis, genetic factors, undiagnosed food allergies, and changes in bacterial microflora may all play a role in promoting and perpetuating this low grade inflammatory process. Human and animal studies support the concept that inflammation may perturb gastrointestinal reflexes and activate the visceral sensory system even when the inflammatory response is minimal and confined to the mucosa. Thus abnormal neuroimmune interactions may contribute to the altered gastrointestinal physiology and hypersensitivity that underlies IBS. A brief review of the human and animal studies that have focused on the putative role of intestinal inflammation and infections in the pathogenesis of IBS is given.

Fasting and postprandial gastrointestinal motility in ulcer and non-ulcer dyspepsia.

This study aimed to compare fasting and postprandial gastrointestinal motor patterns in patients with ulcer and non-ulcer dyspepsia. Forty five subjects were studied: 10 with uncomplicated gastric ulcer, eight with uncomplicated duodenal ulcer, 18 with chronic idiopathic dyspepsia, and nine healthy asymptomatic controls. Gastrointestinal fasting and postprandial motor patterns were recorded using a low compliance perfusion technique. The interdigestive antral cumulative motility index, computed for 30 minutes before the appearance of duodenal activity fronts, and the number of activity fronts with an antral component were significantly less in patients with ulcers and those with non-ulcer dyspepsia compared with asymptomatic controls. The patient groups also had a reduced antral motor response to a solid-liquid test meal compared with healthy controls. Intestinal motor abnormalities (bursts of non-propagated phasic pressure activity and discrete clustered contractions) were recorded in a minority of patients, all with associated irritable bowel symptoms. In conclusion, antral hypomotility is a frequent but nonspecific motor abnormality in dyspepsia; abnormal motor patterns of the small bowel are less frequent and seem to be confined to patients with concomitant irritable bowel syndrome.

Upper gastrointestinal motor activity in patients with slow-transit constipation. Further evidence for an enteric neuropathy.

Recent evidence indicates that patients complaining of severe chronic idiopathic constipation may have motor abnormalities not limited to the colon. We studied by manometric means gastric and small bowel motility in a homogeneous group of patients with chronic idiopathic constipation ie, the slow transit type. Twenty-one patients were recruited for the study and compared to 33 healthy subjects. Manometric examination was carried out for about 5 hr fasting and 1 hr after a standard meal. Analysis of the manometric tracings revealed during fasting no abnormalities in number and configuration of migrating motor complex with respect to controls. However, in 70% of patients motor abnormalities were detected, represented by bursts of nonpropagated contractions and discrete clustered contractions. After feeding, the patient group displayed a significantly shorter antral motor response to the meal with respect to controls; moreover, intestinal bursts of nonpropagated contractions were found in 19% of patients, and 14% of them had an early return of the activity fronts. We conclude that patients with slow transit constipation frequently display motor abnormalities of the upper gut. These findings further strengthen the concept that this condition may represent a panenteric disorder.

Primary Enteric Neuropathies Underlying Gastrointestinal Motor Dysfunction

Gastrointestinal functions are controlled by a neural network composed of a multitude of intramural neural elements that constitute the enteric nervous system (ENS) (1–7). The ENS encompasses diverse functionally distinct subclasses of enteric neurons, including primary intrinsic afferent neurons, ascending and descending interneurons, excitatory and inhibitory motor neurons, vasomotor neurons, and secretomotor neurons, which are functionally linked in neural circuitries regulating reflexes and peristalsis (1–7). This highly integrated neural system, localized within the wall of the alimentary tract and extending throughout its entire length, is referred to as the ‘brain of the digestive system’ because of its ability to function in the absence of nerve inputs from the central nervous system (1–6). Along with the intrinsic innervation, extrinsic nerve pathways also contribute to the regulatory mechanisms underlying gut functions (1, 2, 4, 6). In addition to exocrine and endocrine secretions, microcirculation, and motility, recent evidence shows that the ENS is also involved in the control of immune mechanisms and inflammatory processes that occur in the digestive system (8). Damage, either congenital or acquired, to the ENS circuitries may cause a wide array of disorders that are rarely fatal but whose clinical severity can markedly compromise the patient’s quality of life. This review is intended to provide coverage of current knowledge on primary enteric neuropathies as a key pathophysiologic mechanism underlying gastrointestinal motor disorders. In addition to neurons, consistent evidence suggests that interstitial cells of Cajal play an important role in the regulation and pathophysiology of intestinal motility. Since coverage of this aspect is beyond the aim of this review, the reader is referred to a recent article (9).

Intestinal inflammation and activation of sensory nerve pathways: a functional and morphological study in the nematode infected rat

BACKGROUND In the rat, gastric distension elicits an intensity dependent pseudoaffective bradycardia mediated via capsaicin sensitive afferent and cholinergic efferent vagal pathways. Inflammation alters visceral perception although the mediators responsible have not been identified. In the nematode infected rat, there is a substantial increase in neuronal substance P (SP) content of the gut. AIMS To examine the effects of inflammation on perception of a noxious visceral stimulus and on SP and neurokinin 1 (NK-1) receptor immunoreactivity (IR) in visceral afferent pathways. METHODS Immunohistochemistry was performed on sections from the jejunum, dorsal root ganglia (DRG), and spinal cord (T1–L1) using SP and NK-1 rabbit polyclonal antibodies. In the DRG, the number of SP-IR or NK-1-IR neurones per section was visually quantified. The pseudoaffective cardiac reflex response to gastric stimulation was compared in control andTrichinella spiralis infected rats. RESULTS Intestinal inflammation induced a rightward shift in the intensity dependent bradycardic response to gastric distension. This was associated with a marked increase in SP-IR not only in the gut wall but also in the DRG and dorsal horn of the spine. In contrast, NK-1-IR was not increased in the gut wall. Moreover, inflammation evoked a decrease in NK-1-IR in the dorsal horn. No NK-1-IR was identified in the DRG of either control or infected animals. CONCLUSIONS Intestinal inflammation modulates the capsaicin sensitive pseudoaffective autonomic response to gastric distension, increases SP-IR in afferent pathways, and downregulates dorsal horn NK-1-IR. As the pseudoaffective response is capsaicin sensitive, the rightward shift of the response is likely the consequence of the decrease in NK-1 receptors in the sensory pathways.

Clinical Findings and Anti-Neuronal Antibodies in Coeliac Disease with Neurological Disorders

Background: Little is known about the clinical and immunological features of coeliac disease patients with neurological disorders. In a large series of adult coeliac disease patients, we investigated the prevalence of neurological disorders and anti-neuronal antibodies, along with the clinical course. Methods: Neurological symptoms were investigated in 160 consecutive patients (120 F, 40 M) with biopsy-proven coeliac disease. Anti-neuronal antibodies to central/enteric nervous systems were investigated in all neurological patients, 20 unaffected ones and 20 controls. Results: Thirteen (8%) patients had neurological disorders, including epilepsy ( n = 3), attention/memory impairment ( n = 3), cerebellar ataxia ( n = 2), peripheral neuropathy ( n = 2), multiple sclerosis ( n = 1), Moyamoya disease ( n = 1) and Steinerts disease ( n = 1). No significant demographic or clinical differences (gastrointestinal or other gluten-related signs) were found between patients with and without neurological involvement. In all but 2 of the 13 cases, the neurological disorder preceded diagnosis of coeliac disease. Neurological symptoms improved or disappeared in 7 patients who started a gluten-free diet within 6 months after neurological onset, and in none of 4 patients who began later. Prevalence of central nervous system antineuronal antibodies was significantly higher in neurological (61%) than in other patients (5%) ( P = 0.0007) or controls (0%) ( P = 0.00001). Conclusions: Coeliac disease can sometimes present in the guise of a neurological disorder, which may greatly improve when a gluten-free diet is started promptly. Therefore, the possible presence of coeliac disease needs to be carefully considered in patients with cerebellar ataxia, epilepsy, attention/memory impairment or peripheral neuropathy.

Submucous rather than myenteric neurons are activated by mucosal biopsy supernatants from irritable bowel syndrome patients

Backgroundu2002 We previously showed that colonic mucosal biopsy supernatants from patients with irritable bowel syndrome (IBS) activate neurons of the human submucous plexus, an area with densely packed immune cells. Based on the concept that mucosa‐nerve signaling is altered in IBS, we tested in this study whether the nerve sensitizing effect of IBS mucosal biopsy supernatants is more prominent in the submucous than myenteric plexus.

Patient-reported outcomes and gut dysmotility in functional gastrointestinal disorders.

Backgroundu2002 Unlike chronic idiopathic intestinal pseudo‐obstruction (CIIP), severe digestive syndromes that are not characterized by episodes resembling mechanical obstruction remain poorly characterized. The present study compared clinical features, small bowel motility, and quality of life (QoL) in patients with CIIP or severe functional gastrointestinal disorders (SFGID), compared to irritable bowel syndrome (IBS).

Neutral endopeptidase (EC 3.4.24.11) downregulates the onset of intestinal inflammation in the nematode infected mouse

Background and aims: Substance P (SP) release from sensory nerves induces neurogenic inflammation. Neutral endopeptidase (NEP) degrades SP, thereby limiting its proinflammatory effects. Intestinal inflammation following Trichinella spiralis infection markedly downregulates NEP, resulting in diminished SP degradation, with unknown functional consequences. We hypothesised that diminished expression of NEP would exacerbate T spiralis induced enteritis. Methods: NEP knockout (NEP−/−) and wild-type (NEP+/+) mice were infected with T spiralis and studied at 6, 12, 24, and 48 hours post infection (PI). Tissue inflammation was quantified by computerised cell counting and myeloperoxidase activity (MPO). The leucocyte adhesion molecule, intercellular adhesion molecule 1 (ICAM-1), and SP were assessed by immunohistochemistry. Results: Before infection, the lack of NEP was not associated with changes in mucosal cellularity or MPO activity. Twelve hours PI, NEP−/− mice showed a 2.5-fold increase in MPO activity at a time when values in NEP+/+ mice were still within normal limits. MPO activity and cellularity peaked at 24 hours PI. This was accompanied by increased staining for both ICAM-1 and SP in NEP−/− mice. Infusion of rhNEP to NEP−/− mice significantly reduced MPO activity 24 hours PI. Conclusions: These findings demonstrate that NEP downregulates the early onset of nematode intestinal inflammation and that increased bioavailability of SP and overexpression of ICAM-1 in NEP−/− mice likely play a role in the earlier onset of intestinal inflammation.

Analysis of candidate genes for intrinsic neuropathy in a family with chronic idiopathic intestinal pseudo-obstruction

To the Editor: Chronic idiopathic intestinal pseudo-obstruction (CIIP) is a rare disease characterized by a severe impairment of intestinal propulsion, mimicking mechanical obstruction in the absence of any lesion of the gut lumen (1–3). CIIP can be due to abnormalities of both the neurogenic and myogenic control mechanisms of gut motility. Although most CIIP patients are referred to as sporadic (1–3), familial forms have also been described with either autosomal recessive or dominant transmission (1–4). Furthermore, an X-linked locus has been mapped to the Xq28 region (5, 6). Among intrinsic neuropathies, Hirschsprung’s disease, characterized by a complete absence of the enteric ganglia usually in the distal portion of the rectum and/or large intestine, is one the most frequent forms of localized neurogenic CIIP (1–4). Abnormalities in several genes, regulating the normal development of the enteric innervation, have been identified in Hirschsprung’s patients (2–4). Genes that have been implicated include the RET proto-oncogene, the glial-cell line derived neurotrophic factor (GDNF), and its receptor-a (GFRA1), the endothelin 3 (EDN3) and its receptor B (EDNRB) and SOX10 (2–4). These genes, along with HOX11L1, are all potential candidates for familial forms of more extensive neuropathic enteric disorders, such as those detectable in some CIIP patients. We report on a large Italian pedigree with recurrence of CIIP phenotype in two first cousins both suffering from severe digestive symptoms with recurrent sub-occlusive episodes without additional clinical features. In these 2 patients, gastrointestinal manometry showed motor abnormalities compatible with abnormal intrinsic neural control in the absence of smooth muscle impairment (1). Segregation analysis in our pedigree (Fig. 1) suggests the presence of an autosomal dominant trait with incomplete penetrance and/or variable expressivity. This model of inheritance accounts for the presence of the same phenotype in the two affected first cousins and for moderate-to-severe digestive symptoms with recurrent constipation in several family members. Furthermore, a second cousin of the two affected individuals died in the postnatal period from unspecified intestinal problems. X-linked transmission cannot be excluded if we consider only the two affected individuals (III-7 and III-24). In order to exclude the involvement of RET, GFRA1, GDNF, EDNRB, and EDN3 genes in the pathogenesis of CIIP, one intragenic (RET-int5) (7) and nine flanking (sTCL-2, D5S2025, D5S2101, D10S1773, D10S187, D13S160, D13S170, D20S173, D20S171) (8, 9) polymorphic markers were used. Exclusion of HOX11L1 and SOX10 genes was performed by SSCP analysis (10) of the whole coding region and by direct sequencing, respectively. Table 1 shows the haplotype reconstruction for the genes studied by linkage analysis (RET, GFRA1, GDNF, EDNRB, and EDN3) in the two affected individuals. The exclusion of these different candidate genes was achieved on the basis of different haplotypes inherited by the two affected individuals at the same loci, as well as on the basis of linkage analysis. Two-point lod scores estimated at these markers were all less than −2 except for markers sTLC-2 and D13S170, where lod scores were 0.12 and 0.30, respectively. Nevertheless, a two-point lod score of −2.67 at RETint5, an intragenic marker localized in RET intron 5, was enough to exclude the involvement of the RET proto-oncogene. Furthermore, negative multipoint lod scores (less than −2) were obtained in the whole RET-int5/sTCL-2 and D13S160/ D13S170 regions. Finally, no alterations were identified in the coding regions of SOX10 and HOX11L1 genes by direct sequencing and SSCP analysis. In conclusion, our results suggest that the genetically determined defects of enteric neurons so far described in Hirschsprung’s patients do not occur in CIIP, at least in the investigated family. Alterations in other currently unknown or unidentified genes regulating enteric neuron differentiation and/or function may play a pathogenetic role in CIIP.