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Reid G.,Lawson Health Research Institute | Reid G.,University of Western Ontario | Gaudier E.,Unilever | Guarner F.,Digestive System Research Unit | And 8 more authors.
Gut Microbes | Year: 2010

As with many clinical studies, trials using probiotics have shown clearly that some patients benefit from the treatment while others do not. For example if treatment with probiotics leads to 36% cure rate of diarrhea, why did the other 64% not have the same result? The issue is important for human and indeed experimental animal studies for two main reasons: (i) Would changing the design of the study result in more subjects responding to treatment? (ii) If a subject does not respond what are the mechanistic reasons? In order to tackle the issue of responders and non-responders to therapy, a workshop was held by the International Scientific Association for Probiotics and Prebiotics (ISAPP). The outcome was four recommendations. (1) Clearly define the end goal: this could be supporting a health claim or having the highest clinical effect and impact. (2) Design the study to maximize the chance of a positive response by identifying precise parameters and defining the level of response that will be tested. (3) Base the selection of the intervention on scientific investigations: which strain(s) and/or product formulation should be used and why. (4) Carefully select the study cohort: use biological or genetic markers when available to stratify the patient population before enrollment and decide at what point intervention will provide the best outcome (for example, in acute phase of disease, or during remission, with or without use of pharmaceutical agents). By following these recommendations and selecting an appropriate primary outcome, it is hoped that clinical data will emerge in the future that expands our knowledge of which probiotics benefits which subjects and by what mechanism. © 2010 Landes Bioscience.

Martinez C.,Digestive System Research Unit | Lobo B.,Digestive System Research Unit | Pigrau M.,Digestive System Research Unit | Ramos L.,Digestive System Research Unit | And 13 more authors.
Gut | Year: 2013

Objective Recently, the authors demonstrated altered gene expression in the jejunal mucosa of diarrhoeapredominant irritable bowel syndrome patients (IBS-D); specifically, the authors showed that genes related to mast cells and the intercellular apical junction complex (AJC) were expressed differently than in healthy subjects. The aim of the authors here was to determine whether these alterations are associated with structural abnormalities in AJC and their relationship with mast cell activation and IBS-D clinical manifestations. Design A clinical assessment and a jejunal biopsy were obtained in IBS-D patients (n=45) and healthy subjects (n=30). Mucosal mast cell number and activation were determined by quantifying CD117+ cells/hpf and tryptase expression, respectively. Expression and distribution of AJC specific proteins were evaluated by western blot and confocal microscopy. AJC ultrastructure was assessed by transmission electron microscopy. Results Compared with healthy subjects, IBS-D patients exhibited: (a) increased mast cell counts and activation; (b) increased protein expression of claudin-2, reduced occludin phosphorylation and enhanced redistribution from the membrane to the cytoplasm; and (c) increased myosin kinase expression, reduced myosin phosphatase and, consequently, enhanced phosphorylation of myosin. These molecular alterations were associated with ultrastructural abnormalities at the AJC, specifically, perijunctional cytoskeleton condensation and enlarged apical intercellular distance. Moreover, AJC structural alterations positively correlated both with mast cell activation and clinical symptoms. Conclusion The jejunal mucosa of IBS-D patients displays disrupted apical junctional complex integrity associated with mast cell activation and clinical manifestations. These results provide evidence for the organic nature of IBS-D, a heretofore model disease of functional gastrointestinal disorders.

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