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Saccharomyces cerevisiae I-3856 in irritable bowel syndrome with predominant constipation.
Mourey, F, Decherf, A, Jeanne, JF, Clément-Ziza, M, Grisoni, ML, Machuron, F, Legrain-Raspaud, S, Bourreille, A, Desreumaux, P
World journal of gastroenterology. 2022;(22):2509-2522
Abstract
BACKGROUND Probiotics are a promising solution for managing irritable bowel syndrome (IBS). Saccharomyces cerevisiae (S. cerevisiae) I-3856 has already demonstrated beneficial effects in IBS subjects, particularly in IBS with predominant constipation (IBS-C). AIM: To confirm the efficacy of S. cerevisiae I-3856 in the management of gastrointestinal symptoms in IBS-C. METHODS A randomized, double-blind, placebo-controlled clinical study was performed in a total of 456 subjects. After a run-in period, subjects were randomly assigned to the group receiving S. cerevisiae I-3856 (8 × 109 CFU daily) or the placebo for 8 wk, and they performed daily self-evaluations of gastrointestinal symptoms. The primary objective was to assess the effect of the probiotic on abdominal pain. The secondary objectives were the evaluation of other gastrointestinal symptoms, bowel movement frequency and consistency, and quality of life (QOL). RESULTS A significantly higher proportion of abdominal pain responders was reported in the Probiotic group (45.1% vs 33.9%, P = 0.017). A nonsignificant difference in the area under the curve for abdominal pain over the second month of supplementation was observed in subjects receiving probiotic vs placebo [P = 0.073, 95%CI: -0.59 (-1.23; 0.05)]. No statistically significant differences were reported in the evolution of bowel movement frequency and stool consistency between the groups. After 8 wk of supplementation, the overall QOL score was significantly higher in the Probiotic group than in the Placebo group [P = 0.047, 95%CI: 3.86 (0.52; 7.20)]. Furthermore, exploratory analyses showed statistically significant and clinically relevant improvements in QOL scores in abdominal pain responders vs nonresponders. CONCLUSION The results of this clinical study confirmed the abdominal pain alleviation properties of S. cerevisiae I-3856 in IBS-C. Abdominal pain relief was associated with improved QOL. ClinicalTrials.gov identifier: NCT03150212.
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Safety, pharmacokinetic, and pharmacodynamic study of sibofimloc, a novel FimH blocker in patients with active Crohn's disease.
Reinisch, W, Hébuterne, X, Buisson, A, Schreiber, S, Desreumaux, P, Primas, C, Paillarse, JM, Chevalier, G, Bonny, C
Journal of gastroenterology and hepatology. 2022;(5):832-840
Abstract
BACKGROUND AND AIM Expression of FimH adhesin by invasive Escherichia coli in the gastrointestinal tract of patients with Crohn's disease (CD) facilitates binding to epithelial glycoproteins and release of pro-inflammatory cytokines. Sibofimloc is a first-in-class FimH blocker that showed little systemic absorption in healthy volunteers. The current study evaluated systemic absorption, safety, and effect on inflammatory biomarkers of sibofimloc in patients with CD. METHODS This was an open-label, multicenter phase 1b study in adults with active CD. In part 1, two patients received a single oral dose of 3000-mg sibofimloc followed by 1500 mg b.i.d. for 13 days. In part 2, six patients received 1500-mg sibofimloc b.i.d. for 13 days. Blood was drawn for pharmacokinetic and biomarker analysis, and stool was collected for biomarker and microbiome analysis. RESULTS Eight patients with active ileal or ileocolonic CD were enrolled into the study. Systemic sibofimloc exposure was low. Sibofimloc was well tolerated with only grade 1-2 events observed. Several pro-inflammatory biomarkers, including IL-1β, IL-6, IL-8, TNF-α, IFN-γ, and calprotectin, were decreased in stool by end of study. CONCLUSIONS This first study of the novel FimH blocker, sibofimloc, in patients with active CD demonstrated minimal systemic exposure with good tolerance, while decreasing several inflammatory biomarkers. EudraCT number: 2017-003279-70.
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Treatments for Crohn's Disease-Associated Bowel Damage: A Systematic Review.
Pariente, B, Hu, S, Bettenworth, D, Speca, S, Desreumaux, P, Meuwis, MA, Danese, S, Rieder, F, Louis, E
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2019;(5):847-856
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Abstract
BACKGROUND & AIMS Despite significant advances in the treatment of Crohn's disease (CD), most patients still develop stricturing or penetrating complications that require surgical resections. We performed a systematic review of mechanisms and potential treatments for tissue damage lesions in CD patients. METHODS We searched the PubMed, MBASE, and Cochrane databases from January 1960 to July 2017 for full-length articles on CD, fibrosis, damage lesions, mesenchymal stem cells, and/or treatment. We also searched published conference abstracts and performed manual searches of all reference lists of relevant articles. RESULTS Mechanisms of intestinal damage in patients with CD include fibroblast proliferation and migration, activation of stellate cells, recruitment of intestinal or extra-intestinal fibroblast, and cell trans-differentiation. An altered balance of metalloproteinases and tissue inhibitors of metalloproteinases might contribute to fistula formation. Treatment approaches that reduce excessive transforming growth factor beta (TGFB) activation might be effective in treating established intestinal damage. Stem cell therapies have been effective in tissue damage lesions in CD. Particularly, randomized controlled trials have shown local injections of mesenchymal stem cells to heal perianal fistulas. CONCLUSION In a systematic review of mechanisms and treatments of bowel wall damage in patients with CD, we found a need to test drugs that reduce TGFB and increase healing of transmural damage lesions and to pursue research on local injection of mesenchymal stem cells.
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Saccharomyces cerevisiae CNCM I-3856 in irritable bowel syndrome: An individual subject meta-analysis.
Cayzeele-Decherf, A, Pélerin, F, Leuillet, S, Douillard, B, Housez, B, Cazaubiel, M, Jacobson, GK, Jüsten, P, Desreumaux, P
World journal of gastroenterology. 2017;23(2):336-344
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Plain language summary
Irritable bowel syndrome (IBS) is a digestive disorder with various symptoms, affecting a significant number of the population. Gut bacteria are known to play a role in triggering the syndrome and research is exploring the manipulation of the gut microbiome in treating and managing symptoms. One yeast strain of interest is Saccharomyces Cerevisiae CNCM-I 3856. This meta-analysis of 2 randomised controlled trial, including 579 patients diagnosed with IBS, aimed to confirm previous conclusions on the effectiveness of supplementation of Saccharomyces Cerevisiae on typical IBS-C (constipation predominant IBS) symptoms. The pooled results showed a statistically significant improvement in abdominal pain, bloating and stool consistency when compared to placebo, after 2 months. It is important to note that positive effects were not reported after 1 month, but required 2 months of supplementation. When compiling nutrition protocols for IBS patients, Nutrition Practitioners need to take account of the length of intervention required to have the desired impact, as well as the choice of protocol itself.
Abstract
AIM: To confirm previous conclusions on Saccharomyces cerevisiae (S. cerevisiae) CNCM I-3856 for irritable bowel syndrome (IBS) management. METHODS An individual patient data meta-analysis was performed on two randomized clinical trials studying the effect of S. cerevisiae CNCM I-3856 supplementation on gastrointestinal (GI) symptoms in IBS subjects. A total of 579 IBS subjects were included. Outcomes were the daily Likert scale scores of abdominal pain/discomfort and bloating [area under the curve (AUC) and weekly means], responder status, and bowel movements (stool frequency and consistency). Statistical analyses were conducted in Intent to Treat (ITT) population, IBS-C subjects and IBS-C subjects with an abdominal pain/discomfort score higher than or equal to 2 at baseline ("IBS-C ≥ 2 subpopulation"). RESULTS S. cerevisiae CNCM I-3856 significantly improved abdominal pain/discomfort and bloating during the second month of supplementation [AUC (W5-W8)] with improvement up to the minimal clinically relevant threshold of 10%: a 12.3% reduction of abdominal pain/discomfort in the ITT population compared to the Placebo group (P = 0.0134) has been observed. In the IBS-C ≥ 2 subpopulation, there were a 13.1% reduction of abdominal pain/discomfort and a 14.9% reduction of bloating compared to the Placebo group (P = 0.0194 and P = 0.0145, respectively). GI symptoms significantly decreased during supplementation but no statistical differences were reported between groups at the end of the supplementation period. Responder status was defined as a subject who experienced a decrease of 1 arbitrary unit (a.u.) or 50% of the abdominal discomfort score from baseline for at least 2 wk out of the last 4 wk of the study. A significant difference between groups was reported in the ITT population, when considering the first definition: subjects in the Active group had 1.510 higher odds to be a responder (reduction of 1 a.u. of abdominal pain/discomfort) compared with subjects in the Placebo group (P = 0.0240). At the end of supplementation period, stool consistency in the Active group of the ITT population was significantly improved and classified as "normal" compared to Placebo (respectively 3.13 ± 1.197 a.u. vs 2.58 ± 1.020 a.u., P = 0.0003). Similar results were seen in the IBS-C ≥ 2 subpopulation (Active group: 3.14 ± 1.219 a.u. vs Placebo group: 2.59 ± 1.017 a.u., P = 0.0009). CONCLUSION This meta-analysis supports previous data linking S. cerevisiae I-3856 and improvement of GI symptoms, in IBS overall population and in the IBS-C and IBS-C ≥ 2 subpopulations.
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Toxicological consequences of experimental exposure to aluminum in human intestinal epithelial cells.
Djouina, M, Esquerre, N, Desreumaux, P, Vignal, C, Body-Malapel, M
Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association. 2016;:108-16
Abstract
Aluminum (Al), a non-essential element, is ubiquitous in industrialized societies. Whereas adult intake is estimated between 3 and 12 mg/day according to dietary aluminum studies conducted in many countries, it is not known if aluminum may have a toxic effect on intestinal epithelium. The aim of this work was to evaluate the cytotoxicity and RNA expression patterns induced in HT-29 cells by aluminum. Both classical toxicological methods and a global transcriptomic approach were used. Cytotoxicity determined by MTT assay showed a time and dose dependent decrease of cell viability in aluminum treated cells compared to control cells. Cell cycle analysis by flow cytometry revealed that aluminum induced accumulation of cells in phase G0/G1, associated with a decrease in the proportion of cells in S and G2/M phases. Aluminum led to apoptosis as evidenced by nuclear morphology changes and mitochondrial membrane perturbations, and induced reactive oxygen species generation. Transcriptomic pattern argued in favor of pro-tumorigenic and pro-inflammatory effects of aluminum in intestinal epithelial cells. These results highlight several pathways by which aluminum has a disturbing impact on intestinal epithelial cells, supporting that the effects of aluminum on intestine warrants further investigation.
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A randomized clinical trial of Saccharomyces cerevisiae versus placebo in the irritable bowel syndrome.
Pineton de Chambrun, G, Neut, C, Chau, A, Cazaubiel, M, Pelerin, F, Justen, P, Desreumaux, P
Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2015;(2):119-24
Abstract
BACKGROUND We aimed to evaluate clinical symptoms in subjects with irritable bowel syndrome receiving Saccharomyces cerevisiae in a randomized double-blind placebo-controlled clinical trial. METHODS Overall, 179 adults with irritable bowel syndrome (Rome III criteria) were randomized to receive once daily 500 mg of Saccharomyces cerevisiae, delivered by one capsule (n = 86, F: 84%, age: 42.5 ± 12.5), or placebo (n = 93, F: 88%, age: 45.4 ± 14) for 8 weeks followed by a 3-week washout period. After a 2-week run-in period, cardinal symptoms (abdominal pain/discomfort, bloating/distension, bowel movement difficulty) and changes in stool frequency and consistency were recorded daily and assessed each week. A safety assessment was carried out throughout the study. RESULTS The proportion of responders, defined by an improvement of abdominal pain/discomfort, was significantly higher (p = 0.04) in the treated group than the placebo group (63% vs 47%, OR = 1.88, 95%, CI: 0.99-3.57) in the last 4 weeks of treatment. A non-significant trend of improvement was observed with Saccharomyces cerevisiae for the other symptoms. Saccharomyces cerevisiae was well tolerated and did not affect stool frequency and consistency. CONCLUSION Saccharomyces cerevisiae is well tolerated and reduces abdominal pain/discomfort scores without stool modification. Thus, Saccharomyces cerevisiae may be a new promising candidate for improving abdominal pain in subjects with irritable bowel syndrome.
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Eosinophilic enteritis.
Pineton de Chambrun, G, Desreumaux, P, Cortot, A
Digestive diseases (Basel, Switzerland). 2015;(2):183-189
Abstract
BACKGROUND Eosinophilic enteritis, also known as eosinophilic gastroenteritis, is a rare primary eosinophilic gastrointestinal disorder (EGID) of unknown etiology characterized by the presence of an intense eosinophilic infiltrate on histopathology of the intestinal mucosa. KEY MESSAGES The etiology of eosinophilic enteritis remains obscure. There is growing evidence to support the role of aeroallergens and food allergens in the pathogenesis of this disorder as children and adults with EGIDs often have positive skin testing for food allergens and a familial history of allergic diseases. Moreover, significant progress has been made in elucidating that EGIDs involve mechanisms that fall between pure IgE-mediated and delayed Th2 type responses. Preclinical studies have identified a contributory role for the cytokine IL-5 and eotaxin chemokines, providing a rationale for specific disease therapy. Eosinophilic enteritis causes a wide array of gastrointestinal symptoms such as abdominal pain, diarrhea, nausea, vomiting, bloating or ascites, and its diagnosis requires a high degree of clinical likelihood given the nonspecific presentation and physical examination findings. The Klein classification arbitrarily divided patients with eosinophilic enteritis into those with predominantly mucosal, muscle layer or subserosal disease relying on the concept that clinical presentation is dependent on the predominant involved layer of the gastrointestinal tract. Main therapeutic options are represented by oral corticosteroids for a short period with good efficacy. Antihistaminic drugs and sodium cromoglycate have also been used to treat patients with eosinophilic enteritis. CONCLUSION Eosinophilic enteritis is generally considered as a benign disease with no relapse, but half of the patients may present a more complex natural history characterized by unpredictable relapses and a chronic course.
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Safety and efficacy of antigen-specific regulatory T-cell therapy for patients with refractory Crohn's disease.
Desreumaux, P, Foussat, A, Allez, M, Beaugerie, L, Hébuterne, X, Bouhnik, Y, Nachury, M, Brun, V, Bastian, H, Belmonte, N, et al
Gastroenterology. 2012;(5):1207-1217.e2
Abstract
BACKGROUND & AIMS New therapeutic strategies are needed for patients with refractory Crohn's disease (CD). We evaluated data from the Crohn's And Treg Cells Study (CATS1) to determine the safety and efficacy of antigen-specific T-regulatory (Treg) cells for treatment of patients with refractory CD. METHODS We performed a 12-week, open-label, multicenter, single-injection, escalating-dose, phase 1/2a clinical study in 20 patients with refractory CD. Ovalbumin-specific Treg cells (ova-Tregs) were isolated from patients' peripheral blood mononuclear cells (PBMCs), exposed to ovalbumin, and administrated intravenously. Safety and efficacy were assessed using clinical and laboratory parameters. We evaluated proliferation of PBMCs in response to ovalbumin. RESULTS Injections of ova-Tregs were well tolerated, with 54 adverse events (2 related to the test reagent) and 11 serious adverse events (3 related to the test reagent, all recovered). Overall, a response, based on a reduction in Crohn's Disease Activity Index (CDAI) of 100 points, was observed in 40% of patients at weeks 5 and 8. Six of the 8 patients (75%) who received doses of 10(6) cells had a response at weeks 5 and 8, with a statistically significant reduction in CDAI. In this group, remission (based on CDAI ≤150) was observed in 3 of 8 patients (38%) at week 5 and 2 of 8 patients (25%) at week 8. CONCLUSIONS Administration of antigen-specific Tregs to patients with refractory CD (CATS1) was well tolerated and had dose-related efficacy. The ovalbumin-specific immune response correlated with clinical response, supporting immune-suppressive mechanisms of ova-Tregs. The consistency of results among different assessment methods supports the efficacy of ova-Tregs; this immune therapy approach warrants further clinical and mechanistic studies in refractory CD. Eudract, Number: 2006-004712-44.
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PPARgamma as a new therapeutic target in inflammatory bowel diseases.
Dubuquoy, L, Rousseaux, C, Thuru, X, Peyrin-Biroulet, L, Romano, O, Chavatte, P, Chamaillard, M, Desreumaux, P
Gut. 2006;(9):1341-9
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The peroxisome proliferator activated receptor gamma(PPARgamma) is a nuclear receptor highly expressed in the colon and playing a key role in bacterial induced inflammation. Regulation of colon inflammation by this receptor has been well demonstrated in many experimental models of colitis but also in patients with ulcerative colitis, characterised by impaired expression of PPARgamma confined to their colon epithelial cells. Recent data showing that PPARgamma was the major functional receptor mediating the common aminosalicylate activities in inflammatory bowel diseases (IBD) have also reinforced the roles of this receptor in the control of intestinal inflammation. The aims of this review are to discuss the potential roles of PPARgamma in the physiopathology of IBD, as well as the emerging therapeutic strategies targeting this receptor.
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[NOD2/CARD15 and Crohn's disease].
Desreumaux, P
Gastroenterologie clinique et biologique. 2005;(6-7):696-700