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González-Castro AM, Fernández-Bañares F, Zabana Y, Farago-Pérez G, Ortega-Barrionuevo J, Expósito E, Guagnozzi D. Microscopic Colitis and Celiac Disease: Sharing More than a Diagnostic Overlap. Nutrients 2024; 16:2233. [PMID: 39064676 PMCID: PMC11279699 DOI: 10.3390/nu16142233] [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: 06/02/2024] [Revised: 07/01/2024] [Accepted: 07/04/2024] [Indexed: 07/28/2024] Open
Abstract
Microscopic colitis (MC) is an emergent group of chronic inflammatory diseases of the colon, and celiac disease (CD) is a chronic gluten-induced immune-mediated enteropathy affecting the small bowel. We performed a narrative review to provide an overview regarding the relationship between both disorders, analyzing the most recent studies published at the epidemiological, clinical and pathophysiological levels. In fact, MC and CD are concomitantly prevalent in approximately 6% of the cases, mainly in the subset of refractory patients. Thus, physicians should screen refractory patients with CD against MC and vice versa. Both disorders share more than a simple epidemiological association, being multifactorial diseases involving innate and adaptive immune responses to known or unknown luminal factors based on a rather common genetic ground. Moreover, autoimmunity is a shared characteristic between the patients with MC and those with CD, with autoimmunity in the latter being quite well-established. Furthermore, CD and MC share some common clinical symptoms and risk factors and overlap with other gastrointestinal diseases, but some differences exist between both disorders. More studies are therefore needed to better understand the complex mechanisms involving the common pathogenetic ground contributing to the CD and MC epidemiological association.
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Affiliation(s)
- Ana María González-Castro
- Translational Mucosal Immunology Laboratory, Vall d’Hebron Institut de Recerca, 08035 Barcelona, Spain; (A.M.G.-C.); (E.E.)
- Neuro-Immuno-Gastroenterology Laboratory, Vall d’Hebron Institut de Recerca, 08035 Barcelona, Spain
| | - Fernando Fernández-Bañares
- Gastroenterology Department, University Hospital Mútua Terrassa, 08221 Terrassa, Spain (Y.Z.)
- Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd, Instituto Carlos III), 28029 Madrid, Spain
| | - Yamile Zabana
- Gastroenterology Department, University Hospital Mútua Terrassa, 08221 Terrassa, Spain (Y.Z.)
- Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd, Instituto Carlos III), 28029 Madrid, Spain
| | - Georgina Farago-Pérez
- Translational Mucosal Immunology Laboratory, Vall d’Hebron Institut de Recerca, 08035 Barcelona, Spain; (A.M.G.-C.); (E.E.)
| | - Jonathan Ortega-Barrionuevo
- Translational Mucosal Immunology Laboratory, Vall d’Hebron Institut de Recerca, 08035 Barcelona, Spain; (A.M.G.-C.); (E.E.)
| | - Elba Expósito
- Translational Mucosal Immunology Laboratory, Vall d’Hebron Institut de Recerca, 08035 Barcelona, Spain; (A.M.G.-C.); (E.E.)
- Neuro-Immuno-Gastroenterology Laboratory, Vall d’Hebron Institut de Recerca, 08035 Barcelona, Spain
| | - Danila Guagnozzi
- Translational Mucosal Immunology Laboratory, Vall d’Hebron Institut de Recerca, 08035 Barcelona, Spain; (A.M.G.-C.); (E.E.)
- Neuro-Immuno-Gastroenterology Laboratory, Vall d’Hebron Institut de Recerca, 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd, Instituto Carlos III), 28029 Madrid, Spain
- Gastroenterology Department, University Hospital Vall d’Hebron, 08035 Barcelona, Spain
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Wang P, Yang X, Zhang L, Sha S, Huang J, Peng J, Gu J, Pearson JA, Hu Y, Zhao H, Wong FS, Wang Q, Wen L. Tlr9 deficiency in B cells leads to obesity by promoting inflammation and gut dysbiosis. Nat Commun 2024; 15:4232. [PMID: 38762479 PMCID: PMC11102548 DOI: 10.1038/s41467-024-48611-8] [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: 08/02/2023] [Accepted: 05/02/2024] [Indexed: 05/20/2024] Open
Abstract
Toll-like receptor 9 (TLR9) recognizes bacterial, viral and self DNA and play an important role in immunity and inflammation. However, the role of TLR9 in obesity is less well-studied. Here, we generate B-cell-specific Tlr9-deficient (Tlr9fl/fl/Cd19Cre+/-, KO) B6 mice and model obesity using a high-fat diet. Compared with control mice, B-cell-specific-Tlr9-deficient mice exhibited increased fat tissue inflammation, weight gain, and impaired glucose and insulin tolerance. Furthermore, the frequencies of IL-10-producing-B cells and marginal zone B cells were reduced, and those of follicular and germinal center B cells were increased. This was associated with increased frequencies of IFNγ-producing-T cells and increased follicular helper cells. In addition, gut microbiota from the KO mice induced a pro-inflammatory state leading to immunological and metabolic dysregulation when transferred to germ-free mice. Using 16 S rRNA gene sequencing, we identify altered gut microbial communities including reduced Lachnospiraceae, which may play a role in altered metabolism in KO mice. We identify an important network involving Tlr9, Irf4 and Il-10 interconnecting metabolic homeostasis, with the function of B and T cells, and gut microbiota in obesity.
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Affiliation(s)
- Pai Wang
- Department of Gastrocolorectal Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
- Section of Endocrinology, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, USA
| | - Xin Yang
- Section of Endocrinology, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, USA
- Department of Food Science and Technology, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai, China
| | - Luyao Zhang
- Department of Gastrocolorectal Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
- Section of Endocrinology, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, USA
| | - Sha Sha
- Section of Endocrinology, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, USA
- Department of Nephrology, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China
| | - Juan Huang
- Section of Endocrinology, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, USA
| | - Jian Peng
- Section of Endocrinology, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, USA
| | - Jianlei Gu
- Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA
| | - James Alexander Pearson
- Section of Endocrinology, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, USA
- Division of Infection and Immunity, School of Medicine and Systems Immunity University Research Institute, Cardiff University, Cardiff, UK
| | - Youjia Hu
- Section of Endocrinology, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, USA
| | - Hongyu Zhao
- Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA
| | - F Susan Wong
- Division of Infection and Immunity, School of Medicine and Systems Immunity University Research Institute, Cardiff University, Cardiff, UK
| | - Quan Wang
- Department of Gastrocolorectal Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China.
| | - Li Wen
- Section of Endocrinology, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, USA.
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Jordi SBU, Misselwitz B. Refining the Concept of Microscopic Colitis: HLA Signatures Discriminating Collagenous and Lymphocytic Colitis. J Crohns Colitis 2024; 18:339-340. [PMID: 38174741 DOI: 10.1093/ecco-jcc/jjad211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2024]
Affiliation(s)
- Sebastian Bruno Ulrich Jordi
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Department for Biomedical Research, University of Bern, Bern, Switzerland
| | - Benjamin Misselwitz
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Department for Biomedical Research, University of Bern, Bern, Switzerland
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Zheng T, Roda G, Zabana Y, Escudero-Hernández C, Liu X, Chen Y, Camargo Tavares L, Bonfiglio F, Mellander MR, Janczewska I, Vigren L, Sjöberg K, Ohlsson B, Almer S, Halfvarson J, Miehlke S, Madisch A, Lieb W, Kupčinskas J, Weersma RK, Bujanda L, Julià A, Marsal S, Esteve M, Guagnozzi D, Fernández-Bañares F, Ferrer C, Peter I, Ludvigsson JF, Pardi D, Verhaegh B, Jonkers D, Pierik M, Münch A, Franke A, Bresso F, Khalili H, Colombel JF, D'Amato M. Human Leukocyte Antigen Signatures as Pathophysiological Discriminants of Microscopic Colitis Subtypes. J Crohns Colitis 2024; 18:349-359. [PMID: 37768647 DOI: 10.1093/ecco-jcc/jjad165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 07/29/2023] [Accepted: 09/26/2023] [Indexed: 09/29/2023]
Abstract
BACKGROUND AND AIMS Microscopic colitis [MC] is currently regarded as an inflammatory bowel disease that manifests as two subtypes: collagenous colitis [CC] and lymphocytic colitis [LC]. Whether these represent a clinical continuum or distinct entities is, however, an open question. Genetic investigations may contribute important insight into their respective pathophysiologies. METHODS We conducted a genome-wide association study [GWAS] meta-analysis in 1498 CC, 373 LC patients, and 13 487 controls from Europe and the USA, combined with publicly available MC GWAS data from UK Biobank and FinnGen [2599 MC cases and 552 343 controls in total]. Human leukocyte antigen [HLA] alleles and polymorphic residues were imputed and tested for association, including conditional analyses for the identification of key causative variants and residues. Genetic correlations with other traits and diagnoses were also studied. RESULTS We detected strong HLA association with CC, and conditional analyses highlighted the DRB1*03:01 allele and its residues Y26, N77, and R74 as key to this association (best p = 1.4 × 10-23, odds ratio [OR] = 1.96). Nominally significant genetic correlations were detected between CC and pneumonia [rg = 0.77; p = 0.048] and oesophageal diseases [rg = 0.45, p = 0.023]. An additional locus was identified in MC GWAS analyses near the CLEC16A and RMI2 genes on chromosome 16 [rs35099084, p = 2.0 × 10-8, OR = 1.31]. No significant association was detected for LC. CONCLUSION Our results suggest CC and LC have distinct pathophysiological underpinnings, characterised by an HLA predisposing role only in CC. This challenges existing classifications, eventually calling for a re-evaluation of the utility of MC umbrella definitions.
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Affiliation(s)
- Tenghao Zheng
- School of Biological Sciences, Monash University, Clayton, VIC, Australia
- Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
- Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Giulia Roda
- Biostructures and Biosystems National Institute, Rome, Italy
| | - Yamile Zabana
- Gastroenterology Department, Hospital Universitari Mútua de Terrassa, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
| | - Celia Escudero-Hernández
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
- Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Xingrong Liu
- Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
- Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Ye Chen
- Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA
| | | | - Ferdinando Bonfiglio
- School of Biological Sciences, Monash University, Clayton, VIC, Australia
- Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | | | | | - Lina Vigren
- Department of Clinical Sciences, Lund University, Lund, Sweden
| | - Klas Sjöberg
- Department of Clinical Sciences, Lund University, Skane University Hospital, Malmo, Sweden
| | - Bodil Ohlsson
- Department of Clinical Sciences, Lund University, Skane University Hospital, Malmo, Sweden
| | - Sven Almer
- Division of Gastroenterology, Department of Gastroenterology, Dermatology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden
| | - Jonas Halfvarson
- Department of Gastroenterology, Faculty of Medicine and Health, Orebro University Hospital, Örebro, Sweden
| | - Stephan Miehlke
- Centre for Digestive Diseases, Internal Medicine Centre Eppendorf, and Centre for Oesophageal Disorders, University Hospital Eppendorf, Hamburg, Germany
| | - Ahmed Madisch
- Department of Gastroenterology, CRH Clinic Siloah, Hannover, Germany
| | - Wolfgang Lieb
- Institute of Epidemiology, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Juozas Kupčinskas
- Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Rinse K Weersma
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
| | - Luis Bujanda
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, Universidad del País Vasco, San Sebastian, Spain
| | - Antonio Julià
- Rheumatology Research Group, Vall d' Hebron Research Institute, Barcelona, Spain
| | - Sara Marsal
- Rheumatology Research Group, Vall d' Hebron Research Institute, Barcelona, Spain
| | - Maria Esteve
- Gastroenterology Department, Hospital Universitari Mútua de Terrassa, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
| | - Danila Guagnozzi
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
- Department of Gastroenterology, Vall d'Hebron University Hospital, Neuro-Immuno-Gastroenterology Group, Digestive System Research Unit, Vall d'Hebron Institut de Recerca, Barcelona, Spain
| | - Fernando Fernández-Bañares
- Gastroenterology Department, Hospital Universitari Mútua de Terrassa, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
| | - Carmen Ferrer
- Pathology Department, Hospital Universitari Mútua de Terrassa, Barcelona, Spain
| | - Inga Peter
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jonas F Ludvigsson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Darrell Pardi
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Bas Verhaegh
- Division Gastroenterology-Hepatology, Department of Internal Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - Daisy Jonkers
- Division Gastroenterology-Hepatology, Department of Internal Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - Marieke Pierik
- Division Gastroenterology-Hepatology, Department of Internal Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - Andreas Münch
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
- Department of Gastroenterology and Hepatology, Linköping University, Linköping, Sweden
- Department of Health, Medicine, and Caring Sciences, Linköping University, Linköping, Sweden
| | - Andre Franke
- Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Francesca Bresso
- Division of Gastroenterology, Department of Gastroenterology, Dermatology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden
| | - Hamed Khalili
- Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
| | - Jean-Frederic Colombel
- Dr Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Mauro D'Amato
- Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
- Gastrointestinal Genetics Lab, CIC bioGUNE - BRTA, Derio, Spain
- Ikerbasque, Basque Foundation for Science, Bilbao, Spain
- Department of Medicine and Surgery, LUM University, Casamassima, Italy
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Yde Aagaard ME, Frahm Kirk K, Linde Nielsen H, Steffensen R, Nielsen H. Campylobacter concisus from chronic inflammatory bowel diseases stimulates IL-8 production in HT-29 cells. Gut Pathog 2023; 15:5. [PMID: 36782333 PMCID: PMC9926846 DOI: 10.1186/s13099-023-00532-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Accepted: 02/06/2023] [Indexed: 02/15/2023] Open
Abstract
The emerging pathogen Campylobacter concisus has been isolated from patients with gastrointestinal diseases; however, it is also present in the gut of healthy individuals. The aim of this study was to compare IL-8 production in HT-29 cells after infection with C. concisus from different gastrointestinal disease phenotypes. Additionally, to investigate whether differentiation of isolates in genomospecies (GS1 and GS2) or presence of the zot gene, encoding the Zot toxin, affects IL-8 production. A total of 37 C. concisus isolates from patients with microscopic colitis (n = 20), ulcerative colitis (n = 5), Crohn's disease (n = 5), diarrhoea (n = 2) and from healthy controls (n = 5) were used. Intestinal HT-29 cells were infected and incubated for 24 h. Supernatants were subsequently removed and analysed for IL-8 by MILLIPLEX. All isolates were able to stimulate IL-8 production and IL-8 levels were higher than in non-infected HT-29 cells. No difference was observed between disease phenotypes or GS1 and GS2, whereas presence of the zot gene showed a tendency towards higher IL-8 production. Further investigations in other inflammatory and physiological models are needed to conclude whether C. concisus strains from different gastrointestinal disease phenotypes differ in pathogenic potential and play a part in gastrointestinal disease.
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Affiliation(s)
- Marta Emilie Yde Aagaard
- Department of Infectious Diseases, Aalborg University Hospital, Hobrovej 18-22, 9000, Aalborg, Denmark.
| | - Karina Frahm Kirk
- grid.27530.330000 0004 0646 7349Department of Infectious Diseases, Aalborg University Hospital, Hobrovej 18-22, 9000 Aalborg, Denmark
| | - Hans Linde Nielsen
- grid.5117.20000 0001 0742 471XDepartment of Clinical Medicine, Aalborg University, Søndre Skovvej 15, 9000 Aalborg, Denmark ,grid.27530.330000 0004 0646 7349Department of Clinical Microbiology, Aalborg University Hospital, Mølleparkvej 10, 9000 Aalborg, Denmark
| | - Rudi Steffensen
- grid.27530.330000 0004 0646 7349Department of Clinical Immunology, Aalborg University Hospital, Urbansgade 32, 9000 Aalborg, Denmark
| | - Henrik Nielsen
- grid.27530.330000 0004 0646 7349Department of Infectious Diseases, Aalborg University Hospital, Hobrovej 18-22, 9000 Aalborg, Denmark ,grid.5117.20000 0001 0742 471XDepartment of Clinical Medicine, Aalborg University, Søndre Skovvej 15, 9000 Aalborg, Denmark
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Daferera N, Nyström S, Hjortswang H, Ignatova S, Jenmalm MC, Ström M, Münch A. Mucosa associated invariant T and natural killer cells in active and budesonide treated collagenous colitis patients. Front Immunol 2022; 13:981740. [PMID: 36591297 PMCID: PMC9798420 DOI: 10.3389/fimmu.2022.981740] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 11/28/2022] [Indexed: 12/23/2022] Open
Abstract
Introduction Collagenous colitis (CC) is an inflammatory bowel disease, which usually responds to budesonide treatment. Our aim was to study the immunological background of the disease. Methods Analyses of peripheral and mucosal MAIT (mucosa associated invariant T cells) and NK (natural killer) cells were performed with flow cytometry. Numbers of mucosal cells were calculated using immunohistochemistry. We studied the same patients with active untreated CC (au-CC) and again while in remission on budesonide treatment. Budesonide refractory patients and healthy controls were also included. The memory marker CD45R0 and activation marker CD154 and CD69 were used to further study the cells. Finally B cells, CD4+ and CD8+ T cells were also analysed. Results The percentages of circulating CD56dimCD16+ NK cells as well as MAIT cells (CD3+TCRVa7.2+CD161+) were decreased in au-CC compared to healthy controls. This difference was not seen in the mucosa; where we instead found increased numbers of mucosal CD4+ T cells and CD8+ T cells in au-CC. Mucosal immune cell numbers were not affected by budesonide treatment. In refractory CC we found increased mucosal numbers of MAIT cells, CD4+ and CD8+ T cells compared to au-CC. Discussion Patients with active collagenous colitis have lower percentages of circulating MAIT and NK cells. However, there was no change of these cells in the colonic mucosa. Most mucosal cell populations were increased in budesonide refractory as compared to au-CC patients, particularly the number of MAIT cells. This may indicate that T cell targeting therapy could be an alternative in budesonide refractory CC.
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Affiliation(s)
- Niki Daferera
- Department of Gastroenterology, Faculty of Health Sciences, Linköping University, Linköping, Sweden,*Correspondence: Niki Daferera,
| | - Sofia Nyström
- Department of Biomedical and Clinical Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden,Department of Clinical Immunology and Transfusion Medicine, Linköping University, Linköping, Sweden
| | - Henrik Hjortswang
- Department of Gastroenterology, Faculty of Health Sciences, Linköping University, Linköping, Sweden
| | - Simone Ignatova
- Department of Pathology, Linköping University, Linköping, Sweden
| | - Maria C. Jenmalm
- Department of Biomedical and Clinical Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden
| | - Magnus Ström
- Department of Gastroenterology, Faculty of Health Sciences, Linköping University, Linköping, Sweden
| | - Andreas Münch
- Department of Gastroenterology, Faculty of Health Sciences, Linköping University, Linköping, Sweden
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Boivineau G, Zallot C, Zerbib F, Plastaras L, Amiot A, Boivineau L, Koch S, Peyrin-Biroulet L, Vuitton L. Biologic Therapy for Budesonide-refractory, -dependent or -intolerant Microscopic Colitis: a Multicentre Cohort Study from the GETAID. J Crohns Colitis 2022; 16:1816-1824. [PMID: 35793161 DOI: 10.1093/ecco-jcc/jjac089] [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] [Indexed: 12/12/2022]
Abstract
BACKGROUND Budesonide remains the backbone therapy for microscopic colitis [MC]; however, relapses are frequent, and some patients are intolerant or dependent. Anti-TNF therapy is increasingly used to treat these patients, but available evidence is still limited. The aim of this study was to evaluate the effectiveness and safety of anti-TNF therapy in MC patients failing budesonide. METHODS In a multicentre retrospective cohort study, budesonide-refractory, -dependent, or -intolerant MC patients treated with anti-TNF agents were included. Clinical remission was defined as fewer than three bowel movements per day, and clinical response was defined as an improvement in stool frequency of at least 50%. RESULTS Fourteen patients were included. Median age was 58.5 years, median disease duration was 25 months, and median follow-up was 29.5 months. Seven patients were treated with infliximab [IFX], and seven with adalimumab. Clinical remission without steroids at 12 weeks was reached in 5/14 [35.7%] patients; all of these received IFX. Clinical response at 12 and 52 weeks, was obtained in 9/14 [64.3%] and 7/14 [50%] patients, respectively. Five patients switched to another anti-TNF agent. When considering both first- and second-line anti-TNF therapies, 7 [50%] patients were in clinical remission at Week 52. Mild to moderate adverse events were reported in six ptients. Two patients were treated with vedolizumab, of whom one had clinical response; one patient treated with ustekinumab had no response. CONCLUSIONS This is the first multicentre cohort study showing that half of patients treated with anti-TNF therapy for MC achieved clinical remission in case of budesonide failure.
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Affiliation(s)
- Grégoire Boivineau
- Gastroenterology Department, Besançon University Hospital, Besançon, France
| | - Camille Zallot
- Department of Gastroenterology, University of Lorraine, CHRU-Nancy, France
| | - Franck Zerbib
- Gastroenterology Department, Bordeaux University Hospital, Centre Medico-chirurgical Magellan, Hôpital Haut-Lévêque, Bordeaux, France
| | | | - Aurélien Amiot
- Department of Gastroenterology, Hopitaux Universitaires Bicêtre, AP-HP, Universite Paris Est Creteil, INSERM UMR1018, Le Kremlin Bicêtre, France
| | - Lucile Boivineau
- Hepatogastroenterology Department, Montpellier University Hospital, Montpellier, France
| | - Stéphane Koch
- Gastroenterology Department, Besançon University Hospital, Besançon, France
| | | | - Lucine Vuitton
- Gastroenterology Department, Besançon University Hospital, Besançon, France.,Department of Gastroenterology and UMR 1098, University Hospital of Besançon, University Bourgogne-Franche-Comté, Besançon, France
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Carrasco A, Tristán E, Fernández‐Bañares F, Martín‐Cardona A, Aceituno M, Zabana Y, Fluvià L, Hernández JM, Lorén V, Manyé J, Salas A, Andújar X, Loras C, Esteve M. Mucosal Interleukin-10 depletion in steroid-refractory Crohn's disease patients. Immun Inflamm Dis 2022; 10:e710. [PMID: 36169258 PMCID: PMC9514060 DOI: 10.1002/iid3.710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 08/25/2022] [Accepted: 08/29/2022] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Previous studies suggested that Interleukin-10 (IL-10) depletion in Crohn's disease (CD) could predict outcome. AIM To determine IL-10 in blood and at different intestinal locations in patients with active CD and to assess its potential prognostic capacity to identify aggressive CD. METHODS Twenty-three patients with CD were included. Ulcerative colitis (UC), infectious colitis and healthy individuals acted as controls. Serum and mucosal samples were taken at baseline and 1 month after steroid initiation in CD patients. Patients were classified according to steroid response. Control samples were obtained from different intestinal locations. IL-10 expression was measured with real-time polymerase chain reaction, immunofluorescence (intestine) and ELISA (serum, biopsy cultures' supernatants and tissue homogenates). RESULTS CD and UC showed an increase in IL-10 messenger RNA (mRNA) versus controls (p < .0001) in mucosa, whereas IL-10 protein secretion was increased in all types of intestinal inflammation (p < .001). No differences in IL-10 mRNA were found in CD at baseline regarding steroid response, but levels decreased in non-responders versus responders (p = .027) and were restored with rescue therapy. Serum IL-10 was increased in steroid-refractory CD at baseline and after treatment. CONCLUSIONS Abnormal IL-10 levels in refractory patients in both mucosa and blood have physiopathological relevance and may have potential clinical applications.
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Affiliation(s)
- Anna Carrasco
- Department of Gastroenterology, Hospital Universitari Mútua TerrassaUniversitat de BarcelonaCataloniaSpain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)MadridSpain
| | - Eva Tristán
- Department of Gastroenterology, Hospital Universitari Mútua TerrassaUniversitat de BarcelonaCataloniaSpain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)MadridSpain
| | - Fernando Fernández‐Bañares
- Department of Gastroenterology, Hospital Universitari Mútua TerrassaUniversitat de BarcelonaCataloniaSpain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)MadridSpain
| | - Albert Martín‐Cardona
- Department of Gastroenterology, Hospital Universitari Mútua TerrassaUniversitat de BarcelonaCataloniaSpain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)MadridSpain
| | - Montserrat Aceituno
- Department of Gastroenterology, Hospital Universitari Mútua TerrassaUniversitat de BarcelonaCataloniaSpain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)MadridSpain
| | - Yamile Zabana
- Department of Gastroenterology, Hospital Universitari Mútua TerrassaUniversitat de BarcelonaCataloniaSpain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)MadridSpain
| | - Lourdes Fluvià
- Proteomics and Metabolomics Core Facility, Institut de Recerca Germans Trias i Pujol (IGTP)BadalonaSpain
| | - José María Hernández
- Proteomics and Metabolomics Core Facility, Institut de Recerca Germans Trias i Pujol (IGTP)BadalonaSpain
| | - Violeta Lorén
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)MadridSpain
- Research Group in Inflammatory Bowel Diseases, Institut de Recerca Germans Trias i Pujol (IGTP)BadalonaSpain
| | - Josep Manyé
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)MadridSpain
- Research Group in Inflammatory Bowel Diseases, Institut de Recerca Germans Trias i Pujol (IGTP)BadalonaSpain
| | - Antonio Salas
- Department of PathologyHospital Universitari Mutua Terrassa, Universitat de BarcelonaCataloniaSpain
| | - Xavier Andújar
- Department of Gastroenterology, Hospital Universitari Mútua TerrassaUniversitat de BarcelonaCataloniaSpain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)MadridSpain
| | - Carme Loras
- Department of Gastroenterology, Hospital Universitari Mútua TerrassaUniversitat de BarcelonaCataloniaSpain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)MadridSpain
| | - Maria Esteve
- Department of Gastroenterology, Hospital Universitari Mútua TerrassaUniversitat de BarcelonaCataloniaSpain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)MadridSpain
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9
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Liu Y, Chen M. Insights into the underlying mechanisms and clinical management of microscopic colitis in relation to other gastrointestinal disorders. Gastroenterol Rep (Oxf) 2022; 10:goac011. [PMID: 35401986 PMCID: PMC8988210 DOI: 10.1093/gastro/goac011] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 01/26/2022] [Accepted: 02/28/2022] [Indexed: 11/14/2022] Open
Abstract
Microscopic colitis (MC) is a chronic inflammatory disease of the large intestine and as a relatively late recognized condition, its relationship with other disorders of the gastrointestinal tract is gradually being understood and investigated. As a multifactorial disease, MC interacts with inflammatory bowel disease, celiac disease, and irritable bowel syndrome through genetic overlap, immunological factors, and gut microflora. The risk of colorectal cancer was significantly lower in MC, gastrointestinal infections increased the risk of developing MC, and there was an inverse association between Helicobacter pylori infection and MC. A variety of associations are found between MC and other gastrointestinal disorders, where aspects such as genetic effects, resemblance of immunological profiles, and intestinal microecology are potential mechanisms behind the relationships. Clinicians should be aware of these connections to achieve a better understanding and management of MC.
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Affiliation(s)
- Yuanbin Liu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei, P. R. China
| | - Mingkai Chen
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei, P. R. China
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10
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Pisani LF, Tontini G, Vecchi M, Croci GA, Pastorelli L. NF-kB pathway is involved in microscopic colitis pathogenesis. J Int Med Res 2022; 50:3000605221080104. [PMID: 35301900 PMCID: PMC8935566 DOI: 10.1177/03000605221080104] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVE To investigate the potential inflammatory pathways involved in the development of microscopic colitis (MC). METHODS This prospective study analysed human intestinal tissue that was collected and classified as healthy controls (HC), microscopic colitis (MC) and ulcerative colitis (UC). An RT2 Profiler PCR Array for human inflammatory response and autoimmunity was used to evaluate the expression of 84 specific genes related to the inflammatory and autoimmunity pathways. Data were validated by means of real-time polymerase chain reaction on an independent group of MC intestinal tissue samples. RESULTS This study measured the expression of inflammatory genes in HC (n = 10), in patients with MC (n = 8) and in patients with active UC (n = 10). Of the 84 genes included in the array, the expression of the C-C motif chemokine ligand 19, C-C motif chemokine ligand 21, lymphotoxin beta and complement C3 genes that are involved in the non-canonical nuclear transcription factor kappa B (NF-kB) pathway was increased by 2.96, 6.05, 5.96 and 5.93 times in MC compared with HC, respectively. These results were confirmed by real-time polymerase chain reaction. CONCLUSIONS The findings suggest that an impairment of the non-canonical NF-kB pathway is involved in the development of MC.
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Affiliation(s)
- Laura Francesca Pisani
- Gastroenterology and Endoscopy Unit, IRCCS Policlinico San Donato, San Donato Milanese, Italy
- Laura Francesca Pisani, Gastroenterology and Endoscopy Unit, IRCCS Policlinico San Donato, Piazza Malan, San Donato Milanese, Lombardy 20097, Milano, Italy.
| | - Gianeugenio Tontini
- Department of Medical-Surgical Physiopathology and Transplantation, Università degli Studi di Milano, Milano, Italy
- Gastroenterology and Endoscopy Unit, IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico di Milano, Milano, Italy
| | - Maurizio Vecchi
- Department of Medical-Surgical Physiopathology and Transplantation, Università degli Studi di Milano, Milano, Italy
- Gastroenterology and Endoscopy Unit, IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico di Milano, Milano, Italy
| | - Giorgio Alberto Croci
- Department of Medical-Surgical Physiopathology and Transplantation, Università degli Studi di Milano, Milano, Italy
- Pathology Unit, IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico di Milano, Milano, Italy
| | - Luca Pastorelli
- Gastroenterology and Liver Unit, ASST Santi Paolo e Carlo, ASST Santi Paolo e Carlo, Milano, Italy
- Department of Health Sciences, School of Medicine Ospedale San Paolo, Università degli Studi di Milano, Milano, Italy
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11
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Intraepithelial and lamina propria lymphocytes do not correlate with symptoms or exposures in microscopic colitis. Clin Transl Gastroenterol 2022; 13:e00467. [PMID: 35166714 PMCID: PMC8963857 DOI: 10.14309/ctg.0000000000000467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 12/28/2021] [Indexed: 11/25/2022] Open
Abstract
Microscopic colitis, a common cause of diarrhea, is characterized by a largely normal appearance of the mucosa but increased numbers of lymphocytes in the epithelium and lamina propria on microscopy. We sought to determine whether T-cell percentage was associated with exposures or symptoms.
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12
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Zabana Y, Tontini G, Hultgren-Hörnquist E, Skonieczna-Żydecka K, Latella G, Østvik AE, Marlicz W, D'Amato M, Arias A, Mielhke S, Münch A, Fernández-Bañares F, Lucendo AJ. Pathogenesis of Microscopic Colitis: A Systematic Review. J Crohns Colitis 2022; 16:143-161. [PMID: 34272945 DOI: 10.1093/ecco-jcc/jjab123] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND Whereas the exact aetiology of microscopic colitis [MC] remains unknown, a dysregulated immune response to luminal factors or medications is the most accepted pathogenesis hypothesis. METHODS We conducted a systematic review of the pathogenesis of MC. We applied the Joanna Briggs Institute methodologies and the PRISMA statement for the reporting of systematic reviews [PROSPERO Trial Identifier: CRD42020145008]. Populations, Exposure of interest, and Outcome [PEO] questions were used to explore the following topics in MC: 1] intestinal luminal factors; 2] autoimmunity; 3] innate immunity; 4] adaptive immunity; 5] extracellular matrix; 6] genetic risk factors; and 7] mechanism of diarrhoea. A search was done in PubMed, Embase, and Web of Science up to February 2020. A narrative description was performed explaining the findings for each aspect of MC aetiopathogenesis. RESULTS Thirty-eight documents provided evidence for PEO1, 100 for PEO2, 72 for PEO3 and 4, 38 for PEO5, 20 for PEO6, and 23 for PEO7. The majority of documents were cohorts, case reports, and case series, with a few case-control and some experimental studies. Consistency among data provided by different studies was considered to support pathogenetic hypotheses. MC is a multifactorial disease believed to involve innate and adaptive immune responses to luminal factors, genetic risk, autoimmunity, and extracellular matrix alterations, all contributing by varied mechanisms to watery diarrhoea. CONCLUSIONS This is the first systematic review on the aetiology of MC supporting the notion that MC is a multifactorial disease. However, high-profile studies are lacking, and most evidence derives from small heterogeneous studies.
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Affiliation(s)
- Yamile Zabana
- Gastroenterology Department, Hospital Universitari Mútua de Terrassa, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
| | - Gian Tontini
- Department of Pathophysiology and Transplantation, University of Milan and Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico, Milan, Italy
| | | | | | - Giovanni Latella
- Gastroenterology Unit, Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Ann Elisabeth Østvik
- Department of Clinical and Molecular Medicine [IKOM], Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
- Department of Gastroenterology and Hepatology, Clinic of Medicine, St. Olav's University Hospital, Trondheim, Norway
| | - Wojciech Marlicz
- Department of Gastroenterology, Pomeranian Medical University, Szczecin, Poland
- Centre for Digestive Diseases Endoklinika, Szczecin, Poland
| | - Mauro D'Amato
- Gastrointestinal Genetics Lab, CIC bioGUNE - BRTA, Derio, Spain
- Ikerbasque, Basque Foundation for Science, Bilbao, Spain
| | - Angel Arias
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
- Research Unit, Hospital General Mancha Centro, Alcázar de San Juan, Ciudad Real, Spain
| | - Stephan Mielhke
- Centre for Digestive Diseases, Internal Medicine Centre Eppendorf & Endoscopy Centre, University Hospital Hamburg Eppendorf, Hamburg, Germany
| | - Andreas Münch
- Department of Health, Medicine, and Caring Sciences, Linköping University, Linköping, Sweden
| | - Fernando Fernández-Bañares
- Gastroenterology Department, Hospital Universitari Mútua de Terrassa, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
| | - Alfredo J Lucendo
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
- Gastroenterology Department, Hospital General de Tomelloso-Spain and Instituto de Investigación Sanitaria Princesa [IIS-IP], Madrid, Spain
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13
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Mihaly E, Patai Á, Tulassay Z. Controversials of Microscopic Colitis. Front Med (Lausanne) 2021; 8:717438. [PMID: 34712675 PMCID: PMC8546222 DOI: 10.3389/fmed.2021.717438] [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: 05/31/2021] [Accepted: 08/11/2021] [Indexed: 11/21/2022] Open
Abstract
Microscopic colitis (MC) has become a disease with increased awareness due to the availability of new data about the pathogenesis, diagnosis and therapy of this disease. The incidence of MC is increasing, reaching the incidence of the inflammatory bowel disease (IBD) in some populations. However, some aspects of MC are still controversial. It is unknown whether the changes of microbiome play a role in the pathogenesis and what is in the background of the different subtypes of disease that can transform into each other. Is there a connection between MC and IBD or why the histological changes do not follow the clinical activity? We do not know what the etiology of the incomplete MC is, and what its natural course is. The association of MC with celiac disease is well-known- is there a common pathogenesis? The MC treatment is budesonide. Its effectiveness is high, but the relapse rate is high, as well. Why would biologics be effective in these cases when budesonide is not? This mini-review makes an attempt to summarize the data about MC and highlight that there are still unanswered questions in the pathogenesis, diagnosis and therapy of the disease, which can initiate further investigations in the future.
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Affiliation(s)
- Emese Mihaly
- Gastroenterology Unit, Department of Internal Medicine and Hematology, Semmelweis University, Budapest, Hungary
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14
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Daferera N, Escudero-Hernández C, Nyström S, Jenmalm MC, Hjortswang H, Ignatova S, Ström M, Münch A. Collagenous Colitis Mucosa Is Characterized by an Expansion of Nonsuppressive FoxP3+ T Helper Cells. Inflamm Bowel Dis 2021; 27:1482-1490. [PMID: 33319252 DOI: 10.1093/ibd/izaa322] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIM Increased frequencies of T regulatory (Treg) cells, key players in immune regulation, have been reported in inflammatory bowel diseases, including collagenous colitis (CC). However, traditional Treg identification techniques might have misinterpreted the frequencies of Treg cells in CC. Thus, we investigated the presence of genuine Treg cells in CC. METHODS Treg cells were analyzed in mucosal and peripheral blood samples of CC patients before and during treatment with the corticosteroid drug budesonide and in healthy controls. Samples were analyzed by flow cytometry by classifying CD3+CD4+ cells as activated FoxP3highCD45RA- Treg cells, resting FoxP3dimCD45RA+ Treg cells, and nonsuppressive FoxP3dimCD45RA- T helper cells. Traditional gating strategies that classified Treg cells as CD25highCD127low, FoxP3+CD127low, and CD4+CD25+FoxP3+ were also used to facilitate comparison with previous studies. RESULTS Activated and resting Treg cell frequencies did not change in active CC mucosa or peripheral blood and were not affected by budesonide treatment. Instead, nonsuppressive FoxP3dimCD45RA- T helper cells were increased in active CC mucosa, and budesonide helped restore them to normal levels. In contrast, traditional Treg cell gating strategies resulted in increased Treg cell frequencies in active CC mucosa. No alterations were found in peripheral blood samples, independently of patient treatment or gating techniques. CONCLUSION Previously reported increase of Treg cells is a result of incomplete Treg phenotyping, which included nonsuppressive FoxP3dimCD45RA- T helper cells. Because budesonide did not affect Treg percentage, its therapeutic effect in CC might involve alternative mechanisms.
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Affiliation(s)
- Niki Daferera
- Division of Gastroenterology and Hepatology, Department of Biomedical and Clinical Sciences (BKV), Faculty of Health Science, Linköping University, Linköping, Sweden
| | - Celia Escudero-Hernández
- Institute of Clinical Molecular Biology, Christian-Albrecht's-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Sofia Nyström
- Department of Biomedical and Clinical Sciences (BKV), Linköping University, Linköping, Sweden
| | - Maria C Jenmalm
- Department of Biomedical and Clinical Sciences (BKV), Linköping University, Linköping, Sweden
| | - Henrik Hjortswang
- Division of Gastroenterology and Hepatology, Department of Biomedical and Clinical Sciences (BKV), Faculty of Health Science, Linköping University, Linköping, Sweden
| | - Simone Ignatova
- Department of Pathology, Linköping University, Linköping, Sweden
| | - Magnus Ström
- Division of Gastroenterology and Hepatology, Department of Biomedical and Clinical Sciences (BKV), Faculty of Health Science, Linköping University, Linköping, Sweden
| | - Andreas Münch
- Division of Gastroenterology and Hepatology, Department of Biomedical and Clinical Sciences (BKV), Faculty of Health Science, Linköping University, Linköping, Sweden
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15
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Honjo H, Watanabe T, Tomooka M, Matsubara T, Kono M, Sekai I, Hara A, Kurimoto M, Yoshikawa K, Masuta Y, Otsuka Y, Takada R, Yoshikawa T, Kamata K, Minaga K, Matsui S, Kimura M, Kudo M. Case Report: Regulatory T Cell-Independent Induction of Remission in a Patient With Collagenous Colitis. Front Med (Lausanne) 2021; 8:678268. [PMID: 34350195 PMCID: PMC8326450 DOI: 10.3389/fmed.2021.678268] [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: 03/09/2021] [Accepted: 06/25/2021] [Indexed: 11/24/2022] Open
Abstract
Collagenous colitis (CC), a prototypical microscopic colitis, is a chronic inflammatory disorder of the colon. The diagnosis of CC depends on the pathological examination. The colonic mucosa of patients with CC is characterized by the presence of a substantially thickened collagen band (>10μm) under the surface epithelium. In addition, intraepithelial and lamina propria lymphocytes are markedly increased in patients with CC. However, the roles played by the lymphocytes accumulating in the colonic mucosa of patients with CC are poorly defined. Recent studies indicate that T cells infiltrating the colonic mucosa of patients with CC are mainly represented by CD4+ T cells, CD8+ T cells, and forkhead box P3 (FOXP3)+ regulatory T cells (Tregs). Given that activation of CD4+/CD8+ T cells and FOXP3+ Tregs usually mediates pro-inflammatory and anti-inflammatory responses, respectively, alterations in the colonic numbers of these adaptive T cells might be related to the resolution of colitis in patients with CC. We determined alterations in the composition of colonic T cells by extensive immunohistochemical (IHC) analyses in a case of CC successfully treated with budesonide and metronidazole. Colonic lamina propria immune cells mainly comprised CD3+ T cells, CD4+ T cells, CD8+ T cells, CD68+ macrophages, and FOXP3+ Tregs, but not CD20+ B cells or myeloperoxidase (MPO)+ granulocytes in the active phase. During remission, the numbers of CD3+ T cells, CD4+ T cells, CD8+ T cells, and CD68+ macrophages did not change significantly in the colonic lamina propria, whereas FOXP3+ Tregs were markedly decreased, suggesting that induction of remission was achieved in a Treg-independent manner. Thus, our study indicates that accumulation of FOXP3+ Tregs in the colonic mucosa of patients with CC might be a counter-regulatory mechanism reflecting persistent inflammation and that induction of remission might be achieved without activation of Tregs.
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Affiliation(s)
- Hajime Honjo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Tomohiro Watanabe
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Mizuki Tomooka
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Takuya Matsubara
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Masashi Kono
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Ikue Sekai
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Akane Hara
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Masayuki Kurimoto
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Keisuke Yoshikawa
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Yasuhiro Masuta
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Yasuo Otsuka
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Ryutaro Takada
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Tomoe Yoshikawa
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Ken Kamata
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Kosuke Minaga
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Shigenaga Matsui
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Masatomo Kimura
- Department of Diagnostic Pathology, Kindai University Hospital, Osaka, Japan
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
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16
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Abstract
Microscopic colitis (MC) is an inflammatory disease of the large intestine associated with urgent watery diarrhoea. MC may occur in people of all ages, although the disease primarily affects older women. Once believed to be rare, MC is now known to be a common cause of chronic watery diarrhoea in high-income countries, affecting 1 in 115 women and 1 in 286 men during their lifetime in Swedish population-based estimates. An inappropriate immune response to disturbances in the gut microenvironment is implicated in the pathogenesis of MC. Evidence also supports an underlying genetic basis for disease. The diagnosis of MC relies on clinical symptoms and microscopic assessment of colonic biopsy samples. MC is categorized histologically into collagenous colitis, lymphocytic colitis and their incomplete forms. The mainstay of treatment includes the use of budesonide, with or without adjunctive therapies, and withdrawal of offending drugs. Emerging studies suggest a role for biologicals and immunosuppressive therapies for the management of budesonide-refractory or budesonide-dependent disease. MC can have a substantial negative effect on patient quality of life. The outlook for MC includes a better understanding of the immune response, genetics and the microbiome in disease pathogenesis along with progress in disease management through robust clinical trials.
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Affiliation(s)
- Kristin E Burke
- Gastroenterology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, USA.
| | - Mauro D'Amato
- Gastrointestinal Genetics Lab, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), Derio, Spain
- Ikerbasque, Basque Foundation for Science, Bilbao, Spain
| | - Siew C Ng
- Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, LK Institute of Health Science, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, China
| | - Darrell S Pardi
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Jonas F Ludvigsson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- Department of Paediatrics, Örebro University Hospital, Örebro University, Örebro, Sweden
| | - Hamed Khalili
- Gastroenterology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, USA.
- Institute of Environmental Medicine, Nutrition Epidemiology, Karolinska Institutet, Solna, Sweden.
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17
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Escudero-Hernández C, van Beelen Granlund A, Bruland T, Sandvik AK, Koch S, Østvik AE, Münch A. Transcriptomic Profiling of Collagenous Colitis Identifies Hallmarks of Nondestructive Inflammatory Bowel Disease. Cell Mol Gastroenterol Hepatol 2021; 12:665-687. [PMID: 33930606 PMCID: PMC8267496 DOI: 10.1016/j.jcmgh.2021.04.011] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 04/16/2021] [Accepted: 04/19/2021] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND AIMS The pathophysiology of the inflammatory bowel disease collagenous colitis (CC) is poorly described. Our aim was to use RNA sequencing of mucosal samples from patients with active CC, CC in remission, refractory CC, ulcerative colitis (UC), and control subjects to gain insight into CC pathophysiology, identify genetic signatures linked to CC, and uncover potentially druggable disease pathways. METHODS We performed whole transcriptome sequencing of CC samples from patients before and during treatment with the corticosteroid drug budesonide, CC steroid-refractory patients, UC patients, and healthy control subjects (n = 9-13). Bulk mucosa and laser-captured microdissected intestinal epithelial cell (IEC) gene expression were analyzed by gene set enrichment and gene set variation analyses to identify significant pathways and cells, respectively, altered in CC. Leading genes and cells were validated using reverse-transcription quantitative polymerase chain reaction or immunohistochemistry. RESULTS We identified an activation of the adaptive immune response to bacteria and viruses in active CC that could be mediated by dendritic cells. Moreover, IECs display hyperproliferation and increased antigen presentation in active CC. Further analysis revealed that genes related to the immune response (DUOX2, PLA2G2A, CXCL9), DNA transcription (CTR9), protein processing (JOSD1, URI1), and ion transport (SLC9A3) remained dysregulated even after budesonide-induced remission. Budesonide-refractory CC patients fail to restore normal gene expression, and displayed a transcriptomic profile close to UC. CONCLUSIONS Our study confirmed the implication of innate and adaptive immune responses in CC, governed by IECs and dendritic cells, respectively, and identified ongoing epithelial damage. Refractory CC could share pathomechanisms with UC.
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Affiliation(s)
| | - Atle van Beelen Granlund
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway; Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
| | - Torunn Bruland
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway; Clinic of Medicine, St Olav's University Hospital, Trondheim, Norway
| | - Arne Kristian Sandvik
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway; Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway; Clinic of Medicine, St Olav's University Hospital, Trondheim, Norway; Department of Gastroenterology and Hepatology, St Olav's University Hospital, Trondheim, Norway
| | - Stefan Koch
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden; Wallenberg Centre for Molecular Medicine, Linköping University, Linköping, Sweden
| | - Ann Elisabet Østvik
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway; Clinic of Medicine, St Olav's University Hospital, Trondheim, Norway; Department of Gastroenterology and Hepatology, St Olav's University Hospital, Trondheim, Norway
| | - Andreas Münch
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden; Department of Gastroenterology and Hepatology, Linköping University, Linköping, Sweden; Department of Health, Medicine, and Caring Sciences, Linköping University, Linköping, Sweden
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18
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Quantifying intraepithelial lymphocytes and subepithelial collagen band in microscopic colitis, extracting insights into the interrelationship of lymphocytic and collagenous colitis. Ann Diagn Pathol 2021; 52:151741. [PMID: 33865186 DOI: 10.1016/j.anndiagpath.2021.151741] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 02/11/2021] [Accepted: 03/28/2021] [Indexed: 01/10/2023]
Abstract
Microscopic colitis (MC) is the umbrella term for the conditions termed lymphocytic colitis (LC) and collagenous colitis (CC). LC with thickening of the subepithelial collagen band or CC with increased number of intraepithelial T- lymphocytes (IELs) is often seen in MC and may lead to difficulties in correct histological classification. We investigated the extent of overlapping features of CC and LC in 60 cases of MC by measuring the exact thickness of the subepithelial collagen band in Van Gieson stained slides and quantifying number of IELs in CD3 stained slides by digital image analysis. A thickened collagen band was observed in nine out of 29 cases with LC (31%) and an increased number of IELs in all 23 cases of CC (100%). There was no correlation between the thickness of the collagen band and number of IELs. Due to the increased number of IELs in all cases of CC we consider the lymphocytic inflammatory infiltration of the mucosa to be the essential histopathological feature of MC. However, although LC and CC are related due to the lymphocytic inflammation, the non-linear correlation of number of IELs and thickness of the collagenous band indicate differences in their pathogenesis.
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Kang X, Ploner A, Roelstraete B, Khalili H, Williams DM, Pedersen NL, Ludvigsson JF, Wirdefeldt K. Association Between Microscopic Colitis and Parkinson's Disease in a Swedish Population. Mov Disord 2021; 36:1919-1926. [PMID: 33764622 DOI: 10.1002/mds.28594] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 02/04/2021] [Accepted: 03/08/2021] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND Gastrointestinal inflammation has been linked with Parkinson's disease (PD). Microscopic colitis (MC) is an intestinal inflammatory disease with unknown relationship with PD. OBJECTIVE This study aimed to examine the association of MC with PD risk. METHODS In this nationwide matched cohort study in Sweden, PD incidence was compared between 12,609 patients with histologically confirmed MC and a matched population cohort of 58,879 MC-free individuals and a sibling cohort comprising all unaffected siblings of the MC patients (NMC /NSibling = 6281/12,351). Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression models. RESULTS During a mean follow-up of ~7 years, we identified 449 incident PD diagnoses among the MC patients and the population cohort. Overall, MC was associated with an adjusted HR of 1.76 for PD, but the association attenuated substantially during follow-up. In the time-varying effects model, PD hazard was 3.45-fold (95% CI: 2.42, 4.93) higher during the first 2 years after biopsy and 1.80-fold (95% CI: 1.23, 2.64) higher during the following 3 years among MC versus MC-free individuals but was not different beyond 5 years after biopsy (HR: 1.03; 95% CI: 0.68, 1.54). This temporal pattern of MC-PD associations persisted when comparing MC patients to their siblings. In a post hoc case-control analysis, we also detected a strong association between MC and preexisting PD (odds ratio: 3.46; 95% CI: 2.91, 4.12). CONCLUSIONS Our findings suggest that MC may not be a risk factor for PD; instead, it may co-occur with PD as a comorbidity or develop after a diagnosis of PD. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Xiaoying Kang
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Alexander Ploner
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Bjorn Roelstraete
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Hamed Khalili
- Massachusetts General Hospital, Crohn's and Colitis Center and Harvard Medical School, Boston, Massachusetts, USA.,Division of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Dylan M Williams
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.,MRC Unit for Lifelong Health and Ageing, University College London, London, United Kingdom
| | - Nancy L Pedersen
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Jonas F Ludvigsson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.,Department of Pediatrics, Örebro University Hospital, Örebro, Sweden
| | - Karin Wirdefeldt
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.,Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
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20
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Wan XM, Wang ZL, Wang LY, Cai XT, Wan CM, Xie YM. Collagenous colitis in a child induced by chronic respiratory allergy: A case report. Medicine (Baltimore) 2020; 99:e21920. [PMID: 32871927 PMCID: PMC7458195 DOI: 10.1097/md.0000000000021920] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
INTRODUCTION Collagen colitis (CC) is a microscopic colitis diagnosed by mucosal biopsy and is extremely rare in children. PATIENT CONCERNS We reported a child with severe persistent diarrhea that could not be relieved with traditional diarrheal treatment. No abnormalities were found after multiple colonoscopies. DIAGNOSES A significant increase in total IgE levels was found in the patient's blood. He had a history of mild chronic allergic rhinitis and slightly intermittent wheezing. However, we found that the child had a hyperallergic reaction to multiple respiratory antigens and had mild pulmonary dysfunction. Finally, colonoscopy with biopsy identified the diagnosis of CC. INTERVENTION Considering that a respiratory allergic reaction was one of the causes of diarrhea, anti-allergic treatment was given to the child, and his severe diarrhea was soon relieved. Corticosteroid treatment was suggested to the patient, but his parents firmly refused steroid therapy. According to the patient's specific allergic reaction to mites, desensitization treatment was finally chosen for him. OUTCOMES After 1 year of desensitization for dust mites, the patient's respiratory symptoms improved, total IgE levels decreased, autoantibodies declined, and diarrhea did not reoccur. Colonoscopy with biopsy showed a significant improvement in pathology. CONCLUSION CC in children is rare, and childhood CC induced by a respiratory allergic reaction has not been previously reported. Therefore, this is a special case of CC in a patient who was cured with anti-allergy treatments and desensitization instead of steroid therapy.
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Affiliation(s)
- Xue-Meng Wan
- Department of Pediatrics, Sichuan University West China Second University Hospital, NO. 20, Section 3, Ren Min Nan Lu Road
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan, P.R. China
| | - Zhi-Ling Wang
- Department of Pediatrics, Sichuan University West China Second University Hospital, NO. 20, Section 3, Ren Min Nan Lu Road
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan, P.R. China
| | - Li-Yuan Wang
- Department of Pediatrics, Sichuan University West China Second University Hospital, NO. 20, Section 3, Ren Min Nan Lu Road
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan, P.R. China
| | - Xiao-Tang Cai
- Department of Pediatrics, Sichuan University West China Second University Hospital, NO. 20, Section 3, Ren Min Nan Lu Road
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan, P.R. China
| | - Chao-Min Wan
- Department of Pediatrics, Sichuan University West China Second University Hospital, NO. 20, Section 3, Ren Min Nan Lu Road
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan, P.R. China
| | - Yong-Mei Xie
- Department of Pediatrics, Sichuan University West China Second University Hospital, NO. 20, Section 3, Ren Min Nan Lu Road
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan, P.R. China
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Escudero-Hernández C, Münch A, Østvik AE, Granlund AVB, Koch S. The Water Channel Aquaporin 8 is a Critical Regulator of Intestinal Fluid Homeostasis in Collagenous Colitis. J Crohns Colitis 2020; 14:962-973. [PMID: 32016376 PMCID: PMC7393183 DOI: 10.1093/ecco-jcc/jjaa020] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIMS Diarrhoea is a common, debilitating symptom of gastrointestinal disorders. Pathomechanisms probably involve defects in trans-epithelial water transport, but the role of aquaporin [AQP] family water channels in diarrhoea-predominant diseases is unknown. We investigated the involvement of AQPs in the pathobiology of collagenous colitis [CC], which features chronic, watery diarrhoea despite overtly normal intestinal epithelial cells [IECs]. METHODS We assessed the expression of all AQP family members in mucosal samples of CC patients before and during treatment with the corticosteroid drug budesonide, steroid-refractory CC patients and healthy controls. Samples were analysed by genome-wide mRNA sequencing [RNA-seq] and quantitative real-time PCR [qPCR]. In some patients, we performed tissue microdissection followed by RNA-seq to explore the IEC-specific CC transcriptome. We determined changes in the protein levels of the lead candidates in IEC by confocal microscopy. Finally, we investigated the regulation of AQP expression by corticosteroids in model cell lines. RESULTS Using qPCR and RNA-seq, we identified loss of AQP8 expression as a hallmark of active CC, which was reverted by budesonide treatment in steroid-responsive but not refractory patients. Consistently, decreased AQP8 mRNA and protein levels were observed in IECs of patients with active CC, and steroid drugs increased AQP8 expression in model IECs. Moreover, low APQ8 expression was strongly associated with higher stool frequency in CC patients. CONCLUSION Down-regulation of epithelial AQP8 may impair water resorption in active CC, resulting in watery diarrhoea. Our results suggest that AQP8 is a potential drug target for the treatment of diarrhoeal disorders.
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Affiliation(s)
| | - Andreas Münch
- Department of Biomedical and Clinical Sciences [BKV), Linköping University, Linköping, Sweden,Division of Gastroenterology and Hepatology, Department of Biomedical and Clinical Sciences [BKV), Faculty of Health Science, Linköpings University, Linköping, Sweden,Corresponding authors: Andreas Münch, MD PhD, Division of Gastroenterology and Hepatology, Department of Biomedical and Clinical Sciences [BKV), Faculty of Health Sciences, Linköping University, Linköping, 58185, Sweden. Tel: +46 100130000; ; Stefan Koch, PhD, BKV/MII—Plan 13, s-581 83 Linköping, Sweden. Tel: +46 13 282969;
| | - Ann-Elisabet Østvik
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway,Department of Gastroenterology and Hepatology, St Olav’s University Hospital, Trondheim, Norway,Clinic of Medicine, St Olav’s University Hospital, Trondheim, Norway
| | - Atle van Beelen Granlund
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway,Clinic of Medicine, St Olav’s University Hospital, Trondheim, Norway,Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
| | - Stefan Koch
- Department of Biomedical and Clinical Sciences [BKV), Linköping University, Linköping, Sweden,Wallenberg Centre for Molecular Medicine (WCMM), Linköping University, Linköping, Sweden,Corresponding authors: Andreas Münch, MD PhD, Division of Gastroenterology and Hepatology, Department of Biomedical and Clinical Sciences [BKV), Faculty of Health Sciences, Linköping University, Linköping, 58185, Sweden. Tel: +46 100130000; ; Stefan Koch, PhD, BKV/MII—Plan 13, s-581 83 Linköping, Sweden. Tel: +46 13 282969;
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22
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Miehlke S, Verhaegh B, Tontini GE, Madisch A, Langner C, Münch A. Microscopic colitis: pathophysiology and clinical management. Lancet Gastroenterol Hepatol 2020; 4:305-314. [PMID: 30860066 DOI: 10.1016/s2468-1253(19)30048-2] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 01/18/2019] [Accepted: 01/18/2019] [Indexed: 12/12/2022]
Abstract
Microscopic colitis is a chronic inflammatory disease of the colon that frequently causes chronic watery diarrhoea that might be accompanied by abdominal pain, nocturnal diarrhoea, urgency, and faecal incontinence. These symptoms lead to poor quality of life and increased health-care costs. Diagnosis relies on histological examination of multiple biopsy samples from the colonic mucosa, which often show no or only few abnormalities on endoscopy. Two major histological subtypes can be distinguished-collagenous colitis and lymphocytic colitis-but incomplete and variant forms with fewer characteristic features have been reported. Here we summarise the latest evidence on epidemiology, pathogenesis, and risk factors, and discuss established and novel therapeutic options for clinical remission. Finally, we propose an updated treatment algorithm. Further prospective studies are needed to clarify the natural history of microscopic colitis, supported by validated criteria for the assessment of disease activity.
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Affiliation(s)
- Stephan Miehlke
- Centre for Digestive Diseases, Internal Medicine Centre Eppendorf, Hamburg, Germany; Centre for Oesophageal Disorders, University Hospital Eppendorf, Hamburg, Germany.
| | - Bas Verhaegh
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, Netherlands
| | - Gian Eugenio Tontini
- Gastroenterology and Endoscopy, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Ahmed Madisch
- Department of Gastroenterology, CRH Clinic Siloah, Hannover, Germany
| | - Cord Langner
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Andreas Münch
- Department of Gastroenterology, Linköping University, Linköping, Sweden
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23
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Khalili H, Burke KE, Roelstraete B, Sachs MC, Olén O, Ludvigsson JF. Microscopic Colitis and Risk of Inflammatory Bowel Disease in a Nationwide Cohort Study. Gastroenterology 2020; 158:1574-1583.e2. [PMID: 31926169 DOI: 10.1053/j.gastro.2019.12.028] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 12/11/2019] [Accepted: 12/28/2019] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS Microscopic colitis shares pathogenetic mechanisms with inflammatory bowel disease (IBD). We studied the association between microscopic colitis and risk of incident IBD using data from a nationwide cohort study. METHODS We conducted a prospective cohort study of all adults who received a diagnosis of microscopic colitis from 1990 through 2017 in Sweden and risk of incident IBD. Cases of microscopic colitis (n= 13,957) were identified through Systematized Nomenclature of Medicine codes from the ESPRESSO (Epidemiology Strengthened by histoPathology Reports in Sweden) study, which included gastrointestinal pathology reports from all of Sweden's 28 centers. Individuals with microscopic colitis were matched to 5 general population controls (n = 66,820) and to unaffected siblings (n =13,943). Cox regression was used to estimate adjusted hazard ratio (aHRs) and 95% confidence intervals (CIs). RESULTS Through December of 2017, we identified 323 incident cases of ulcerative colitis (UC) and 108 incident cases of Crohn's disease (CD) in patients with microscopic colitis compared with 94 UC and 42 CD cases in population comparators. Mean times from diagnosis of microscopic colitis to diagnosis of CD was 3.3 ± 3.2 years and to diagnosis of UC was 3.2 ± 3.5 years. In multivariable models, microscopic colitis was associated with an aHR of 12.6 (95% CI 8.8-18.1) for CD, 17.3 (95% CI 13.7-21.8) for UC, and 16.8 (95% CI 13.9-20.3) for IBD. The 10-year absolute excess risks of CD and UC were 0.9 (95% CI 0.7-1.1) and 2.6 (95% CI 2.2-2.9) percentage points, respectively. In sensitivity analyses, comparing patients with microscopic colitis with their unaffected siblings, the aHRs of CD and UC were 5.4 (95% CI 3.2-9.2) and 9.4 (95% CI 6.4-13.8), respectively. CONCLUSIONS In a population-based study in Sweden, we found a significant increase in risk of incident IBD among patients with microscopic colitis. Future studies should focus on potential mechanisms underlying these observed associations.
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Affiliation(s)
- Hamed Khalili
- Massachusetts General Hospital, Crohn's and Colitis Center and Harvard Medical School, Boston, Massachusetts; Division of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
| | - Kristin E Burke
- Massachusetts General Hospital, Crohn's and Colitis Center and Harvard Medical School, Boston, Massachusetts
| | - Bjorn Roelstraete
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Michael C Sachs
- Division of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Ola Olén
- Division of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Sachs' Children and Youth Hospital, Stockholm South General Hospital, Stockholm, Sweden
| | - Jonas F Ludvigsson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Pediatrics, Orebro University Hospital, Orebro, Sweden; Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, United Kingdom; Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York
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24
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Liu Q, Harpaz N. Expression Profiling of Inflammatory and Immunological Genes in Collagenous Colitis. J Crohns Colitis 2019; 13:764-771. [PMID: 31131860 PMCID: PMC6535503 DOI: 10.1093/ecco-jcc/jjy224] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Revised: 11/27/2018] [Indexed: 12/16/2022]
Abstract
BACKGROUND Collagenous colitis [CC] is a common idiopathic cause of chronic watery diarrhoea. We investigated its pathogenesis by means of gene expression analysis. METHODS We analysed the expression of genes implicated in immunological and inflammatory pathways in paired colonic biopsies of histologically involved and uninvolved mucosa from five patients with histologically patchy CC, in pooled colonic biopsies of eight other patients with diffuse CC, and in pooled biopsies of eight normal controls. Analyses were performed with the Nanostring nCounter system. Expression ratios were generated and confirmed by quantitative reverse transcription PCR. RESULTS CC mucosa was characterized by enhanced expression of nitric oxide synthase 2; of matrix metalloproteinases 3 and 9 and tissue inhibitor of metalloproteinase 1, but not transforming growth factor β1; of mediators of T-helper 1 immunity including interleukins 12A [IL12A], 12B, IL12 receptor B1 and interferon γ; of immune mediators of the leukocyte immunoglobulin-like receptor subfamily B; and of multiple T cell cytokines and their receptors. The mitogen-activated protein kinase signalling pathway was unchanged. There were no increases in IL22, IL22RA2 or tumour necrosis factor α, which are reportedly elevated in chronic inflammatory bowel disease. In four of five patients with patchy CC, similar gene expression profiles were observed in histologically involved and uninvolved mucosa. CONCLUSIONS CC is characterized by altered expression of a limited repertoire of genes involved in nitric oxide synthesis, extracellular matrix remodelling, T-helper 1 immunity and immune modulation. The abnormal gene expression in patchy CC may be expressed in mucosa with and without histological disease manifestations.
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Affiliation(s)
- Qingqing Liu
- The Department of Pathology, Molecular and Cell-based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Noam Harpaz
- The Department of Pathology, Molecular and Cell-based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA,Corresponding author: Noam Harpaz, MD, PhD, Department of Pathology, Annenberg 15-38E, Icahn School of Medicine at Mount Sinai, 1468 Madison Avenue, New York, NY 10029, USA. Tel: [212) 241-6692; Fax: [212) 828-4188;
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25
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Mosso E, Boano V, Grassini M, Battaglia E, Pellicano R. Microscopic colitis: a narrative review with clinical approach. MINERVA GASTROENTERO 2019; 65:53-62. [PMID: 30486642 DOI: 10.23736/s1121-421x.18.02539-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Microscopic colitis (MC) is diagnosed in presence of microscopic alterations of colonic mucosa, in patients without macroscopic lesions who referred for chronic diarrhea. The two types of MC are lymphocytic colitis (LC) and collagenous colitis (CC), but it is unclear whether these are the different expression of one unique disease or if they are distinct conditions. Today, although MC represents a consistent health problem, being responsible for a large part of gastroenterological consultations for diarrhea, it remains often underestimated. The detailed pathogenesis of MC has not been determined yet. Probably, it is the result of an interaction between individual, environmental and genetic factors. The most relevant risk factor for the development of MC is the use of certain drugs (such as non-steroidal anti-inflammatory drugs [NSAIDs], proton pump inhibitors [PPIs], selective serotonin reuptake inhibitors, beta-blockers, statins). Smoking is another relevant factor reported as associated with the development of MC. Diagnosis needs the execution of a colonoscopy in patients complaining about chronic diarrhea and abdominal pain. The crucial role is played by histology: MC is characterized by the presence of colonic mucosal lymphocytic infiltrate, with intraepithelial lymphocytes ≥20 per 100 enteric surface cells, in CC there is a typical subepithelial collagen layer, whose thickness is ≥10 μm. We carried out a review of the current literature to rule out what is new on epidemiology, diagnosis and therapy of MC.
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Affiliation(s)
- Elena Mosso
- Department of Gastroenterology, University of Turin, Turin, Italy
| | - Valentina Boano
- Department of Gastroenterology, University of Turin, Turin, Italy
| | - Mario Grassini
- Section of Physiopathology and Manometry, Unit of Gastroenterology and Endoscopy, Cardinal Massaja Hospital, Asti, Italy
| | - Edda Battaglia
- Section of Physiopathology and Manometry, Unit of Gastroenterology and Endoscopy, Cardinal Massaja Hospital, Asti, Italy
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Setia N, Alpert L, van der Sloot KWJ, Colussi D, Stewart KO, Misdraji J, Khalili H, Lauwers GY. Lymphocytic colitis: pathologic predictors of response to therapy. Hum Pathol 2018; 78:1-7. [DOI: 10.1016/j.humpath.2018.02.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2017] [Revised: 01/27/2018] [Accepted: 02/01/2018] [Indexed: 12/22/2022]
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Torres J, Palmela C, Gomes de Sena P, Santos MPC, Gouveia C, Oliveira MH, Henriques AR, Rodrigues C, Cravo M, Borralho P. Farnesoid X Receptor Expression in Microscopic Colitis: A Potential Role in Disease Etiopathogenesis. GE-PORTUGUESE JOURNAL OF GASTROENTEROLOGY 2017; 25:30-37. [PMID: 29457048 DOI: 10.1159/000481197] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Revised: 09/04/2017] [Indexed: 12/20/2022]
Abstract
Introduction Microscopic colitis (MC) is a chronic inflammatory bowel disease with unclear etiology. Bile acid (BA) malabsorption has been described in MC patients. Farnesoid X receptor (FXR) is the main BA receptor; FXR-mediated mechanisms prevent the noxious effects of BA accumulation, preserving the integrity of the intestinal epithelial barrier and preventing intestinal inflammation. Aim Our aim was to describe the expression of FXR in patients with MC. Methods Archival formalin-fixed paraffin-embedded samples from the terminal ileum, right and left colon were obtained from patients with MC and matched controls. Immunohistochemistry was performed and nuclear FXR expression scored in a semi-quantitative way. Results 169 formalin-fixed paraffin-embedded samples from 35 patients with MC and 31 controls were retrieved. There was a significant reduction of FXR expression in patients with MC versus controls both in the right colon (moderate-strong FXR expression: 21.1 vs. 64.3%; p = 0.003) and left colon (moderate-strong FXR expression: 8.3 vs. 38.7%; p = 0.027). No significant differences in FXR expression were observed in the ileum of patients with MC (moderate-strong FXR expression: 76.9 vs. 90.9%; p = 0.5). We found no difference in FXR expression between the two types of MC. No association between the degree of lymphocyte infiltration or the thickness of collagen band and FXR expression was found. Conclusions Patients with MC present a significantly lower expression of FXR in the colon. This could render colonic epithelial cells more susceptible to the deleterious effects of BA, contributing to disease pathogenesis and symptoms in MC.
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Affiliation(s)
- Joana Torres
- Gastroenterology Department, Hospital Beatriz Ângelo, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Carolina Palmela
- Gastroenterology Department, Hospital Beatriz Ângelo, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Pedro Gomes de Sena
- Pathology Department, Hospital Beatriz Ângelo, Loures, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Maria Pia Costa Santos
- Gastroenterology Department, Hospital Beatriz Ângelo, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Catarina Gouveia
- Gastroenterology Department, Hospital Beatriz Ângelo, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Maria Helena Oliveira
- Pathology Department, Hospital Beatriz Ângelo, Loures, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Ana Raquel Henriques
- Faculty of Medicine, Universidade de Lisboa, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Cecília Rodrigues
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Marília Cravo
- Gastroenterology Department, Hospital Beatriz Ângelo, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Paula Borralho
- Gastroenterology Department, Hospital Beatriz Ângelo, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.,Pathology Department, Hospital Cuf Descobertas, Lisbon, Portugal
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Early Life Exposure, Lifestyle, and Comorbidity as Risk Factors for Microscopic Colitis: A Case-Control Study. Inflamm Bowel Dis 2017; 23:1040-1046. [PMID: 28471835 DOI: 10.1097/mib.0000000000001103] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND The pathophysiology of microscopic colitis (MC) is not fully understood. A dysregulation of the adaptive immune response has been hypothesized, of which the maturation and function is imprinted in early life. Various other factors (e.g., hormonal factors) have also been found to be associated, sometimes, with minimal or conflicting evidence. The aims of this study were to evaluate whether an exposure to (microbial) agents in early life might be protective for MC development and to assess the role of several less well-established risk factors in one study. METHODS A case-control study was conducted including MC cases diagnosed in the Southern part of the Netherlands between 2000 and 2012. Cases were matched to non-MC controls from the same area, based on gender and year of birth, and assigned the same index date. All subjects filled out the same study questionnaire on various risk factors. RESULTS In total, 171 MC cases and 361 controls were included. In the multivariable logistic regression analysis, current smoking (odds ratio 6.23, 95% confidence interval, 3.10-12.49), arthrosis, and a cardiac disorder were associated with MC. No association was observed, for example, factors related to early life exposure to microbial antigens, passive smoking, rheumatoid arthritis, celiac disease, or hormonal factors. CONCLUSIONS Early life exposure to microbial antigens and increased hormonal exposure were not found to be protective for MC. Current smoking seems to be an incontestable risk factor for MC. Therefore, exposure to environmental risk factors later may be of relevance in MC pathogenesis and warrants further investigation.
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Günaltay S, Rademacher L, Hultgren Hörnquist E, Bohr J. Clinical and immunologic effects of faecal microbiota transplantation in a patient with collagenous colitis. World J Gastroenterol 2017; 23:1319-1324. [PMID: 28275312 PMCID: PMC5323457 DOI: 10.3748/wjg.v23.i7.1319] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Revised: 11/20/2016] [Accepted: 01/02/2017] [Indexed: 02/06/2023] Open
Abstract
One to six percent of patients with microscopic colitis are refractory to medical treatment. The effect of faecal microbiota transplantation (FMT) in active collagenous colitis (CC) has, to the best of our knowledge, never been reported before. Here, we report the effect of repeated FMT in a patient with CC. The patient presented with severe symptoms including profuse diarrhea and profound weight loss. Although she responded to budesonide in the beginning, she became gradually refractory to medical treatment, and was therefore treated with FMT. The patient remained in remission for 11 mo after the third faecal transplantation. The immunomodulatory effect of the therapy was evaluated using flow cytometry, which showed alterations in the profile of intraepithelial and lamina propria lymphocyte subsets after the second transplantation. Our observations indicate that FMT can have an effect in CC, which support the hypothesis that luminal factors, influencing the intestinal microbiota, are involved in the pathogenesis of CC.
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Pisani LF, Tontini GE, Marinoni B, Villanacci V, Bruni B, Vecchi M, Pastorelli L. Biomarkers and Microscopic Colitis: An Unmet Need in Clinical Practice. Front Med (Lausanne) 2017; 4:54. [PMID: 28540290 PMCID: PMC5423903 DOI: 10.3389/fmed.2017.00054] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2017] [Accepted: 04/21/2017] [Indexed: 12/19/2022] Open
Abstract
One of the most common causes of chronic diarrhea is ascribed to microscopic colitis (MC). MC is classified in subtypes: collagenous colitis (CC) and lymphocytic colitis (LC). Patients with MC report watery, non-bloody diarrhea of chronic course, abdominal pain, weight loss, and fatigue that may impair patient's health-related quality of life. A greater awareness, and concomitantly an increasing number of diagnoses over the last years, has demonstrated that the incidence and prevalence of MC are on the rise. To date, colonoscopy with histological analysis on multiple biopsies collected along the colon represents the unique accepted procedure used to assess the diagnosis of active MC and to evaluate the response to medical therapy. Therefore, the emerging need for less-invasive procedures that are also rapid, convenient, standardized, and reproducible, has encouraged scientists to turn their attention to the identification of inflammatory markers and other molecules in blood or feces and within the colonic tissue that can confirm a MC diagnosis. This review gives an update on the biomarkers that are potentially available for the identification of inflammatory activity, related to CC and LC.
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Affiliation(s)
- Laura Francesca Pisani
- Gastroenterology and Digestive Endoscopy Unit, IRCCS Policlinico San Donato, San Donato Milanese, Italy
| | - Gian Eugenio Tontini
- Gastroenterology and Digestive Endoscopy Unit, IRCCS Policlinico San Donato, San Donato Milanese, Italy
| | - Beatrice Marinoni
- Gastroenterology and Digestive Endoscopy Unit, IRCCS Policlinico San Donato, San Donato Milanese, Italy
| | | | - Barbara Bruni
- Pathology and Cytodiagnostic Unit, IRCCS Policlinico San Donato, San Donato Milanese, Italy
| | - Maurizio Vecchi
- Gastroenterology and Digestive Endoscopy Unit, IRCCS Policlinico San Donato, San Donato Milanese, Italy
- Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
| | - Luca Pastorelli
- Gastroenterology and Digestive Endoscopy Unit, IRCCS Policlinico San Donato, San Donato Milanese, Italy
- Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
- *Correspondence: Luca Pastorelli,
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Diagnosis and treatment of microscopic colitis. Clin J Gastroenterol 2016; 9:169-74. [DOI: 10.1007/s12328-016-0656-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2016] [Accepted: 05/20/2016] [Indexed: 02/07/2023]
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