Rosanna Cogliandro

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.

Natural History of Chronic Idiopathic Intestinal Pseudo-Obstruction in Adults: A Single Center Study

BACKGROUND & AIMS Chronic idiopathic intestinal pseudo-obstruction (CIIP) is a rare disease characterized by episodes resembling mechanical obstruction in the absence of organic, systemic, or metabolic disorders. Intestinal motor abnormalities have long been identified in CIIP patients. Little is known of the natural history of the disease in adults. This study evaluated the clinical course of CIIP over time. METHODS Fifty-nine consecutive CIIP patients without underlying collagen, vascular diseases, or mitochondrial cytopathies were evaluated between 1985 and 2001. Family history, onset of digestive symptoms, previous surgeries, episodes suggestive of subacute intestinal obstruction, digestive symptoms, body mass index, and feeding habits were recorded. Small bowel manometry was performed by a perfusion technique, and abnormal motor patterns were visually identified. Full-thickness biopsies were available in 11 cases and were processed for immunohistochemical analysis of myogenic and neurogenic components of the gut wall. RESULTS Patients were prospectively followed up for a median of 4.6 years (range, 1-13 years). Diagnosis was often made several years after symptom onset (median, 8 years). Thus, the majority of patients (88%) underwent useless and potentially dangerous surgeries (mean, 2.96 per patient). Manometry invariably showed abnormal motor patterns. Pathologic findings included neuropathies in all investigated cases and abnormalities of interstitial cells of Cajal in 5 of 11 cases. Long-term outcome was generally poor despite surgical and medical therapies; 4 patients died of disease-related complications, 4 underwent small bowel transplantation, almost one third required long-term home parenteral nutrition, and two thirds had some sort of nutritional limitations. CONCLUSIONS CIIP is a severe, often unrecognized disease characterized by disabling and potentially life-threatening complications over time.

Intestinal Serotonin Release, Sensory Neuron Activation, and Abdominal Pain in Irritable Bowel Syndrome

OBJECTIVES:Serotonin (5-hydroxytryptamine, 5-HT) metabolism may be altered in gut disorders, including in the irritable bowel syndrome (IBS). We assessed in patients with IBS vs. healthy controls (HCs) the number of colonic 5-HT-positive cells; the amount of mucosal 5-HT release; their correlation with mast cell counts and mediator release, as well as IBS symptoms; and the effects of mucosal 5-HT on electrophysiological responses in vitro.METHODS:We enrolled 25 Rome II IBS patients and 12 HCs. IBS symptom severity and frequency were graded 0–4. 5-HT-positive enterochromaffin cells and tryptase-positive mast cells were assessed with quantitative immunohistochemistry on colonic biopsies. Mucosal 5-HT and mast cell mediators were assessed by high-performance liquid chromatography or immunoenzymatic assay, respectively. The impact of mucosal 5-HT on electrophysiological activity of rat mesenteric afferent nerves was evaluated in vitro.RESULTS:Compared with HCs, patients with IBS showed a significant increase in 5-HT-positive cell counts (0.37±0.16% vs. 0.56±0.26%; P=0.039), which was significantly greater in patients with diarrhea-predominant IBS vs. constipation-predominant IBS (P=0.035). Compared with HCs, 5-HT release in patients with IBS was 10-fold significantly increased (P<0.001), irrespective of bowel habit, and was correlated with mast cell counts. A significant correlation was found between the mucosal 5-HT release and the severity of abdominal pain (rs=0.582, P=0.047). The area under the curve, but not peak sensory afferent discharge evoked by IBS samples in rat jejunum, was significantly inhibited by the 5-HT3 receptor antagonist granisetron (P<0.005).CONCLUSIONS:In patients with IBS, 5-HT spontaneous release was significantly increased irrespective of bowel habit and correlated with mast cell counts and the severity of abdominal pain. Our results suggest that increased 5-HT release contributes to development of abdominal pain in IBS, probably through mucosal immune activation.

Chronic intestinal pseudo-obstruction: manifestations, natural history and management

Abstract  Chronic intestinal pseudo‐obstruction (CIPO) is a rare pathological condition characterized by a marked derangement of gut propulsive motility mimicking mechanical obstruction, in the absence of any lesion occluding the gut lumen. This disease is often associated with a disabling and potentially life‐threatening complications and is still too often unrecognized even in referral centres. As a result, patients receive neither appropriate care nor recognition of their severe health condition. Medical and surgical therapies are often unsatisfactory and long‐term outcome turns out to be poor in the vast majority of cases. This article focuses on the main clinical features, the management and long‐term outcome of patients affected by CIPO, with particular emphasis on those aspects which remain a matter of debate.

Effect of mesalazine on mucosal immune biomarkers in irritable bowel syndrome: a randomized controlled proof-of-concept study

Background  Intestinal immune infiltration contributes to symptoms in patients with irritable bowel syndrome (IBS).

Dyspeptic symptoms and gastric emptying in the irritable bowel syndrome

OBJECTIVES:Irritable bowel syndrome (IBS) and dyspepsia often overlap. Delayed gastric emptying has been reported in IBS patients, although conflicting results exist. Whether overlapping dyspepsia correlates with gastric emptying abnormalities in IBS patients has not been clarified. This study aimed to evaluate gastric emptying of solids and its relationship with dyspeptic symptoms in IBS patients.METHODS:A total of 146 IBS outpatients seen in a referral center were evaluated for dyspeptic symptoms using a validated questionnaire. Gastric emptying of solids was evaluated scintigraphically in all patients and in 50 healthy controls.RESULTS:Overlapping dyspepsia was diagnosed in 96 (66%) IBS patients. On average, gastric emptying rates were lower in IBS patients (mean ± SEM, 33%± 1%/h) compared with controls (40%± 2%/h; p < 0.01). Specifically, gastric emptying was delayed in IBS patients with overlapping dyspepsia (31%± 1%/h; p < 0.01), whereas IBS patients without dyspeptic complaints showed gastric emptying rates (37%± 2%/h) that were similar to those of healthy controls (40%± 2%/h). Relevant postprandial fullness (OR = 4.7, 95% CI = 1.8–12.5) and relevant nausea (OR = 3.3, 95% CI 1.2–9.3) were independently associated with delayed gastric emptying.CONCLUSIONS:IBS patients without overlapping dyspepsia have normal gastric emptying of solids. A significant association exists in IBS patients between delayed gastric emptying and overlapping relevant postprandial fullness and nausea.

Chronic Intestinal Pseudo-Obstruction: Clinical Features, Diagnosis, and Therapy

CIPO is the very “tip of the iceberg” of functional gastrointestinal disorders, being a rare and frequently misdiagnosed condition characterized by an overall poor outcome. Diagnosis should be based on clinical features, natural history and radiologic findings. There is no cure for CIPO and management strategies include a wide array of nutritional, pharmacologic, and surgical options which are directed to minimize malnutrition, promote gut motility and reduce complications of stasis (ie, bacterial overgrowth). Pain may become so severe to necessitate major analgesic drugs. Underlying causes of secondary CIPO should be thoroughly investigated and, if detected, treated accordingly. Surgery should be indicated only in a highly selected, well characterized subset of patients, while isolated intestinal or multivisceral transplantation is a rescue therapy only in those patients with intestinal failure unsuitable for or unable to continue with TPN/HPN. Future perspectives in CIPO will be directed toward an accurate genomic/proteomic phenotying of these rare, challenging patients. Unveiling causative mechanisms of neuro-ICC-muscular abnormalities will pave the way for targeted therapeutic options for patients with CIPO.

JC virus infects the enteric glia of patients with chronic idiopathic intestinal pseudo-obstruction

Background and aim: Chronic idiopathic intestinal pseudo-obstruction (CIIP) is characterised by severe impairment of intestinal propulsive motility that mimics bowel obstruction. JC virus (JCV) is a polyomavirus that can infect brain glial cells causing a fatal disease, but may also be found throughout the normal gastrointestinal tract. The hypothesis that JCV infects the myenteric plexuses of patients with CIIP was tested. Methods: 10 patients with CIIP and 61 normal specimens (30 ascending colon and 31 ileum) from patients with uncomplicated colon cancer were studied. DNA was extracted from the myenteric plexuses, and JCV T antigen (TAg) DNA and the viral regulatory region were detected by PCR and sequencing. Immunohistochemistry was performed to detect JCV viral protein expression, neuronal and glial markers. Fluorescence in situ hybridisation was performed for cellular localisation of the JCV infection. Results: Clinical studies demonstrated neurogenic impairment, and pathological analyses showed neuropathy in each patient with CIIP. JCV TAg DNA was found in the myenteric plexuses of 8/10 (80%) of the patients with CIIP and 3/31 (9.7%) of the control patients (p<0.001). All samples were JCV Mad-1 strains. Seven of the 10 CIIP specimens expressed both JCV TAg and the JCV viral protein VP1, while none of the controls expressed either. JCV infection co-localised with glial fibrillary acidic protein expression, a marker of enteric glial cells. Conclusion: JCV infection occurs in the myenteric plexuses of patients with CIIP. The JCV localisation in enteroglial cells suggests a possible pathological role for this virus in enteric neuropathy.

Idiopathic myenteric ganglionitis underlying intractable vomiting in a young adult.

Inflammatory infiltration of intestinal myenteric plexuses (i.e. myenteric ganglionitis), along with severe intestinal motor abnormalities, may accompany paraneoplastic syndromes, neurological disorders and gastrointestinal infections, although rare cases can be idiopathic. In this report, we describe the case of a patient who presented with chronic intractable vomiting and weight loss associated with idiopathic myenteric ganglionitis mainly involving the stomach. Tissue analysis showed that the inflammatory infiltrate comprised T lymphocytes (CD4+ and CD8+), and peptide immunolabelling revealed a marked decrease of substance P/tachykinin immunoreactive staining in nerve fibres and myenteric neurones. Following systemic steroid therapy, the patients symptoms dramatically improved, and after one year of follow-up his general condition remains satisfactory. The possible mechanisms leading to symptom generation and gastric dysmotility in the context of an idiopathic myenteric ganglionitis are discussed.

Intestinal transplantation for chronic intestinal pseudo-obstruction in adult patients.

Intestinal transplantation (ITx) has become a life‐saving procedure for patients with irreversible intestinal failure who can no longer be maintained on parenteral nutrition (PN). This report presents the results of our experience on ITx in patients suffering from chronic intestinal pseudo‐obstruction (CIPO). Between December 30, 2000 and May 30, 2003 six adult patients affected by CIPO underwent primary ITx at our Center. Pre‐transplant evaluation, indication for ITx and surgical technique are reported. On December 30 2003, the mean follow‐up was 25.0 months. No peri‐operative deaths occurred in the study population and five out of six patients are alive, with 1‐year patient and graft survival of 83.3% and 66.6%. Although our series is limited by the number of patients, our experience suggests that ITx transplantation should be considered in adult patients suffering from CIPO and PN life‐threatening complication.