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BACKGROUND & AIMS: We aimed to identify biomarkers that might be used to predict responses of patients with inflammatory bowel diseases (IBD) to vedolizumab therapy. METHODS: We obtained biopsies from inflamed colon of patients with IBD who began treatment with vedolizumab (n = 31) or tumor necrosis factor (TNF) antagonists (n = 20) and performed RNA-sequencing analyses. We compared gene expression patterns between patients who did and did not enter endoscopic remission (absence of ulcerations at month 6 for patients with Crohn's disease or Mayo endoscopic subscore ≤1 at week 14 for patients with ulcerative colitis) and performed pathway analysis and cell deconvolution for training (n = 20) and validation (n = 11) datasets. Colon biopsies were also analyzed by immunohistochemistry. We validated a baseline gene expression pattern associated with endoscopic remission after vedolizumab therapy using 3 independent datasets (n = 66). RESULTS: We identified significant differences in expression levels of 44 genes between patients who entered remission after vedolizumab and those who did not; we found significant increases in leukocyte migration in colon tissues from patients who did not enter remission (P < .006). Deconvolution methods identified a significant enrichment of monocytes (P = .005), M1-macrophages (P = .05), and CD4+ T cells (P = .008) in colon tissues from patients who did not enter remission, whereas colon tissues from patients in remission had higher numbers of naïve B cells before treatment (P = .05). Baseline expression levels of PIWIL1, MAATS1, RGS13, and DCHS2 identified patients who did vs did not enter remission with 80% accuracy in the training set and 100% accuracy in validation dataset 1. We validated these findings in the 3 independent datasets by microarray, RNA sequencing and quantitative PCR analysis (P = .003). Expression levels of these 4 genes did not associate with response to anti-TNF agents. We confirmed the presence of proteins encoded by mRNAs using immunohistochemistry. CONCLUSIONS: We identified 4 genes whose baseline expression levels in colon tissues of patients with IBD associate with endoscopic remission after vedolizumab, but not anti-TNF, treatment. We validated this signature in 4 independent datasets and also at the protein level. Studies of these genes might provide insights into the mechanisms of action of vedolizumab.
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Colitis Ulcerosa , Enfermedades Inflamatorias del Intestino , Proteínas RGS , Anticuerpos Monoclonales Humanizados , Proteínas Argonautas , Colitis Ulcerosa/tratamiento farmacológico , Colon , Fármacos Gastrointestinales/uso terapéutico , Humanos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Inducción de Remisión , Resultado del Tratamiento , Inhibidores del Factor de Necrosis TumoralRESUMEN
Acetate-producing Saccharomyces cerevisiae var. boulardii strains could exert improved effects on ulcerative colitis, which here, was preclinically evaluated in an acute dextran sodium sulphate induced model of colitis. Nine-week-old female mice were divided into 12 groups, receiving either drinking water or 2.75% dextran sodium sulphate for 7 days, combined with a daily gavage of various treatments with different levels of acetate accumulation: sham control (phosphate buffered saline, no acetate), non-probiotic control (Baker's yeast, no acetate), probiotic control (Enterol®, transient acetate), and additionally several Saccharomyces cerevisiae var. boulardii strains with respectively no, high, and extra-high acetate accumulation. Disease activity was monitored daily, and feces samples were collected at different timepoints. On day 14, the mice were sacrificed, upon which blood and colonic tissue were collected for analysis. Disease activity in inflamed mice was lower when treated with the high-acetate-producing strain compared to sham and non-probiotic controls. The non-acetate-producing strain showed higher disease activity compared to the acetate-producing strains. Accordingly, higher histologic inflammation was observed in non- or transient-acetate-producing strains compared to the sham control, whereas this increase was not observed for high- and extra-high-acetate-producing strains upon induction of inflammation. These anti-inflammatory findings were confirmed by transcriptomic analysis of differentially expressed genes. Moreover, only the strain with the highest acetate production was superior in maintaining a stable gut microbial alpha-diversity upon inflammation. These findings support new possibilities for acetate-mediated management of inflammation in inflammatory bowel disease by administrating high-acetate-producing Saccharomyces cerevisae var. boulardii strains.
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Acetatos , Colitis , Sulfato de Dextran , Probióticos , Saccharomyces cerevisiae , Animales , Femenino , Ratones , Saccharomyces cerevisiae/genética , Colitis/inducido químicamente , Colitis/terapia , Modelos Animales de Enfermedad , Colon/metabolismo , Colon/microbiología , Colon/patología , Saccharomyces boulardii , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/terapia , Colitis Ulcerosa/microbiología , Mutación , Microbioma Gastrointestinal , Heces/microbiología , Ratones Endogámicos C57BLRESUMEN
Crohn's disease (CD) is marked by recurring intestinal inflammation and tissue injury, often resulting in fibrostenosis and bowel obstruction, necessitating surgical intervention with high recurrence rates. To elucidate the mechanisms underlying fibrostenosis in CD, we analyzed the transcriptome of cells isolated from the transmural ileum of patients with CD, including a trio of lesions from each patient: non-affected, inflamed, and stenotic ileum samples, and compared them with samples from patients without CD. Our computational analysis revealed that profibrotic signals from a subset of monocyte-derived cells expressing CD150 induced a disease-specific fibroblast population, resulting in chronic inflammation and tissue fibrosis. The transcription factor TWIST1 was identified as a key modulator of fibroblast activation and extracellular matrix (ECM) deposition. Genetic and pharmacological inhibition of TWIST1 prevents fibroblast activation, reducing ECM production and collagen deposition. Our findings suggest that the myeloid-stromal axis may offer a promising therapeutic target to prevent fibrostenosis in CD.
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Enfermedad de Crohn , Fibroblastos , Fibrosis , Monocitos , Proteína 1 Relacionada con Twist , Enfermedad de Crohn/metabolismo , Enfermedad de Crohn/patología , Enfermedad de Crohn/inmunología , Humanos , Fibroblastos/metabolismo , Fibroblastos/patología , Proteína 1 Relacionada con Twist/metabolismo , Proteína 1 Relacionada con Twist/genética , Monocitos/metabolismo , Monocitos/patología , Monocitos/inmunología , Masculino , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Femenino , Matriz Extracelular/metabolismo , Matriz Extracelular/patología , Receptores de Superficie Celular/metabolismo , Receptores de Superficie Celular/genética , Íleon/patología , Íleon/metabolismo , Íleon/inmunología , Comunicación Celular , Adulto , Endopeptidasas/metabolismo , Endopeptidasas/genética , Animales , RatonesRESUMEN
OBJECTIVE: To infer potential mechanisms driving disease subtypes among patients with inflammatory bowel disease (IBD), we profiled the transcriptome of purified circulating monocytes and CD4 T-cells. DESIGN: RNA extracted from purified monocytes and CD4 T-cells derived from the peripheral blood of 125 endoscopically active patients with IBD was sequenced using Illumina HiSeq 4000NGS. We used complementary supervised and unsupervised analytical methods to infer gene expression signatures associated with demographic/clinical features. Expression differences and specificity were validated by comparison with publicly available single cell datasets, tissue-specific expression and meta-analyses. Drug target information, druggability and adverse reaction records were used to prioritise disease subtype-specific therapeutic targets. RESULTS: Unsupervised/supervised methods identified significant differences in the expression profiles of CD4 T-cells between patients with ileal Crohn's disease (CD) and ulcerative colitis (UC). Following a pathway-based classification (Area Under Receiver Operating Characteristic - AUROC=86%) between ileal-CD and UC patients, we identified MAPK and FOXO pathways to be downregulated in UC. Coexpression module/regulatory network analysis using systems-biology approaches revealed mediatory core transcription factors. We independently confirmed that a subset of the disease location-associated signature is characterised by T-cell-specific and location-specific expression. Integration of drug-target information resulted in the discovery of several new (BCL6, GPR183, TNFAIP3) and repurposable drug targets (TUBB2A, PRKCQ) for ileal CD as well as novel targets (NAPEPLD, SLC35A1) for UC. CONCLUSIONS: Transcriptomic profiling of circulating CD4 T-cells in patients with IBD demonstrated marked molecular differences between the IBD-spectrum extremities (UC and predominantly ileal CD, sandwiching colonic CD), which could help in prioritising particular drug targets for IBD subtypes.
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Colitis Ulcerosa , Enfermedad de Crohn , Enfermedades Inflamatorias del Intestino , Proteínas de Transporte de Nucleótidos , Humanos , Enfermedades Inflamatorias del Intestino/genética , Colitis Ulcerosa/genética , Colitis Ulcerosa/tratamiento farmacológico , Enfermedad de Crohn/genética , Enfermedad de Crohn/tratamiento farmacológico , Perfilación de la Expresión Génica , Íleon , Proteínas de Transporte de Nucleótidos/genéticaRESUMEN
Inflammatory responses of the intestinal epithelial barrier in patients with Crohn's disease (CD), a chronic inflammatory bowel disease (IBD), are associated with gut microbial alterations. At a community level, there is scarce mechanistic evidence on the effects of gut microbial alterations on host mucosal barrier responses. We used a computational microbe-host interaction prediction framework based on network diffusion and systems biology to integrate publicly available paired gut microbial and intestinal gene expression datasets. The ileal signaling network potentially modulated by the microbiota was enriched with immune-related pathways such as those associated with IL-4, IL-2, IL-13, NFkB, and toll-like receptors. We identified bacterial proteins eliciting post-translational modifications on host receptors, resulting in the de-repression of pro-inflammatory cytokines via critical hub proteins such as NFkB. The signaling networks were over-represented with CD associated genes and CD drug targets. Using datasets generated from our validation cohorts, we confirmed some of the results.
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Inflammatory bowel disease [IBD] has a multifactorial origin and originates from a complex interplay of environmental factors with the innate immune system at the intestinal epithelial interface in a genetically susceptible individual. All these factors make its aetiology intricate and largely unknown. Multi-omic datasets obtained from IBD patients are required to gain further insights into IBD biology. We here review the landscape of multi-omic data availability in IBD and identify barriers and gaps for future research. We also outline the various technical and non-technical factors that influence the utility and interpretability of multi-omic datasets and thereby the study design of any research project generating such datasets. Coordinated generation of multi-omic datasets and their systemic integration with clinical phenotypes and environmental exposures will not only enhance understanding of the fundamental mechanisms of IBD but also improve therapeutic strategies. Finally, we provide recommendations to enable and facilitate generation of multi-omic datasets.
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Enfermedades Inflamatorias del Intestino , Exposición a Riesgos Ambientales , Predisposición Genética a la Enfermedad , Humanos , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/terapia , FenotipoRESUMEN
Microbial dysbiosis is an established finding in patients with inflammatory bowel disease (IBD), but host-microbial interactions are poorly understood. We aimed to unravel the effect of microbiota exposure on intestinal epithelial cells. Confluent Transwell® organoid monolayers of eight UC patients and eight non-IBD controls were co-cultured for six hours with microbiota (3x108 cells) of UC patients or a healthy volunteer (HV), in the presence or absence of an inflammatory cytokine mix. Transepithelial electrical resistance (TEER), fluorescein isothiocyanate (FITC) dextran measurements, and RNA sequencing were performed on epithelial cells, and 16S rRNA sequencing on microbiota samples before and after co-culture. Transcriptomic response following microbiota exposure was not different between epithelial cells from UC patients or non-IBD controls. Following UC microbiota exposure, but not HV microbiota, a strong decrease in epithelial barrier integrity was observed in both UC and HV epithelial cells by TEER and FITC dextran measurements. Exposure of inflamed epithelium to UC microbiota induced transcriptomic stress pathways including activation of EGR1, MAPK and JAK/STAT signaling, as well as AP-1 family and FOSL transcripts. Stress responses after HV microbiota stimulation were milder. We conclude that not the epithelial cell origin (UC versus non-IBD) but the microbial donor drives transcriptomic responses, as exposure to UC microbiota was sufficient to induce stress responses in all epithelial cells. Further research on therapies to restore the microbial balance, to remove the constant trigger of dysbiosis, is required.
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Colitis Ulcerosa , Microbioma Gastrointestinal , Enfermedades Inflamatorias del Intestino , Microbiota , Disbiosis/metabolismo , Microbioma Gastrointestinal/genética , Humanos , Enfermedades Inflamatorias del Intestino/metabolismo , Mucosa Intestinal/metabolismo , ARN Ribosómico 16S/genéticaRESUMEN
BACKGROUND: Early detection of individuals at risk for Alzheimer's disease (AD) is highly important. Amyloid accumulation is an early pathological AD event, but the genetic association with known AD risk variants beyond the APOE4 effect is largely unknown. We investigated the association between different AD polygenic risk scores (PRS) and amyloid accumulation in the Flemish Prevent AD Cohort KU Leuven (F-PACK). METHODS: We calculated PRS with and without the APOE region in 90 cognitively healthy F-PACK participants (baseline age 67.8 (52-80) years, 41 APOE4 carriers), with baseline and follow-up amyloid-PET (time interval 6.1 (3.4-10.9) years). Individuals were genotyped using Illumina GSA and imputed. PRS were calculated using three p-value thresholds (pT) for variant inclusion: 5 × 10-8, 1 × 10-5, and 0.1, based on the stage 1 summary statistics from Kunkle et al. (Nat Genet 51:414-30, 2019). Linear regression models determined if these PRS predicted amyloid accumulation. RESULTS: A score based on PRS excluding the APOE region at pT = 5 × 10-8 plus the weighted sum of the two major APOE variants (rs429358 and rs7412) was significantly associated with amyloid accumulation (p = 0.0126). The two major APOE variants were also significantly associated with amyloid accumulation (p = 0.0496). The other PRS were not significant. CONCLUSIONS: Specific PRS are associated with amyloid accumulation in the asymptomatic phase of AD.
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Enfermedad de Alzheimer , Amiloidosis , Anciano , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Amiloide , Péptidos beta-Amiloides , Proteínas Amiloidogénicas , Apolipoproteína E4/genética , Humanos , Factores de RiesgoRESUMEN
Crohn's disease (CD), a form of inflammatory bowel disease (IBD), is characterized by heterogeneity along multiple clinical axes, which in turn impacts disease progression and treatment modalities. Using advanced data integration approaches and systems biology tools, we studied the contribution of CD susceptibility variants and gene expression in distinct peripheral immune cell subsets (CD14+ monocytes and CD4+ T cells) to relevant clinical traits. Our analyses revealed that most clinical traits capturing CD heterogeneity could be associated with CD14+ and CD4+ gene expression rather than disease susceptibility variants. By disentangling the sources of variation, we identified molecular features that could potentially be driving the heterogeneity of various clinical traits of CD patients. Further downstream analyses identified contextual hub proteins such as genes encoding barrier functions, antimicrobial peptides, chemokines, and their receptors, which are either targeted by drugs used in CD or other inflammatory diseases or are relevant to the biological functions implicated in disease pathology. These hubs could be used as cell type-specific targets to treat specific subtypes of CD patients in a more individualized approach based on the underlying biology driving their disease subtypes. Our study highlights the importance of data integration and systems approaches to investigate complex and heterogeneous diseases such as IBD.
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Enfermedad de Crohn , Péptidos Antimicrobianos , Linfocitos T CD4-Positivos , Quimiocinas , Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/inmunología , Humanos , Biología de SistemasRESUMEN
BACKGROUND: Oncostatin M (OSM) has been implicated in the pathogenesis of inflammatory bowel disease (IBD) and as a marker for nonresponsiveness to anti-tumor necrosis factor (TNF) therapy. We further unraveled the potential of OSM and related receptors as markers of diagnosis, prognosis, and therapy response in IBD. METHODS: We collected inflamed mucosal biopsies and serum from patients with Crohn disease (CD) and with ulcerative colitis: (1) newly diagnosed patients who were treatment-naïve, (2) patients initiating anti-TNF or (3) vedolizumab therapy, (4) postoperative patients with CD, and (5) multiple-affected families with IBD including unaffected first-degree relatives (FDRs). We measured the gene expression of mucosal OSM and its receptors OSMR/LIFR and co-receptor IL6ST, and the protein expression of serum OSM. Statistical significance was defined as P < 0.05. RESULTS: Newly diagnosed patients showed significantly increased mucosal OSM/OSMR compared with control patients, with the highest enrichment for OSM (fold change [FC] >17.9). Likewise, ileal OSM/OSMR were significantly upregulated in postoperative recurrent CD. Serum OSM was increased in newly diagnosed patients and postoperative patients with recurrent CD (FC ≥ 2.6). In families with IBD, higher serum levels were observed in FDRs than in control families (FC = 2.2). Furthermore, elevated colonic OSM/OSMR (but not serum OSM) were associated with the early need for biologic therapy (FC ≥ 1.9), and higher OSM was also predictive of primary nonresponse to both anti-TNF and vedolizumab therapy (FC ≥ 2.4). Immunohistochemistry highlighted mucosal OSM expression in macrophages. CONCLUSIONS: We found that OSM is a diagnostic biomarker in the tissue and serum not only of newly diagnosed patients with IBD and postoperative patients with recurrent CD but also of their FDRs. Higher colonic OSM levels are furthermore associated with poor prognosis and with primary nonresponse to biologic therapies. Therefore, OSM could guide clinical decision-making.
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Colitis , Enfermedad de Crohn , Enfermedades Inflamatorias del Intestino , Oncostatina M , Biomarcadores , Humanos , Enfermedades Inflamatorias del Intestino/diagnóstico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Oncostatina M/metabolismo , Pronóstico , Inhibidores del Factor de Necrosis TumoralRESUMEN
BACKGROUND: Patients with inflammatory bowel disease [IBD] are considered immunosuppressed, but do not seem more vulnerable for COVID-19. Nevertheless, intestinal inflammation has shown to be an important risk factor for SARS-CoV-2 infection and prognosis. Therefore, we investigated the role of intestinal inflammation on the viral intestinal entry mechanisms, including ACE2, in IBD. METHODS: We collected inflamed and uninflamed mucosal biopsies from Crohn's disease [CD] [nâ =â 193] and ulcerative colitis [UC] [nâ =â 158] patients, and from 51 matched non-IBD controls for RNA sequencing, differential gene expression, and co-expression analysis. Organoids from UC patients were subjected to an inflammatory mix and processed for RNA sequencing. Transmural ileal biopsies were processed for single-cell [sc] sequencing. Publicly available colonic sc-RNA sequencing data, and microarrays from tissue pre/post anti-tumour necrosis factor [TNF] therapy, were analysed. RESULTS: In inflamed CD ileum, ACE2 was significantly decreased compared with control ileum [pâ =â 4.6E-07], whereas colonic ACE2 was higher in inflamed colon of CD/UC compared with control [pâ =â 8.3E-03; pâ =â 1.9E-03]. Sc-RNA sequencing confirmed this ACE2 dysregulation and exclusive epithelial ACE2 expression. Network analyses highlighted HNF4A as key regulator of ileal ACE2, and pro-inflammatory cytokines and interferon regulating factors regulated colonic ACE2. Inflammatory stimuli upregulated ACE2 in UC organoids [pâ =â 1.7E-02], but not in non-IBD controls [pâ =â 9.1E-01]. Anti-TNF therapy restored colonic ACE2 regulation in responders. CONCLUSIONS: Intestinal inflammation alters SARS-CoV-2 coreceptors in the intestine, with opposing dysregulations in ileum and colon. HNF4A, an IBD susceptibility gene, seems an important upstream regulator of ACE2 in ileum, whereas interferon signalling might dominate in colon.
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Enzima Convertidora de Angiotensina 2/inmunología , COVID-19 , Colitis Ulcerosa , Colon , Enfermedad de Crohn , Factor Nuclear 4 del Hepatocito , Íleon , Interferones/inmunología , SARS-CoV-2/fisiología , Biopsia/métodos , COVID-19/inmunología , COVID-19/patología , COVID-19/fisiopatología , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/patología , Colitis Ulcerosa/virología , Colon/inmunología , Colon/patología , Colon/virología , Enfermedad de Crohn/inmunología , Enfermedad de Crohn/patología , Enfermedad de Crohn/virología , Citocinas/inmunología , Femenino , Regulación de la Expresión Génica , Factor Nuclear 4 del Hepatocito/genética , Factor Nuclear 4 del Hepatocito/inmunología , Humanos , Íleon/inmunología , Íleon/patología , Íleon/virología , Masculino , Persona de Mediana Edad , Análisis de Secuencia de ARN , Transducción de Señal , Análisis de la Célula IndividualRESUMEN
Ulcerative colitis is a chronic inflammatory disease confined to the colon. Although the etiopathogenesis remains unknown, small bowel dysfunctions like histological and permeability alterations have been described in ulcerative colitis. We evaluated the molecular gene signature in the non-inflamed terminal ileum of 36 ulcerative colitis patients (7 active, with Mayo endoscopic subscore ≥2, and 29 inactive) as compared to 15 non-inflammatory bowel disease controls. Differential gene expression analysis with DESeq2 showed distinct expression patterns depending on disease activity and maximal disease extent. We found 84 dysregulated genes in patients with active extensive colitis and 20 in inactive extensive colitis, compared to controls. There was an overlap of 5 genes: REG1B, REG1A, MUC4, GRAMD2, and CASP10. In patients with left-sided colitis, ileal gene expression levels were similar to controls. Based on gene co-expression analysis, ileal changes in active ulcerative colitis patients were related to immune functions. The ileal changes in the inactive ulcerative colitis subjects converged into the maintenance of the intestinal barrier through increased mitochondrial function and dampened immune functions. In conclusion, we identified molecular changes in the non-inflamed ileum of ulcerative colitis that are dependent on colonic inflammation.
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Colitis Ulcerosa/fisiopatología , Íleon/fisiopatología , Mucosa Intestinal/patología , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND AND AIMS: Ulcerative colitis [UC] is associated with excessive neutrophil infiltration and collateral tissue damage, but the link is not yet completely understood. Since c-MET receptor tyrosine kinase [MET] is required for neutrophil chemoattraction and cytotoxicity in response to its ligand hepatocyte growth factor [HGF], we aimed to identify the function of HGF-MET signalling in neutrophils in UC patients and in mice during intestinal inflammation. METHODS: Serum and colonic biopsies from healthy controls and UC patients with active [Mayo endoscopic subscore 2-3] and inactive [Mayo endoscopic subscore 0-1] disease were collected to assess the level of serum and colonic HGF. Disease progression and immune cell infiltration were assessed during dextran sodium sulphate [DSS] colitis in wild-type and MRP8-Cre MET-LoxP mice. RESULTS: Increased mucosal HGF expression was detected in patients with active UC, and in mice during the inflammatory phase of DSS colitis. Similarly, serum HGF was significantly increased in active UC patients and positively correlated with C-reactive protein and blood neutrophil counts. Flow cytometric analysis also demonstrated an upregulation of colonic MET+ neutrophils during DSS colitis. Genetic ablation of MET in neutrophils reduced the severity of DSS-induced colitis. Concomitantly, there was a decreased number of TH17 cells, which could be due to a decreased production of IL-1ß by MET-deficient neutrophils. CONCLUSIONS: These data highlight the central role of neutrophilic HGF-MET signalling in exacerbating damage during intestinal inflammation. Hence, selective blockade of this pathway in neutrophils could be considered as a novel therapeutic approach in UC.
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Colitis Ulcerosa/genética , Factor de Crecimiento de Hepatocito/farmacología , Proteínas Proto-Oncogénicas c-met/farmacología , Transducción de Señal/fisiología , Brote de los Síntomas , Animales , Bélgica , Colitis Ulcerosa/fisiopatología , Colon/metabolismo , Colon/patología , Colon/fisiopatología , Modelos Animales de Enfermedad , Citometría de Flujo/métodos , Citometría de Flujo/estadística & datos numéricos , Factor de Crecimiento de Hepatocito/genética , Masculino , Ratones , Proteínas Proto-Oncogénicas c-met/genética , Transducción de Señal/inmunologíaRESUMEN
Introduction: Given the high rate of primary and acquired resistance to current inflammatory bowel disease (IBD) treatments, novel drug targets and biomarkers that aid in therapeutic prediction are eagerly awaited. Furthermore, postponing treatment initiation because of a diagnostic delay profoundly affects patient well-being and overall disease evolution. Among the emerging targets and biomarkers, oncostatin M (OSM) has gained much interest in the past few years.Areas covered: A literature search to June 2019 was performed to identify the most relevant reports on Oncostatin M. The authors summarize the biology of OSM, its role in health and disease, its potential as a diagnostic, prognostic and therapeutic biomarker in the field of IBD and how it might be a drug target of the future.Expert opinion: OSM has diagnostic, prognostic and therapeutic capabilities. High mucosal OSM predicts primary non-response to anti-TNF antibodies. However, one could question whether a single cytokine can capture the complexity and heterogeneity of IBD. Neutralizing OSM in patients with elevated mucosal OSM appears to be attractive and should be considered as a valid option for the first biomarker-stratified, proof-of-concept trial that studies a novel therapeutic compound in IBD.
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Biomarcadores/metabolismo , Enfermedades Inflamatorias del Intestino/fisiopatología , Oncostatina M/metabolismo , Animales , Humanos , Enfermedades Inflamatorias del Intestino/diagnóstico , Enfermedades Inflamatorias del Intestino/terapia , PronósticoRESUMEN
Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory condition affecting mainly the gastro-intestinal tract with two main entities: Crohn's disease (CD) and ulcerative colitis (UC). Although the exact mechanisms underlying the initial development of IBD are not fully understood, it is believed that an abnormal immune response is elicited against the intestinal microbiota in genetically predisposed individuals. Crucial elements of the etiopathogenesis have been elucidated by research using human biological materials. The estimated prevalence of IBD is 0.5% in the Western world. Although incidence rates are increasing, both conditions are not "common" in general terms mandating a multicentric approach. Biological material from numerous Belgian patients have been collected over time in a number of university hospitals in Belgium (UH Ghent: 800 CD patients, 350 UC patients, 600 normal controls; UH Leuven: 2,600 CD patients, 1,380 UC patients, 98 IC/IBDU patients, 6,260 normal controls). Within the setting of the Flemish Center Medical Innovation (CMI) initiative and later on the Flemish biobank network a prospective study was set-up across three Belgian IBD centers (University Hospitals Brussels, Ghent, and Leuven). Human biological materials and data have been collected prospectively from newly diagnosed CD and UC patients. The analyses hereof have generated new insights which have been published in the most renowned journals. The approach of well-thought off, multi-centric, structured, and systematic biobanking has proven to be a success-story and thus a textbook case for multi-centric banking of human biological materials. This story is being told in this article.
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BACKGROUND: Ileocolonic expression of IL13RA2 has been identified as a predictive marker for nonresponsiveness to infliximab (IFX) in patients with Crohn's disease (CD). AIM: To validate the IL13RA2 biomarker, study its anti-TNF specificity and get a better understanding of the underlying biology driving its expression. METHODS: IL13RA2 mucosal expression was studied in a cohort of adalimumab and vedolizumab treated patients. To identify the upstream regulators of anti-TNF nonresponsiveness, weighted gene co-expression network analysis was applied on publicly available microarray data of IFX-treated patients. Selected serum proteins, including TNF, were measured prior to first IFX exposure and compared between healers and nonhealers. RESULTS: Increased mucosal IL13RA2 expression prior to start of biological therapy was predictive for anti-TNF nonresponsiveness specifically (AUROC, area under the curve = 0.90, P < 0.001 in anti-TNF vs AUROC = 0.63, P = 0.30 in vedolizumab treated patients). In baseline biopsies, TNF-driven pathways were significantly enriched in future anti-TNF nonhealers (P = 5.0 × 10-34 ). We found an increased baseline mucosal TNF burden in nonhealers (P = 0.02), and TNF mRNA correlated significantly with IL13RA2 expression (ρ = 0.55, P = 0.02). Baseline serum TNF levels were significantly lower in nonhealers (P = 0.04), and correlated inversely with IFX serum induction levels (r = -0.45, P = 0.002 at week 6). CONCLUSIONS: Increased mucosal IL13RA2 expression is associated with an increased mucosal TNF burden in CD patients. In view of its specificity for prediction of anti-TNF therapy resistance, mucosal IL13RA2 expression is a potential biomarker for therapy selection and/or for the need of increased anti-TNF drug dosing.
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Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/metabolismo , Fármacos Gastrointestinales/uso terapéutico , Subunidad alfa2 del Receptor de Interleucina-13/biosíntesis , Membrana Mucosa/metabolismo , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adalimumab/farmacología , Adalimumab/uso terapéutico , Adulto , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Biomarcadores/metabolismo , Estudios de Cohortes , Enfermedad de Crohn/genética , Femenino , Fármacos Gastrointestinales/farmacología , Expresión Génica , Humanos , Inmunoterapia/métodos , Infliximab/farmacología , Infliximab/uso terapéutico , Subunidad alfa2 del Receptor de Interleucina-13/genética , Masculino , Persona de Mediana Edad , Membrana Mucosa/efectos de los fármacos , Valor Predictivo de las Pruebas , Resultado del TratamientoRESUMEN
BACKGROUND: With the changed therapeutic armamentarium for Crohn's disease (CD) and ulcerative colitis (UC), biomarkers predicting treatment response are urgently needed. We studied whole blood and mucosal expression of genes previously reported to predict outcome to anti-TNF therapy, and investigated if the signature was specific for anti-TNF agents. METHODS: We prospectively included 54 active IBD patients (24CD, 30UC) initiating anti-TNF therapy, as well as 22 CD patients initiating ustekinumab and 51 patients initiating vedolizumab (25CD, 26UC). Whole blood expression of OSM, TREM1, TNF and TNFR2 was measured prior to start of therapy using qPCR, and mucosal gene expression in inflamed biopsies using RNA-sequencing. Response was defined as endoscopic remission (SES-CDâ¯≤â¯2 at week 24 for CD and Mayo endoscopic sub-scoreâ¯≤â¯1 at week 10 for UC). FINDINGS: Baseline whole blood TREM1 was downregulated in future anti-TNF responders, both in UC (FCâ¯=â¯0.53, pâ¯=â¯.001) and CD (FCâ¯=â¯0.66, pâ¯=â¯.007), as well as in the complete cohort (FCâ¯=â¯0.67, pâ¯<â¯.001). Receiver operator characteristic statistics showed an area under the curve (AUC) of 0.78 (pâ¯=â¯.001). A similar accuracy could be achieved with mucosal TREM1 (AUC 0.77, pâ¯=â¯.003), which outperformed the accuracy of serum TREM1 (AUC 0.58, pâ¯=â¯.31). Although differentially expressed in tissue, OSM, TNF and TNFR2 were not differentially expressed in whole blood. The TREM1 predictive signal was anti-TNF specific, as no changes were seen in ustekinumab and vedolizumab treated patients. INTERPRETATION: We identified low TREM-1 as a specific biomarker for anti-TNF induced endoscopic remission. These results can aid in the selection of therapy in biologic-naïve patients.
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Anticuerpos Monoclonales/uso terapéutico , Enfermedades Inflamatorias del Intestino/sangre , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Receptor Activador Expresado en Células Mieloides 1/sangre , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adulto , Biomarcadores , Colitis Ulcerosa/sangre , Colitis Ulcerosa/diagnóstico , Colitis Ulcerosa/tratamiento farmacológico , Enfermedad de Crohn/sangre , Enfermedad de Crohn/diagnóstico , Enfermedad de Crohn/tratamiento farmacológico , Femenino , Expresión Génica , Humanos , Enfermedades Inflamatorias del Intestino/diagnóstico , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Nomogramas , Pronóstico , Resultado del Tratamiento , Receptor Activador Expresado en Células Mieloides 1/genéticaRESUMEN
BACKGROUND AND AIMS: Early treatment of Crohn's disease [CD] is required in order to optimize patient outcomes. To this end, we need to gain a better understanding of the molecular changes at the onset of CD. METHODS: As a model for the earliest mucosal CD lesions, we study post-operative recurrent CD [Rutgeerts score ≥ i2b]. We are the first to analyse gene and microRNA [miRNA] expression profiles in ileal biopsies from these patients, and compare them with those of newly diagnosed [≤18 months] and late-stage [>10 years after diagnosis] CD patients. RESULTS: Except for one gene [WNT5A], there are no differential genes in CD patients without post-operative recurrence [i0], showing that previous disease did not influence gene expression in the neoterminal ileum, and that this model can be used to study early mucosal CD lesions. Gene expression and co-expression network dysregulation is more pronounced in newly diagnosed and late-stage CD than in post-operative recurrent CD, with most important modules associated with [a]granulocyte adhesion/diapedesis, and cholesterol biosynthesis. In contrast, we found a role for snoRNAs/miRNAs in recurrent CD, highlighting the potential importance of regulatory RNAs in early disease stages. Immunohistochemistry confirmed the expression of key dysregulated genes in damaged/regenerating epithelium and immune cells in recurrent CD. CONCLUSIONS: Aside from regulatory RNAs, there are no clear gene signatures separating post-operative recurrent, newly diagnosed, and late-stage CD. The relative contribution of dysregulated genes and networks differs, and suggests that surgery may reset the disease at the mucosal site, and therefore post-operative recurrent CD might be a good model a good model to study to study early mucosal CD lesions.