Background It is unknown which maintenance therapy is the most effective option for patients admitted for an acute severe ulcerative colitis (ASUC) episode responding to intravenous steroids.Methods We conducted a multicentre, parallel-group, open-label randomised controlled trial among 23 French centres in thiopurine and biologics-na & iuml;ve adults admitted for ASUC responding to intravenous steroids. Eligible patients were randomly assigned to receive infliximab (IFX) and azathioprine (AZA) with a 7-day steroid tapering scheme (IFX+AZA arm) or AZA and conventional standardised steroid tapering regimen (AZA arm). The primary composite endpoint was treatment failure at week 52, defined as the absence of steroid-free clinical remission, the absence of endoscopic response, the use of a prohibited treatment for relapse, severe adverse event leading to treatment interruption, colectomy or death. Multiple imputation for missing data was performed.Findings Among the 64 patients randomised (Lichtiger score 13.5 +/- 2.0; median age of 34.5 (P25-P75 26.3-50.3) years, median C reactive protein of 29.0 (12.8-96.8) mg/L at baseline): 32 were assigned to the IFX+AZA arm and 32 to the AZA arm. In the ITT population, treatment failure at week 52 was observed in 22/27 (81.5%) in the AZA arm and 16/30 (53.3%) in the IFX+AZA arm (risk ratio 3.85, 95% CI (1.15 to 12.88), p=0.03). 29 adverse events were severe, including 13 disease exacerbations, 6 severe infections without any difference between both arms.Interpretation Combination therapy with IFX+AZA was more effective at 1 year than AZA alone to avoid treatment failure in patients with ASUC responding to intravenous steroids.Trial registration number NCT02425852.

BACKGROUND The prevalence of obesity and the number of bariatric surgeries in both the general population and in patients with inflammatory bowel disease (IBD) have increased significantly in recent years. Due to small sample sizes and the lack of adequate controls, no definite conclusions can be drawn from the available studies on the safety and efficacy of bariatric surgery (BS) in patients with IBD. Our aim was to assess safety, weight loss, and deficiencies in patients with IBD and obesity who underwent BS and compare findings to a control group. METHODS Patients with IBD and a history of BS were retrospectively recruited to centers belonging to the Groupe d'Etude Thérapeutique des Affections Inflammatoires du Tube Digestif (GETAID). Patients were matched 1:2 for age, sex, body mass index (BMI), hospital of surgery, and type of BS with non-IBD patients who underwent BS. Complications, rehospitalizations, weight, and deficiencies after BS were collected in cases and controls. RESULTS We included 88 procedures in 85 patients (64 Crohn's disease, 20 ulcerative colitis, 1 unclassified IBD) with a mean BMI of 41.6 ± 5.9 kg/m2. Bariatric surgery included Roux-en-Y gastric bypass (n = 3), sleeve gastrectomy (n = 73), and gastric banding (n = 12). Eight (9%) complications were reported, including 4 (5%) requiring surgery. At a mean follow-up of 34 months, mean weight was 88.6 ± 22.4 kg. No difference was observed between cases and controls for postoperative complications (P = .31), proportion of weight loss (P = .27), or postoperative deficiencies (P = .99). CONCLUSIONS Bariatric surgery is a safe and effective procedure in patients with IBD and obesity; outcomes in this patient group were similar to those observed in a control population.

INTRODUCTION:New therapeutic options for patients with Crohn's disease (CD) with perianal lesions failing anti-tumor necrosis factor (TNF) agents are needed. We aimed to assess the effectiveness of ustekinumab in perianal CD (pCD) and predictors of clinical success in a real-life multicenter cohort.METHODS:We conducted a national multicenter retrospective cohort study in patients with either active or inactive pCD who received ustekinumab. In patients with active pCD at treatment initiation, the success of ustekinumab was defined by clinical success at 6 months assessed by the physician's judgment without additional medical or surgical treatment for pCD. Univariate and multivariable logistic regression analyses were performed to identify predictors of success. In patients with inactive pCD at ustekinumab initiation, the pCD recurrence-free survival was calculated using the Kaplan-Meier method.RESULTS:Two hundred seven patients were included, the mean age was 37.7 years, the mean duration of CD was 14.3 years, and the mean number of prior perianal surgeries was 2.8. Two hundred five (99%) patients had previously been exposed to at least 1 anti-TNF and 58 (28%) to vedolizumab. The median follow-up time was 48 weeks; 56/207 (27%) patients discontinued therapy after a median time of 43 weeks. In patients with active pCD, success was reached in 57/148 (38.5%) patients. Among patients with setons at initiation, 29/88 (33%) had a successful removal. The absence of optimization was associated with treatment success (P = 0.044, odds ratio 2.74; 95% confidence interval: 0.96-7.82). In multivariable analysis, the number of prior anti-TNF agents (≥3) was borderline significant (P = 0.056, odds ratio 0.4; 95% confidence interval: 0.15-1.08). In patients with inactive pCD at initiation, the probability of recurrence-free survival was 86.2% and 75.1% at weeks 26 and 52, respectively.DISCUSSION:Ustekinumab appears as a potential effective therapeutic option in perianal refractory CD. Further prospective studies are warranted.

BACKGROUND:The management of Crohn's disease patients with perianal lesions and anti-TNF failure is challenging.AIMS:To assess the effectiveness of vedolizumab in perianal Crohn's disease and the predictors of success in a real-life cohort.METHODS:We conducted a nationwide multicentre cohort study in patients with perianal Crohn's disease who received vedolizumab. In patients with active perianal Crohn's disease, the success of vedolizumab was defined by clinical success (no draining fistula at clinical examination and no anal ulcers for primary lesions) at 6 months without medical or surgical treatment for perianal Crohn's disease. Logistic regression analyses were performed to identify predictors of success. In patients with inactive perianal Crohn's disease, recurrence was defined by the occurrence of lesions and/or the need for medical or surgical treatments.RESULTS:One hundred and fifty-one patients were included. Among them 102 patients had active perianal disease, 33 (32.4%) males, mean age 39.8 years, mean Crohn's disease duration 14.6 years; 101 (99%) had received at least one anti-TNF. The median follow-up time was 52 weeks. Sixty-eight per cent of patients discontinued therapy after a median time of 33 weeks. Vedolizumab success was reached in 23/102 (22.5%). Among patients with setons at initiation, 9/61(15%) had a successful removal. In multivariable analysis, factors associated with success were the number of prior biologic agents (≥3, odds ratio, OR: 0.20, 95% CI 0.04-0.98) and no antibiotics at initiation (OR: 4.76, 95% CI 1.25-18.19). In 49 patients with inactive perianal Crohn's disease, perianal disease recurred in 15/49 (30.6%), 11/49 (22.4%) needed dedicated treatments. Median time to recurrence was 22 weeks.CONCLUSIONS:We identified a low rate of success of vedolizumab in patients with active perianal Crohn's disease, and nearly one third of patients with inactive perianal Crohn's disease had perianal recurrence. Further evaluation is warranted in prospective studies.

BACKGROUND:Whether therapeutic drug monitoring (TDM) of infliximab should be implemented in daily practice is an ongoing controversy.AIMS:To assess the real-world use of TDM in an observational multicentre cohort study with consecutive patients with inflammatory bowel disease (IBD) treated with CT-P13.METHODS:Between September 2015 and December 2016, 364 patients with IBD were treated with CT-P13 in 13 gastroenterology departments and were followed up for 54 weeks. Disease activity, CT-P13 trough concentration and anti-CT-P13 antibody (ACA) were recorded.RESULTS:Steroid-free clinical remission rates at week 54 were 67.0% and 56.4% in patients with CD and UC, respectively. CT-P13 trough concentrations were measured in 70.7% of the patients. The mean CT-P13 trough concentration was 4.2±4.3μg/mL. The presence of ACA was observed in 53 (15.9%) patients. CT-P13 trough concentration was collected in a proactive approach in 62.8% of cases and in a reactive approach in 37.2%. Among patients who submitted to TDM, CT-P13 therapy was optimized in 88.7% of the reactive group and in 22.5% of the proactive group (P<0.001).CONCLUSION:In a real-world cohort of patients with IBD treated with CT-P13, more than two-thirds of the patients underwent TDM. CT-P13 optimization was much less common in the proactive approach than in the reactive approach.

SummaryBackgroundAbdominal or pelvic radiotherapy in inflammatory bowel disease (IBD) patients raises concerns regarding the risk of worsening of underlying disease.AimTo assess the impact of radiotherapy on IBD course.MethodsA retrospective multicentre study including IBD patients exposed to abdominal or pelvic irradiation was conducted, retrieving IBD activity by semester (6‐month periods) before (from S‐4 to S‐1) and after (from S + 1 to S + 6) radiotherapy and IBD flare during follow‐up.ResultsSixty‐one patients (32 women, mean age 59 years), with 467 patient semesters of follow‐up, treated for digestive (n = 31), urinary tract (n = 23) and gynaecological cancers (n = 7) were included. Rates of IBD activity per semester were, respectively, 21% (95% CI: 16‐27) from S‐4 to S‐1; 12% (7‐19) from S + 1 to S + 3 (P = 0.15 vs S‐4 to S‐1) and 16% (10‐25) from S + 4 to S + 6 (P = 0.45 vs S‐4 to S‐1). With a median follow‐up of 156 weeks (interquartile range: 82‐365), rates of survival without IBD flare at 1 and 3 years after radiotherapy were 82.5% (73.2‐93.0) and 70.6% (58.8‐84.7). Moderate‐to‐severe acute radiotherapy‐induced gut toxicity and the absence of concomitant chemotherapy were independently associated with an increased risk of flare.ConclusionMost patients with non‐active IBD can be safely treated with abdominal or pelvic radiotherapy. Patients having acute gut toxicity and those without concomitant chemotherapy should be more closely monitored in the post‐radiotherapy period.

T cell clonal expansions are present in the inflamed mucosa of patients with Crohn’s disease (CD) and may be implicated in postoperative recurrence after ileocolonic resection.MethodsT cell receptor (TCR) analysis was performed in 57 patients included in a prospective multicentre cohort. Endoscopic recurrence was defined by a Rutgeerts score >i0. DNA and mRNA were extracted from biopsies collected from the surgical specimen and endoscopy, and analysed by high throughput sequencing and microarray, respectively.ResultsTCR repertoire in the mucosa of patients with CD displayed diverse clonal expansions. Active smokers at time of surgery had a significantly increased proportion of clonal expansions as compared with non-smokers (25.9%vs17.9%, p=0.02). The percentage of high frequency clones in the surgical specimen was significantly higher in patients with recurrence and correlated with postoperative endoscopic recurrence (area under the curve (AUC) 0.69, 95% CI 0.54 to 0.83). All patients with clonality above 26.8% (18/57) had an endoscopic recurrence. These patients with a high clonality were more frequently smokers than patients with a low clonality (61% vs 23%, p=0.005). The persistence of a similar TCR repertoire at postoperative endoscopy was associated with smoking and disease recurrence. Patients with high clonality showed increased expression of genes associated with CD8 T cells and reduced expression of inflammation-related genes. Expanded clones were found predominantly in the CD8 T cell compartment.ConclusionClonal T cell expansions are implicated in postoperative endoscopic recurrence. CD patients with increased proportion of clonal T cell expansions in the ileal mucosa represent a subgroup associated with smoking and where pathogenesis appears as T cell driven.Trial registration numberNCT03458195.

Objectives: Clostridium difficile infection (CDI) is a common complication in inflammatory bowel disease (IBD) and has been associated with poor IBD outcome. The aims of our study were to look for predictive factors of CDI in patients hospitalized for IBD flare and to evaluate a rapid testing strategy in this population.Methods: Consecutive patients hospitalized for IBD flare in Saint-Antoine Hospital (Paris, France) were prospectively tested for CDI with a defined strategy involving rapid testing and reference methods. Risk factors for CDI were investigated and performances of diagnostic tests were evaluated.Results: C. difficile testing was performed at admission in 461 hospitalizations for IBD flare. CDI was diagnosed in 35 cases (7.6%) and non-toxigenic C. difficile was identified in 10 cases (2.2%). In multivariate analysis, UC phenotype was associated with CDI (OR 2.2, 95% CI 1.03-4.6, p = 0.047). Glutamate dehydrogenase (GDH) test had a 97.1% sensitivity and a 100% negative predictive value for CDI diagnosis but a positive predictive value of 79.1%. Enzyme immunoassay (EIA)-based toxin detection (C. Diff Quik Chek complete (R), Alere) had a poor sensitivity and diagnosis was rescued by toxin PCR in 100% of cases.Conclusion: CDI is frequent in patients hospitalized for IBD flare. Clinical parameters do not help for the diagnosis and rapid testing should be performed in all patients. Currently, a negative result of an EIA-based toxin search associated with a positive GDH test cannot rule out a CDI and should not delay initiation of specific treatment in case of severe symptoms or high presumption. (C) 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

BACKGROUND & AIMS: Stricturing or penetrating lesions develop over time in most patients with Crohn's disease. The Lemann Index indicates the degree of digestive damage at a given time in an individual. We tracked changes in Lemann Index scores in an inception cohort of patients and looked for factors associated with digestive damage.METHODS: We studied 221 patients diagnosed with Crohn's disease from 2004 through 2011 who received 2 or 3 serial morphologic evaluations over a period of 2 to 10 years. We collected cross-sectional images and had them reviewed by a gastroenterologist and a radiologist; Lemann index scores were calculated. A value of 2 was chosen as the cut-off value for substantial transparietal damage. Factors associated with a score greater than 2 at the last evaluation and progression of index scores were identified using univariate analysis and logistic regression analyses.RESULTS: The median index Lemann Index scores were 2.3 (interquartile range [IQR], 1.2-3.9) at first evaluation, 3.5 (IQR, 1.2-8.6) at 2 to 5 years after diagnosis, and 8.3 (IQR, 1.2-12.1) at 5 to 10 years after diagnosis. Index scores increased significantly at each stage compared with initial or previous values (P < .0001). After 73 months (IQR, 51-96 mo) of follow-up evaluation, 138 patients had a Lemann Index score greater than 2.0. The only early factor that predicted later damage was the first index value. Intestinal resection, time, and the percentage of time elapsed with a clinically active disease were associated with progressing damage.CONCLUSIONS: Based on an analysis of patients with Crohn's disease using the Lemann Index, nearly two thirds had substantial mucosal damage 2 to 10 years after diagnosis. High Lemann index scores at the first evaluation, time, persistent clinical activity, and intestinal resection are associated with damage.

Background: Stricturing or penetrating lesions develop over time in most patients with CD leading eventually to surgical resection.The Lémann Index (LI) measures the digestive damage at a given time.The aim of this study was to describe the evolution of LI in an incipient cohort of CD patients and to search for predictors of digestive damage.Methods: We studied 221 patients (114 M, 107 F, median age 24 yr [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]) diagnosed with CD between 2004 and 2011, followed up prospectively in our center, and who had 2 or 3 serial morphological determinations of LI.Abdominal CT scan (n=204), abdominal MRI (n=332), and pelvic MRI (n=56) were re-read by a couple gastroenterologist and radiologist.LI was then calculated taking into account clinical and endoscopic data and radiological re-assessment.The cut-off of LI >2.0, corresponding to the 75th percentile value of pre-operative LI in patients led to surgery, was assigned to identify patients with a substantial damage.In addition we analyzed intervals between 2 evaluations.Factors associated with damage and progression of LI during one interval were searched for using univariate analysis and logistic regression.Results: Median LI was 2.3 (1.2-3.9) at first evaluation, 3.9 (1.6-9.8)2-5 yr after diagnosis, and 8.3 (1-12.3)at 5-10 yr.LI increased significantly (p< 0.0001) at 2-5 yr and 5-10 yr compared to its initial value and from 2-5 yr to 5-10 yr.Last value of LI after 73 months (51-96) was >2.0 in 138 patients (63%).These patients did not differ from those without digestive damage regarding demographic data and characteristics of CD collected at diagnosis, however their earliest LI was significantly increased.90 patients eventually required intestinal resection.Among 313 intervals between 2 morphological evaluations, LI increased (>0.1) during 161 intervals (51%), remained unchanged (± 0.1) during 59 intervals (19%), and decreased (>0.1) during 93 intervals (30%).In addition to intestinal resection, the percentage of time with clinically active disease was associated with increase of LI (p<0.001).Elevated CRP and treatment with immunomodulators or anti-TNF had no significant effect.However the increase of LI was mild in the 57 patients who received anti-TNF more than 80% of time (from 3.5 [1.6-7.2] to 4.1 [0.6-10.3])and significantly reduced compared to those not on anti-TNF (n=204: from 2.9 [1.2-8.3] to 4.8 [1.0-10.8])(p<0.01).Conclusions: Digestive damage measured by LI increases significantly during the first years following diagnosis of CD.Factors associated with damage are elevated LI at first evaluation, duration of clinical activity and intestinal resection.These Results underline the importance of achieving prolonged clinical remission for preventing digestive damage.

Ces dernières années, l'implication du microbiote intestinal dans la physiopathogénie des maladies inflammatoires chroniques de l'intestin (MICI) a été mise en évidence. Le but de nos travaux est de déterminer l'impact de la dysbiose sur l'écosystème intestinal au cours des MICI. Ces trois études nous ont permis de confirmer le rôle central de la dysbiose associée aux MICI : d'une part comme outil potentiellement prédictif de rechute, précédant une inflammation locale ou systémique, d'autre part comme acteur dans l'apparition d'un déséquilibre de l'écosystème intestinal. Ce déséquilibre est marqué par l'altération de l'activité enzymatique du microbiote modifiant le pool d'acides biliaires dans la lumière intestinale et pouvant affecter les effets anti-inflammatoires de certains acides biliaires sur les cellules épithéliales intestinales participant ainsi à une inflammation chronique au cours des MICI. Par ailleurs, cette dysbiose est possiblement entretenue par un déficit en défensine hBD1 et HD5, perpétuant une inflammation chronique intestinale.Ces résultats renforcent le rôle proéminent du microbiote dans l'évolution des MICI et suggèrent que la restauration de la normobiose au cours de la maladie devrait être un nouveau but dans la prise en charge de ces patients.

BACKGROUND:Crohn's disease (CD)-associated dysbiosis could predispose patients to relapse. Gut microbiota composition of patients from the prospective cohort study designed to identify predictive factors of clinical relapse after infliximab discontinuation (STORI Study) was investigated to determine the impact of dysbiosis in CD relapse.METHODS:Fecal samples from 33 patients with CD in this cohort were collected at baseline, 2 months, 6 months, and at the end of the follow-up period (19 relapsers and 14 nonrelapsers). Healthy volunteers subjects (n = 29) were used as a control group. The fecal microbiota composition was assessed using quantitative PCR, and comparisons between the patient groups were made at different time points using the Wilcoxon test. The analysis of the time-to-relapse was performed according to the baseline median level of each bacterial signal.RESULTS:Dysbiosis was observed in patients with CD compared with healthy subjects, and it was characterized by low mean counts of Firmicutes (Clostridium coccoides [P = 0.0003], C. leptum [P < 0.0001], and Faecalibacterium prausnitzii [P = 0.003]). Lower rates of Firmicutes were seen in relapsers compared with nonrelapsers. Moreover, a low rate of F. prausnitzii (P = 0.014) and a low rate of Bacteroides (P = 0.030) predicted relapse independently from high C reactive protein level (P = 0.0001).CONCLUSIONS:In this work, we report that CD-associated dysbiosis, characterized by a decrease in Firmicutes, correlates with the time-to-relapse after infliximab withdrawal. A deficit in some bacterial groups or species, such as F. prausnitzii, may represent a predictive factor for relapse. Restoring normobiosis in CD could be a new goal for optimal CD management.

The bile acids receptors Farsenoid X and TGR5 protect against the formation of atheroma in mice, though no evidence have linked coronary atheroma and bile acid in human. Bile acids links these receptors with more or less efficient activation, depending on the species. To test the hypothesis that changes in concentrations of circulating bile acid species influence the risk of developing coronary atheromas in humans. Pilot, prospective, observational study conducted between June and September 2010. The serum concentrations of cholic, chenodeoxycholic, deoxycholic, and lithocholic acids were measured in a fasting blood sample. Consecutive hospitalized or ambulatory patients undergoing emergency or elective coronary angiograms were eligible for inclusion. Post-cardiac arrest and non-fasting states, hepatic disease, and treatment with antimicrobials, corticosteroids, statins or fibrates were exclusion criteria. Of 393 screened patients, 44 met the study entry criteria, and were divided between 27 patients with (Group A) and 17 without (Group B) angiographically visible coronary atheromas. The pool of circulating bile acids was analyzed to measure the plasmatic concentrations of 28 different bile acid species. The variables associated with the presence of angiographically visible coronary atheromas were examined by single and multiple variable logistic regression analysis. The serum lithocholic acid concentration was significantly lower in group A than in group B. By multiple variable analysis, lithocholic acid was the only predictor of coronary atheroma independently of patient gender (odds ratio 2.41 per 0.05 decrease; 95% confidence interval 1.11 to 5.25, P=0.027 A low serum concentration of lithocholic acid was an independent predictor of coronary atheroma in human.Download : Download full-size image

Although low-density lipoprotein (LDL) cholesterol, synthesized by liver, is one of the main risk factors of coronary atheroma in humans, clinical practice has taught us that meetings between our 2 specialties are not about this subject, except maybe when discussing the opportunity of a liver transplantation in patients with severe coronary disease. Recent works demonstrating a strong protective effect of the bile acids receptor FXR and TGR5 in a mice models of atheroma1, 2 could change this old rule in the not so distant future, but so far no evidences exists in humans. The level of activation of these receptors depends on the type of bile acids that activate them.3 We designed a pilot prospective and observational study conducted between June 2010 and September 2010 to search for variations in the bile acid pool composition between 2 populations: patients with or without coronary atheroma. We determined the serum concentrations of cholic, chenodeoxycholic, deoxycholic, and lithocholic acids in a fasting blood sample in all consecutive patients undergoing coronary angiograms in the cathlab unit of Cochin Hospital. Applying very restrictive exclusions criteria to avoid artificial variations of the bile acid pool (post-cardiac arrest; nonfasting states; hepatic disease; treatment with antimicrobials, corticosteroids, statins, or fibrates) of 393 screened patients, 44 met the criteria and were divided between 27 with (group A) and 17 without (group B) angiographically visible coronary atheromas. Except for more males in group A, the groups were comparable. The serum lithocholic acid (LCA) concentration was significantly lower in group A (median 0.03 μmol/L; interquartile range 0.02–0.05) than in group B (0.08 μmol/L; interquartile range 0.05–0.11; P = 0.015) (Fig. 1). In the multivariate analysis, LCA was the only predictor of coronary atheroma independently of patient gender (odds ratio 2.41 per 0.05 decrease; 95% confidence interval 1.11-5.25; P = 0.027). (A) Box and whisker plots showing the median, and 25th and 75th percentiles of the distribution (box) and whiskers extending to the most extreme data point, which is no more than 1.5 times the interquartile range from the box. (B) Receiver operating characteristics curve. The area under the curve (AUC) is presented with its 95% confidence interval (95% CI). LCA, lithocholic acid. Although the populations were small, we believe this observation connecting LCA and coronary atheroma is a field worth investigating further, as LCA is the most powerful activator of TGR5.3 A study targeting the proinflammatory mechanism acting in atheroma plaque evidenced that the activation of the TGR5 receptor significantly limits the formation of plaques in LDL−/− mice by decreasing the inflammation inside the plaque and the proinflammatory cytokines secretion by macrophages. This raises the hypothesis that lowering the most prominent activator of TGR5 is likely to lower the protection against plaque development in humans. Further studies are needed to confirm this observation, to better understand the origin and the extent to which a decrease in LCA is implicated in the development of coronary atheromatous plaques, and to maybe put us hepatologists and cardiologists more often around the same table. Henri Duboc M.D. , Hélène Aelion M.D.*, Dominique Rainteau Ph.D. , Sylvie Rajca M.D. , Harry Sokol M.D., Ph.D. , Lydie Humbert , Dominique Farabos , Benoit Coffin M.D., Ph.D. , Simon Weber M.D.*, Raphaël Porcher Ph.D.§, Olivier Varenne M.D., Ph.D.*, Denis Duboc M.D.*, * University Paris Descartes, AP-HP, Cochin Hospital, Department of Cardiology, Paris, France, University Paris Diderot, Sorbonne Paris Cité, AP-HP, Louis Mourier Hospital, Department of Gastroenterology and Hepatology, Paris, France, University Pierre and Marie Curie, ERL INSERM U 1057/UMR 7203, AP-HP, Saint-Antoine Hospital, Paris, France, § University Paris Diderot, Sorbonne Paris Cité, UMR-S 717, APHP, Saint Louis Hospital, Biostatistic and Medical Informatics Department, Paris, France.

OBJECTIVE:Gut microbiota metabolises bile acids (BA). As dysbiosis has been reported in inflammatory bowel diseases (IBD), we aim to investigate the impact of IBD-associated dysbiosis on BA metabolism and its influence on the epithelial cell inflammation response. DESIGN:Faecal and serum BA rates, expressed as a proportion of total BA, were assessed by high-performance liquid chromatography tandem mass spectrometry in colonic IBD patients (42) and healthy subjects (29). The faecal microbiota composition was assessed by quantitative real-time PCR. Using BA profiles and microbiota composition, cluster formation between groups was generated by ranking models. The faecal BA profiles in germ-free and conventional mice were compared. Direct enzymatic activities of BA biotransformation were measured in faeces. The impact of BA on the inflammatory response was investigated in vitro using Caco-2 cells stimulated by IL-1β. RESULTS:IBD-associated dysbiosis was characterised by a decrease in the ratio between Faecalibacterium prausntizii and Escherichia coli. Faecal-conjugated BA rates were significantly higher in active IBD, whereas, secondary BA rates were significantly lower. Interestingly, active IBD patients exhibited higher levels of faecal 3-OH-sulphated BA. The deconjugation, transformation and desulphation activities of the microbiota were impaired in IBD patients. In vitro, secondary BA exerted anti-inflammatory effects, but sulphation of secondary BAs abolished their anti-inflammatory properties. CONCLUSIONS:Impaired microbiota enzymatic activity observed in IBD-associated dysbiosis leads to modifications in the luminal BA pool composition. Altered BA transformation in the gut lumen can erase the anti-inflammatory effects of some BA species on gut epithelial cells and could participate in the chronic inflammation loop of IBD.

Aim:Dysbiosis, an alteration of intestinal microbiota, has been previously described in Crohn's Disease (CD).It appears deeper in active disease than in remission and could predispose to relapse.The GETAID conducted a prospective cohort study to look for predictive factors of CD clinical relapse after infliximab discontinuation in patients treated for at least one year by a combined therapy with immunosuppressant.Faecal samples from a subset of patients in this cohort allowed seeking out whether dysbiosis could be predictive of CD relapse.Materials and Methods: Fecal samples from 31 healthy subjects and 37 CD patients included in the cohort were collected at D-1 (date of infliximab discontinuation), M2 (two months) and M6 (six months).At the end of the observation period (30 months), 18 of the CD patients remained in remission while 19 exhibited clinical relapse.A characterisation of the microbiota of fecal samples in groups (Bacteroides, C. coccoides, C. leptum, Lactobacilles, Bifidobactéries) and bacterial species (F.prausnitzii, E. coli), was performed using quantitative real-time polymerase chain reaction and expressed as a proportion of the total number of bacteria of each sample.Comparisons between groups (control vs CD, sustained remission vs future relapse) were made at different time points using Wilcoxon test.CD relapse-free survival analysis using Kaplan-Meier method (log rank test) was performed according to D-1 median rate of each bacterial species or group looking for the relapse predictive value of dysbiosis.Results: At D-1, dysbiosis was observed in CD patients in remission compared to healthy subjects.Dysbiosis was characterized by a low counts of Firmicutes (C.coccoïdes p=0.0003 and C. leptum p<0.0001) and F. prausnitzii (p=0.0003).This dysbiosis (C.coccoides and F. prausnitzii decrease) was more pronounced in patients with future relapse compared to patients with sustained remission (p=0.02).Same tendency was observed at different time points.Moreover, after infliximab drop out, a decrease in C. coccoides (p = 0.01), Bacteroides (P = 0.03) or F. prausnitzii (p = 0.03) at D-1 was significantly associated with a shorter time to relapse.Écouter Lire phonétiquement Conclusion: This work confirms dysbiosis in CD patients even in remission.This dysbiosis was characterized by a decrease in Firmicutes.Moreover, a deficit in some bacterial groups or species such as F. prausnitzii appears as a predictive factor of CD relapse after infliximab discontinuation.Further studies are needed to validate these findings and to assess the benefit of restoring normobiosis in CD management.

BACKGROUND:Epidemiologic data suggest that smoking increases the risk and the severity of Crohn's disease (CD), although it may protect patients with ulcerative colitis (UC). To investigate this paradox, we evaluated the effect of cigarette smoke in the function of blood mononuclear cells from healthy subjects and patients with CD or UC in flare up.METHODS:The production of mediators associated with inflammation but also with protective functions was evaluated by enzyme-linked immunosorbent assay (ELISA) and enzyme immunoassay (EIA), following either in vivo or in vitro exposure to cigarette smoke.RESULTS:We found that mononuclear cells from smokers with CD were functionally impaired. These cells secreted lower levels of chemokines and cytokines as compared with nonsmoker counterparts, whereas healthy smokers or smokers with UC were not affected. Similar findings were noted after in vitro exposure to cigarette smoke extract. In addition, cells from patients with CD who smoke presented a defective sensitivity to antiinflammatory or antioxidant protection, and particularly synthesized lower levels of cytoprotective Hsp70. The effects observed were not due to diminished cell viability. Our experiments suggest that cigarette smoke-related responses were largely dependent on oxidative stress generated, and not on the nicotine component.CONCLUSIONS:Overall, our data point out the presence of biological differences between blood mononuclear cells from patients with CD and UC toward cigarette smoke that might support its opposite role in both diseases.

regulon is upregulated in luminal E. coli from long-term monoassociated IL-10-/-mice (KO) with colitis compared to bacteria from healthy wild-type (WT) controls.Since colonic inflammation is associated with lower luminal pH, we chose to focus on two members of the stress response regulon that encode enzymes important for bacterial fitness in acidic environments, gadA and B. We hypothesized that gadAB expression varies with the phase of colitis and may also be enhanced by biologically relevant pro-inflammatory factors.METHODS: WT and KO mice were monoassociated with a commensal E. coli strain (NC101).Cecal bacterial gadAB expression was measured using real-time PCR, histological inflammation was quantified using a validated scoring system, and spontaneous secretion of IL-12/ 23p40 from intestinal explant cultures was assessed using ELISA.GadAB expression in cultured NC101 treated with conditioned media from stimulated splenocytes or recombinant cytokines was measured using real-time PCR.The effect of phagocytosis of NC101 by macrophages on gadAB transcription was also assessed.RESULTS: Interestingly, during the first 2 weeks of monoassociation, prior to onset of histological inflammation, gadAB expression is higher in NC101 from WT than KO mice.However, at later time points, when aggressive histological inflammation is present, expression of gadAB in NC101 from KO mice is greater compared to WT. NC101 gadAB mRNA was also significantly increased in bacteria grown In Vitro and stimulated with recombinant TNF and IFNγ compared to media control.Furthermore, NC101 ingested by macrophages increase gadAB transcription 1 hour postinfection, coinciding with the predicted time of phagolysosomal acidification.CONCLU-SIONS: The E. coli stress response genes, gadAB, are differentially regulated in a bimodal fashion during the early phases of experimental colitis and are increased in response to proinflammatory cytokines and macrophage phagocytosis In Vitro.Further investigation of the impact of E. coli gadAB expression on the development of colitis is warranted and will provide novel insights into the pathogenesis of IBD.GadAB expression relative to bacterial 16S (fold difference) (n=4 mice/group)