Objective Although anti-tumour necrosis factor alpha (anti-TNFα) therapies represent a major breakthrough in IBD therapy, their cost–benefit ratio is hampered by an overall 30% non-response rate, adverse side effects and high costs. Thus, finding predictive biomarkers of non-response prior to commencing anti-TNFα therapy is of high value. Design We analysed publicly available whole-genome expression profiles of colon biopsies obtained from multiple cohorts of patients with IBD using a combined computational deconvolution—meta-analysis paradigm which allows to estimate immune cell contribution to the measured expression and capture differential regulatory programmes otherwise masked due to variation in cellular composition. Insights from this in silico approach were experimentally validated in biopsies and blood samples of three independent test cohorts. Results We found the proportion of plasma cells as a robust pretreatment biomarker of non-response to therapy, which we validated in two independent cohorts of immune-stained colon biopsies, where a plasma cellular score from inflamed biopsies was predictive of non-response with an area under the curve (AUC) of 82%. Meta-analysis of the cell proportion-adjusted gene expression data suggested that an increase in inflammatory macrophages in anti-TNFα non-responding individuals is associated with the upregulation of the triggering receptor expressed on myeloid cells 1 (TREM-1) and chemokine receptor type 2 (CCR2)-chemokine ligand 7 (CCL7) –axes. Blood gene expression analysis of an independent cohort, identified TREM-1 downregulation in non-responders at baseline, which was predictive of response with an AUC of 94%. Conclusions Our study proposes two clinically feasible assays, one in biopsy and one in blood, for predicting non-response to anti-TNFα therapy prior to initiation of treatment. Moreover, it suggests that mechanism-driven novel drugs for non-responders should be developed.

ESBL-producing Enterobacteriaceae and carbapenem-resistant Enterobacteriaceae (CRE) are rapidly spreading worldwide. Their natural reservoir is intestinal. We carried out a systematic review and meta-analysis to estimate CRE and ESBL carriage duration and to evaluate the effect of decolonization therapy. We included cohort and comparative studies examining the natural history of CRE/ESBL colonization, examining rates of carriage following decolonization or comparing decolonization and no decolonization conducted in the healthcare setting or in the community. A comprehensive search was conducted until November 2015. We compiled carriage rates at 1, 3, 6 and 12 months with and without decolonization therapy and assessed the effect of decolonization. Thirty-seven studies fulfilled inclusion criteria. In healthcare settings, pooled ESBL/CRE colonization rates decreased without intervention from 76.7% (95% CI = 69.3%–82.8%) at 1 month to 35.2% (95% CI = 28.2%–42.9%) at 12 months of follow-up. Following decolonization, the rate was 37.1% (95% CI = 27.5%–47.7%) at end of therapy and 57.9% (95% CI = 43.1%–71.4%) at 1 month. In two randomized trials, carriage was significantly reduced at end of therapy (risk ratio = 0.42, 95% CI = 0.25–0.65), but the effect was not significant after 1 month (risk ratio = 0.72, 95% CI = 0.48–1.05), with no longer follow-up. Heterogeneity was explained by surveillance methodology, with no differences observed between ESBLs and CREs. Among community dwellers, ESBL colonization decreased from 52.3% (95% CI = 29.5%–74.2%) at 1 month to 19.2% (95% CI = 9.7%–34.4%) at 6 months. A significant proportion of ESBL and CRE carriers remain colonized up to 1 year in the healthcare setting. While short-term decolonization therapy reduces carriage during therapy, its longer-term effects are unclear.

Summary: Background: Primary nonresponse, defined as lack of clinical benefit during the induction phase, occurs in up to 30% of IBD patients treated with infliximab. The mechanisms underlying primary nonresponse have not yet been clearly defined.Aim: To evaluate the association of early (week 2 and week 6) induction infliximab and anti‐infliximab antibody levels with primary nonresponse.Methods: A retrospective observational case‐control study of inflammatory bowel disease patients treated with infliximab and followed at Sheba Medical Center between 2009 and 2016 was performed. Pre‐infusion infliximab and antibodies to infliximab (ATI) levels were measured by our previously described drug‐tolerant ELISA assay.Results: Thirty‐five primary nonresponders have been identified and matched with 105 primary responders (1:3 ratios). Both week 2 and week 6 infliximab levels were significantly lower among primary nonresponders compared to responders (week 2, 6: median level 7.2, 2.2 μg/mL vs 13.5, 9.5 μg/mL, P = .0019, P < .0001 respectively). Antibodies to infliximab appeared more frequently (either week 2 or 6, 68% vs 28% prevalence, P = .0004) and at higher levels in nonresponders compared to responders (week 2, 6: median ATI 7.3, 10.8 μg/mL‐eq vs 3.8, 4.4 μg/mL‐eq, P = .005, P = .008 respectively). Moreover, week 2 infliximab levels <6.8 μg/mL (AUC = 0.68, P = .002, sensitivity 50%, specificity 86%) and antibodies to infliximab levels >4.3 μg/mL‐eq (AUC = 0.78, P = .0004, sensitivity 77%, specificity 71%) were predictive of primary nonresponse. Among the other clinical and demographic variables, higher baseline ulcerative colitis clinical score, infliximab monotherapy, prior adalimumab therapy and previous Crohn's disease‐related surgeries were also associated with an increased risk of primary nonresponse.Conclusions: Infliximab levels below 6.8 μg/mL and antibodies to infliximab levels above 4.3 μg/mL‐eq before the second infusion are associated with primary nonresponse, especially among Crohn's disease patients.

Carbapenemase-producing Enterobacteriaceae (CPE) infections lead to considerable morbidity and mortality. We assessed the potential of fecal microbiota transplantation (FMT) to eradicate CPE carriage and aimed to explain failure or success through microbiome analyses. In this prospective cohort study, all consenting eligible CPE carriers were treated with oral capsulized FMT for 2 days. The primary outcome was CPE eradication at 1 month, defined by 3 consecutive negative rectal swabs, the last also negative for carbapenemase gene by PCR. Comprehensive metagenomics analysis of the intestinal microbiome of donors and recipients before and after FMT was performed. Fifteen CPE carriers received FMT, 13 of which completed 2 days of treatment. CPE eradication at 1 month was successful in 9/15 and 9/13, respectively. Bacterial communities showed significant changes in both beta and alpha diversity metrics among participants achieving CPE eradication that were not observed among failures. Post-FMT samples' beta-diversity clustered according to the treatment outcome, both in taxonomy and in function. We observed a significant decrease in beta diversity in participants who received post-FMT antibiotics. Enterobacteriaceae abundance decreased in post-FMT samples of the responders, but increased among failures. Functionally, a clear demarcation between responders (who were similar to the donors) and failures was shown, driven by antimicrobial resistance genes. Our study provides the biological explanation for the effect of FMT against CPE carriage. Decolonization of CPE by FMT is likely mediated by compositional and functional shifts in the microbiome. Thus, FMT might be an efficient strategy for sustained CPE eradication.

Background and Aims: The growing use of glucagon-like peptide 1 (GLP-1) analogs for type 2 diabetes mellitus (DM2) and obesity necessitates studies about their use in patients with inflammatory bowel diseases (IBD). Methods: Data on patients with DM2 were retrieved from an Israeli nationwide cohort of patients with IBD (epi-IIRN), recording GLP-1 analog exposure for at least 6 months. The primary outcome was poor disease outcomes (ie, composite of steroid dependence, initiation of advanced IBD therapy, hospitalization, surgery, or death). Cox proportional hazard models with time-varying covariables were used to assess the impact of GLP-1 use on outcomes during follow-up. Results: We included 3737 patients (24 338 patient-years) with IBD and DM2 [50.4% ulcerative colitis (UC)], of whom 633 were treated with GLP-1 analogs. Accounting for demographics IBD/DM2 related variables, medication use, and laboratory measurements, GLP-1 analog use was associated with reduced composite outcome in the full cohort (adjusted hazard ratio [aHR] 0.74, 95% confidence interval [CI] 0.62-0.89) and in each subtype [UC (aHR 0.71, 95% CI 0.52-0.96) and Crohn’s disease (aHR 0.78, 95% CI 0.62-0.99)]. Similar trends were seen in multivariate analyses of each individual outcome, although only hospitalization was significant (aHR 0.74, 95% CI 0.61-0.91). The protective effect of GLP-1 analogs was seen in patients with obesity (aHR 0.61, 95% CI 0.50-0.77), but not in non-obese (aHR 0.94, 95% CI 0.67-1.31). Conclusions: GLP-1 analogs are associated with improved outcomes in IBD, specifically in patients with obesity. The mechanisms of these effects require further investigation as well as their role in patients without DM2.