Jean Paul Galmiche

Saccharomyces boulardii does not prevent relapse of Crohn's disease.

BACKGROUND & AIMS Saccharomyces boulardii is a probiotic yeast that has been shown to have beneficial effects on the intestinal epithelial barrier and digestive immune system. There is preliminary evidence that S boulardii could be used to treat patients with Crohns disease (CD). We performed a randomized, placebo-controlled trial to evaluate the effects of S boulardii in patients with CD who underwent remission during therapy with steroids or aminosalicylates. METHODS We performed a prospective study of 165 patients who achieved remission after treatment with steroids or salicylates; they were randomly assigned to groups given S boulardii (1 g/day) or placebo for 52 weeks. The primary end point was the percentage of patients in remission at week 52. Time to relapse, Crohns disease activity index scores, and changes in parameters of inflammation were secondary end points. RESULTS CD relapsed in 80 patients, 38 in the S boulardii group (47.5%) and 42 in the placebo group (53.2%, a nonsignificant difference). The median time to relapse did not differ significantly between patients given S boulardii (40.7 weeks) vs placebo (39.0 weeks). There were no significant differences between groups in mean Crohns disease activity index scores or erythrocyte sedimentation rates or in median levels of C-reactive protein. In a post hoc analysis, nonsmokers given S boulardii were less likely to experience a relapse of CD than nonsmokers given placebo, but this finding requires confirmation. CONCLUSIONS Although the probiotic yeast S boulardii is safe and well tolerated, it does not appear to have any beneficial effects for patients with CD in remission after steroid or salicylate therapies.

Endoluminal therapies for gastro-oesophageal reflux disease

CONTEXT Gastro-oesophageal reflux disease (GORD) is a common chronic disorder that has severe impact on quality of life and often requires continuous acid-suppression therapy. Proton-pump inhibitors (PPIs) are extremely effective but expensive, and do not restore the normal antireflux barrier at the gastro-oesophageal junction. Antireflux surgery, even with the laparoscopic approach, has not proven more cost-effective than maintenance therapy with PPIs. Postoperative morbidity is substantial, especially when procedures are done outside expert centres. In the past few years several endoscopic techniques have been developed to treat chronic GORD on an outpatient basis. These techniques include radiofrequency-energy delivery and endoscopic suturing, although other approaches are now under development. STARING POINT: Two prospective open-label studies have recently reported 1-year follow-up of GORD patients treated either by radiofrequency-energy delivery (G Triadafilopoulos and colleagues Gastrointest Endosc 2002; 55:149-56) or endoscopic suturing (Z Mahmood and colleagues Gut 2003; 52:34-39). In a US multicentre trial, Triadafilopoulos and colleagues delivered radiofrequency energy to the cardia and distal oesophagus in patients with chronic heartburn, regurgitation or both (the Stretta procedure). All patients were on continuous acid-suppression therapy, but none had severe oesophagitis or hiatus hernia of more than 2 cm. At 12 months, 94 patients available for follow-up showed significant improvement in GORD symptoms, quality of life, and oesophageal acid-exposure. The need for PPI therapy fell from 98% to 30% of patients. In the Mahmood study, 26 similar patients had endoscopic suturing in a single centre. After 1 year, symptoms and quality of life improved and the need for PPIs was reduced to 36% from 100%. In both studies, only minor complications occurred, none of which required specific therapeutic intervention. WHERE NEXT? An effective outpatient procedure to treat chronic GORD would represent a major step forward. However, further studies are needed before an endoscopic approach can be adopted, as none of the published trials are well-controlled studies. Longer follow-up is needed to ensure that relapses do not occur rapidly, complications do not occur more frequently with less skilled operators, or that endoscopic-induced changes do not complicate or compromise subsequent antireflux surgery. Comparative studies of the cost-effectiveness of endoscopic therapy should also include medical strategies such as intermittent or on-demand PPI therapy.

Projections of excitatory and inhibitory motor neurones to the circular and longitudinal muscle of the guinea pig colon.

Abstract. The aim of this study was to identify myenteric pathways to the circular and longitudinal muscle of the guinea pig proximal colon. To identify excitatory and inhibitory muscle motoneurones, we applied the neuronal retrograde tracer DiI onto the circular or longitudinal muscle layer and performed additional immunohistochemistry for nitric oxide synthase (NOS) and choline acetyltransferase (ChAT). On average 166±81 circular muscle motoneurones (CMMN) and 100±74 longitudinal muscle motoneurones (LMMN) were labelled by DiI tracing. Myenteric pathways innervating the muscle were either ascending (DiI-labelled neurones with oral projections) or descending (DiI-labelled neurones with anal projections). The circular muscle was preferentially innervated by ascending pathways (66.0±9.1%). Most ascending CMMN were ChAT-positive (87.2±8.5%), whereas descending CMMN were mainly NOS-positive (82.3±14.6%). Most ascending (62.2±11.1%) and descending (82.0±12.5%) CMMN had circumferential projection preferences (circumferential projections were longer than projections along the longitudinal gut axis). In contrast to the polarised projections to the circular muscle, the longitudinal muscle was equally innervated by ascending (46.2±15.1%) and descending (53.9±15.1%) neurones. Ascending and descending pathways to the longitudinal muscle consisted predominantly of ChAT-positive neurones (98.1±1.9% and 68.0±8.5%, respectively), and both pathways had prominent longitudinal projection preferences. Only 25.5% of the descending LMMN were NOS-positive. In conclusion, the circular muscle in the proximal colon is innervated by descending inhibitory (NOS-positive neurones) and ascending excitatory (ChAT-positive neurones) pathways. In contrast, the longitudinal muscle is primarily innervated by ascending and descending excitatory motoneurones, and only a small proportion of the descending pathway consisted of inhibitory motoneurones.

Review article: gene therapy, recent developments and future prospects in gastrointestinal oncology

Aliment Pharmacol Ther 2010; 32: 953–968

Characterisation of Early Mucosal and Neuronal Lesions Following Shigella flexneri Infection in Human Colon

Background Shigella, an enteroinvasive bacteria induces a major inflammatory response responsible for acute rectocolitis in humans. However, early effect of Shigella flexneri (S. flexneri) infection upon the human mucosa and its microenvironement, in particular the enteric nervous system, remains currently unknown. Therefore, in this study, we sought to characterize ex vivo the early events of shigellosis in a model of human colonic explants. In particular, we aimed at identifying factors produced by S. flexneri and responsible for the lesions of the barrier. We also aimed at determining the putative lesions of the enteric nervous system induced by S. flexneri. Methodology/Principal Findings We first showed that, following 3 h of infection, the invasive but not the non-invasive strain of S. flexneri induced significant desquamation of the intestinal epithelial barrier and a reduction of epithelial height. These changes were significantly reduced following infection with SepA deficient S. flexneri strains. Secondly, S. flexneri induced rapid neuronal morphological alterations suggestive of cell death in enteric submucosal neurones. These alterations were associated with a significant increase in the proportion of vasoactive intestinal peptide (VIP) immunoreactive (IR) neurons but not in total VIP levels. The NMDA receptor antagonist MK-801 blocked neuronal morphological changes induced by S. flexneri, but not the increase in the proportion of VIP-IR. Conclusions/Significance This human explant model can be used to gain better insight into the early pathogenic events following S. flexneri infection and the mechanisms involved.

Interleukin-15 and Its Soluble Receptor Mediate the Response to Infliximab in Patients With Crohn's Disease

BACKGROUND & AIMS Infliximab is a monoclonal antibody against tumor necrosis factor that is used to treat patients with inflammatory bowel disease. We investigated serum levels and cellular expression of interleukin (IL)-15 and its receptor (sIL-15Ralpha) in patients with Crohns disease (CD) treated with infliximab; and the effect on sIL-15Ralpha secretion by epithelial cells. METHODS CD patients were given infliximab (n = 40; 3 infusions); 37 healthy controls were studied. Serum levels of IL-15, sIL-15Ralpha, and complex were determined by radioimmunoassay and cytokine levels by enzyme-linked immunosorbent assay. IL-15Ralpha and A Desintegrin and Metalloproteinase 17 levels were assessed by immunohistochemistry. Epithelial cell lines (HT-29 and Caco-2) were cultured with infliximab, adalimumab, or etanercept. Patients were classified as responders and nonresponders according to their Crohns Disease Activity Index and clinical observations. RESULTS Before infliximab, IL-15 was higher in responders than in controls and nonresponders. After infliximab, IL-15 decreased in responders while remaining stable in nonresponders. sIL-15Ralpha and IL-15/sIL-15Ralpha complex levels were higher in CD than in controls and increased only in responders after infliximab. IL-15Ralpha and A Desintegrin and Metalloproteinase 17 colocalized in epithelial cells and were higher in CD patients. In vitro, infliximab but not adalimumab and etanercept induced sIL-15Ralpha secretion by epithelial cells. CONCLUSIONS Serum level of sIL-15Ralpha and the IL-15/sIL-15Ralpha complex increased in responder patients and the response was associated with a decrease of IL-15. Infliximab induced the release of the IL-15 receptor alpha, suggesting a specific modulation of IL-15 and its soluble receptor by reverse signaling through transmembrane tumor necrosis factor alpha.

Treatment of Gastroesophageal Reflux Disease in Adults: An Individualized Approach

Until the 1990s, most therapeutic trials in gastroesophageal reflux disease (GERD) focussed upon endoscopic lesions. In fact the correlation between patient symptoms and both the presence and grade of esophagitis is very poor. The classical criteria for the assessment of therapeutic efficacy in GERD have therefore been revised, and there is now a consensus that the relief of symptoms and the long-term control of the disease are the primary aims of therapy for the majority of patients. Proton pump inhibitors (PPIs) represent the mainstay of therapy for patients with non-erosive reflux disease (NERD) as well as esophagitis. Although a stepwise strategy has been recommended in the past, a step-down strategy (starting with a full-dose PPI) appears to be a more cost-effective approach. There are as yet insufficient data to establish the clear superiority of one PPI over others. PPIs have a number of limitations. Symptom relief is significantly inferior in NERD than in erosive esophagitis. The heterogeneity of the NERD group may be one of the most influential factors, but the role of esophageal hypersensitivity has been suggested especially in patients with normal acid exposure. The role of non-acid reflux should also be scrutinized. Long-term control of the disease can be achieved by drug therapy, anti-reflux surgery and now with a variety of endoscopic procedures. The different drug management strategies can be divided into (i) continuous maintenance therapy and (ii) discontinuous therapy which can again be divided into two categories, intermittent and on-demand drug therapy. A case-by-case approach is recommended to determine the personal therapeutic needs and preferences of each individual. Many patients with NERD or mild esophagitis do not require continuous maintenance therapy and recent studies have shown excellent results with different PPI on-demand therapy regimens. Finally when making a choice between different long-term strategies both the clinician and the informed patient have to consider efficacy, safety, tolerability and cost. The potential efficacy of new drugs, especially the GABA(B) agonists and the fast onset acid suppressors, as well as the cost-effectiveness of non-drug strategies (surgery and endoluminal therapies) should be further evaluated.

GORD and functional disorders of upper gut.

Gastro-oesophageal reflux disease (GORD) is one of the most frequent disorders seen in the primary-care setting as well as in secondary and tertiary referral centres. It is caused by the retrograde passage of gastric (or gastroduodenal) contents through the cardia into the oesophagus. From a clinical standpoint, the term ‘GORD’ encompasses all individuals who are at risk of physical complications as a result of exposure to gastrooesophageal reflux or who experience a clinically significant impairment of health-related wellbeing due to reflux-related symptoms (following adequate reassurance of their benign nature) [1]. The expression ‘endoscopy-negative reflux disease’ should be reserved for individuals who satisfy the definition of GORD but who do not have Barrett’s oesophagus or definite endoscopic oesophageal mucosal breaks (oesophageal mucosal erosion or ulceration). The prevalence of typical symptoms such as heartburn and regurgitation in the community is as high as 40% on a monthly basis. This figure may, however, correlate to an overestimation of the disease prevalence, as it has been shown that only symptoms of moderate intensity occurring at least once a week have a significant impact on quality of life [2]. During recent years, GORD has remained an extremely active area of research for both clinical and mechanistic studies; the use of a Medline search identifies approximately 2000 articles published within the past 3 years. In this review in depth, we do not attempt to address all of the different aspects of GORD, such as its epidemiology, natural history or even the various therapeutic modalities that have now been made available, namely endoscopic endoluminal treatments, since reviews have been recently published elsewhere [3]. Our choice was rather to focus on selected issues that represent the basis of major publications concerning pathogenesis (the role of non-acid reflux and the importance of hiatus hernia) and/or are of relevance to clinical practice (proton-pump inhibitor (PPI) test, extra-oesophageal manifestations and longterm strategies with a medico-economic perspective).