Implications des N-acyl homosérine lactones, molécules du quorum sensing dans les maladies inflammatoires chroniques intestinales

Quorum sensing molecules N-acyl-homoserine lactones (AHLs) involved in bacterial communication network are also able to interact with eukaryotic cells. Searching for these molecules in the context of inflammatory bowel diseases (IBD) and more precisely when studying consequences of dysbiosis on gut inflammation pathways is appealing. Using mass spectrometry, we identified for the first time AHLs in human intestinal ecosystem, and among them a new AHL, 3-oxo-C12:2 which is prominent. This AHL correlates with normobiosis, is lost IBD and exerts protective effect on gut epithelial cells. In fact, 3-oxo-C12:2 exerts anti-inflammatory effect in vitro on Caco-2 cells without increased paracellular permeability. Furthermore, first results from in vivo experiments show that 3-oxo-C12:2 is also able to influence mice gut microbiota composition. These results open multiple perspectives especially on new ecological treatments in IBD.Les N-acyl homosérine lactones sont des molécules du quorum sensing impliquées dans la communication interbactérienne mais elles sont également capables d'intéragir avec les cellules eucaryotes. Rechercher ces molécules dans le contexte des maladies inflammatoires chroniques intestinlaes (MICI) et plus particulièrement dans le cadre de l'étude des conséquences de la dysbiose sur les voies de l'inflammation intestinale est séduisant. En utilisant la spectrométrie de mase, nous avons mis en évidence pour la première fois des AHLs dans l'écosystème intestinal humain, et plus particulièrement une nouvelle AHL, 3-oxo-C12 :2, qui est prédominante. Cette AHL est corrélée à la normobiose, est perdue au cours des MICI et exerce un effet protecteur sur les cellules épithéliales intestinales. En effet, la 3-oxo-C12 :2 exerce un effet anti-inflammatoire in vitro sur les cellules Caco-2 sans augmenter la perméabilité paracellulaire. De plus, les premiers résultats in vivo montrent que la 3-oxo-C12 est également capable d'influencer la composition du microbiote intestinal des souris. Ces résultats ouvrent de nombreuses perspectives notamment dans la recherche de traitements écologiques au cours des MICI

Involvement of N-acyl homoserine lactones, quorum sensing molecules, in inflammatory bowel diseases

Les N-acyl homosérine lactones sont des molécules du quorum sensing impliquées dans la communication interbactérienne mais elles sont également capables d'intéragir avec les cellules eucaryotes. Rechercher ces molécules dans le contexte des maladies inflammatoires chroniques intestinlaes (MICI) et plus particulièrement dans le cadre de l'étude des conséquences de la dysbiose sur les voies de l'inflammation intestinale est séduisant. En utilisant la spectrométrie de mase, nous avons mis en évidence pour la première fois des AHLs dans l'écosystème intestinal humain, et plus particulièrement une nouvelle AHL, 3-oxo-C12 :2, qui est prédominante. Cette AHL est corrélée à la normobiose, est perdue au cours des MICI et exerce un effet protecteur sur les cellules épithéliales intestinales. En effet, la 3-oxo-C12 :2 exerce un effet anti-inflammatoire in vitro sur les cellules Caco-2 sans augmenter la perméabilité paracellulaire. De plus, les premiers résultats in vivo montrent que la 3-oxo-C12 est également capable d'influencer la composition du microbiote intestinal des souris. Ces résultats ouvrent de nombreuses perspectives notamment dans la recherche de traitements écologiques au cours des MICI.Quorum sensing molecules N-acyl-homoserine lactones (AHLs) involved in bacterial communication network are also able to interact with eukaryotic cells. Searching for these molecules in the context of inflammatory bowel diseases (IBD) and more precisely when studying consequences of dysbiosis on gut inflammation pathways is appealing. Using mass spectrometry, we identified for the first time AHLs in human intestinal ecosystem, and among them a new AHL, 3-oxo-C12:2 which is prominent. This AHL correlates with normobiosis, is lost IBD and exerts protective effect on gut epithelial cells. In fact, 3-oxo-C12:2 exerts anti-inflammatory effect in vitro on Caco-2 cells without increased paracellular permeability. Furthermore, first results from in vivo experiments show that 3-oxo-C12:2 is also able to influence mice gut microbiota composition. These results open multiple perspectives especially on new ecological treatments in IBD

Thrombose du système porte au cours des maladies inflammatoires chroniques

Background: Inflammatory bowel disease (IBD) is associated with a high risk of deep venous thromboembolism. However, few data are available so far on portomesenteric vein thrombosis (PMVT). The aim of this study was to describe the characteristics of PMVT in patients with IBD.Methods: A retrospective study was conducted at 13 GETAID (Groupe d’Etude Thérapeutique des Affections Inflammatoires du Tube Digestif) centers from January 1995 to June 2010. The following data were collected, using a standardized questionnaire: characteristics of IBD, disease status at the time of PMVT, PMVT characteristics and mode of discovery, concomitant prothrombotic disorders, anticoagulant therapy, and evolution of PMVT.Results: Fifty cases (29 men and 21 women; median age, 41 years) were identified, including 14 patients with ulcerative colitis and 36 with Crohn’s disease. Thirty-one patients (62%) presented with acute PMVT. Twenty-four patients had previously undergone surgical treatment, and IBD was active in 23 cases (77%) of acute thrombosis. The discovery of PMVT was fortuitous in 40% of our cases. Among the 43 patients screened for a prothrombotic disorder, abnormalities were observed in 17 patients (40%) (mainly hyperhomocysteinemia, n = 12). Forty-four patients (88%) were treated with anticoagulants. Recanalization of the vein was significantly more successful in patients with acute thrombosis (65% versus 37%, P = 0.05).Conclusions: PMVT can occur when IBD is inactive, and its diagnosis was fortuitous in 40% of our cases. Screening for prothrombotic disorders is essential because it is positive in more than one third of cases.Le risque de thrombose veineuse profonde est augmenté au cours des maladies inflammatoires chroniques intestinales (MICI). Cependant, les données concernant les thromboses portomésentériques (TPM) sont rares. Le but de cette étude était de décrire les caractéristiques des TPM au cours des MICI.Patients et méthodes : une étude rétrospective a été menée dans 13 centres du GETAID, entre janvier 1995 et juin 2010. Les données suivantes ont été recueillies à partir d’un questionnaire standardisé : caractéristiques de la MICI, activité de la maladie au moment de la TPM, caractéristiques et mode de révélation de la TPM, facteurs de thrombophilie, traitement anticoagulant et évolution.Résultats : 50 cas de TPM (29 hommes et 21 femmes ; âge médian 41 ans) ont été identifiés. Quatorze patients avaient une rectocolite hémorragique et 36 une maladie de Crohn. Trente et un patients (62%) ont présenté une TPM aiguë. La MICI était active dans 23 (77%) des 31 cas de TPM aiguë. Les circonstances de diagnostic de la TPM étaient fortuites dans 40% des cas. Parmi les 43 patients chez lesquels un bilan de thrombophilie a été réalisé, au moins 1 anomalie prothrombotique a été identifiée chez 17 patients (40%) (principalement une hyperhomocystéinémie, n=12). Quarante-quatre patients (88%) ont reçu un traitement anticoagulant. Le taux de reperméabilisation était significativement plus élevé en cas de thrombose aiguë (65% versus 37%, p=0,05).Conclusion : dans cette série rétrospective, une TPM peut survenir lorsque la MICI est inactive et son diagnostic est fortuit dans 40% des cas. La recherche d’une anomalie prothrombotique est essentielle car elle est présente dans plus d’un tiers des cas

Increased incidence of systemic serious viral infections in patients with inflammatory bowel disease associates with active disease and use of thiopurines

International audienceBackground: The magnitude and drivers of the risk of serious viral infections in Inflammatory Bowel diseases (IBD) are unclear.Objective: The objective of this study was to assess the incidence and risk factors for systemic serious viral infections in IBD patients.Methods: Using MICISTA, a database detailing prospective characteristics and complications of IBD, we identified patients that were followed for IBD in 2005–2014 outside the context of organ transplantation, HIV infection or chronic viral hepatitis. We estimated incidences of systemic serious viral infections, defined by the need for hospitalization or permanent organ damage. Standardized incidence ratios (SIRs) were calculated using the French hospital database. We performed a case-control study nested in MICISTA for assessing the role of exposure to IBD drugs and IBD clinical activity in the risk of developing infection.Results: We identified 31 patients with serious viral infections among 2645 patients followed for 15,383 person-years. We observed 13 cases of cytomegalovirus, 10 Epstein–Barr virus, 5 varicella zoster virus and 3 herpes simplex virus infections. No deaths occurred. The incidence rate of infections in patients with IBD was 2.02/1000 person-years, and the SIR was 3.09 (95% confidence interval (CI), 1.98–4.20; p = 0.0002) in the study population. By multivariate analysis, increased risk of infection was associated with exposure to thiopurines (odds ratio (OR), 3.48; 95% CI, 1.36–8.90; p = 0.009), and clinically active IBD at onset of infection (OR, 3.35; 95% CI, 1.23–9.23; p = 0.02).Conclusions: The incidence of systemic serious viral infections in patients with IBD is tripled compared to general population. Clinically active IBD and exposure to thiopurines are the main drivers of the risk

A Scoring System to Determine Patients' Risk of Colectomy Within 1 Year After Hospital Admission for Acute Severe Ulcerative Colitis Short title: Predictors of colectomy in patients with ASUC

International audienceBackground & AimsThere is consensus on the criteria used to define acute severe ulcerative colitis (ASUC) and on patient management, but it has been a challenge to identify patients at risk for colectomy based on data collected at hospital admission. We aimed to develop a system to determine patients’ risk of colectomy within 1 y of hospital admission for ASUC based on clinical, biomarker, and endoscopy data.MethodsWe performed a retrospective analysis of consecutive patients with ASUC treated with corticosteroids, ciclosporin, or tumor necrosis factor (TNF) antagonists and admitted to 2 hospitals in France from 2002 through 2017. Patients were followed until colectomy or loss of follow up. A total of 270 patients with ASUC were included in the final analysis, with a median follow-up time of 30 months (derivation cohort). Independent risk factors identified by Cox multivariate analysis were used to develop a system to identify patients at risk for colectomy 1 y after ASUC. We developed a scoring system based on these 4 factors (1 point for each item) to identify high-risk (score 3 or 4) vs low-risk (score 0) patients. We validated this system using data from an independent cohort of 185 patients with ASUC treated from 2006 through 2017 at 2 centers in France.ResultsIn the derivation cohort, the cumulative risk of colectomy was 12.3% (95% CI, 8.6–16.8). Based on multivariate analysis, previous treatment with TNF antagonists or thiopurines (hazard ratio [HR], 3.86; 95% CI, 1.82–8.18), Clostridioides difficile infection (HR, 3.73; 95% CI, 1.11–12.55), serum level of C-reactive protein above 30 mg/L (HR, 3.06; 95% CI, 1.11–8.43), and serum level of albumin below 30 g/L (HR, 2.67; 95% CI, 1.20–5.92) were associated with increased risk of colectomy. In the derivation cohort, the cumulative risks of colectomy within 1 y in patients with scores of 0, 1, 2, 3, or 4 were 0.0%, 9.4% (95% CI, 4.3%–16.7%), 10.6% (95% CI, 5.6%–17.4%), 51.2% (95% CI, 26.6%–71.3%), and 100%. Negative predictive values ranged from 87% (95% CI, 82%–91%) to 92% (95% CI, 88%–95.0%). Findings from the validation cohort were consistent with findings from the derivation cohort.ConclusionsWe developed a scoring system to identify patients at low-risk vs high-risk for colectomy within 1 y of hospitalization for ASUC, based on previous treatment with TNF antagonists or thiopurines, C difficile infection, and serum levels of CRP and albumin. The system was validated in an external cohort

Portomesenteric Vein Thrombosis in Patients With Inflammatory Bowel Disease.

International audienc

Inter-kingdom effect on epithelial cells of the N-Acyl homoserine lactone 3-oxo-C12:2, a major quorum-sensing molecule from gut microbiota.

BACKGROUND AND AIMS:N-acyl homoserine lactones (AHLs), which are autoinducer quorum-sensing molecules involved in the bacterial communication network, also interact with eukaryotic cells. Searching for these molecules in the context of inflammatory bowel disease (IBD) is appealing. The aims of our study were to look for AHL molecules in faecal samples from healthy subjects (HS) and IBD patients to correlate AHL profiles with the microbiome and investigate the effect of AHLs of interest on epithelial cells. METHODS:Using mass spectrometry, we characterised AHL profiles in faecal samples from HS (n = 26) and IBD patients in remission (n = 24) and in flare (n = 25) and correlated the presence of AHLs of interest with gut microbiota composition obtained by real-time qPCR and 16S sequencing. We synthesised AHLs of interest to test the inflammatory response after IL1β stimulation and paracellular permeability on Caco-2 cells. RESULTS:We observed 14 different AHLs, among which one was prominent. This AHL corresponded to 3-oxo-C12:2 and was found significantly less frequently in IBD patients in flare (16%) and in remission (37.5%) versus HS (65.4%) (p = 0.001). The presence of 3-oxo-C12:2 was associated with significantly higher counts of Firmicutes, especially Faecalbacterium prausnitzii, and lower counts of Escherichia coli. In vitro, 3-oxo-C12:2 exerted an anti-inflammatory effect on Caco-2 cells. Interestingly, although 3-oxo-C12, the well-known AHL from Pseudomonas aeruginosa, increased paracellular permeability, 3-oxo-C12:2 did not. CONCLUSIONS:We identified AHLs in the human gut microbiota and discovered a new and prominent AHL, 3-oxo-C12:2, which correlates with normobiosis and exerts a protective effect on gut epithelial cells

Efficacy and safety of combination targeted therapies in immune-mediated inflammatory disease: the COMBIO study

International audienceBACKGROUND: Use of a combination of targeted therapies (COMBIO) in patients with refractory/overlapping immune-mediated inflammatory diseases (IMIDs) has increased, but reported data remain scarce. We aimed to assess effectiveness and safety of COMBIO in patients with IMIDs. METHODS: We conducted a French ambispective multicenter cohort study from September 2020 to May 2021, including adults' patients with 1 or 2 IMIDs and treated at least 3-month with COMBIO. RESULTS: Overall, 143 patients were included. The most common IMIDs were Crohn's disease (63.6%), axial spondyloarthritis (37.7%), and ulcerative colitis (14%). Half of patients had only one IMID, of which 60% were Crohn's disease. Mean duration of COMBIO was 274.5±59.3 weeks, and COMBIO persistence at 104 weeks was estimated at 64.1%. The most frequent COMBIOs combined anti-TNF agents with vedolizumab (30%) or ustekinumab (28.7%). Overall, 50% of patients achieved significant and 27% mild-to-moderate improvement in patient-reported outcomes. Extended duration of COMBIO (aOR=1.09; 95% CI: 1.03-1.14; p=0.002) and diagnoses of two IMIDs (aOR=3.46; 95%CI: 1.29-9.26; p=0.013) were associated with significant improvement in patient-reported outcomes. Incidence of serious infection during COMBIO was 4.51 per 100 person-years (95% CI 2.20-8.27) and 5 COMBIOs were discontinued due to adverse events. CONCLUSIONS: COMBIO can be effective and safe in patients with refractory/overlapping IMIDs

Impact of the Ileal microbiota on surgical site infections in Crohn’s disease: a nationwide prospective cohort

International audienceAbstract Background and Aims Surgery is performed in 50–70% of Crohn’s disease [CD] patients, and its main risk is surgical site infection [SSI]. The microbiota has been extensively assessed in CD but not as a potential risk factor for septic morbidity. The objective of this study was to assess the impact of the gut microbiota on SSI in CD. Methods We used the multicentric REMIND prospective cohort to identify all patients who experienced SSI after ileocolonic resection for CD, defined as any postoperative local septic complication within 90 days after surgery: wound abscess, intra-abdominal collection, anastomotic leakage or enterocutaneous fistula. The mucosa-associated microbiota of the ileal resection specimen was analysed by 16S gene sequencing in 149 patients. The variable selection and prediction were performed with random forests [R package VSURF] on clinical and microbiotal data. The criterion of performance that we considered was the area under the Receiver Operating Characteristic [ROC] curve [AUC]. Results SSI occurred in 24 patients [16.1%], including 15 patients [10.1%] with major morbidity. There were no significant differences between patients with or without SSI regarding alpha and beta diversity. The top selected variables for the prediction of SSI were all microbiota-related. The maximum AUC [0.796] was obtained with a model including 14 genera, but an AUC of 0.78 had already been obtained with a model including only six genera [Hungatella, Epulopiscium, Fusobacterium, Ruminococcaceae_ucg_009, Actinomyces and Ralstonia]. Conclusion The gut microbiota has the potential to predict SSI after ileocolonic resection for CD. It might play a role in this frequent postoperative complication

A clinical decision support tool may help to optimise vedolizumab therapy in Crohn's disease

International audienceBackground A clinical decision support tool (CDST) has been validated for predicting treatment effectiveness of vedolizumab (VDZ) in Crohn's disease. Aim To assess the utility of this CDST for predicting exposure-efficacy and disease outcomes. Methods Using data from three independent datasets (GEMINI, GETAID and VICTORY), we assessed clinical remission rates and measured VDZ exposure, rapidity of onset of action, response to dose optimisation and progression to surgery by CDST-defined response groups (low, intermediate and high). Results A linear relationship existed between CDST-defined groups, measured VDZ exposure, rapidity of onset of action and efficacy in GEMINI through week 52 (P < 0.001 at all time points across three CDST-defined groups). In GETAID, CDST predicted differences in clinical remission at week 14 (AUC = 0.68) and rapidity of onset of action (P = 0.04) between probability groups. The high-probability patients did not benefit from shortening of infusion intervals, and differences in onset of action between the high-intermediate and low-probability groups within GETAID were no longer significant when including low-probability patients who received a week 10 infusion. CDST predicted a twofold increase in surgery risk over 12 months of VDZ therapy among low- to intermediate-probability vs high-probability patients (adjusted HR 2.06, 95% CI 1.33-3.21). Conclusions We further extended the clinical utility of a previously validated VDZ CDST, which accurately predicts at baseline exposure-efficacy relationships and rapidity of onset of action and could be used to help identify patients who would most benefit from interval shortening and those most likely to require surgery while on active therapy