Anne Bourrier

CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands

Complex interactions between the host and the gut microbiota govern intestinal homeostasis but remain poorly understood. Here we reveal a relationship between gut microbiota and caspase recruitment domain family member 9 (CARD9), a susceptibility gene for inflammatory bowel disease (IBD) that functions in the immune response against microorganisms. CARD9 promotes recovery from colitis by promoting interleukin (IL)-22 production, and Card9−/− mice are more susceptible to colitis. The microbiota is altered in Card9−/− mice, and transfer of the microbiota from Card9−/− to wild-type, germ-free recipients increases their susceptibility to colitis. The microbiota from Card9−/− mice fails to metabolize tryptophan into metabolites that act as aryl hydrocarbon receptor (AHR) ligands. Intestinal inflammation is attenuated after inoculation of mice with three Lactobacillus strains capable of metabolizing tryptophan or by treatment with an AHR agonist. Reduced production of AHR ligands is also observed in the microbiota from individuals with IBD, particularly in those with CARD9 risk alleles associated with IBD. Our findings reveal that host genes affect the composition and function of the gut microbiota, altering the production of microbial metabolites and intestinal inflammation.

Fungal microbiota dysbiosis in IBD

Objective The bacterial intestinal microbiota plays major roles in human physiology and IBDs. Although some data suggest a role of the fungal microbiota in IBD pathogenesis, the available data are scarce. The aim of our study was to characterise the faecal fungal microbiota in patients with IBD. Design Bacterial and fungal composition of the faecal microbiota of 235 patients with IBD and 38 healthy subjects (HS) was determined using 16S and ITS2 sequencing, respectively. The obtained sequences were analysed using the Qiime pipeline to assess composition and diversity. Bacterial and fungal taxa associated with clinical parameters were identified using multivariate association with linear models. Correlation between bacterial and fungal microbiota was investigated using Spearmans test and distance correlation. Results We observed that fungal microbiota is skewed in IBD, with an increased Basidiomycota/Ascomycota ratio, a decreased proportion of Saccharomyces cerevisiae and an increased proportion of Candida albicans compared with HS. We also identified disease-specific alterations in diversity, indicating that a Crohns disease-specific gut environment may favour fungi at the expense of bacteria. The concomitant analysis of bacterial and fungal microbiota showed a dense and homogenous correlation network in HS but a dramatically unbalanced network in IBD, suggesting the existence of disease-specific inter-kingdom alterations. Conclusions Besides bacterial dysbiosis, our study identifies a distinct fungal microbiota dysbiosis in IBD characterised by alterations in biodiversity and composition. Moreover, we unravel here disease-specific inter-kingdom network alterations in IBD, suggesting that, beyond bacteria, fungi might also play a role in IBD pathogenesis.

Long-term Outcome of Patients With Crohn's Disease Who Respond to Azathioprine

BACKGROUND & AIMS Little is known about the long-term outcomes of patients with Crohns disease (CD) who have a complete response to therapy with azathioprine. We assessed the long-term effects of azathioprine in responders. METHODS We collected data from the MICISTA registry (a database from the Rothschild and Saint-Antoine Hospitals, Paris, France) on consecutive CD patients treated with azathioprine from 1987 to 1999 who responded to therapy (steroid-free clinical remission at 1 y); they were followed up until 2011 (n = 220; 86 men; median age, 32 y; median follow-up period, 12.6 y). Data were compared with those from 440 matched patients with CD who did not receive immunosuppressants during the same inclusion period (controls). RESULTS The cumulative rate of sustained remission 10 years after treatment with azathioprine was 38%. Among patients exposed to azathioprine during a prospective follow-up period (1995-2011, 1936 patient-years), the percentage of patient-years with active disease (flare or complication during the calendar year) was 17.6%. Compared with the control group, at baseline, responders were more often active smokers with significantly more extensive disease, perianal lesions, and extradigestive manifestations. During follow-up evaluation, responders had a significantly reduced risk of intestinal surgery (adjusted odds ratio, 0.69; 95% confidence interval, 0.52-0.91) and perianal surgery (adjusted odds ratio, 0.36; 95% confidence interval, 0.27-0.46). A significantly higher percentage of responders developed cancers, including nonmelanoma skin cancers, compared with controls (9.5% vs 4.1%; P < .01). Survival rates after 20 years were 92.8% ± 2.3% of responders vs 97.9% ± 0.8% of controls (P = .01). CONCLUSIONS Based on a study at a single center, patients with CD who responded to azathioprine had a smaller proportion of patient-years with active disease, and were less likely to be hospitalized or undergo intestinal surgery, than patients with CD who did not receive immunosuppressants. These benefits, however, could be offset by an increased risk of malignancies.

Factors affecting outcomes in Crohn's disease over 15 years

Crohns disease (CD) progression is marked by the occurrence of stricturing complications or intestinal and perianal penetrating complications, typically requiring surgery.1 ,2 We previously reported three factors at the time of diagnosis that increased the chance of disabling disease during the 5 years following: (1) age <40 years old, (2) presence of perianal lesions and (3) the requirement for steroids to control the first flare.3 However, as the median age of diagnosis is 27 years, the course of CD may last more than 50 years in the Western world, where the life expectancy of patients exceeds 70 years. Therefore, identifying predictive criteria throughout such a long period remains challenging. We believe the assessment of CD severity should not be skewed by only taking into account occasional disease events.4 For example, one patient may be operated on once and then experience a long period of quiescent disease. CD manifestations are often quite active during the early few years before subsequently resolving and becoming more stable.5 One may consider a CD complication as an acute phenomenon without recurrence,6 and, in the absence of significant sequelae, such an event should therefore not be regarded as a marker of severe disease. Notably, most therapeutic strategies aim to avoid short-term complications; however, CD is a chronic disease requiring lifelong monitoring. Very little is known about the long-term evolution of CD. Therefore, the aim of our study was to identify predictable factors associated with a mild-to-moderate, long-term CD course; for this purpose, we prospectively analysed a large cohort of patients with CD over 15-year period. ### Patients Patients with complete 15-year follow-up records were selected from the MICISTA Registry. This tertiary clinical database of more …

The impact of cytomegalovirus reactivation and its treatment on the course of inflammatory bowel disease

Consequences of latent cytomegalovirus (CMV) infection reactivation on inflammatory bowel disease (IBD) flare, as a flare‐worsening factor or simple bystander, are debated. Impact of anti‐viral treatment on IBD course is poorly known.

Efficacy of adalimumab in patients with Crohn's disease and symptomatic small bowel stricture: a multicentre, prospective, observational cohort (CREOLE) study

Objective The efficacy of anti-tumour necrosis factors (anti-TNFs) in patients with Crohns disease (CD) and symptomatic small bowel stricture (SSBS) is controversial. The aim of this study was to estimate the efficacy of adalimumab in these patients and to identify the factors predicting success. Design We performed a multicentre, prospective, observational cohort study in patients with CD and SSBS. The included patients underwent magnetic resonance enterography at baseline and subsequently received adalimumab. The primary endpoint was success at week 24, defined as adalimumab continuation without prohibited treatment (corticosteroids after the eight week following inclusion, other anti-TNFs), endoscopic dilation or bowel resection. The baseline factors independently associated with success were identified using a logistic regression model, leading to a simple prognostic score. Secondary endpoints were prolonged success after week 24 (still on adalimumab, without dilation nor surgery) and time to bowel resection in the whole cohort. Results From January 2010 to December 2011, 105 patients were screened and 97 were included. At week 24, 62/97 (64%) patients had achieved success. The prognostic score defined a good prognosis group with 43/49 successes, an intermediate prognosis group with 17/28 successes and a poor prognosis group with 1/16 successes. After a median follow-up time of 3.8 years, 45.7%±6.6% (proportion±SE) of patients who were in success at week 24 (ie, 29% of the whole cohort) were still in prolonged success at 4 years. Among the whole cohort, 50.7%±5.3% of patients did not undergo bowel resection 4 years after inclusion. Conclusions A successful response to adalimumab was observed in about two-thirds of CD patients with SSBS and was prolonged in nearly half of them till the end of follow-up. More than half of the patients were free of surgery 4 years after treatment initiation. Clinical Trial registration number NCT01183403; Results.

One-year effectiveness and safety of vedolizumab therapy for inflammatory bowel disease: a prospective multicentre cohort study

We recently showed that vedolizumab is effective in patients with Crohns disease (CD) and ulcerative colitis (UC) with prior anti‐TNF failure in a multicentre compassionate early‐access programme before marketing authorisation was granted to vedolizumab.

Negative Screening Does Not Rule Out the Risk of Tuberculosis in Patients with Inflammatory Bowel Disease Undergoing Anti-TNF Treatment: A Descriptive Study on the GETAID Cohort

AIM to describe the characteristics of incident cases of tuberculosis [TB] despite negative TB screening tests, in patients with inflammatory bowel disease [IBD] undergoing anti-TNF treatment, and to identify the risk factors involved. METHODS A retrospective descriptive study was conducted at GETAID centers on all IBD patients undergoing anti-TNF treatment who developed TB even though their initial screening test results were negative. The following data were collected using a standardized anonymous questionnaire: IBD, and TB characteristics and evolution, initial screening methods and results, and time before anti-TNF treatment was restarted. RESULTS A total of 44 IBD patients [including 23 men; median age 37 years] were identified at 20 French and Swiss centers at which TB screening was performed [before starting anti-TNF treatment] based on Tuberculin Skin Tests [n = 25], Interferon Gamma Release Assays [n = 12], or both [n = 7]. The median interval from the start of anti-TNF treatment to TB diagnosis was 14.5 months (interquartile range [IQR] 25-75: 4.9-43.3). Pulmonary TB involvement was observed in 25 [57%] patients, and 40 [91%] had at least one extrapulmonary location. One TB patient died as the result of cardiac tamponade. Mycobacterium tuberculosis exposure was thought to be a possible cause of TB in 14 cases [32%]: 7 patients [including 6 health care workers] were exposed to occupational risks, and 7 had travelled to endemic countries. Biotherapy was restarted on 27 patients after a median period of 11.2 months [IQR 25-75: 4.4-15.2] after TB diagnosis without any recurrence of the infection. CONCLUSION Tuberculosis can occur in IBD patients undergoing anti-TNF treatment, even if their initial screening results were negative. In the present population, TB was mostly extrapulmonary and disseminated. TB screening tests should be repeated on people exposed to occupational risks and/or travelers to endemic countries. Restarting anti-TNF treatment seems to be safe.

Prevalence and risk factors of Clostridium difficile infection in patients hospitalized for flare of inflammatory bowel disease: A retrospective assessment

BACKGROUND Recent studies have identified a high frequency of Clostridium difficile infections in patients with active inflammatory bowel disease. AIMS To retrospectively assess the determinants and results of Clostridium difficile testing upon the admission of patients hospitalized with active inflammatory bowel disease in a tertiary care centre and to determine the predicting factors of Clostridium difficile infections. METHODS We reviewed all admissions from January 2008 and December 2010 for inflammatory bowel disease flare-ups. A toxigenic culture and a stool cytotoxicity assay were performed for all patients tested for Clostridium difficile. RESULTS Out of 813 consecutive stays, Clostridium difficile diagnostic assays have been performed in 59% of inpatients. The independent predictive factors for the testing were IBD (ulcerative colitis: OR 2.0, 95% CI 1.5-2.9; p<0.0001) and colonic involvement at admission (OR 2.2, 95% CI 1.5-3.1, p<0.0001). Clostridium difficile infection was present in 7.0% of the inpatients who underwent testing. In a multivariate analysis, the only independent predictor was the intake of nonsteroidal anti-inflammatory drugs within the two months before admission (OR 3.8, 95% CI 1.2-12.3; p=0.02). CONCLUSIONS Clostridium difficile infection is frequently associated with active inflammatory bowel disease. Our study suggests that a recent intake of nonsteroidal anti-inflammatory drugs is a risk factor for inflammatory bowel disease -associated Clostridium difficile infection.

Adalimumab or infliximab as monotherapy, or in combination with an immunomodulator, in the treatment of Crohn's disease

The comparative efficacy of adalimumab (ADA) and infliximab (IFX) in Crohns disease, and the benefit of initial combotherapy with an immunomodulator, are debated.