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Verstockt B, Alsoud D, van Oostrom J, Verstockt S, Smith J, Stylli J, Singh S, van Gennep S, Rahimian P, Sabino J, Ferrante M, Kelman A, Singh S, D'Haens G, Vermeire S. Drug tissue concentration and STAT3 modulation as determinants of tofacitinib response in ulcerative colitis. J Crohns Colitis 2025; 19:jjaf063. [PMID: 40243193 DOI: 10.1093/ecco-jcc/jjaf063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Indexed: 04/18/2025]
Abstract
INTRODUCTION Inflammatory bowel disease management has advanced with therapies like Janus kinase inhibitors (JAKi). Despite their promise, JAKi pharmacokinetic-pharmacodynamic (PK-PD) profiles and tissue-level effects remain underexplored. This study investigates tissue and serum tofacitinib levels, their correlation with therapeutic efficacy, and molecular mechanisms underlying treatment response. METHODS Thirty refractory ulcerative colitis (UC) patients receiving tofacitinib were prospectively studied. Tissue biopsies and serum samples were collected pre- and post-induction for PK analysis using liquid chromatography mass spectrometry. RNA sequencing and cytokine profiling were performed on tissue samples to explore molecular responses. Endoscopic improvement was defined as a Mayo endoscopic subscore of 0-1 by week 16. RESULTS Tofacitinib tissue concentrations were 25-fold higher than serum levels and significantly correlated (ρ=0.92, P < .001). Responders showed significantly higher tissue drug exposure (1047.5 ng/g vs 467.1 ng/g, P = .02) at the time of endoscopic assessment. Tofacitinib treatment reduced phosphorylated STAT3 (pSTAT3) levels, particularly in responders (P = .02). RNA sequencing revealed gene modules linked to tissue drug and pSTAT3 concentrations. Gene set enrichment analysis showed that these were more frequent in non-responders and associated with JAK-STAT pathways. CONCLUSIONS This study underscores the importance of tissue tofacitinib levels in UC treatment efficacy, with pSTAT3 reduction serving as a potential marker of drug efficacy. RNA sequencing identified molecular pathways for potential biomarkers and novel therapeutic targets in tofacitinib non-responders.
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Affiliation(s)
- Bram Verstockt
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
- Translational Research in Gastrointestinal Disorders, Department of Chronic Disease and Metabolism, KU Leuven, Leuven, Belgium
| | - Dahham Alsoud
- Translational Research in Gastrointestinal Disorders, Department of Chronic Disease and Metabolism, KU Leuven, Leuven, Belgium
| | - Joep van Oostrom
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Amsterdam, The Netherlands
| | - Sare Verstockt
- Translational Research in Gastrointestinal Disorders, Department of Chronic Disease and Metabolism, KU Leuven, Leuven, Belgium
| | - Jeff Smith
- Biora Therapeutics, San Diego California, San Diego, CA, United States
| | - Jack Stylli
- Biora Therapeutics, San Diego California, San Diego, CA, United States
| | - Sujay Singh
- Biora Therapeutics, San Diego California, San Diego, CA, United States
| | - Sara van Gennep
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Amsterdam, The Netherlands
| | - Pejman Rahimian
- Biora Therapeutics, San Diego California, San Diego, CA, United States
| | - João Sabino
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
- Translational Research in Gastrointestinal Disorders, Department of Chronic Disease and Metabolism, KU Leuven, Leuven, Belgium
| | - Marc Ferrante
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
- Translational Research in Gastrointestinal Disorders, Department of Chronic Disease and Metabolism, KU Leuven, Leuven, Belgium
| | - Ariella Kelman
- Biora Therapeutics, San Diego California, San Diego, CA, United States
| | - Sharat Singh
- Biora Therapeutics, San Diego California, San Diego, CA, United States
| | - Geert D'Haens
- Translational Research in Gastrointestinal Disorders, Department of Chronic Disease and Metabolism, KU Leuven, Leuven, Belgium
| | - Séverine Vermeire
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
- Translational Research in Gastrointestinal Disorders, Department of Chronic Disease and Metabolism, KU Leuven, Leuven, Belgium
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Grad S, Farcas RA, Dumitrascu DL, Surdea-Blaga T, Ismaiel A, Popa S. Predictors of Immunogenicity and Loss of Response to ANTI-TNFα Therapy in Crohn Disease-A Systematic Review. Am J Ther 2025; 32:e262-e268. [PMID: 40338684 DOI: 10.1097/mjt.0000000000001867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/10/2025]
Abstract
BACKGROUND As the use of anti-tumor necrosis factor-α (TNFα) therapies in Crohn disease (CD) is spread, the loss-of-response (LOR) to it is increasingly encountered. Discovering a pathological pathway and biomarkers that can predict LOR would assist in the management of patients with CD. In this article, we provide a comprehensive systematic review of studies assessing predictors of immunogenicity and loss-of-response to anti-TNFα drugs in patients with CD. DATA SOURCES We performed a systematic review of PubMed to identify citations pertaining to predictors of immunogenicity and loss-of-response to anti-TNFα drugs in patients with CD through April 27, 2024, using a predefined string of keywords. Data extraction and quality assessment were performed independently by 2 reviewers. RESULTS A total of 18 eligible studies were included in the review. Four major groups of studies were identified: genetic factors, factors linked with colonic inflammation, serum and anthropological markers, and prevention of LOR. Promising predictors of LOR to infliximab or adalimumab include the carriage of HLA-DQA1*05, visceral adiposity, intestinal abundant presence of CD96, IL-17, and IL-23. Substantial heterogeneity was observed, and none of the markers had undergone formal validation. Specific limitations to acceptance of these factors included failure to use a standardized definition of LOR to anti-TNFα treatment, lack of specificity, and insufficient relevance to the pathogenesis of LOR. CONCLUSIONS This review underlines the lack of well-defined studies and controlled trials investigating predictors of LOR to anti-TNFα therapies in CD. A research priority is the development of reliable and accurate biomarkers that can shed light on the pathogenesis of the implied LOR. These biomarkers, along with genetic factors, have the potential to enhance clinical management by aiding in patient stratification and monitoring.
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Affiliation(s)
- Simona Grad
- 2nd Department of Internal Medicine, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
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Chen L, Zhang C, Niu R, Xiong S, He J, Wang Y, Zhang P, Su F, Liu Z, Zhou L, Mao R, Hu S, Chen M, Qiu Y, Feng R. Multi-Omics Biomarkers for Predicting Efficacy of Biologic and Small-Molecule Therapies in Adults With Inflammatory Bowel Disease: A Systematic Review. United European Gastroenterol J 2025; 13:517-530. [PMID: 39656426 PMCID: PMC12090831 DOI: 10.1002/ueg2.12720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 10/09/2024] [Accepted: 10/14/2024] [Indexed: 05/21/2025] Open
Abstract
The heterogeneity and suboptimal efficacy of biological treatments and small molecule drugs necessitate their precise selection based on biomarkers that predict therapeutic responses in inflammatory bowel disease. Recent studies have identified numerous novel biomarkers predictive of responses to biologics and small molecule modulators, utilizing a variety of omics approaches in inflammatory bowel disease. In this review, we systematically examine baseline omics biomarkers that predict responses to biological therapies and small molecule drugs, drawing on literature from PubMed. Our analysis spans multiple omics disciplines, including genomics, transcriptomics (both bulk RNA and single-cell RNA sequencing), proteomics, microbiomics, and metabolomics, with particular emphasis on the impact of models integrating multiple omics datasets. Additionally, to further the field of precision medicine, we evaluated specific biomarkers that may exhibit distinct effects on responses to multiple therapeutic interventions.
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Affiliation(s)
- Liru Chen
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Chuhan Zhang
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Ruixuan Niu
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Shanshan Xiong
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Jinshen He
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Yu Wang
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Pingxin Zhang
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Fengyuan Su
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
- Institute of Precision MedicineThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Zishan Liu
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Longyuan Zhou
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Ren Mao
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Shixian Hu
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
- Institute of Precision MedicineThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Minhu Chen
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Yun Qiu
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Rui Feng
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
- Guangxi Hospital DivisionThe First Affiliated HospitalSun Yat‐sen UniversityNanningChina
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Stanton MB, Solinski MA, Hanauer SB. Genetic polymorphisms impacting clinical pharmacology of drugs used to treat inflammatory bowel disease: a precursor to multi-omics approach to precision medicine. Expert Rev Clin Immunol 2025; 21:461-472. [PMID: 39885730 DOI: 10.1080/1744666x.2025.2461584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 01/29/2025] [Indexed: 02/01/2025]
Abstract
INTRODUCTION Inflammatory bowel diseases (IBDs), comprised of ulcerative colitis (UC) and Crohn's disease (CD), are chronic inflammatory diseases of the gastrointestinal tract. Clinicians and patients must vigilantly manage these complex diseases over the course of the patient's lifetime to mitigate risks of the disease, surgical complications, progression to neoplasia, and complications from medical or surgical therapies. Over the past several decades, the armamentarium of IBD therapeutics has expanded; now with biologics and advanced small molecules complementing conventional drugs such as aminosalicylates, corticosteroids and thiopurines. Significant attention has been paid to the potential of precision medicine to assist clinicians in tailoring therapeutics based on patients' genetic signatures to maximize therapeutic benefit while minimizing adverse effects. AREAS COVERED In this paper, we review the published literature on genetic polymorphisms relevant to each class of IBD therapeutics. EXPERT OPINION Finally, we envision a paradigm shift in IBD research toward an omics-based network analysis approach. Through global collaboration, organization and goal setting, we predict the next decade of IBD research will revolutionize existing disease frameworks by developing precise molecular diagnoses, validated biomarkers, predictive models and novel molecularly targeted therapeutics.
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Affiliation(s)
- Matthew B Stanton
- Division of Gastroenterology and Hepatology, Northwestern Medicine, Chicago, IL, USA
| | - Mark A Solinski
- Division of Gastroenterology and Hepatology, Northwestern Medicine, Chicago, IL, USA
| | - Stephen B Hanauer
- Division of Gastroenterology and Hepatology, Northwestern Medicine, Chicago, IL, USA
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Peruhova M, Stoyanova D, Miteva DG, Kitanova M, Mirchev MB, Velikova T. Genetic factors that predict response and failure of biologic therapy in inflammatory bowel disease. World J Exp Med 2025; 15:97404. [PMID: 40115750 PMCID: PMC11718585 DOI: 10.5493/wjem.v15.i1.97404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 10/09/2024] [Accepted: 11/14/2024] [Indexed: 12/26/2024] Open
Abstract
Inflammatory bowel disease (IBD) represents a significant disease burden marked by chronic inflammation and complications that adversely affect patients' quality of life. Effective diagnostic strategies involve clinical assessments, endoscopic evaluations, imaging studies, and biomarker testing, where early diagnosis is essential for effective management and prevention of long-term complications, highlighting the need for continual advancements in diagnostic methods. The intricate interplay between genetic factors and the outcomes of biological therapy is of critical importance. Unraveling the genetic determinants that influence responses and failures to biological therapy holds significant promise for optimizing treatment strategies for patients with IBD on biologics. Through an in-depth examination of current literature, this review article synthesizes critical genetic markers associated with therapeutic efficacy and resistance in IBD. Understanding these genetic actors paves the way for personalized approaches, informing clinicians on predicting, tailoring, and enhancing the effectiveness of biological therapies for improved outcomes in patients with IBD.
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Affiliation(s)
- Milena Peruhova
- Department of Gastroenterology, University Hospital Heart and Brain, Burgas 1000, Bulgaria
| | - Daniela Stoyanova
- Department of Gastroenterology, Military Medical Academy, Sofia 1606, Bulgaria
| | | | - Meglena Kitanova
- Department of Genetics, Faculty of Biology, Sofia University St. Kliment Ohridski, Sofia 1164, Bulgaria
| | | | - Tsvetelina Velikova
- Department of Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
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Zheng M, Zhai Y, Yu Y, Shen J, Chu S, Focaccia E, Tian W, Wang S, Liu X, Yuan X, Wang Y, Li L, Feng B, Li Z, Guo X, Qiu J, Zhang C, Hou J, Sun Y, Yang X, Zuo X, Heikenwalder M, Li Y, Yuan D, Li S. TNF compromises intestinal bile-acid tolerance dictating colitis progression and limited infliximab response. Cell Metab 2024; 36:2086-2103.e9. [PMID: 38971153 DOI: 10.1016/j.cmet.2024.06.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 03/28/2024] [Accepted: 06/07/2024] [Indexed: 07/08/2024]
Abstract
The intestine constantly encounters and adapts to the external environment shaped by diverse dietary nutrients. However, whether and how gut adaptability to dietary challenges is compromised in ulcerative colitis is incompletely understood. Here, we show that a transient high-fat diet exacerbates colitis owing to inflammation-compromised bile acid tolerance. Mechanistically, excessive tumor necrosis factor (TNF) produced at the onset of colitis interferes with bile-acid detoxification through the receptor-interacting serine/threonine-protein kinase 1/extracellular signal-regulated kinase pathway in intestinal epithelial cells, leading to bile acid overload in the endoplasmic reticulum and consequent apoptosis. In line with the synergy of bile acids and TNF in promoting gut epithelial damage, high intestinal bile acids correlate with poor infliximab response, and bile acid clearance improves infliximab efficacy in experimental colitis. This study identifies bile acids as an "opportunistic pathogenic factor" in the gut that would represent a promising target and stratification criterion for ulcerative colitis prevention/therapy.
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Affiliation(s)
- Mengqi Zheng
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, China; Shandong Provincial Clinical Research Center for Digestive Diseases, Jinan, China
| | - Yunjiao Zhai
- Advanced Medical Research Institute, Shandong University, Jinan 250012, China
| | - Yanbo Yu
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, China; Shandong Provincial Clinical Research Center for Digestive Diseases, Jinan, China; Laboratory of Translational Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, China; Robot Engineering Laboratory for Precise Diagnosis and Therapy of GI Tumor, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Jing Shen
- Advanced Medical Research Institute, Shandong University, Jinan 250012, China
| | - Shuzheng Chu
- Advanced Medical Research Institute, Shandong University, Jinan 250012, China
| | - Enrico Focaccia
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Wenyu Tian
- Advanced Medical Research Institute, Shandong University, Jinan 250012, China
| | - Sui Wang
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Xuesong Liu
- Advanced Medical Research Institute, Shandong University, Jinan 250012, China
| | - Xi Yuan
- Advanced Medical Research Institute, Shandong University, Jinan 250012, China
| | - Yue Wang
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Lixiang Li
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, China; Shandong Provincial Clinical Research Center for Digestive Diseases, Jinan, China; Laboratory of Translational Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, China; Robot Engineering Laboratory for Precise Diagnosis and Therapy of GI Tumor, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Bingcheng Feng
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Zhen Li
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, China; Shandong Provincial Clinical Research Center for Digestive Diseases, Jinan, China; Laboratory of Translational Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, China; Robot Engineering Laboratory for Precise Diagnosis and Therapy of GI Tumor, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Xiaohuan Guo
- Institute for Immunology, School of Medicine, Tsinghua University, Beijing 100084, China; Beijing Key Laboratory for Immunological Research on Chronic Diseases, Tsinghua University, Beijing 100084, China
| | - Ju Qiu
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Cuijuan Zhang
- Institute of Pathology and Pathophysiology, Shandong University School of Medicine, Jinan 250012, China; Department of Pathology, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Jiajie Hou
- Cancer Centre, Faculty of Health Sciences University of Macau, Macau SAR, China; MOE Frontier Science Centre for Precision Oncology, University of Macau, Macau SAR, China
| | - Yiyuan Sun
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Xiaoyun Yang
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, China; Shandong Provincial Clinical Research Center for Digestive Diseases, Jinan, China; Laboratory of Translational Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, China; Robot Engineering Laboratory for Precise Diagnosis and Therapy of GI Tumor, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Xiuli Zuo
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, China; Shandong Provincial Clinical Research Center for Digestive Diseases, Jinan, China; Laboratory of Translational Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, China; Robot Engineering Laboratory for Precise Diagnosis and Therapy of GI Tumor, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany; The M3 Research Center, Medical faculty, University Tübingen, Ottfried-Müller Strasse 37, Tübingen, Germany.
| | - Yanqing Li
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, China; Shandong Provincial Clinical Research Center for Digestive Diseases, Jinan, China; Laboratory of Translational Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, China; Robot Engineering Laboratory for Precise Diagnosis and Therapy of GI Tumor, Qilu Hospital of Shandong University, Jinan 250012, China.
| | - Detian Yuan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shandong University, Jinan 250012, China.
| | - Shiyang Li
- Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, China; Shandong Provincial Clinical Research Center for Digestive Diseases, Jinan, China; Advanced Medical Research Institute, Shandong University, Jinan 250012, China; Key Laboratory for Experimental Teratology of Ministry of Education, Shandong University, Jinan 250012, China.
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Atreya R, Neurath MF. Biomarkers for Personalizing IBD Therapy: The Quest Continues. Clin Gastroenterol Hepatol 2024; 22:1353-1364. [PMID: 38320679 DOI: 10.1016/j.cgh.2024.01.026] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 01/13/2024] [Accepted: 01/16/2024] [Indexed: 02/08/2024]
Abstract
Despite recent advances in the understanding of the pathogenesis of inflammatory bowel diseases (IBD) and advent of multiple targeted therapies, approximately one-third of patients are primary non-responders to initiated treatment, and half of patients lose response over time. There is currently a lack of available biomarkers that would prognosticate therapeutic effectiveness of these advanced therapies. This is partly explained by insufficient characterization of the functional roles assumed by the chosen molecular targets during disease treatment. There is a dire need for validated objective biomarkers, which could be indicators of a biological process, that can be applied in clinical practice to assist us in assigning therapies to patients with the highest probability of response. An appropriate molecular and cellular characterization that accounts for the interindividual differences in drug efficacy and potential side effects would help to guide clinicians in the management of patients with IBD and represent a major step to tailor a more personalized approach to treatment. An appropriate combination of complementing biomarkers should ideally incorporate a multimodal analysis in which genetic, microbial, transcriptional, proteomic, metabolic, and immunologic data are combined to enable a truly personalized approach. This would classify patients into disease subgroups according to molecular characteristics, which would enable us to initiate the most appropriate therapeutic substance. Emergence of single-cell technologies to map the intestinal cellular landscape and multiomic approaches have helped to further dissect the pathogenic mechanisms of mucosal inflammation, but the clinical translation of potential biomarkers remains cumbersome, and an ongoing concerted effort by the IBD community is required.
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Affiliation(s)
- Raja Atreya
- First Department of Medicine, Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany.
| | - Markus F Neurath
- First Department of Medicine, Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
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Palmieri O, Bossa F, Castellana S, Latiano T, Carparelli S, Martino G, Mangoni M, Corritore G, Nardella M, Guerra M, Biscaglia G, Perri F, Mazza T, Latiano A. Deciphering Microbial Composition in Patients with Inflammatory Bowel Disease: Implications for Therapeutic Response to Biologic Agents. Microorganisms 2024; 12:1260. [PMID: 39065032 PMCID: PMC11278628 DOI: 10.3390/microorganisms12071260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 06/19/2024] [Indexed: 07/28/2024] Open
Abstract
Growing evidence suggests that alterations in the gut microbiome impact the development of inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC). Although IBD often requires the use of immunosuppressant drugs and biologic therapies to facilitate clinical remission and mucosal healing, some patients do not benefit from these drugs, and the reasons for this remain poorly understood. Despite advancements, there is still a need to develop biomarkers to help predict prognosis and guide treatment decisions. The aim of this study was to investigate the gut microbiome of IBD patients using biologics to identify microbial signatures associated with responses, following standard accepted criteria. Microbiomes in 66 stool samples from 39 IBD patients, comprising 20 CD and 19 UC patients starting biologic therapies, and 29 samples from healthy controls (HCs) were prospectively analyzed via NGS and an ensemble of metagenomics analysis tools. At baseline, differences were observed in alpha and beta metrics among patients with CD, UC and HC, as well as between the CD and UC groups. The degree of dysbiosis was more pronounced in CD patients, and those with dysbiosis exhibited a limited response to biological drugs. Pairwise differential abundance analyses revealed an increasing trend in the abundance of an unannotated genus from the Clostridiales order, Gemmiger genus and an unannotated genus from the Rikenellaceae family, which were consistently identified in greater abundance in HC. The Clostridium genus was more abundant in CD patients. At baseline, a greater abundance of the Odoribacter and Ruminococcus genera was found in IBD patients who responded to biologics at 14 weeks, whereas a genus identified as SMB53 was more enriched at 52 weeks. The Collinsella genus showed a higher prevalence among non-responder IBD patients. Additionally, a greater abundance of an unclassified genus from the Barnesiellaceae family and one from Lachnospiraceae was observed in IBD patients responding to Vedolizumab at 14 weeks. Our analyses showed global microbial diversity, mainly in CD. This indicated the absence or depletion of key taxa responsible for producing short-chain fatty acids (SCFAs). We also identified an abundance of pathobiont microbes in IBD patients at baseline, particularly in non-responders to biologic therapies. Furthermore, specific bacteria-producing SCFAs were abundant in patients responding to biologics and in those responding to Vedolizumab.
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Affiliation(s)
- Orazio Palmieri
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS “Casa Sollievo della Sofferenza”, 71013 San Giovanni Rotondo, Italy; (F.B.); (T.L.); (S.C.); (G.M.); (G.C.); (M.G.); (G.B.); (F.P.); (A.L.)
| | - Fabrizio Bossa
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS “Casa Sollievo della Sofferenza”, 71013 San Giovanni Rotondo, Italy; (F.B.); (T.L.); (S.C.); (G.M.); (G.C.); (M.G.); (G.B.); (F.P.); (A.L.)
| | - Stefano Castellana
- Unit of Bioinformatics, Fondazione IRCCS “Casa Sollievo della Sofferenza”, 71013 San Giovanni Rotondo, Italy (M.M.); (T.M.)
| | - Tiziana Latiano
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS “Casa Sollievo della Sofferenza”, 71013 San Giovanni Rotondo, Italy; (F.B.); (T.L.); (S.C.); (G.M.); (G.C.); (M.G.); (G.B.); (F.P.); (A.L.)
| | - Sonia Carparelli
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS “Casa Sollievo della Sofferenza”, 71013 San Giovanni Rotondo, Italy; (F.B.); (T.L.); (S.C.); (G.M.); (G.C.); (M.G.); (G.B.); (F.P.); (A.L.)
| | - Giuseppina Martino
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS “Casa Sollievo della Sofferenza”, 71013 San Giovanni Rotondo, Italy; (F.B.); (T.L.); (S.C.); (G.M.); (G.C.); (M.G.); (G.B.); (F.P.); (A.L.)
| | - Manuel Mangoni
- Unit of Bioinformatics, Fondazione IRCCS “Casa Sollievo della Sofferenza”, 71013 San Giovanni Rotondo, Italy (M.M.); (T.M.)
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - Giuseppe Corritore
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS “Casa Sollievo della Sofferenza”, 71013 San Giovanni Rotondo, Italy; (F.B.); (T.L.); (S.C.); (G.M.); (G.C.); (M.G.); (G.B.); (F.P.); (A.L.)
| | - Marianna Nardella
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS “Casa Sollievo della Sofferenza”, 71013 San Giovanni Rotondo, Italy; (F.B.); (T.L.); (S.C.); (G.M.); (G.C.); (M.G.); (G.B.); (F.P.); (A.L.)
| | - Maria Guerra
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS “Casa Sollievo della Sofferenza”, 71013 San Giovanni Rotondo, Italy; (F.B.); (T.L.); (S.C.); (G.M.); (G.C.); (M.G.); (G.B.); (F.P.); (A.L.)
| | - Giuseppe Biscaglia
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS “Casa Sollievo della Sofferenza”, 71013 San Giovanni Rotondo, Italy; (F.B.); (T.L.); (S.C.); (G.M.); (G.C.); (M.G.); (G.B.); (F.P.); (A.L.)
| | - Francesco Perri
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS “Casa Sollievo della Sofferenza”, 71013 San Giovanni Rotondo, Italy; (F.B.); (T.L.); (S.C.); (G.M.); (G.C.); (M.G.); (G.B.); (F.P.); (A.L.)
| | - Tommaso Mazza
- Unit of Bioinformatics, Fondazione IRCCS “Casa Sollievo della Sofferenza”, 71013 San Giovanni Rotondo, Italy (M.M.); (T.M.)
| | - Anna Latiano
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS “Casa Sollievo della Sofferenza”, 71013 San Giovanni Rotondo, Italy; (F.B.); (T.L.); (S.C.); (G.M.); (G.C.); (M.G.); (G.B.); (F.P.); (A.L.)
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9
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Syed S, Boland BS, Bourke LT, Chen LA, Churchill L, Dobes A, Greene A, Heller C, Jayson C, Kostiuk B, Moss A, Najdawi F, Plung L, Rioux JD, Rosen MJ, Torres J, Zulqarnain F, Satsangi J. Challenges in IBD Research 2024: Precision Medicine. Inflamm Bowel Dis 2024; 30:S39-S54. [PMID: 38778628 DOI: 10.1093/ibd/izae084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Indexed: 05/25/2024]
Abstract
Precision medicine is part of 5 focus areas of the Challenges in IBD Research 2024 research document, which also includes preclinical human IBD mechanisms, environmental triggers, novel technologies, and pragmatic clinical research. Building on Challenges in IBD Research 2019, the current Challenges aims to provide a comprehensive overview of current gaps in inflammatory bowel diseases (IBDs) research and deliver actionable approaches to address them with a focus on how these gaps can lead to advancements in interception, remission, and restoration for these diseases. The document is the result of multidisciplinary input from scientists, clinicians, patients, and funders, and represents a valuable resource for patient-centric research prioritization. In particular, the precision medicine section is focused on the main research gaps in elucidating how to bring the best care to the individual patient in IBD. Research gaps were identified in biomarker discovery and validation for predicting disease progression and choosing the most appropriate treatment for each patient. Other gaps were identified in making the best use of existing patient biosamples and clinical data, developing new technologies to analyze large datasets, and overcoming regulatory and payer hurdles to enable clinical use of biomarkers. To address these gaps, the Workgroup suggests focusing on thoroughly validating existing candidate biomarkers, using best-in-class data generation and analysis tools, and establishing cross-disciplinary teams to tackle regulatory hurdles as early as possible. Altogether, the precision medicine group recognizes the importance of bringing basic scientific biomarker discovery and translating it into the clinic to help improve the lives of IBD patients.
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Affiliation(s)
- Sana Syed
- Department of Pediatrics, University of Virginia, Charlottesville, VA, USA
- Patient representative for Crohn's & Colitis Foundation, New York, NY, USA
| | - Brigid S Boland
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Lauren T Bourke
- Precision Medicine Drug Development, Early Respiratory and Immunology, AstraZeneca, Boston, MA, USA
| | - Lea Ann Chen
- Division of Gastroenterology, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Laurie Churchill
- Leona M. and Harry B. Helmsley Charitable Trust, New York, NY, USA
| | | | - Adam Greene
- Department of Pediatrics, University of Virginia, Charlottesville, VA, USA
| | | | | | | | - Alan Moss
- Crohn's & Colitis Foundation, New York, NY, USA
| | | | - Lori Plung
- Patient representative for Crohn's & Colitis Foundation, New York, NY, USA
| | - John D Rioux
- Research Center, Montreal Heart Institute, Université de Montréal, Montréal, Québec, Canada
| | - Michael J Rosen
- Division of Pediatric Gastroenterology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
| | - Joana Torres
- Division of Gastroenterology, Hospital Beatriz Ângelo, Hospital da Luz, Lisbon, Portugal
- Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Fatima Zulqarnain
- Department of Pediatrics, University of Virginia, Charlottesville, VA, USA
| | - Jack Satsangi
- Translational Gastroenterology Unit, Experimental Medicine Division, Nuffield Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
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10
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Krauthammer A, Cozacov T, Fried S, Har-Zahav A, Shamir R, Assa A, Waisbourd-Zinman O. Tissue markers may predict treatment response to antitumor necrosis factor-α agents in children with Crohn's disease. J Pediatr Gastroenterol Nutr 2024; 78:662-669. [PMID: 38299301 DOI: 10.1002/jpn3.12146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 01/15/2024] [Accepted: 01/20/2024] [Indexed: 02/02/2024]
Abstract
OBJECTIVES Patients with moderate-severe Crohn's disease (CD) who are treated with antitumor necrosis factor alpha (TNF-α) agents may be subjected to primary nonresponse or partial response. We aimed to identify tissue markers that may predict response to these agents. METHODS Pediatric patients (6-18 years) with either ileal or ileo-colonic CD who were treated with anti-TNF-α were stratified into three different groups based on their overall response to therapy at the end of induction including clinical and laboratory parameters (group 1-full responders [FR], group 2-partial responders [PR], group 3-nonresponders [NR]). Seven tissue markers (fibronectin, interleukin [IL]-23R, IL-23, TNF-α, collagen-III, IL-13R, and hypoxia-inducible factors [HIF]-1α) were evaluated. Immunofluorescence (IF) analyses were performed on biopsies from the terminal ileum, which were retrieved up to 6 months before treatment initiation. RESULTS Twenty-six CD patients (16 [61.5%] males; age 13.9 ± 2.9 years), including 8 (30.8%) with ileal disease and 18 (69.2%) with ileo-colonic disease, were enrolled. Terminal ileum biopsies from nine patients from group 1, nine from group 2, and eight from group 3 were evaluated. Three antibodies were found to be significantly different between NR and FR groups; Collagen III and fibronectin stains were significantly more prominent in NR patients, while TNF-α stain was significantly more pronounced in FR, p < 0.05 for each. PR could not have been predicted with neither of markers. CONCLUSIONS Decreased tissue IF intensity of fibronectin and collagen III and increased intensity of TNF-α may predict response to anti-TNF-α treatment.
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Affiliation(s)
- Alexander Krauthammer
- Schneider Children's Medical Center of Israel, Institute of Gastroenterology, Nutrition and Liver Diseases, Petah Tikva, Israel
- Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Tal Cozacov
- Schneider Children's Medical Center of Israel, Institute of Gastroenterology, Nutrition and Liver Diseases, Petah Tikva, Israel
- Felsenstein Medical Research Center, Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Sophia Fried
- Schneider Children's Medical Center of Israel, Institute of Gastroenterology, Nutrition and Liver Diseases, Petah Tikva, Israel
- Felsenstein Medical Research Center, Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Adi Har-Zahav
- Schneider Children's Medical Center of Israel, Institute of Gastroenterology, Nutrition and Liver Diseases, Petah Tikva, Israel
- Felsenstein Medical Research Center, Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Raanan Shamir
- Schneider Children's Medical Center of Israel, Institute of Gastroenterology, Nutrition and Liver Diseases, Petah Tikva, Israel
- Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Amit Assa
- The Juliet Keidan Institute of Pediatric Gastroenterology and Nutrition, Shaare Zedek Medical Center, The Hebrew University, Jerusalem, Israel
| | - Orith Waisbourd-Zinman
- Schneider Children's Medical Center of Israel, Institute of Gastroenterology, Nutrition and Liver Diseases, Petah Tikva, Israel
- Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
- Felsenstein Medical Research Center, Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
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11
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Puca P, Capobianco I, Coppola G, Di Vincenzo F, Trapani V, Petito V, Laterza L, Pugliese D, Lopetuso LR, Scaldaferri F. Cellular and Molecular Determinants of Biologic Drugs Resistance and Therapeutic Failure in Inflammatory Bowel Disease. Int J Mol Sci 2024; 25:2789. [PMID: 38474034 DOI: 10.3390/ijms25052789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 02/22/2024] [Accepted: 02/26/2024] [Indexed: 03/14/2024] Open
Abstract
The advent of biologic drugs has revolutionized the treatment of Inflammatory Bowel Disease, increasing rates of response and mucosal healing in comparison to conventional therapies by allowing the treatment of corticosteroid-refractory cases and reducing corticosteroid-related side effects. However, biologic therapies (anti-TNFα inhibitors, anti-α4β7 integrin and anti-IL12/23) are still burdened by rates of response that hover around 40% (in biologic-naïve patients) or lower (for biologic-experienced patients). Moreover, knowledge of the mechanisms underlying drug resistance or loss of response is still scarce. Several cellular and molecular determinants are implied in therapeutic failure; genetic predispositions, in the form of single nucleotide polymorphisms in the sequence of cytokines or Human Leukocyte Antigen, or an altered expression of cytokines and other molecules involved in the inflammation cascade, play the most important role. Accessory mechanisms include gut microbiota dysregulation. In this narrative review of the current and most recent literature, we shed light on the mentioned determinants of therapeutic failure in order to pave the way for a more personalized approach that could help avoid unnecessary treatments and toxicities.
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Affiliation(s)
- Pierluigi Puca
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Ivan Capobianco
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Gaetano Coppola
- IBD Unit, UOC CEMAD Centro Malattie dell'Apparato Digerente, Dipartimento di Scienze Mediche e Chirurgiche Addominali ed Endocrino Metaboliche, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Federica Di Vincenzo
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Valentina Trapani
- Alleanza Contro il Cancro, Istituto Superiore di Sanità, 00144 Rome, Italy
| | - Valentina Petito
- IBD Unit, UOC CEMAD Centro Malattie dell'Apparato Digerente, Dipartimento di Scienze Mediche e Chirurgiche Addominali ed Endocrino Metaboliche, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Lucrezia Laterza
- IBD Unit, UOC CEMAD Centro Malattie dell'Apparato Digerente, Dipartimento di Scienze Mediche e Chirurgiche Addominali ed Endocrino Metaboliche, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Daniela Pugliese
- IBD Unit, UOC CEMAD Centro Malattie dell'Apparato Digerente, Dipartimento di Scienze Mediche e Chirurgiche Addominali ed Endocrino Metaboliche, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Loris Riccardo Lopetuso
- IBD Unit, UOC CEMAD Centro Malattie dell'Apparato Digerente, Dipartimento di Scienze Mediche e Chirurgiche Addominali ed Endocrino Metaboliche, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Department of Medicine and Ageing Sciences, "G. d'Annunzio" University of Chieti-Pescara, 66100 Chieti, Italy
- Center for Advanced Studies and Technology (CAST), "G. d'Annunzio" University of Chieti-Pescara, 66100 Chieti, Italy
| | - Franco Scaldaferri
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
- IBD Unit, UOC CEMAD Centro Malattie dell'Apparato Digerente, Dipartimento di Scienze Mediche e Chirurgiche Addominali ed Endocrino Metaboliche, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
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12
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Jiang L, Liu X, Su Y, Chen Y, Yang S, Ke X, Yao K, Guo Z. A metabolomics-driven model for early remission prediction following vedolizumab treatment in patients with moderate-to-severe active ulcerative colitis. Int Immunopharmacol 2024; 128:111527. [PMID: 38215655 DOI: 10.1016/j.intimp.2024.111527] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 01/06/2024] [Accepted: 01/07/2024] [Indexed: 01/14/2024]
Abstract
To predict early remission following anti-integrin therapy (vedolizumab [VDZ]) in patients with moderate-to-severe active ulcerative colitis (UC) using non-invasive biomarkers. The clinical data of a cohort of 33 patients with moderate-to-severe active UC admitted to the Department of Gastroenterology at Suzhou Municipal Hospital between January 2021 and December 2022 were collected. Of these, 9 patients declined VDZ treatment, and 21 received VDZ at doses of 300 mg weeks 0, 2, and 6, each administered within a 30-minute infusion period. The treatment regimen aimed to induce remission of clinical symptoms; hence, the same dose was administered every 8 weeks. At weeks 0 and 14, serum C-reactive protein (CRP) and erythrocyte sedimentation rate were measured using a modified Mayo score. In addition to clinical assessment, stool samples at baseline and weeks 14 were collected and evaluated using 16SrRNA gene sequencing and gas chromatography-mass spectrometry (GC-MS). Clinical remission was determined based on the clinical symptoms and partial Mayo scores. In patients who received VDZ, the strains of bifidobacterium longum (P = 0.022) and bacteroides sartorii (P = 0.039) significantly increased after treatment than before treatment. GC-MS analysis showed that taurine (P = 0.047) and putrescine (P = 0.035) significantly decreased after treatment. Furthermore, while acetamide exhibited a notable increase (P = 0.001), arachidic acid (P < 0.001) and behenic acid (P = 0.005) demonstrated statistically significant elevations. The combined prediction model of acetamide, taurine, and putrescine demonstrated a high predictive value of early remission in patients with moderate-to-severe active UC following VDZ treatment (area under the curve = 0.911, P = 0.014).
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Affiliation(s)
- Leilei Jiang
- Department of Gastroenterology, Suzhou Hospital of Anhui Medical University (Suzhou Municipal Hospital of Anhui Province), No. 616 Bianyangsan Road, Suzhou 234000, Anhui, China
| | - Xiaoming Liu
- Department of Gastroenterology, Huaihe Hospital of Henan University, 115 Ximen Street, Kaifeng 475000, Henan, China
| | - Yue Su
- Department of Gastroenterology, Suzhou Hospital of Anhui Medical University (Suzhou Municipal Hospital of Anhui Province), No. 616 Bianyangsan Road, Suzhou 234000, Anhui, China
| | - Yujie Chen
- Department of Gastroenterology, Suzhou Hospital of Anhui Medical University (Suzhou Municipal Hospital of Anhui Province), No. 616 Bianyangsan Road, Suzhou 234000, Anhui, China
| | - Shaozhi Yang
- Department of Gastroenterology, Suzhou Hospital of Anhui Medical University (Suzhou Municipal Hospital of Anhui Province), No. 616 Bianyangsan Road, Suzhou 234000, Anhui, China
| | - Xiquan Ke
- Department of Gastroenterology, The First Affiliated Hospital of Bengbu Medical College, No. 287 Changhuai Road, Bengbu, Anhui 233004, China.
| | - Kunhou Yao
- Department of General Surgery, Huaihe Hospital of Henan University, 115 Ximen Street, Kaifeng 475000, Henan, China.
| | - Zhiguo Guo
- Department of Gastroenterology, Suzhou Hospital of Anhui Medical University (Suzhou Municipal Hospital of Anhui Province), No. 616 Bianyangsan Road, Suzhou 234000, Anhui, China.
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13
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Derakhshan Nazari MH, Shahrokh S, Ghanbari-Maman L, Maleknia S, Ghorbaninejad M, Meyfour A. Prediction of anti-TNF therapy failure in ulcerative colitis patients by ensemble machine learning: A prospective study. Heliyon 2023; 9:e21154. [PMID: 37928018 PMCID: PMC10623293 DOI: 10.1016/j.heliyon.2023.e21154] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 09/05/2023] [Accepted: 10/17/2023] [Indexed: 11/07/2023] Open
Abstract
Nowadays, anti-TNF therapy remarkably improves the medical management of ulcerative colitis (UC), but approximately 40 % of patients do not respond to this treatment. In this study, we used 79 anti-TNF-naive patients with moderate-to-severe UC from four cohorts to discover alternative therapeutic targets and develop a personalized medicine approach that can diagnose UC non-responders (UCN) prior to receiving anti-TNF therapy. To this end, two microarray data series were integrated to create a discovery cohort with 35 UC samples. A comprehensive gene expression and functional analysis was performed and identified 313 significantly altered genes, among which IL6 and INHBA were highlighted as overexpressed genes in the baseline mucosal biopsies of UCN, whose cooperation may lead to a decrease in the Tregs population. Besides, screening the abundances of immune cell subpopulations showed neutrophils' accumulation increasing the inflammation. Furthermore, the correlation of KRAS signaling activation with unresponsiveness to anti-TNF mAb was observed using network analysis. Using 50x repeated 10-fold cross-validation LASSO feature selection and a stack ensemble machine learning algorithm, a five-mRNA prognostic panel including IL13RA2, HCAR3, CSF3, INHBA, and MMP1 was introduced that could predict the response of UC patients to anti-TNF antibodies with an average accuracy of 95.3 %. The predictive capacity of the introduced biomarker panel was also validated in two independent cohorts (44 UC patients). Moreover, we presented a distinct immune cell landscape and gene signature for UCN to anti-TNF drugs and further studies should be considered to make this predictive biomarker panel and therapeutic targets applicable in the clinical setting.
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Affiliation(s)
- Mohammad Hossein Derakhshan Nazari
- Basic and Molecular Epidemiology of Gastrointestinal Disorders, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shabnam Shahrokh
- Research Center for Gastroenterology and Liver Diseases, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Leila Ghanbari-Maman
- Basic and Molecular Epidemiology of Gastrointestinal Disorders, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Computer Science, Faculty of Mathematical Sciences, University of Kashan, Kashan, Iran
| | - Samaneh Maleknia
- Basic and Molecular Epidemiology of Gastrointestinal Disorders, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahsa Ghorbaninejad
- Basic and Molecular Epidemiology of Gastrointestinal Disorders, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Anna Meyfour
- Basic and Molecular Epidemiology of Gastrointestinal Disorders, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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14
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Liu J, Fang H, Hong N, Lv C, Zhu Q, Feng Y, Wang B, Tian J, Yu Y. Gut Microbiome and Metabonomic Profile Predict Early Remission to Anti-Integrin Therapy in Patients with Moderate to Severe Ulcerative Colitis. Microbiol Spectr 2023; 11:e0145723. [PMID: 37199618 PMCID: PMC10269848 DOI: 10.1128/spectrum.01457-23] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 05/09/2023] [Indexed: 05/19/2023] Open
Abstract
Patients with ulcerative colitis (UC) have low response rates to anti-integrin medications, necessitating the identification of noninvasive biomarkers for predicting remission to anti-integrin therapy. In this study, patients with moderate to severe UC commencing anti-integrin therapy (n = 29), inactive to mild UC patients (n = 13), and healthy controls (n = 11) were selected. Besides clinical evaluation, fecal samples were collected at baseline and week 14 from moderate to severe UC patients. The clinical remission was defined based on the Mayo score. Fecal samples were assessed with 16S rRNA gene sequencing, liquid chromatography-tandem mass spectrometry, and gas chromatography-mass spectrometry (GC-MS). We identified that Verrucomicrobiota was significantly more abundant in the remission group (P < 0.001) than that of nonremission group at phylum level for patients commencing vedolizumab. GC-MS analysis revealed that the concentrations of butyric acid (P = 0.024) and isobutyric acid (P = 0.042) were significantly higher in the remission group compared to the nonremission group at baseline. Finally, the combination of Verrucomicrobiota, butyric acid, and isobutyric acid improved the diagnosis of early remission to anti-integrin therapy (area under the concentration-time curve = 0.961). We identified significantly higher phylum level diversity of Verrucomicrobiota in remission than the nonremission groups at baseline. Notably, the combination of gut microbiome and metabonomic profiles improved the diagnosis of early remission to anti-integrin therapy. IMPORTANCE It is reported that patients with ulcerative colitis (UC) have low response rates to anti-integrin medications in the latest VARSITY study. Therefore, our primary goals were to discover differences in the gut microbiome and metabonomics patterns between early remission and nonremission patients and to explore the diagnostic value in predicting clinical remission to anti-integrin therapy accurately. In this study, we found that Verrucomicrobiota was significantly more abundant in the remission group (P < 0.001) than that of nonremission group at phylum level for patients commencing vedolizumab. Gas chromatography-mass spectrometry analysis revealed that the concentrations of butyric acid (P = 0.024) and isobutyric acid (P = 0.042) were significantly higher in the remission group compared with the nonremission group at baseline. Notably, the combination of Verrucomicrobiota, butyric acid, and isobutyric acid improved the diagnosis of early remission to anti-integrin therapy (area under the concentration-time curve = 0.961).
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Affiliation(s)
- Jie Liu
- Department of Gastroenterology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, People’s Republic of China
| | - Huaying Fang
- Department of Gastroenterology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, People’s Republic of China
- Endoscopy Center Department, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, People’s Republic of China
| | - Na Hong
- Department of Gastroenterology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, People’s Republic of China
- Endoscopy Center Department, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, People’s Republic of China
| | - Chaolan Lv
- Department of Gastroenterology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, People’s Republic of China
- Endoscopy Center Department, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, People’s Republic of China
| | - Qihua Zhu
- Department of Gastroenterology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, People’s Republic of China
- Department of Nursing, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, People’s Republic of China
| | - Yinping Feng
- Department of Gastroenterology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, People’s Republic of China
- Department of Nursing, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, People’s Republic of China
| | - Bo Wang
- Department of Gastroenterology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, People’s Republic of China
| | - Jiashuang Tian
- Department of Gastroenterology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, People’s Republic of China
| | - Yue Yu
- Department of Gastroenterology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, People’s Republic of China
- Endoscopy Center Department, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, People’s Republic of China
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15
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Kriger-Sharabi OA, Kopylov U. Harnessing the Power of Precision Medicine and Novel Biomarkers to Treat Crohn’s Disease. J Clin Med 2023; 12:jcm12072696. [PMID: 37048779 PMCID: PMC10094767 DOI: 10.3390/jcm12072696] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 03/11/2023] [Accepted: 03/21/2023] [Indexed: 04/08/2023] Open
Abstract
Crohn’s disease (CD) is a chronic inflammatory condition that affects the gastrointestinal tract. It is part of a spectrum of inflammatory Bowel Diseases (IBD). The disease is complex, characterized by significant inter and intra-individual heterogeneity, which contributes to a diverse and multifaceted portrayal of the disease. Consequently, applying specific and accurate treatment is challenging, and therapeutic success rates remain disappointing and insufficient. In recent years, significant advances in the therapeutic potential of CD have been made. Hope has been provided by these developments in the form of an expanding treatment toolkit. However, even with these beneficial adjustments, patients are frequently treated using an ineffective “one size fits all” treatment protocol, ultimately leading to a plateau in drug effectiveness and a decline in overall treatment success rates. Furthermore, with the advancement in the genome-wide association study, in combination with significant bioinformatic developments, the world of medicine has moved in the direction of personalized, tailored-treatment medicine, and this trend has not escaped the world of IBDs. Prediction models, novel biomarkers, and complex algorithms are emerging and inspiring optimism that CD patients will be treated with “precision medicine” in the near future, meaning that their treatments will be selected based on the patient’s various unique features. In this review, we will outline the current diagnostic and therapeutic limitations that lead to a glass ceiling effect and thus send us in pursuit of discovering novel biomarkers. We will illustrate the challenges and difficulties in discovering relevant and innovative biomarkers and implementing them into everyday clinical practice. We will also heighten the progress made in practicing personalized medicine for CD patients and shed light on future directions and horizons.
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Affiliation(s)
- Ofra Aviva Kriger-Sharabi
- Department of Gatsroenterology, Assuta Ashdod Medical Center, Affiliated to The Ben-Gurion University (BGU) Medical School, Ashdod 7747629, Israel
| | - Uri Kopylov
- Department of Gastroenterology, Sheba Medical Center, Tel Hashomer, Affliated to Sackler School of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
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Clarkston K, Karns R, Jegga AG, Sharma M, Fox S, Ojo BA, Minar P, Walters TD, Griffiths AM, Mack DR, Boyle B, LeLeiko NS, Markowitz J, Rosh JR, Patel AS, Shah S, Baldassano RN, Pfefferkorn M, Sauer C, Kugathasan S, Haberman Y, Hyams JS, Denson LA, Rosen MJ. Targeted Assessment of Mucosal Immune Gene Expression Predicts Clinical Outcomes in Children with Ulcerative Colitis. J Crohns Colitis 2022; 16:1735-1750. [PMID: 35665804 PMCID: PMC9683081 DOI: 10.1093/ecco-jcc/jjac075] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS We aimed to determine whether a targeted gene expression panel could predict clinical outcomes in paediatric ulcerative colitis [UC] and investigated putative pathogenic roles of predictive genes. METHODS In total, 313 rectal RNA samples from a cohort of newly diagnosed paediatric UC patients (PROTECT) were analysed by a real-time PCR microfluidic array for expression of type 1, 2 and 17 inflammation genes. Associations between expression and clinical outcomes were assessed by logistic regression. Identified prognostic markers were further analysed using existing RNA sequencing (RNA-seq) data sets and tissue immunostaining. RESULTS IL13RA2 was associated with a lower likelihood of corticosteroid-free remission (CSFR) on mesalamine at week 52 (p = .002). A model including IL13RA2 and only baseline clinical parameters was as accurate as an established clinical model, which requires week 4 remission status. RORC was associated with a lower likelihood of colectomy by week 52. A model including RORC and PUCAI predicted colectomy by 52 weeks (area under the receiver operating characteristic curve 0.71). Bulk RNA-seq identified IL13RA2 and RORC as hub genes within UC outcome-associated expression networks related to extracellular matrix and innate immune response, and lipid metabolism and microvillus assembly, respectively. Adult UC single-cell RNA-seq data revealed IL13RA2 and RORC co-expressed genes were localized to inflammatory fibroblasts and undifferentiated epithelial cells, respectively, which was supported by protein immunostaining. CONCLUSION Targeted assessment of rectal mucosal immune gene expression predicts 52-week CSFR in treatment-naïve paediatric UC patients. Further exploration of IL-13Rɑ2 as a therapeutic target in UC and future studies of the epithelial-specific role of RORC in UC pathogenesis are warranted.
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Affiliation(s)
- Kathryn Clarkston
- Division of Gastroenterology, Hepatology and Nutrition
- Division of Pediatric Gastroenterology, Children’s Mercy Hospital, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA
| | - Rebekah Karns
- Division of Gastroenterology, Hepatology and Nutrition
| | - Anil G Jegga
- Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Mihika Sharma
- Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
| | - Sejal Fox
- Division of Gastroenterology, Hepatology and Nutrition
| | - Babajide A Ojo
- Division of Pediatric Gastroenterology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
| | - Phillip Minar
- Division of Gastroenterology, Hepatology and Nutrition
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Thomas D Walters
- Division of Pediatric Gastroenterology, Hospital for Sick Children, Toronto, ON, Canada
| | - Anne M Griffiths
- Division of Pediatric Gastroenterology, Hospital for Sick Children, Toronto, ON, Canada
| | - David R Mack
- Division of Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Eastern Ontario and University of Ottawa, Ottawa, ON, Canada
| | - Brendan Boyle
- Division of Gastroenterology, Hepatology, and Nutrition, Nationwide Children’s Hospital, Columbus, OH, USA
| | - Neal S LeLeiko
- Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons and NewYork-Presbyterian Morgan Stanley Children’s Hospital, New York, NY, USA
| | - James Markowitz
- Division of Gastroenterology, Hepatology, and Nutrition, Cohen Children’s Medical Center of New York, New Hyde Park, NY, USA
| | - Joel R Rosh
- Division of Gastroenterology, Hepatology, and Nutrition, Goryeb Children’s Hospital, Atlantic Health, Morristown, NJ, USA
| | - Ashish S Patel
- Division of Gastroenterology, Phoenix Children’s Hospital, Phoenix, AZ, USA
| | - Sapana Shah
- Division of Gastroenterology, Hepatology and Nutrition, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Robert N Baldassano
- Division of Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
| | - Marian Pfefferkorn
- Division of Gastroenterology, Hepatology, and Nutrition, Riley Children’s Hospital, Indianapolis, IN, USA
| | - Cary Sauer
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Emory University and Children’s Healthcare of Atlanta, Atlanta, GA, USA
| | - Subra Kugathasan
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Emory University and Children’s Healthcare of Atlanta, Atlanta, GA, USA
| | - Yael Haberman
- Division of Gastroenterology, Hepatology and Nutrition
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Sheba Medical Center, Tel Hashomer, Israel
| | - Jeffrey S Hyams
- Division of Digestive Diseases, Hepatology, and Nutrition, Connecticut Children’s Medical Center, Hartford, CT, USA
| | - Lee A Denson
- Division of Gastroenterology, Hepatology and Nutrition
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Michael J Rosen
- Division of Pediatric Gastroenterology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
- Division of Gastroenterology, Hepatology and Nutrition
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
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17
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Longitudinal multi-omics analysis identifies early blood-based predictors of anti-TNF therapy response in inflammatory bowel disease. Genome Med 2022; 14:110. [PMID: 36153599 PMCID: PMC9509553 DOI: 10.1186/s13073-022-01112-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 09/02/2022] [Indexed: 11/10/2022] Open
Abstract
Background and aims Treatment with tumor necrosis factor α (TNFα) antagonists in IBD patients suffers from primary non-response rates of up to 40%. Biomarkers for early prediction of therapy success are missing. We investigated the dynamics of gene expression and DNA methylation in blood samples of IBD patients treated with the TNF antagonist infliximab and analyzed the predictive potential regarding therapy outcome. Methods We performed a longitudinal, blood-based multi-omics study in two prospective IBD patient cohorts receiving first-time infliximab therapy (discovery: 14 patients, replication: 23 patients). Samples were collected at up to 7 time points (from baseline to 14 weeks after therapy induction). RNA-sequencing and genome-wide DNA methylation data were analyzed and correlated with clinical remission at week 14 as a primary endpoint. Results We found no consistent ex ante predictive signature across the two cohorts. Longitudinally upregulated transcripts in the non-remitter group comprised TH2- and eosinophil-related genes including ALOX15, FCER1A, and OLIG2. Network construction identified transcript modules that were coherently expressed at baseline and in non-remitting patients but were disrupted at early time points in remitting patients. These modules reflected processes such as interferon signaling, erythropoiesis, and platelet aggregation. DNA methylation analysis identified remission-specific temporal changes, which partially overlapped with transcriptomic signals. Machine learning approaches identified features from differentially expressed genes cis-linked to DNA methylation changes at week 2 as a robust predictor of therapy outcome at week 14, which was validated in a publicly available dataset of 20 infliximab-treated CD patients. Conclusions Integrative multi-omics analysis reveals early shifts of gene expression and DNA methylation as predictors for efficient response to anti-TNF treatment. Lack of such signatures might be used to identify patients with IBD unlikely to benefit from TNF antagonists at an early time point. Supplementary Information The online version contains supplementary material available at 10.1186/s13073-022-01112-z.
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18
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Kinoshita N, Kakimoto K, Shimizu H, Nishida K, Numa K, Kawasaki Y, Tawa H, Nakazawa K, Koshiba R, Hirata Y, Sakiyama N, Koubayashi E, Takeuchi T, Miyazaki T, Higuchi K, Nakamura S, Nishikawa H. Serum IL-13 Predicts Response to Golimumab in Bio-Naïve Ulcerative Colitis. J Clin Med 2022; 11:jcm11174952. [PMID: 36078882 PMCID: PMC9456517 DOI: 10.3390/jcm11174952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/17/2022] [Accepted: 08/20/2022] [Indexed: 11/28/2022] Open
Abstract
A certain number of patients with ulcerative colitis (UC) are refractory to anti-TNF-α antibodies; biomarkers are thus needed to predict treatment efficacy. This study aimed to evaluate whether serum biomarkers that were reported to be associated with UC or anti-TNF-α antibody could predict the response to golimumab, a human anti-TNF-α monoclonal antibody, in bio-naïve patients with UC. We prospectively enrolled 23 consecutive patients with UC who were treated with golimumab. Serum samples were collected before the first golimumab dose. Eleven molecules were measured by electrochemiluminescence (ECL) or enzyme-linked immunosorbent assay (ELISA) and their association with efficacy after 10 weeks of golimumab treatment. Among the serum biomarkers, IL-13 levels were significantly higher in the non-remission group than in the remission group (p = 0.014). IL-15 levels were significantly lower in the non-response group than in the response group (p = 0.04). For clinical remission at week 10, the IL-13 0.20 concentration of pg/mL was associated with a sensitivity and specificity of 82.4% and 83.3%, respectively. Serum IL-13 may be a biomarker to predict golimumab efficacy in biologic-naïve patients with UC, and thus may help to tailor personalized treatment strategies.
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Affiliation(s)
| | - Kazuki Kakimoto
- Correspondence: ; Tel.: +81-726-83-1221; Fax: +81-726-84-6532
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19
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Wong ECL, Yusuf A, Pokryszka J, Dulai PS, Colombel JF, Marshall JK, Reinisch W, Narula N. Increased Expression of Interleukin-13 Receptor in Ileum Associated With Nonresponse to Adalimumab in Ileal Crohn's Disease. Inflamm Bowel Dis 2022:6650010. [PMID: 35880680 DOI: 10.1093/ibd/izac157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND The terminal ileum poses a predilection for Crohn's disease (CD) but is less susceptible to undergo healing to treatment with biologics and small molecules. This study aimed to evaluate histologic features associated with endoscopic remission (ER). METHODS This is a post hoc analysis of patients with moderately to severely active CD, defined as Crohn's disease activity index 220 to 450, and terminal ileal ulceration treated with antitumor necrosis factor (TNF)-α inhibitor adalimumab from the EXTEND trial. We studied whether baseline total Global Histologic Disease Activity Scores (GHAS), any individual histologic element, and specific immunohistochemical (IHC) markers of chronic inflammation from biopsy specimens were associated with postinduction (week 12) and maintenance (week 52) ER, defined as Simple Endoscopic Score for Crohn's Disease of 0. Multivariable logistic regression models adjusted for confounders were used to assess the relationship between histologic markers and 1-year outcomes. RESULTS Seventy-one adult patients with CD affecting the ileum were included in this analysis. Both baseline ileal GHAS scores and individual histologic components were not found to be associated with ER at weeks 12 or 52. Increased expression of interleukin-13 receptor (IL-13R) on IHC stains was associated with reduced likelihood of achieving 1-year ER (adjusted odds ratio, 0.06; 95% CI, 0.01-0.92; P = .044). No other biomarker assessed was associated with 1-year ER. CONCLUSIONS Ileal histologic disease activity and IHC activation markers of chronic mucosal inflammation were not associated with 1-year ER. However, strong staining for IL-13 receptor in the ileum was associated with reduced odds of 1-year ER using adalimumab. Mucosal cellular disease profiles might pose an opportunity to guide treatment of CD.
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Affiliation(s)
- Emily C L Wong
- Department of Medicine, Division of Gastroenterology, and Farncombe Family Digestive Health Research Institute; McMaster University, Hamilton ON, Canada
| | - Arif Yusuf
- Department of Medicine, Division of Gastroenterology, and Farncombe Family Digestive Health Research Institute; McMaster University, Hamilton ON, Canada
| | - Jagoda Pokryszka
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Währinger Gürtel 18-20, Vienna, Austria
| | - Parambir S Dulai
- Division of Gastroenterology, Northwestern University, Chicago, IL, USA
| | - Jean-Frederic Colombel
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - John K Marshall
- Department of Medicine, Division of Gastroenterology, and Farncombe Family Digestive Health Research Institute; McMaster University, Hamilton ON, Canada
| | - Walter Reinisch
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Währinger Gürtel 18-20, Vienna, Austria
| | - Neeraj Narula
- Department of Medicine, Division of Gastroenterology, and Farncombe Family Digestive Health Research Institute; McMaster University, Hamilton ON, Canada
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20
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Verstockt B, Parkes M, Lee JC. How Do We Predict a Patient's Disease Course and Whether They Will Respond to Specific Treatments? Gastroenterology 2022; 162:1383-1395. [PMID: 34995535 DOI: 10.1053/j.gastro.2021.12.245] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 12/09/2021] [Accepted: 12/09/2021] [Indexed: 02/07/2023]
Abstract
Gastroenterologists will be all too familiar with the difficult decisions that managing inflammatory bowel disease often presents. How aggressively should I treat this patient? Do I expect them to have a mild or aggressive form of disease? Do they need a biologic? If so, which one? And when should I start it? The reality is that the answers that would be right for one patient might be disastrous for another. The growing therapeutic armamentarium will only make these decisions more difficult, and yet, we have seen how other specialties have begun to use the molecular heterogeneity in their diseases to provide some answers. Here, we review the progress that has been made in predicting the future for any given patient with inflammatory bowel disease-whether that is the course of disease that they will experience or whether or not they will respond to, or indeed tolerate, a particular therapy.
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Affiliation(s)
- Bram Verstockt
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Katholieke Universiteit Leuven, Leuven, Belgium; Department of Chronic Diseases and Metabolism, Translational Research Center for Gastrointestinal Disorders-Inflammatory Bowel Disease (TARGID-IBD), Katholieke Universiteit Leuven, Leuven, Belgium
| | - Miles Parkes
- Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, United Kingdom
| | - James C Lee
- Genetic Mechanisms of Disease Laboratory, Francis Crick Institute, London, United Kingdom; Institute for Liver & Digestive Health, Royal Free London Hospital, University College London, London, United Kingdom.
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21
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Yau TO, Vadakekolathu J, Foulds GA, Du G, Dickins B, Polytarchou C, Rutella S. Hyperactive neutrophil chemotaxis contributes to anti-tumor necrosis factor-α treatment resistance in inflammatory bowel disease. J Gastroenterol Hepatol 2022; 37:531-541. [PMID: 34931384 PMCID: PMC9303672 DOI: 10.1111/jgh.15764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 08/16/2021] [Accepted: 12/07/2021] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM Anti-tumor necrosis factor-α (anti-TNF-α) agents have been used for inflammatory bowel disease; however, it has up to 30% nonresponse rate. Identifying molecular pathways and finding reliable diagnostic biomarkers for patient response to anti-TNF-α treatment are needed. METHODS Publicly available transcriptomic data from inflammatory bowel disease patients receiving anti-TNF-α therapy were systemically collected and integrated. In silico flow cytometry approaches and Metascape were applied to evaluate immune cell populations and to perform gene enrichment analysis, respectively. Genes identified within enrichment pathways validated in neutrophils were tracked in an anti-TNF-α-treated animal model (with lipopolysaccharide-induced inflammation). The receiver operating characteristic curve was applied to all genes to identify the best prediction biomarkers. RESULTS A total of 449 samples were retrieved from control, baseline, and after primary anti-TNF-α therapy or placebo. No statistically significant differences were observed between anti-TNF-α treatment responders and nonresponders at baseline in immune microenvironment scores. Neutrophil, endothelial cell, and B-cell populations were higher in baseline nonresponders, and chemotaxis pathways may contribute to the treatment resistance. Genes related to chemotaxis pathways were significantly upregulated in lipopolysaccharide-induced neutrophils, but no statistically significant changes were observed in neutrophils treated with anti-TNF-α. Interleukin 13 receptor subunit alpha 2 (IL13RA2) is the best predictor (receiver operating characteristic curve: 80.7%, 95% confidence interval: 73.8-87.5%), with a sensitivity of 68.13% and specificity of 84.93%, and significantly higher in nonresponders compared with responders (P < 0.0001). CONCLUSIONS Hyperactive neutrophil chemotaxis influences responses to anti-TNF-α treatment, and IL13RA2 is a potential biomarker to predict anti-TNF-α treatment response.
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Affiliation(s)
- Tung On Yau
- John van Geest Cancer Research Centre, School of Science and TechnologyNottingham Trent University, Clifton CampusNottinghamUnited Kingdom
- Centre for Health, Ageing and Understanding DiseaseNottingham Trent University, Clifton CampusNottinghamUnited Kingdom
| | - Jayakumar Vadakekolathu
- John van Geest Cancer Research Centre, School of Science and TechnologyNottingham Trent University, Clifton CampusNottinghamUnited Kingdom
- Centre for Health, Ageing and Understanding DiseaseNottingham Trent University, Clifton CampusNottinghamUnited Kingdom
| | - Gemma Ann Foulds
- John van Geest Cancer Research Centre, School of Science and TechnologyNottingham Trent University, Clifton CampusNottinghamUnited Kingdom
- Centre for Health, Ageing and Understanding DiseaseNottingham Trent University, Clifton CampusNottinghamUnited Kingdom
| | - Guodong Du
- Department of Artificial IntelligenceXiamen UniversityXiamenChina
| | - Benjamin Dickins
- John van Geest Cancer Research Centre, School of Science and TechnologyNottingham Trent University, Clifton CampusNottinghamUnited Kingdom
- Centre for Health, Ageing and Understanding DiseaseNottingham Trent University, Clifton CampusNottinghamUnited Kingdom
| | - Christos Polytarchou
- John van Geest Cancer Research Centre, School of Science and TechnologyNottingham Trent University, Clifton CampusNottinghamUnited Kingdom
- Centre for Health, Ageing and Understanding DiseaseNottingham Trent University, Clifton CampusNottinghamUnited Kingdom
| | - Sergio Rutella
- John van Geest Cancer Research Centre, School of Science and TechnologyNottingham Trent University, Clifton CampusNottinghamUnited Kingdom
- Centre for Health, Ageing and Understanding DiseaseNottingham Trent University, Clifton CampusNottinghamUnited Kingdom
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22
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Sudhakar P, Alsoud D, Wellens J, Verstockt S, Arnauts K, Verstockt B, Vermeire S. Tailoring Multi-omics to Inflammatory Bowel Diseases: All for One and One for All. J Crohns Colitis 2022; 16:1306-1320. [PMID: 35150242 PMCID: PMC9426669 DOI: 10.1093/ecco-jcc/jjac027] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 02/02/2022] [Accepted: 02/10/2022] [Indexed: 12/13/2022]
Abstract
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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Affiliation(s)
- Padhmanand Sudhakar
- Corresponding author: Padhmanand Sudhakar, Translational Research in Gastrointestinal Disorders [TARGID], ON I, Herestraat 49, box 701, 3000 Leuven, Belgium. Tel.: 0032 [0]16 19 49 40;
| | - Dahham Alsoud
- KU Leuven Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders [TARGID], Leuven, Belgium
| | - Judith Wellens
- KU Leuven Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders [TARGID], Leuven, Belgium
| | - Sare Verstockt
- KU Leuven Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders [TARGID], Leuven, Belgium
| | - Kaline Arnauts
- KU Leuven Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders [TARGID], Leuven, Belgium
| | - Bram Verstockt
- KU Leuven Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders [TARGID], Leuven, Belgium,Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Severine Vermeire
- KU Leuven Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders [TARGID], Leuven, Belgium,Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
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23
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Colorectal cancer in Crohn's disease evaluated with genes belonging to fibroblasts of the intestinal mucosa selected by NMF. Pathol Res Pract 2021; 229:153728. [PMID: 34953405 DOI: 10.1016/j.prp.2021.153728] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 11/26/2021] [Accepted: 11/27/2021] [Indexed: 12/16/2022]
Abstract
Crohn's disease (CD) is a type of chronic, inflammatory bowel disease (IBD) which affects any part of the gastrointestinal tract. This study aims to understand the mechanism which activate mucosal fibroblasts in the microenvironment of the colon in CD and colorectal carcinomas and to extract fibroblasts phenotypes via a novel framework based on non-negative factorization of matrix (NMF). The results identify a fibroblast phenotype characterized by intense pro-inflammatory activity ensured by the presence of genes belonging to the APOBEC1 family, such as APOBEC3F and APOBEC3G. These results demonstrated that there is a difference in fibroblast response in producing a pro-tumorigenic effect in CD. The different activation mechanisms could represent useful biomarkers in controlling CD development without generalizing its significance as IBD.
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24
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Jacobs I, Ceulemans M, Wauters L, Breynaert C, Vermeire S, Verstockt B, Vanuytsel T. Role of Eosinophils in Intestinal Inflammation and Fibrosis in Inflammatory Bowel Disease: An Overlooked Villain? Front Immunol 2021; 12:754413. [PMID: 34737752 PMCID: PMC8560962 DOI: 10.3389/fimmu.2021.754413] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 09/30/2021] [Indexed: 12/20/2022] Open
Abstract
Eosinophils are leukocytes which reside in the gastrointestinal tract under homeostatic conditions, except for the esophagus which is normally devoid of eosinophils. Research on eosinophils has primarily focused on anti-helminth responses and type 2 immune disorders. In contrast, the search for a role of eosinophils in chronic intestinal inflammation and fibrosis has been limited. With a shift in research focus from adaptive to innate immunity and the fact that the eosinophilic granules are filled with inflammatory mediators, eosinophils are becoming a point of interest in inflammatory bowel diseases. In the current review we summarize eosinophil characteristics and recruitment as well as the current knowledge on presence, inflammatory and pro-fibrotic functions of eosinophils in inflammatory bowel disease and other chronic inflammatory conditions, and we identify research gaps which should be covered in the future.
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Affiliation(s)
- Inge Jacobs
- Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Matthias Ceulemans
- Department of Chronic Diseases and Metabolism, Translational Research Center for Gastrointestinal Disorders (TARGID), Katholieke Universiteit Leuven, Leuven, Belgium
| | - Lucas Wauters
- Department of Chronic Diseases and Metabolism, Translational Research Center for Gastrointestinal Disorders (TARGID), Katholieke Universiteit Leuven, Leuven, Belgium
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - Christine Breynaert
- Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, Katholieke Universiteit Leuven, Leuven, Belgium
- Department of General Internal Medicine, Allergy and Clinical Immunology, University Hospitals Leuven, Leuven, Belgium
| | - Séverine Vermeire
- Department of Chronic Diseases and Metabolism, Translational Research Center for Gastrointestinal Disorders (TARGID), Katholieke Universiteit Leuven, Leuven, Belgium
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - Bram Verstockt
- Department of Chronic Diseases and Metabolism, Translational Research Center for Gastrointestinal Disorders (TARGID), Katholieke Universiteit Leuven, Leuven, Belgium
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - Tim Vanuytsel
- Department of Chronic Diseases and Metabolism, Translational Research Center for Gastrointestinal Disorders (TARGID), Katholieke Universiteit Leuven, Leuven, Belgium
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
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25
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Raine T, Verstockt B, Kopylov U, Karmiris K, Goldberg R, Atreya R, Burisch J, Burke J, Ellul P, Hedin C, Holubar SD, Katsanos K, Lobaton T, Schmidt C, Cullen G. ECCO Topical Review: Refractory Inflammatory Bowel Disease. J Crohns Colitis 2021; 15:1605-1620. [PMID: 34160593 DOI: 10.1093/ecco-jcc/jjab112] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Inflammatory bowel disease is a chronic disease with variable degrees of extent, severity, and activity. A proportion of patients will have disease that is refractory to licensed therapies, resulting in significant impairment in quality of life. The treatment of these patients involves a systematic approach by the entire multidisciplinary team, with particular consideration given to medical options including unlicensed therapies, surgical interventions, and dietetic and psychological support. The purpose of this review is to guide clinicians through this process and provide an accurate summary of the available evidence for different strategies.
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Affiliation(s)
- Tim Raine
- Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Bram Verstockt
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
- Department of Chronic Diseases and Metabolism, TARGID - IBD, KU Leuven, Leuven, Belgium
| | - Uri Kopylov
- Department of Gastroenterology, Sheba Medical Center, Ramat Gan, Israel
- Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | | | - Rimma Goldberg
- Department of Gastroenterology, Monash Health and School of Clinical Sciences, Monash University, Melbourne, VIC, Australia
| | - Raja Atreya
- Department of Medicine 1, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Johan Burisch
- Gastrounit, Medical Division, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark
| | - John Burke
- Colorectal and General Surgery, Beaumont Hospital, Dublin, Ireland
| | - Pierre Ellul
- Department of Medicine, Division of Gastroenterology, Mater Dei Hospital, Msida, Malta
| | - Charlotte Hedin
- Karolinska Institutet, Department of Medicine Solna, Stockholm, Sweden
- Karolinska University Hospital, Gastroenterology Unit, Department of Gastroenterology, Dermatovenereology and Rheumatology, Stockholm, Sweden
| | - Stefan D Holubar
- Department of Colon & Rectal Surgery, Cleveland Clinic, Cleveland, OH, USA
| | - Konstantinos Katsanos
- Department of Gastroenterology and Hepatology, University and Medical School of Ioannina, Ioannina, Greece
| | - Triana Lobaton
- Department of Gastroenterology, Ghent University Hospital, Ghent, Belgium
| | - Carsten Schmidt
- Medical Faculty of the Friedrich Schiller University, Jena, Germany
| | - Garret Cullen
- Centre for Colorectal Disease, St Vincent's University Hospital and School of Medicine, University College Dublin, Gastroenterology, Dublin, Ireland
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26
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Verstockt B, Noor NM, Marigorta UM, Pavlidis P, Deepak P, Ungaro RC. Results of the Seventh Scientific Workshop of ECCO: Precision Medicine in IBD-Disease Outcome and Response to Therapy. J Crohns Colitis 2021; 15:1431-1442. [PMID: 33730756 PMCID: PMC8681673 DOI: 10.1093/ecco-jcc/jjab050] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Inflammatory bowel diseases [IBD] are a heterogeneous spectrum with two extreme phenotypes, Crohn's disease [CD] and ulcerative colitis [UC], which both represent numerous phenotypical variations. Hence, we should no longer approach all IBD patients similarly, but rather aim to rethink clinical classifications and modify treatment algorithms to usher in a new era of precision medicine in IBD. This scientific ECCO workshop aims to provide a state-of-the-art overview on prognostic and predictive markers, shed light on key questions in biomarker development, propose best practices in IBD biomarker development [including trial design], and discuss the potential for multi-omic data integration to help drive further advances to make precision medicine a reality in IBD.
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Affiliation(s)
- Bram Verstockt
- University Hospitals Leuven Department of Gastroenterology and Hepatology, KU Leuven, Leuven, Belgium
- KU Leuven Department of Chronic Diseases and Metabolism, Translational Research Center for Gastrointestinal Disorders [TARGID], Leuven, Belgium
| | - Nurulamin M Noor
- Department of Gastroenterology, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Trust, Cambridge, UK
- Medical Research Council Clinical Trials Unit, University College London, London, UK
| | - Urko M Marigorta
- Integrative Genomics Lab, Center for Cooperative Research in Biosciences [CIC bioGUNE], Basque Research and Technology Alliance [BRTA], Derio, Spain
- IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - Polychronis Pavlidis
- Department of Gastroenterology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK
- School of Immunology and Microbial Sciences, King’s College London, London, UK
| | - Parakkal Deepak
- Inflammatory Bowel Diseases Center, Washington University in Saint Louis School of Medicine, St Louis, MO, USA
| | - Ryan C Ungaro
- Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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27
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Hedin CRH, Sonkoly E, Eberhardson M, Ståhle M. Inflammatory bowel disease and psoriasis: modernizing the multidisciplinary approach. J Intern Med 2021; 290:257-278. [PMID: 33942408 DOI: 10.1111/joim.13282] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 01/11/2021] [Accepted: 01/18/2021] [Indexed: 12/11/2022]
Abstract
Psoriasis and inflammatory bowel disease (IBD) are immune-mediated diseases occurring in barrier organs whose main task is to protect the organism from attack. These disorders are highly prevalent especially in northern Europe where psoriasis has a prevalence of around 3-4% and IBD around 0.3%. The prevalence of IBD in North America has been estimated at around 0.4%. The total incidence rates in northern Europe have been estimated at around 6 for Crohn's disease and 11 for ulcerative colitis per 100 000 person-years, compared with an incidence rate of around 280 per 100 000 person-years for psoriasis. Both diseases are less common in countries with a lower index of development. The rise in IBD appears to occur as populations adopt a westernized lifestyle, whereas psoriasis seems more stable and prevalence differences may derive more from variation in genetic susceptibility. The gut microbiota is clearly an important driver of IBD pathogenesis; in psoriasis, changes in gut and skin microbiota have been reported, but it is less clear whether and how these changes contribute to the pathogenesis. Large studies show that most identified genes are involved in the immune system. However, psoriasis and IBD are highly heterogeneous diseases and there is a need for more precise and deeper phenotyping to identify specific subgroups and their genetic, epigenetic and molecular signatures. Epigenetic modifications of DNA such as histone modifications, noncoding RNA effects on transcription and translation and DNA methylation are increasingly recognized as the mechanism underpinning much of the gene-environment interaction in the pathogenesis of both IBD and psoriasis. Our understanding of underlying pathogenetic mechanisms has deepened fundamentally over the past decades developing hand in hand with novel therapies targeting pathways and proinflammatory cytokines incriminated in disease. There is not only substantial overlap between psoriasis and IBD, but also there are differences with implication for therapy. In psoriasis, drugs targeting interleukin-23 and interleukin-17 have shown superior efficacy compared with anti-TNFs, whilst in IBD, drugs targeting interleukin-17 may be less beneficial. The therapeutic toolbox for psoriasis is impressive and is enlarging also for IBD. Still, there are unmet needs reflecting the heterogeneity of both diseases and there is a need for closer molecular diagnostics to allow for the development of precise therapeutics.
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Affiliation(s)
- C R H Hedin
- From the, Department of Medicine, Karolinska Institutet, Solna, Stockholm, Sweden.,Division of Gastroenterology, Medical Unit Gastroenterology, Dermatovenereology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden
| | - E Sonkoly
- From the, Department of Medicine, Karolinska Institutet, Solna, Stockholm, Sweden.,Division of Dermatology, Medical Unit Gastroenterology, Dermatovenereology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden
| | - M Eberhardson
- From the, Department of Medicine, Karolinska Institutet, Solna, Stockholm, Sweden.,Department of Gastroenterology, University Hospital in Linkoping, Linkoping, Sweden
| | - M Ståhle
- From the, Department of Medicine, Karolinska Institutet, Solna, Stockholm, Sweden.,Division of Dermatology, Medical Unit Gastroenterology, Dermatovenereology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden
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28
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Breaking the therapeutic ceiling in drug development in ulcerative colitis. Lancet Gastroenterol Hepatol 2021; 6:589-595. [PMID: 34019798 DOI: 10.1016/s2468-1253(21)00065-0] [Citation(s) in RCA: 105] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Revised: 02/15/2021] [Accepted: 02/18/2021] [Indexed: 12/15/2022]
Abstract
Increased knowledge of the intricate pathogenesis of ulcerative colitis has triggered an advance in drug development during the past two decades, resulting in the advent of several biological agents and small-molecule therapies. Although the increase in therapeutic options is positive, remission rates of patients with ulcerative colitis given new therapeutic agents in induction trials remain at a modest 20-30%, seemingly facing a so-called therapeutic ceiling. This therapeutic ceiling requires a critical appraisal and highlights the need for alternative strategies for drug development. In this Review, we objectively itemise the boundaries of therapeutic efficacy in ulcerative colitis, provide possible explanations for the shortcomings of current strategies, and propose solutions to achieve better therapeutic outcomes in ulcerative colitis.
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Anti-IL-4Ralpha monoclonal antibody dupilumab mimics ulcerative colitis: a case report. BMC Gastroenterol 2021; 21:207. [PMID: 33964871 PMCID: PMC8105910 DOI: 10.1186/s12876-021-01803-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 05/03/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Various molecular-targeted therapeutic agents that inhibit cytokines and immune checkpoints are used in clinical practice. Some of these biologics that control immunity, such as anti-interleukin-17, anti-programmed cell death protein-1, and anti-cytotoxic T-lymphocyte-associated protein antibodies, affect intestinal immune homeostasis and cause intestinal inflammation. Development of enteritis due to dupilumab (an anti-IL-4Ralpha monoclonal antibody) therapy is not yet reported in the literature. CASE PRESENTATION A 17-year-old man was administered an injection of dupilumab and continued to receive it for refractory atopic dermatitis. After 3 months of initiating dupilumab therapy, he developed intermittent abdominal pain, tenesmus, and had diarrhea. Colonoscopy examination showed decreased vascularity, mild friability, and erythema in the cecum, part of the ascending colon, sigmoid colon, and rectum without any pathogenic bacteria. Histological examination revealed moderate mixed inflammatory cell infiltration, cryptitis, destruction of the crypt, decreased goblet cells, mucosal erosions, and edema. He was diagnosed with UC and was prescribed oral mesalazine (4800 mg/day) treatment. Within a month of the treatment, his diarrhea improved and the frequency of defecation decreased. CONCLUSIONS This is a first report that dupilumab mimicked ulcerative colitis. Careful monitoring for adverse effects with the onset of an intestinal inflammation will be recommended after dupilumab administration.
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30
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Treatments of inflammatory bowel disease toward personalized medicine. Arch Pharm Res 2021; 44:293-309. [PMID: 33763844 DOI: 10.1007/s12272-021-01318-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Accepted: 03/06/2021] [Indexed: 12/12/2022]
Abstract
Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is a chronic inflammatory disease characterized by intestinal inflammation and epithelial injury. For the treatment of IBD, 5-aminosalicylic acids, corticosteroids, immunomodulators, and biologic agents targeting tumor necrosis factor (TNF)-α, α4β7-integrin, and interleukin (IL)-12/23 have been widely used. Especially, anti-TNF-α antibodies are the first biologic agents that presently remain at the forefront. However, 10-30% of patients resist biologic agents, including anti-TNF-α agents (primary non-responder; PNR), and 20-50% of primary responders develop treatment resistance within one year (secondary loss of response; SLR). Nonetheless, the etiologies of PNR and SLR are not clearly understood, and predictors of response to biologic agents are also not defined yet. Numerous studies are being performed to discover prediction markers of the response to biologic agents, and this review will introduce currently available therapeutic options for IBD, biologics under investigation, and recent studies exploring various predictive factors related to PNR and SLR.
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Prins MM, Verstockt B, Ferrante M, Vermeire S, Wildenberg ME, Koelink PJ. Monocyte TREM-1 Levels Associate With Anti-TNF Responsiveness in IBD Through Autophagy and Fcγ-Receptor Signaling Pathways. Front Immunol 2021; 12:627535. [PMID: 33790898 PMCID: PMC8005579 DOI: 10.3389/fimmu.2021.627535] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 02/25/2021] [Indexed: 01/14/2023] Open
Abstract
The expression of Triggering Receptor Expressed on Myeloid cells (TREM)-1 has been described as a predictive marker for anti-Tumor Necrosis Factor (TNF)-α monoclonal antibody (mAb) therapy responsiveness in patients with inflammatory bowel disease (IBD). Here we investigated expression of TREM-1 specifically in CD14+ monocytes in relation to anti-TNF response. The pretreatment TREM-1 expression levels of CD14+ monocytes of Crohn's disease (CD) patients were predictive of outcome to anti-TNF mAb therapy, with low TREM-1 expression associated with response to anti-TNF. FACSorting of CD14+ monocytes with different TREM-1 levels showed that differentiation towards regulatory CD206+ M2 type macrophages by anti-TNF was suppressed in CD14+ monocytes with high TREM-1 expression. Activity of the Fcγ-Receptor and autophagy pathway, both necessary for M2 type differentiation and the response to anti-TNF, were decreased in CD14+ monocytes with high expression of TREM-1. We confirmed that the activity of the Fcγ-Receptor pathway was decreased in the CD patients that did not respond to anti-TNF therapy and that it was negatively correlated with TREM-1 expression levels in the CD patient cohort. In conclusion, our results indicate that TREM-1 expression levels in CD14+ monocytes associate with decreased autophagy and FcγR activity resulting in decreased differentiation to M2 type regulatory macrophages upon anti-TNF mAb treatment, which may explain anti-TNF non-response in IBD patients with high expression levels of TREM-1.
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Affiliation(s)
- Marileen M Prins
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, Location AMC, Amsterdam, Netherlands
| | - Bram Verstockt
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium.,Translational Research Center for Gastrointestinal Disorders [TARGID], Department of Chronic Diseases, Metabolism and Ageing [CHROMETA], KU Leuven, Leuven, Belgium
| | - Marc Ferrante
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium.,Translational Research Center for Gastrointestinal Disorders [TARGID], Department of Chronic Diseases, Metabolism and Ageing [CHROMETA], KU Leuven, Leuven, Belgium
| | - Séverine Vermeire
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium.,Translational Research Center for Gastrointestinal Disorders [TARGID], Department of Chronic Diseases, Metabolism and Ageing [CHROMETA], KU Leuven, Leuven, Belgium
| | - Manon E Wildenberg
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, Location AMC, Amsterdam, Netherlands.,Department of Gastroenterology and Hepatology, Amsterdam UMC, Location AMC, Amsterdam, Netherlands
| | - Pim J Koelink
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, Location AMC, Amsterdam, Netherlands
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32
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Predictors and Early Markers of Response to Biological Therapies in Inflammatory Bowel Diseases. J Clin Med 2021; 10:jcm10040853. [PMID: 33669579 PMCID: PMC7922976 DOI: 10.3390/jcm10040853] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 02/10/2021] [Accepted: 02/11/2021] [Indexed: 12/22/2022] Open
Abstract
Inflammatory bowel diseases (IBD) are chronic conditions that primarily affect the gastrointestinal tract, with a complex pathogenesis; they are characterized by a significant heterogeneity of clinical presentations and of inflammatory pathways that sustain intestinal damage. After the introduction of the first biological therapies, the pipeline of therapies for IBD has been constantly expanding, and a significant number of new molecules is expected in the next few years. Evidence from clinical trials and real-life experiences has taught us that up to 40% of patients do not respond to a specific drug. Unfortunately, to date, clinicians lack a valid tool that can predict each patient’s response to therapies and that could help them in choosing what drug to administer. Several candidate biomarkers have been investigated so far, with conflicting results: clinical, genetic, immunological, pharmacokinetic and microbial markers have been tested, but no ideal marker has been identified so far. Based on recent evidence, multiparametric models seemingly hold the greatest potential for predicting response to therapy. In this narrative review, we aim to summarize the current knowledge on predictors and early markers of response to biological therapies in IBD.
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33
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Fernandes Â, Dias AM, Silva MC, Gaifem J, Azevedo CM, Carballo I, Pinho SS. The Role of Glycans in Chronic Inflammatory Gastrointestinal and Liver Disorders and Cancer. COMPREHENSIVE GLYCOSCIENCE 2021:444-470. [DOI: 10.1016/b978-0-12-819475-1.00036-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Mahajna H, Ben-Horin S. Novel bio-genetic predictors of response to biologic treatment in inflammatory bowel diseases. Curr Opin Pharmacol 2020; 55:132-140. [PMID: 33249396 DOI: 10.1016/j.coph.2020.10.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 09/29/2020] [Accepted: 10/11/2020] [Indexed: 02/07/2023]
Abstract
Despite the evolving therapeutic armamentarium, the treatment of IBD patients remains challenging and many patients fail to respond to biologic agents. With the limited yield of clinical factors to predict the outcome of biologic treatments, studies have focused on identifying genetic alterations and circulating or tissue biomarkers to identify patients who are likely to respond to therapy. In this review, we examine the current knowledge and status of genetic, expression biomarkers, and microbiome predictors. The search for genetic predictors has yielded many genetic loci variants, but few were reproducible. Expression studies of putative biomarkers show promising results, especially with TREM1, oncostatin M and TNF biomarkers, but confirmatory studies are warranted. Finally, the microbiome is emerging as an important player with specific taxa and functional pathways differentially abundant and enriched in responders versus non-responders to certain biologics. Integrating different factors into a robust predictive model, which is both reproducible, accurate and affordable, remains the main challenge before these individualized strategies can reach clinical use.
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Affiliation(s)
- Hussein Mahajna
- Gastroenterology Department, Sheba Medical Center, Affiliated to Tel-Aviv University, Tel-Aviv, Israel.
| | - Shomron Ben-Horin
- Gastroenterology Department, Sheba Medical Center, Affiliated to Tel-Aviv University, Tel-Aviv, Israel
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35
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Verstockt B, Matteoli G. Invited Editorial: Targeting Alpha 4 Beta 7, More Trafficking Inhibition Than We Thought? J Crohns Colitis 2020; 14:1183-1184. [PMID: 32935846 DOI: 10.1093/ecco-jcc/jjaa069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Bram Verstockt
- University Hospitals Leuven Department of Gastroenterology and Hepatology, KU Leuven, Leuven, Belgium.,KU Leuven Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders [TARGID], Leuven, Belgium
| | - Gianluca Matteoli
- KU Leuven Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders [TARGID], Leuven, Belgium
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36
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Verstockt B, Verstockt S, Abdu Rahiman S, Ke BJ, Arnauts K, Cleynen I, Sabino J, Ferrante M, Matteoli G, Vermeire S. Intestinal Receptor of SARS-CoV-2 in Inflamed IBD Tissue Seems Downregulated by HNF4A in Ileum and Upregulated by Interferon Regulating Factors in Colon. J Crohns Colitis 2020; 15:485-498. [PMID: 32915959 PMCID: PMC7543339 DOI: 10.1093/ecco-jcc/jjaa185] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
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] [n = 193] and ulcerative colitis [UC] [n = 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 [p = 4.6E-07], whereas colonic ACE2 was higher in inflamed colon of CD/UC compared with control [p = 8.3E-03; p = 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 [p = 1.7E-02], but not in non-IBD controls [p = 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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Affiliation(s)
- Bram Verstockt
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium,Department of Chronic Diseases, Metabolism and Ageing [CHROMETA], Translational Research Center for Gastrointestinal Disorders [TARGID], KU Leuven, Leuven, Belgium
| | - Sare Verstockt
- Department of Chronic Diseases, Metabolism and Ageing [CHROMETA], Translational Research Center for Gastrointestinal Disorders [TARGID], KU Leuven, Leuven, Belgium
| | - Saeed Abdu Rahiman
- Department of Chronic Diseases, Metabolism and Ageing [CHROMETA], Translational Research Center for Gastrointestinal Disorders [TARGID], KU Leuven, Leuven, Belgium
| | - Bo-jun Ke
- Department of Chronic Diseases, Metabolism and Ageing [CHROMETA], Translational Research Center for Gastrointestinal Disorders [TARGID], KU Leuven, Leuven, Belgium
| | - Kaline Arnauts
- Department of Chronic Diseases, Metabolism and Ageing [CHROMETA], Translational Research Center for Gastrointestinal Disorders [TARGID], KU Leuven, Leuven, Belgium,Department of Development and Regeneration, Stem Cell Institute Leuven [SCIL], KU Leuven, Leuven, Belgium
| | - Isabelle Cleynen
- Department of Human Genetics, Laboratory for Complex Genetics, KU Leuven, Leuven, Belgium
| | - João Sabino
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium,Department of Chronic Diseases, Metabolism and Ageing [CHROMETA], Translational Research Center for Gastrointestinal Disorders [TARGID], KU Leuven, Leuven, Belgium
| | - Marc Ferrante
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium,Department of Chronic Diseases, Metabolism and Ageing [CHROMETA], Translational Research Center for Gastrointestinal Disorders [TARGID], KU Leuven, Leuven, Belgium
| | - Gianluca Matteoli
- Department of Chronic Diseases, Metabolism and Ageing [CHROMETA], Translational Research Center for Gastrointestinal Disorders [TARGID], KU Leuven, Leuven, Belgium
| | - Séverine Vermeire
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium,Department of Chronic Diseases, Metabolism and Ageing [CHROMETA], Translational Research Center for Gastrointestinal Disorders [TARGID], KU Leuven, Leuven, Belgium,Corresponding author: Séverine Vermeire, MD, PhD, Department of Gastroenterology and Hepatology, University Hospitals Leuven, Herestraat 49 3000 Leuven, Belgium. Tel.: 0032 [0]16 34 42 18;
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37
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Ding NS, McDonald JAK, Perdones-Montero A, Rees DN, Adegbola SO, Misra R, Hendy P, Penez L, Marchesi JR, Holmes E, Sarafian MH, Hart AL. Metabonomics and the Gut Microbiome Associated With Primary Response to Anti-TNF Therapy in Crohn's Disease. J Crohns Colitis 2020; 14:1090-1102. [PMID: 32119090 DOI: 10.1093/ecco-jcc/jjaa039] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Anti-tumour necrosis factor [anti-TNF] therapy is indicated for treatment of moderate to severe inflammatory bowel disease [IBD], but has a primary non-response rate of around 30%. We aim to use metabonomic and metataxonomic profiling to identify predictive biomarkers of anti-TNF response in Crohn's disease. METHODS Patients with luminal Crohn's disease, commencing anti-TNF therapy, were recruited with urine, faeces, and serum samples being collected at baseline and 3-monthly. Primary response was defined according to a combination of clinical and objective markers of inflammation. Samples were measured using three UPLC-MS assays: lipid, bile acid, and Hydrophillic Interaction Liquid Chromatography [HILIC] profiling with 16S rRNA gene sequencing of faeces. RESULTS Samples were collected from 76 Crohn's disease patients who were anti-TNF naïve and from 13 healthy controls. There were 11 responders, 37 non-responders, and 28 partial responders in anti-TNF-treated Crohn's patients. Histidine and cysteine were identified as biomarkers of response from polar metabolite profiling [HILIC] of serum and urine. Lipid profiling of serum and faeces found phosphocholines, ceramides, sphingomyelins, and triglycerides, and bile acid profiling identified primary bile acids to be associated with non-response to anti-TNF therapy, with higher levels of phase 2 conjugates in non-responders. Receiver operating curves for treatment response demonstrated 0.94 +/ -0.10 [faecal lipid], 0.81 +/- 0.17 [faecal bile acid], and 0.74 +/- 0.15 [serum bile acid] predictive ability for anti-TNF response in Crohn's disease. CONCLUSIONS This prospective, longitudinal cohort study of metabonomic and 16S rRNA gene sequencing analysis demonstrates that a range of metabolic biomarkers involving lipid, bile acid, and amino acid pathways may contribute to prediction of response to anti-TNF therapy in Crohn's disease. PODCAST This article has an associated podcast which can be accessed at https://academic.oup.com/ecco-jcc/pages/podcast.
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Affiliation(s)
- N S Ding
- St Vincent's Hospital, Inflammatory Bowel Disease, Melbourne, VIC, Australia.,St Mark's Hospital, Inflammatory Bowel Disease Unit, London, UK.,Division of Computational Systems Medicine, Department of Surgery and Cancer, Imperial College London, London, UK
| | - J A K McDonald
- Division of Digestive Diseases, Department of Surgery and Cancer, St Mary's Hospital, Imperial College London, London, UK
| | - A Perdones-Montero
- Division of Computational Systems Medicine, Department of Surgery and Cancer, Imperial College London, London, UK
| | - Douglas N Rees
- Division of Digestive Diseases, Department of Surgery and Cancer, St Mary's Hospital, Imperial College London, London, UK
| | - S O Adegbola
- St Mark's Hospital, Inflammatory Bowel Disease Unit, London, UK.,Division of Computational Systems Medicine, Department of Surgery and Cancer, Imperial College London, London, UK
| | - R Misra
- St Mark's Hospital, Inflammatory Bowel Disease Unit, London, UK.,Division of Computational Systems Medicine, Department of Surgery and Cancer, Imperial College London, London, UK
| | - P Hendy
- St Mark's Hospital, Inflammatory Bowel Disease Unit, London, UK
| | - L Penez
- St Mark's Hospital, Inflammatory Bowel Disease Unit, London, UK
| | - J R Marchesi
- School of Biosciences, Cardiff University, Cardiff, UK.,Division of Digestive Diseases, Department of Surgery and Cancer, St Mary's Hospital, Imperial College London, London, UK
| | - E Holmes
- Division of Computational Systems Medicine, Department of Surgery and Cancer, Imperial College London, London, UK.,Institute of Health Futures, Murdoch University, Perth, WA, Australia
| | - M H Sarafian
- Division of Computational Systems Medicine, Department of Surgery and Cancer, Imperial College London, London, UK
| | - A L Hart
- St Mark's Hospital, Inflammatory Bowel Disease Unit, London, UK.,Division of Computational Systems Medicine, Department of Surgery and Cancer, Imperial College London, London, UK
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38
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Atreya R, Neurath MF, Siegmund B. Personalizing Treatment in IBD: Hype or Reality in 2020? Can We Predict Response to Anti-TNF? Front Med (Lausanne) 2020; 7:517. [PMID: 32984386 PMCID: PMC7492550 DOI: 10.3389/fmed.2020.00517] [Citation(s) in RCA: 87] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 07/27/2020] [Indexed: 12/12/2022] Open
Abstract
The advent of anti-TNF agents as the first approved targeted therapy in the treatment of inflammatory bowel disease (IBD) patients has made a major impact on our existing therapeutic algorithms. They have not only been approved for induction and maintenance treatment in IBD patients, but have also enabled us to define and achieve novel therapeutic outcomes, such as combination of clinical symptom control and endoscopic remission, as well as mucosal healing. Nevertheless, approximately one third of treated patients do not respond to initiated anti-TNF therapy and these treatments are associated with sometimes severe systemic side-effects. There is therefore the currently unmet clinical need do establish predictive markers of response to identify the subgroup of IBD patients, that have a heightened probability of response. There have so far been approaches from different fields of IBD research, to descry markers that would empower us to apply TNF-inhibitors in a more rational manner. These markers encompass findings from disease-related and clinical factors, pharmacokinetics, biochemical markers, blood and stool derived parameters, pharmacogenomics, microbial species, metabolic compounds, and mucosal factors. Furthermore, changes in the intestinal immune cell composition in response to therapeutic pressure of anti-TNF treatment have recently been implicated in the process of molecular resistance to these drugs. Insights into factors that determine resistance to anti-TNF therapy give reasonable hope, that a more targeted approach can then be utilized in these non-responders. Here, IL-23 could be identified as one of the key factors determining resistance to TNF-inhibitors. Growing insights into the molecular mechanism of action of TNF-inhibitors might also enable us to derive critical molecular markers that not only mediate the clinical effects of anti-TNF therapy, but which level of expression might also correlate with its therapeutic efficacy. In this narrative review, we present an overview of currently identified possible predictive markers for successful anti-TNF therapy and discuss identified molecular pathways that drive resistance to these substances. We will also point out the necessity and difficulty of developing and validating a diagnostic marker concerning clinically relevant outcome parameters, before they can finally enter daily clinical practice and enable a more personalized therapeutic approach.
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Affiliation(s)
- Raja Atreya
- Department of Medicine, Medical Clinic 1, University Hospital Erlangen, University of Erlangen-Nürnberg Erlangen, Erlangen, Germany.,Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany.,The Transregio 241 IBDome Consortium, Erlangen, Germany
| | - Markus F Neurath
- Department of Medicine, Medical Clinic 1, University Hospital Erlangen, University of Erlangen-Nürnberg Erlangen, Erlangen, Germany.,Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
| | - Britta Siegmund
- The Transregio 241 IBDome Consortium, Berlin, Germany.,Medizinische Klinik m. S. Gastroenterologie, Infektiologie und Rheumatologie, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.,Berlin Institute of Health, Berlin, Germany
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39
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Seyed Tabib NS, Madgwick M, Sudhakar P, Verstockt B, Korcsmaros T, Vermeire S. Big data in IBD: big progress for clinical practice. Gut 2020; 69:1520-1532. [PMID: 32111636 PMCID: PMC7398484 DOI: 10.1136/gutjnl-2019-320065] [Citation(s) in RCA: 128] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 02/05/2020] [Accepted: 02/06/2020] [Indexed: 12/12/2022]
Abstract
IBD is a complex multifactorial inflammatory disease of the gut driven by extrinsic and intrinsic factors, including host genetics, the immune system, environmental factors and the gut microbiome. Technological advancements such as next-generation sequencing, high-throughput omics data generation and molecular networks have catalysed IBD research. The advent of artificial intelligence, in particular, machine learning, and systems biology has opened the avenue for the efficient integration and interpretation of big datasets for discovering clinically translatable knowledge. In this narrative review, we discuss how big data integration and machine learning have been applied to translational IBD research. Approaches such as machine learning may enable patient stratification, prediction of disease progression and therapy responses for fine-tuning treatment options with positive impacts on cost, health and safety. We also outline the challenges and opportunities presented by machine learning and big data in clinical IBD research.
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Affiliation(s)
| | - Matthew Madgwick
- Organisms and Ecosystems, Earlham Institute, Norwich, UK
- Gut microbes in health and disease, Quadram Institute Bioscience, Norwich, UK
| | - Padhmanand Sudhakar
- Department of Chronic Diseases, Metabolism and Ageing, TARGID, KU Leuven, Leuven, Belgium
- Organisms and Ecosystems, Earlham Institute, Norwich, UK
- Gut microbes in health and disease, Quadram Institute Bioscience, Norwich, UK
| | - Bram Verstockt
- Translational Research in GastroIntestinal Disorders, KU Leuven, Leuven, Belgium
- Department of Gastroenterology and Hepatology, KU Leuven University Hospitals Leuven, Leuven, Belgium
| | - Tamas Korcsmaros
- Organisms and Ecosystems, Earlham Institute, Norwich, UK
- Gut microbes in health and disease, Quadram Institute Bioscience, Norwich, UK
| | - Séverine Vermeire
- Department of Chronic Diseases, Metabolism and Ageing, TARGID, KU Leuven, Leuven, Belgium
- Department of Gastroenterology and Hepatology, KU Leuven University Hospitals Leuven, Leuven, Belgium
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40
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Verstockt B, Verstockt S, Veny M, Dehairs J, Arnauts K, Van Assche G, De Hertogh G, Vermeire S, Salas A, Ferrante M. Expression Levels of 4 Genes in Colon Tissue Might Be Used to Predict Which Patients Will Enter Endoscopic Remission After Vedolizumab Therapy for Inflammatory Bowel Diseases. Clin Gastroenterol Hepatol 2020; 18:1142-1151.e10. [PMID: 31446181 PMCID: PMC7196933 DOI: 10.1016/j.cgh.2019.08.030] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2019] [Accepted: 08/09/2019] [Indexed: 02/06/2023]
Abstract
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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Affiliation(s)
- Bram Verstockt
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium,Translational Research Center for Gastrointestinal Disorders, Department of Chronic Disease, Metabolism and Ageing, KU Leuven, Leuven, Belgium
| | - Sare Verstockt
- Laboratory for Complex Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium
| | - Marisol Veny
- Department of Gastroenterology, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
| | - Jonas Dehairs
- Laboratory of Lipid Metabolism and Cancer, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Kaline Arnauts
- Translational Research Center for Gastrointestinal Disorders, Department of Chronic Disease, Metabolism and Ageing, KU Leuven, Leuven, Belgium,Stem Cell Institute Leuven, Department of Development and Regeneration, KU Leuven, Leuven, Belgium
| | - Gert Van Assche
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium,Translational Research Center for Gastrointestinal Disorders, Department of Chronic Disease, Metabolism and Ageing, KU Leuven, Leuven, Belgium
| | - Gert De Hertogh
- Translational Cell & Tissue Research Unit, Department of Imaging & Pathology, KU Leuven, Leuven, Belgium
| | - Séverine Vermeire
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium,Translational Research Center for Gastrointestinal Disorders, Department of Chronic Disease, Metabolism and Ageing, KU Leuven, Leuven, Belgium
| | - Azucena Salas
- Department of Gastroenterology, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
| | - Marc Ferrante
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium; Translational Research Center for Gastrointestinal Disorders, Department of Chronic Disease, Metabolism and Ageing, KU Leuven, Leuven, Belgium.
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Mateos B, Sáez-González E, Moret I, Hervás D, Iborra M, Cerrillo E, Tortosa L, Nos P, Beltrán B. Plasma Oncostatin M, TNF-α, IL-7, and IL-13 Network Predicts Crohn's Disease Response to Infliximab, as Assessed by Calprotectin Log Drop. Dig Dis 2020; 39:1-9. [PMID: 32325460 DOI: 10.1159/000508069] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Accepted: 04/22/2020] [Indexed: 02/02/2023]
Abstract
BACKGROUND Cytokines emerge as possible biomarkers of response in Crohn's disease (CD). We aimed to determine the plasmatic cytokine profiles of active CD patients who started infliximab (IFX) treatment and their capacity to predict the response to IFX. METHODS A total of 30 active CD patients receiving an induction therapy of IFX were enrolled in the study. Peripheral blood samples pretreatment were collected. Concentrations of 15 cytokines were measured by Luminex technology. Responses to IFX were evaluated by the drop in fecal calprotectin based on its logarithm-transformed values. A random forest (RF) predictive model was used for data analyses. RESULTS Samples of 22 patients were analyzed. The RF model ranked the following cytokines as the top predictors of the response: tumor necrosis factor alpha (TNFα), interleukin (IL)-13, oncostatin M (OSM), and IL-7 (p < 0.005). Partial dependency plots showed that high levels of IL-13 pretreatment, low TNFα levels, and low IL-7 levels were associated with a favorable IFX response. Increased levels of OSM and TNFα predicted unfavorable responses to IFX. CONCLUSIONS We here show that a log drop in calprotectin strongly correlates with clinical parameters and it can be proposed as a useful objective clinical response predictor. Plasma TNFα, IL-13, Il-7, and OSM network could predict CD response to IFX before induction therapy, as assessed by calprotectin log drop.
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Affiliation(s)
- Beatriz Mateos
- Inflammatory Bowel Disease Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, Valencia, Spain
| | - Esteban Sáez-González
- Inflammatory Bowel Disease Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, Valencia, Spain.,Inflammatory Bowel Disease Research Group, Health Research Institute Hospital La Fe (IIS La Fe), Valencia, Spain
| | - Inés Moret
- Inflammatory Bowel Disease Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, Valencia, Spain.,Inflammatory Bowel Disease Research Group, Health Research Institute Hospital La Fe (IIS La Fe), Valencia, Spain.,Centro de Investigación Biomédica en Red de Enfermedades hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - David Hervás
- Biostatictics Unit, Health Research Institute Hospital La Fe (IIS La Fe), Valencia, Spain
| | - Marisa Iborra
- Inflammatory Bowel Disease Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, Valencia, Spain.,Inflammatory Bowel Disease Research Group, Health Research Institute Hospital La Fe (IIS La Fe), Valencia, Spain.,Centro de Investigación Biomédica en Red de Enfermedades hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Elena Cerrillo
- Inflammatory Bowel Disease Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, Valencia, Spain.,Inflammatory Bowel Disease Research Group, Health Research Institute Hospital La Fe (IIS La Fe), Valencia, Spain
| | - Luis Tortosa
- Inflammatory Bowel Disease Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, Valencia, Spain.,Inflammatory Bowel Disease Research Group, Health Research Institute Hospital La Fe (IIS La Fe), Valencia, Spain.,Centro de Investigación Biomédica en Red de Enfermedades hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Pilar Nos
- Inflammatory Bowel Disease Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, Valencia, Spain.,Inflammatory Bowel Disease Research Group, Health Research Institute Hospital La Fe (IIS La Fe), Valencia, Spain.,Centro de Investigación Biomédica en Red de Enfermedades hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Belén Beltrán
- Inflammatory Bowel Disease Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, Valencia, Spain, .,Inflammatory Bowel Disease Research Group, Health Research Institute Hospital La Fe (IIS La Fe), Valencia, Spain, .,Centro de Investigación Biomédica en Red de Enfermedades hepáticas y Digestivas (CIBEREHD), Madrid, Spain,
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42
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Verstockt B, Ferrante M. Editorial: a clinical decision tool to identify patients who might benefit most from intensified dosing in the biological era-getting nearer? Aliment Pharmacol Ther 2020; 51:737-738. [PMID: 32162373 DOI: 10.1111/apt.15634] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- Bram Verstockt
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium.,KU Leuven Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium
| | - Marc Ferrante
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium.,KU Leuven Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium
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43
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Verstockt B, Mertens E, Dreesen E, Outtier A, Noman M, Tops S, Schops G, Van Assche G, Vermeire S, Gils A, Ferrante M. Influence of Drug Exposure on Vedolizumab-Induced Endoscopic Remission in Anti-Tumour Necrosis Factor [TNF] Naïve and Anti-TNF Exposed IBD Patients. J Crohns Colitis 2020; 14:332-341. [PMID: 31504343 DOI: 10.1093/ecco-jcc/jjz151] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND OBJECTIVES Vedolizumab has demonstrated efficacy and safety in patients with Crohn's disease [CD] and ulcerative colitis [UC]. Endoscopic outcome data are limited, especially in anti-tumour necrosis factor [TNF] naïve patients. The present study compared endoscopic outcome in anti-TNF naïve and exposed patients, and explored if this was affected by drug exposure. METHODS We retrospectively analysed all patients initiating vedolizumab at our tertiary referral centre since 2015. For UC, endoscopic improvement was defined as a Mayo endoscopic subscore ≤1 at week 14. For CD, endoscopic remission was defined as absence of ulcerations at week 22. Vedolizumab trough concentrations were measured at week 6, week 14 and during maintenance. RESULTS A total of 336 patients were identified [53.3% CD], 20% of them being anti-TNF naïve. Endoscopic improvement was achieved by 56.1% of UC patients and endoscopic remission by 39.1% of CD patients. Endoscopic outcomes were significantly better in anti-TNF naïve vs exposed patients [all: 67.2% vs 42.0%, p = 0.0002; UC: 74.4% vs 50.0%, p = 0.02; CD: 57.1% vs 35.8%, p = 0.03]. Achievement of endoscopic end points significantly impacted long-term treatment continuation [p = 9.7 × 10-13]. A better endoscopic outcome was associated with significantly higher drug exposure in both CD and UC. CONCLUSIONS The results of this observational, single-centre real-life study suggest that vedolizumab may induce endoscopic remission in both CD and UC. Although anti-TNF naïve patients had a significantly better outcome, 42% of anti-TNF exposed patients still benefited endoscopically. A clear exposure-endoscopic response relationship exists, but not all patients will benefit from treatment intensification. Hence, predictive biomarkers remain necessary. PODCAST This article has an associated podcast which can be accessed at https://academic.oup.com/ecco-jcc/pages/podcast.
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Affiliation(s)
- Bram Verstockt
- University Hospitals Leuven, Department of Gastroenterology and Hepatology, KU Leuven, Leuven, Belgium.,KU Leuven Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium
| | - Evelien Mertens
- University Hospitals Leuven, Department of Gastroenterology and Hepatology, KU Leuven, Leuven, Belgium
| | - Erwin Dreesen
- KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Laboratory for Therapeutic and Diagnostic Antibodies
| | - An Outtier
- University Hospitals Leuven, Department of Gastroenterology and Hepatology, KU Leuven, Leuven, Belgium
| | - Maja Noman
- University Hospitals Leuven, Department of Gastroenterology and Hepatology, KU Leuven, Leuven, Belgium
| | - Sophie Tops
- KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Laboratory for Therapeutic and Diagnostic Antibodies
| | - Ganel Schops
- University Hospitals Leuven, Department of Gastroenterology and Hepatology, KU Leuven, Leuven, Belgium
| | - Gert Van Assche
- University Hospitals Leuven, Department of Gastroenterology and Hepatology, KU Leuven, Leuven, Belgium.,KU Leuven Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium
| | - Séverine Vermeire
- University Hospitals Leuven, Department of Gastroenterology and Hepatology, KU Leuven, Leuven, Belgium.,KU Leuven Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium
| | - Ann Gils
- KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Laboratory for Therapeutic and Diagnostic Antibodies
| | - Marc Ferrante
- University Hospitals Leuven, Department of Gastroenterology and Hepatology, KU Leuven, Leuven, Belgium.,KU Leuven Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium
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Pugliese N, Roda G, Peyrin-Biroulet L, Danese S. Emerging therapies for the treatment of ulcerative colitis. Expert Opin Emerg Drugs 2020; 25:1-9. [PMID: 32148112 DOI: 10.1080/14728214.2020.1737009] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Accepted: 02/27/2020] [Indexed: 12/16/2022]
Abstract
Introduction: Ulcerative colitis (UC) is a chronic idiopathic autoimmune inflammatory disorder, primarily affecting the gastrointestinal system. There are many patients affected that do not respond well to therapy and many others to which there is a loss of efficacy every year. The proportion of patients who have already experienced anti-TNF therapy is constantly increasing, making the development of new drugs with alternative mechanisms of action an important need for the treatment of UC.Areas covered: This review aims on emerging drugs in the treatment of UC and reviews data on their efficacy and safety.Expert opinion: UC, for many years, comparatively to CD, received little attention for several possible reasons, especially because it was not considered as a progressive disease able to induce irreversible bowel damage. This has led to lower investments by the scientific community and a slower development of therapeutic options for UC. In the past few years, this trend has started to change. In fact, new promising drugs have been developed and others are emerging with positive results. Although many treatment modalities have recently been approved, additional drugs are currently being investigated and will probably be part of the UC treatment regimen in the coming years.
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Affiliation(s)
- Nicola Pugliese
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Giulia Roda
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Laurent Peyrin-Biroulet
- Department of Hepato-Gastroenterology and Inserm U954, University of Lorraine, Vandoeuvre-lès-Nancy, France
| | - Silvio Danese
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
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Lee HS, Cleynen I. Molecular Profiling of Inflammatory Bowel Disease: Is It Ready for Use in Clinical Decision-Making? Cells 2019; 8:E535. [PMID: 31167397 PMCID: PMC6627070 DOI: 10.3390/cells8060535] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 05/29/2019] [Accepted: 05/30/2019] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a heterogeneous disorder in terms of age at onset, clinical phenotypes, severity, disease course, and response to therapy. This underlines the need for predictive and precision medicine that can optimize diagnosis and disease management, provide more cost-effective strategies, and minimize the risk of adverse events. Ideally, we can leverage molecular profiling to predict the risk to develop IBD and disease progression. Despite substantial successes of genome-wide association studies in the identification of genetic variants affecting IBD susceptibility, molecular profiling of disease onset and progression as well as of treatment responses has lagged behind. Still, thanks to technological advances and good study designs, predicting phenotypes using genomics and transcriptomics in IBD has been rapidly evolving. In this review, we summarize the current status of prediction of disease risk, clinical course, and response to therapy based on clinical case presentations. We also discuss the potential and limitations of the currently used approaches.
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Affiliation(s)
- Ho-Su Lee
- Laboratory of Complex Genetics, Department of Human Genetics, KU Leuven, Herestraat 49 - box 610, 3000 Leuven, Belgium.
- Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul 05505, Korea.
| | - Isabelle Cleynen
- Laboratory of Complex Genetics, Department of Human Genetics, KU Leuven, Herestraat 49 - box 610, 3000 Leuven, Belgium.
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46
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Sabino J, Verstockt B, Vermeire S, Ferrante M. New biologics and small molecules in inflammatory bowel disease: an update. Therap Adv Gastroenterol 2019; 12:1756284819853208. [PMID: 31205488 PMCID: PMC6537282 DOI: 10.1177/1756284819853208] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Accepted: 04/03/2019] [Indexed: 02/04/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a spectrum of immune-mediated inflammatory disorders with a complex multifactorial pathogenesis, where different pathways may predominate in different individuals. This complexity will most likely require a panoply of drugs targeting different pathways if one wants to treat to steroid-free sustained remission and mucosal healing. Presently, the mainstay of medical management of IBD is based on 5-aminosalicylates, corticosteroids, thiopurines, methotrexate, antitumor necrosis factor, anti-alpha4 beta7 (α4β7) integrin and anti-interleukin (IL)-12/IL-23 therapies. The discovery of new pathways involved in the pathogenesis of IBD resulted in new drugs targeting Janus kinase/signal transducers and activators of transcription, IL-6, spingosine-1-phosphate, and phosphodiesterase 4, among others. These new therapies might result in more advantageous safety profiles. Several of these new drugs have already been successfully tested in other inflammatory disorders, such as psoriasis or rheumatoid arthritis. In this review, evidence from phase II and phase III randomized controlled clinical trials in patients with IBD involving new biologicals and small molecules are summarized.
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Affiliation(s)
| | | | | | - Marc Ferrante
- Universtaire Ziekenhuizen Leuven, Herestraat 49,
Leuven B3000, Belgium
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47
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Shouval DS, Ben-Horin S. Editorial: biomarker predictors of non-response to TNFα antagonists-the quest continues. Aliment Pharmacol Ther 2019; 49:1089-1090. [PMID: 30920039 DOI: 10.1111/apt.15198] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
- Dror S Shouval
- Pediatric Gastroenterology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Shomron Ben-Horin
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Institute of Gastroenterology, Sheba Medical Center, Tel Hashomer, Israel
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48
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Verstockt B, Vermeire S, Ferrante M, Breynaert C. Editorial: biomarker predictors of non-response to TNFα antagonists - the quest continues. Authors' reply. Aliment Pharmacol Ther 2019; 49:1091-1092. [PMID: 30920040 DOI: 10.1111/apt.15212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Affiliation(s)
- Bram Verstockt
- KU Leuven Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium.,University Hospitals Leuven Department of Gastroenterology and Hepatology, KU Leuven, Leuven, Belgium
| | - Séverine Vermeire
- KU Leuven Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium.,University Hospitals Leuven Department of Gastroenterology and Hepatology, KU Leuven, Leuven, Belgium
| | - Marc Ferrante
- KU Leuven Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium.,University Hospitals Leuven Department of Gastroenterology and Hepatology, KU Leuven, Leuven, Belgium
| | - Christine Breynaert
- KU Leuven Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, Leuven, Belgium
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Verstockt B, Verstockt S, Dehairs J, Ballet V, Blevi H, Wollants WJ, Breynaert C, Van Assche G, Vermeire S, Ferrante M. Low TREM1 expression in whole blood predicts anti-TNF response in inflammatory bowel disease. EBioMedicine 2019; 40:733-742. [PMID: 30685385 PMCID: PMC6413341 DOI: 10.1016/j.ebiom.2019.01.027] [Citation(s) in RCA: 127] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2018] [Revised: 01/04/2019] [Accepted: 01/11/2019] [Indexed: 02/07/2023] Open
Abstract
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-CD ≤ 2 at week 24 for CD and Mayo endoscopic sub-score ≤ 1 at week 10 for UC). FINDINGS Baseline whole blood TREM1 was downregulated in future anti-TNF responders, both in UC (FC = 0.53, p = .001) and CD (FC = 0.66, p = .007), as well as in the complete cohort (FC = 0.67, p < .001). Receiver operator characteristic statistics showed an area under the curve (AUC) of 0.78 (p = .001). A similar accuracy could be achieved with mucosal TREM1 (AUC 0.77, p = .003), which outperformed the accuracy of serum TREM1 (AUC 0.58, p = .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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Affiliation(s)
- Bram Verstockt
- University Hospitals Leuven, Department of Gastroenterology and Hepatology, KU Leuven, Leuven, Belgium; KU Leuven Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium
| | - Sare Verstockt
- KU Leuven Department of Human Genetics, Laboratory for Complex Genetics, Leuven, Belgium
| | - Jonas Dehairs
- KU Leuven Department of Oncology, Laboratory of Lipid Metabolism and Cancer, Leuven, Belgium
| | - Vera Ballet
- University Hospitals Leuven, Department of Gastroenterology and Hepatology, KU Leuven, Leuven, Belgium
| | - Helene Blevi
- KU Leuven Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium
| | - Willem-Jan Wollants
- KU Leuven Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium
| | - Christine Breynaert
- KU Leuven Department of Microbiology and Immunology, Laboratory of Clinical Immunology, Leuven, Belgium
| | - Gert Van Assche
- University Hospitals Leuven, Department of Gastroenterology and Hepatology, KU Leuven, Leuven, Belgium; KU Leuven Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium
| | - Séverine Vermeire
- University Hospitals Leuven, Department of Gastroenterology and Hepatology, KU Leuven, Leuven, Belgium; KU Leuven Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium
| | - Marc Ferrante
- University Hospitals Leuven, Department of Gastroenterology and Hepatology, KU Leuven, Leuven, Belgium; KU Leuven Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium.
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Verstockt B, Perrier C, De Hertogh G, Cremer J, Creyns B, Van Assche G, Ferrante M, Ceuppens JL, Vermeire S, Breynaert C. Effects of Epithelial IL-13Rα2 Expression in Inflammatory Bowel Disease. Front Immunol 2018; 9:2983. [PMID: 30619339 PMCID: PMC6305625 DOI: 10.3389/fimmu.2018.02983] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Accepted: 12/04/2018] [Indexed: 12/21/2022] Open
Abstract
Background: Mucosal IL-13 Receptor alpha 2 (IL13RA2) mRNA expression is one of the best predictive markers for primary non-responsiveness to infliximab therapy in patients with inflammatory bowel disease (IBD). The objective of this study was to understand how IL-13Rα2, a negative regulator of IL-13 signaling, can contribute to IBD pathology. Methods:IL13RA2 knockout (KO) and wild type (WT) mice were exposed to dextran sodium sulfate (DSS) in drinking water to induce colitis. Furthermore, mucosal biopsies and resection specimen of healthy individuals and IBD patients before the start of anti-tumor necrosis factor (anti-TNF) therapy were obtained for immunohistochemistry and gene expression analysis. Results: After induction of DSS colitis, IL13RA2 KO mice had similar disease severity, but recovered more rapidly than WT animals. Goblet cell numbers and mucosal architecture were also more rapidly restored in IL13RA2 KO mice. In mucosal biopsies of active IBD patients, immunohistochemistry revealed that IL-13Rα2 protein was highly expressed in epithelial cells, while expression was restricted to goblet cells in healthy controls. Mucosal IL13RA2 mRNA negatively correlated with mRNA of several goblet cell-specific and barrier genes, and with goblet cell numbers. Conclusions: The data suggest that IL-13Rα2 on epithelial cells contributes to IBD pathology by negatively influencing goblet cell recovery, goblet cell function and epithelial restoration after injury. Therefore, blocking IL-13Rα2 could be a promising target for restoration of the epithelial barrier in IBD.
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Affiliation(s)
- Bram Verstockt
- KU Leuven, Department of Chronic Diseases, Metabolism and Ageing, Translational Research for Gastrointestinal Disorders, Leuven, Belgium
- University Hospitals Leuven, Department of Gastroenterology and Hepatology, Leuven, Belgium
| | - Clémentine Perrier
- KU Leuven, Department of Chronic Diseases, Metabolism and Ageing, Translational Research for Gastrointestinal Disorders, Leuven, Belgium
- KU Leuven, Laboratory of Clinical Immunology, Department of Microbiology and Immunology, Leuven, Belgium
| | - Gert De Hertogh
- KU Leuven, Department of Imaging & Pathology, Translational Cell & Tissue Research, Leuven, Belgium
| | - Jonathan Cremer
- KU Leuven, Department of Chronic Diseases, Metabolism and Ageing, Translational Research for Gastrointestinal Disorders, Leuven, Belgium
- KU Leuven, Laboratory of Clinical Immunology, Department of Microbiology and Immunology, Leuven, Belgium
| | - Brecht Creyns
- KU Leuven, Department of Chronic Diseases, Metabolism and Ageing, Translational Research for Gastrointestinal Disorders, Leuven, Belgium
- KU Leuven, Laboratory of Clinical Immunology, Department of Microbiology and Immunology, Leuven, Belgium
| | - Gert Van Assche
- KU Leuven, Department of Chronic Diseases, Metabolism and Ageing, Translational Research for Gastrointestinal Disorders, Leuven, Belgium
- University Hospitals Leuven, Department of Gastroenterology and Hepatology, Leuven, Belgium
| | - Marc Ferrante
- KU Leuven, Department of Chronic Diseases, Metabolism and Ageing, Translational Research for Gastrointestinal Disorders, Leuven, Belgium
- University Hospitals Leuven, Department of Gastroenterology and Hepatology, Leuven, Belgium
| | - Jan L. Ceuppens
- KU Leuven, Laboratory of Clinical Immunology, Department of Microbiology and Immunology, Leuven, Belgium
| | - Séverine Vermeire
- KU Leuven, Department of Chronic Diseases, Metabolism and Ageing, Translational Research for Gastrointestinal Disorders, Leuven, Belgium
- University Hospitals Leuven, Department of Gastroenterology and Hepatology, Leuven, Belgium
| | - Christine Breynaert
- KU Leuven, Laboratory of Clinical Immunology, Department of Microbiology and Immunology, Leuven, Belgium
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