Papers by Ana Maria Corraliza
Journal of Crohn's and Colitis, 2022
Autologous haematopoietic stem cell transplantation [AHSCT] is a therapeutic option for patients ... more Autologous haematopoietic stem cell transplantation [AHSCT] is a therapeutic option for patients with refractory Crohn’s disease [CD]. Although the safety of the procedure has been improved over the last decade, AHSCT is still burdened by high adverse event rate due to chemotherapy toxicity and immunosuppression. The aim of this study was to evaluate the safety and efficacy of AHSCT by using a cyclophosphamide (Cy)-free mobilisation regimen followed by a standard conditioning approach. A prospective observational study was conducted at Hospital Clínic of Barcelona in refractory CD patients undergoing AHSCT. Outpatient regimen with G-CSF 12–16 μg/kg/daily for 5 days was used for mobilisation. Patients who failed to achieve >2x106 CD34+ cells received Plerixafor 240 μg/d (1–2 doses). For conditioning, Cy and ATG were administered according to standard protocols. After transplant, patients were followed-up at regular intervals. Colonoscopy and/or magnetic resonance imaging were perf...
Journal of Crohn's and Colitis, 2017
Background: Imbalanced microbial composition has been linked to the pathogenesis of inflammatory ... more Background: Imbalanced microbial composition has been linked to the pathogenesis of inflammatory bowel diseases (IBD). Hematopoietic stem cell transplantation (HSCT) proved to be successful in inducing remission in severe, highly refractory Crohn's disease (CD) patients, possibly by erasing immune responses against gut microbes. Gnotobiotic mouse models colonized with human microbiota brought insights into the mechanistic aspects of host-microbe interactions. The aim of this study was to assess the functional role of microbiota signatures associated with different disease states. Methods: High-throughput 16S rRNA gene amplicon sequencing was performed on (n=147) fecal samples collected from (n=13) healthy donors and (n=31) HSCT-treated CD patients. Germ-free (GF) wild-type (WT) and IL10-/mice (129 Sv/Ev; n=12 mice/group) were colonized with fecal microbiota from CD patients before and after HSCT at different disease states. Selection of CD patients for transfer into GF mice was based on clinical and endoscopic disease activity, including paired patient samples collected under remission or relapse following HSCT. Results: Microbiota profiling showed a significantly reduced microbial diversity in patients compared with healthy controls. Patients in remission showed higher microbial diversity than patients in relapse or at active state of the disease. Patients with fistulating or ileal phenotype had the least diverse ecosystems. High level of inter-individual variation was observed. Despite an incomplete transfer of donor microbiota with a 20-40% loss of species-level taxa, humanized mice reflected the dysbiotic features of their respective human donors, indicated by richness and diversity measures. Histopathological evaluation showed moderate to severe inflammation in colon and cecum of the IL10-/mice associated with microbiota from patients in relapse. In contrast, IL10-/mice associated with microbiota from patients in remission remained disease-free. To validate the phenotype transfer, we gavaged the mice three times with donor microbiota during the first week of colonization. Remission-associated mice showed higher species richness but still remained disease-free, while relapseassociated mice developed enhanced inflammation measured at the level of fecal complement C3 concentrations. Endpoint microbial composition remained similar, regardless of the number of inoculations and F1 generation of mice displayed a stable engraftment of human microbiota. Conclusions: Transfer of patient-derived fecal microbiota mimics the disease phenotype in gnotobiotic IL10-/mice. Bacterial composition, not the number of species is responsible for disease initiation. Humanized mice represent a potential tool for recapitulating disease phenotypes in IBD.
Nature Communications
Gut microbial and metabolite alterations have been linked to the pathogenesis of inflammatory bow... more Gut microbial and metabolite alterations have been linked to the pathogenesis of inflammatory bowel diseases. Here we perform a multi-omics microbiome and metabolite analysis of a longitudinal cohort of Crohn’s disease patients undergoing autologous hematopoietic stem cell transplantation, and investigational therapy that induces drug free remission in a subset of patients. Via comparison of patients who responded and maintained remission, responded but experienced disease relapse and patients who did not respond to therapy, we identify shared functional signatures that correlate with disease activity despite the variability of gut microbiota profiles at taxonomic level. These signatures reflect the disease state when transferred to gnotobiotic mice. Taken together, the integration of microbiome and metabolite profiles from human cohort and mice improves the predictive modelling of disease outcome, and allows the identification of a network of bacteria-metabolite interactions involv...
Gut
T cell clonal expansions are present in the inflamed mucosa of patients with Crohn’s disease (CD)... more 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 pat...
Frontiers in immunology, 2018
Despite the negative results of blocking IL-17 in Crohn's disease (CD) patients, selective mo... more Despite the negative results of blocking IL-17 in Crohn's disease (CD) patients, selective modulation of Th17-dependent responses warrants further study. Inhibition of retinoic acid-related orphan receptor gamma (RORγt), the master regulator of the Th17 signature, is currently being explored in inflammatory diseases. Our aim was to determine the effect of a novel oral RORγt antagonist (BI119) in human CD and on an experimental model of intestinal inflammation. 51 CD patients and 11 healthy subjects were included. The effects of BI119 were tested on microbial-stimulated peripheral blood mononuclear cells (PBMCs), intestinal crypts and biopsies from CD patients. The ability of BI119 to prevent colitis was assessed in the CD4CD45RB T cell transfer model. In bacterial antigen-stimulated PBMCs from CD patients, BI119 inhibits Th17-related genes and proteins, while upregulating Treg and preserving Th1 and Th2 signatures. Intestinal crypts cultured with supernatants from BI119-treated ...
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Papers by Ana Maria Corraliza