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Varley RB, Lee JC. Misinterpretation and misapplication of biomarkers in inflammatory bowel disease: how do we avoid this? Expert Rev Gastroenterol Hepatol 2025; 19:359-363. [PMID: 40110976 PMCID: PMC11974923 DOI: 10.1080/17474124.2025.2482980] [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: 01/09/2025] [Revised: 03/07/2025] [Accepted: 03/18/2025] [Indexed: 03/22/2025]
Abstract
INTRODUCTION The management of inflammatory bowel disease (IBD) has evolved substantially over the past decade, with the emergence of new advanced therapies presenting unprecedented challenges in clinical decision-making. While these therapies provide patients with more opportunities to get better, biomarkers to guide their use remain elusive. AREAS COVERED This article highlights the challenges associated with biomarker discovery, interpretation, and application in IBD - based on literature review, first-hand experience of biomarker discovery, and personal opinion. We highlight problems including the misinterpretation of predictive capabilities, lack of independent validation, and reverse causation in retrospective studies, and explain why associations with clinical parameters or seropositivity to microbial antigens often fail to meet the rigorous performance metrics required for clinical utility. The relative need for different biomarkers is also discussed - particularly in light of recent evidence from the PROFILE trial, which emphasizes the considerably greater risk posed by uncontrolled disease than by the potential side-effects of medications. EXPERT OPINION Despite multiple challenges, the potential of biomarkers for precision medicine in IBD remains promising, particularly in combination with other clinical and biochemical parameters. Further research into combinatorial biomarker approaches is needed, but must be combined with learning how to communicate results that are inherently uncertain.
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Affiliation(s)
| | - James C. Lee
- Department of Gastroenterology, Royal Free Hospital, London, UK
- Genetic Mechanisms of Disease Lab, The Francis Crick Institute, London, UK
- Institute for Liver and Digestive Health, Division of Medicine, University College London, London, UK
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2
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Bourgonje AR, Hörstke NV, Fehringer M, Innocenti G, Vogl T. Systemic antibody responses against gut microbiota flagellins implicate shared and divergent immune reactivity in Crohn's disease and chronic fatigue syndrome. MICROBIOME 2024; 12:141. [PMID: 39075559 DOI: 10.1186/s40168-024-01858-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Accepted: 06/12/2024] [Indexed: 07/31/2024]
Abstract
BACKGROUND Elevated systemic antibody responses against gut microbiota flagellins are observed in both Crohn's disease (CD) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), suggesting potential serological biomarkers for diagnosis. However, flagellin-specific antibody repertoires and functional roles in the diseases remain incompletely understood. Bacterial flagellins can be categorized into three types depending on their interaction with toll-like receptor 5 (TLR5): (1) "stimulator" and (2) "silent" flagellins, which bind TLR5 through a conserved N-terminal motif, with only stimulators activating TLR5 (involving a C-terminal domain); (3) "evader" flagellins of pathogens, which entirely circumvent TLR5 activation via mutations in the N-terminal TLR5 binding motif. RESULTS Here, we show that both CD and ME/CFS patients exhibit elevated antibody responses against distinct regions of flagellins compared to healthy individuals. N-terminal binding to Lachnospiraceae flagellins was comparable in both diseases, while C-terminal binding was more prevalent in CD. N-terminal antibody-bound flagellin sequences were similar across CD and ME/CFS, resembling "stimulator" and "silent" flagellins more than evaders. However, C-terminal antibody-bound flagellins showed a higher resemblance to the stimulator than to silent flagellins in CD, which was not observed in ME/CFS. CONCLUSIONS These findings suggest that antibody binding to the N-terminal domain of stimulator and silent flagellins may impact TLR5 activation in both CD and ME/CFS patients. Blocking this interaction could lead commensal bacteria to be recognized as pathogenic evaders, potentially contributing to dysregulation in both diseases. Furthermore, elevated antibody binding to the C-terminal domain of stimulator flagellins in CD may explain pathophysiological differences between the diseases. Overall, these results highlight the diagnostic potential of these antibody responses and lay a foundation for deeper mechanistic studies of flagellin/TLR5 interactions and their impact on innate/adaptive immunity balance.
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Affiliation(s)
- Arno R Bourgonje
- The Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Nicolai V Hörstke
- Center for Cancer Research, Medical University of Vienna, Vienna, Austria
| | - Michaela Fehringer
- Center for Cancer Research, Medical University of Vienna, Vienna, Austria
| | - Gabriel Innocenti
- Center for Cancer Research, Medical University of Vienna, Vienna, Austria
| | - Thomas Vogl
- Center for Cancer Research, Medical University of Vienna, Vienna, Austria.
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Wang A, Zhai Z, Ding Y, Wei J, Wei Z, Cao H. The oral-gut microbiome axis in inflammatory bowel disease: from inside to insight. Front Immunol 2024; 15:1430001. [PMID: 39131163 PMCID: PMC11310172 DOI: 10.3389/fimmu.2024.1430001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 07/09/2024] [Indexed: 08/13/2024] Open
Abstract
Inflammatory bowel disease (IBD) is an idiopathic and persistent inflammatory illness of the bowels, leading to a substantial burden on both society and patients due to its high incidence and recurrence. The pathogenesis of IBD is multifaceted, partly attributed to the imbalance of immune responses toward the gut microbiota. There is a correlation between the severity of the disease and the imbalance in the oral microbiota, which has been discovered in recent research highlighting the role of oral microbes in the development of IBD. In addition, various oral conditions, such as angular cheilitis and periodontitis, are common extraintestinal manifestations (EIMs) of IBD and are associated with the severity of colonic inflammation. However, it is still unclear exactly how the oral microbiota contributes to the pathogenesis of IBD. This review sheds light on the probable causal involvement of oral microbiota in intestinal inflammation by providing an overview of the evidence, developments, and future directions regarding the relationship between oral microbiota and IBD. Changes in the oral microbiota can serve as markers for IBD, aiding in early diagnosis and predicting disease progression. Promising advances in probiotic-mediated oral microbiome modification and antibiotic-targeted eradication of specific oral pathogens hold potential to prevent IBD recurrence.
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Affiliation(s)
- Aili Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China
- Department of Gastroenterology and Hepatology, Binzhou Medical University Hospital, Binzhou Medical University, Binzhou, Shandong, China
| | - Zihan Zhai
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China
- Department of Gastroenterology and Hepatology, Binzhou Medical University Hospital, Binzhou Medical University, Binzhou, Shandong, China
| | - Yiyun Ding
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China
| | - Jingge Wei
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China
| | - Zhiqiang Wei
- Department of Orthodontics, Tianjin Stomatological Hospital School of Medicine, Nankai University, Tianjin, China
- Tianjin Key laboratory of Oral and Maxillofacial Function Reconstruction, Tianjin, China
| | - Hailong Cao
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China
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Marafini I, Laudisi F, Salvatori S, Lavigna D, Venuto C, Giannarelli D, Monteleone G. Diagnostic value of anti-integrin αvβ6 antibodies in ulcerative colitis. Dig Liver Dis 2024; 56:55-60. [PMID: 37407314 DOI: 10.1016/j.dld.2023.06.024] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 06/09/2023] [Accepted: 06/20/2023] [Indexed: 07/07/2023]
Abstract
Ulcerative colitis (UC)-related mucosal inflammation is characterized by the production of various autoantibodies with limited clinical relevance. Recent studies have shown that circulating levels of IgG against integrin αvβ6 are increased in UC patients as compared to Crohn's disease (CD) patients and healthy controls (HC). The present study assessed the diagnostic value of circulating IgG anti-αvβ6 in UC. Sera were prospectively collected from 108 outpatients with UC, 103 patients with CD, and 62 HC, and the levels of IgG anti-αvβ6 were measured using a commercially available ELISA kit. The cut-off for positive results was defined as the 95th percentile of the values of the autoantibodies in HC serum samples. Levels of IgG anti-αvβ6 were significantly higher in UC than in CD patients, including those with colonic localization, and HC. Fifty-six of the 108 (51.8%) UC patients had a positive test whereas only 17/103 (16.5%) patients with CD, and among these, 4/16 (25%) patients with colonic CD, were positive. In UC, there was no statistical difference between patients with IgG anti-αvβ6 positivity and those negative in terms of clinical disease activity, fecal calprotectin values, and disease extent. The sensitivity, specificity, predictive positive value, and predictive negative value of the test to differentiate between UC and CD were 51.9% (C.I.42.4-61.3), 83.5% (C.I. 76.3-90.7), 76.7% (C.I. 67.0-86.4), and 62.3% (C.I. 54.2-70.4) respectively. Our study confirms that anti-αvβ6 antibodies are demonstrable in the serum of the majority of UC patients and suggests the necessity of further research to understand if the anti-αvβ6 antibody determination could have a place in the clinical decision-making of IBD.
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Affiliation(s)
- Irene Marafini
- Gastroenterology Unit, Azienda Ospedaliera Policlinico Tor Vergata, Rome, Italy
| | - Federica Laudisi
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Silvia Salvatori
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Diletta Lavigna
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Chiara Venuto
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Diana Giannarelli
- Facility of Epidemiology and Biostatistics, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Giovanni Monteleone
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
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Buttar J, Kon E, Lee A, Kaur G, Lunken G. Effect of diet on the gut mycobiome and potential implications in inflammatory bowel disease. Gut Microbes 2024; 16:2399360. [PMID: 39287010 PMCID: PMC11409510 DOI: 10.1080/19490976.2024.2399360] [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: 09/07/2023] [Revised: 07/31/2024] [Accepted: 08/28/2024] [Indexed: 09/19/2024] Open
Abstract
The gut microbiome is a complex, unique entity implicated in the prevention, pathogenesis, and progression of common gastrointestinal diseases. While largely dominated by bacterial populations, advanced sequencing techniques have identified co-inhabiting fungal communities, collectively referred to as the mycobiome. Early studies identified that gut inflammation is associated with altered microbial composition, known as gut dysbiosis. Altered microbial profiles are implicated in various pathological diseases, such as inflammatory bowel disease (IBD), though their role as a cause or consequence of systemic inflammation remains the subject of ongoing research. Diet plays a crucial role in the prevention and management of various diseases and is considered to be an essential regulator of systemic inflammation. This review compiles current literature on the impact of dietary modulation on the mycobiome, showing that dietary changes can alter the fungal architecture of the gut. Further research is required to understand the impact of diet on gut fungi, including the metabolic pathways and enzymes involved in fungal fermentation. Additionally, investigating whether dietary modulation of the gut mycobiome could be utilized as a therapy in IBD is essential.
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Affiliation(s)
- J Buttar
- Department of Medicine, University of British Columbia, Vancouver, Canada
| | - E Kon
- Department of Pediatrics, University of British Columbia, Vancouver, Canada
- BC Children's Hospital Research Institute, Vancouver, Canada
| | - A Lee
- Faculty of Land and Food Systems, University of British Columbia, Vancouver, Canada
| | - G Kaur
- Department of Pediatrics, University of British Columbia, Vancouver, Canada
| | - G Lunken
- Department of Medicine, University of British Columbia, Vancouver, Canada
- Department of Pediatrics, University of British Columbia, Vancouver, Canada
- BC Children's Hospital Research Institute, Vancouver, Canada
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6
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Zangara MT, Darwish L, Coombes BK. Characterizing the Pathogenic Potential of Crohn's Disease-Associated Adherent-Invasive Escherichia coli. EcoSal Plus 2023; 11:eesp00182022. [PMID: 37220071 PMCID: PMC10729932 DOI: 10.1128/ecosalplus.esp-0018-2022] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Accepted: 05/04/2023] [Indexed: 01/28/2024]
Abstract
The microbiome of Crohn's disease (CD) patients is composed of a microbial community that is considered dysbiotic and proinflammatory in nature. The overrepresentation of Enterobacteriaceae species is a common feature of the CD microbiome, and much attention has been given to understanding the pathogenic role this feature plays in disease activity. Over 2 decades ago, a new Escherichia coli subtype called adherent-invasive E. coli (AIEC) was isolated and linked to ileal Crohn's disease. Since the isolation of the first AIEC strain, additional AIEC strains have been isolated from both inflammatory bowel disease (IBD) patients and non-IBD individuals using the original in vitro phenotypic characterization methods. Identification of a definitive molecular marker of the AIEC pathotype has been elusive; however, significant advancements have been made in understanding the genetic, metabolic, and virulence determinants of AIEC infection biology. Here, we review the current knowledge of AIEC pathogenesis to provide additional, objective measures that could be considered in defining AIEC and their pathogenic potential.
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Affiliation(s)
- Megan T. Zangara
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
| | - Lena Darwish
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
| | - Brian K. Coombes
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
- Michael G. DeGroote Institute for Infectious Disease Research, Hamilton, Ontario, Canada
- Farncombe Family Digestive Health Research Institute, Hamilton, Ontario, Canada
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Zeng Z, Jiang M, Li X, Yuan J, Zhang H. Precision medicine in inflammatory bowel disease. PRECISION CLINICAL MEDICINE 2023; 6:pbad033. [PMID: 38638127 PMCID: PMC11025389 DOI: 10.1093/pcmedi/pbad033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Accepted: 12/13/2023] [Indexed: 04/20/2024] Open
Abstract
Inflammatory bowel disease (IBD) is an incurable disease characterized by remission-relapse cycles throughout its course. Both Crohn's disease (CD) and ulcerative colitis (UC), the two main forms of IBD, exhibit tendency to develop complications and substantial heterogeneity in terms of frequency and severity of relapse, thus posing great challenges to the clinical management for IBD. Current treatment strategies are effective in different ways in induction and maintenance therapies for IBD. Recent advances in studies of genetics, pharmacogenetics, proteomics and microbiome provide a strong driving force for identifying molecular markers of prognosis and treatment response, which should help clinicians manage IBD patients more effectively, and then, improve clinical outcomes and reduce treatment costs of patients. In this review, we summarize and discuss precision medicine in IBD, focusing on predictive markers of disease course and treatment response, and monitoring indices during therapeutic drug monitoring.
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Affiliation(s)
- Zhen Zeng
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 610041, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Mingshan Jiang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 610041, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xi Li
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jing Yuan
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 610041, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Hu Zhang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 610041, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
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8
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Rimmer P, Iqbal T. Prognostic modelling in IBD. Best Pract Res Clin Gastroenterol 2023; 67:101877. [PMID: 38103929 DOI: 10.1016/j.bpg.2023.101877] [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: 11/16/2023] [Accepted: 11/24/2023] [Indexed: 12/19/2023]
Abstract
In the ideal world prognostication or predicting disease course in any chronic condition would allow the clinician to anticipate disease behaviour, providing crucial information for the patient and data regarding best use of resources. Prognostication also allows an understanding of likely response to treatment and the risk of adverse effects of a treatment leading to withdrawal in any individual patient. Therefore, the ability to predict outcomes from the onset of disease is the key step to developing precision personalised medicine, which is the design of medical care to optimise efficiency or therapeutic benefit based on careful profiling of patients. An important corollary is to prevent unnecessary healthcare costs. This paper outlines currently available predictors of disease outcome in IBD and looks to the future which will involve the use of artificial intelligence to interrogate big data derived from various important 'omes' to tease out a more holistic approach to IBD.
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Affiliation(s)
- Peter Rimmer
- Queen Elizabeth Hospital Birmingham, B15 2TH, UK; University of Birmingham, College of Medical and Dental Science, UK.
| | - Tariq Iqbal
- Queen Elizabeth Hospital Birmingham, B15 2TH, UK; University of Birmingham, College of Medical and Dental Science, UK.
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James JP, Nielsen BS, Christensen IJ, Langholz E, Malham M, Poulsen TS, Holmstrøm K, Riis LB, Høgdall E. Mucosal expression of PI3, ANXA1, and VDR discriminates Crohn's disease from ulcerative colitis. Sci Rep 2023; 13:18421. [PMID: 37891214 PMCID: PMC10611705 DOI: 10.1038/s41598-023-45569-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Accepted: 10/20/2023] [Indexed: 10/29/2023] Open
Abstract
Differential diagnosis of inflammatory bowel disease (IBD) to Crohn's disease (CD) or ulcerative colitis (UC) is crucial for treatment decision making. With the aim of generating a clinically applicable molecular-based tool to classify IBD patients, we assessed whole transcriptome analysis on endoscopy samples. A total of 408 patient samples were included covering both internal and external samples cohorts. Whole transcriptome analysis was performed on an internal cohort of FFPE IBD samples (CD, n = 16 and UC, n = 17). The 100 most significantly differentially expressed genes (DEG) were tested in two external cohorts. Ten of the DEG were further processed by functional enrichment analysis from which seven were found to show consistent significant performance in discriminating CD from UC: PI3, ANXA1, VDR, MTCL1, SH3PXD2A-AS1, CLCF1, and CD180. Differential expression of PI3, ANXA1, and VDR was reproduced by RT-qPCR, which was performed on an independent sample cohort of 97 patient samples (CD, n = 44 and UC, n = 53). Gene expression levels of the three-gene profile, resulted in an area under the curve of 0.84 (P = 0.02) in discriminating CD from UC, and therefore appear as an attractive molecular-based diagnostic tool for clinicians to distinguish CD from UC.
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Affiliation(s)
| | | | - Ib Jarle Christensen
- Department of Pathology, Herlev University Hospital, Borgmester Ib Juuls Vej 73, 2730, Herlev, Denmark
| | - Ebbe Langholz
- Gastroenheden D, Herlev University Hospital, 2730, Herlev, Denmark
- Institute for Clinical Medicine, University of Copenhagen, 2200, Copenhagen, Denmark
| | - Mikkel Malham
- The Department of Pediatric and Adolescence Medicine, Copenhagen University Hospital-Amager and Hvidovre, 2650, Hvidovre, Denmark
- Copenhagen Center for Inflammatory Bowel Disease in Children, Adolescents and Adults, Hvidovre Hospital, University of Copenhagen, 2650, Hvidovre, Denmark
| | - Tim Svenstrup Poulsen
- Department of Pathology, Herlev University Hospital, Borgmester Ib Juuls Vej 73, 2730, Herlev, Denmark
| | - Kim Holmstrøm
- Bioneer A/S, Hørsholm, Kogle Allé 2, 2970, Hørsholm, Denmark
| | - Lene Buhl Riis
- Department of Pathology, Herlev University Hospital, Borgmester Ib Juuls Vej 73, 2730, Herlev, Denmark
- Institute for Clinical Medicine, University of Copenhagen, 2200, Copenhagen, Denmark
| | - Estrid Høgdall
- Department of Pathology, Herlev University Hospital, Borgmester Ib Juuls Vej 73, 2730, Herlev, Denmark
- Institute for Clinical Medicine, University of Copenhagen, 2200, Copenhagen, Denmark
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Martini GR, Tikhonova E, Rosati E, DeCelie MB, Sievers LK, Tran F, Lessing M, Bergfeld A, Hinz S, Nikolaus S, Kümpers J, Matysiak A, Hofmann P, Saggau C, Schneiders S, Kamps AK, Jacobs G, Lieb W, Maul J, Siegmund B, Seegers B, Hinrichsen H, Oberg HH, Wesch D, Bereswill S, Heimesaat MM, Rupp J, Kniemeyer O, Brakhage AA, Brunke S, Hube B, Aden K, Franke A, Iliev ID, Scheffold A, Schreiber S, Bacher P. Selection of cross-reactive T cells by commensal and food-derived yeasts drives cytotoxic T H1 cell responses in Crohn's disease. Nat Med 2023; 29:2602-2614. [PMID: 37749331 PMCID: PMC10579100 DOI: 10.1038/s41591-023-02556-5] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 08/22/2023] [Indexed: 09/27/2023]
Abstract
Aberrant CD4+ T cell reactivity against intestinal microorganisms is considered to drive mucosal inflammation in inflammatory bowel diseases. The disease-relevant microbial species and the corresponding microorganism-specific, pathogenic T cell phenotypes remain largely unknown. In the present study, we identified common gut commensal and food-derived yeasts, as direct activators of altered CD4+ T cell reactions in patients with Crohn's disease (CD). Yeast-responsive CD4+ T cells in CD display a cytotoxic T helper cell (TH1 cell) phenotype and show selective expansion of T cell clones that are highly cross-reactive to several commensal, as well as food-derived, fungal species. This indicates cross-reactive T cell selection by repeated encounter with conserved fungal antigens in the context of chronic intestinal disease. Our results highlighted a role of yeasts as drivers of aberrant CD4+ T cell reactivity in patients with CD and suggest that both gut-resident fungal commensals and daily dietary intake of yeasts might contribute to chronic activation of inflammatory CD4+ T cell responses in patients with CD.
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Affiliation(s)
- Gabriela Rios Martini
- Institute of Immunology, Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Ekaterina Tikhonova
- Institute of Immunology, Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Elisa Rosati
- Institute of Immunology, Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Meghan Bialt DeCelie
- The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA
| | - Laura Katharina Sievers
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
- Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Florian Tran
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
- Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Matthias Lessing
- Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Arne Bergfeld
- Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Sophia Hinz
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
- Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Susanna Nikolaus
- Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Julia Kümpers
- Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Anna Matysiak
- Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Philipp Hofmann
- Institute of Immunology, Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Carina Saggau
- Institute of Immunology, Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Stephan Schneiders
- Institute of Immunology, Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Ann-Kristin Kamps
- Institute of Immunology, Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Gunnar Jacobs
- Institute of Epidemiology, Christian-Albrechts-University of Kiel and popgen Biobank, University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Wolfgang Lieb
- Institute of Epidemiology, Christian-Albrechts-University of Kiel and popgen Biobank, University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Jochen Maul
- Gastroenterologie am Bayerischen Platz, Berlin, Germany
- Department of Gastroenterology, Rheumatology and Infectious Diseases, Charité-Universitätsmedizin Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Britta Siegmund
- Department of Gastroenterology, Rheumatology and Infectious Diseases, Charité-Universitätsmedizin Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | | | | | - Hans-Heinrich Oberg
- Institute of Immunology, Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Daniela Wesch
- Institute of Immunology, Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Stefan Bereswill
- Institute of Microbiology, Infectious Diseases and Immunology, Charité-Universitätsmedizin Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Markus M Heimesaat
- Institute of Microbiology, Infectious Diseases and Immunology, Charité-Universitätsmedizin Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
| | - Jan Rupp
- Department of Infectious Diseases and Microbiology, University of Lübeck, Lübeck, Germany
| | - Olaf Kniemeyer
- Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knoell Institute, Jena, Germany
| | - Axel A Brakhage
- Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knoell Institute, Jena, Germany
- Friedrich Schiller Universität, Jena, Germany
| | - Sascha Brunke
- Institute of Microbiology, Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knoell Institute, Jena, Germany
| | - Bernhard Hube
- Friedrich Schiller Universität, Jena, Germany
- Institute of Microbiology, Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knoell Institute, Jena, Germany
| | - Konrad Aden
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
- Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Andre Franke
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Iliyan D Iliev
- The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA
- Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA
| | - Alexander Scheffold
- Institute of Immunology, Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Stefan Schreiber
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
- Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Petra Bacher
- Institute of Immunology, Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.
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11
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Kamal S, Parkash N, Beattie W, Christensen B, Segal JP. Are We Ready to Reclassify Crohn's Disease Using Molecular Classification? J Clin Med 2023; 12:5786. [PMID: 37762727 PMCID: PMC10532006 DOI: 10.3390/jcm12185786] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 08/21/2023] [Accepted: 09/02/2023] [Indexed: 09/29/2023] Open
Abstract
Crohn's disease (CD) is a type of inflammatory bowel disease. The number of IBD cases worldwide was estimated to be 4.9 million in 2019. CD exhibits heterogeneity in clinical presentation, anatomical involvement, disease behaviour, clinical course and response to treatment. The classical description of CD involves transmural inflammation with skip lesions anywhere along the entire gastrointestinal tract. The complexity and heterogeneity of Crohn's disease is not currently reflected in the conventional classification system. Though the knowledge of Crohn's pathophysiology remains far from understood, the established complex interplay of the omics-genomics, transcriptomics, proteomics, epigenomics, metagenomics, metabolomics, lipidomics and immunophenomics-provides numerous targets for potential molecular markers of disease. Advancing technology has enabled identification of small molecules within these omics, which can be extrapolated to differentiate types of Crohn's disease. The multi-omic future of Crohn's disease is promising, with potential for advancements in understanding of its pathogenesis and implementation of personalised medicine.
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Affiliation(s)
- Shahed Kamal
- Department of Gastroenterology, Northern Hospital, Epping, Melbourne VIC 3076, Australia
| | - Nikita Parkash
- Department of Gastroenterology, Royal Melbourne Hospital, Parkville, Melbourne VIC 3052, Australia
| | - William Beattie
- Department of Gastroenterology, Royal Melbourne Hospital, Parkville, Melbourne VIC 3052, Australia
| | - Britt Christensen
- Department of Gastroenterology, Royal Melbourne Hospital, Parkville, Melbourne VIC 3052, Australia
- Department of Gastroenterology, The University of Melbourne, Parkville, Melbourne VIC 3010, Australia
| | - Jonathan P. Segal
- Department of Gastroenterology, Royal Melbourne Hospital, Parkville, Melbourne VIC 3052, Australia
- Department of Gastroenterology, The University of Melbourne, Parkville, Melbourne VIC 3010, Australia
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12
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Rodríguez-Lago I, Blackwell J, Mateos B, Marigorta UM, Barreiro-de Acosta M, Pollok R. Recent Advances and Potential Multi-Omics Approaches in the Early Phases of Inflammatory Bowel Disease. J Clin Med 2023; 12:jcm12103418. [PMID: 37240524 DOI: 10.3390/jcm12103418] [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: 03/20/2023] [Revised: 05/01/2023] [Accepted: 05/09/2023] [Indexed: 05/28/2023] Open
Abstract
Inflammatory bowel disease leads to debilitating gastrointestinal symptoms and reduced quality of life, resulting in a significant burden on healthcare utilization and costs. Despite substantial advancements in diagnosis and treatment, there may still be considerable delays in diagnosing some patients. To reduce disease progression before the full disease spectrum appears and improve prognostic outcomes, several strategies have concentrated on early intervention and prevention. Recent evidence shows that initial immune response changes and endoscopic lesions may exist for years before diagnosis, implying the existence of a preclinical phase of inflammatory bowel disease comparable to findings in other immune-mediated disorders. In this review, we highlight the most relevant findings regarding preclinical inflammatory bowel disease and the prospective role of novel omics techniques in this field.
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Affiliation(s)
- Iago Rodríguez-Lago
- Gastroenterology Department, Hospital Universitario de Galdakao, 48960 Galdakao, Spain
- Biocruces Bizkaia Health Research Institute, 48960 Galdakao, Spain
- Deusto University, 48007 Bilbao, Spain
| | | | - Beatriz Mateos
- Integrative Genomics Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain
| | - Urko M Marigorta
- Integrative Genomics Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain
- IKERBASQUE, Basque Foundation for Sciences, 48009 Bilbao, Spain
| | - Manuel Barreiro-de Acosta
- Gastroenterology Department, Hospital Clínico Universitario de Santiago, 15706 Santiago de Compostela, Spain
| | - Richard Pollok
- Gastroenterology Department, St George's University of London, London SW17 0RE, UK
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13
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Cheah E, Huang JG. Precision medicine in inflammatory bowel disease: Individualizing the use of biologics and small molecule therapies. World J Gastroenterol 2023; 29:1539-1550. [PMID: 36970587 PMCID: PMC10037250 DOI: 10.3748/wjg.v29.i10.1539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 01/17/2023] [Accepted: 02/21/2023] [Indexed: 03/14/2023] Open
Abstract
The advent of biologics and small molecules in inflammatory bowel disease (IBD) has marked a significant turning point in the prognosis of IBD, decreasing the rates of corticosteroid dependence, hospitalizations and improving overall quality of life. The introduction of biosimilars has also increased affordability and enhanced access to these otherwise costly targeted therapies. Biologics do not yet represent a complete panacea: A subset of patients do not respond to first-line anti-tumor necrosis factor (TNF)-alpha agents or may subsequently demonstrate a secondary loss of response. Patients who fail to respond to anti-TNF agents typically have a poorer response rate to second-line biologics. It is uncertain which patient would benefit from a different sequencing of biologics or even a combination of biologic agents. The introduction of newer classes of biologics and small molecules may provide alternative therapeutic targets for patients with refractory disease. This review examines the therapeutic ceiling in current treatment strategies of IBD and the potential paradigm shifts in the future.
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Affiliation(s)
- Eric Cheah
- Department of Gastroenterology and Clinical Nutrition, The Royal Children's Hospital Melbourne, Parkville, VIC 3052, Australia
| | - James Guoxian Huang
- Department of Paediatrics, Khoo Teck Puat-National University Children's Medical Institute, National University Health System, Singapore 119228, Singapore
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
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14
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Cheah E, Huang JG. Precision medicine in inflammatory bowel disease: Individualizing the use of biologics and small molecule therapies. World J Gastroenterol 2023; 29:1395-1406. [DOI: 10.3748/wjg.v29.i10.1395] [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] [Indexed: 03/10/2023] Open
Abstract
The advent of biologics and small molecules in inflammatory bowel disease (IBD) has marked a significant turning point in the prognosis of IBD, decreasing the rates of corticosteroid dependence, hospitalizations and improving overall quality of life. The introduction of biosimilars has also increased affordability and enhanced access to these otherwise costly targeted therapies. Biologics do not yet represent a complete panacea: A subset of patients do not respond to first-line anti-tumor necrosis factor (TNF)-alpha agents or may subsequently demonstrate a secondary loss of response. Patients who fail to respond to anti-TNF agents typically have a poorer response rate to second-line biologics. It is uncertain which patient would benefit from a different sequencing of biologics or even a combination of biologic agents. The introduction of newer classes of biologics and small molecules may provide alternative therapeutic targets for patients with refractory disease. This review examines the therapeutic ceiling in current treatment strategies of IBD and the potential paradigm shifts in the future.
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Affiliation(s)
- Eric Cheah
- Department of Gastroenterology and Clinical Nutrition, The Royal Children's Hospital Melbourne, Parkville, VIC 3052, Australia
| | - James Guoxian Huang
- Department of Paediatrics, Khoo Teck Puat-National University Children's Medical Institute, National University Health System, Singapore 119228, Singapore,Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
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15
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Bodecker-Zingmark L, Widbom L, Hultdin J, Eriksson C, Karling P. Anti-Saccharomyces cerevisiae Antibodies Are Only Modestly More Common in Subjects Later Developing Crohn's Disease. Dig Dis Sci 2023; 68:608-615. [PMID: 35989383 PMCID: PMC9905166 DOI: 10.1007/s10620-022-07630-5] [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: 04/03/2022] [Accepted: 07/16/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND The pathogenic processes in the preclinical phase of inflammatory bowel disease (IBD) are mainly unknown. AIMS To study typical antibodies for IBD in the preclinical phase in a cohort of Northern Sweden. METHODS Antibodies typical for IBD (ASCA, pANCA, lactoferrin-ANCA, antibodies to goblet cells, and pancreas antigen) were analyzed in 123 subjects with preclinical ulcerative colitis (UC), 54 subjects with preclinical Crohn's disease (CD) and in 390 sex- and age-matched controls. In addition, in a subset of subjects, inflammatory markers (CRP, albumin, calprotectin and ferritin) were measured in plasma. RESULTS The mean years between blood samples and IBD diagnosis were for UC 5.1 (SD 3.5) years and CD 5.6 (SD 3.5) years. There was no difference in the proportion of overall positive antibodies between subjects who later developed IBD compared to controls (16.9% vs. 12.3%; p = 0.137). The subjects who later developed CD had a significantly higher proportion of positive ASCA compared to controls (9.3% vs 2.8%; p = 0.034), but for all other antibodies, there were no differences compared to control subjects. Subjects with preclinical IBD and elevated antibodies showed significantly higher plasma calprotectin levels compared to subjects without antibodies (980 μg/L vs 756 μg/L; p = 0.042), but there was no difference in the levels of CRP, albumin and ferritin. CONCLUSIONS We found no significant increase in antibodies typical for IBD years before diagnosis except for ASCA, which was slightly more common in subjects who later developed CD. Very few subjects had detectable antibodies to goblet cells and pancreas antigen.
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Affiliation(s)
- L Bodecker-Zingmark
- Department of Clinical Microbiology, Section of Infection and Immunology, Umeå University, Umeå, Sweden
| | - L Widbom
- Department of Medical Biosciences, Clinical Chemistry, Umeå University, Umeå, Sweden
| | - J Hultdin
- Department of Medical Biosciences, Clinical Chemistry, Umeå University, Umeå, Sweden
| | - C Eriksson
- Department of Clinical Microbiology, Section of Infection and Immunology, Umeå University, Umeå, Sweden
| | - P Karling
- Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
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16
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Vieujean S, Louis E. Precision medicine and drug optimization in adult inflammatory bowel disease patients. Therap Adv Gastroenterol 2023; 16:17562848231173331. [PMID: 37197397 PMCID: PMC10184262 DOI: 10.1177/17562848231173331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 04/16/2023] [Indexed: 05/19/2023] Open
Abstract
Inflammatory bowel diseases (IBD) encompass two main entities including ulcerative colitis and Crohn's disease. Although having a common global pathophysiological mechanism, IBD patients are characterized by a significant interindividual heterogeneity and may differ by their disease type, disease locations, disease behaviours, disease manifestations, disease course as well as treatment needs. Indeed, although the therapeutic armamentarium for these diseases has expanded rapidly in recent years, a proportion of patients remains with a suboptimal response to medical treatment due to primary non-response, secondary loss of response or intolerance to currently available drugs. Identifying, prior to treatment initiation, which patients are likely to respond to a specific drug would improve the disease management, avoid unnecessary side effects and reduce the healthcare expenses. Precision medicine classifies individuals into subpopulations according to clinical and molecular characteristics with the objective to tailor preventative and therapeutic interventions to the characteristics of each patient. Interventions would thus be performed only on those who will benefit, sparing side effects and expense for those who will not. This review aims to summarize clinical factors, biomarkers (genetic, transcriptomic, proteomic, metabolic, radiomic or from the microbiota) and tools that could predict disease progression to guide towards a step-up or top-down strategy. Predictive factors of response or non-response to treatment will then be reviewed, followed by a discussion about the optimal dose of drug required for patients. The time at which these treatments should be administered (or rather can be stopped in case of a deep remission or in the aftermath of a surgery) will also be addressed. IBD remain biologically complex, with multifactorial etiopathology, clinical heterogeneity as well as temporal and therapeutic variabilities, which makes precision medicine especially challenging in this area. Although applied for many years in oncology, it remains an unmet medical need in IBD.
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Affiliation(s)
- Sophie Vieujean
- Hepato-Gastroenterology and Digestive Oncology, University Hospital CHU of Liège, Liège, Belgium
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17
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Goren I, Sharar Fischler T, Yanai H, Pal P, Adigopula B, Pendyala S, Ganesh G, Vishnubhotla R, Rabinowitz KM, Shaham Barda E, Yadamreddy D, Godny L, Peleg N, Banerjee R, Dotan I. Newly Diagnosed Crohn's Disease Patients in India and Israel Display Distinct Presentations and Serological Markers: Insights from Prospective Cohorts. J Clin Med 2022; 11:jcm11236899. [PMID: 36498474 PMCID: PMC9737641 DOI: 10.3390/jcm11236899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 11/12/2022] [Accepted: 11/20/2022] [Indexed: 11/24/2022] Open
Abstract
Background: Crohn’s disease (CD) incidence is rising in India. However, features of newly diagnosed patients with CD in this population are largely unknown. The Indo-Israeli IBD GastroEnterology paRtnership (TiiiGER) aimed to investigate differences in presentation among patients with newly diagnosed CD in India and Israel, and to explore phenotype−serotype correlations. Methods: A prospective observational cohort study of consecutive adults (>18 years) conducted in two large referral centers in India and Israel (2014−2018). Clinical data, an antiglycan serological panel, and 20 CD-associated genetic variants were analyzed. Outcomes: complicated phenotype at diagnosis and early complicated course (hospitalizations/surgeries) within 2 years of diagnosis. Results: We included 260 patients (104, Indian (65.4%, male; age, 37.8); 156 Israeli (49.4%, male; 31.8, age)). Median lag time from symptoms onset to diagnosis was 10.5 (IQR 3−38) vs. 3 (IQR 1−8) months in Indian vs. Israeli patients (p < 0.001). Complicated phenotype at diagnosis was observed in 48% of Indian and 30% of Israeli patients (p = 0.003). Complicated phenotype was associated with higher anti-Saccharomyces cerevisiae antibody (ASCA) seropositivity rate among Israeli patients (p < 0.001), but not among Indian patients. Antiglycan serology did not correlate with the tested genetic variants. Early complicated course occurred in 28 (18%) Israeli and 13 (12.5%) Indian patients. The time from diagnosis to complication was comparable (log rank p = 0.152). Antiglycan serology did not correlate with a complicated early course in either cohort. Conclusions: There are significant differences in patients presenting with newly diagnosed CD in India and Israel, including phenotype and distinct biomarkers at diagnosis. These differences suggest different genetic and environmental disease modifiers.
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Affiliation(s)
- Idan Goren
- IBD Center, Division of Gastroenterology, Rabin Medical Center Affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Petah Tikva 49100, Israel
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
- Correspondence:
| | - Tali Sharar Fischler
- IBD Center, Division of Gastroenterology, Rabin Medical Center Affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Petah Tikva 49100, Israel
| | - Henit Yanai
- IBD Center, Division of Gastroenterology, Rabin Medical Center Affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Petah Tikva 49100, Israel
| | - Partha Pal
- Department of Gastroenterology, Asian Institute of Gastroenterology, Hyderabad 501301, India
| | - Bhargavi Adigopula
- Department of Gastroenterology, Asian Institute of Gastroenterology, Hyderabad 501301, India
| | - Sushmitha Pendyala
- Department of Gastroenterology, Asian Institute of Gastroenterology, Hyderabad 501301, India
| | - Girish Ganesh
- Department of Gastroenterology, Asian Institute of Gastroenterology, Hyderabad 501301, India
| | - Ravikanth Vishnubhotla
- Department of Genomics and Molecular Biology, Institute of Translational Research, Asian Institute of Gastroenterology and AIG Hospitals, Hyderabad 500032, India
| | - Keren Masha Rabinowitz
- IBD Center, Division of Gastroenterology, Rabin Medical Center Affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Petah Tikva 49100, Israel
- Felsenstein Medical Research Center, Rabin Medical Center, Beilinson Hospital Affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Petah Tikva 49414, Israel
| | - Efrat Shaham Barda
- IBD Center, Division of Gastroenterology, Rabin Medical Center Affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Petah Tikva 49100, Israel
- Felsenstein Medical Research Center, Rabin Medical Center, Beilinson Hospital Affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Petah Tikva 49414, Israel
| | - Durga Yadamreddy
- Department of Genomics and Molecular Biology, Institute of Translational Research, Asian Institute of Gastroenterology and AIG Hospitals, Hyderabad 500032, India
| | - Lihi Godny
- IBD Center, Division of Gastroenterology, Rabin Medical Center Affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Petah Tikva 49100, Israel
| | - Noam Peleg
- IBD Center, Division of Gastroenterology, Rabin Medical Center Affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Petah Tikva 49100, Israel
| | - Rupa Banerjee
- Department of Gastroenterology, Asian Institute of Gastroenterology, Hyderabad 501301, India
| | - Iris Dotan
- IBD Center, Division of Gastroenterology, Rabin Medical Center Affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Petah Tikva 49100, Israel
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18
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Le C, Zeffren N, Kramer N, Rosenstein ED. Rheumatologic Associations of Microscopic Colitis: A Narrative Review. Mod Rheumatol 2022; 33:441-447. [PMID: 35993773 DOI: 10.1093/mr/roac080] [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: 03/11/2022] [Revised: 05/22/2022] [Accepted: 07/31/2022] [Indexed: 11/12/2022]
Abstract
Extra-intestinal manifestations are frequent complications of the classical inflammatory bowel diseases, Crohn's disease and ulcerative colitis. However, in addition to the classical diseases, there is a spectrum of conditions, often termed "microscopic colitis", in which extra-intestinal manifestations are less well described. Our objective was to review the literature regarding the extra-intestinal manifestations complicating microscopic colitis and describe the association with systemic autoimmune rheumatic diseases. A comprehensive search and review of peer-reviewed English-language and international journals and reports was completed based on key terms, including "microscopic colitis", "lymphocytic colitis", "collagenous colitis", "inflammatory bowel disease", "extraintestinal manifestations", and the specific disease associations utilizing the PubMed Central database and MEDLINE. A broad spectrum of rheumatologic manifestations has been reported in patients with microscopic colitis. The identification of rheumatoid arthritis and limited scleroderma as co-morbidities with microscopic colitis was noteworthy. Inflammatory arthropathy was frequently seen in microscopic colitis, usually preceding or occurring in conjunction with the onset of gastrointestinal symptoms. A variety of presentations of associated arthritis were reported: migratory, symmetric or asymmetric, peripheral or axial, oligoarticular or polyarticular, erosive or non-erosive. There was a high incidence of autoantibodies in these patients, supporting a potential autoimmune association. On the basis of these anecdotal reports, we would suggest development of a clinical registry to help define the incidence of extra-intestinal manifestations and systemic autoimmune rheumatic diseases among microscopic colitis patients to help elucidate shared predispositions, pathogenic mechanisms and therapeutic opportunities.
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Affiliation(s)
- Christopher Le
- Department of Medicine, Bayonne Medical Center, CarePoint Health, Bayonne, NJ, USA
| | - Noam Zeffren
- Department of Medicine, Bayonne Medical Center, CarePoint Health, Bayonne, NJ, USA
| | - Neil Kramer
- Institute for Rheumatic & Autoimmune Diseases, Overlook Medical Center, Atlantic Health System, Summit, USA.,Division of Rheumatology, Department of Medicine, NYU Langone Medical Center, New York, USA
| | - Elliot D Rosenstein
- Institute for Rheumatic & Autoimmune Diseases, Overlook Medical Center, Atlantic Health System, Summit, USA.,Division of Rheumatology, Department of Medicine, NYU Langone Medical Center, New York, USA
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19
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Yorulmaz E, Adalı G, Yorulmaz H, Taşan G, Gürses S, Ayaş MR, Tuncer İ. The Correlation between New Serological Markers and Disease Phenotype and Activation in Inflammatory Bowel Disease. Middle East J Dig Dis 2022; 14:294-303. [PMID: 36619271 PMCID: PMC9489435 DOI: 10.34172/mejdd.2022.286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 06/07/2022] [Indexed: 11/06/2022] Open
Abstract
Background: The aim of the study is to assess the correlation between a new antibody panel that is developed against glycans on Crohn's disease (CD) and ulcerative colitis (UC) differentiative diagnosis and disease properties. Methods: In the study, 137 CD and 122 UC patients and 90 controls were included. Anti-saccharomyces cerevisiae IgG (ASCA), anti-laminaribioside IgG (ALCA), anti-chitobioside IgA (ACCA), and anti-mannobioside IgG (AMCA) were tested in serum. Results: While at least 1 of the other 3 serological markers was positive in 89% of ASCA-positive patients, at least 1 of the other 3 serological markers was positive in 77% of ASCA-negative patients. Positivity ratio for a single anticarbohydrate was ALCA 18 (22%), ACCA 5 (12%), and AMCA 16 (23%). A significant correlation was found between ASCA positivity (P<0.001) in operated patients and between ASCA, ALCA, and ACCA positivity (P<0.05) in patients with stricturing and fistulizing CD. According to the ROC analysis, ASCA was found to have the highest area under the curve (0.70-0.82) (correlation coefficient interval 95%). A significant correlation was found between ASCA, ALCA, and ACCA positivity and high serum antibody levels and disease activation (P<0.05). Conclusion: ASCA, ALCA, and ACCA were found to be correlated with the disease complication and activation in CD. ASCA and ALCA were determined as the best markers in the differentiation between CD and UC.
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Affiliation(s)
- Elif Yorulmaz
- Department of Gastroenterology, University of Health Sciences, Bağcılar Training and Research Hospital, Istanbul, Turkey,Corresponding Author: Elif Yorulmaz, MD Department of Gastroenterology, University of Health Sciences, Bağcılar Training and Research Hospital, İstanbul, Turkey Tel:+90 0212 440 40 00 Fax:+90 0212 440 42 42
| | - Gupse Adalı
- Department of Gastroenterology, University of Health Sciences, Umraniye Training and Research Hospital, Istanbul, Turkey
| | - Hatice Yorulmaz
- Faculty of Health Sciences, Haliç University, Eyüp, İstanbul, Turkey
| | - Güralp Taşan
- Department of Gastroenterology, Istanbul Medeniyet University, School of Medicine, Goztepe, Istanbul, Turkey
| | - Seval Gürses
- Department of Biology, Trakya University, Edirne, Turkey
| | | | - İlyas Tuncer
- Department of Gastroenterology, Istanbul Medeniyet University, School of Medicine, Goztepe, Istanbul, Turkey
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20
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Bourgonje AR, Vogl T, Segal E, Weersma RK. Antibody signatures in inflammatory bowel disease: current developments and future applications. Trends Mol Med 2022; 28:693-705. [DOI: 10.1016/j.molmed.2022.05.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 05/01/2022] [Accepted: 05/03/2022] [Indexed: 11/25/2022]
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21
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Jiang M, Zeng Z, Chen K, Dang Y, Li L, Ma C, Cheng R, Hu K, Li X, Zhang H. Enterogenous Microbiotic Markers in the Differential Diagnosis of Crohn's Disease and Intestinal Tuberculosis. Front Immunol 2022; 13:820891. [PMID: 35371004 PMCID: PMC8966387 DOI: 10.3389/fimmu.2022.820891] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 02/18/2022] [Indexed: 02/05/2023] Open
Abstract
Crohn's disease (CD) is a chronic intestinal disorder characterized by refractory gastrointestinal ulcerations. Intestinal tuberculosis (ITB) is one common intestinal disease in east Asia. The two diseases share similar clinical manifestations and endoscopic characteristics. Thus, it is difficult to establish a definite diagnosis of CD, CD concomitant with ITB (CD-ITB), and ITB in practice. Some enterogeneous microbiotic markers have been applied to differentiate CD and ITB, but it remains unknown how they work for the three groups of patients. The aim of our study was to explore the diagnostic values of these enterogeneous microbiotic markers (ASCA IgG, ASCA IgA, ACCA, Anti-I2 and AMCA) among CD, CD-ITB, and ITB patients. A total of 124 individuals were retrospectively enrolled in this study, namely, 103 CD patients, 10 CD-ITB patients, 9 ITB patients, and 68 healthy controls. The demographic and clinical characteristics of these patients were collected and analyzed. The values of these individual or combined enterogeneous microbiotic markers in diagnosis and classification were assessed in CD, CD-ITB, and ITB patients. ASCA IgG, ASCA IgA, and AMCA could accurately differentiate CD patients from healthy controls with an area under curve (AUC) of 0.688, 0.601, and 0.638, respectively. ASCA IgG was significantly higher in CD patients than in CD-ITB patients (P = 0.0003). The Anti-I2 antibody was appropriate for distinguishing CD-ITB from ITB patients (P = 0.039). In CD patients, ASCA IgG was higher in severe patients than in mild (P <0.0001) and inactive patients (P <0.0001), respectively. AMCA was significantly elevated in severe and moderate patients compared to inactive patients (P = 0.001, P = 0.003, respectively). AMCA was associated with a higher risk of CD-related surgery with a significant P-value of 0.0038. In our cohort, ASCAs and AMCA could accurately distinguish CD from healthy controls with an acceptable AUC. A combination of elevated ASCA IgG and AMCA antibodies established a higher sensitivity in differentiating CD from healthy controls. Elevated ASCA IgG demonstrated a differential diagnostic value between CD and CD-ITB. Anti-I2 could also distinguish CD-ITB from ITB. The level of AMCA was associated with both disease severity and CD-related surgery. Likewise, the level of ASCA IgG was also related to disease severity.
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Affiliation(s)
- Mingshan Jiang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Zhen Zeng
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Kexin Chen
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Yuan Dang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Lili Li
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Chunxiang Ma
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Rui Cheng
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Kehan Hu
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Xi Li
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Hu Zhang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
- Laboratory of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
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The Role of Biomarkers in Surgery for Ulcerative Colitis: A Review. J Clin Med 2021; 10:jcm10153362. [PMID: 34362144 PMCID: PMC8348722 DOI: 10.3390/jcm10153362] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 07/25/2021] [Accepted: 07/28/2021] [Indexed: 12/19/2022] Open
Abstract
Ulcerative colitis (UC) is an inflammatory condition that generally affects the rectum and extends proximally into the colon in a continuous, distal-to-proximal pattern. Surgical resection (total proctocolectomy) is the only cure for UC and is often necessary in managing complicated or refractory disease. However, recent advances in biologically targeted therapies have resulted in improved disease control, and surgery is required in only a fraction of cases. This ever-increasing array of options for medical management has added complexity to surgical decision-making. In some circumstances, the added time required to ensure failure of medical therapy can delay colectomy in patients who will ultimately need it. Indeed, many patients with severe disease undergo trials of multiple medical therapies prior to considering surgery. In severe cases of UC, continued medical management has been associated with a delay to surgical intervention and higher rates of morbidity and mortality. Biomarkers represent a burgeoning field of research, particularly in inflammatory bowel disease and cancer. This review seeks to highlight the different possible settings for surgery in UC and the role various biomarkers might play in each.
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A Pilot Clinical Study on Post-Operative Recurrence Provides Biological Clues for a Role of Candida Yeasts and Fluconazole in Crohn's Disease. J Fungi (Basel) 2021; 7:jof7050324. [PMID: 33922391 PMCID: PMC8146386 DOI: 10.3390/jof7050324] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 04/15/2021] [Accepted: 04/16/2021] [Indexed: 02/06/2023] Open
Abstract
Background and aims: This study prompted by growing evidence of the relationship between the yeast Candida albicans and Crohn’s disease (CD) was intended to assess the effect of a 6-month course of the antifungal fluconazole (FCZ) on post-operative recurrence of CD. Methods: Mycological samples (mouth swabs and stools) and serum samples were collected from 28 CD patients randomized to receive either FCZ (n = 14) or placebo (n = 14) before surgical resection. Serological analysis focused on levels of calprotectin, anti-glycan antibodies, and antibody markers of C. albicans pathogenic transition. Levels of galectin-3 and mannose binding lectin (MBL) involved in C. albicans sensing and inflammation were also measured. Results: 1, 2, 3, and 6 months after surgery, endoscopy revealed recurrence in 5/12 (41.7%) patients in the FCZ group and 5/9 (55.6%) in the placebo group, the small cohort preventing any clinical conclusions. In both groups, surgery was followed by a marked decrease in C. albicans colonization and biomarkers of C. albicans pathogenic transition decreased to non-significant levels. Anti-glycan antibodies also decreased but remained significant for CD. Galectin-3 and calprotectin also decreased. Conversely, MBL levels, which inversely correlated with anti-C. albicans antibodies before surgery, remained stable. Building biostatistical multivariate models to analyze he changes in antibody and lectin levels revealed a significant relationship between C. albicans and CD. Conclusion: Several combinations of biomarkers of adaptive and innate immunity targeting C. albicans were predictive of CD recurrence after surgery, with area under the curves (AUCs) as high as 0.86. FCZ had a positive effect on biomarkers evolution. ClinicalTrials.gov ID: NCT02997059, 19 December 2016. University Hospital Lille, Ministry of Health, France. Effect of Fluconazole on the Levels of Anti-Saccharomyces cerevisiae Antibodies (ASCA) After Surgical Resection for Crohn’s Disease. Multicenter, Randomized, and Controlled in Two Parallel Groups Versus Placebo.
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Aleksandrova EN, Novikov AA, Lukina GV, Parfenov AI. [Clinical value of antibodies in inflammatory bowel diseases]. TERAPEVT ARKH 2021; 93:228-235. [PMID: 36286642 DOI: 10.26442/00403660.2021.02.200610] [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: 04/05/2021] [Accepted: 04/05/2021] [Indexed: 11/22/2022]
Abstract
Inflammatory bowel disease IBD (Crohns disease CD, ulcerative colitis UC) immune-mediated diseases of the digestive tract of unknown etiology. The basis of the pathogenesis of IBD is a violation of the protective mechanisms of the intestinal barrier as a result of a complex interaction of environmental factors, a genetic predisposition and defects in the activation of the immune response in the lymphoid tissue of the intestinal mucosa. Three groups of antibodies are detected in the sera of IBD patients: autoantibodies, antimicrobial antibodies and antibodies to peptide antigens. In CD, the most useful diagnostic markers are ASCA; in UC patients pANCA. Antibodies are not among the diagnostic criteria for CD and UC, the diagnosis of which is traditionally made on the basis of a complex of clinical, radiological, endoscopic and histological signs, but can be used as useful additional non-invasive markers for early diagnosis, assessment of clinical phenotypes, prognosis and effectiveness of treatment of these diseases.
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Affiliation(s)
| | - A A Novikov
- Loginov Moscow Clinical Research and Practical Center
| | - G V Lukina
- Loginov Moscow Clinical Research and Practical Center
| | - A I Parfenov
- Loginov Moscow Clinical Research and Practical Center
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Abstract
Background and aim: The diagnosis of Crohn's disease (CD) is challenging. Ongoing search for biomarkers to facilitate the diagnosis is a worthwhile endeavor. The aim of this study was to explore the role of serological markers in the diagnosis of CD at an inflammatory bowel disease (IBD) referral center.Methods: This was a retrospective study including 196 suspected CD patients. The expression of ASCA-IgG, ASCA-IgA, AYMA-IgG, AYCA-IgA, FI2Y-IgG, and pANCA in the patient's serum was determined by enzyme-linked immunosorbent assay (ELISA) and indirect immunofluorescence (IF).Results: ASCA was a relatively specific marker for CD (p = 0.0005), but not AYMA-IgG, AYCA-IgA, F12Y-IgG (p = 0.5936, 0.7974, 0.1085, respectively). However, a high sensitivity of 96.77% (95% CI 90.19%-99.83%) was noted for ASCA+/FI2Y+ to identify CD patients among the suspected cases, albeit with low PPV. The more combinations of serological markers, the higher sensitivity, and NPV. No correlation was found between the age of onset or disease location and the expression of ASCA, AYMA, AYCA, FI2Y, or pANCA. There was no significant difference between the expression of ASCA and the disease behavior at diagnosis (p = 0.3307). However, a decreased proportion of AYMA+ CD patients was found in those who received surgery compared with their non-surgical counterparts (p = 0.0488).Conclusions: ASCA was found to be the most accurate serological marker for the differential diagnosis of CD. Combinations of ASCA, AYMA, AYCA, and FI2Y improved diagnostic accuracy of CD.
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Affiliation(s)
- Xin Gao
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Yan Zhang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
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26
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Lee DS, Lee KL, Jeong JB, Shin S, Kim SH, Kim JW. Expression of Chemokine CCL28 in Ulcerative Colitis Patients. Gut Liver 2021; 15:70-76. [PMID: 32102131 PMCID: PMC7817927 DOI: 10.5009/gnl19273] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2019] [Revised: 12/05/2019] [Accepted: 12/06/2019] [Indexed: 12/14/2022] Open
Abstract
Background/Aims Ulcerative colitis (UC) is an inflammatory bowel disease for which new serological markers are required. The purpose of this study was to assess the role of the mucosa-associated epithelial chemokine CCL28 in UC. Methods The study included 50 patients; of these, 25 were patients with UC, and 25 were healthy controls. The levels of serum CCL28 were analyzed using enzyme-linked immunosorbent assay. CCL28 expression was analyzed by immunohistochemistry (IHC) in 15 representative colon tissues biopsied based on disease activity (UC patients with severe activity, five samples; UC patients with mild activity, five samples; healthy controls, five samples). Results The serum CCL28 levels were remarkably higher (p<0.05) in patients with UC (median, 235.7 pg/mL; IQR, 63.8 to 117.2 pg/mL) than in healthy controls (median, 48.9, pg/mL; IQR, 35.9 to 42.0 pg/mL). However, there was no significant difference in serum CCL28 according to disease extent or activity. In contrast, IHC analysis revealed a significant difference in CCL28 consistent with disease status, disease extent, and disease activity. Conclusions CCL28 could be useful for diagnosing UC. However, further validations of CCL28 on disease activity and severity are needed.
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Affiliation(s)
- Dong Seok Lee
- Departments of Gastroenterology, SMG-SNU Boramae Medical Center, Seoul National University of College of Medicine, Seoul, Korea
| | - Kook Lae Lee
- Departments of Gastroenterology, SMG-SNU Boramae Medical Center, Seoul National University of College of Medicine, Seoul, Korea
| | - Ji Bong Jeong
- Departments of Gastroenterology, SMG-SNU Boramae Medical Center, Seoul National University of College of Medicine, Seoul, Korea
| | - Sue Shin
- Departments of Laboratory Medicine, SMG-SNU Boramae Medical Center, Seoul National University of College of Medicine, Seoul, Korea
| | - Su Hwan Kim
- Departments of Gastroenterology, SMG-SNU Boramae Medical Center, Seoul National University of College of Medicine, Seoul, Korea
| | - Ji Won Kim
- Departments of Gastroenterology, SMG-SNU Boramae Medical Center, Seoul National University of College of Medicine, Seoul, Korea
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Castro-Dopico T, Clatworthy MR. Mucosal IgG in inflammatory bowel disease - a question of (sub)class? Gut Microbes 2020; 12:1-9. [PMID: 31480888 PMCID: PMC7524157 DOI: 10.1080/19490976.2019.1651596] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 08/01/2019] [Accepted: 07/31/2019] [Indexed: 02/06/2023] Open
Abstract
Immunoglobulins (Igs) form a cornerstone of mucosal immunity. In the gastrointestinal tract, secretory IgA and IgM bind to commensal microorganisms within the intestinal lumen to prevent them from breaching the intestinal epithelium - a process known as immune exclusion. In recent years, there has been renewed interest in the role of IgG in intestinal immunity, driven in part by a genetic association of an affinity-lowering variant of an IgG receptor, FcγRIIA, with protection from ulcerative colitis (UC), a subclass of inflammatory bowel disease (IBD). We recently demonstrated a role for IgG and Fcγ receptor signalling in driving pathogenic IL-1β production by colonic mononuclear phagocytes and the subsequent induction of a local type 17 response in UC. Here, we discuss the potential relevance of our observations to the other major subclass of IBD - Crohn's disease (CD) - where the genetic association with FCGR variants is less robust and consider how this may impact therapeutic interventions in these disease subsets.
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Affiliation(s)
- Tomas Castro-Dopico
- Molecular Immunity Unit, Department of Medicine, University of Cambridge, Cambridge, UK
| | - Menna R. Clatworthy
- Molecular Immunity Unit, Department of Medicine, University of Cambridge, Cambridge, UK
- NIHR Cambridge Biomedical Research Centre, Cambridge, UK
- Cellular Genetics, Wellcome Trust Sanger Institute, Hinxton, UK
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Zhang Y, Chen Z, He Y, Wang J, Jiang M, Xu J, Chen M, Feng Y. Identification of Differentially Expressed Proteins in Serum of Obese Patients by Isobaric Tags for Relative and Absolute Quantification (iTRAQ)-Coupled 2D LC-MS. Med Sci Monit 2020; 26:e924882. [PMID: 32740648 PMCID: PMC7418484 DOI: 10.12659/msm.924882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND The aim of this study was to identify the differentially expressed proteins of obese patients compared with normal participants and to provide a potential target for future investigation of obesity. MATERIAL AND METHODS We enrolled 10 obese male adults and 10 matched normal subjects. Serum samples were collected to get total protein extraction, denaturation, deoxidation, and enzymatic hydrolysis. Differentially expressed proteins were distinguished with mass spectrometry after samples were labeled with iTRAQ. RESULTS A total of 9622 differentially expressed peptides were identified, corresponding to 733 proteins; 118 proteins of these showed significant differential expression, with 15 upregulated and 103 downregulated. CONCLUSIONS iTRAQ is an effective technique to identify differentially expressed proteins in obese patients. The development of obesity is correlated with a series of complex elements and mutual effects. The proteins identified in this study may provide novel directions and targets for future pathological studies of obesity.
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Affiliation(s)
- Ying Zhang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China (mainland)
| | - Zhong Chen
- Department of Obstetrics and Gynecology, Wuxi Maternal and Child Health Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu, China (mainland)
| | - Yue He
- Department of Obstetrics and Gynecology, Wuxi Maternal and Child Health Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu, China (mainland)
| | - Jianxia Wang
- Department of Obstetrics and Gynecology, Wuxi Maternal and Child Health Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu, China (mainland)
| | - Minhui Jiang
- Department of Obstetrics and Gynecology, Wuxi Maternal and Child Health Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu, China (mainland)
| | - Jianjuan Xu
- Department of Obstetrics and Gynecology, Wuxi Maternal and Child Health Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu, China (mainland)
| | - Minghua Chen
- Department of Obstetrics and Gynecology, Wuxi Maternal and Child Health Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu, China (mainland)
| | - Yaling Feng
- Department of Obstetrics and Gynecology, Wuxi Maternal and Child Health Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu, China (mainland)
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Noor NM, Verstockt B, Parkes M, Lee JC. Personalised medicine in Crohn's disease. Lancet Gastroenterol Hepatol 2020; 5:80-92. [PMID: 31818474 DOI: 10.1016/s2468-1253(19)30340-1] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Revised: 08/19/2019] [Accepted: 08/21/2019] [Indexed: 12/13/2022]
Abstract
Similar to many immune-mediated diseases, Crohn's disease follows a relapsing-remitting pattern, with a variable disease course and heterogeneous clinical outcomes. Frequency of flare-ups, development of complications, and response to treatment collectively determine the effect on a patient's quality of life, which can vary from minimal disruption to profound disability or death. Despite recent advances in the understanding of complex disease pathogenesis, including for Crohn's disease, management decisions are still typically made using a one-size-fits-all approach. Indeed, the inability to reliably predict clinical outcomes in a way that could guide future therapy represents a major unmet need. Recently, several important insights have been made into the biology underlying outcomes in Crohn's disease. In this Review, we will summarise these insights and discuss how greater understanding of these disease mechanisms can be used to develop clinically useful biomarkers, identify novel approaches to optimise disease control, and help deliver the goal of personalised medicine.
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Affiliation(s)
- Nurulamin M Noor
- Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK; Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Trust, Cambridge, UK; Medical Research Council Clinical Trials Unit, University College London, London, UK
| | - Bram Verstockt
- Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK; Department of Gastroenterology and Hepatology, University Hospitals Leuven, Katholieke Universiteit Leuven, Leuven, Belgium; Translational Research in Gastrointestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Miles Parkes
- Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK; Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Trust, Cambridge, UK
| | - James C Lee
- Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK; Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Trust, Cambridge, UK; Cambridge Institute for Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Building, Cambridge Biomedical Campus, Cambridge, UK.
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Caruso R, Lo BC, Núñez G. Host-microbiota interactions in inflammatory bowel disease. Nat Rev Immunol 2020; 20:411-426. [PMID: 32005980 DOI: 10.1038/s41577-019-0268-7] [Citation(s) in RCA: 464] [Impact Index Per Article: 92.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/16/2019] [Indexed: 12/25/2022]
Abstract
The mammalian intestine is colonized by trillions of microorganisms that have co-evolved with the host in a symbiotic relationship. The presence of large numbers of symbionts near the epithelial surface of the intestine poses an enormous challenge to the host because it must avoid the activation of harmful inflammatory responses to the microorganisms while preserving its ability to mount robust immune responses to invading pathogens. In patients with inflammatory bowel disease, there is a breakdown of the multiple strategies that the immune system has evolved to promote the separation between symbiotic microorganisms and the intestinal epithelium and the effective killing of penetrant microorganisms, while suppressing the activation of inappropriate T cell responses to resident microorganisms. Understanding the complex interactions between intestinal microorganisms and the host may provide crucial insight into the pathogenesis of inflammatory bowel disease as well as new avenues to prevent and treat the disease.
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Affiliation(s)
- Roberta Caruso
- Department of Pathology and Rogel Cancer Center, the University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Bernard C Lo
- Department of Pathology and Rogel Cancer Center, the University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Gabriel Núñez
- Department of Pathology and Rogel Cancer Center, the University of Michigan Medical School, Ann Arbor, Michigan, USA.
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31
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He JS, Tan JY, Li XZ, Feng R, Xiong SS, Lin SN, Qiu Y, Mao R. Serum biomarkers of fibrostenotic Crohn's disease: Where are we now? J Dig Dis 2020; 21:336-341. [PMID: 32496631 DOI: 10.1111/1751-2980.12913] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 06/01/2020] [Accepted: 06/02/2020] [Indexed: 12/11/2022]
Abstract
Intestinal fibrosis and subsequent stricture formation are major clinical challenges in inflammatory bowel disease, resulting in an increased rate of operation and poor prognosis compared with those without. With the changing perception that intestinal fibrosis is irreversible to the point of view that it is reversible in recent years, various candidate serum biomarkers have been studied over the past decades, which may stratify patients based on their risks of developing stenosis and enable the detection of early stages of fibrosis. However, reliable and accurate biomarkers are still unavailable due to conflicting results and the lack of high-quality evidence. In this review we summarized the serum biomarkers that have been proposed for intestinal fibrosis in recent years, which includes gene polymorphisms or variants, epigenetic markers, extracellular matrix components, growth factors, and antibodies, aiming to provide clues for future research.
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Affiliation(s)
- Jin Shen He
- Department of Gastroenterology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Jin Yu Tan
- Department of Gastroenterology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Xiao Zhi Li
- Department of Gastroenterology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Rui Feng
- Department of Gastroenterology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Shan Shan Xiong
- Department of Gastroenterology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Si Nan Lin
- Department of Gastroenterology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Yun Qiu
- Department of Gastroenterology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Ren Mao
- Department of Gastroenterology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
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Leppkes M, Neurath MF. Cytokines in inflammatory bowel diseases - Update 2020. Pharmacol Res 2020; 158:104835. [PMID: 32416212 DOI: 10.1016/j.phrs.2020.104835] [Citation(s) in RCA: 121] [Impact Index Per Article: 24.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 04/15/2020] [Accepted: 04/15/2020] [Indexed: 02/06/2023]
Abstract
Inflammatory Bowel Diseases (IBD), namely Crohn's Disease and Ulcerative Colitis, cause a significant disease burden in modern civilization. Ever since the introduction of anti-TNF-directed therapies 20 years ago, cytokines have attracted a lot of research attention and several cytokine-directed therapies have been implemented in the clinical treatment of these diseases. The research progress in these past years has underlined the importance of both myeloid and lymphoid elements of the immune system in the pathogenesis of IBD and their cytokine-mediated interplay. The conceptual framework of the mucosal cytokine network has shifted during these years from a T helper (Th) dichotomy (Th1/Th2) to the effector/regulatory T cell balance, while nowadays, the importance of myeloid cell instruction of lymphocytes, namely by IL-12 and IL-23, is increasingly recognized. Anti-IL-12p40 agents, like ustekinumab, groundbreakingly changed patient care, and anti-IL23p19-directed approaches are on the verge of grand success. In this review we present a modular approach to understand the cytokine network and put it into the context of the pathogenesis of IBD with a special focus on publications since 2014.
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Affiliation(s)
- M Leppkes
- Department of Medicine, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research, Erlangen, Germany.
| | - M F Neurath
- Department of Medicine, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research, Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
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Bermont A, Broide E, Matalon S, Richter V, Lazarovitch T, Bar-Yoseph H, Shirin H. New-Onset of Crohn's Disease Is Associated with Antistreptolysin O Positive Titers. Clin Exp Gastroenterol 2020; 13:187-191. [PMID: 32494182 PMCID: PMC7227782 DOI: 10.2147/ceg.s245770] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 04/07/2020] [Indexed: 11/30/2022] Open
Abstract
Objective Different infectious agents have been presumed to be candidates acting as an etiologic factor or trigger of Crohn’s disease (CD). Group A Streptococcus (GAS) is a common human infection agent that can also trigger post-infectious immune-mediated conditions. The current study aimed to examine whether the immunogenic activity induced by GAS may trigger new-onset of CD. Methods Data for antistreptolysin O (ASO) level, throat culture for GAS, and history of streptococcal infection were collected from 91 patients with CD that were divided into three groups including; new-onset CD, CD in remission and active CD. The data were compared with the control group. Results All participants had negative results of throat culture for GAS and had no history of documented streptococcal infection in the past year. Our results indicate that new-onset CD, but not CD in remission or active CD, is associated with significantly increased positive ASO compared to controls. Half of the patients in the new-onset CD group were ASO positive, which was significantly higher compared to the control group in a univariant (OR: 4.00; 95% CI 1.27–12.58; P=0.02) and multivariant analysis (OR: 4.41; 95% CI 1.35–14.37; P=0.014). Conclusion Our study is the first to focus on ASO levels in patients with CD and to demonstrate a significant association between ASO and new-onset of CD. Large prospective randomized controlled studies are needed to confirm the validity of this data and to further clarify the clinical significance of our findings.
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Affiliation(s)
- Anton Bermont
- The Gonczarowski Family Institute of Gastroenterology and Liver Diseases, Shamir (Assaf Harofeh) Medical Center, Tel Aviv University, Tel Aviv, Israel
| | - Efrat Broide
- The Gonczarowski Family Institute of Gastroenterology and Liver Diseases, Shamir (Assaf Harofeh) Medical Center, Tel Aviv University, Tel Aviv, Israel
| | - Shay Matalon
- The Gonczarowski Family Institute of Gastroenterology and Liver Diseases, Shamir (Assaf Harofeh) Medical Center, Tel Aviv University, Tel Aviv, Israel
| | - Vered Richter
- The Gonczarowski Family Institute of Gastroenterology and Liver Diseases, Shamir (Assaf Harofeh) Medical Center, Tel Aviv University, Tel Aviv, Israel
| | - Tsilia Lazarovitch
- The Microbiology Laboratory, Shamir (Assaf Harofeh) Medical Center, Tel Aviv University, Tel Aviv, Israel
| | - Haggai Bar-Yoseph
- Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel; Bruce Rappaport School of Medicine, Technion Israel Institute of Technology, Haifa, Israel
| | - Haim Shirin
- The Gonczarowski Family Institute of Gastroenterology and Liver Diseases, Shamir (Assaf Harofeh) Medical Center, Tel Aviv University, Tel Aviv, Israel
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Huhn M, Herrero San Juan M, Melcher B, Dreis C, Schmidt KG, Schwiebs A, Collins J, Pfeilschifter JM, Vieth M, Stein J, Radeke HH. Inflammation-Induced Mucosal KYNU Expression Identifies Human Ileal Crohn's Disease. J Clin Med 2020; 9:1360. [PMID: 32384670 PMCID: PMC7290775 DOI: 10.3390/jcm9051360] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 04/30/2020] [Accepted: 05/05/2020] [Indexed: 12/31/2022] Open
Abstract
The widely varying therapeutic response of patients with inflammatory bowel disease (IBD) continues to raise questions regarding the unclarified heterogeneity of pathological mechanisms promoting disease progression. While biomarkers for the differentiation of Crohn's disease (CD) versus ulcerative colitis (UC) have been suggested, specific markers for a CD subclassification in ileal CD versus colonic CD are still rare. Since an altered signature of the tryptophan metabolism is associated with chronic inflammatory disease, we sought to characterize potential biomarkers by focusing on the downstream enzymes and metabolites of kynurenine metabolism. Using immunohistochemical stainings, we analyzed and compared the mucosal tryptophan immune metabolism in bioptic samples from patients with active inflammation due to UC or CD versus healthy controls. Localization-specific quantification of immune cell infiltration, tryptophan-metabolizing enzyme expression and mucosal tryptophan downstream metabolite levels was performed. We found generally increased immune cell infiltrates in the tissue of all patients with IBD. However, in patients with CD, significant differences were found between regulatory T cell and neutrophil granulocyte infiltration in the ileum compared with the colon. Furthermore, we observed decreased kynurenine levels as well as strong kynureninase (KYNU) expression specifically in patients with ileal CD. Correspondingly, significantly elevated levels of the kynurenine metabolite 3-hydroxyanthranilic acid were detected in the ileal CD samples. Highlighting the heterogeneity of the different phenotypes of CD, we identified KYNU as a potential mucosal biomarker allowing the localization-specific differentiation of ileal CD versus colonic CD.
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Affiliation(s)
- Meik Huhn
- Goethe Universität, pharmazentrum frankfurt/ZAFES, Institute of Pharmacology and Toxicology, Hospital of the Goethe University, 60590 Frankfurt/Main, Germany; (M.H.); (M.H.S.J.); (C.D.); (K.G.S.); (A.S.); (J.M.P.)
| | - Martina Herrero San Juan
- Goethe Universität, pharmazentrum frankfurt/ZAFES, Institute of Pharmacology and Toxicology, Hospital of the Goethe University, 60590 Frankfurt/Main, Germany; (M.H.); (M.H.S.J.); (C.D.); (K.G.S.); (A.S.); (J.M.P.)
| | - Balint Melcher
- Institute of Pathology, Klinikum Bayreuth, 95445 Bayreuth, Germany; (B.M.); (M.V.)
| | - Caroline Dreis
- Goethe Universität, pharmazentrum frankfurt/ZAFES, Institute of Pharmacology and Toxicology, Hospital of the Goethe University, 60590 Frankfurt/Main, Germany; (M.H.); (M.H.S.J.); (C.D.); (K.G.S.); (A.S.); (J.M.P.)
| | - Katrin G. Schmidt
- Goethe Universität, pharmazentrum frankfurt/ZAFES, Institute of Pharmacology and Toxicology, Hospital of the Goethe University, 60590 Frankfurt/Main, Germany; (M.H.); (M.H.S.J.); (C.D.); (K.G.S.); (A.S.); (J.M.P.)
| | - Anja Schwiebs
- Goethe Universität, pharmazentrum frankfurt/ZAFES, Institute of Pharmacology and Toxicology, Hospital of the Goethe University, 60590 Frankfurt/Main, Germany; (M.H.); (M.H.S.J.); (C.D.); (K.G.S.); (A.S.); (J.M.P.)
| | - Janet Collins
- Interdisciplinary Crohn-Colitis Center Rhein-Main, Schifferstrasse 59, 60594 Frankfurt/Main, Germany; (J.C.); (J.S.)
| | - Josef M. Pfeilschifter
- Goethe Universität, pharmazentrum frankfurt/ZAFES, Institute of Pharmacology and Toxicology, Hospital of the Goethe University, 60590 Frankfurt/Main, Germany; (M.H.); (M.H.S.J.); (C.D.); (K.G.S.); (A.S.); (J.M.P.)
| | - Michael Vieth
- Institute of Pathology, Klinikum Bayreuth, 95445 Bayreuth, Germany; (B.M.); (M.V.)
| | - Jürgen Stein
- Interdisciplinary Crohn-Colitis Center Rhein-Main, Schifferstrasse 59, 60594 Frankfurt/Main, Germany; (J.C.); (J.S.)
| | - Heinfried H. Radeke
- Goethe Universität, pharmazentrum frankfurt/ZAFES, Institute of Pharmacology and Toxicology, Hospital of the Goethe University, 60590 Frankfurt/Main, Germany; (M.H.); (M.H.S.J.); (C.D.); (K.G.S.); (A.S.); (J.M.P.)
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Escherichiacoli-Specific CD4+ T Cells Have Public T-Cell Receptors and Low Interleukin 10 Production in Crohn's Disease. Cell Mol Gastroenterol Hepatol 2020; 10:507-526. [PMID: 32361018 PMCID: PMC7385044 DOI: 10.1016/j.jcmgh.2020.04.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 04/23/2020] [Accepted: 04/24/2020] [Indexed: 01/07/2023]
Abstract
BACKGROUND & AIMS Crohn's disease (CD) likely represents decreased immune tolerance to intestinal bacterial antigens. Most CD patients have high titers of antibodies to intestinal commensal proteins, including the outer membrane porin C (OmpC) of Escherichia coli. METHODS By using major histocompatibility complex II tetramers, we identified an HLA-DRB1∗15:01-restricted peptide epitope of OmpC recognized by CD4+ T cells in peripheral blood mononuclear cells from HLA-DRB1∗15:01+ healthy control (HC) and CD patients. RESULTS The precursor frequency of these cells in CD correlated with anti-OmpC IgA titers, but did not differ from that of HCs. In both cohorts, they showed a CD161+, integrin α4β7+ phenotype ex vivo by flow cytometry, distinct from the C-X-C Motif Chemokine Receptor 3 phenotype of autologous influenza hemagglutinin (Flu) peptide-specific T cells. The T-cell receptor α and β chains of in vitro-expanded OmpC-specific T-cell clones often contained public amino acid sequences that were identical in cells from different patients. Expanded T-cell clones from CD subjects produced significantly less interleukin (IL)10 (P < .0001) than those from HCs, and a trend toward decreased production of the T helper 2 cell-associated IL4, IL5, and IL13 by CD clones also was seen. CONCLUSIONS Both HCs and CD patients have detectable OmpC-specific T cells in circulation, with similar immunophenotypes and often identical T-cell-receptor sequences. However, expanded clones from patients with CD produce less of the immunoregulatory cytokine IL10, showing a selective defect in the regulatory function of intestinal microbial antigen-specific T cells in patients with CD.
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Schirmer M, Garner A, Vlamakis H, Xavier RJ. Microbial genes and pathways in inflammatory bowel disease. Nat Rev Microbiol 2020; 17:497-511. [PMID: 31249397 DOI: 10.1038/s41579-019-0213-6] [Citation(s) in RCA: 572] [Impact Index Per Article: 114.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Perturbations in the intestinal microbiome are implicated in inflammatory bowel disease (IBD). Studies of treatment-naive patients have identified microbial taxa associated with disease course and treatment efficacy. To gain a mechanistic understanding of how the microbiome affects gastrointestinal health, we need to move from census to function. Bacteria, including those that adhere to epithelial cells as well as several Clostridium species, can alter differentiation of T helper 17 cells and regulatory T cells. Similarly, microbial products such as short-chain fatty acids and sphingolipids also influence immune responses. Metagenomics and culturomics have identified strains of Ruminococcus gnavus and adherent invasive Escherichia coli that are linked to IBD and gut inflammation. Integrated analysis of multiomics data, including metagenomics, metatranscriptomics and metabolomics, with measurements of host response and culturomics, have great potential in understanding the role of the microbiome in IBD. In this Review, we highlight current knowledge of gut microbial factors linked to IBD pathogenesis and discuss how multiomics data from large-scale population studies in health and disease have been used to identify specific microbial strains, transcriptional changes and metabolic alterations associated with IBD.
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Affiliation(s)
| | - Ashley Garner
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Hera Vlamakis
- Broad Institute of MIT and Harvard, Cambridge, MA, USA. .,Center for Microbiome Informatics and Therapeutics, MIT, Cambridge, MA, USA.
| | - Ramnik J Xavier
- Broad Institute of MIT and Harvard, Cambridge, MA, USA. .,Center for Microbiome Informatics and Therapeutics, MIT, Cambridge, MA, USA.
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37
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Lindholm CR, Siegel CA. Are We Ready to Include Prognostic Factors in Inflammatory Bowel Disease Trials? Curr Pharm Des 2020; 25:64-68. [PMID: 30864506 DOI: 10.2174/1381612825666190312113935] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2019] [Accepted: 03/06/2019] [Indexed: 12/24/2022]
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disease characterized by periodic episodes of flares and remission. Treatment is aimed at healing the bowel, to ultimately decrease hospitalization rates, need for surgeries and overall disability. In more recent years, treatment has transitioned from a reactive approach to a more proactive approach focusing on treating disease earlier and preventing complications. The challenge lies in identifying patients who need more intensive treatment early and trying to determine who will respond to which medications. Biomarkers and clinical activity scoring systems can be used to help guide treatment decisions. However, IBDs are very heterogeneous and the significance of these biomarkers can be difficult to discern on an individual basis. Recently, prognostic tools have been developed to aid in determining a patient's prognosis as well as their likelihood to respond to different therapies. Despite this progress, clinical trials have not routinely adopted this approach in their study design. Tools for stratification of disease severity and to personalize treatment choices have the potential to improve our studies both by enriching the patient population and further guiding clinical decision making in practice. This review aims to discuss biomarkers, current prognosticating tools, tools that determine response to therapy and how incorporating these into clinical trials will be beneficial.
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Affiliation(s)
- Christopher R Lindholm
- Dartmouth Hitchcock Medical Center, Department of Medicine, Lebanon, NH 03766, United States
| | - Corey A Siegel
- Dartmouth Hitchcock Medical Center, Section of Gastroenterology and Hepatology, Lebanon, NH 03756, United States
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38
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Wang C, Baer HM, Gaya DR, Nibbs RJB, Milling S. Can molecular stratification improve the treatment of inflammatory bowel disease? Pharmacol Res 2019; 148:104442. [PMID: 31491469 PMCID: PMC6902263 DOI: 10.1016/j.phrs.2019.104442] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Revised: 09/02/2019] [Accepted: 09/02/2019] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel disease (IBD) is a debilitating chronic inflammatory disease of the gastrointestinal (GI) tract. It affects more than 3.5 million people in the western world and places a huge financial burden on healthcare systems. IBD is highly heterogeneous; disease severity and outcomes in IBD are highly variable, and patients may experience episodes of relapse and remission. However, treatment often follows a step-up model whereby the patients start with anti-inflammatory agents (corticosteroids or immunosuppressants) and step-up to monoclonal anti-tumour necrosis factor-α (TNFα) antibodies and then other biologics if the initial drugs cannot control disease. Unfortunately, many patients do not respond to the costly biologics, and thus often still require gut-resective surgery, which decreases quality of life. In order to decrease rates of surgery and ineffective treatments, it is important to identify markers that accurately predict disease progression and treatment responses, to inform decisions about the best choice of therapeutics. Here we examine molecular approaches to patient stratification that aim to increase the effectiveness of treatments and potentially reduce healthcare costs. In the future, it may become possible to stratify patients based on their suitability for specific molecular-targeted therapeutic agents, and eventually use molecular stratification for personalised medicine in IBD.
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Affiliation(s)
- Claire Wang
- Institute of Infection, Inflammation & Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Hannah M Baer
- Institute of Infection, Inflammation & Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Daniel R Gaya
- Gastroenterology Unit, Glasgow Royal Infirmary, Glasgow, UK
| | - Robert J B Nibbs
- Institute of Infection, Inflammation & Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Simon Milling
- Institute of Infection, Inflammation & Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
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39
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Biasci D, Lee JC, Noor NM, Pombal DR, Hou M, Lewis N, Ahmad T, Hart A, Parkes M, McKinney EF, Lyons PA, Smith KGC. A blood-based prognostic biomarker in IBD. Gut 2019; 68:1386-1395. [PMID: 31030191 PMCID: PMC6691955 DOI: 10.1136/gutjnl-2019-318343] [Citation(s) in RCA: 144] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Revised: 03/11/2019] [Accepted: 04/04/2019] [Indexed: 02/06/2023]
Abstract
OBJECTIVE We have previously described a prognostic transcriptional signature in CD8 T cells that separates patients with IBD into two phenotypically distinct subgroups, termed IBD1 and IBD2. Here we sought to develop a blood-based test that could identify these subgroups without cell separation, and thus be suitable for clinical use in Crohn's disease (CD) and ulcerative colitis (UC). DESIGN Patients with active IBD were recruited before treatment. Transcriptomic analyses were performed on purified CD8 T cells and/or whole blood. Phenotype data were collected prospectively. IBD1/IBD2 patient subgroups were identified by consensus clustering of CD8 T cell transcriptomes. In a training cohort, machine learning was used to identify groups of genes ('classifiers') whose differential expression in whole blood recreated the IBD1/IBD2 subgroups. Genes from the best classifiers were quantitative (q)PCR optimised, and further machine learning was used to identify the optimal qPCR classifier, which was locked down for further testing. Independent validation was sought in separate cohorts of patients with CD (n=66) and UC (n=57). RESULTS In both validation cohorts, a 17-gene qPCR-based classifier stratified patients into two distinct subgroups. Irrespective of the underlying diagnosis, IBDhi patients (analogous to the poor prognosis IBD1 subgroup) experienced significantly more aggressive disease than IBDlo patients (analogous to IBD2), with earlier need for treatment escalation (hazard ratio=2.65 (CD), 3.12 (UC)) and more escalations over time (for multiple escalations within 18 months: sensitivity=72.7% (CD), 100% (UC); negative predictive value=90.9% (CD), 100% (UC)). CONCLUSION This is the first validated prognostic biomarker that can predict prognosis in newly diagnosed patients with IBD and represents a step towards personalised therapy.
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Affiliation(s)
- Daniele Biasci
- Department of Medicine, University of Cambridge, Cambridge, UK
| | - James C Lee
- Department of Medicine, University of Cambridge, Cambridge, UK
- Cambridge Institute of Therapeutic Immunology & Infectious Disease, University of Cambridge, Cambridge, UK
| | | | - Diana R Pombal
- Department of Medicine, University of Cambridge, Cambridge, UK
- Cambridge Institute of Therapeutic Immunology & Infectious Disease, University of Cambridge, Cambridge, UK
| | | | - Nina Lewis
- Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Tariq Ahmad
- University of Exeter Medical School, Exeter, UK
| | - Ailsa Hart
- St Mark's Hospital, London, UK
- Antigen Presentation Research Group, Imperial College, London, UK
| | - Miles Parkes
- Department of Medicine, University of Cambridge, Cambridge, UK
| | - Eoin F McKinney
- Department of Medicine, University of Cambridge, Cambridge, UK
- Cambridge Institute of Therapeutic Immunology & Infectious Disease, University of Cambridge, Cambridge, UK
| | - Paul A Lyons
- Department of Medicine, University of Cambridge, Cambridge, UK
- Cambridge Institute of Therapeutic Immunology & Infectious Disease, University of Cambridge, Cambridge, UK
| | - Kenneth G C Smith
- Department of Medicine, University of Cambridge, Cambridge, UK
- Cambridge Institute of Therapeutic Immunology & Infectious Disease, University of Cambridge, Cambridge, UK
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40
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Gawel DR, Serra-Musach J, Lilja S, Aagesen J, Arenas A, Asking B, Bengnér M, Björkander J, Biggs S, Ernerudh J, Hjortswang H, Karlsson JE, Köpsen M, Lee EJ, Lentini A, Li X, Magnusson M, Martínez-Enguita D, Matussek A, Nestor CE, Schäfer S, Seifert O, Sonmez C, Stjernman H, Tjärnberg A, Wu S, Åkesson K, Shalek AK, Stenmarker M, Zhang H, Gustafsson M, Benson M. A validated single-cell-based strategy to identify diagnostic and therapeutic targets in complex diseases. Genome Med 2019; 11:47. [PMID: 31358043 PMCID: PMC6664760 DOI: 10.1186/s13073-019-0657-3] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Accepted: 07/10/2019] [Indexed: 12/17/2022] Open
Abstract
Background Genomic medicine has paved the way for identifying biomarkers and therapeutically actionable targets for complex diseases, but is complicated by the involvement of thousands of variably expressed genes across multiple cell types. Single-cell RNA-sequencing study (scRNA-seq) allows the characterization of such complex changes in whole organs. Methods The study is based on applying network tools to organize and analyze scRNA-seq data from a mouse model of arthritis and human rheumatoid arthritis, in order to find diagnostic biomarkers and therapeutic targets. Diagnostic validation studies were performed using expression profiling data and potential protein biomarkers from prospective clinical studies of 13 diseases. A candidate drug was examined by a treatment study of a mouse model of arthritis, using phenotypic, immunohistochemical, and cellular analyses as read-outs. Results We performed the first systematic analysis of pathways, potential biomarkers, and drug targets in scRNA-seq data from a complex disease, starting with inflamed joints and lymph nodes from a mouse model of arthritis. We found the involvement of hundreds of pathways, biomarkers, and drug targets that differed greatly between cell types. Analyses of scRNA-seq and GWAS data from human rheumatoid arthritis (RA) supported a similar dispersion of pathogenic mechanisms in different cell types. Thus, systems-level approaches to prioritize biomarkers and drugs are needed. Here, we present a prioritization strategy that is based on constructing network models of disease-associated cell types and interactions using scRNA-seq data from our mouse model of arthritis, as well as human RA, which we term multicellular disease models (MCDMs). We find that the network centrality of MCDM cell types correlates with the enrichment of genes harboring genetic variants associated with RA and thus could potentially be used to prioritize cell types and genes for diagnostics and therapeutics. We validated this hypothesis in a large-scale study of patients with 13 different autoimmune, allergic, infectious, malignant, endocrine, metabolic, and cardiovascular diseases, as well as a therapeutic study of the mouse arthritis model. Conclusions Overall, our results support that our strategy has the potential to help prioritize diagnostic and therapeutic targets in human disease. Electronic supplementary material The online version of this article (10.1186/s13073-019-0657-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Danuta R Gawel
- Centre for Personalized Medicine, Linköping University, Linköping, Sweden
| | - Jordi Serra-Musach
- Centre for Personalized Medicine, Linköping University, Linköping, Sweden
| | - Sandra Lilja
- Centre for Personalized Medicine, Linköping University, Linköping, Sweden
| | - Jesper Aagesen
- Department of Internal Medicine, Region Jönköping County, Jönköping, Sweden
| | - Alex Arenas
- Departament d'Enginyeria Informàtica i Matemàtiques, Universitat Rovira i Virgili, Tarragona, Spain
| | - Bengt Asking
- Department of Surgery, Region Jönköping County, Jönköping, Sweden
| | - Malin Bengnér
- Office for Control of Communicable Diseases, Region Jönköping County, Jönköping, Sweden
| | - Janne Björkander
- Department of Internal Medicine, Region Jönköping County, Jönköping, Sweden
| | - Sophie Biggs
- Division of Rheumatology, Autoimmunity, and Immune Regulation, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
| | - Jan Ernerudh
- Department of Clinical Immunology and Transfusion Medicine, Linköping University, Linköping, Sweden
| | - Henrik Hjortswang
- Department of Gastroenterology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
| | - Jan-Erik Karlsson
- Department of Internal Medicine, Region Jönköping County, Jönköping, Sweden.,Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
| | - Mattias Köpsen
- Bioinformatics, Department of Physics, Chemistry and Biology, Linköping University, Linköping, Sweden
| | - Eun Jung Lee
- Centre for Personalized Medicine, Linköping University, Linköping, Sweden.,Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Korea
| | - Antonio Lentini
- Department of Clinical and Experimental Medicine, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
| | - Xinxiu Li
- Centre for Personalized Medicine, Linköping University, Linköping, Sweden
| | - Mattias Magnusson
- Division of Rheumatology, Autoimmunity, and Immune Regulation, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
| | - David Martínez-Enguita
- Bioinformatics, Department of Physics, Chemistry and Biology, Linköping University, Linköping, Sweden
| | - Andreas Matussek
- Clinical Microbiology, Region Jönköping County, Jönköping, Sweden.,Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden.,Karolinska University Laboratory, Karolinska University Hospital, Solna, Sweden
| | - Colm E Nestor
- Department of Clinical and Experimental Medicine, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
| | - Samuel Schäfer
- Centre for Personalized Medicine, Linköping University, Linköping, Sweden
| | - Oliver Seifert
- Department of Dermatology and Venereology, Region Jönköping County, Jönköping, Sweden.,Department of Clinical and Experimental Medicine, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
| | - Ceylan Sonmez
- Bioinformatics, Department of Physics, Chemistry and Biology, Linköping University, Linköping, Sweden
| | - Henrik Stjernman
- Department of Internal Medicine, Region Jönköping County, Jönköping, Sweden
| | - Andreas Tjärnberg
- Bioinformatics, Department of Physics, Chemistry and Biology, Linköping University, Linköping, Sweden
| | - Simon Wu
- Bioinformatics, Department of Physics, Chemistry and Biology, Linköping University, Linköping, Sweden
| | - Karin Åkesson
- Department of Clinical and Experimental Medicine, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden.,Futurum - Academy for Health and Care, Department of Pediatrics, Region Jönköping County, Jönköping, Sweden
| | - Alex K Shalek
- Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.,Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA.,Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.,Broad Institute of MIT and Harvard, Cambridge, MA, USA.,Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
| | - Margaretha Stenmarker
- Futurum - Academy for Health and Care, Department of Pediatrics, Region Jönköping County, Jönköping, Sweden.,Department of Pediatrics, Institution for Clinical Sciences, Göteborg, Sweden
| | - Huan Zhang
- Centre for Personalized Medicine, Linköping University, Linköping, Sweden.
| | - Mika Gustafsson
- Bioinformatics, Department of Physics, Chemistry and Biology, Linköping University, Linköping, Sweden
| | - Mikael Benson
- Centre for Personalized Medicine, Linköping University, Linköping, Sweden.
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Schwartzberg DM, Brandstetter S, Grucela AL. Crohn's Disease of the Esophagus, Duodenum, and Stomach. Clin Colon Rectal Surg 2019; 32:231-242. [PMID: 31275069 PMCID: PMC6606321 DOI: 10.1055/s-0039-1683850] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Upper gastrointestinal Crohn's is an under-reported, under-recognized phenotype of Crohn's disease. Routine screening in the pediatric population has shown a higher prevalence compared with adults; however, most adult patients remain asymptomatic with respect to upper gastrointestinal Crohn's disease. For the patients who are symptomatic, medical treatment is the first line of management, except for cases of obstruction, perforation, or bleeding. Though most patients respond to medical therapy, mainly steroids, with the addition of immunomodulators and more recently biologics agents, surgical intervention is usually required only for obstructing gastroduodenal disease secondary to strictures. Strictureplasty and bypass are safe operations with comparable morbidity, although bypass has higher rates of dumping syndrome and marginal ulceration in the long term. Rare cases of gastroduodenal fistulous disease from active distal disease may involve the stomach or duodenum, and esophageal Crohn's disease can fistulize to surrounding structures in the mediastinum which may require the highly morbid esophagectomy.
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Affiliation(s)
- David M. Schwartzberg
- Department of Colorectal Surgery, Digestive Disease Institute, Cleveland Clinic Foundation, Cleveland, Ohio
| | - Stephen Brandstetter
- Department of Colorectal Surgery, Digestive Disease Institute, Cleveland Clinic Foundation, Cleveland, Ohio
| | - Alexis L. Grucela
- Division of Colon and Rectal Surgery, New York University Langone Medical Center, New York, New York
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Linneman Z, Reis C, Balaji K, Moore J, Braude S. The vitamin D positive feedback hypothesis of inflammatory bowel diseases. Med Hypotheses 2019; 127:154-158. [PMID: 31088641 DOI: 10.1016/j.mehy.2019.04.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2018] [Revised: 03/28/2019] [Accepted: 04/11/2019] [Indexed: 11/28/2022]
Abstract
While it appears that there are a variety of factors that exacerbate IBD, it is frustrating that symptoms can persist and worsen even when environmental insults are removed. We suggest that there may be a positive feedback loop which perpetuates the inflammatory response in IBD patients. The loop is triggered by vitamin D deficiency which reduces calcium uptake. Lowered vitamin D and calcium interfere with anti-inflammatory pathways. Inflammation of the mucosa inhibits absorption of calcium and thus perpetuates the reduced anti-inflammatory response. A number of predictions follow from this hypothesis and are supported by geographic and lifestyle patterns in IBD incidence and prevalence.
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Affiliation(s)
- Z Linneman
- Biology Department, Washington University, United States
| | - C Reis
- Biology Department, Washington University, United States
| | - K Balaji
- Radiation Oncology, Washington U. School of Medicine, United States
| | - J Moore
- Radiation Oncology, Washington U. School of Medicine, United States
| | - S Braude
- Biology Department, Washington University, United States.
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Ning L, Shan G, Sun Z, Zhang F, Xu C, Lou X, Li S, Du H, Chen H, Xu G. Quantitative Proteomic Analysis Reveals the Deregulation of Nicotinamide Adenine Dinucleotide Metabolism and CD38 in Inflammatory Bowel Disease. BIOMED RESEARCH INTERNATIONAL 2019; 2019:3950628. [PMID: 31179321 PMCID: PMC6507272 DOI: 10.1155/2019/3950628] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Revised: 03/25/2019] [Accepted: 04/02/2019] [Indexed: 12/12/2022]
Abstract
Inflammatory bowel disease (IBD) has become a major health challenge worldwide. However, the precise etiological and pathophysiological factors involved in IBD remain unclear. Proteomics can be used for large-scale protein identification analysis. In the current study, using tandem mass tag- (TMT-) based shotgun proteomics, proteomic differences between intestinal tissue from health controls, patients with Crohn's disease (CD), and patients with ulcerative colitis (UC) were compared. Proteins with fold change >2 or <0.5 and P value < 0.05 between groups were considered differentially expressed. ProteinAtlas was used to analyze the tissue specificity of differentially expressed proteins (DEPs). Reactome pathway analysis was applied to cluster functional pathways. A total of 4786 proteins were identified, with 59 proteins showing higher levels and 43 showing lower levels in patients with IBD than in controls. Seventeen proteins, including angiotensin converting enzyme 2 (ACE2) and angiotensin converting enzyme 1 (ACE), showed higher levels in CD than in UC. Several novel proteins such as CD38, chitinase 3-like 1 (CHI3L1), olfactomedin 4 (OLFM4), and intelectin 1 were screened out between patients with IBD and controls. When proteins with fold change >1.2 or <0.84 and P value < 0.05 between groups were considered differentially expressed, the expression of 10 proteins, including CD38, involved in the nicotinamide adenine dinucleotide (NAD) metabolism and signaling pathway showed significant changes in IBD. Using the NCBI GEO database, we confirmed increased CD38 mRNA expression in patients with UC and in mouse colitis models. Protein CD38 expression was higher in CD and UC than in normal controls. CD38 expression was higher in inflamed tissues than in noninflamed tissues, and CD38 was located in F4/80-positive cells. Our study may provide novel insights into the molecular pathogenesis of IBD. Further studies are required on the role of NAD metabolism and CD38 in intestinal inflammation.
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Affiliation(s)
- LongGui Ning
- Department of Gastroenterology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Guodong Shan
- Department of Gastroenterology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zeyu Sun
- Proteomics & Metabolomics Platform, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Hangzhou, China
| | - Fenming Zhang
- Department of Gastroenterology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Chengfu Xu
- Department of Gastroenterology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xinhe Lou
- Department of Gastroenterology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Sha Li
- Department of Gastroenterology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Haojie Du
- Department of Gastroenterology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hongtan Chen
- Department of Gastroenterology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Guoqiang Xu
- Department of Gastroenterology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Goren I, Godny L, Reshef L, Yanai H, Gophna U, Tulchinsky H, Dotan I. Starch Consumption May Modify Antiglycan Antibodies and Fecal Fungal Composition in Patients With Ileo-Anal Pouch. Inflamm Bowel Dis 2019; 25:742-749. [PMID: 30535148 DOI: 10.1093/ibd/izy370] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND Inflammatory bowel diseases (IBDs) are characterized by serologic responses to glycans. Patients with ulcerative colitis (UC) after proctocolectomy with ileo-anal anastomosis (pouch surgery) may develop inflammation (pouchitis) that resembles Crohn's disease (CD). We hypothesized that patients' serologic responses were affected by their consumption of dietary sugars. This study analyzed the correlations between antiglycan antibody expression and dietary sugar consumption in patients with UC pouch and the evolution in antibody levels over time. METHODS Patients were followed prospectively for 2 consecutive visits. The following antiglycan carbohydrate antibodies were detected by enzyme-linked immunosorbent assay: antichitobioside (ACCA), antilaminaribioside (ALCA), antimannobioside (AMCA), and anti-Saccharomyces cerevisiae (ASCA) antibodies. Patients completed a food frequency questionnaire. The fungal community in patients' fecal samples was analyzed by sequencing the internal transcribed spacer 2 (ITS2) region of nuclear ribosomal DNA. RESULTS We included 75 UC pouch patients aged 45.2 ± 14 years who underwent pouch surgery 9.8 ± 6.7 years previously. Of these patients, 34.7% (n = 26) showed seropositivity for antiglycan antibodies. Starch consumption was significantly higher in patients with positive serologic responses (P = 0.05). Higher starch consumption was associated with higher AMCA and ACCA titers, which increased by 4.08% (0.8%-7.4%; P = 0.014) and 4.8% (0.7%-9.1%; P = 0.007), respectively, for each 10-g increase of dietary starch. The per-patient change in the relative abundance of Candida albicans in fecal samples correlated positively with changes in starch consumption (Spearman's r = 0.72; P = 0.012). CONCLUSIONS Starch consumption correlated with positive antiglycan serology (ACCA and AMCA), suggesting that increased dietary starch intake may promote a specific immune response in patients with IBD.
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Affiliation(s)
- Idan Goren
- Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Lihi Godny
- Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Leah Reshef
- Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Henit Yanai
- Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Uri Gophna
- Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Hagit Tulchinsky
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Department of Surgery, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Iris Dotan
- Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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45
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Maaser C, Sturm A, Vavricka SR, Kucharzik T, Fiorino G, Annese V, Calabrese E, Baumgart DC, Bettenworth D, Borralho Nunes P, Burisch J, Castiglione F, Eliakim R, Ellul P, González-Lama Y, Gordon H, Halligan S, Katsanos K, Kopylov U, Kotze PG, Krustinš E, Laghi A, Limdi JK, Rieder F, Rimola J, Taylor SA, Tolan D, van Rheenen P, Verstockt B, Stoker J. ECCO-ESGAR Guideline for Diagnostic Assessment in IBD Part 1: Initial diagnosis, monitoring of known IBD, detection of complications. J Crohns Colitis 2019; 13:144-164. [PMID: 30137275 DOI: 10.1093/ecco-jcc/jjy113] [Citation(s) in RCA: 1117] [Impact Index Per Article: 186.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Christian Maaser
- Outpatients Department of Gastroenterology, Hospital Lüneburg, Lüneburg, Germany
| | - Andreas Sturm
- Department of Gastroenterology, DRK Kliniken Berlin I Westend, Berlin, Germany
| | | | - Torsten Kucharzik
- Department of Internal Medicine and Gastroenterology, Hospital Lüneburg, Lüneburg, Germany
| | - Gionata Fiorino
- Department of Gastroenterology, Humanitas Clinical and Research Institute, Milan, Italy
| | - Vito Annese
- Department of Gastroenterology, Valiant Clinic & American Hospital, Dubai, UAE
| | - Emma Calabrese
- Department of Systems Medicine, University of Rome, Tor Vergata, Italy
| | - Daniel C Baumgart
- Division of Gastroenterology, University of Alberta, Edmonton, AB, Canada
| | - Dominik Bettenworth
- Department of Medicine B, Gastroenterology and Hepatology, University Hospital Münster, Münster, Germany
| | - Paula Borralho Nunes
- Department of Anatomic Pathology, Hospital Cuf Descobertas; Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
| | - Johan Burisch
- Department of Gastroenterology, North Zealand University Hospital; Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Frederiksberg, Denmark
| | - Fabiana Castiglione
- Department of Clinical Medicine and Surgery, "Federico II" University of Naples, Naples, Italy
| | - Rami Eliakim
- Department of Gastroenterology, Sheba Medical Center, Sackler School of Medicine, Tel Aviv, Israel
| | - Pierre Ellul
- Department of Medicine, Mater Dei Hospital, Msida, Malta
| | - Yago González-Lama
- Department of Gastroenterology, University Hospital Puerta De Hierro, Majadahonda [Madrid], Spain
| | - Hannah Gordon
- Department of Gastroenterology, Royal London Hospital, London, UK
| | - Steve Halligan
- Centre for Medical Imaging, University College London, London, UK
| | - Konstantinos Katsanos
- Department of Gastroenterology and Hepatology, University and Medical School of Ioannina, Ioannina, Greece
| | - Uri Kopylov
- Department of Gastroenterology, Sheba Medical Center, Sackler School of Medicine, Tel Aviv, Israel
| | - Paulo G Kotze
- Colorectal Surgery Unit, Catholic University of Paraná [PUCPR], Curitiba, Brazil
| | - Eduards Krustinš
- Department of of Gastroenterology, Hepatology and Nutrition, Pauls Stradins Clinical University Hospital, Riga, Latvia
| | - Andrea Laghi
- Department of Clinical and Surgical Translational Medicine, Sapienza University of Rome, Rome, Italy
| | - Jimmy K Limdi
- Department of Gastroenterology, Pennine Acute Hospitals NHS Trust, Manchester; Manchester Academic Health Sciences Centre, University of Manchester, UK
| | - Florian Rieder
- Department of Gastroenterology, Hepatology & Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Jordi Rimola
- Department of Radiology, Hospital Clínic Barcelona, Barcelona, Spain
| | - Stuart A Taylor
- Centre for Medical Imaging, University College London, London, UK
| | - Damian Tolan
- Clinical Radiology, St James's University Hospital, Leeds, UK
| | - Patrick van Rheenen
- Department of Paediatric Gastroenterology, Hepatology and Nutrition, University Medical Center Groningen, Groningen, The Netherlands
| | - Bram Verstockt
- Department of Gastroenterology and Hepatology, University Hospitals Leuven and CHROMETA - Translational Research in Gastrointestinal Disorders, KU Leuven, Leuven, Belgium
| | - Jaap Stoker
- Department of Radiology and Nuclear Medicine, Academic Medical Center [AMC], University of Amsterdam, Amsterdam, The Netherlands
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46
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Nonspecific Ulcerative Colitis in Practice of Family Doctor. Fam Med 2018. [DOI: 10.30841/2307-5112.5.2018.163902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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47
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Zhang H, Zeng Z, Mukherjee A, Shen B. Molecular diagnosis and classification of inflammatory bowel disease. Expert Rev Mol Diagn 2018; 18:867-886. [PMID: 30152711 DOI: 10.1080/14737159.2018.1516549] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Traditional diagnosis and classification of inflammatory bowel diseases (IBDs) have been based on clinical evaluation, laboratory testing, endoscopy, imaging, and histological examinations. With the advancement of medical technology, an increasing number of molecular surrogates are playing a key role in diagnosis, differential diagnosis, assessment of disease activity, prediction of clinical course, and therapeutic response of IBD. Areas covered: The authors review roles of both existing and emerging surrogates including genetic, serological, histologic, and fecal markers in diagnosis and classification of IBD. Comparisons in advantages and disadvantages of different markers have also been discussed. In addition, this review underscores controversial and unclear aspects which need further study. Expert commentary: IBD is characteristic of chronicity, relapse-remission and destructiveness. It is of great importance for clinicians to make an accurate diagnosis and classification. Current and new molecular markers perform well with acceptable sensitivity and specificity. The use of molecular markers in clinical practice needs to be further explored and then generalized. More work is warranted to identify novel useful markers and elucidate how to apply them together with current markers in clinical settings.
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Affiliation(s)
- Hu Zhang
- a Center for Inflammatory Bowel Disease & Department of Gastroenterology , West China Hospital, Sichuan University , Chengdu , China
| | - Zhen Zeng
- a Center for Inflammatory Bowel Disease & Department of Gastroenterology , West China Hospital, Sichuan University , Chengdu , China
| | - Arjudeb Mukherjee
- b West China School of Medicine , Sichuan University , Chengdu , China
| | - Bo Shen
- c Center for Inflammatory Bowel Disease, Digestive Disease and Surgery Institute, The Cleveland Clinic Foundation , Cleveland , Ohio , USA
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48
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Yao F, Fan Y, Lv B, Ji C, Xu L. Diagnostic utility of serological biomarkers in patients with Crohn's disease: A case-control study. Medicine (Baltimore) 2018; 97:e11772. [PMID: 30095633 PMCID: PMC6133474 DOI: 10.1097/md.0000000000011772] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
The aim of this study was to examine the expression of serological markers in patients with inflammatory bowel disease in China, and determine the diagnostic utility of serological markers, individually and in combination, for the diagnosis and differential diagnosis of Crohn's disease (CD).Serum samples were obtained from 160 participants in Eastern China. Among the participants, 98 were diagnosed with CD, 33 had ulcerative colitis (UC), and 29 were healthy controls (HC). The serum samples were tested for the presence of antibodies against outer membrane porin C (anti-OmpC), Pseudomonas fluorescens bacterial sequence I2 (anti-I2), anti-laminarin (anti-L), anti-chitin (anti-C), anti-chitobioside carbohydrate antibody (ACCA), anti-laminaribioside carbohydrate antibody (ALCA), anti-mannobioside carbohydrate antibody (AMCA), and anti-Saccharomyces cerevisiae antibody (ASCA) by indirect enzyme-linked immunosorbent assay (ELISA).Individually, anti-C, anti-L, ASCA-IgG, and ALCA lacked diagnostic value in the differentiation of CD. ASCA-IgA remained the most accurate marker for the diagnosis of CD, with an area under the curve (AUC) of 0.77; however, its sensitivity and specificity were both lower than 75%. Among the combinations of the 5 markers with significant diagnosing ability for CD, combinations with any 2 of the 3 markers, ASCA IgA, AMCA, and ACCA positive, provided the best accuracy in the diagnosis and differential diagnosis of CD (sensitivity and specificity both above 75%) and had the highest Youden index.Serological antibodies, when considered in combination, have remarkable value in the diagnosis and differential diagnosis of CD. Especially, the combination of any 2 of the 3 markers, ASCA-IgA, AMCA, ACCA positive, appears to be optimal.
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Affiliation(s)
| | | | - Bin Lv
- Department of Gastroenterology
| | - Conghua Ji
- Statistics Department, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, China
| | - Li Xu
- Department of Gastroenterology
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49
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Kamm F, Strauch U, Degenhardt F, Lopez R, Kunst C, Rogler G, Franke A, Klebl F, Rieders F. Serum anti-glycan-antibodies in relatives of patients with inflammatory bowel disease. PLoS One 2018; 13:e0194222. [PMID: 29596443 PMCID: PMC5875751 DOI: 10.1371/journal.pone.0194222] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2017] [Accepted: 02/27/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Serum anti-glycan antibodies are a promising tool for differential diagnosis, disease stratification and prediction of Crohn's disease (CD). To investigate possible heritability of the markers we assessed the presence of serum anti-glycan antibodies in affected and unaffected relatives of patients with CD. METHODS Serum samples of 169 IBD patients of the German inflammatory bowel disease (IBD) network (140 CD & 29 Ulcerative colitis (UC)), 349 relatives of CD patients, 63 relatives of UC patients and 46 healthy controls were tested for the presence of anti-glycan antibodies by ELISA in a blinded fashion. Clinical data of the IBD patients and controls were available. RESULTS A higher proportion of non-affected CD relatives was positive for anti-glycan antibodies compared to healthy subjects. No inheritance of a specific pattern of anti-glycan antibodies could be detected. No difference in marker expression depending on the degree of relationship in the non-affected relatives was noted and the presence of family history did not lead to a difference in marker levels in the affected CD subjects. CONCLUSIONS Non-affected CD relatives had a higher frequency of anti-glycan antibodies compared to healthy subjects. This difference was mild and was found to be true for the overall reactivity to glycan antigens, but not for specific patterns. This may indicate an inherited mechanism resulting in a non-specific increased reactivity to microbial antigens in IBD.
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Affiliation(s)
- Florian Kamm
- Department of Internal Medicine I, University of Regensburg, Regensburg, Germany
| | - Ulrike Strauch
- Department of Internal Medicine I, University of Regensburg, Regensburg, Germany
| | - Frauke Degenhardt
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Rocio Lopez
- Department of Quantitative Health Sciences, Cleveland Clinic Foundation, Cleveland, United States of America
| | - Claudia Kunst
- Department of Internal Medicine I, University of Regensburg, Regensburg, Germany
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
- Zurich Center for Integrative Human Physiology, University of Zürich, Zürich, Switzerland
| | - Andre Franke
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Frank Klebl
- Department of Internal Medicine I, University of Regensburg, Regensburg, Germany
| | - Florian Rieders
- Department of Internal Medicine I, University of Regensburg, Regensburg, Germany
- Department of Pathobiology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, United States of America
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50
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Pernat Drobež C, Ferkolj I, Potočnik U, Repnik K. Crohn's Disease Candidate Gene Alleles Predict Time to Progression from Inflammatory B1 to Stricturing B2, or Penetrating B3 Phenotype. Genet Test Mol Biomarkers 2018; 22:143-151. [PMID: 29446656 DOI: 10.1089/gtmb.2017.0210] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM Crohn's disease (CD) patients are mostly diagnosed with the uncomplicated inflammatory form of disease; however, the majority will progress to complicated stricturing or penetrating disease over time. It is important to identify patients at risk for disease progression at an early stage. The aim of our study was to examine the role of 33 candidate CD genes as possible predictors of disease progression and their influence on time to progression from an inflammatory to a stricturing or penetrating phenotype. METHODS Patients with an inflammatory phenotype at diagnosis were followed for 10 years and 33 CD-associated polymorphisms were genotyped. To test for association with CD, 449 healthy individuals were analyzed as the control group. RESULTS Ten years after diagnosis, 39.1% of patients had not progressed beyond an inflammatory phenotype, but 60.9% had progressed to complicated disease, with average time to progression being 5.91 years. Association analyses of selected single nucleotide polymorphisms (SNPs) confirmed associations with CD for 12 SNPs. Furthermore, seven loci were associated with disease progression, out of which SNP rs4263839 in the gene TNFSF15 showed the strongest association with disease progression and the frameshift mutation rs2066847 in the gene NOD2 showed the strongest association with time to progression. CONCLUSIONS The results of our study identified specific genetic biomarkers as useful predictors of both disease progression and speed of disease progression in patients with CD.
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Affiliation(s)
- Cvetka Pernat Drobež
- 1 Department of Gastroenterology, University Medical Centre Maribor , Maribor, Slovenia
| | - Ivan Ferkolj
- 2 Department of Gastroenterology, Division of Internal Medicine, University Medical Centre Ljubljana , Ljubljana, Slovenia
| | - Uroš Potočnik
- 3 Center for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor , Maribor, Slovenia .,4 Laboratory for Biochemistry, Molecular Biology and Genomics, Faculty for Chemistry and Chemical Engineering, University of Maribor , Maribor, Slovenia
| | - Katja Repnik
- 3 Center for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor , Maribor, Slovenia .,4 Laboratory for Biochemistry, Molecular Biology and Genomics, Faculty for Chemistry and Chemical Engineering, University of Maribor , Maribor, Slovenia
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