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Background Crohn's disease (CD) is characterized by persistent inflammation and ulceration of the small or large bowel, and expansion of mesenteric adipose tissue, termed creeping fat (CF). We previously demonstrated that human adipose-derived stem cells (hASCs) from CF of patients with CD exhibit dysfunctional phenotypes, including a pro-inflammatory profile, high phagocytic capacity, and weak immunosuppressive properties. Importantly, these phenotypes persist in patients in remission and are found in all adipose depots explored including subcutaneous fat. We hypothesized that changes in hASCs are a consequence of epigenetic modifications. Methods We applied epigenome-wide profiling with a methylation array (Illumina EPIC/850k array) and gene expression analysis to explore the impact of CD on the methylation signature of hASCs isolated from the subcutaneous fat of patients with CD and healthy controls (n = 7 and 5, respectively; cohort I). Differentially methylated positions (p value cutoff < 1 x 10(-4) and ten or more DMPs per gene) and regions (inclusion threshold 0.2, p value cutoff < 1 x 10(-2) and more than 2 DMRs per gene) were identified using dmpfinder and Bumphunter (minfi), respectively. Changes in the expression of differentially methylated genes in hASCs were validated in a second cohort (n = 10/10 inactive and active CD and 10 controls; including patients from cohort I) and also in peripheral blood mononuclear cells (PBMCs) of patients with active/inactive CD and of healthy controls (cohort III; n = 30 independent subjects). Results We found a distinct DNA methylation landscape in hASCs from patients with CD, leading to changes in the expression of differentially methylated genes involved in immune response, metabolic, cell differentiation, and development processes. Notably, the expression of several of these genes in hASCs and PBMCs such as tumor necrosis factor alpha (TNFA) and PR domain zinc finger protein 16 (PRDM16) were not restored to normal (healthy) levels after disease remission. Conclusions hASCs of patients with CD exhibit a unique DNA methylation and gene expression profile, but the expression of several genes are only partially restored in patients with inactive CD, both in hASCs and PBMCs. Understanding how CD shapes the functionality of hASCs is critical for investigating the complex pathophysiology of this disease, as well as for the success of cell-based therapies.

Background Cohort studies comparing the characteristics of childhood-onset and adulthood-onset inflammatory bowel disease (IBD) in the biologics era are scarce. Aim To compare disease characteristics, the use of immunomodulators and biologic agents and the need for surgery between childhood- and adulthood-onset IBD. Methods Inflammatory bowel disease patients from the ENEIDA registry diagnosed between 2007 and 2017 were included. The childhood-onset cohort comprised patients diagnosed at 16 years. The cumulative incidences of immunosuppressive therapy, biologic therapy and surgery were estimated using Kaplan-Meier curves, compared by the log-rank test. Cox regression analysis was performed to identify potential predictive factors of treatment with immunosuppressants, biologic agents or surgery. Results The adulthood-onset cohort comprised 21 200 patients out of 20 354 (96%) and the childhood-onset cohort 846 (4%). Median follow-up was 54 months in the childhood-onset cohort and 38 months in the adulthood-onset cohort (P < 0.01). Proportions of Crohn's disease, ileocolonic involvement and inflammatory behaviour at diagnosis were higher in the childhood-onset cohort. In the multivariate analysis, after adjusting for sex, type of IBD, extraintestinal manifestations, family history and smoking habit, childhood-onset IBD was associated with higher risk of immunomodulator use (hazard ratio [HR] = 1.2, 95% confidence interval [95% CI] = 1.1-1.2) and higher probability of receiving biologic treatment (HR = 1.2, 95% CI = 1.1-1.3). However, childhood-onset IBD was not associated with higher risk of surgery (HR = 0.9, 95% CI = 0.8-1.2). Conclusions Childhood-onset IBD has differential characteristics and higher risk of treatment with immunomodulators and biologic agents, compared with adulthood-onset IBD. Nevertheless, paediatric IBD is not associated with higher risk of surgery.

OBJECTIVES: The aims of this study were to assess the risk of relapse after discontinuation of anti-tumor necrosis factor (anti-TNF) drugs in patients with inflammatory bowel disease (IBD), to identify the factors associated with relapse, and to evaluate the overcome after retreatment with the same anti-TNF in those who relapsed. METHODS: This was a retrospective, observational, multicenter study. IBD patients who had been treated with anti-TNFs and in whom these drugs were discontinued after clinical remission was achieved were included. RESULTS: A total of 1,055 patients were included. The incidence rate of relapse was 19% and 17% per patient-year in Crohn's disease and ulcerative colitis patients, respectively. In both Crohn's disease and ulcerative colitis patients in deep remission, the incidence rate of relapse was 19% per patient-year. The treatment with adalimumab vs. infliximab (hazard ratio (HR)=1.29; 95% confi dence interval (CI)= 1.01-1.66), elective discontinuation of anti-TNFs (HR=1.90; 95% CI= 1.07-3.37) or discontinuation because of adverse events (HR= 2.33; 95% CI= 1.27-2.02) vs. a top-down strategy, colonic localization (HR= 1.51; 95% CI= 1.13-2.02) vs. ileal, and stricturing behavior (HR= 1.5; 95% CI= 1.09-2.05) vs. inflammatory were associated with a higher risk of relapse in Crohn's disease patients, whereas treatment with immunomodulators after discontinuation (HR= 0.67; 95% CI= 0.51-0.87) and age (HR= 0.98; 95% CI= 0.97-0.99) were protective factors. None of the factors were predictive in ulcerative colitis patients. Retreatment of relapse with the same anti-TNF was effective (80% responded) and safe. CONCLUSIONS: The incidence rate of infl ammatory bowel disease relapse after anti-TNF discontinuation is relevant. Some predictive factors of relapse after anti-TNF withdrawal have been identifi ed. Retreatment with the same anti-TNF drug was effective and safe.

Succinic acid; Bacteria translocation; Beige adipose tissue Àcid succínic; Translocació de bacteris; Teixit adipós beige Ácido succínico; Translocación de bacterias; Tejido adiposo beige Background and Aims Crohn’s disease [CD] is associated with complex microbe–host interactions, involving changes in microbial communities, and gut barrier defects, leading to the translocation of microorganisms to surrounding adipose tissue [AT]. We evaluated the presence of beige AT depots in CD and questioned whether succinate and/or bacterial translocation promotes white-to-beige transition in adipocytes. Methods Visceral [VAT] and subcutaneous [SAT] AT biopsies, serum and plasma were obtained from patients with active [n = 21] or inactive [n = 12] CD, and from healthy controls [n = 15]. Adipose-derived stem cells [ASCs] and AT macrophages [ATMs] were isolated from VAT biopsies. Results Plasma succinate levels were significantly higher in patients with active CD than in controls and were intermediate in those with inactive disease. Plasma succinate correlated with the inflammatory marker high-sensitivity C-reactive protein. Expression of the succinate receptor SUCNR1 was higher in VAT, ASCs and ATMs from the active CD group than from the inactive or control groups. Succinate treatment of ASCs elevated the expression of several beige AT markers from controls and from patients with inactive disease, including uncoupling protein-1 [UCP1]. Notably, beige AT markers were prominent in ASCs from patients with active CD. Secretome profiling revealed that ASCs from patients with active disease secrete beige AT-related proteins, and co-culture assays showed that bacteria also trigger the white-to-beige switch of ASCs from patients with CD. Finally, AT depots from patients with CD exhibited a conversion from white to beige AT together with high UCP1 expression, which was corroborated by in situ thermal imaging analysis. Conclusions Succinate and bacteria trigger white-to-beige AT transition in CD. Understanding the role of beige AT in CD might aid in the development of therapeutic or diagnostic interventions. This study was supported by grants from the Spanish Ministry of Science and Innovation [PI18/00037 (Instituto de Salud Carlos III, ISCIII) to C.S.; PI17/01503 and PI20/00338 (ISCIII) to J.V. and RTI2018-093919 to S.F.-V.], co-financed by the European Regional Development Fund [ERDF] and a European Crohn’s and Colitis Organization grant to C.S. The Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders [CIBERDEM] [CB07708/0012] is an initiative of the Instituto de Salud Carlos ISCIII acknowledges support from the ‘Ramón y Cajal’ programme from the Ministerio de Educación y Ciencia [RYC2013-13186], co-financed by the ERDF. S.F.-V. acknowledge support from the ‘Miguel Servet’ tenure track programme [CP10/00438, CPII16/0008] from the Fondo de Investigación Sanitaria, co-financed by the ERDF. D.M.-F. acknowledges support from PERIS-PFI-Salut SLT01720000021.

Cell therapy; Chronic inflammatory disease; Cigarette Terapia celular; Enfermedad inflamatoria crónica; Cigarrillo Teràpia cel·lular; Malaltia inflamatòria crònica; Cigarret Patients with Crohn’s disease (CD) who smoke are known to have a worse prognosis than never-smokers and a higher risk for post-surgical recurrence, whereas patients who quit smoking after surgery have significantly lower post-operative recurrence. The hypothesis was that smoking induces epigenetic changes that impair the capacity of adipose stem cells (ASCs) to suppress the immune system. It was also questioned whether this impairment remains in ex-smokers with CD. ASCs were isolated from non-smokers, smokers and ex-smokers with CD and their interactions with immune cells were studied. The ASCs from both smokers and ex-smokers promoted macrophage polarization to an M1 pro-inflammatory phenotype, were not able to inhibit T- and B-cell proliferation in vitro and enhanced the gene and protein expression of inflammatory markers including interleukin-1b. Genome-wide epigenetic analysis using two different bioinformatic approaches revealed significant changes in the methylation patterns of genes that are critical for wound healing, immune and metabolic response and p53-mediated DNA damage response in ASCs from smokers and ex-smokers with CD. In conclusion, cigarette smoking induces a pro-inflammatory epigenetic signature in ASCs that likely compromises their therapeutic potential. This study was supported by a grant from the Spanish Ministry of Economy and Competitiveness (PI18/00037 to CS), co-financed by the European Regional Development Fund (ERDF). C.S. acknowledges support from “Ramón y Cajal’ program from the Ministerio de Educación y Ciencia (RYC2013-13186), co-financed by the ERDF. A.B.-T. acknowledge support from PI-AGAUR 2022-B00577. I.V. acknowledges support from INVESTIGO-AGAUR (100036TC2). D.M.-F. acknowledges support from PERIS-PFI-Salut SLT01720000021.

Adalimumab; Adipose tissue; Infliximab Adalimumab; Tejido adiposo; Infliximab Adalimumab; Teixit adipós; Infliximab Anti-TNF biologics have been shown to markedly improve the quality of life for patients with Crohn’s disease (CD), yet one-third of patients fail to benefit from this treatment. Patients with CD develop a characteristic wrapping of visceral adipose tissue (VAT) in the inflamed intestinal area, termed creeping fat, and it is known that adipose tissue expansion influences the efficacy of anti-TNF drugs. We questioned whether anti-TNF therapies impact the creeping fat in CD, which might affect the outcome of the disease. Adipose tissue biopsies were obtained from a cohort of 14 patients with CD that received anti-TNF drugs and from 29 non-anti-TNF-treated patients (control group) matched by sex, age, and body mass index undergoing surgical interventions for symptomatic complications. We found that anti-TNF therapies restored adipose tissue morphology and suppressed immune cell infiltration in the creeping fat. Additionally, anti-TNF treatments appeared to markedly improve the pro-inflammatory phenotype of adipose-tissue macrophages and adipose-tissue-derived stem cells. Our study provides evidence that anti-TNF medications influence immune cells and progenitor cells in the creeping of patients with CD, suppressing inflammation. We propose that perilesional VAT should be considered when administering anti-TNF therapy in patients with CD. This study was supported by a grant from the Spanish Ministry of Economy and Competitiveness (PI18/00037 to C.S.), co-financed by the European Regional Development Fund (ERDF). C.S. acknowledges support from the “Ramón y Cajal” program from the Ministerio de Educación y Ciencia (RYC2013-13186), co-financed by the ERDF. A.B.-T. acknowledges support from PI-AGAUR 2022-B00577. D.M.-F. acknowledges support from PERIS-PFI-Salut SLT01720000021.

Crohn&rsquo, s disease (CD) is characterized by compromised immune tolerance to the intestinal commensal microbiota, intestinal barrier inflammation, and hyperplasia of creeping fat (CF) and mesenteric adipose tissue (AT), which seems to be directly related to disease activity. Gut microbiota dysbiosis might be a determining factor in CD etiology, manifesting as a low microbial diversity and a high abundance of potentially pathogenic bacteria. We tested the hypothesis that CF is a reservoir of bacteria through 16S-rRNA sequencing of several AT depots of patients with active and inactive disease and controls. We found a microbiome signature within CF and mesenteric AT from patients, but not in subcutaneous fat. We failed to detect bacterial DNA in any fat depot of controls. Proteobacteria was the most abundant phylum in both CF and mesenteric AT, and positively correlated with fecal calprotectin/C-reactive protein. Notably, the clinical status of patients seemed to be related to the microbiome signature, as those with the inactive disease showed a reduction in the abundance of pathogenic bacteria. Predictive functional profiling revealed many metabolic pathways including lipopolysaccharide biosynthesis and sulfur metabolism overrepresented in active CD relative to that in inactive CD. Our findings demonstrate that microbiota dysbiosis associated with CD pathophysiology is reflected in AT and might contribute to disease severity.