|
1
|
Jin X, Han Y, Yang M, Ye Q, Wang Q, Zheng D, Mei Z. Global trends in surgically based treatment of anal fistula in Crohn's disease: a bibliometric and visualization analysis. Int J Surg 2025; 111:2578-2589. [PMID: 39869383 DOI: 10.1097/js9.0000000000002238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 11/27/2024] [Indexed: 01/28/2025]
Abstract
BACKGROUND Crohn's disease (CD) is a chronic, recurrent gastrointestinal disorder characterized by a complex etiology. Among its perianal complications, anal fistulas represent a challenging comorbidity. With the increase of surgical options, a comprehensive bibliometric analysis was deemed necessary to consolidate the vast array of research in this field. METHODS We extracted 1608 articles spanning from 1 January 1994, to 1 May 2024, from the Web of Science Core Collection. Using VOSviewer, CiteSpace, and Scimago Graphica for visual analytics, we synthesized key trends across multiple bibliometric indicators, encompassing geographic and institutional contributions, individual authorship, journal prominence, citation metrics, and thematic prevalence. RESULTS From the delineated corpus, we identified publications from 325 countries and 5110 research institutions, with the US and UK at the forefront of publication volume and academic impact. The data indicated a leading role for institutions like the Cleveland Clinic and Imperial College London. "Diseases of the Colon and Rectum" emerged as a central journal due to its high publication and citation frequency. Distinctly, the analysis uncovered trending keywords, signifying the field's prioritization on surgical intervention, biologic therapy, imaging modalities, and emerging biological treatments. CONCLUSION Our findings elucidate a trajectory toward prominent advancements in CD fistula research. This analysis underscores the field's shift towards integrative treatment strategies, spotlighting the pressing need for comprehensive comparative studies of surgical approaches. It underscores the imperative for robust clinical trials to standardize treatments and extend care to a broader CD patient population.
Collapse
Affiliation(s)
- Xingtao Jin
- Department of Anorectal Surgery, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ye Han
- Department of Anorectal Surgery, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Min Yang
- Department of Anorectal Surgery, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qianqian Ye
- Department of Anorectal Surgery, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qingming Wang
- Department of Anorectal Surgery, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - De Zheng
- Department of Anorectal Surgery, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Anorectal Disease Institute of Shuguang Hospital, Shanghai, China
| | - Zubing Mei
- Department of Anorectal Surgery, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Anorectal Disease Institute of Shuguang Hospital, Shanghai, China
| |
Collapse
|
|
2
|
Yang D, Li P, Dang Y, Zhu S, Shi H, Wu T, Zhang Z, Chen C, Zong Y. Identifying the importance of PCK1 in maintaining ileal epithelial barrier integrity in Crohn's disease. Gene 2024; 931:148872. [PMID: 39159791 DOI: 10.1016/j.gene.2024.148872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 08/03/2024] [Accepted: 08/15/2024] [Indexed: 08/21/2024]
Abstract
BACKGROUND Crohn's disease (CD) is marked by disruption of intestinal epithelial barrier, with unclear underlying molecular mechanisms. This study aimed to investigate key genes regulating the intestinal barrier in CD patients. METHODS Differential gene expression analysis and gene set enrichment analysis were conducted to identify potential key genes involved in CD within the GEO database. Single-cell RNA sequencing from ileum samples in GSE134809 of 59,831 inflamed and uninflamed cells from 11 CD patients and microarray data from ileal tissues in GSE69762 (3 controls and 4 CD patients) and GSE75214 (11 controls and 51 CD patients) with GSE179285 (49 uninflamed and 33 inflamed from CD patients) as the validation set. Protein-protein interaction and logistic regression analyses identified key downregulated genes in CD. A key gene was then investigated through immunohistochemistry of ileal tissues from 5 CD patients and in the Caco-2 cell line with RNA interference and treatment with IFN-γ and TNF-α to stimulate inflammation. RESULTS Single-cell RNA-seq identified 33 genes and microarray identified 167 genes with significant downregulation in inflamed CD samples. PCK1 was identified and validated as one of the most promising candidate genes. Reduced PCK1 expression was evident in inflamed ileal tissues. In vitro, knockdown of PCK1 resulted in decreased cell viability, increased apoptosis, and reduced nectin-2 production, while combination of IFN-γ and TNF-α significantly reduced PCK1. CONCLUSIONS PCK1 is downregulated in inflamed ileal tissues of CD patients and may be a key factor in maintaining epithelial integrity during inflammation in Crohn's disease.
Collapse
Affiliation(s)
- Deyi Yang
- Department of Gastroenterology, State Key Laboratory of Digestive Health, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Pengchong Li
- Department of Gastroenterology, State Key Laboratory of Digestive Health, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Yan Dang
- Department of Gastroenterology, State Key Laboratory of Digestive Health, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Shengtao Zhu
- Department of Gastroenterology, State Key Laboratory of Digestive Health, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Haiyun Shi
- Department of Gastroenterology, State Key Laboratory of Digestive Health, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Ting Wu
- Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zinan Zhang
- Department of Gastroenterology, State Key Laboratory of Digestive Health, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Chuyan Chen
- Department of Gastroenterology, State Key Laboratory of Digestive Health, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Ye Zong
- Department of Gastroenterology, State Key Laboratory of Digestive Health, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
| |
Collapse
|
|
3
|
Chandwaskar R, Dalal R, Gupta S, Sharma A, Parashar D, Kashyap VK, Sohal JS, Tripathi SK. Dysregulation of T cell response in the pathogenesis of inflammatory bowel disease. Scand J Immunol 2024; 100:e13412. [PMID: 39394898 DOI: 10.1111/sji.13412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 08/26/2024] [Accepted: 09/17/2024] [Indexed: 10/14/2024]
Abstract
Inflammatory bowel disease (IBD), comprised of Crohn's disease (CD) and ulcerative colitis (UC), are gut inflammatory diseases that were earlier prevalent in the Western Hemisphere but now are on the rise in the East, with India standing second highest in the incidence rate in the world. Inflammation in IBD is a cause of dysregulated immune response, wherein helper T (Th) cell subsets and their cytokines play a major role in the pathogenesis of IBD. In addition, gut microbiota, environmental factors such as dietary factors and host genetics influence the outcome and severity of IBD. Dysregulation between effector and regulatory T cells drives gut inflammation, as effector T cells like Th1, Th17 and Th9 subsets Th cell lineages were found to be increased in IBD patients. In this review, we attempted to discuss the role of different Th cell subsets together with other T cells like CD8+ T cells, NKT and γδT cells in the outcome of gut inflammation in IBD. We also highlighted the potential therapeutic candidates for IBD.
Collapse
Affiliation(s)
- Rucha Chandwaskar
- Amity Institute of Microbial Technology (AIMT), Amity University Jaipur, Rajasthan, India
| | - Rajdeep Dalal
- Infection and Immunology Lab, Translational Health Science and Technology Institute, NCR-Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, Haryana, India
| | - Saurabh Gupta
- Centre for Vaccines and Diagnostic Research, GLA University, Mathura, Uttar Pradesh, India
| | - Aishwarya Sharma
- Sri Siddhartha Medical College and Research Center, Tumkur, Karnataka, India
| | - Deepak Parashar
- Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Vivek K Kashyap
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, Texas, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, Texas, USA
| | - Jagdip Singh Sohal
- Centre for Vaccines and Diagnostic Research, GLA University, Mathura, Uttar Pradesh, India
| | - Subhash K Tripathi
- Center for Immunity and Immunotherapies and Program for Cell and Gene Therapy, Seattle Children's Research Institute, Seattle, Washington, USA
| |
Collapse
|
|
4
|
Brown M, Dodd A, Shi F, Greenwood E, Nagpal S, Kolachala VL, Kugathasan S, Gibson G. Concordant B and T Cell Heterogeneity Inferred from the Multiomic Landscape of Peripheral Blood Mononuclear Cells in a Crohn's Disease Cohort. J Crohns Colitis 2024; 18:jjae055. [PMID: 38613150 PMCID: PMC11637485 DOI: 10.1093/ecco-jcc/jjae055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Indexed: 04/14/2024]
Abstract
BACKGROUND AND AIMS Crohn's disease is characterized by inflammation in the gastrointestinal tract due to a combination of genetic, immune, and environmental factors. Transcriptomic and epigenomic profiling of intestinal tissue of Crohn's disease patients have revealed valuable insights into pathology, however have not been conducted jointly on less invasive peripheral blood mononuclear cells (PBMCs). Furthermore, the heterogeneous responses to treatments among individuals with Crohn's disease imply hidden diversity of pathological mechanisms. METHODS We employed single nucleus multiomic analysis, integrating both snRNA-seq and snATAC-seq of PBMCs with a variety of open source bioinformatics applications. RESULTS Our findings reveal a diverse range of transcriptional signatures among individuals, highlighting the heterogeneity in PBMC profiles. Nevertheless, striking concordance between three heterogeneous groups was observed across B cells and T cells. Differential gene regulatory mechanisms partially explain these profiles, notably including a signature involving TGFß signaling in two individuals with Crohn's disease. A mutation mapped to a transcription factor binding site within a differentially accessible peak associated with the expression of this pathway, with implications for a personalized approach to understanding disease pathology. CONCLUSIONS This study highlights how multiomic analysis can reveal common regulatory mechanisms that underlie heterogeneity of PBMC profiles, one of which may be specific to inflammatory disease.
Collapse
Affiliation(s)
- Margaret Brown
- School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, USA
| | - Anne Dodd
- Department of Pediatrics, Emory University, Atlanta, GA, USA
| | - Fang Shi
- School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, USA
| | - Emily Greenwood
- School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, USA
| | - Sini Nagpal
- School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, USA
| | | | | | - Greg Gibson
- School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, USA
| |
Collapse
|
|
5
|
Yamamoto-Furusho J, López-Gómez J, Bosques-Padilla F, Martínez-Vázquez M, De-León-Rendón J. Primer consenso mexicano de la enfermedad de Crohn. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2024; 89:280-311. [DOI: 10.1016/j.rgmx.2024.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2024]
|
|
6
|
Yamamoto-Furusho JK, López-Gómez JG, Bosques-Padilla FJ, Martínez-Vázquez MA, De-León-Rendón JL. First Mexican Consensus on Crohn's disease. REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2024; 89:280-311. [PMID: 38762431 DOI: 10.1016/j.rgmxen.2024.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 03/19/2024] [Indexed: 05/20/2024]
Abstract
INTRODUCTION Crohn's disease (CD) is a subtype of chronic and incurable inflammatory bowel disease. It can affect the entire gastrointestinal tract and its etiology is unknown. OBJECTIVE The aim of this consensus was to establish the most relevant aspects related to definitions, diagnosis, follow-up, medical treatment, and surgical treatment of Crohn's disease in Mexico. MATERIAL AND METHODS Mexican specialists in the areas of gastroenterology and inflammatory bowel disease were summoned. The consensus was divided into five modules, with 69 statements. Applying the Delphi panel method, the pre-meeting questions were sent to the participants, to be edited and weighted. At the face-to-face meeting, all the selected articles were shown, underlining their level of clinical evidence; all the statements were discussed, and a final vote was carried out, determining the percentage of agreement for each statement. RESULTS The first Mexican consensus on Crohn's disease was produced, in which recommendations for definitions, classifications, diagnostic aspects, follow-up, medical treatment, and surgical treatment were established. CONCLUSIONS Updated recommendations are provided that focus on definitions, classifications, diagnostic criteria, follow-up, and guidelines for conventional medical treatment, biologic therapy, and small molecule treatment, as well as surgical management.
Collapse
Affiliation(s)
- J K Yamamoto-Furusho
- Clínica de Enfermedad Inflamatoria Intestinal, Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
| | - J G López-Gómez
- Clínica de Enfermedad Inflamatoria Intestinal, Servicio de Gastroenterología, Centro Médico Nacional 20 de Noviembre, Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado (ISSSTE), Mexico City, Mexico
| | - F J Bosques-Padilla
- Departamento de Gastroenterología, Hospital Universitario de la Universidad Autónoma de Nuevo León, Monterrey, Mexico
| | | | - J L De-León-Rendón
- Clínica de Enfermedad Inflamatoria Intestinal, Servicio de Coloproctología, Hospital General de México, Mexico City, Mexico
| |
Collapse
|
|
7
|
Yuan Z, Ye J, Liu B, Zhang L. Unraveling the role of autophagy regulation in Crohn's disease: from genetic mechanisms to potential therapeutics. ADVANCED BIOTECHNOLOGY 2024; 2:14. [PMID: 39883213 PMCID: PMC11740883 DOI: 10.1007/s44307-024-00021-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Revised: 02/29/2024] [Accepted: 03/10/2024] [Indexed: 01/31/2025]
Abstract
Autophagy serves as the primary intracellular degradation mechanism in which damaged organelles and self-cytoplasmic proteins are transported to the lysosome for degradation. Crohn's disease, an idiopathic chronic inflammatory disorder of the gastrointestinal tract, manifests in diverse regions of the digestive system. Recent research suggests that autophagy modulation may be a new avenue for treating Crohn's disease, and several promising small-molecule modulators of autophagy have been reported as therapeutic options. In this review, we discuss in detail how mutations in autophagy-related genes function in Crohn's disease and summarize the modulatory effects on autophagy of small-molecule drugs currently used for Crohn's disease treatment. Furthermore, we delve into the therapeutic potential of small-molecule autophagy inducers on Crohn's disease, emphasizing the prospects for development in this field. We aim to highlight the significance of autophagy modulation in Crohn's disease, with the aspiration of contributing to the development of more efficacious treatments that can alleviate their suffering, and improve their quality of life.
Collapse
Affiliation(s)
- Ziyue Yuan
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, China
| | - Jing Ye
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Bo Liu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Lan Zhang
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, China.
| |
Collapse
|
|
8
|
Caenepeel C, Falony G, Machiels K, Verstockt B, Goncalves PJ, Ferrante M, Sabino J, Raes J, Vieira-Silva S, Vermeire S. Dysbiosis and Associated Stool Features Improve Prediction of Response to Biological Therapy in Inflammatory Bowel Disease. Gastroenterology 2024; 166:483-495. [PMID: 38096956 DOI: 10.1053/j.gastro.2023.11.304] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 11/13/2023] [Accepted: 11/25/2023] [Indexed: 01/09/2024]
Abstract
BACKGROUND & AIMS Dysbiosis of the gut microbiota is considered a key contributor to inflammatory bowel disease (IBD) etiology. Here, we investigated potential associations between microbiota composition and the outcomes to biological therapies. METHODS The study prospectively recruited 296 patients with active IBD (203 with Crohn's disease, 93 with ulcerative colitis) initiating biological therapy. Quantitative microbiome profiles of pretreatment and posttreatment fecal samples were obtained combining flow cytometry with 16S amplicon sequencing. Therapeutic response was assessed by endoscopy, patient-reported outcomes, and changes in fecal calprotectin. The effect of therapy on microbiome variation was evaluated using constrained ordination methods. Prediction of therapy outcome was performed using logistic regression with 5-fold cross-validation. RESULTS At baseline, 65.9% of patients carried the dysbiotic Bacteroides2 (Bact2) enterotype, with a significantly higher prevalence among patients with ileal involvement (76.8%). Microbiome variation was associated with the choice of biological therapy rather than with therapeutic outcome. Only anti-tumor necrosis factor-α treatment resulted in a microbiome shift away from Bact2, concomitant with an increase in microbial load and butyrogen abundances and a decrease in potentially opportunistic Veillonella. Remission rates for patients hosting Bact2 at baseline were significantly higher with anti-tumor necrosis factor-α than with vedolizumab (65.1% vs 35.2%). A prediction model, based on anthropometrics and clinical data, stool features (microbial load, moisture, and calprotectin), and Bact2 detection predicted treatment outcome with 73.9% accuracy for specific biological therapies. CONCLUSION Fecal characterization based on microbial load, moisture content, calprotectin concentration, and enterotyping may aid in the therapeutic choice of biological therapy in IBD.
Collapse
Affiliation(s)
- Clara Caenepeel
- Translational Research Center for Gastrointestinal Disorders (TARGID), Katholieke Universiteit Leuven, Leuven, Belgium; Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - Gwen Falony
- Laboratory of Molecular Bacteriology, Department of Microbiology and Immunology, Rega Institute, Katholieke Universiteit Leuven, Leuven, Belgium; Center for Microbiology, Vlaams Instituut voor Biotechnologie (VIB), Leuven, Belgium; Institute of Medical Microbiology and Hygiene and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Kathleen Machiels
- Translational Research Center for Gastrointestinal Disorders (TARGID), Katholieke Universiteit Leuven, Leuven, Belgium; Pfizer Biopharmaceuticals, Brussels, Belgium
| | - Bram Verstockt
- Translational Research Center for Gastrointestinal Disorders (TARGID), Katholieke Universiteit Leuven, Leuven, Belgium; Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - Pedro J Goncalves
- Machine Learning in Science, Excellence Cluster "Machine Learning," Tübingen University, Tübingen, Germany
| | - Marc Ferrante
- Translational Research Center for Gastrointestinal Disorders (TARGID), Katholieke Universiteit Leuven, Leuven, Belgium; Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - João Sabino
- Translational Research Center for Gastrointestinal Disorders (TARGID), Katholieke Universiteit Leuven, Leuven, Belgium; Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - Jeroen Raes
- Laboratory of Molecular Bacteriology, Department of Microbiology and Immunology, Rega Institute, Katholieke Universiteit Leuven, Leuven, Belgium; Center for Microbiology, Vlaams Instituut voor Biotechnologie (VIB), Leuven, Belgium
| | - Sara Vieira-Silva
- Laboratory of Molecular Bacteriology, Department of Microbiology and Immunology, Rega Institute, Katholieke Universiteit Leuven, Leuven, Belgium; Institute of Medical Microbiology and Hygiene and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; Institute of Molecular Biology (IMB), Mainz, Germany
| | - Séverine Vermeire
- Translational Research Center for Gastrointestinal Disorders (TARGID), Katholieke Universiteit Leuven, Leuven, Belgium; Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium.
| |
Collapse
|
|
9
|
Waheed S, Ramzan K, Ahmad S, Khan MS, Wajid M, Ullah H, Umar A, Iqbal R, Ullah R, Bari A. Identification and In-Silico study of non-synonymous functional SNPs in the human SCN9A gene. PLoS One 2024; 19:e0297367. [PMID: 38394191 PMCID: PMC10889873 DOI: 10.1371/journal.pone.0297367] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 12/29/2023] [Indexed: 02/25/2024] Open
Abstract
Single nucleotide polymorphisms are the most common form of DNA alterations at the level of a single nucleotide in the genomic sequence. Genome-wide association studies (GWAS) were carried to identify potential risk genes or genomic regions by screening for SNPs associated with disease. Recent studies have shown that SCN9A comprises the NaV1.7 subunit, Na+ channels have a gene encoding of 1988 amino acids arranged into 4 domains, all with 6 transmembrane regions, and are mainly found in dorsal root ganglion (DRG) neurons and sympathetic ganglion neurons. Multiple forms of acute hypersensitivity conditions, such as primary erythermalgia, congenital analgesia, and paroxysmal pain syndrome have been linked to polymorphisms in the SCN9A gene. Under this study, we utilized a variety of computational tools to explore out nsSNPs that are potentially damaging to heath by modifying the structure or activity of the SCN9A protein. Over 14 potentially damaging and disease-causing nsSNPs (E1889D, L1802P, F1782V, D1778N, C1370Y, V1311M, Y1248H, F1237L, M936V, I929T, V877E, D743Y, C710W, D623H) were identified by a variety of algorithms, including SNPnexus, SNAP-2, PANTHER, PhD-SNP, SNP & GO, I-Mutant, and ConSurf. Homology modeling, structure validation, and protein-ligand interactions also were performed to confirm 5 notable substitutions (L1802P, F1782V, D1778N, V1311M, and M936V). Such nsSNPs may become the center of further studies into a variety of disorders brought by SCN9A dysfunction. Using in-silico strategies for assessing SCN9A genetic variations will aid in organizing large-scale investigations and developing targeted therapeutics for disorders linked to these variations.
Collapse
Affiliation(s)
- Sana Waheed
- Faculty of Life Science, Department of Zoology, University of Okara, Okara, Pakistan
| | - Kainat Ramzan
- Faculty of Life Science, Department of Biochemistry, University of Okara, Okara, Pakistan
| | - Sibtain Ahmad
- Faculty of Animal Husbandry, Institute of Animal and Dairy Sciences, University of Agriculture, Faisalabad, Pakistan
| | - Muhammad Saleem Khan
- Faculty of Life Science, Department of Zoology, University of Okara, Okara, Pakistan
| | - Muhammad Wajid
- Faculty of Life Science, Department of Zoology, University of Okara, Okara, Pakistan
| | - Hayat Ullah
- Department of Chemistry, University of Okara, Okara, Pakistan
| | - Ali Umar
- Faculty of Life Science, Department of Zoology, University of Okara, Okara, Pakistan
| | - Rashid Iqbal
- Faculty of Agriculture and Environment, Department of Agronomy, The Islamia University of Bahawalpur, Bahawalpur, Pakistan
| | - Riaz Ullah
- Department of Pharmacognosy College of Pharmacy King Saud University, Riyadh, Saudi Arabia
| | - Ahmed Bari
- Department of Pharmaceutical Chemistry, College of Pharmacy King Saud University, Riyadh, Saudi Arabia
| |
Collapse
|
|
10
|
Alizadeh M, Sampaio Moura N, Schledwitz A, Patil SA, El-Serag H, Ravel J, Raufman JP. A Practical Guide to Evaluating and Using Big Data in Digestive Disease Research. Gastroenterology 2024; 166:240-247. [PMID: 38052336 PMCID: PMC10872385 DOI: 10.1053/j.gastro.2023.11.292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 11/01/2023] [Accepted: 11/27/2023] [Indexed: 12/07/2023]
Affiliation(s)
- Madeline Alizadeh
- The Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland
| | - Natalia Sampaio Moura
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Alyssa Schledwitz
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Seema A Patil
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Hashem El-Serag
- Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Jacques Ravel
- The Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland
| | - Jean-Pierre Raufman
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, Maryland; VA Maryland Healthcare System, Baltimore, Maryland; Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland; Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland.
| |
Collapse
|
|
11
|
Arehart CH, Sterrett JD, Garris RL, Quispe-Pilco RE, Gignoux CR, Evans LM, Stanislawski MA. Poly-omic risk scores predict inflammatory bowel disease diagnosis. mSystems 2024; 9:e0067723. [PMID: 38095449 PMCID: PMC10805030 DOI: 10.1128/msystems.00677-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 11/02/2023] [Indexed: 01/11/2024] Open
Abstract
Inflammatory bowel disease (IBD) is characterized by complex etiology and a disrupted colonic ecosystem. We provide a framework for the analysis of multi-omic data, which we apply to study the gut ecosystem in IBD. Specifically, we train and validate models using data on the metagenome, metatranscriptome, virome, and metabolome from the Human Microbiome Project 2 IBD multi-omic database, with 1,785 repeated samples from 130 individuals (103 cases and 27 controls). After splitting the participants into training and testing groups, we used mixed-effects least absolute shrinkage and selection operator regression to select features for each omic. These features, with demographic covariates, were used to generate separate single-omic prediction scores. All four single-omic scores were then combined into a final regression to assess the relative importance of the individual omics and the predictive benefits when considered together. We identified several species, pathways, and metabolites known to be associated with IBD risk, and we explored the connections between data sets. Individually, metabolomic and viromic scores were more predictive than metagenomics or metatranscriptomics, and when all four scores were combined, we predicted disease diagnosis with a Nagelkerke's R2 of 0.46 and an area under the curve of 0.80 (95% confidence interval: 0.63, 0.98). Our work supports that some single-omic models for complex traits are more predictive than others, that incorporating multiple omic data sets may improve prediction, and that each omic data type provides a combination of unique and redundant information. This modeling framework can be extended to other complex traits and multi-omic data sets.IMPORTANCEComplex traits are characterized by many biological and environmental factors, such that multi-omic data sets are well-positioned to help us understand their underlying etiologies. We applied a prediction framework across multiple omics (metagenomics, metatranscriptomics, metabolomics, and viromics) from the gut ecosystem to predict inflammatory bowel disease (IBD) diagnosis. The predicted scores from our models highlighted key features and allowed us to compare the relative utility of each omic data set in single-omic versus multi-omic models. Our results emphasized the importance of metabolomics and viromics over metagenomics and metatranscriptomics for predicting IBD status. The greater predictive capability of metabolomics and viromics is likely because these omics serve as markers of lifestyle factors such as diet. This study provides a modeling framework for multi-omic data, and our results show the utility of combining multiple omic data types to disentangle complex disease etiologies and biological signatures.
Collapse
Affiliation(s)
- Christopher H. Arehart
- Interdisciplinary Quantitative Biology PhD Program, University of Colorado, Boulder, Colorado, USA
- Department of Ecology and Evolutionary Biology, University of Colorado, Boulder, Colorado, USA
- Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado, USA
| | - John D. Sterrett
- Interdisciplinary Quantitative Biology PhD Program, University of Colorado, Boulder, Colorado, USA
- Department of Integrative Physiology, University of Colorado, Boulder, Colorado, USA
| | - Rosanna L. Garris
- Interdisciplinary Quantitative Biology PhD Program, University of Colorado, Boulder, Colorado, USA
- Department of Biochemistry, University of Colorado, Boulder, Colorado, USA
| | - Ruth E. Quispe-Pilco
- Interdisciplinary Quantitative Biology PhD Program, University of Colorado, Boulder, Colorado, USA
- Department of Ecology and Evolutionary Biology, University of Colorado, Boulder, Colorado, USA
| | - Christopher R. Gignoux
- Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Luke M. Evans
- Department of Ecology and Evolutionary Biology, University of Colorado, Boulder, Colorado, USA
- Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado, USA
| | - Maggie A. Stanislawski
- Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| |
Collapse
|
|
12
|
Di Petrillo A, Kumar A, Onali S, Favale A, Fantini MC. GPR120/FFAR4: A Potential New Therapeutic Target for Inflammatory Bowel Disease. Inflamm Bowel Dis 2023; 29:1981-1989. [PMID: 37542525 DOI: 10.1093/ibd/izad161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Indexed: 08/07/2023]
Abstract
Inflammatory bowel disease, whose major forms are Crohn's disease and ulcerative colitis, is characterized by chronic inflammation of the gut due to the loss of tolerance toward antigens normally contained in the gut lumen. G protein-coupled receptor (GPR) 120 has gained considerable attention as a potential therapeutic target for metabolic disorders due to its implication in the production of the incretin hormone glucagon-like peptide 1 and the secretion of cholecystokinin. Recent studies have also highlighted the role of GPR120 in regulating immune system activity and inflammation. GPR120, expressed by intestinal epithelial cells, proinflammatory macrophages, enteroendocrine L cells, and CD4+ T cells, suppresses proinflammatory and enhances anti-inflammatory cytokine production, suggesting that GPR120 might have a pivotal role in intestinal inflammation and represent a possible therapeutic target in inflammatory bowel disease. This narrative review aims at summarizing the role of GPR120 in the maintenance of intestinal homeostasis through the analysis of the most recent studies.
Collapse
Affiliation(s)
- Amalia Di Petrillo
- Department of Medical Sciences and Public Health, University of Cagliari, Monserrato, Italy
| | - Amit Kumar
- Department of Electrical and Electronic Engineering, University of Cagliari, Cagliari, Italy
| | - Sara Onali
- Department of Medical Sciences and Public Health, University of Cagliari, Monserrato, Italy
| | - Agnese Favale
- Department of Medical Sciences and Public Health, University of Cagliari, Monserrato, Italy
| | | |
Collapse
|
|
13
|
Zhu Z, Lei Y, Lin Z. Effects of Crohn's disease exclusion diet on remission: a systematic review. Therap Adv Gastroenterol 2023; 16:17562848231184056. [PMID: 37655057 PMCID: PMC10467299 DOI: 10.1177/17562848231184056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Accepted: 05/26/2023] [Indexed: 09/02/2023] Open
Abstract
Background Dietary therapy may potentially reduce inflammation and promote mucosal healing in patients with Crohn's disease and is associated with fewer side effects and lower cost compared to medical therapy. Recently the Crohn's disease exclusion diet (CDED) has been developed to reduce exposure to individualized dietary components which negatively affect the intestine in patients with Crohn's disease. Objectives This systematic review aimed to explore the effectiveness of CDED in Crohn's disease patients. Design A systematic review. Data sources and methods A systematic search was performed on the PubMed, EBSCOhost, Cochrane library, OVID, Embase, Scopus, and CINHAL to identify relevant clinical trials published from 1 January 2014 to 31 August 2022. Results A total of 1120 studies were identified and 7 studies were finally included in the analysis. The study was reported according to Preferred Reporting Items for Systematic Reviews and Meta-analysis statement. Conclusion Our findings suggested that the use of CDED seemed to be effective for induction and maintenance of remission in children and adults with mild to moderate Crohn's disease. However, heterogeneity and limitations existed among the studies included. Further investigation in the form of well-designed randomized clinical trials is needed to validate the present findings. Registration PROSPERO registration number CRD42022335453.
Collapse
Affiliation(s)
- Zhanhui Zhu
- School of Nursing, Nanjing Medical University, Nanjing, China
| | - Yang Lei
- School of Nursing, Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing 211166, P.R. China
| | - Zheng Lin
- School of Nursing, Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing 211166, P.R. China
- Nursing Department, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, P.R. China
| |
Collapse
|
|
14
|
Identification of Specific Biomarkers and Pathways in the Treatment Response of Infliximab for Inflammatory Bowel Disease: In-Silico Analysis. Life (Basel) 2023; 13:life13030680. [PMID: 36983834 PMCID: PMC10057676 DOI: 10.3390/life13030680] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 02/19/2023] [Accepted: 02/20/2023] [Indexed: 03/06/2023] Open
Abstract
Background: Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract. In biological therapy, infliximab became the first anti-tumor necrosis factor (TNF) agent approved for IBD. Despite this success, infliximab is expensive, often ineffective, and associated with adverse events. Prediction of infliximab resistance would improve overall potential outcomes. Therefore, there is a pressing need to widen the scope of investigating the role of genetics in IBD to their association with therapy response. Methods: In the current study, an in-silico analysis of publicly available IBD patient transcriptomics datasets from Gene Expression Omnibus (GEO) are used to identify subsets of differentially expressed genes (DEGs) involved in the pathogenesis of IBD and may serve as potential biomarkers for Infliximab response. Five datasets were found that met the inclusion criteria. The DEGs for datasets were identified using limma R packages through the GEOR2 tool. The probes’ annotated genes in each dataset intersected with DGEs from all other datasets. Enriched gene Ontology Clustering for the identified genes was performed using Metascape to explore the possible connections or interactions between the genes. Results: 174 DEGs between IBD and healthy controls were found from analyzing two datasets (GSE14580 and GSE73661), indicating a possible role in the pathogenesis of IBD. Of the 174 DEGs, five genes (SELE, TREM1, AQP9, FPR2, and HCAR3) were shared between all five datasets. Moreover, these five genes were identified as downregulated in the infliximab responder group compared to the non-responder group. Conclusions: We hypothesize that alteration in the expression of these genes leads to an impaired response to infliximab in IBD patients. Thus, these genes can serve as potential biomarkers for the early detection of compromised infliximab response in IBD patients.
Collapse
|
|
15
|
Joustra V, Li Yim AYF, Hageman I, Levin E, Adams A, Satsangi J, de Jonge WJ, Henneman P, D'Haens G. Long-term Temporal Stability of Peripheral Blood DNA Methylation Profiles in Patients With Inflammatory Bowel Disease. Cell Mol Gastroenterol Hepatol 2023; 15:869-885. [PMID: 36581079 PMCID: PMC9972576 DOI: 10.1016/j.jcmgh.2022.12.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 12/20/2022] [Accepted: 12/20/2022] [Indexed: 12/31/2022]
Abstract
BACKGROUND & AIMS There is great current interest in the potential application of DNA methylation alterations in peripheral blood leukocytes (PBLs) as biomarkers of susceptibility, progression, and treatment response in inflammatory bowel disease (IBD). However, the intra-individual stability of PBL methylation in IBD has not been characterized. Here, we studied the long-term stability of all probes located on the Illumina HumanMethylation EPIC BeadChip array. METHODS We followed a cohort of 46 adult patients with IBD (36 Crohn's disease [CD], 10 ulcerative colitis [UC]; median age, 44 years; interquartile range [IQR] 27-56 years; 50% female) that received standard care follow-up at the Amsterdam University Medical Centers. Paired PBL samples were collected at 2 time points with a median of 7 years (range, 2-9 years) in between. Differential methylation and intra-class correlation (ICC) analyses were used to identify time-associated differences and temporally stable CpGs, respectively. RESULTS Around 60% of all EPIC array loci presented poor intra-individual stability (ICC <0.50); 78.114 (≈9%) showed good (ICC, 0.75-0.89), and 41.274 (≈5%) showed excellent (ICC ≥0.90) stability, between both measured time points. Focusing on previously identified consistently differentially methylated positions indicated that 22 CD-, 11 UC-, and 24 IBD-associated loci demonstrated high stability (ICC ≥0.75) over time; of these, we observed a marked stability of CpG loci associated to the HLA genes. CONCLUSIONS Our data provide insight into the long-term stability of the PBL DNA methylome within an IBD context, facilitating the selection of biologically relevant and robust IBD-associated epigenetic biomarkers with increased potential for independent validation. These data also have potential implications in understanding disease pathogenesis.
Collapse
Affiliation(s)
- Vincent Joustra
- Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Andrew Y F Li Yim
- Genome Diagnostics Laboratory, Department of Human Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Ishtu Hageman
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Evgeni Levin
- Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Horaizon BV, Delft, the Netherlands
| | - Alex Adams
- Oxford University- Hospitals NHS Foundation Trust- John Radcliffe Hospital, Translational Gastroenterology Unit- NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom
| | - Jack Satsangi
- Oxford University- Hospitals NHS Foundation Trust- John Radcliffe Hospital, Translational Gastroenterology Unit- NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom
| | - Wouter J de Jonge
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Peter Henneman
- Genome Diagnostics Laboratory, Department of Human Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Geert D'Haens
- Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
| |
Collapse
|
|
16
|
Xu R, Weber MC, Hu X, Neumann PA, Kamaly N. Annexin A1 based inflammation resolving mediators and nanomedicines for inflammatory bowel disease therapy. Semin Immunol 2022; 61-64:101664. [PMID: 36306664 DOI: 10.1016/j.smim.2022.101664] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Inflammatory bowel diseases (IBD) such as Crohn's Disease (CD) and Ulcerative Colitis (UC) are chronic, progressive, and relapsing disorders of the gastrointestinal tract (GIT), characterised by intestinal epithelial injury and inflammation. Current research shows that in addition to traditional anti-inflammatory therapy, resolution of inflammation and repair of the epithelial barrier are key biological requirements in combating IBD. Resolution mediators include endogenous lipids that are generated during inflammation, e.g., lipoxins, resolvins, protectins, maresins; and proteins such as Annexin A1 (ANXA1). Nanoparticles can specifically deliver these potent inflammation resolving mediators in a spatiotemporal manner to IBD lesions, effectively resolve inflammation, and promote a return to homoeostasis with minimal collateral damage. We discuss these exciting and timely concepts in this review.
Collapse
Affiliation(s)
- Runxin Xu
- Imperial College London, Department of Chemistry, Molecular Sciences Research Hub, United Kingdom
| | - Marie-Christin Weber
- Technical University of Munich, School of Medicine, Klinikum rechts der Isar, Department of Surgery, Germany
| | - Xinkai Hu
- Imperial College London, Department of Chemistry, Molecular Sciences Research Hub, United Kingdom
| | - Philipp-Alexander Neumann
- Technical University of Munich, School of Medicine, Klinikum rechts der Isar, Department of Surgery, Germany.
| | - Nazila Kamaly
- Imperial College London, Department of Chemistry, Molecular Sciences Research Hub, United Kingdom.
| |
Collapse
|
|
17
|
Autophagy in Hematological Malignancies. Cancers (Basel) 2022; 14:cancers14205072. [PMID: 36291856 PMCID: PMC9600546 DOI: 10.3390/cancers14205072] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Revised: 10/10/2022] [Accepted: 10/13/2022] [Indexed: 11/29/2022] Open
Abstract
Simple Summary Autophagy is a dynamic and tightly regulated process that seems to have dual effects in cancer. In some contexts, it can induce carcinogenesis and promote cancer cell survival, whereas in others, it acts preventing tumor cell growth and tumor progression. Thus, autophagy functions seem to strictly depend on cancer ontogenesis, progression, and type. Here, we will dive into the current knowledge of autophagy in hematological malignancies and will highlight the main genetic components involved in each cancer type. Abstract Autophagy is a highly conserved metabolic pathway via which unwanted intracellular materials, such as unfolded proteins or damaged organelles, are digested. It is activated in response to conditions of oxidative stress or starvation, and is essential for the maintenance of cellular homeostasis and other vital functions, such as differentiation, cell death, and the cell cycle. Therefore, autophagy plays an important role in the initiation and progression of tumors, including hematological malignancies, where damaged autophagy during hematopoiesis can cause malignant transformation and increase cell proliferation. Over the last decade, the importance of autophagy in response to standard pharmacological treatment of hematological tumors has been observed, revealing completely opposite roles depending on the tumor type and stage. Thus, autophagy can promote tumor survival by attenuating the cellular damage caused by drugs and/or stabilizing oncogenic proteins, but can also have an antitumoral effect due to autophagic cell death. Therefore, autophagy-based strategies must depend on the context to create specific and safe combination therapies that could contribute to improved clinical outcomes. In this review, we describe the process of autophagy and its role on hematopoiesis, and we highlight recent research investigating its role as a potential therapeutic target in hematological malignancies. The findings suggest that genetic variants within autophagy-related genes modulate the risk of developing hemopathies, as well as patient survival.
Collapse
|
|
18
|
Ashton JJ, Cheng G, Stafford IS, Kellermann M, Seaby EG, Cummings JRF, Coelho TAF, Batra A, Afzal NA, Beattie RM, Ennis S. Prediction of Crohn's Disease Stricturing Phenotype Using a NOD2-derived Genomic Biomarker. Inflamm Bowel Dis 2022; 29:511-521. [PMID: 36161322 PMCID: PMC10069659 DOI: 10.1093/ibd/izac205] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND Crohn's disease (CD) is highly heterogenous and may be complicated by stricturing behavior. Personalized prediction of stricturing will inform management. We aimed to create a stricturing risk stratification model using genomic/clinical data. METHODS Exome sequencing was performed on CD patients, and phenotype data retrieved. Biallelic variants in NOD2 were identified. NOD2 was converted into a per-patient deleteriousness metric ("GenePy"). Using training data, patients were stratified into risk groups for fibrotic stricturing using NOD2. Findings were validated in a testing data set. Models were modified to include disease location at diagnosis. Cox proportional hazards assessed performance. RESULTS Six hundred forty-five patients were included (373 children and 272 adults); 48 patients fulfilled criteria for monogenic NOD2-related disease (7.4%), 24 of whom had strictures. NOD2 GenePy scores stratified patients in training data into 2 risk groups. Within testing data, 30 of 161 patients (18.6%) were classified as high-risk based on the NOD2 biomarker, with stricturing in 17 of 30 (56.7%). In the low-risk group, 28 of 131 (21.4%) had stricturing behavior. Cox proportional hazards using the NOD2 risk groups demonstrated a hazard ratio (HR) of 2.092 (P = 2.4 × 10-5), between risk groups. Limiting analysis to patients diagnosed aged < 18-years improved performance (HR-3.164, P = 1 × 10-6). Models were modified to include disease location, such as terminal ileal (TI) disease or not. Inclusion of NOD2 risk groups added significant additional utility to prediction models. High-risk group pediatric patients presenting with TI disease had a HR of 4.89 (P = 2.3 × 10-5) compared with the low-risk group patients without TI disease. CONCLUSIONS A NOD2 genomic biomarker predicts stricturing risk, with prognostic power improved in pediatric-onset CD. Implementation into a clinical setting can help personalize management.
Collapse
Affiliation(s)
- James J Ashton
- Department of Human Genetics and Genomic Medicine, University of Southampton, Southampton, UK.,Department of Paediatric Gastroenterology, Southampton Children's Hospital, Southampton, UK
| | - Guo Cheng
- Department of Human Genetics and Genomic Medicine, University of Southampton, Southampton, UK.,NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, UK
| | - Imogen S Stafford
- Department of Human Genetics and Genomic Medicine, University of Southampton, Southampton, UK.,Institute for Life Sciences, University of Southampton, Southampton, UK
| | - Melina Kellermann
- Department of Human Genetics and Genomic Medicine, University of Southampton, Southampton, UK
| | - Eleanor G Seaby
- Department of Human Genetics and Genomic Medicine, University of Southampton, Southampton, UK
| | - J R Fraser Cummings
- Department of Gastroenterology, University Hospital Southampton, Southampton, UK
| | - Tracy A F Coelho
- Department of Paediatric Gastroenterology, Southampton Children's Hospital, Southampton, UK
| | - Akshay Batra
- Department of Paediatric Gastroenterology, Southampton Children's Hospital, Southampton, UK
| | - Nadeem A Afzal
- Department of Paediatric Gastroenterology, Southampton Children's Hospital, Southampton, UK
| | - R Mark Beattie
- Department of Paediatric Gastroenterology, Southampton Children's Hospital, Southampton, UK
| | - Sarah Ennis
- Department of Human Genetics and Genomic Medicine, University of Southampton, Southampton, UK
| |
Collapse
|
|
19
|
Chatterjee G, Negi S, Basu S, Faintuch J, O'Donovan A, Shukla P. Microbiome systems biology advancements for natural well-being. THE SCIENCE OF THE TOTAL ENVIRONMENT 2022; 838:155915. [PMID: 35568180 DOI: 10.1016/j.scitotenv.2022.155915] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Revised: 05/09/2022] [Accepted: 05/09/2022] [Indexed: 06/15/2023]
Abstract
Throughout the years all data from epidemiological, physiological and omics have suggested that the microbial communities play a considerable role in modulating human health. The population of microorganisms residing in the human intestine collectively known as microbiota presents a genetic repertoire that is higher in magnitude than the human genome. They play an essential role in host immunity and neuronal signaling. Rapid enhancement of sequence based screening and development of humanized gnotobiotic model has sparked a great deal of interest among scientists to probe the dynamic interactions of the commensal bacteria. This review focuses on systemic analysis of the gut microbiome to decipher the complexity of the host-microbe intercommunication and gives a special emphasis on the evolution of targeted precision medicine through microbiome engineering. In addition, we have also provided a comprehensive description of how interconnection between metabolism and biochemical reactions in a specific organism can be obtained from a metabolic network or a flux balance analysis and combining multiple datasets helps in the identification of a particular metabolite. The review highlights how genetic modification of the critical components and programming the resident microflora can be employed for targeted precision medicine. Inspite of the ongoing debate on the utility of gut microbiome we have explored on the probable new therapeutic avenues like FMT (Fecal microbiota transplant) can be utilized. This review also recapitulates integrating human-relevant 3D cellular models coupled with computational models and the metadata obtained from interventional and epidemiological studies may decipher the complex interactome of diet-microbiota-disease pathophysiology. In addition, it will also open new avenues for the development of therapeutics derived from microbiome or implementation of personalized nutrition. In addition, the identification of biomarkers can also help towards the development of new diagnostic tools and eventually will lead to strategic management of the disease. Inspite of the ongoing debate on the utility of the gut microbiome we have explored how probable new therapeutic avenues like FMT (Fecal microbiota transplant) can be utilized. This review also summarises integrating human-relevant 3D cellular models coupled with computational models and the metadata obtained from interventional and epidemiological studies may decipher the complex interactome of diet- microbiota-disease pathophysiology. In addition, it will also open new avenues for the development of therapeutics derived from the microbiome or implementation of personalized nutrition. In addition, the identification of biomarkers can also help towards the development of new diagnostic tools and eventually will lead to strategic management of disease.
Collapse
Affiliation(s)
| | - Sangeeta Negi
- NMC Biolab, New Mexico Consortium, Los Alamos, NM, USA; Los Alamos National Laboratory, Los Alamos, NM 87544, USA
| | - Supratim Basu
- NMC Biolab, New Mexico Consortium, Los Alamos, NM, USA
| | - Joel Faintuch
- Department of Gastroenterology, Sao Paulo University Medical School, São Paulo, SP 01246-903, Brazil
| | | | - Pratyoosh Shukla
- Enzyme Technology and Protein Bioinformatics Laboratory, School of Biotechnology, Institute of Science, Banaras Hindu University, Varanasi 221005, India.
| |
Collapse
|
|
20
|
Ashton JJ, Seaby EG, Beattie RM, Ennis S. NOD2 in Crohn's disease- unfinished business. J Crohns Colitis 2022; 17:450-458. [PMID: 36006803 PMCID: PMC10069614 DOI: 10.1093/ecco-jcc/jjac124] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Indexed: 01/01/2023]
Abstract
Studies of Crohn's disease consistently implicate NOD2 as the most important gene in disease pathogenesis since first being identified in 2001. Since this point, genome-wide association, next-generation sequencing, and functional analyses have all confirmed a key role for NOD2, but despite this, NOD2 also has significant unresolved complexity. More recent studies have reinvigorated an early hypothesis that NOD2 may be a single-gene cause of disease, and the distinct ileal stricturing phenotype seen with NOD2-related disease presents an opportunity for personalised diagnosis, disease prediction and targeted therapy. The genomics of NOD2 has much that remains unknown, including the role of rare variation, phasing of variants across the haplotype block and the role of variation in the NOD2-regulatory regions. Here, we discuss the evidence and the unmet needs of NOD2-research, based on recently published evidence, and suggest methods that may meet these requirements.
Collapse
Affiliation(s)
- James J Ashton
- Department of Human Genetics and Genomic Medicine, University of Southampton, Southampton, UK.,Department of Paediatric Gastroenterology, Southampton Children's Hospital, Southampton, UK
| | - Eleanor G Seaby
- Department of Human Genetics and Genomic Medicine, University of Southampton, Southampton, UK
| | - R Mark Beattie
- Department of Paediatric Gastroenterology, Southampton Children's Hospital, Southampton, UK
| | - Sarah Ennis
- Department of Human Genetics and Genomic Medicine, University of Southampton, Southampton, UK
| |
Collapse
|
|
21
|
Wang CC, Weng JJ, Chen HC, Lee MC, Ko PS, Su SL. Differential gene expression orchestrated by transcription factors in osteoporosis: bioinformatics analysis of associated polymorphism elaborating functional relationships. Aging (Albany NY) 2022; 14:5163-5176. [PMID: 35748775 PMCID: PMC9271311 DOI: 10.18632/aging.204136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 05/19/2022] [Indexed: 11/25/2022]
Abstract
Background: Identification of candidate SNPs from transcription factors (TFs) is a novel concept, while systematic large-scale studies on these SNPs are scarce. Purpose: This study aimed to identify the SNPs of six TF binding sites (TFBSs) and examine the association between candidate SNPs and osteoporosis. Methods: We used the Taiwan BioBank database; University of California, Santa Cruz, reference genome; and a chromatin immunoprecipitation sequencing database to detect 14 SNPs at the potential binding sites of six TFs. Moreover, we performed a case–control study and genotyped 109 patients with osteoporosis (T-score ≤ −2.5 evaluated by dual-energy X-ray absorptiometry) and 262 healthy individuals (T-score ≥ −1) at Tri-Service General Hospital from 2015 to 2019. Furthermore, we used the expression quantitative trait loci (eQTL) from the Genotype-Tissue Expression database to identify downstream gene expression as a criterion for the function of candidate SNPs. Results: Bioinformatic analysis identified 14 SNPs of TFBSs influencing osteoporosis. Of these SNPs, the rs130347 CC + TC genotype had 0.57 times higher risk than the TT genotype (OR = 0.57, p = 0.031). Validation of eQTL analysis revealed that rs130347 T allele influences mRNA expression of downstream A4GALT in whole blood (p = 0.0041) and skeletal tissues (p = 0.011). Conclusions: We successfully identified the unique osteoporosis locus rs130347 in the Taiwanese and functionally validated this finding. In the future, this strategy can be expanded to other diseases to identify susceptible loci and achieve personalized precision medicine.
Collapse
Affiliation(s)
- Chih-Chien Wang
- Department of Orthopedics, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan, R.O.C
| | - Jen-Jie Weng
- School of Public Health, National Defense Medical Center, Taipei, Taiwan, R.O.C
| | - Hsiang-Cheng Chen
- Division of Rheumatology, Immunology and Allergy, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, R.O.C
| | - Meng-Chang Lee
- School of Public Health, National Defense Medical Center, Taipei, Taiwan, R.O.C
| | - Pi-Shao Ko
- School of Public Health, National Defense Medical Center, Taipei, Taiwan, R.O.C.,Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, R.O.C
| | - Sui-Lung Su
- School of Public Health, National Defense Medical Center, Taipei, Taiwan, R.O.C
| |
Collapse
|
|
22
|
Jemec GBE, Del Marmol V, Bettoli V, Augustin M, Prens EP, Zouboulis CC. Register, multicenter and genome-wide association studies in hidradenitis suppurativa. Exp Dermatol 2022; 31 Suppl 1:22-28. [PMID: 35582836 DOI: 10.1111/exd.14610] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 05/04/2022] [Accepted: 05/15/2022] [Indexed: 11/28/2022]
Abstract
The European Hidradenitis Suppurativa Foundation (EHSF) e.V. has taken several initiatives to collaborative studies. They result from the data of the European Registry of Hidradenitis Suppurativa (ERHS) based on the knowledge obtained from the regional Northern countries (HISREG) and Italian (IRHIS) registries and the real-world data generated from claims data from insurance databases. Multicenter studies, such as the Hidradenitis Suppurativa collaborative study of subtypes (HORUS) and the Global Hidradenitis Suppurativa Atlas (GHISA) are planned to provide an ideal complement to the register studies. Most recently, the role of EHSF as a coordinator or key player is being explored in multiple genetic studies, such as a genome-wide association study (GWAS) and the exome sequencing and cellular/molecular profiling project, which will speed up gene and drug discovery in HS.
Collapse
Affiliation(s)
- G B E Jemec
- Department of Dermatology, Zealand University Hospital, Roskilde, Denmark.,European Hidradenitis Suppurativa Foundation e.V., Dessau, Germany
| | - V Del Marmol
- Department of Dermatology, Hopital Erasme, Université Libre de Bruxelles, Belgium.,European Hidradenitis Suppurativa Foundation e.V., Dessau, Germany
| | - V Bettoli
- Department of Dermatology, University of Ferrara, Ferrara, Italy.,European Hidradenitis Suppurativa Foundation e.V., Dessau, Germany
| | - M Augustin
- Institute for Health Services Research in Dermatology and Nursing, University Hospital Hamburg-Eppendorf, Hamburg, Germany.,European Hidradenitis Suppurativa Foundation e.V., Dessau, Germany
| | - E P Prens
- Department of Dermatology, Erasmus Medical Center, University of Rotterdam, Rotterdam, Netherlands.,European Hidradenitis Suppurativa Foundation e.V., Dessau, Germany
| | - C C Zouboulis
- Departments of Dermatology, Venereology, Allergollogy and Immunology, Dessau Medical Center, Brandenburg Medical School Theodor Fontane and Faculty of Health Sciences Brandenburg, Dessau, Germany.,European Hidradenitis Suppurativa Foundation e.V., Dessau, Germany
| |
Collapse
|
|
23
|
Yang W, Dong H, Wang P, Xu Z, Xian J, Chen J, Wu H, Lou Y, Lin D, Zhong B. IL-36γ and IL-36Ra Reciprocally Regulate Colon Inflammation and Tumorigenesis by Modulating the Cell-Matrix Adhesion Network and Wnt Signaling. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2103035. [PMID: 35119210 PMCID: PMC8981487 DOI: 10.1002/advs.202103035] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 12/14/2021] [Indexed: 05/07/2023]
Abstract
Inflammatory bowel disease and colorectal cancer are associated with dysregulation of cytokine networks. However, it is challenging to target cytokines for effective intervention because of the overlapping functions and unpredictable interactions of cytokines in such diverse networks. Here, it is shown that IL-36γ and IL-36Ra, an agonist and an antagonist for IL-36R signaling respectively, reciprocally regulate the experimental colitis and the colon cancer development in mice. Knockout or neutralization of IL-36γ alleviates dextran sulfate sodium (DSS)-induced colitis and inhibits colon cancer development, whereas knockout of IL-36Ra exacerbates DSS-induced colitis and promotes colonic tumorigenesis in multiple colon cancer models in mice. Mechanistically, IL-36γ upregulates extracellular matrix and cell-matrix adhesion molecules and facilitates Wnt signaling, which is mitigated by IL-36Ra or IL-36γ neutralizing antibody. Consistently, IL-36γ levels are positively correlated with extracellular matrix levels and β-catenin levels in human colorectal tumor biopsies. These findings suggest the critical role of IL-36γ and IL-36Ra in gut inflammation and tumorigenesis and indicate that targeting the IL-36γ/IL-36Ra signal balance provides potential therapeutic strategy for inflammatory bowel disease and gastrointestinal cancers.
Collapse
Affiliation(s)
- Wei Yang
- Department of Gastrointestinal SurgeryMedical Research InstituteZhongnan Hospital of Wuhan UniversityWuhan430071China
- Department of Pulmonary and Critical Care MedicineZhongnan Hospital of Wuhan UniversityWuhan430071China
- Frontier Science Center for Immunology and MetabolismWuhan UniversityWuhan430071China
- Department of VirologyCollege of Life SciencesWuhan UniversityWuhan430072China
- Wuhan Research Center for Infectious Diseases and CancerChinese Academy of Medical SciencesWuhan430071China
| | - Hong‐Peng Dong
- Department of Gastrointestinal SurgeryMedical Research InstituteZhongnan Hospital of Wuhan UniversityWuhan430071China
- Department of Pulmonary and Critical Care MedicineZhongnan Hospital of Wuhan UniversityWuhan430071China
- Frontier Science Center for Immunology and MetabolismWuhan UniversityWuhan430071China
- Department of VirologyCollege of Life SciencesWuhan UniversityWuhan430072China
| | - Peng Wang
- Department of Gastrointestinal SurgeryMedical Research InstituteZhongnan Hospital of Wuhan UniversityWuhan430071China
- Department of Pulmonary and Critical Care MedicineZhongnan Hospital of Wuhan UniversityWuhan430071China
- Frontier Science Center for Immunology and MetabolismWuhan UniversityWuhan430071China
- Department of VirologyCollege of Life SciencesWuhan UniversityWuhan430072China
| | - Zhi‐Gao Xu
- Institute of Hepatobiliary Diseases and Transplant CenterZhongnan Hospital of Wuhan UniversityWuhan430071China
| | - Jiahuan Xian
- Yurogen Biosystems LLC (Wuhan)666 Gaoxin Avenue, Building C6, Donghu DistrictWuhan430064China
| | - Jiachen Chen
- Yurogen Biosystems LLC (Wuhan)666 Gaoxin Avenue, Building C6, Donghu DistrictWuhan430064China
| | - Hai Wu
- Yurogen Biosystems LLC (Wuhan)666 Gaoxin Avenue, Building C6, Donghu DistrictWuhan430064China
| | - Yang Lou
- Yurogen Biosystems LLC (Wuhan)666 Gaoxin Avenue, Building C6, Donghu DistrictWuhan430064China
| | - Dandan Lin
- Cancer CenterRenmin Hospital of Wuhan UniversityWuhan430061China
| | - Bo Zhong
- Department of Gastrointestinal SurgeryMedical Research InstituteZhongnan Hospital of Wuhan UniversityWuhan430071China
- Department of Pulmonary and Critical Care MedicineZhongnan Hospital of Wuhan UniversityWuhan430071China
- Frontier Science Center for Immunology and MetabolismWuhan UniversityWuhan430071China
- Department of VirologyCollege of Life SciencesWuhan UniversityWuhan430072China
- Wuhan Research Center for Infectious Diseases and CancerChinese Academy of Medical SciencesWuhan430071China
| |
Collapse
|
|
24
|
Parigi SM, Larsson L, Das S, Ramirez Flores RO, Frede A, Tripathi KP, Diaz OE, Selin K, Morales RA, Luo X, Monasterio G, Engblom C, Gagliani N, Saez-Rodriguez J, Lundeberg J, Villablanca EJ. The spatial transcriptomic landscape of the healing mouse intestine following damage. Nat Commun 2022; 13:828. [PMID: 35149721 PMCID: PMC8837647 DOI: 10.1038/s41467-022-28497-0] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 01/28/2022] [Indexed: 12/12/2022] Open
Abstract
The intestinal barrier is composed of a complex cell network defining highly compartmentalized and specialized structures. Here, we use spatial transcriptomics to define how the transcriptomic landscape is spatially organized in the steady state and healing murine colon. At steady state conditions, we demonstrate a previously unappreciated molecular regionalization of the colon, which dramatically changes during mucosal healing. Here, we identified spatially-organized transcriptional programs defining compartmentalized mucosal healing, and regions with dominant wired pathways. Furthermore, we showed that decreased p53 activation defined areas with increased presence of proliferating epithelial stem cells. Finally, we mapped transcriptomics modules associated with human diseases demonstrating the translational potential of our dataset. Overall, we provide a publicly available resource defining principles of transcriptomic regionalization of the colon during mucosal healing and a framework to develop and progress further hypotheses.
Collapse
Affiliation(s)
- Sara M Parigi
- Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institute and University Hospital, Stockholm, Sweden
- Center of Molecular Medicine, Stockholm, Sweden
| | - Ludvig Larsson
- Science for Life Laboratory, Department of Gene Technology, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Srustidhar Das
- Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institute and University Hospital, Stockholm, Sweden
- Center of Molecular Medicine, Stockholm, Sweden
| | - Ricardo O Ramirez Flores
- Heidelberg University, Faculty of Medicine, and Heidelberg University Hospital, Institute for Computational Biomedicine, Bioquant, Heidelberg, Germany
| | - Annika Frede
- Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institute and University Hospital, Stockholm, Sweden
- Center of Molecular Medicine, Stockholm, Sweden
| | - Kumar P Tripathi
- Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institute and University Hospital, Stockholm, Sweden
- Center of Molecular Medicine, Stockholm, Sweden
| | - Oscar E Diaz
- Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institute and University Hospital, Stockholm, Sweden
- Center of Molecular Medicine, Stockholm, Sweden
| | - Katja Selin
- Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institute and University Hospital, Stockholm, Sweden
- Center of Molecular Medicine, Stockholm, Sweden
| | - Rodrigo A Morales
- Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institute and University Hospital, Stockholm, Sweden
- Center of Molecular Medicine, Stockholm, Sweden
| | - Xinxin Luo
- Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institute and University Hospital, Stockholm, Sweden
- Center of Molecular Medicine, Stockholm, Sweden
| | - Gustavo Monasterio
- Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institute and University Hospital, Stockholm, Sweden
- Center of Molecular Medicine, Stockholm, Sweden
| | - Camilla Engblom
- Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden
| | - Nicola Gagliani
- Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institute and University Hospital, Stockholm, Sweden
- Center of Molecular Medicine, Stockholm, Sweden
- I. Department of Medicine and Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Julio Saez-Rodriguez
- Heidelberg University, Faculty of Medicine, and Heidelberg University Hospital, Institute for Computational Biomedicine, Bioquant, Heidelberg, Germany
| | - Joakim Lundeberg
- Science for Life Laboratory, Department of Gene Technology, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Eduardo J Villablanca
- Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institute and University Hospital, Stockholm, Sweden.
- Center of Molecular Medicine, Stockholm, Sweden.
| |
Collapse
|
|
25
|
Ben-Yosef N, Frampton M, Schiff ER, Daher S, Abu Baker F, Safadi R, Israeli E, Segal AW, Levine AP. Genetic analysis of four consanguineous multiplex families with inflammatory bowel disease. Gastroenterol Rep (Oxf) 2021; 9:521-532. [PMID: 34925849 PMCID: PMC8677555 DOI: 10.1093/gastro/goab007] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 11/03/2020] [Accepted: 11/26/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Family studies support a genetic predisposition to inflammatory bowel diseases (IBD), but known genetic variants only partially explain the disease heritability. Families with multiple affected individuals potentially harbour rare and high-impact causal variants. Long regions of homozygosity due to recent inbreeding may increase the risk of individuals bearing homozygous loss-of-function variants. This study aimed to identify rare and homozygous genetic variants contributing to IBD. METHODS Four families with known consanguinity and multiple cases of IBD were recruited. In a family-specific analysis, we utilised homozygosity mapping complemented by whole-exome sequencing. RESULTS We detected a single region of homozygosity shared by Crohn's disease cases from a family of Druze ancestry, spanning 2.6 Mb containing the NOD2 gene. Whole-exome sequencing did not identify any potentially damaging variants within the region, suggesting that non-coding variation may be involved. In addition, affected individuals in the families harboured several rare and potentially damaging homozygous variants in genes with a role in autophagy and innate immunity including LRRK1, WHAMM, DENND3, and C5. CONCLUSION This study examined the potential contribution of rare, high-impact homozygous variants in consanguineous families with IBD. While the analysis was not designed to achieve statistical significance, our findings highlight genes or loci that warrant further research. Non-coding variants affecting NOD2 may be of importance in Druze patients with Crohn's disease.
Collapse
Affiliation(s)
- Noam Ben-Yosef
- Centre for Molecular Medicine, Division of Medicine, University College London, London, UK
- Institute of Gastroenterology and Liver disease, Hadassah Medical Center, Jerusalem, Israel
| | - Matthew Frampton
- Centre for Molecular Medicine, Division of Medicine, University College London, London, UK
| | - Elena R Schiff
- Institute of Ophthalmology, Moorfields Eye Hospital, University College London, London, UK
| | - Saleh Daher
- Institute of Gastroenterology and Liver disease, Hadassah Medical Center, Jerusalem, Israel
| | - Fadi Abu Baker
- Institue of Gastroenterology and Hepatology, Hillel Yaffe Medical Center, Hadera, Israel
| | - Rifaat Safadi
- Institute of Gastroenterology and Liver disease, Hadassah Medical Center, Jerusalem, Israel
| | - Eran Israeli
- Institute of Gastroenterology and Liver disease, E. Wolfson Medical Center, Holon, Israel
| | - Anthony W Segal
- Centre for Molecular Medicine, Division of Medicine, University College London, London, UK
| | - Adam P Levine
- Centre for Molecular Medicine, Division of Medicine, University College London, London, UK
- Department of Pathology, University College London, London, UK
| |
Collapse
|
|
26
|
Abstract
Current practice in IBD is to classify patients based on clinical signs and symptoms and provide treatments accordingly. However, the response of IBD patients to available treatments is highly variable, highlighting clinically significant heterogeneity among patients. Thus, more accurate patient stratification is urgently needed to more effectively target therapeutic interventions to specific patients. Here we review the degree of heterogeneity in IBD, discussing how the microbiota, genetics, and immune system may contribute to the variation among patients. We highlight how molecular heterogeneity may relate to clinical phenotype, but in other situations may be independent of clinical phenotype, encouraging future studies to fill the gaps. Finally, we discuss novel stratification methodologies as a foundation for precision medicine, in particular a novel stratification strategy based on conserved genes across species. All of these dimensions of heterogeneity have potential to provide strategies for patient stratification and move IBD practice towards personalised medicine.
Collapse
Affiliation(s)
- Katja A Selin
- Division of Immunology and Allergy, Department of Medicine, Solna, Karolinska Institutet and University Hospital, Stockholm, Sweden
- Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
- Gastroenterology Unit, Patient Area Gastroenterology, Dermatovenereology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden
- Department of Medicine, Solna, Division of Clinical Medicine, Karolinska Institutet, Solna, Sweden
| | - Charlotte R H Hedin
- Gastroenterology Unit, Patient Area Gastroenterology, Dermatovenereology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden
- Department of Medicine, Solna, Division of Clinical Medicine, Karolinska Institutet, Solna, Sweden
| | - Eduardo J Villablanca
- Division of Immunology and Allergy, Department of Medicine, Solna, Karolinska Institutet and University Hospital, Stockholm, Sweden
- Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Medicine, Solna, Division of Clinical Medicine, Karolinska Institutet, Solna, Sweden
| |
Collapse
|
|
27
|
Díez-Obrero V, Moratalla-Navarro F, Ibáñez-Sanz G, Guardiola J, Rodríguez-Moranta F, Obón-Santacana M, Díez-Villanueva A, Dampier CH, Devall M, Carreras-Torres R, Casey G, Moreno V. Transcriptome-Wide Association Study for Inflammatory Bowel Disease Reveals Novel Candidate Susceptibility Genes in Specific Colon Subsites and Tissue Categories. J Crohns Colitis 2021; 16:275-285. [PMID: 34286847 PMCID: PMC8864630 DOI: 10.1093/ecco-jcc/jjab131] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
BACKGROUND AND AIMS Genome-wide association studies [GWAS] for inflammatory bowel disease [IBD] have identified 240 risk variants. However, the benefit of understanding the genetic architecture of IBD remains to be exploited. Transcriptome-wide association studies [TWAS] associate gene expression with genetic susceptibility to disease, providing functional insight into risk loci. In this study, we integrate relevant datasets for IBD and perform a TWAS to nominate novel genes implicated in IBD genetic susceptibility. METHODS We applied elastic net regression to generate gene expression prediction models for the University of Barcelona and University of Virginia RNA sequencing project [BarcUVa-Seq] and correlated expression and disease association research [CEDAR] datasets. Together with Genotype-Tissue Expression project [GTEx] data, and GWAS results from about 60 000 individuals, we employed Summary-PrediXcan and Summary-MultiXcan for single and joint analyses of TWAS results, respectively. RESULTS BarcUVa-Seq TWAS revealed 39 novel genes whose expression in the colon is associated with IBD genetic susceptibility. They included expression markers for specific colon cell types. TWAS meta-analysis including all tissues/cell types provided 186 novel candidate susceptibility genes. Additionally, we identified 78 novel susceptibility genes whose expression is associated with IBD exclusively in immune (N = 19), epithelial (N = 25), mesenchymal (N = 22) and neural (N = 12) tissue categories. Associated genes were involved in relevant molecular pathways, including pathways related to known IBD therapeutics, such as tumour necrosis factor signalling. CONCLUSION These findings provide insight into tissue-specific molecular processes underlying IBD genetic susceptibility. Associated genes could be candidate targets for new therapeutics and should be prioritized in functional studies.
Collapse
Affiliation(s)
- Virginia Díez-Obrero
- Oncology Data Analytics Program, Catalan Institute of Oncology (ICO), L’Hospitalet de Llobregat, Barcelona, Spain,ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain,Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain,Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain
| | - Ferran Moratalla-Navarro
- Oncology Data Analytics Program, Catalan Institute of Oncology (ICO), L’Hospitalet de Llobregat, Barcelona, Spain,Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain,Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain
| | - Gemma Ibáñez-Sanz
- Oncology Data Analytics Program, Catalan Institute of Oncology (ICO), L’Hospitalet de Llobregat, Barcelona, Spain,ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain,Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain,Gastroenterology Department, Bellvitge University Hospital, L’Hospitalet de Llobregat, Spain
| | - Jordi Guardiola
- Gastroenterology Department, Bellvitge University Hospital, L’Hospitalet de Llobregat, Spain
| | | | - Mireia Obón-Santacana
- Oncology Data Analytics Program, Catalan Institute of Oncology (ICO), L’Hospitalet de Llobregat, Barcelona, Spain,ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain,Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain
| | - Anna Díez-Villanueva
- Oncology Data Analytics Program, Catalan Institute of Oncology (ICO), L’Hospitalet de Llobregat, Barcelona, Spain,ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain,Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain
| | - Christopher Heaton Dampier
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA,Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA
| | - Matthew Devall
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA,Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA
| | - Robert Carreras-Torres
- Oncology Data Analytics Program, Catalan Institute of Oncology (ICO), L’Hospitalet de Llobregat, Barcelona, Spain,ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain,Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain
| | - Graham Casey
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA,Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA
| | - Victor Moreno
- Oncology Data Analytics Program, Catalan Institute of Oncology (ICO), L’Hospitalet de Llobregat, Barcelona, Spain,ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain,Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain,Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain,Corresponding author: Dr Victor Moreno, Catalan Institute of Oncology, Oncology Data Analytics Program, Hospital Duran i Reynals, Gran Via de l’Hospitalet, 199–203, 08908 L’Hospitalet de Llobregat (Barcelona) Spain. Tel: +34 932 607 434;
| |
Collapse
|
|
28
|
To Be or to Have Been Lucky, That Is the Question. PHILOSOPHIES 2021. [DOI: 10.3390/philosophies6030057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Is it possible to measure the dispersion of ex ante chances (i.e., chances “before the event”) among people, be it gambling, health, or social opportunities? We explore this question and provide some tools, including a statistical test, to evidence the actual dispersion of ex ante chances in various areas, with a focus on chronic diseases. Using the principle of maximum entropy, we derive the distribution of the risk of becoming ill in the global population as well as in the population of affected people. We find that affected people are either at very low risk, like the overwhelming majority of the population, but still were unlucky to become ill, or are at extremely high risk and were bound to become ill.
Collapse
|
|
29
|
Lu S, Zhu K, Guo Y, Wang E, Huang J. Evaluation of animal models of Crohn's disease with anal fistula (Review). Exp Ther Med 2021; 22:974. [PMID: 34335916 PMCID: PMC8290422 DOI: 10.3892/etm.2021.10406] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 06/09/2021] [Indexed: 12/28/2022] Open
Abstract
Anal fistula is a common and serious complication of Crohn's disease (CD). A sufficiently suitable animal model that may be used to simulate this disease is yet to be established. The aim of the present review was to summarize the different characteristics and experimental methods of commonly used animal models of CD with anal fistula. Electronic databases were searched for studies reporting on the use of this type of animal model. A total of 234 related articles were retrieved, of which six articles met the inclusion criteria; these were used as references for the present review article. The characteristics of the animal models, the advantages and disadvantages of the modeling methods and the similarities with patients with CD and anal fistula were summarized and analyzed. The evidence suggests that a sufficiently suitable animal preclinical model requires to be established.
Collapse
Affiliation(s)
- Shuangshuang Lu
- Department of Internal Medicine, School of Medicine, Dalian Medical University, Dalian, Liaoning 116044, P.R. China.,Gastrointestinal Center, Changzhou Second People's Hospital of Nanjing Medical University, Changzhou, Jiangsu 213000, P.R. China
| | - Keyuan Zhu
- Department of Internal Medicine, School of Medicine, Dalian Medical University, Dalian, Liaoning 116044, P.R. China.,Gastrointestinal Center, Changzhou Second People's Hospital of Nanjing Medical University, Changzhou, Jiangsu 213000, P.R. China
| | - Yongxin Guo
- Department of Internal Medicine, School of Medicine, Dalian Medical University, Dalian, Liaoning 116044, P.R. China.,Gastrointestinal Center, Changzhou Second People's Hospital of Nanjing Medical University, Changzhou, Jiangsu 213000, P.R. China
| | - Enjing Wang
- Gastrointestinal Center, Changzhou Second People's Hospital of Nanjing Medical University, Changzhou, Jiangsu 213000, P.R. China.,Department of Internal Medicine, School of Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China
| | - Jin Huang
- Department of Internal Medicine, School of Medicine, Dalian Medical University, Dalian, Liaoning 116044, P.R. China.,Gastrointestinal Center, Changzhou Second People's Hospital of Nanjing Medical University, Changzhou, Jiangsu 213000, P.R. China
| |
Collapse
|
|
30
|
Cai C, Zhu S, Tong J, Wang T, Feng Q, Qiao Y, Shen J. Relating the transcriptome and microbiome by paired terminal ileal Crohn disease. iScience 2021; 24:102516. [PMID: 34113837 PMCID: PMC8170125 DOI: 10.1016/j.isci.2021.102516] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 03/28/2021] [Accepted: 05/03/2021] [Indexed: 12/16/2022] Open
Abstract
Management of terminal ileal Crohn disease (CD) is difficult due to fibrotic prognosis and failure to achieve mucosal healing. A limited number of synchronous analyses have been conducted on the transcriptome and microbiome in unpaired terminal ileum tissues. Therefore, our study focused on the transcriptome and mucosal microbiome in terminal ileal tissues of patients with CD with the aim of determining the role of cross-talk between the microbiome and transcriptome in the pathogenesis of terminal ileal CD. Mucosa-attached microbial communities were significantly associated with segmental inflammation status. Interaction-related transcription factors (TFs) are the panel nodes for cross-talk between the gene patterns and microbiome for terminal ileal CD. The transcriptome and microbiome in terminal ileal CD can be differently related to the local inflammatory status, and specific differentially expressed genes may be targeted for mucosal healing. TFs connect gene patterns with the microbiome by reflecting environmental stimuli and signals from microbiota.
Collapse
Affiliation(s)
- Chenwen Cai
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 160# Pu Jian Avenue, Shanghai 200127, China
- Department of Gastroenterology, Huashan Hospital North, Fudan University, No.108 LuXiang Road, Shanghai 201907, China
| | - Sibo Zhu
- MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai 200438, China
| | - Jinlu Tong
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 160# Pu Jian Avenue, Shanghai 200127, China
| | - Tianrong Wang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 160# Pu Jian Avenue, Shanghai 200127, China
| | - Qi Feng
- Department of Radiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pu Jian Road, Shanghai 200127, China
| | - Yuqi Qiao
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 160# Pu Jian Avenue, Shanghai 200127, China
| | - Jun Shen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 160# Pu Jian Avenue, Shanghai 200127, China
| |
Collapse
|
|
31
|
Jaschke N, Sipos W, Hofbauer LC, Rachner TD, Rauner M. Skeletal endocrinology: where evolutionary advantage meets disease. Bone Res 2021; 9:28. [PMID: 34050126 PMCID: PMC8163738 DOI: 10.1038/s41413-021-00149-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 02/16/2021] [Accepted: 02/23/2021] [Indexed: 02/06/2023] Open
Abstract
The regulation of whole-body homeostasis by the skeleton is mediated by its capacity to secrete endocrine signaling molecules. Although bone-derived hormones confer several adaptive benefits, their physiological functions also involve trade-offs, thus eventually contributing to disease. In this manuscript, we discuss the origins and functions of two of the best-studied skeletal mediators, fibroblast growth factor 23 and osteocalcin, in an evolutionary context. Moreover, we provide a theoretical framework seeking to explain the broad involvement of these two hormones in amniote physiology as well as their potential to fuel the development and progression of diseases. Vice versa, we outline which perturbations might be amenable to manipulation of these systems and discuss limitations and ongoing challenges in skeletal endocrine research. Finally, we summarize unresolved questions and potential future studies in this thriving field.
Collapse
Affiliation(s)
- Nikolai Jaschke
- Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
| | - Wolfgang Sipos
- Clinical Department for Farm Animals, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Lorenz C Hofbauer
- Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
| | - Tilman D Rachner
- Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
| | - Martina Rauner
- Department of Medicine III & Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany.
| |
Collapse
|
|
32
|
Devaprasad A, Radstake TRDJ, Pandit A. Integration of Immunome With Disease-Gene Network Reveals Common Cellular Mechanisms Between IMIDs and Drug Repurposing Strategies. Front Immunol 2021; 12:669400. [PMID: 34108969 PMCID: PMC8181425 DOI: 10.3389/fimmu.2021.669400] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 05/04/2021] [Indexed: 01/25/2023] Open
Abstract
Objective Development and progression of immune-mediated inflammatory diseases (IMIDs) involve intricate dysregulation of the disease-associated genes (DAGs) and their expressing immune cells. Identifying the crucial disease-associated cells (DACs) in IMIDs has been challenging due to the underlying complex molecular mechanism. Methods Using transcriptome profiles of 40 different immune cells, unsupervised machine learning, and disease-gene networks, we constructed the Disease-gene IMmune cell Expression (DIME) network and identified top DACs and DAGs of 12 phenotypically different IMIDs. We compared the DIME networks of IMIDs to identify common pathways between them. We used the common pathways and publicly available drug-gene network to identify promising drug repurposing targets. Results We found CD4+Treg, CD4+Th1, and NK cells as top DACs in inflammatory arthritis such as ankylosing spondylitis (AS), psoriatic arthritis, and rheumatoid arthritis (RA); neutrophils, granulocytes, and BDCA1+CD14+ cells in systemic lupus erythematosus and systemic scleroderma; ILC2, CD4+Th1, CD4+Treg, and NK cells in the inflammatory bowel diseases (IBDs). We identified lymphoid cells (CD4+Th1, CD4+Treg, and NK) and their associated pathways to be important in HLA-B27 type diseases (psoriasis, AS, and IBDs) and in primary-joint-inflammation-based inflammatory arthritis (AS and RA). Based on the common cellular mechanisms, we identified lifitegrast as a potential drug repurposing candidate for Crohn's disease and other IMIDs. Conclusions Existing methods are inadequate in capturing the intricate involvement of the crucial genes and cell types essential to IMIDs. Our approach identified the key DACs, DAGs, common mechanisms between IMIDs, and proposed potential drug repurposing targets using the DIME network. To extend our method to other diseases, we built the DIME tool (https://bitbucket.org/systemsimmunology/dime/) to help scientists uncover the etiology of complex and rare diseases to further drug development by better-determining drug targets, thereby mitigating the risk of failure in late clinical development.
Collapse
Affiliation(s)
- Abhinandan Devaprasad
- Division Internal Medicine and Dermatology, University Medical Center Utrecht, Utrecht, Netherlands
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Timothy R. D. J. Radstake
- Division Internal Medicine and Dermatology, University Medical Center Utrecht, Utrecht, Netherlands
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Aridaman Pandit
- Division Internal Medicine and Dermatology, University Medical Center Utrecht, Utrecht, Netherlands
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands
| |
Collapse
|
|
33
|
Abdul-Hussein SS, Ali EN, Zaki NH, Ad’hiah AH. Genetic polymorphism of HLA-G gene (G*01:03, G*01:04, and G*01:05N) in Iraqi patients with inflammatory bowel disease (ulcerative colitis and Crohn’s disease). EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2021. [DOI: 10.1186/s43042-021-00158-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Abstract
Background
Human leukocyte antigen-G (HLA-G) has been proposed to influence susceptibility to inflammatory bowel disease (IBD). Therefore, the genetic association between HLA-G alleles and two clinical phenotypes of IBD (ulcerative colitis [UC] and Crohn’s disease [CD]) was evaluated in Iraqi patients. A case-control study was performed on 50 UC and 50 CD patients and 100 healthy controls (HC). Three HLA-G alleles (G*01:03, G*01:04, and G*01:05N) were determined using sequence-specific polymerase chain reaction assay followed by product digestion with restriction endonucleases (Hinf-I, BseR-I, and PpuM-I, respectively).
Results
The G*01:03 allele was not detected in IBD patients (UC and CD) or HC, while G*01:04 and G*01:05N alleles showed polymorphic frequencies. The allele G*01:04 was significantly associated with susceptibility to UC (odds ratio [OR] = 2.55; 95% confidence interval [CI] = 1.27–5.13; corrected probability [pc] = 0.018) and CD (OR = 4.45; 95% CI = 2.11–9.41; pc < 0.001). The allele G*01:05N was also associated with increased risk of UC (OR = 4.17; 95% CI = 1.32–13.21; pc = 0.032) and CD (OR = 4.75; 95% CI = 1.53–14.78; pc = 0.014). These associations were more pronounced in IBD (UC + CD), and a significantly increased risk for IBD was found with the alleles G*01:04 (OR = 3.32; 95% CI = 1.86–5.95; pc < 0.001) and G*01:05N (OR = 4.46; 95% CI = 1.59–12.47; pc = 0.008). A stratification of IBD patients according to some demographic and clinical characteristics revealed that frequencies of both alleles showed no significant differences between the subgroups of patients in each stratum. Soluble HLA-G was not influenced by HLA-G alleles in patients or HC. UC was an exception, and the presence of G*01:04 allele was associated with a significantly higher mean of soluble HLA-G compared to patients without the allele (189.6 ± 24.0 vs. 168.6 ± 27.2 ng/mL; p = 0.033).
Conclusion
This study indicated that HLA-G*01:04 and HLA-G*01:05N alleles may influence susceptibility to UC and CD in Iraqi patients.
Collapse
|
|
34
|
Wu Y, Murray GK, Byrne EM, Sidorenko J, Visscher PM, Wray NR. GWAS of peptic ulcer disease implicates Helicobacter pylori infection, other gastrointestinal disorders and depression. Nat Commun 2021; 12:1146. [PMID: 33608531 PMCID: PMC7895976 DOI: 10.1038/s41467-021-21280-7] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 01/06/2021] [Indexed: 01/31/2023] Open
Abstract
Genetic factors are recognized to contribute to peptic ulcer disease (PUD) and other gastrointestinal diseases, such as gastro-oesophageal reflux disease (GORD), irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). Here, genome-wide association study (GWAS) analyses based on 456,327 UK Biobank (UKB) individuals identify 8 independent and significant loci for PUD at, or near, genes MUC1, MUC6, FUT2, PSCA, ABO, CDX2, GAST and CCKBR. There are previously established roles in susceptibility to Helicobacter pylori infection, response to counteract infection-related damage, gastric acid secretion or gastrointestinal motility for these genes. Only two associations have been previously reported for duodenal ulcer, here replicated trans-ancestrally. The results highlight the role of host genetic susceptibility to infection. Post-GWAS analyses for PUD, GORD, IBS and IBD add insights into relationships between these gastrointestinal diseases and their relationships with depression, a commonly comorbid disorder.
Collapse
Affiliation(s)
- Yeda Wu
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
| | - Graham K Murray
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
- Department of Psychiatry, University of Cambridge, Cambridge, UK
- Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK
- Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK
| | - Enda M Byrne
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
| | - Julia Sidorenko
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
| | - Peter M Visscher
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
| | - Naomi R Wray
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
- Queensland Brain Institute, The University of Queensland, Brisbane, Australia.
| |
Collapse
|
|
35
|
Fernández-Ponce C, Navarro Quiroz R, Díaz Perez A, Aroca Martinez G, Cadena Bonfanti A, Acosta Hoyos A, Gómez Escorcia L, Hernández Agudelo S, Orozco Sánchez C, Villarreal Camacho J, Atencio Ibarra L, Consuegra Machado J, Espinoza Garavito A, García-Cózar F, Navarro Quiroz E. MicroRNAs overexpressed in Crohn's disease and their interactions with mechanisms of epigenetic regulation explain novel aspects of Crohn's disease pathogenesis. Clin Epigenetics 2021; 13:39. [PMID: 33602320 PMCID: PMC7890887 DOI: 10.1186/s13148-021-01022-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 02/02/2021] [Indexed: 12/14/2022] Open
Abstract
Background In this review, we were interested to identify the wide universe of enzymes associated with epigenetic modifications, whose gene expression is regulated by miRNAs with a high relative abundance in Crohn's disease (CD) affected tissues, with the aim to determine their impact in the pathogenesis and evolution of the disease. Methods We used HMDD and Bibliometrix R-package in order to identify the miRNAs overexpressed in CD. The identified enzymes associated with epigenetic mechanisms and post-translational modifications, regulated by miRNAs upregulated in CD, were analyzed using String v11 database. Results We found 190 miRNAs with great abundance in patients with CD, of which 26 miRNAs regulate the gene expression of enzymes known to catalyze epigenetic modifications involved in essentials pathophysiological processes, such as chromatin architecture reorganization, immune response regulation including CD4+ T cells polarization, integrity of gut mucosa, gut microbiota composition and tumorigenesis. Conclusion The integrated analysis of miRNAs with a high relative abundance in patients with CD showed a combined and superimposed gene expression regulation of enzymes associated with relevant epigenetic mechanisms and that could explain, in part, the pathogenesis of CD. Supplementary Information The online version contains supplementary material available at 10.1186/s13148-021-01022-8.
Collapse
Affiliation(s)
- Cecilia Fernández-Ponce
- Department of Biomedicine, Biotechnology and Public Health, University of Cadiz, Cadiz, Spain
| | - Roberto Navarro Quiroz
- CMCC-Centro de Matemática, Computação E Cognição, Laboratório do Biología Computacional e Bioinformática-LBCB, Universidade Federal Do ABC, Sao Paulo, 01023, Brazil
| | - Anderson Díaz Perez
- Facultad de Ciencias Básicas y Biomédicas, Universidad Simon Bolivar, 080001, Barranquilla, Colombia.,Universidad Rafael Nuñez, 130001, Cartagena, Colombia
| | - Gustavo Aroca Martinez
- Facultad de Ciencias Básicas y Biomédicas, Universidad Simon Bolivar, 080001, Barranquilla, Colombia.,Department of Nephrology, Clinica de La Costa, 080001, Barranquilla, Colombia
| | - Andrés Cadena Bonfanti
- Facultad de Ciencias Básicas y Biomédicas, Universidad Simon Bolivar, 080001, Barranquilla, Colombia.,Department of Nephrology, Clinica de La Costa, 080001, Barranquilla, Colombia
| | - Antonio Acosta Hoyos
- Facultad de Ciencias Básicas y Biomédicas, Universidad Simon Bolivar, 080001, Barranquilla, Colombia
| | - Lorena Gómez Escorcia
- Facultad de Ciencias Básicas y Biomédicas, Universidad Simon Bolivar, 080001, Barranquilla, Colombia.,Universidad Rafael Nuñez, 130001, Cartagena, Colombia
| | - Sandra Hernández Agudelo
- Facultad de Ciencias Básicas y Biomédicas, Universidad Simon Bolivar, 080001, Barranquilla, Colombia.,Department of Nephrology, Clinica de La Costa, 080001, Barranquilla, Colombia
| | - Christian Orozco Sánchez
- Facultad de Ciencias Básicas y Biomédicas, Universidad Simon Bolivar, 080001, Barranquilla, Colombia
| | | | | | | | - Alberto Espinoza Garavito
- Facultad de Ciencias Básicas y Biomédicas, Universidad Simon Bolivar, 080001, Barranquilla, Colombia
| | - Francisco García-Cózar
- Department of Biomedicine, Biotechnology and Public Health, University of Cadiz, Cadiz, Spain
| | - Elkin Navarro Quiroz
- Facultad de Ciencias Básicas y Biomédicas, Universidad Simon Bolivar, 080001, Barranquilla, Colombia. .,Centro de Investigación E Innovación en Biomoléculas, C4U S.A.S, 080001, Barranquilla, Colombia.
| |
Collapse
|
|
36
|
Verburgt CM, Ghiboub M, Benninga MA, de Jonge WJ, Van Limbergen JE. Nutritional Therapy Strategies in Pediatric Crohn's Disease. Nutrients 2021; 13:212. [PMID: 33450982 PMCID: PMC7828385 DOI: 10.3390/nu13010212] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 01/07/2021] [Accepted: 01/09/2021] [Indexed: 12/12/2022] Open
Abstract
The increase in incidences of pediatric Crohn's Disease (CD) worldwide has been strongly linked with dietary shifts towards a Westernized diet, ultimately leading to altered gut microbiota and disturbance in intestinal immunity and the metabolome. Multiple clinical studies in children with CD have demonstrated the high efficacy of nutritional therapy with exclusive enteral nutrition (EEN) to induce remission with an excellent safety profile. However, EEN is poorly tolerated, limiting its compliance and clinical application. This has spiked an interest in the development of alternative and better-tolerated nutritional therapy strategies. Several nutritional therapies have now been designed not only to treat the nutritional deficiencies seen in children with active CD but also to correct dysbiosis and reduce intestinal inflammation. In this review, we report the most recent insights regarding nutritional strategies in children with active CD: EEN, partial enteral nutrition (PEN), Crohn's disease exclusive diet (CDED), and CD treatment-with-eating diet (CD-TREAT). We describe their setup, efficacy, safety, and (dis)advantages as well as some of their potential mechanisms of action and perspectives. A better understanding of different nutritional therapeutic options and their mechanisms will yield better and safer management strategies for children with CD and may address the barriers and limitations of current strategies in children.
Collapse
Affiliation(s)
- Charlotte M. Verburgt
- Department of Pediatric Gastroenterology and Nutrition, Emma Children’s Hospital, Amsterdam University Medical Centers, 1105 AZ Amsterdam, The Netherlands; (C.M.V.); (M.G.); (M.A.B.)
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, University of Amsterdam, 1105 BK Amsterdam, The Netherlands;
| | - Mohammed Ghiboub
- Department of Pediatric Gastroenterology and Nutrition, Emma Children’s Hospital, Amsterdam University Medical Centers, 1105 AZ Amsterdam, The Netherlands; (C.M.V.); (M.G.); (M.A.B.)
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, University of Amsterdam, 1105 BK Amsterdam, The Netherlands;
| | - Marc A. Benninga
- Department of Pediatric Gastroenterology and Nutrition, Emma Children’s Hospital, Amsterdam University Medical Centers, 1105 AZ Amsterdam, The Netherlands; (C.M.V.); (M.G.); (M.A.B.)
| | - Wouter J. de Jonge
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, University of Amsterdam, 1105 BK Amsterdam, The Netherlands;
- Department of Surgery, University of Bonn, 53127 Bonn, Germany
| | - Johan E. Van Limbergen
- Department of Pediatric Gastroenterology and Nutrition, Emma Children’s Hospital, Amsterdam University Medical Centers, 1105 AZ Amsterdam, The Netherlands; (C.M.V.); (M.G.); (M.A.B.)
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, University of Amsterdam, 1105 BK Amsterdam, The Netherlands;
- Department of Pediatrics, Dalhousie University, Halifax, NS B3K 6R8, Canada
| |
Collapse
|
|
37
|
Oliveira MC, Elias JB, Moraes DAD, Simões BP, Rodrigues M, Ribeiro AAF, Piron-Ruiz L, Ruiz MA, Hamerschlak N. A review of hematopoietic stem cell transplantation for autoimmune diseases: multiple sclerosis, systemic sclerosis and Crohn's disease. Position paper of the Brazilian Society of Bone Marrow Transplantation. Hematol Transfus Cell Ther 2021; 43:65-86. [PMID: 32418777 PMCID: PMC7910166 DOI: 10.1016/j.htct.2020.03.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Revised: 03/19/2020] [Accepted: 03/23/2020] [Indexed: 12/16/2022] Open
Abstract
Autoimmune diseases are an important field for the development of bone marrow transplantation, or hematopoietic stem cell transplantation. In Europe alone, almost 3000 procedures have been registered so far. The Brazilian Society for Bone Marrow Transplantation (Sociedade Brasileira de Transplantes de Medula Óssea) organized consensus meetings for the Autoimmune Diseases Group, to review the available literature on hematopoietic stem cell transplantation for autoimmune diseases, aiming to gather data that support the procedure for these patients. Three autoimmune diseases for which there are evidence-based indications for hematopoietic stem cell transplantation are multiple sclerosis, systemic sclerosis and Crohn's disease. The professional stem cell transplant societies in America, Europe and Brazil (Sociedade Brasileira de Transplantes de Medula Óssea) currently consider hematopoietic stem cell transplantation as a therapeutic modality for these three autoimmune diseases. This article reviews the evidence available.
Collapse
Affiliation(s)
- Maria Carolina Oliveira
- Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (FMRP-USP), Ribeirão Preto, SP, Brazil
| | - Juliana Bernardes Elias
- Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (FMRP-USP), Ribeirão Preto, SP, Brazil
| | | | - Belinda Pinto Simões
- Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (FMRP-USP), Ribeirão Preto, SP, Brazil
| | | | | | - Lilian Piron-Ruiz
- Associação Portuguesa de Beneficência de São José do Rio Preto, São José do Rio Preto, SP, Brazil
| | - Milton Arthur Ruiz
- Associação Portuguesa de Beneficência de São José do Rio Preto, São José do Rio Preto, SP, Brazil
| | | |
Collapse
|
|
38
|
Donnini EK, Walugembe M, Rothschild MF, Jergens AE, Allenspach K. An initial genome-wide investigation of protein-losing enteropathy in Gordon setters: Exploratory observations. CANADIAN JOURNAL OF VETERINARY RESEARCH = REVUE CANADIENNE DE RECHERCHE VETERINAIRE 2021; 85:51-60. [PMID: 33390653 PMCID: PMC7747665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Accepted: 06/14/2020] [Indexed: 06/12/2023]
Abstract
The objective of this preliminary study was to identify genomic regions that may predispose Gordon setters from the United Kingdom to familial protein-losing enteropathy (PLE) at a young age. A total of 106 related Gordon setters was used, including 6 affected dogs from an affected litter, 6 case controls from the same litter, 10 related/affected dogs, and 84 related/unaffected dogs. Genomic DNA was collected from each Gordon setter and extracted from buccal mucosal swabs. Genotyping of affected and unaffected dogs was carried out using the Canine Illumina HD SNP array and data generated were analyzed with PLINK software, using fixation index (Fst) and runs of homozygosity (ROH) methods. Pairwise Fst analyses between the affected and unaffected Gordon setter dogs identified various regions of differentiation on chromosomes 10, 18, 21, and 23 that contained several important genes. These regions revealed 5 candidate genes, including RARB, TTC7A, SOCS5, PIGF, and RHOD, that are associated with human inflammatory bowel disease (IBD) and could potentially be associated with PLE in Gordon setters. Run of homozygosity (ROH) analyses revealed additional unique regions on chromosomes 15 and 17. These regions contained genes SYT1, UCN, and FNDC that could also be potential candidates for PLE in Gordon setters. The biological functions of the identified genes provided initial insights into the pathophysiology of PLE. Further large-scale studies are warranted to investigate the possible causality of these genomic regions and any possible genetic markers that could be used in predicting susceptibility to PLE syndrome.
Collapse
Affiliation(s)
- Elle K Donnini
- Department of Veterinary Clinical Sciences (Donnini, Jergens, Allenspach), College of Veterinary Medicine, 1809 South Riverside Drive, Iowa State University, Ames, Iowa 50010, USA; Department of Animal Science (Walugembe, Rothschild), College of Agriculture and Life Sciences, 2255 H. Kildee Hall, Iowa State University, Ames, Iowa 20011, USA
| | - Muhammed Walugembe
- Department of Veterinary Clinical Sciences (Donnini, Jergens, Allenspach), College of Veterinary Medicine, 1809 South Riverside Drive, Iowa State University, Ames, Iowa 50010, USA; Department of Animal Science (Walugembe, Rothschild), College of Agriculture and Life Sciences, 2255 H. Kildee Hall, Iowa State University, Ames, Iowa 20011, USA
| | - Max F Rothschild
- Department of Veterinary Clinical Sciences (Donnini, Jergens, Allenspach), College of Veterinary Medicine, 1809 South Riverside Drive, Iowa State University, Ames, Iowa 50010, USA; Department of Animal Science (Walugembe, Rothschild), College of Agriculture and Life Sciences, 2255 H. Kildee Hall, Iowa State University, Ames, Iowa 20011, USA
| | - Albert E Jergens
- Department of Veterinary Clinical Sciences (Donnini, Jergens, Allenspach), College of Veterinary Medicine, 1809 South Riverside Drive, Iowa State University, Ames, Iowa 50010, USA; Department of Animal Science (Walugembe, Rothschild), College of Agriculture and Life Sciences, 2255 H. Kildee Hall, Iowa State University, Ames, Iowa 20011, USA
| | - Karin Allenspach
- Department of Veterinary Clinical Sciences (Donnini, Jergens, Allenspach), College of Veterinary Medicine, 1809 South Riverside Drive, Iowa State University, Ames, Iowa 50010, USA; Department of Animal Science (Walugembe, Rothschild), College of Agriculture and Life Sciences, 2255 H. Kildee Hall, Iowa State University, Ames, Iowa 20011, USA
| |
Collapse
|
|
39
|
Ruiz MA, Junior RLK, Piron-Ruiz L, Saran PS, Castiglioni L, Quadros LGD, Pinho TS, Burt RK. Medical, ethical, and legal aspects of hematopoietic stem cell transplantation for Crohn’s disease in Brazil. World J Stem Cells 2020; 12:1113-1123. [PMID: 33178395 PMCID: PMC7596442 DOI: 10.4252/wjsc.v12.i10.1113] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Revised: 07/08/2020] [Accepted: 08/26/2020] [Indexed: 02/06/2023] Open
Abstract
Crohn's disease (CD) is a chronic inflammatory bowel disease that can affect any part of the gastrointestinal tract. The etiology of CD is unknown; however, genetic, epigenetic, environmental, and lifestyle factors could play an essential role in the onset and establishment of the disease. CD results from immune dysregulation due to loss of the healthy symbiotic relationship between host and intestinal flora and or its antigens. It affects both sexes equally with a male to female ratio of 1.0, and its onset can occur at any age, but the diagnosis is most commonly observed in the range of 20 to 40 years of age. CD diminishes quality of life, interferes with social activities, traumatizes due to the stigma of incontinence, fistulae, strictures, and colostomies, and in severe cases, affects survival when compared to the general population. Symptoms fluctuate between periods of remission and activity in which complications such as fistulas, strictures, and the need for bowel resection, surgery, and colostomy implantation make up the most severe aspects of the disease. CD can be progressive and the complications recurrent despite treatment with anti-inflammatory drugs, corticosteroids, immunosuppressants, and biological agents. However, over time many patients become refractory without treatment alternatives, and in this scenario, hematopoietic stem cell transplantation (HSCT) has emerged as a potential treatment option. The rationale for the use of HSCT for CD is anchored in animal studies and human clinical trials where HSCT could reset a patient's immune system by eliminating disease-causing effector cells and upon immune recovery increase regulatory and suppressive immune cells. Autologous HSCT using a non-myeloablative regimen of cyclophosphamide and anti-thymocyte globulin without CD34+ selection has been to date the most common transplant conditioning regimen adopted. In this review we will address the current situation regarding CD treatment with HSCT and emphasize the medical, ethical, and legal aspects that permeate the procedure in Brazil.
Collapse
Affiliation(s)
- Milton Artur Ruiz
- Department of Bone Marrow Transplant, Beneficência Portuguesa Hospital, São José do Rio Preto 15090 470, Brazil
| | | | - Lilian Piron-Ruiz
- Department of Bone Marrow Transplantation, Beneficência Portuguesa Hospital, São José do Rio Preto 15090 470, Brazil
| | - Priscila Samara Saran
- Department of Bone Marrow Transplantation, Beneficência Portuguesa Hospital, São José do Rio Preto 15090 470, Brazil
| | - Lilian Castiglioni
- Genetics and Molecular Biology, FAMERP- Faculdade de Medicina de São José do Rio Preto, São José do Rio Preto 15090 470 Brazil
| | - Luiz Gustavo de Quadros
- Department of Endoscopy, Beneficência Portuguesa Hospital, ABC Medical School, São Bernardo 15015 110, Brazil
| | - Tainara Souza Pinho
- Department of Bone Marrow Transplantation, Beneficência Portuguesa Hospital, São José do Rio Preto 15090 470, Brazil
| | - Richard K Burt
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States
| |
Collapse
|
|
40
|
Hind J, Lisboa P, Hussain AJ, Al-Jumeily D. A Novel Approach to Detecting Epistasis using Random Sampling Regularisation. IEEE/ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS 2020; 17:1535-1545. [PMID: 31634840 DOI: 10.1109/tcbb.2019.2948330] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Epistasis is a progressive approach that complements the 'common disease, common variant' hypothesis that highlights the potential for connected networks of genetic variants collaborating to produce a phenotypic expression. Epistasis is commonly performed as a pairwise or limitless-arity capacity that considers variant networks as either variant vs variant or as high order interactions. This type of analysis extends the number of tests that were previously performed in a standard approach such as Genome-Wide Association Study (GWAS), in which False Discovery Rate (FDR) is already an issue, therefore by multiplying the number of tests up to a factorial rate also increases the issue of FDR. Further to this, epistasis introduces its own limitations of computational complexity and intensity that are generated based on the analysis performed; to consider the most intense approach, a multivariate analysis introduces a time complexity of O(n!). Proposed in this paper is a novel methodology for the detection of epistasis using interpretable methods and best practice to outline interactions through filtering processes. Using a process of Random Sampling Regularisation which randomly splits and produces sample sets to conduct a voting system to regularise the significance and reliability of biological markers, SNPs. Preliminary results are promising, outlining a concise detection of interactions. Results for the detection of epistasis, in the classification of breast cancer patients, indicated eight outlined risk candidate interactions from five variants and a singular candidate variant with high protective association.
Collapse
|
|
41
|
Chamberlain TC, Cheung ST, Yoon JSJ, Ming-Lum A, Gardill BR, Shakibakho S, Dzananovic E, Ban F, Samiea A, Jawanda K, Priatel J, Krystal G, Ong CJ, Cherkasov A, Andersen RJ, McKenna SA, Van Petegem F, Mui ALF. Interleukin-10 and Small Molecule SHIP1 Allosteric Regulators Trigger Anti-inflammatory Effects through SHIP1/STAT3 Complexes. iScience 2020; 23:101433. [PMID: 32823063 PMCID: PMC7452241 DOI: 10.1016/j.isci.2020.101433] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 07/07/2020] [Accepted: 07/31/2020] [Indexed: 12/12/2022] Open
Abstract
The anti-inflammatory actions of interleukin-10 (IL10) are thought to be mediated primarily by the STAT3 transcription factor, but pro-inflammatory cytokines such as interleukin-6 (IL6) also act through STAT3. We now report that IL10, but not IL6 signaling, induces formation of a complex between STAT3 and the inositol polyphosphate-5-phosphatase SHIP1 in macrophages. Both SHIP1 and STAT3 translocate to the nucleus in macrophages. Remarkably, sesquiterpenes of the Pelorol family, which we previously described as allosteric activators of SHIP1 phosphatase activity, could induce SHIP1/STAT3 complex formation in cells and mimic the anti-inflammatory action of IL10 in a mouse model of colitis. Using crystallography and docking studies we identified a drug-binding pocket in SHIP1. Our studies reveal new mechanisms of action for both STAT3 and SHIP1 and provide a rationale for use of allosteric SHIP1-activating compounds, which mimic the beneficial anti-inflammatory actions of IL10. Video Abstract
Loss of normal interleukin-10 (IL10) function results in inflammatory diseases IL10 or SHIP1 agonists induce formation of SHIP1/STAT3 complexes SHIP1 Y190 phosphorylation is required for SHIP1/STAT3 complex formation SHIP1 agonists mimic IL10 anti-inflammatory action in a mouse model of colitis
Collapse
Affiliation(s)
- Thomas C Chamberlain
- Immunity and Infection Research Centre, Vancouver Coastal Health Research Institute, Vancouver, BC V6H 3Z6, Canada; Department of Surgery, University of British Columbia, Vancouver, Canada; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, Canada
| | - Sylvia T Cheung
- Immunity and Infection Research Centre, Vancouver Coastal Health Research Institute, Vancouver, BC V6H 3Z6, Canada; Department of Surgery, University of British Columbia, Vancouver, Canada; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, Canada
| | - Jeff S J Yoon
- Immunity and Infection Research Centre, Vancouver Coastal Health Research Institute, Vancouver, BC V6H 3Z6, Canada; Department of Surgery, University of British Columbia, Vancouver, Canada; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, Canada
| | - Andrew Ming-Lum
- Immunity and Infection Research Centre, Vancouver Coastal Health Research Institute, Vancouver, BC V6H 3Z6, Canada; Department of Surgery, University of British Columbia, Vancouver, Canada
| | - Bernd R Gardill
- Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, Canada
| | - Soroush Shakibakho
- Immunity and Infection Research Centre, Vancouver Coastal Health Research Institute, Vancouver, BC V6H 3Z6, Canada; Department of Surgery, University of British Columbia, Vancouver, Canada
| | - Edis Dzananovic
- Department of Chemistry, University of Manitoba, Winnipeg, Canada
| | - Fuqiang Ban
- Department of Urological Sciences, University of British Columbia, Vancouver, Canada
| | - Abrar Samiea
- Immunity and Infection Research Centre, Vancouver Coastal Health Research Institute, Vancouver, BC V6H 3Z6, Canada; Department of Surgery, University of British Columbia, Vancouver, Canada
| | - Kamaldeep Jawanda
- Immunity and Infection Research Centre, Vancouver Coastal Health Research Institute, Vancouver, BC V6H 3Z6, Canada; Department of Surgery, University of British Columbia, Vancouver, Canada
| | - John Priatel
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
| | - Gerald Krystal
- British Columbia Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
| | - Christopher J Ong
- Immunity and Infection Research Centre, Vancouver Coastal Health Research Institute, Vancouver, BC V6H 3Z6, Canada; Department of Surgery, University of British Columbia, Vancouver, Canada; Department of Urological Sciences, University of British Columbia, Vancouver, Canada
| | - Artem Cherkasov
- Department of Urological Sciences, University of British Columbia, Vancouver, Canada
| | - Raymond J Andersen
- Department of Chemistry, University of British Columbia, Vancouver, Canada
| | - Sean A McKenna
- Department of Chemistry, University of Manitoba, Winnipeg, Canada
| | - Filip Van Petegem
- Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, Canada
| | - Alice L-F Mui
- Immunity and Infection Research Centre, Vancouver Coastal Health Research Institute, Vancouver, BC V6H 3Z6, Canada; Department of Surgery, University of British Columbia, Vancouver, Canada; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, Canada.
| |
Collapse
|
|
42
|
Zhu S, Guo T, Zhao H, Qiao G, Han M, Liu J, Yuan C, Wang T, Li F, Yue Y, Yang B. Genome-Wide Association Study Using Individual Single-Nucleotide Polymorphisms and Haplotypes for Erythrocyte Traits in Alpine Merino Sheep. Front Genet 2020; 11:848. [PMID: 32849829 PMCID: PMC7411260 DOI: 10.3389/fgene.2020.00848] [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] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 07/13/2020] [Indexed: 11/13/2022] Open
Abstract
Adaptation to high-altitude hypoxia is essential for domestic animals, such as yak, Tibetan chicken, and Tibetan sheep, living on high plateaus, as it ensures efficient oxygen absorption and utilization. Red blood cells are the primary medium for transporting oxygen in the blood. However, little is known about the genetic mechanism of erythrocyte traits. Genome-wide association studies (GWASs) based on single markers or haplotypes have identified potential mechanisms for genetic variation and quantitative traits. To identify loci associated with erythrocyte traits, we performed a GWAS based on the method of the single marker and haplotype in 498 Alpine Merino sheep for six erythrocyte traits: red blood cell count (RBC), hemoglobin (HGB), hematocrit (HCT), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and RBC volume distribution width coefficient of variation (RWD_CV). Forty-two significant single-nucleotide polymorphisms (SNPs) associated with the six erythrocyte traits were detected by means of a single-marker GWAS, and 34 significant haplotypes associated with five erythrocyte traits were detected by means of haplotype analysis. We identified six genes (DHCR24, SPATA9, FLI1, PLCB1, EFNB2, and SH2B3) as potential genes of interest via gene function annotations, location, and expression variation. In particular, FLI1 and PLCB1 were associated with hematopoiesis and erythropoiesis, respectively. These results provide a theoretical basis for analyzing erythrocyte traits and high-altitude hypoxia adaptation in Alpine Merino sheep and will be a useful reference for future studies of plateau-dwelling livestock.
Collapse
Affiliation(s)
- Shaohua Zhu
- Animal Science Department, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou, China
- Sheep Breeding Engineering Technology Center, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Tingting Guo
- Animal Science Department, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou, China
- Sheep Breeding Engineering Technology Center, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Hongchang Zhao
- Animal Science Department, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou, China
- Sheep Breeding Engineering Technology Center, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Guoyan Qiao
- Animal Science Department, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou, China
- Sheep Breeding Engineering Technology Center, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Mei Han
- Animal Science Department, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou, China
- Sheep Breeding Engineering Technology Center, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Jianbin Liu
- Animal Science Department, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou, China
- Sheep Breeding Engineering Technology Center, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Chao Yuan
- Animal Science Department, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou, China
- Sheep Breeding Engineering Technology Center, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Tianxiang Wang
- Gansu Provincial Sheep Breeding Technology Extension Station, Sunan, China
| | - Fanwen Li
- Gansu Provincial Sheep Breeding Technology Extension Station, Sunan, China
| | - Yaojing Yue
- Sheep Breeding Engineering Technology Center, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Bohui Yang
- Animal Science Department, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou, China
| |
Collapse
|
|
43
|
van der Made CI, Hoischen A, Netea MG, van de Veerdonk FL. Primary immunodeficiencies in cytosolic pattern-recognition receptor pathways: Toward host-directed treatment strategies. Immunol Rev 2020; 297:247-272. [PMID: 32640080 DOI: 10.1111/imr.12898] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 06/08/2020] [Accepted: 06/09/2020] [Indexed: 12/14/2022]
Abstract
In the last decade, the paradigm of primary immunodeficiencies (PIDs) as rare recessive familial diseases that lead to broad, severe, and early-onset immunological defects has shifted toward collectively more common, but sporadic autosomal dominantly inherited isolated defects in the immune response. Patients with PIDs constitute a formidable area of research to study the genetics and the molecular mechanisms of complex immunological pathways. A significant subset of PIDs affect the innate immune response, which is a crucial initial host defense mechanism equipped with pattern-recognition receptors. These receptors recognize pathogen- and damage-associated molecular patterns in both the extracellular and intracellular space. In this review, we will focus on primary immunodeficiencies caused by genetic defects in cytosolic pattern-recognition receptor pathways. We discuss these PIDs organized according to their mutational mechanisms and consequences for the innate host response. The advanced understanding of these pathways obtained by the study of PIDs creates the opportunity for the development of new host-directed treatment strategies.
Collapse
Affiliation(s)
- Caspar I van der Made
- Department of Internal Medicine, Radboud Center for Infectious Diseases (RCI), Radboud Institute of Molecular Life Sciences (RIMLS), Radboud Institute of Health Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands.,Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Alexander Hoischen
- Department of Internal Medicine, Radboud Center for Infectious Diseases (RCI), Radboud Institute of Molecular Life Sciences (RIMLS), Radboud Institute of Health Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands.,Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Mihai G Netea
- Department of Internal Medicine, Radboud Center for Infectious Diseases (RCI), Radboud Institute of Molecular Life Sciences (RIMLS), Radboud Institute of Health Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands.,Department for Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany
| | - Frank L van de Veerdonk
- Department of Internal Medicine, Radboud Center for Infectious Diseases (RCI), Radboud Institute of Molecular Life Sciences (RIMLS), Radboud Institute of Health Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands
| |
Collapse
|
|
44
|
Brown EM, Kenny DJ, Xavier RJ. Gut Microbiota Regulation of T Cells During Inflammation and Autoimmunity. Annu Rev Immunol 2020; 37:599-624. [PMID: 31026411 DOI: 10.1146/annurev-immunol-042718-041841] [Citation(s) in RCA: 214] [Impact Index Per Article: 42.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The intestinal microbiota plays a crucial role in influencing the development of host immunity, and in turn the immune system also acts to regulate the microbiota through intestinal barrier maintenance and immune exclusion. Normally, these interactions are homeostatic, tightly controlled, and organized by both innate and adaptive immune responses. However, a combination of environmental exposures and genetic defects can result in a break in tolerance and intestinal homeostasis. The outcomes of these interactions at the mucosal interface have broad, systemic effects on host immunity and the development of chronic inflammatory or autoimmune disease. The underlying mechanisms and pathways the microbiota can utilize to regulate these diseases are just starting to emerge. Here, we discuss the recent evidence in this area describing the impact of microbiota-immune interactions during inflammation and autoimmunity, with a focus on barrier function and CD4+ T cell regulation.
Collapse
Affiliation(s)
- Eric M Brown
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA; , .,Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
| | - Douglas J Kenny
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA; , .,Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
| | - Ramnik J Xavier
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA; , .,Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.,Gastrointestinal Unit, Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA;
| |
Collapse
|
|
45
|
Evaluation of Intestinal Epithelial Barrier Function in Inflammatory Bowel Diseases Using Murine Intestinal Organoids. Tissue Eng Regen Med 2020; 17:641-650. [PMID: 32594459 DOI: 10.1007/s13770-020-00278-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 05/21/2020] [Accepted: 05/24/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Intestinal organoids have evolved as potential molecular tools that could be used to study host-microbiome interactions, nutrient uptake, and drug screening. Gut epithelial barrier functions play a crucial role in health and diseases, especially in autoimmune diseases, such as inflammatory bowel diseases (IBDs), because they disrupt the epithelial mucosa and impair barrier function. METHODS In this study, we generated an in vitro IBD model based on dextran sodium sulfate (DSS) and intestinal organoids that could potentially be used to assess barrier integrity. Intestinal organoids were long-term cultivated and characterized with several specific markers, and the key functionality of paracellular permeability was determined using FITC-dextran 4 kDa. Intestinal organoids that had been treated with 2 µM DSS for 3 h were developed and the intestinal epithelial barrier function was sequentially evaluated. RESULTS The results indicated that the paracellular permeability represented epithelial characteristics and their barrier function had declined when they were exposed to FITC-dextran 4 kDa after DSS treatment. In addition, we analyzed the endogenous mRNA expression of pro-inflammatory cytokines and their downstream effector genes. The results demonstrated that the inflammatory cytokines genes significantly increased in inflamed organoids compared to the control, leading to epithelial barrier damage and dysfunction. CONCLUSION The collective results showed that in vitro 3D organoids mimic in vivo tissue topology and functionality with minor limitations, and hence are helpful for testing disease models.
Collapse
|
|
46
|
Imawana RA, Smith DR, Goodson ML. The relationship between inflammatory bowel disease and Helicobacter pylori across East Asian, European and Mediterranean countries: a meta-analysis. Ann Gastroenterol 2020; 33:485-494. [PMID: 32879595 PMCID: PMC7406810 DOI: 10.20524/aog.2020.0507] [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: 01/30/2020] [Accepted: 05/06/2020] [Indexed: 12/12/2022] Open
Abstract
Background The current literature suggests a protective benefit of Helicobacter pylori (H. pylori) infection against inflammatory bowel disease (IBD). Here we assessed whether this effect varied by IBD subtype—Crohn’s disease (CD) or ulcerative colitis (UC)—and geographic region: East Asia, Europe (non-Mediterranean) or Mediterranean region. Methods A database search was performed up to July 2019 inclusive for all studies that compared H. pylori infection in IBD patients vs. non-IBD controls. The relative risk (RR) was used to quantify the association between IBD and H. pylori, and the effects were combined across studies using a mixed-effects meta-regression model, which included IBD subtype and geographic region as categorical moderator variables. Results Our meta-regression model exhibited moderate heterogeneity (I2=48.74%). Pooled RR depended on both region (P=0.02) and subtype (P<0.001). Pooled RRs were <1 for all subtype and region combinations, indicative of a protective effect of H. pylori against IBD. The pooled RR was 28% (9%, 50%; P=0.001) greater for UC vs. CD and 43% (4%, 96%; P=0.02) greater for Mediterranean countries vs. East Asia. The pooled RR was 18% (-13%, 60%; P=0.48) greater for Europe vs. East Asia and 21% (-13%, 68%; P=0.42) greater for Mediterranean vs. Europe, though these differences were not statistically significant. Conclusions The protective effect of H. pylori on IBD varied by both subtype (more protection against CD vs. UC) and region (East Asia more protected than Mediterranean regions). Variation due to these effects could provide insight into IBD etiology.
Collapse
Affiliation(s)
| | - Daniel Robert Smith
- Medical Research Department, Faculty of Medical Sciences, Newcastle University Medicine Malaysia
| | - Michaela Louise Goodson
- Medical Research Department, Faculty of Medical Sciences, Newcastle University Medicine Malaysia
| |
Collapse
|
|
47
|
Chen X, Li M, Li D, Luo T, Xie Y, Gao L, Zhang Y, Chen S, Li S, Huang G, Li W, Su J, Lai X. Ethanol extract of Pycnoporus sanguineus relieves the dextran sulfate sodium-induced experimental colitis by suppressing helper T cell-mediated inflammation via apoptosis induction. Biomed Pharmacother 2020; 127:110212. [PMID: 32422567 DOI: 10.1016/j.biopha.2020.110212] [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: 02/04/2020] [Revised: 04/18/2020] [Accepted: 04/28/2020] [Indexed: 01/01/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic relapsing inflammation involving the gut system, and disequilibrium of T helper (Th) cell paradigm has been recognized as critical pathogenesis. Pycnoporus sanguineus (L.) Murrill is a species of the white-rot basidiomycetes listed as food- and cosmetic-grade microorganisms. In this study, anti-inflammatory activity of the ethanol extract from P. sanguineus (PSE) was investigated in dextran sulfate sodium (DSS)-induced experimental colitis model. PSE recovered the DSS-caused weight loss, reversed the colon shortening, and ameliorated the histopathological lesion in colon, resulting in lower disease activity index (DAI). Levels of serumal lipopolysaccharide (LPS), colonic myeloperoxidase (MPO) in the colitis-suffering mice were declined by PSE treatment. PSE also improved the mucosal integrity by enhancing the expression of tight junction and adherens junction proteins in the colon, including ZO-1, occludin, claudin-1, and E-cadherin. Besides, PSE reduced helper T cells (Th) in the colon, together with an evident decrease of several Th cell-related cytokines. Moreover, it was found that in vitro, PSE suppressed T cells and the Th subset upon Concanavalin A (ConA)-stimulation by inducing apoptosis. In summary, PSE displayed a remission on the colitis-related inflammation, which would possibly rely on the epithelial barrier restoration by suppressing Th cells via apoptosis induction, highlighting a promising potential in the treatment for IBD.
Collapse
Affiliation(s)
- Xiaohong Chen
- Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China; State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, Guangdong, PR China; Guangdong Yuewei Edible Fungi Technology Co. Ltd., Guangzhou, Guangdong, PR China
| | - Muxia Li
- Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China; State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, Guangdong, PR China; Guangdong Yuewei Edible Fungi Technology Co. Ltd., Guangzhou, Guangdong, PR China
| | - Dan Li
- Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China; State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, Guangdong, PR China; Guangdong Yuewei Edible Fungi Technology Co. Ltd., Guangzhou, Guangdong, PR China
| | - Ting Luo
- Jinan University, Guangzhou, Guangdong, PR China; Guangdong Laboratory Animals Monitoring Institute, Guangdong Provincial Key Laboratory of Laboratory Animals, Guangzhou, Guangdong, PR China
| | - Yizhen Xie
- State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, Guangdong, PR China; Guangdong Yuewei Edible Fungi Technology Co. Ltd., Guangzhou, Guangdong, PR China
| | - Liang Gao
- State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, Guangdong, PR China
| | - Yifan Zhang
- State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, Guangdong, PR China
| | - Shaodan Chen
- State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, Guangdong, PR China
| | - Shunxian Li
- Guangdong Yuewei Edible Fungi Technology Co. Ltd., Guangzhou, Guangdong, PR China
| | - Guoxin Huang
- Macau University of Science and Technology, Macau, PR China
| | - Wenzhi Li
- Infinitus (China) Company Ltd., Guangzhou, Guangdong, PR China
| | - Jiyan Su
- State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangdong Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, Guangdong, PR China.
| | - Xiaoping Lai
- Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China.
| |
Collapse
|
|
48
|
Ccr6 Deficiency Attenuates Spontaneous Chronic Colitis in Winnie. GASTROINTESTINAL DISORDERS 2020. [DOI: 10.3390/gidisord2010004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Background: The immune-modulator behaviour of the CCR6/CCL20 axis in multi -system pathophysiology and molecular signalling was investigated at two clinically significant time points, using a Ccr6—deficient mouse model of spontaneous colitis. Methods:Four groups of mice, (C57BL/6J, Ccr6−/− of C57BL/6J, Winnie × Ccr6−/− and Winnie) were utilized and (I) colonic clinical parameters (2) histology of colon, spleen, kidney and liver (3) T and B lymphocyte distribution in the spleen and MLN by flowcytometry (5) colonic CCL20, phosphorylated PI3K and phosphorylated Akt expression by immunohistochemistry and (6) colonic cytokine expression by RT-PCR were evaluated. Results: CCR6 deficiency was shown to attenuate inflammation in the spleen, liver and gut while renal histology remained unaffected. Marked focal lobular inflammation with reactive nuclear features were observed in hepatocytes and a significant neutrophil infiltration in red pulp with extra medullary hemopoiesis in the spleen existed in Winnie. These changes were considerably reduced in Winnie × Ccr6−/− with elevated goblet cell numbers and mucus production in the colonic epithelium. Conclusions: Results indicate that Ccr6-deficiency in the colitis model contributes towards resolution of disease. Our findings demonstrate an intricate networking role for CCR6 in immune activation, which is downregulated by Ccr6 deficiency, and could provide newer clinical therapies in colitis.
Collapse
|
|
49
|
Borg-Bartolo SP, Boyapati RK, Satsangi J, Kalla R. Precision medicine in inflammatory bowel disease: concept, progress and challenges. F1000Res 2020; 9:F1000 Faculty Rev-54. [PMID: 32047622 PMCID: PMC6993839 DOI: 10.12688/f1000research.20928.1] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/16/2020] [Indexed: 12/12/2022] Open
Abstract
Crohn's disease and ulcerative colitis are increasingly prevalent, relapsing and remitting inflammatory bowel diseases (IBDs) with variable disease courses and complications. Their aetiology remains unclear but current evidence shows an increasingly complex pathophysiology broadly centring on the genome, exposome, microbiome and immunome. Our increased understanding of disease pathogenesis is providing an ever-expanding arsenal of therapeutic options, but these can be expensive and patients can lose response or never respond to certain therapies. Therefore, there is now a growing need to personalise therapies on the basis of the underlying disease biology and a desire to shift our approach from "reactive" management driven by disease complications to "proactive" care with an aim to prevent disease sequelae. Precision medicine is the tailoring of medical treatment to the individual patient, encompassing a multitude of data-driven (and multi-omic) approaches to foster accurate clinical decision-making. In IBD, precision medicine would have significant benefits, enabling timely therapy that is both effective and appropriate for the individual. In this review, we summarise some of the key areas of progress towards precision medicine, including predicting disease susceptibility and its course, personalising therapies in IBD and monitoring response to therapy. We also highlight some of the challenges to be overcome in order to deliver this approach.
Collapse
Affiliation(s)
- Simon P. Borg-Bartolo
- Department of Gastroenterology, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Southmoor Road, Wythenshawe, Manchester, M23 9LT, UK
| | - Ray Kiran Boyapati
- Department of Gastroenterology, Monash Health, Clayton, Victoria, Australia
- Faculty of Medicine, Nursing & Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Jack Satsangi
- Translational Gastroenterology Unit, Nuffield Department of Medicine, Experimental Medicine Division, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Rahul Kalla
- Department of Gastroenterology, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh, EH16 4SA, UK
| |
Collapse
|
|
50
|
Abstract
PURPOSE OF REVIEW This article aims to review recent literature linking epithelial barrier inflammation and arthritis in spondyloarthritis (SpA), with a critical view on how they are bound by genetic, immunological and environmental ties. RECENT FINDINGS The epithelia-joint axis has become an intense area of both basic and clinical SpA research. The penultimate goal is to understand the immunopathologic links between epithelial inflammation and arthritis in SpA. Inflammatory bowel disease (IBD) and psoriasis (PsO) have strong links to SpA at several levels. Clinically, there is a strong association of IBD, PsO and SpA. Genetically, there are many shared risk factors; however, there are also distinct differences in the genetics of the respective diseases. Immunologically, type 3 immunity, especially interleukin (IL)-17 and IL-23 dysregulation, has been shown to play a central role in IBD, PsO and SpA. Environmentally, a microbial dysbiosis has been noted in each of these diseases, but whether the microbial signature is similar between diseases is not clear, nor is the effect of dysbiosis on the immune response known. SUMMARY It will be crucial to determine whether the relationship between epithelia inflammation and SpA is truly causal for both the understanding of pathogenesis and for future treatment strategies.
Collapse
|