Project description:A role for immunoproteasome in the regulation of intestinal permeability has been previously suggested both in mice during water avoidance stress (WAS) and in patients with irritable bowel syndrome (IBS). We thus aimed (i) to evaluate the colonic proteome in wild-type (wt) and β2i immunoproteasome subunit knock-out (β2i-/-) mice during WAS and (ii) to investigate the colonic expression of 49 ubiquitinated-proteins in diarrhea-predominant IBS patients (IBS-D).
Project description:IBS: Patients who have undergone a diagnostic program for gastrointestinal symptoms and where the diagnosis irritable bowel syndrome was reached. UC: Patients with well-diagnosed ulcerative colitis
Project description:Opioid-dependent immune-mediated analgesic effects have been broadly reported upon inflammation. In preclinical mouse models of intestinal inflammatory diseases, the local release of enkephalins (endogenous opioids) by colitogenic T lymphocytes alleviate inflammationinduced pain by down-modulating gut-innervating nociceptor activation in periphery. In this study, we wondered whether this immune cell-derived enkephalin-mediated regulation of the nociceptor activity also operates under steady state conditions. Here, we show that chimeric mice engrafted with enkephalin-deficient bone marrow cells exhibit not only visceral hypersensitivity but also an increase in both epithelial paracellular and transcellular permeability, an alteration of the microbial topography resulting in increased bacteriaepithelium interactions and a higher frequency of IgA-producing plasma cells in Peyer’s patches. All these alterations of the intestinal homeostasis are associated with an anxiety-like behavior despite the absence of an overt inflammation as observed in patients with irritable bowel syndrome. Thus, our results show that immune cell-derived enkephalins play a pivotal role in maintaining gut homeostasis and normal behavior in mice. Because a defect in the mucosal opioid system remarkably mimics some major clinical symptoms of the irritable bowel syndrome, its identification might help to stratify subgroups of patients.
Project description:The role of environmental factors and gender disparities as determinants of health is incontrovertible. In the digestive sphere, it is noteworthy that one of the most prevalent diseases such as irritable bowel syndrome (IBS) has a predominance in females. The origin of IBS is related to mucosal microinflammation phenomena, psychosocial stress, and in the last years, alterations in gut microbiota. Recent observations from our group in healthy subjects, demonstrate that both chronic psychosocial stress, and female gender per se determine a significant intestinal epithelial barrier dysfunction in response to intercurrent stimuli, which, in susceptible individuals, could result in an early stage in the development of more lasting changes and the onset of clinical manifestations of IBS. Although the intimate mechanisms involved in stress-induced intestinal pathophysiology are not well known, diverse studies suggest that gut microbiota alteration, through epigenetic modifications of the main stress-mediators could be one of them. However, solid scientific evidence demonstrating the influence of stress on gut microbiota and epigenetics of the main stress-mediators is missing. Therefore, we want to investigate and characterize gender-dependent epigenetic modifications involved in intestinal barrier dysfunction in response to acute stress. The identification of gender-dependent abnormal epigenetic patterns related to female gender dysfunction can make a breakthrough in the understanding of the pathophysiology of the regulation of intestinal permeability, and promote positive diagnostic and therapeutic future progress in IBS.
Project description:Changes in microbiome composition have been associated with a wide array of human diseases, turning the human microbiota into an attractive target for therapeutic intervention. Yet clinical translation of these findings requires the establishment of causative connections between specific microbial taxa and their functional impact on host tissues. Here, we infused gut organ cultures with longitudinal microbiota samples collected from therapy-naïve irritable bowel syndrome (IBS) patients under low-FODMAP (fermentable Oligo-, Di-, Mono-saccharides and Polyols) diet. We show that post-diet microbiota regulates intestinal expression of inflammatory and neuro-muscular gene-sets. Specifically, we identify Bifidobacterium adolescentis as a diet-sensitive pathobiont that alters tight junction integrity and disrupts gut barrier functions. Collectively, we present a unique pathway discovery approach for mechanistic dissection and identification of functional diet-host-microbiota modules. Our data support the hypothesis that the gut microbiota mediates the beneficial effects of low-FODMAP diet and reinforce the potential feasibility of microbiome based-therapies in IBS.
Project description:Changes in microbiome composition have been associated with a wide array of human diseases, turning the human microbiota into an attractive target for therapeutic intervention. Yet clinical translation of these findings requires the establishment of causative connections between specific microbial taxa and their functional impact on host tissues. Here, we infused gut organ cultures with longitudinal microbiota samples collected from therapy-naïve irritable bowel syndrome (IBS) patients under low-FODMAP (fermentable Oligo-, Di-, Mono-saccharides and Polyols) diet. We show that post-diet microbiota regulates intestinal expression of inflammatory and neuro-muscular gene-sets. Specifically, we identify Bifidobacterium adolescentis as a diet-sensitive pathobiont that alters tight junction integrity and disrupts gut barrier functions. Collectively, we present a unique pathway discovery approach for mechanistic dissection and identification of functional diet-host-microbiota modules. Our data support the hypothesis that the gut microbiota mediates the beneficial effects of low-FODMAP diet and reinforce the potential feasibility of microbiome based-therapies in IBS.
Project description:Changes in microbiome composition have been associated with a wide array of human diseases, turning the human microbiota into an attractive target for therapeutic intervention. Yet clinical translation of these findings requires the establishment of causative connections between specific microbial taxa and their functional impact on host tissues. Here, we infused gut organ cultures with longitudinal microbiota samples collected from therapy-naïve irritable bowel syndrome (IBS) patients under low-FODMAP (fermentable Oligo-, Di-, Mono-saccharides and Polyols) diet. We show that post-diet microbiota regulates intestinal expression of inflammatory and neuro-muscular gene-sets. Specifically, we identify Bifidobacterium adolescentis as a diet-sensitive pathobiont that alters tight junction integrity and disrupts gut barrier functions. Collectively, we present a unique pathway discovery approach for mechanistic dissection and identification of functional diet-host-microbiota modules. Our data support the hypothesis that the gut microbiota mediates the beneficial effects of low-FODMAP diet and reinforce the potential feasibility of microbiome based-therapies in IBS.