Dysbiosis and relapse-related microbiome in inflammatory bowel disease: A shotgun metagenomic approach

© 2021 The Author(s).Crohn’s disease (CD) and ulcerative colitis (UC), the two main forms of inflammatory bowel disease (IBD), affect several million people worldwide. CD and UC are characterized by periods of clinical remission and relapse. Although IBD patients present chronic alterations of the gut microbiome, called dysbiosis, little attention has been devoted to the relapse-related microbiome. To address this gap, we generated shotgun metagenomic data from the stools of two European cohorts—134 Spanish (followed up for one year) and 49 Belgian (followed up for 6 months) subjects—to characterize the microbial taxonomic and metabolic profiles present. To assess the predictive value of microbiome data, we added the taxonomic profiles generated from a previous study of 130 Americans. Our results revealed that CD was more dysbiotic than UC compared to healthy controls (HC) and that strategies for energy extraction and propionate production were different in CD compared to UC and HC. Remarkably, CD and UC relapses were not associated with alpha- or beta-diversity, or with a dysbiotic score. However, CD relapse was linked to alterations at the species and metabolic pathway levels, including those involved in propionate production. The random forest method using taxonomic profiles allowed the prediction of CD vs. non-CD with an AUC = 0.938, UC vs. HC with an AUC = 0.646, and CD relapse vs. remission with an AUC = 0.769. Our study validates previous taxonomic findings, points to different relapse-related growth and defence mechanisms in CD compared to UC and HC and provides biomarkers to discriminate IBD subtypes and predict disease activity.This study was supported by the Instituto de Salud Carlos III /FEDER, a government agency (grant numbers: PI17/00614; PI20/00130), and by the Crohn’s & Colitis Foundation of America (Award ID: 514634)

Safety and Efficacy of Nivolumab Monotherapy in Recurrent or Metastatic Cervical, Vaginal, or Vulvar Carcinoma: Results From the Phase I/II CheckMate 358 Trial

Purpose: Nivolumab was assessed in patients with virus-associated tumors in the phase I/II CheckMate 358 trial (ClinicalTrials.gov identifier: NCT02488759). We report on patients with recurrent/metastatic cervical, vaginal, or vulvar cancers. Patients and methods: Patients received nivolumab 240 mg every 2 weeks. Although patients with unknown human papillomavirus status were enrolled, patients known to have human papillomavirus-negative tumors were ineligible. The primary end point was objective response rate. Duration of response (DOR), progression-free survival, and overall survival were secondary end points. Safety and patient-reported outcomes were exploratory end points. Results: Twenty-four patients (cervical, n = 19; vaginal/vulvar, n = 5) were enrolled. Most patients had received prior systemic therapy for metastatic disease (cervical, 78.9%; vaginal/vulvar, 80.0%). Objective response rates were 26.3% (95% CI, 9.1 to 51.2) for cervical cancer and 20.0% (95% CI, 0.5 to 71.6) for vaginal/vulvar cancers. At a median follow-up of 19.2 months, median DOR was not reached (range, 23.3 to 29.5+ months; + indicates a censored observation) in the five responding patients in the cervical cohort; the DOR was 5.0 months in the single responding patient in the vaginal/vulvar cohort. Median overall survival was 21.9 months (95% CI, 15.1 months to not reached) among patients with cervical cancer. Any-grade treatment-related adverse events were reported in 12 of 19 patients (63.2%) in the cervical cohort and all five patients in the vaginal/vulvar cohort; there were no treatment-related deaths. In the cervical cohort, nivolumab treatment generally resulted in stabilization of patient-reported outcomes associated with health status and health-related quality of life. Conclusion: The efficacy of nivolumab in patients with recurrent/metastatic cervical and vaginal or vulvar cancers is promising and warrants additional investigation. No new safety signals were identified with nivolumab treatment in this population

Karakterisatie en rol van dysbiose in de pathogenese van inflammatoire darmziekten

status: publishe

Faecal metabolite profiling identifies medium-chain fatty acids as discriminating compounds in IBD

Background: Bacteria play a role in the onset and perpetuation of intestinal inflammation in IBD. Compositional alterations may also change the metabolic capacities of the gut bacteria. Objective: To examine the metabolic activity of the microbiota of patients with Crohn's disease (CD), UC or pouchitis compared with healthy controls (HC) and determine whether eventual differences might be related to the pathogenesis of the disease. Methods: Faecal samples were obtained from 40 HC, 83 patients with CD, 68 with UC and 13 with pouchitis. Disease activity was assessed in CD using the Harvey-Bradshaw Index, in UC using the UC Disease Activity Index and in pouchitis using the Pouchitis Disease Activity Index. Metabolite profiles were analysed using gas chromatography-mass spectrometry. Results: The number of metabolites identified in HC (54) was significantly higher than in patients with CD (44, p<0.001), UC (47, p=0.042) and pouchitis (43, p=0.036). Multivariate discriminant analysis predicted HC, CD, UC and pouchitis group membership with high sensitivity and specificity. The levels of medium-chain fatty acids (MCFAs: pentanoate, hexanoate, heptanoate, octanoate and nonanoate), and of some protein fermentation metabolites, were significantly decreased in patients with CD, UC and pouchitis. Hexanoate levels were inversely correlated to disease activity in CD (correlation coefficient=-0.157, p=0.046), whereas a significant positive correlation was found between styrene levels and disease activity in UC (correlation coefficient=0.338, p=0.001). Conclusions: Faecal metabolic profiling in patients with IBD relative to healthy controls identified MCFAs as important metabolic biomarkers of disease-related changes

Faecal metabolite profiling identifies medium-chain fatty acids as discriminating compounds in IBD

Bacteria play a role in the onset and perpetuation of intestinal inflammation in IBD. Compositional alterations may also change the metabolic capacities of the gut bacteria.status: publishe