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Becker MAJ, Stevens TW, de Voogd FAE, Wildenberg ME, D’Haens GRAM, Gecse KB, Buskens CJ. Clinical relevance of calprotectin in patients with perianal fistulas in Crohn's disease and cryptoglandular fistulas. United European Gastroenterol J 2025; 13:295-304. [PMID: 39680482 PMCID: PMC11999044 DOI: 10.1002/ueg2.12622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Accepted: 05/31/2024] [Indexed: 12/18/2024] Open
Abstract
BACKGROUND AND AIMS Previous literature suggests that faecal calprotectin (FC) discriminates Crohn's disease perianal fistulas from cryptoglandular fistulas, irrespective of luminal disease. This study aims to prospectively validate this and analyse if increased local fistula calprotectin levels are associated with fistula characteristics. METHODS In this prospective study, all consecutive patients with an active perianal fistula undergoing examination under anaesthesia were included. Faecal and fistula tract scraping calprotectin levels were determined. The primary objective was to analyse whether FC levels could be used to differentiate between Crohn's disease and cryptoglandular perianal fistulas. Secondary outcome parameters were the levels of local calprotectin in fistula scrapings and their correlation with fistula characteristics. RESULTS Sixty-three patients were included in this study (perianal Crohn's disease; 45, cryptoglandular; 18). Faecal calprotectin levels were significantly higher in Crohn's disease patients compared with cryptoglandular fistula (354.3 [58.8-1076.3] vs. 47.3 [14.6-233.6] μg/g, p = 0.003). Faecal calprotectin could accurately discriminate Crohn's disease patients with active luminal disease from patients without luminal disease (median [interquartile range]) (1167.0 [557.0-2806.3] vs. 93.0 [47.5-571.6] μg/g, p = 0.001). Faecal calprotectin was not related to calprotectin levels in fistula scrapings. No fistula characteristic was found to be correlated to scraping calprotectin, but a correlation was found with the TOpCLASS classification system, which stratifies fistulas according to disease severity and outcome: class 2a (amenable for repair), class 2b (symptom control) and class 2c (gradually debilitating disease): 140[31.0-149.0]) μg/g versus 706[198.5-1936] μg/g versus 4000[1337-5894] μg/g, p < 0.001). Scraping calprotectin was also related to pronounced hyperintensity of the fistula tract on MRI in Crohn's disease patients: (69.0[30.0-821.0] vs. 1284.0[204.3-4185.5]; p = 0.01)) and cryptoglandular patients: (30.0[13.5-80.5] vs. 3012.0 [923.8-5021.0]; p = 0.002). CONCLUSION Crohn's disease and cryptoglandular perianal fistulas differ in FC levels. Local fistula calprotectin production did not explain this difference, implying FC reflects the luminal condition. A correlation exists between scraping calprotectin levels and Crohn's disease fistula severity, which could be clinically relevant for prognostic cohorts and tailored treatment.
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Affiliation(s)
- Marte A. J. Becker
- Tytgat Institute for Liver and Intestinal ResearchAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
| | - Toer W. Stevens
- Department of Gastroenterology and HepatologyAmsterdam UMCLocation AMCAmsterdamThe Netherlands
| | - Floris A. E. de Voogd
- Department of Gastroenterology and HepatologyAmsterdam UMCLocation AMCAmsterdamThe Netherlands
| | - Manon E. Wildenberg
- Tytgat Institute for Liver and Intestinal ResearchAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands
| | - Geert R. A. M. D’Haens
- Department of Gastroenterology and HepatologyAmsterdam UMCLocation AMCAmsterdamThe Netherlands
| | - Krisztina B. Gecse
- Department of Gastroenterology and HepatologyAmsterdam UMCLocation AMCAmsterdamThe Netherlands
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Li L, Yao Z, Salimian KJ, Kong J, Zaheer A, Parian A, Gearhart SL, Mao HQ, Selaru FM. Extracellular Vesicles Delivered by a Nanofiber-Hydrogel Composite Enhance Healing In Vivo in a Model of Crohn's Disease Perianal Fistula. Adv Healthc Mater 2025; 14:e2402292. [PMID: 39240055 PMCID: PMC11882933 DOI: 10.1002/adhm.202402292] [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: 06/22/2024] [Revised: 08/24/2024] [Indexed: 09/07/2024]
Abstract
Perianal fistulas represent a common, aggressive, and disabling complication of Crohn's disease (CD). Despite recent drug developments, novel surgical interventions as well as multidisciplinary treatment approaches, the outcome is dismal, with >50% therapy failure rates. Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) offer potential therapeutic benefits for treating fistulizing CD, due to the pro-regenerative paracrine signals. However, a significant obstacle to clinical translation of EV-based therapy is the rapid clearance and short half-life of EVs in vivo. Here, an injectable, biodegradable nanofiber-hydrogel composite (NHC) microgel matrix that serves as a carrier to deliver MSC-derived EVs to a rat model of CD perianal fistula (PAF) is reported. It is found that EV-loaded NHC (EV-NHC) yields the best fistula healing when compared to other treatment arms. The MRI assessment reveals that the EV-NHC reduces inflammation at the fistula site and promotes tissue healing. The enhanced therapeutic outcomes are contributed by extended local retention and sustained release of EVs by NHC. In addition, the EV-NHC effectively reduces inflammation at the fistula site and promotes tissue healing and regeneration via macrophage polarization and neo-vascularization. This EV-NHC platform provides an off-the-shelf solution that facilitates its clinical translation.
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Affiliation(s)
- Ling Li
- Division of Gastroenterology and Hepatology, School of Medicine, Johns Hopkins University; Baltimore, Maryland, USA
| | - Zhicheng Yao
- Institute for NanoBioTechnology, Johns Hopkins University; Baltimore, Maryland, USA
- Department of Materials Science and Engineering, Whiting School of Engineering, Johns Hopkins University; Baltimore, Maryland, USA
- Translational Tissue Engineering Center, Johns Hopkins University School of Medicine; Baltimore, Maryland, USA
| | - Kevan J. Salimian
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jiayuan Kong
- Institute for NanoBioTechnology, Johns Hopkins University; Baltimore, Maryland, USA
- Department of Materials Science and Engineering, Whiting School of Engineering, Johns Hopkins University; Baltimore, Maryland, USA
- Translational Tissue Engineering Center, Johns Hopkins University School of Medicine; Baltimore, Maryland, USA
| | - Atif Zaheer
- Department of Radiology & Radiological Sciences, School of Medicine, Johns Hopkins University; Baltimore, Maryland, USA
| | - Alyssa Parian
- Division of Gastroenterology and Hepatology, School of Medicine, Johns Hopkins University; Baltimore, Maryland, USA
| | - Susan L. Gearhart
- Division of Colorectal Surgery, Department of Surgery, Johns Hopkins University School of Medicine; Baltimore, Maryland, USA
| | - Hai-Quan Mao
- Institute for NanoBioTechnology, Johns Hopkins University; Baltimore, Maryland, USA
- Department of Materials Science and Engineering, Whiting School of Engineering, Johns Hopkins University; Baltimore, Maryland, USA
- Translational Tissue Engineering Center, Johns Hopkins University School of Medicine; Baltimore, Maryland, USA
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine; Baltimore, Maryland, USA
| | - Florin M. Selaru
- Division of Gastroenterology and Hepatology, School of Medicine, Johns Hopkins University; Baltimore, Maryland, USA
- Institute for NanoBioTechnology, Johns Hopkins University; Baltimore, Maryland, USA
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine; Baltimore, Maryland, USA
- Department of Oncology, Sidney Kimmel Cancer Center, School of Medicine, Johns Hopkins University; Baltimore, Maryland, USA
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McCurdy JD, Hartley I, Behrenbruch C, Hart A, Tozer P, Ding NS. Management of Perianal Fistulizing Crohn's Disease According to Principles of Wound Repair. Aliment Pharmacol Ther 2025; 61:600-613. [PMID: 39757535 DOI: 10.1111/apt.18466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 11/14/2024] [Accepted: 12/16/2024] [Indexed: 01/07/2025]
Abstract
BACKGROUND Perianal fistulizing Crohn's disease (PFCD) is a challenging and debilitating phenotype of Crohn's disease that can negatively affect quality of life. Studies have begun to uncover the physiologic mechanisms involved in wound repair as it relates to PFCD and how aberrations in these mechanisms may contribute to fistula persistence. AIMS To review the physiologic and pathophysiologic mechanisms of wound repair in PFCD and how specific therapeutic strategies may impact their outcomes. METHODS We reviewed the latest published literature on wound repair as it relates to PFCD. RESULTS Wound repair can be categorised into three overlapping biological phases: localised inflammation, cell recruitment/proliferation and tissue remodelling. Each is tightly regulated since insufficient or excessive activation can result in, respectively, chronic wounds and fibrotic tissue, both of which can impair organ function. In PFCD, the outcomes of wound repair include restitution (complete healing), epithelialisation and chronic wounds. Treatment of PFCD should take into consideration the distinct phases of wound repair. Therefore, the ability to differentiate between each phase of wound repair and their outcomes may help physicians deliver the most effective treatment strategy at the most appropriate time. CONCLUSIONS This review provides a comprehensive overview of the phases of wound repair and specific treatment strategies for each to provide clinicians with a rational framework for managing PFCD.
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Affiliation(s)
- Jeffrey D McCurdy
- Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, Ontario, Canada
| | - Imogen Hartley
- Department of Gastroenterology, St Vincent's Hospital Melbourne, Fitzroy, Victoria, Australia
- The University of Melbourne, St Vincent's Hospital Melbourne, Fitzroy, Victoria, Australia
| | - Corina Behrenbruch
- Department of Gastroenterology, St Vincent's Hospital Melbourne, Fitzroy, Victoria, Australia
- The University of Melbourne, St Vincent's Hospital Melbourne, Fitzroy, Victoria, Australia
| | | | | | - Nik S Ding
- Department of Gastroenterology, St Vincent's Hospital Melbourne, Fitzroy, Victoria, Australia
- The University of Melbourne, St Vincent's Hospital Melbourne, Fitzroy, Victoria, Australia
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Tavares de Sousa H, Ferreira M, Gullo I, Rocha AM, Pedro A, Leitão D, Oliveira C, Carneiro F, Magro F. Fibrosis-related Transcriptome Unveils a Distinctive Remodelling Matrix Pattern in Penetrating Ileal Crohn's Disease. J Crohns Colitis 2024; 18:1741-1752. [PMID: 38700484 DOI: 10.1093/ecco-jcc/jjae064] [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: 12/30/2023] [Revised: 04/02/2024] [Accepted: 05/01/2024] [Indexed: 05/05/2024]
Abstract
BACKGROUND AND AIMS Stricturing [B2] and penetrating [B3] ileal Crohn's disease have been reported to present similar levels of histopathological transmural fibrosis. This study aimed to compare the fibrosis-related transcriptomic profiles of penetrating and stricturing ileal Crohn's disease. METHODS Using Nanostring technology and comparative bioinformatics, we analysed the expression of 787 fibrosis-related genes in 36 ileal surgical specimens, 12 B2 and 24 B3, the latter including 12 cases with associated stricture[s] [B3s] and 12 without [B3o]. Quality control of extracted RNA was performed according to Nanostring parameters and principal component analysis for the distribution analysis. For the selection of the differentially expressed genes, a p-adjusted <0.05 and fold change ≤-1.5 or ≥1.5 were adopted. Quantitative polymerase chain reaction (qPCR) and immunohistochemistry analyses were used to validate selected differentially expressed genes. RESULTS We included 34 patients with B2 and B3 phenotypes, balanced for age at diagnosis, age at surgery, gender, Crohn's disease localisation, perianal disease, and therapy. Inflammation and fibrosis histopathological scoring were similar in all cases. B2 and B3 groups showed a very good clustering regarding 30 significantly differentially expressed genes, all being remarkably upregulated in B3. More than half of these genes were involved in Crohn's disease fibrogenesis, and eight differentially expressed genes were so in other organs. The most significantly active biological processes and pathways in penetrating disease were response to TGFβ and matrix organisation and degradation, as validated by immunohistochemistry. CONCLUSIONS Despite the histopathological similarities in fibrosis between stricturing and penetrating ileal Crohn's disease, their fibrosis-related transcriptomic profiles are distinct. Penetrating disease exhibits a distinctive transcriptomic landscape related to enhanced matrix remodelling.
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Affiliation(s)
- Helena Tavares de Sousa
- Gastroenterology Department, Algarve University Hospital Center [CHUA], Portimão, Portugal
- ABC-Algarve Biomedical Center, University of Algarve, Faro, Portugal
| | - Marta Ferreira
- Computer Science Department, Faculty of Sciences, University of Porto, Porto, Portugal
- Institute of Molecular Pathology and Immunology, University of Porto [IPATIMUP], Porto, Portugal
- Instituto de Investigação e Inovação em Saúde [i3S], University of Porto, Porto, Portugal
| | - Irene Gullo
- Institute of Molecular Pathology and Immunology, University of Porto [IPATIMUP], Porto, Portugal
- Instituto de Investigação e Inovação em Saúde [i3S], University of Porto, Porto, Portugal
- Department of Pathology, Centro Hospitalar de São João, Porto, Portugal
- Department of Pathology, Faculty of Medicine of the University of Porto [FMUP], Porto, Portugal
| | - Ana Mafalda Rocha
- Institute of Molecular Pathology and Immunology, University of Porto [IPATIMUP], Porto, Portugal
- Instituto de Investigação e Inovação em Saúde [i3S], University of Porto, Porto, Portugal
| | - Ana Pedro
- Instituto de Investigação e Inovação em Saúde [i3S], University of Porto, Porto, Portugal
| | - Dina Leitão
- Department of Pathology, Faculty of Medicine of the University of Porto [FMUP], Porto, Portugal
| | - Carla Oliveira
- Institute of Molecular Pathology and Immunology, University of Porto [IPATIMUP], Porto, Portugal
- Instituto de Investigação e Inovação em Saúde [i3S], University of Porto, Porto, Portugal
- Department of Pathology, Centro Hospitalar de São João, Porto, Portugal
| | - Fátima Carneiro
- Institute of Molecular Pathology and Immunology, University of Porto [IPATIMUP], Porto, Portugal
- Instituto de Investigação e Inovação em Saúde [i3S], University of Porto, Porto, Portugal
- Department of Pathology, Centro Hospitalar de São João, Porto, Portugal
- Department of Pathology, Faculty of Medicine of the University of Porto [FMUP], Porto, Portugal
| | - Fernando Magro
- Unit of Pharmacology and Therapeutics, Department of Biomedicine, Faculty of Medicine of the University of Porto [FMUP], Portugal
- Department of Gastroenterology, São João University Hospital Center, Porto, Portugal
- CINTESIS@RISE, Faculty of Medicine, University of Porto, Porto, Portugal
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Singh A, Midha V, Kochhar GS, Shen B, Sood A. Management of Perianal Fistulizing Crohn's Disease. Inflamm Bowel Dis 2024; 30:1579-1603. [PMID: 37672347 DOI: 10.1093/ibd/izad195] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Indexed: 09/08/2023]
Abstract
Perianal fistulizing Crohn's disease (CD) represents a severe phenotype of CD that is associated with significant morbidity and reduction in quality of life. Perianal fistulizing CD is caused by a complex interplay of genetic predisposition, immune dysregulation, gut dysbiosis, and various unknown physiological and mechanical factors. A multidisciplinary approach is hence required for optimal management . A detailed anatomical description and classification of perianal fistula, including comprehensive clinical, endoscopic, and radiological diagnostic workup, is an important prerequisite to treatment. For simple perianal fistulas, use of antibiotics and immunomodulators, with or without fistulotomy, are appropriate measures. The medical management of complex perianal fistula, on the other hand, requires adequate control of infection before initiation of therapy with immunomodulators. In active complex perianal fistula, anti-tumor necrosis factors remain the most accepted therapy, with concomitant use of antibiotics or immunomodulators enhancing the efficacy. For patients refractory to anti-tumor necrosis factors, treatment with anti-integrins, anti-interleukins, and small molecules is being evaluated. Mesenchymal stem cells, hyperbaric oxygen therapy, and exclusive enteral nutrition have also been investigated as adjunct therapies. Despite the expansion of the medical armamentarium, a large proportion of the patients require surgical interventions. In this review, we provide an up-to-date overview of the pathophysiology, clinical presentation, diagnosis, and medical management of perianal fistulizing CD. A brief overview of the surgical management of perianal fistulizing CD is also provided.
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Affiliation(s)
- Arshdeep Singh
- Department of Gastroenterology, Dayanand Medical College, Ludhiana, India
| | - Vandana Midha
- Department of Internal Medicine, Dayanand Medical College, Ludhiana, India
| | - Gursimran Singh Kochhar
- Division of Gastroenterology, Hepatology and Nutrition, Allegheny Health Network, Pittsburgh, PA, USA
| | - Bo Shen
- Center for Interventional Inflammatory Bowel Disease, NewYork-Presbyterian Hospital, Columbia University Irving Medical Center, New York, NY, USA
| | - Ajit Sood
- Department of Gastroenterology, Dayanand Medical College, Ludhiana, India
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Lehmann M, Weixler B, Elezkurtaj S, Loddenkemper C, Kühl AA, Siegmund B. Spatial Single Cell Profiling Using Imaging Mass Cytometry: Inflammatory Versus Penetrating Crohn's Disease. J Crohns Colitis 2024; 18:1305-1318. [PMID: 38465390 DOI: 10.1093/ecco-jcc/jjae033] [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: 01/05/2024] [Revised: 02/14/2024] [Accepted: 03/07/2024] [Indexed: 03/12/2024]
Abstract
BACKGROUND AND AIMS Fistula formation is a major complication in Crohn's disease [CD] and the role of the immune cell compartment remains to be elucidated. Thus, we compared the immune cell compartment of CD fistula to inflammatory CD colitis using imaging mass cytometry [IMC] and immunofluorescence. METHODS A 36-marker panel including structural, functional, and lineage markers for use in IMC was established. This panel was applied to analyse paraffin-embedded CD fistula tract [n = 11], CD colitis [n = 10], and colon samples from non-inflamed controls [n = 12]. Computational methods for cell segmentation, dimensionality reduction, and cell type clustering were used to define cell populations for cell frequency, marker distribution, and spatial neighbourhood analysis. Multiplex immunofluorescence was used for higher resolution spatial analysis. RESULTS Analysis of cell frequencies in CD fistulas compared to CD colitis and control colonic samples revealed a significant increase in neutrophils, effector cytotoxic T cells, and inflammatory macrophages in CD fistula samples, whereas regulatory T cells were decreased. Neutrophils in CD fistula expressed significantly more matrix metalloproteinase 9 [MMP9], correlating with extracellular matrix remodelling. Neighbourhood analysis revealed a strong association between MMP9+ neutrophils and effector cytotoxic T cells in both CD fistulas and colitis. CONCLUSIONS This study presents the first highly multiplexed single cell analysis of the immune cell compartment of CD fistulas and their spatial context. It links immune cell dynamics, particularly MMP9+ neutrophils, to extracellular matrix remodelling in CD fistulas, offering insights into the complex network of cellular interactions and potential therapeutic targets for CD complications.
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Affiliation(s)
- Malte Lehmann
- Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Germany
| | - Benjamin Weixler
- Department of General and Visceral Surgery, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Sefer Elezkurtaj
- Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Christopher Loddenkemper
- PathoTres, Gemeinschaftspraxis für Pathologie und Neuropathologie, Teltowkanalstr. 2, 12247, Berlin, Germany
| | - Anja A Kühl
- iPATH.Berlin, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Britta Siegmund
- Department of Gastroenterology, Infectious Diseases and Rheumatology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Germany
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Levantovsky RM, Tastad C, Zhang J, Gettler K, Sabic K, Werner R, Chasteau C, Korie U, Paguay D, Bao M, Han H, Maskey N, Talware S, Patel M, Argmann C, Suarez-Farinas M, Harpaz N, Chuang LS, Cho JH. Multimodal single-cell analyses reveal mechanisms of perianal fistula in diverse patients with Crohn's disease. MED 2024; 5:886-908.e11. [PMID: 38663404 PMCID: PMC11317226 DOI: 10.1016/j.medj.2024.03.021] [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: 04/13/2023] [Revised: 12/08/2023] [Accepted: 03/28/2024] [Indexed: 08/12/2024]
Abstract
BACKGROUND Crohn's disease complicated by perianal fistulae is more prevalent and severe in patients of African ancestry. METHODS We profiled single cells from diverse patients with Crohn's disease with perianal fistula from colorectal mucosa and fistulous tracts. Immunofluorescence was performed to validate predicted cell-cell interactions. Unstimulated monocytes were chronically cultured in diverse cohorts. A subset was analyzed by single-nucleus RNA + ATAC sequencing. FINDINGS Fistulous tract cells from complete proctectomies demonstrated enrichment of myeloid cells compared to paired rectal tissues. Ligand-receptor analysis highlights myeloid-stromal cross-talk and cellular senescence, with cellular co-localization validated by immunofluorescence. Chitinase-3 like-protein-1 (CHI3L1) is a top upregulated gene in stromal cells from fistulae expressing both destructive and fibrotic gene signatures. Monocyte cultures from patients of African ancestry and controls demonstrated differences in CHI3L1 and oncostatin M (OSM) expression upon differentiation compared to individuals of European ancestry. Activating protein-1 footprints are present in ATAC-seq peaks in stress response genes, including CHI3L1 and OSM; genome-wide chromatin accessibility including JUN footprints was observed, consistent with reported mechanisms of inflammatory memory. Regulon analyses confirm known cell-specific transcription factor regulation and implicate novel ones in fibroblast subsets. All pseudo-bulked clusters demonstrate enrichment of genetic loci, establishing multicellular contributions. In the most significant African American Crohn's genetic locus, upstream of prostaglandin E receptor 4, lymphoid-predominant ATAC-seq peaks were observed, with predicted RORC footprints. CONCLUSIONS Population differences in myeloid-stromal cross-talk implicate fibrotic and destructive fibroblasts, senescence, epigenetic memory, and cell-specific enhancers in perianal fistula pathogenesis. The transcriptomic and epigenetic data provided here may guide optimization of promising mesenchymal stem cell therapies for perianal fistula. FUNDING This work was supported by grants U01DK062422, U24DK062429, and R01DK123758.
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Affiliation(s)
- Rachel M Levantovsky
- Department of Pathology, Molecular, and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Christopher Tastad
- Department of Pathology, Molecular, and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Jiayu Zhang
- Department of Pathology, Molecular, and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Kyle Gettler
- Department of Pathology, Molecular, and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Ksenija Sabic
- Department of Pathology, Molecular, and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Robert Werner
- Department of Pathology, Molecular, and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Colleen Chasteau
- Department of Pathology, Molecular, and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Ujunwa Korie
- Department of Pathology, Molecular, and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Diana Paguay
- Department of Pathology, Molecular, and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Michelle Bao
- Division of Pediatric Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Huajun Han
- Department of Pathology, Molecular, and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | | | - Sayali Talware
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Manishkumar Patel
- Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Carmen Argmann
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Mayte Suarez-Farinas
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Noam Harpaz
- Department of Pathology, Molecular, and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Ling-Shiang Chuang
- Department of Pathology, Molecular, and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Judy H Cho
- Department of Pathology, Molecular, and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
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Shehab M, De Marco D, Lakatos PL, Bessissow T. The potential for medical therapies to address fistulizing Crohn's disease: a state-of-the-art review. Expert Opin Biol Ther 2024; 24:733-746. [PMID: 39045643 DOI: 10.1080/14712598.2024.2383882] [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: 02/27/2024] [Revised: 06/25/2024] [Accepted: 07/20/2024] [Indexed: 07/25/2024]
Abstract
INTRODUCTION Crohn's disease (CD) is a chronic, relapsing immune mediated disease, which is one of the two major types of inflammatory bowel disease (IBD). Fistulizing CD poses a significant clinical challenge for physicians. Effective management of CD requires a multidisciplinary approach, involving a gastroenterologist and a GI surgeon while tailoring treatment to each patient's unique risk factors, clinical representations, and preferences. AREAS COVERED This comprehensive review explores the intricacies of fistulizing CD including its manifestations, types, impact on quality of life, management strategies, and novel therapies under investigation. EXPERT OPINION Antibiotics are often used as first-line therapy to treat symptoms. Biologics that selectively target TNF-α, such infliximab (IFX), have shown high efficacy in randomized controlled trials. However, more than 50% of patients lose response to IFX, prompting them to explore alternative strategies. Current options include adalimumab and certolizumab pegol combination therapies, as well as small-molecule drugs targeting Janus kinases such as Upadacitinib. Furthermore, a promising treatment for complex fistulas is mesenchymal stem cells such as Darvadstrocel (Alofisel), an allogeneic stem cell-based therapy. However, surgical interventions are necessary for complex cases or intra-abdominal complications. Setons and LIFT procedures are the most common surgical options.
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Affiliation(s)
- Mohammad Shehab
- Division of Gastroenterology, Department of Internal Medicine, Mubarak Al-Kabeer University Hospital, Kuwait University, Kuwait City, Kuwait
| | - Davide De Marco
- Division of Gastroenterology and Hepatology, Department of Medicine, McGill University Health Center, Montreal, Canada
| | - Peter L Lakatos
- Division of Gastroenterology and Hepatology, Department of Medicine, McGill University Health Center, Montreal, Canada
- 1st Department of Medicine, Semmelweis University, Budapest, Hungary
| | - Talat Bessissow
- Division of Gastroenterology and Hepatology, Department of Medicine, McGill University Health Center, Montreal, Canada
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Ciorba MA, Konnikova L, Hirota SA, Lucchetta EM, Turner JR, Slavin A, Johnson K, Condray CD, Hong S, Cressall BK, Pizarro TT, Hurtado-Lorenzo A, Heller CA, Moss AC, Swantek JL, Garrett WS. Challenges in IBD Research 2024: Preclinical Human IBD Mechanisms. Inflamm Bowel Dis 2024; 30:S5-S18. [PMID: 38778627 PMCID: PMC11491665 DOI: 10.1093/ibd/izae081] [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: 03/15/2024] [Indexed: 05/25/2024]
Abstract
Preclinical human inflammatory bowel disease (IBD) mechanisms is one of 5 focus areas of the Challenges in IBD Research 2024 document, which also includes environmental triggers, novel technologies, precision medicine, and pragmatic clinical research. Herein, we provide a comprehensive overview of current gaps in inflammatory bowel diseases research that relate to preclinical research and deliver actionable approaches to address them with a focus on how these gaps can lead to advancements in IBD interception, remission, and restoration. The document is the result of multidisciplinary input from scientists, clinicians, patients, and funders and represents a valuable resource for patient-centric research prioritization. This preclinical human IBD mechanisms section identifies major research gaps whose investigation will elucidate pathways and mechanisms that can be targeted to address unmet medical needs in IBD. Research gaps were identified in the following areas: genetics, risk alleles, and epigenetics; the microbiome; cell states and interactions; barrier function; IBD complications (specifically fibrosis and stricturing); and extraintestinal manifestations. To address these gaps, we share specific opportunities for investigation for basic and translational scientists and identify priority actions.
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Affiliation(s)
- Matthew A Ciorba
- Inflammatory Bowel Diseases Center, Division of Gastroenterology, Washington University in St. Louis, Saint Louis, MO, USA
| | - Liza Konnikova
- Departments of Pediatrics, Immunobiology, and Obstetric, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA
| | - Simon A Hirota
- Snyder Institute for Chronic Diseases, Dept. of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada
| | - Elena M Lucchetta
- The Leona M. and Harry B. Helmsley Charitable Trust, New York, NY, USA
| | - Jerrold R Turner
- Departments of Pathology and Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | | | | | - Cass D Condray
- Patient Representative for the Crohn’s & Colitis Foundation, New York, NY, USA
| | - Sungmo Hong
- Patient Representative for the Crohn’s & Colitis Foundation, New York, NY, USA
| | - Brandon K Cressall
- Patient Representative for the Crohn’s & Colitis Foundation, New York, NY, USA
| | - Theresa T Pizarro
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | | | - Caren A Heller
- Research Department, Crohn’s & Colitis Foundation, New York, NY, USA
| | - Alan C Moss
- Research Department, Crohn’s & Colitis Foundation, New York, NY, USA
| | | | - Wendy S Garrett
- Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA
- The Harvard T. H. Chan Microbiome in Public Health Center, Boston, MA, USA
- Kymera Therapeutics, Watertown, MA, USA
- The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
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Mobbs CL, Darling NJ, Przyborski S. An in vitro model to study immune activation, epithelial disruption and stromal remodelling in inflammatory bowel disease and fistulising Crohn's disease. Front Immunol 2024; 15:1357690. [PMID: 38410518 PMCID: PMC10894943 DOI: 10.3389/fimmu.2024.1357690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 01/22/2024] [Indexed: 02/28/2024] Open
Abstract
At present, preclinical models of inflammatory bowel disease (IBD) are insufficient, limiting translation between research and new therapeutics. This is especially true for fistulising Crohn's disease (CD), as the severe lack of relevant models hinders research progression. To address this, we present in vitro human IBD mucosal models that recapitulate multiple pathological hallmarks of IBD simultaneously in one model system - immune cell infiltration, stromal remodelling and epithelial disruption. Stimulation of models induces epithelial aberrations common in IBD tissue including altered morphology, microvilli abnormalities, claudin gene expression changes and increased permeability. Inflammatory biomarkers are also significantly increased including cytokines and chemokines integral to IBD pathogenesis. Evidence of extracellular matrix remodelling, including upregulated matrix-metalloproteinases and altered basement membrane components, suggests the models simulate pathological stromal remodelling events that closely resemble fistulising CD. Importantly, MMP-9 is the most abundant MMP and mimics the unique localisation observed in IBD tissue. The inflamed models were subsequently used to elucidate the involvement of TNF-α and IFN- γ in intestinal stromal remodelling, in which TNF-α but not IFN- γ induced MMP upregulation, specifically of MMP-3 and MMP-9. Collectively, our results demonstrate the potential of the IBD models for use in preclinical research in IBD, particularly for fistulising CD.
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Affiliation(s)
- Claire L. Mobbs
- Department of Biosciences, Durham University, Durham, United Kingdom
- Reprocell Europe Ltd, West of Scotland Science Park, Glasgow, United Kingdom
| | - Nicole J. Darling
- Department of Biosciences, Durham University, Durham, United Kingdom
| | - Stefan Przyborski
- Department of Biosciences, Durham University, Durham, United Kingdom
- Reprocell Europe Ltd, West of Scotland Science Park, Glasgow, United Kingdom
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11
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Shen X, Mo S, Zeng X, Wang Y, Lin L, Weng M, Sugasawa T, Wang L, Gu W, Nakajima T. Identification of antigen-presentation related B cells as a key player in Crohn's disease using single-cell dissecting, hdWGCNA, and deep learning. Clin Exp Med 2023; 23:5255-5267. [PMID: 37550553 DOI: 10.1007/s10238-023-01145-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Accepted: 07/12/2023] [Indexed: 08/09/2023]
Abstract
Crohn's disease (CD) arises from intricate intercellular interactions within the intestinal lamina propria. Our objective was to use single-cell RNA sequencing to investigate CD pathogenesis and explore its clinical significance. We identified a distinct subset of B cells, highly infiltrated in the CD lamina propria, that expressed genes related to antigen presentation. Using high-dimensional weighted gene co-expression network analysis and nine machine learning techniques, we demonstrated that the antigen-presenting CD-specific B cell signature effectively differentiated diseased mucosa from normal mucosa (Independent external testing AUC = 0.963). Additionally, using MCPcounter and non-negative matrix factorization, we established a relationship between the antigen-presenting CD-specific B cell signature and immune cell infiltration and patient heterogeneity. Finally, we developed a gene-immune convolutional neural network deep learning model that accurately diagnosed CD mucosa in diverse cohorts (Independent external testing AUC = 0.963). Our research has revealed a population of B cells with a potential promoting role in CD pathogenesis and represents a fundamental step in the development of future clinical diagnostic tools for the disease.
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Affiliation(s)
- Xin Shen
- Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Shaocong Mo
- Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China.
| | - Xinlei Zeng
- School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China
| | - Yulin Wang
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Lingxi Lin
- Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Meilin Weng
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Takehito Sugasawa
- Laboratory of Clinical Examination and Sports Medicine, Department of Clinical Medicine, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8577, Japan
| | - Lei Wang
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College of Fudan University, Shanghai, China
| | - Wenchao Gu
- Department of Diagnostic and Interventional Radiology, University of Tsukuba, Ibaraki, 305-8577, Japan.
- Department of Diagnostic Radiology and Nuclear Medicine, Gunma University Graduate School of Medicine, Maebashi, 371-8511, Japan.
| | - Takahito Nakajima
- Department of Diagnostic and Interventional Radiology, University of Tsukuba, Ibaraki, 305-8577, Japan
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Anandabaskaran S, Hanna L, Iqbal N, Constable L, Tozer P, Hart A. Where Are We and Where to Next?-The Future of Perianal Crohn's Disease Management. J Clin Med 2023; 12:6379. [PMID: 37835022 PMCID: PMC10573672 DOI: 10.3390/jcm12196379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Revised: 09/26/2023] [Accepted: 09/27/2023] [Indexed: 10/15/2023] Open
Abstract
Perianal fistulizing Crohn's Disease (pCD) affects about 25% of patients with Crohn's Disease (CD). It remains a difficult entity to manage with a therapeutic ceiling of treatment success despite improving medical and surgical management. The refractory nature of the disease calls for an imminent need to better understand its immunopathogenesis and classification to better streamline our treatment options. In this article, we overview the current state of pCD management and discuss where the future of its management may lie.
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Affiliation(s)
- Sulak Anandabaskaran
- Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Hammersmith Campus, Imperial College London, London W12 0NN, UK
- Robin Phillip’s Fistula Research Unit, St Mark’s Hospital and Academic Institute, London HA1 3UJ, UK
- Faculty of Medicine, St Vincent’s Clinical School, University of New South Wales, 390 Victoria Street, Darlinghurst, NSW 2010, Australia
| | - Luke Hanna
- Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Hammersmith Campus, Imperial College London, London W12 0NN, UK
- Robin Phillip’s Fistula Research Unit, St Mark’s Hospital and Academic Institute, London HA1 3UJ, UK
| | - Nusrat Iqbal
- Robin Phillip’s Fistula Research Unit, St Mark’s Hospital and Academic Institute, London HA1 3UJ, UK
- Department of Surgery and Cancer, South Kensington Campus, Imperial College London, London SW7 2BX, UK
| | - Laura Constable
- Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Hammersmith Campus, Imperial College London, London W12 0NN, UK
| | - Phil Tozer
- Robin Phillip’s Fistula Research Unit, St Mark’s Hospital and Academic Institute, London HA1 3UJ, UK
- Department of Surgery and Cancer, South Kensington Campus, Imperial College London, London SW7 2BX, UK
| | - Ailsa Hart
- Robin Phillip’s Fistula Research Unit, St Mark’s Hospital and Academic Institute, London HA1 3UJ, UK
- Department of Surgery and Cancer, South Kensington Campus, Imperial College London, London SW7 2BX, UK
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Parian AM, Li L, Duraes LC, Cheng J, Hu H, Yao Z, Donet J, Salem G, Iuga A, Salimian K, Izzi J, Zaheer A, Mao HQ, Gearhart S, Selaru FM. A Novel Patient-like Swine Model of Perianal Crohn's Disease. Dis Colon Rectum 2023; 66:425-433. [PMID: 35499985 DOI: 10.1097/dcr.0000000000002369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Perianal Crohn's disease is associated with poor outcomes and high medical costs. It is notoriously difficult to treat despite therapeutic advancements for luminal disease. A large animal model that mimics human perianal disease is needed to test innovative therapies. OBJECTIVE This study aimed to create a swine model that replicates the inflammatory component and therapeutic challenges found in patients with perianal Crohn's disease. DESIGN This was an animal preclinical study. SETTINGS The experiments were performed at the animal laboratory at the Johns Hopkins University. PATIENTS Four sus scrufus female pigs were included in the study. INTERVENTIONS Four female pigs underwent creation of 3 surgical perianal fistulas each, 1 rectovaginal and 2 perianal. Size 24 French setons were placed to maintain patency of the fistula tracts for 4 weeks. After removal of the setons, trinitrobenzene sulfonic acid was administered into the fistula tract to create and maintain local inflammation mimicking perianal Crohn's disease. MAIN OUTCOMES MEASURES An MRI was obtained to assess the fistulas and the pigs were euthanized to review histopathology. RESULTS Three inflammatory chronic fistula tracts were successfully created in each pig as confirmed by MRI and examination under anesthesia. This is the first report of maintaining patent fistulas in swine 2 weeks after removal of setons. For the first time, we reported that 2 pigs developed branching fistulas and small abscesses reminiscent of human perianal Crohn's disease. The corresponding histopathologic examination found significant chronic active inflammation on standard hematoxylin and eosin staining. LIMITATIONS The fistulas were surgically induced and did not occur naturally. CONCLUSIONS A chronic perianal fistula model in pigs that strongly resembles human perianal Crohn's disease was successfully created. This model can be used to test novel therapeutics and techniques to pave the path for human trials. See Video Abstract at http://links.lww.com/DCR/B969 . UN NUEVO MODELO PORCINO SIMILAR A UN PACIENTE DE LA ENFERMEDAD DE CROHN PERIANAL ANTECEDENTES La enfermedad de Crohn perianal se asocia con malos resultados y altos costos médicos. Es notoriamente difícil de tratar a pesar de los avances terapéuticos para la enfermedad luminal. Se precisa de un modelo animal grande que imite la enfermedad perianal humana para probar terapias innovadoras.OBJETIVO:Nuestro objetivo de este estudio fue crear un modelo porcino que replique el componente inflamatorio y los desafíos terapéuticos que se encuentran en los pacientes con enfermedad de Crohn perianal.DISEÑO:Este fue un estudio preclínico en animales.AJUSTES:Los experimentos se realizaron en el laboratorio de animales de la Universidad Johns Hopkins.PACIENTES:Se incluyeron en el estudio cuatro cerdas sus scrofa.INTERVENCIONES:Cuatro cerdas fueron sometidas a la creación de 3 fístulas perianales quirúrgicas cada una: 1 recto vaginal y 2 perianales. Se colocaron sedales de 24 French para mantener la permeabilidad de los trayectos fistulosos durante 4 semanas. Tras el retiro de los sedales, se administró ácido trinitrobenceno sulfónico en el trayecto de la fístula para crear y mantener la inflamación local simulando la enfermedad de Crohn perianal.PRINCIPALES MEDIDAS DE RESULTADOS:Se obtuvo una resonancia magnética para evaluar las fístulas y los cerdos fueron sacrificados para revisar la histopatología.RESULTADOS:Se crearon de manera exitosa tres trayectos fistulosos inflamatorios crónicos en cada cerdo, confirmados por imágenes de resonancia magnética y examen bajo anestesia. Este es el primer informe de preservación de fístulas permeables en cerdos 2 semanas tras el retiro de los setones. Por primera vez, informamos que dos cerdos desarrollaron fístulas ramificadas y pequeños abscesos que recuerdan a la enfermedad de Crohn perianal humana. El examen histopatológico correspondiente encontró una significativa inflamación crónica activa en la tinción estándar de hematoxilina y eosina.LIMITACIONES:Las fístulas se indujeron quirúrgicamente y no se produjeron de forma natural.CONCLUSIONES:Se logro recrear con éxito un modelo de fístula perianal crónica en cerdos que se asemeja mucho a la enfermedad de Crohn perianal humana. Este modelo se puede utilizar para probar nuevas terapias y técnicas para allanar el camino para los ensayos en humanos. Consulte Video Resumen en http://links.lww.com/DCR/B969 . (Traducción-Dr Osvaldo Gauto).
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Affiliation(s)
- Alyssa M Parian
- Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, Maryland
| | - Ling Li
- Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, Maryland
| | | | - Jiafei Cheng
- Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, Maryland
| | - Haijie Hu
- Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, Maryland
| | - Zhicheng Yao
- Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland
| | - Jean Donet
- Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, Maryland
| | - George Salem
- Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, Maryland
| | - Alina Iuga
- Division of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina
| | - Kevan Salimian
- Division of Pathology, Johns Hopkins University, Baltimore, Maryland
| | - Jessica Izzi
- Cooperative Animal Medicine, Johns Hopkins, Baltimore, Maryland
| | - Atif Zaheer
- Department of Radiology, Johns Hopkins University, Baltimore, Maryland
| | - Hai-Quan Mao
- Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland
| | - Susan Gearhart
- Division of Surgery, Johns Hopkins University, Baltimore, Maryland
| | - Florin M Selaru
- Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, Maryland
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14
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Li L, Yao ZC, Parian A, Yang YH, Chao J, Yin J, Salimian KJ, Reddy SK, Zaheer A, Gearhart SL, Mao HQ, Selaru FM. A nanofiber-hydrogel composite improves tissue repair in a rat model of Crohn's disease perianal fistulas. SCIENCE ADVANCES 2023; 9:eade1067. [PMID: 36598982 PMCID: PMC9812382 DOI: 10.1126/sciadv.ade1067] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 11/23/2022] [Indexed: 06/17/2023]
Abstract
Perianal fistulas (PAFs) represent a severe complication of Crohn's disease (CD). Despite the advent of biologic and small-molecule therapeutics for luminal disease, PAFs in CD (CD-PAF) are relatively resistant to treatment, with less than 50% responding to any therapy. We report an injectable, biodegradable, mechanically fragmented nanofiber-hydrogel composite (mfNHC) loaded with adipose-derived stem cells (ADSCs) for the treatment of fistulas in a rat model of CD-PAF. The ADSC-loaded mfNHC results in a higher degree of healing when compared to surgical treatment of fistulas, which is a standard treatment. The volume of fistulas treated with mfNHC is decreased sixfold compared to the surgical treatment control. Molecular studies reveal that utilization of mfNHC reduced local inflammation and improved tissue regeneration. This study demonstrates that ADSC-loaded mfNHC is a promising therapy for CD-PAF, and warrants further studies to advance mfNHC toward clinical translation.
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Affiliation(s)
- Ling Li
- Division of Gastroenterology and Hepatology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Zhi-Cheng Yao
- Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA
- Department of Materials Science and Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA
- Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Alyssa Parian
- Division of Gastroenterology and Hepatology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Yueh-Hsun Yang
- Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA
- Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Plastic and Reconstructive Surgery, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Jeffrey Chao
- Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA
- Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Public Health Studies, Krieger School of Arts and Sciences, Johns Hopkins University, Baltimore, MD, USA
| | - Jason Yin
- Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA
- Department of Materials Science and Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA
- Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Kevan J. Salimian
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Sashank K. Reddy
- Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA
- Department of Plastic and Reconstructive Surgery, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Atif Zaheer
- Division of Radiology and Radiological Sciences, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Susan L. Gearhart
- Division of Colorectal Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Hai-Quan Mao
- Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA
- Department of Materials Science and Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA
- Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Florin M. Selaru
- Division of Gastroenterology and Hepatology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
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15
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Porter AP, Pirlot BM, Dyer K, Uwazie CC, Nguyen J, Turner C, Rajan D, Hematti P, Chinnadurai R. Conglomeration of T- and B-Cell Matrix Responses Determines the Potency of Human Bone Marrow Mesenchymal Stromal Cells. Stem Cells 2022; 40:1134-1148. [PMID: 36056823 DOI: 10.1093/stmcls/sxac064] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 08/26/2022] [Indexed: 01/04/2023]
Abstract
Cell manufacturing facilities need to define the potency of mesenchymal stromal cells (MSCs) as cellular therapeutics in advanced clinical trials or marketing approval. Since MSCs' mechanism of action in humans is not well defined, more than a single functional property of MSCs needs to be captured as a surrogate measure of potency utilizing assay matrix technologies. However, the current limitation is the sole investigation of MSC-mediated T-cell suppression as a surrogate measure of potency. We investigated the effect of MSCs on B-cell matrix responses to be incorporated into the assay matrix potency analytical system. Our results demonstrate that MSCs inhibit B-cell differentiation and block pan-antibody secretion upon activation of B cells in the PBMCs. In contrast, MSCs are inferior in blocking B-cell matrix responses when purified B cells are used. Mechanistic analysis has demonstrated that MSC-mediated inhibition of B-cell matrix responses is non-contact dependent and Tryptophan metabolic pathway plays a major role, akin to the mechanism of MSC-mediated T-cell suppression. MSCs also inhibit both T-cell and B-cell responses when both of these lymphoid populations are concurrently activated in the PBMCs. Secretome analysis of MSC and T/B cell-activated PBMC cocultures identified direct and inverse correlative matrix signatures between humoral antibody isotypes and secretory molecules. The current analysis of the combined and concomitant investigation of T-cell and B-cell matrix responses fulfills the potency assay matrix strategy by incorporating MSCs' interaction with more than a single inflammatory immune responder.
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Affiliation(s)
- Amanda P Porter
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA, USA
| | - Bonnie M Pirlot
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA, USA
| | - Kalyn Dyer
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA, USA
| | - Crystal C Uwazie
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA, USA
| | - Jimmy Nguyen
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA, USA
| | - Caitlin Turner
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA, USA
| | - Devi Rajan
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA, USA
| | - Peiman Hematti
- Department of Medicine, University of Wisconsin Madison, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
| | - Raghavan Chinnadurai
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA, USA
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16
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The Intersection of Human and Veterinary Medicine-A Possible Direction towards the Improvement of Cell Therapy Protocols in the Treatment of Perianal Fistulas. Int J Mol Sci 2022; 23:ijms232213917. [PMID: 36430390 PMCID: PMC9696944 DOI: 10.3390/ijms232213917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 10/31/2022] [Accepted: 11/08/2022] [Indexed: 11/16/2022] Open
Abstract
The effective treatment of perianal fistulizing Crohn's disease is still a challenge. Local administration of mesenchymal stromal cells (MSCs) is becoming a part of accepted treatment options. However, as a fledgling technique, it still can be optimized. A new trend in translational research, which is in line with "One Health" approach, bases on exploiting parallels between naturally occurring diseases affecting humans and companion animals. Canine anal furunculosis (AF) has been indicated as condition analogous to human perianal Crohn's disease (pCD). This narrative review provides the first comprehensive comparative analysis of these two diseases based on the published data. The paper also outlines the molecular mechanisms of action of MSCs which are likely to have a role in modulating the perianal fistula niche in humans, and refers them to the current knowledge on the immunomodulatory properties of canine MSCs. Generally, the pathogenesis of both diseases shares main determinants such as the presence of genetic predispositions, dysregulation of immune response and the relation to intestine microbiota. However, we also identified many aspects which should be further specified, such as determining the frequency of true fistulas formation in AF patients, elucidating the role of TNF and Th17 pathway in the pathogenesis of AF, or clarifying the role of epithelial-to-mesenchymal transition phenomenon in the formation of canine fistulae. Nevertheless, the available data support the hypothesis that the results from testing cell therapies in dogs with anal furunculosis have a significant translational value in optimizing MSC transplants procedures in pCD patients.
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17
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Lan N, Shen B. Endoscopic Therapy for Fistulas and Abscesses in Crohn's Disease. Gastrointest Endosc Clin N Am 2022; 32:733-746. [PMID: 36202513 DOI: 10.1016/j.giec.2022.05.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Crohn disease (CD) patients can develop fistula or abscess from persistent active disease or postsurgical complications. Penetrating CD is traditionally treated with medication and surgery. The role of medication alone in the treatment of fistula is limited, except perianal fistulas or enterocutaneous fistula. Surgery is the standard treatment in those with hollow-organ to hollow-organ fistula, like ileovesicular fistula. Surgery is invasive with a higher risk of postoperative complications. Endoscopic therapy has evolved as a valid option. Fistulotomy, surgical or endoscopic, should be considered first-line therapy when feasible. Incision and drainage of perianal abscesses with an endoscopic device may be attempted.
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Affiliation(s)
- Nan Lan
- Center for Inflammatory Bowel Disease, Columbia University Irving Medical Center-NewYork Presbyterian Hospital, 161 Fort Washington Avenue, HIP Floor 8-843, New York, NY 10032, USA
| | - Bo Shen
- Center for Inflammatory Bowel Disease, Columbia University Irving Medical Center-NewYork Presbyterian Hospital, 161 Fort Washington Avenue, HIP Floor 8-843, New York, NY 10032, USA.
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18
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Householder S, Picoraro JA. Diagnosis and Classification of Fistula from Inflammatory Bowel Disease and Inflammatory Bowel Disease-Related Surgery. Gastrointest Endosc Clin N Am 2022; 32:631-650. [PMID: 36202507 DOI: 10.1016/j.giec.2022.04.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Fistula in inflammatory bowel disease (IBD) is a well-known yet poorly understood phenotype. Pathophysiology is largely based on the activation of the epithelial-mesenchymal transition (EMT); however, interactions with the microbiome, genetics, mechanical stress and the presence of stricturing disease, and surgical complications play a role. Perianal penetrating disease represents a more severe phenotype in IBD. Pouch-associated fistula can arise as a result of an anastomotic leak, surgical complications, or Crohn's disease (CD) of the pouch. Classification is site-dependent, includes a range of severity, and informs management. It is important to determine associated symptoms and recognize the complex interplay of underlying etiologies to form the basis of appropriate care.
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Affiliation(s)
| | - Joseph A Picoraro
- Columbia University Irving Medical Center, NewYork-Presbyterian Morgan Stanley Children's Hospital, 622 West 168th Street, PH17-105, New York, NY 10032, USA.
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19
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McGregor CGC, Tandon R, Simmons A. Pathogenesis of Fistulating Crohn's Disease: A Review. Cell Mol Gastroenterol Hepatol 2022; 15:1-11. [PMID: 36184031 PMCID: PMC9667304 DOI: 10.1016/j.jcmgh.2022.09.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 09/20/2022] [Accepted: 09/20/2022] [Indexed: 12/10/2022]
Abstract
Sustained, transmural inflammation of the bowel wall may result in the development of a fistula in Crohn's disease (CD). Fistula formation is a recognized complication and cause of morbidity, occurring in 40% of patients with CD. Despite advanced treatment, one-third of patients experience recurrent fistulae. Development of targeting treatment for fistulae will be dependent on a more in depth understanding of its pathogenesis. Presently, pathogenesis of CD-associated fistulae remains poorly defined, in part due to the lack of accepted in vitro tissue models recapitulating the pathogenic cellular lesions linked to fistulae and limited in vivo models. This review provides a synthesis of the existing knowledge of the histopathological, immune, cellular, genetic, and microbial contributions to the pathogenesis of CD-associated fistulae including the widely accredited contribution of epithelial-to-mesenchymal transition, upregulation of matrix metalloproteinases, and overexpression of invasive molecules, resulting in tissue remodeling and subsequent fistula formation. We conclude by exploring how we might utilize advancing technologies to verify and broaden our current understanding while exploring novel causal pathways to provide further inroads to future therapeutic targets.
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Affiliation(s)
- Colleen Georgette Chantelle McGregor
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom; Translational Gastroenterology Unit, John Radcliffe Hospital, Headington, Oxford, United Kingdom
| | - Ruchi Tandon
- Pathology, Department of Cellular Pathology, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
| | - Alison Simmons
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom; Translational Gastroenterology Unit, John Radcliffe Hospital, Headington, Oxford, United Kingdom.
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20
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Chin Koon Siw K, Engel J, Visva S, Mallick R, Hart A, de Buck van Overstraeten A, McCurdy JD. Strategies to Distinguish Perianal Fistulas Related to Crohn's Disease From Cryptoglandular Disease: Systematic Review With Meta-Analysis. Inflamm Bowel Dis 2022; 28:1363-1374. [PMID: 34792583 DOI: 10.1093/ibd/izab286] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Indexed: 12/09/2022]
Abstract
BACKGROUND Management of perianal fistulas differs based on fistula type. We aimed to assess the ability of diagnostic strategies to differentiate between Crohn's disease (CD) and cryptoglandular disease (CGD) in patients with perianal fistulas. METHODS We performed a diagnostic accuracy systematic review and meta-analysis. A systematic search of electronic databases was performed from inception through February 2021 for studies assessing a diagnostic test's ability to distinguish fistula types. We calculated weighted summary estimates with 95% confidence intervals for sensitivity and specificity by bivariate analysis, using fixed effects models when data were available from 2 or more studies. The Quality Assessment of Diagnostic Accuracy Studies tool was used to assess study quality. RESULTS Twenty-one studies were identified and included clinical symptoms (2 studies; n=154), magnetic resonance imaging (MRI) characteristics (3 studies; n=296), ultrasound characteristics (7 studies; n=1003), video capsule endoscopy (2 studies; n=44), fecal calprotectin (1 study; n=56), and various biomarkers (8 studies; n=440). MRI and ultrasound characteristics had the most robust data. Rectal inflammation, multiple-branched fistula tracts, and abscesses on pelvic MRI and the Crohn's ultrasound fistula sign, fistula debris, and bifurcated fistulas on pelvic ultrasonography had high specificity (range, 80%-95% vs 89%-96%) but poor sensitivity (range, 17%-37% vs 31%-63%), respectively. Fourteen of 21 studies had risk of bias on at least 1 of the Quality Assessment of Diagnostic Accuracy Studies domains. CONCLUSIONS Limited high-quality evidence suggest that imaging characteristics may help discriminate CD from CGD in patients with perianal fistulas. Larger, prospective studies are needed to confirm these findings and to evaluate if combining multiple diagnostic tests can improve diagnostic sensitivity.
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Affiliation(s)
- Kevin Chin Koon Siw
- Division of Gastroenterology and Hepatology, University of Ottawa, Ottawa, ON, Canada
| | - Jake Engel
- Faculty of Medicine, University of Ottawa, ON, Canada
| | | | | | - Ailsa Hart
- Division of Gastroenterology, St Mark's Hospital, London, United Kingdomand the
| | | | - Jeffrey D McCurdy
- Division of Gastroenterology and Hepatology, University of Ottawa, Ottawa, ON, Canada.,Ottawa Hospital Research Institute, Ottawa, ON, Canada
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21
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Pagani K, Lukac D, Bhukhan A, McGee JS. Cutaneous Manifestations of Inflammatory Bowel Disease: A Basic Overview. Am J Clin Dermatol 2022; 23:481-497. [PMID: 35441942 DOI: 10.1007/s40257-022-00689-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/20/2022] [Indexed: 11/30/2022]
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal (GI) tract that is subdivided into Crohn's disease (CD) and ulcerative colitis (UC). CD is characterized by involvement of the entire GI tract, while UC mainly affects the distal GI tract. Moreover, both CD and UC can present with extraintestinal manifestations (EIMs) of the disease affecting multiple organ systems including the hepatobiliary tract, kidney, bones, eyes, joints, and skin. These complications can cause significant morbidity and negatively impact the quality of life for IBD patients. Although the pathogenesis of EIMs is not clearly elucidated, it is postulated that the diseased GI mucosa similarly stimulates excess immune responses at the extraintestinal sites. Cutaneous EIMs occur in up to 15% of patients with IBD, often predating their IBD diagnosis. They are categorized into (1) specific, (2) reactive, (3) associated, and (4) treatment-induced. Here, we review the epidemiological, clinical, diagnostic, and histologic features of the most commonly described cutaneous EIMs of IBD along with their respective treatment options.
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Affiliation(s)
- Kyla Pagani
- Department of Dermatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Danitza Lukac
- Department of Dermatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Aashni Bhukhan
- Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine, Ft. Lauderdale, FL, USA
| | - Jean S McGee
- Department of Dermatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
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22
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Mamie C, Bruckner RS, Lang S, Shpigel NY, Turina M, Rickenbacher A, Cabalzar-Wondberg D, Chvatchko Y, Rogler G, Scharl M. MMP9 expression in intestinal fistula from patients with fistulizing CD and from human xenograft mouse model. Tissue Barriers 2022; 10:1994350. [PMID: 34709129 PMCID: PMC9067458 DOI: 10.1080/21688370.2021.1994350] [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: 08/05/2021] [Revised: 10/07/2021] [Accepted: 10/10/2021] [Indexed: 10/20/2022] Open
Abstract
Fistula treatment represents a major unmet medical need in the therapy of Crohn's disease (CD). Current medical therapies, such as anti-TNF antibody treatments, are often insufficient and do not achieve permanent fistula closure. Previously published data point toward a critical role for metalloproteinase-9 (MMP-9)/gelatinase B in fistula pathogenesis. The aim of this project was to investigate in detail MMP-9 expression in different fistula types and to confirm that MMP-9 is a potential target for fistula therapy in CD patients.Immunohistochemistry for total and active MMP-9, Cytokeratin 8 (CK-8) and co-staining of active MMP-9/CK-8 was performed in specimen derived from perianal fistulas, entero-enteric fistulas and fistulas from patients not responding to anti-TNF therapy. In addition, fistulas from the xenograft mouse model (anti-TNF treated or untreated) were analyzed.Total and active MMP-9 protein was detectable in cells lining the tracts of perianal and entero-enteric fistulas. Of note, total and active MMP-9 was also expressed in fistulas of CD patients non-responding to anti-TNF treatment. Interestingly, we detected considerable co-staining of active MMP-9 and CK-8 in particular in cells lining the fistula tract and in transitional cells around the fistulas. Furthermore, total and active MMP-9 are detectable in both anti-TNF treated and untreated xenograft fistulas.Taken together, our data suggest that MMP-9 is involved in fistula pathogenesis in CD patients, in fistulas of different origins and particularly in patients non-responding to anti-TNF therapy. Our xenograft fistula model is suitable for in vivo studies investigating a possible therapeutic role for MMP-9 targeting as fistula therapy.
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Affiliation(s)
- Céline Mamie
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Ramona S. Bruckner
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Silvia Lang
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Nahum Y. Shpigel
- Koret School of Veterinary Medicine, Hebrew University of Jerusalem, Rehovot, Israel
| | - Matthias Turina
- Department of Visceral and Transplantation Surgery, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Andreas Rickenbacher
- Department of Visceral and Transplantation Surgery, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Daniela Cabalzar-Wondberg
- Department of Visceral and Transplantation Surgery, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | | | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Michael Scharl
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
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23
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An Affordable Approach of Mesenchymal Stem Cell Therapy in Treating Perianal Fistula Treatment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1401:73-95. [DOI: 10.1007/5584_2022_716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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24
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Adegbola SO, Sarafian M, Sahnan K, Ding NS, Faiz OD, Warusavitarne J, Phillips RKS, Tozer PJ, Holmes E, Hart AL. Differences in amino acid and lipid metabolism distinguish Crohn's from idiopathic/cryptoglandular perianal fistulas by tissue metabonomic profiling and may offer clues to underlying pathogenesis. Eur J Gastroenterol Hepatol 2021; 33:1469-1479. [PMID: 33337668 DOI: 10.1097/meg.0000000000001976] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Few studies have investigated perianal fistula etiopathogenesis, and although the cryptoglandular theory is widely accepted in idiopathic cases, in Crohn's disease, it is thought to involve the interplay between microbiological, immunological and genetic factors. A pilot study was conducted to assess for metabolic variations in Crohn's perianal fistula tissue that might differ from that of idiopathic (cryptoglandular) perianal fistula tissue as a comparator. The goal was to identify any potential biomarkers of disease, which may improve the understanding of pathogenesis. AIMS AND METHODS Fistula tract biopsies were obtained from 30 patients with idiopathic perianal fistula and 20 patients with Crohn's anal fistula. Two different assays were used in an ultra-high-performance liquid chromatography system coupled with a mass spectrometric detector to achieve broad metabolome coverage. Univariate and multivariate statistical data analyses were used to identify differentiating metabolic features corresponding to the perianal fistula phenotype (i.e. Crohn's disease vs. idiopathic). RESULTS Significant orthogonal partial least squares discriminant analysis predictive models (validated with cross-validated-analysis of variance P value <0.05) differentiated metabolites from tissue samples from Crohn's vs. idiopathic anal fistula patients using both metabolic profiling platforms. A total of 41 metabolites were identified, suggesting alterations in pathways, including amino acid, carnitine and lipid metabolism. CONCLUSION Metabonomics may reveal biomarkers of Crohn's perianal fistula. Further work in larger numbers is required to validate the findings of these studies as well as cross-correlation with microbiome work to better understand the impact of host-gut/environment interactions in the pathophysiology of Crohn's and idiopathic perianal fistulas and identify novel therapeutic targets.
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Affiliation(s)
- Samuel O Adegbola
- Robin Phillips Fistula Research Unit, St Mark's Hospital and Academic Institute, Harrow, Middlesex
- Department of Surgery and Cancer
| | - Magali Sarafian
- Computational Systems Division, Imperial College London, South Kensington Campus, London, UK
| | - Kapil Sahnan
- Robin Phillips Fistula Research Unit, St Mark's Hospital and Academic Institute, Harrow, Middlesex
- Department of Surgery and Cancer
| | - Nik S Ding
- Department of Gastroenterology, St Vincent's Hospital, Melbourne, Australia
| | - Omar D Faiz
- Robin Phillips Fistula Research Unit, St Mark's Hospital and Academic Institute, Harrow, Middlesex
- Department of Surgery and Cancer
| | - Janindra Warusavitarne
- Robin Phillips Fistula Research Unit, St Mark's Hospital and Academic Institute, Harrow, Middlesex
- Department of Surgery and Cancer
| | - Robin K S Phillips
- Robin Phillips Fistula Research Unit, St Mark's Hospital and Academic Institute, Harrow, Middlesex
- Department of Surgery and Cancer
| | - Phil J Tozer
- Robin Phillips Fistula Research Unit, St Mark's Hospital and Academic Institute, Harrow, Middlesex
- Department of Surgery and Cancer
| | - Elaine Holmes
- Computational Systems Division, Imperial College London, South Kensington Campus, London, UK
| | - Ailsa L Hart
- Robin Phillips Fistula Research Unit, St Mark's Hospital and Academic Institute, Harrow, Middlesex
- Department of Surgery and Cancer
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25
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Rubbino F, Greco L, di Cristofaro A, Gaiani F, Vetrano S, Laghi L, Bonovas S, Piovani D. Journey through Crohn's Disease Complication: From Fistula Formation to Future Therapies. J Clin Med 2021; 10:jcm10235548. [PMID: 34884247 PMCID: PMC8658128 DOI: 10.3390/jcm10235548] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 11/23/2021] [Accepted: 11/25/2021] [Indexed: 12/19/2022] Open
Abstract
Crohn’s Disease (CD) is a chronic inflammatory disorder in which up to 50% of patients develop fistula within 20 years after the initial diagnosis, and half of these patients suffer perianal fistulizing disease. The etiopathogenesis of CD-related perianal fistula is still unclear, and its phenotypical and molecular characteristics are even more indefinite. A better understanding would be crucial to develop targeted and more effective therapeutic strategies. At present, the most accredited theory for the formation of CD-related fistula identifies the epithelial-to-mesenchymal transition (EMT) as the driving force. It has been well recognized that CD carries an increased risk of malignancy, particularly mucinous adenocarcinoma is often associated with long-standing fistula in CD patients. Despite the availability of multiple treatment options, perianal fistulizing CD represents a therapeutic challenge and is associated with an important impact on patients’ quality of life. To date, the most effective management is multidisciplinary with the cooperation of gastroenterologists, surgeons, radiologists, and nutritionists and the best recommended treatment is a combination of medical and surgical approaches.
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Affiliation(s)
- Federica Rubbino
- Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy; (L.G.); (A.d.C.); (L.L.)
- Correspondence: (F.R.); (S.B.)
| | - Luana Greco
- Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy; (L.G.); (A.d.C.); (L.L.)
| | - Alessio di Cristofaro
- Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy; (L.G.); (A.d.C.); (L.L.)
| | - Federica Gaiani
- Department of Medicine and Surgery, University of Parma, Via Gramsci 14, 43126 Parma, Italy;
- Gastroenterology and Endoscopy Unit, University-Hospital of Parma, Via Gramsci 14, 43126 Parma, Italy
| | - Stefania Vetrano
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (S.V.); (D.P.)
| | - Luigi Laghi
- Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy; (L.G.); (A.d.C.); (L.L.)
- Department of Medicine and Surgery, University of Parma, Via Gramsci 14, 43126 Parma, Italy;
| | - Stefanos Bonovas
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (S.V.); (D.P.)
- IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy
- Correspondence: (F.R.); (S.B.)
| | - Daniele Piovani
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy; (S.V.); (D.P.)
- IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy
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26
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Vieujean S, Hu S, Bequet E, Salee C, Massot C, Bletard N, Pierre N, Quesada Calvo F, Baiwir D, Mazzucchelli G, De Pauw E, Coimbra Marques C, Delvenne P, Rieder F, Louis E, Meuwis MA. Potential Role of Epithelial Endoplasmic Reticulum Stress and Anterior Gradient Protein 2 Homologue in Crohn's Disease Fibrosis. J Crohns Colitis 2021; 15:1737-1750. [PMID: 33822017 PMCID: PMC8861373 DOI: 10.1093/ecco-jcc/jjab061] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIMS Intestinal fibrosis is a common complication of Crohn's disease [CD]. It is characterised by an accumulation of fibroblasts differentiating into myofibroblasts secreting excessive extracellular matrix. The potential role of the intestinal epithelium in this fibrotic process remains poorly defined. METHODS We performed a pilot proteomic study comparing the proteome of surface epithelium, isolated by laser-capture microdissection, in normal and fibrotic zones of resected ileal CD strictures [13 zones collected in five patients]. Proteins of interests were validated by immunohistochemistry [IHC] in ileal and colonic samples of stricturing CD [n = 44], pure inflammatory CD [n = 29], and control [n = 40] subjects. The pro-fibrotic role of one selected epithelial protein was investigated through in-vitro experiments using HT-29 epithelial cells and a CCD-18Co fibroblast to myofibroblast differentiation model. RESULTS Proteomic study revealed an endoplasmic reticulum [ER] stress proteins increase in the epithelium of CD ileal fibrotic strictures, including anterior gradient protein 2 homologue [AGR2] and binding-immunoglobulin protein [BiP]. This was confirmed by IHC. In HT-29 cells, tunicamycin-induced ER stress triggered AGR2 intracellular expression and its secretion. Supernatant of these HT-29 cells, pre-conditioned by tunicamycin, led to a myofibroblastic differentiation when applied on CCD-18Co fibroblasts. By using recombinant protein and blocking agent for AGR2, we demonstrated that the secretion of this protein by epithelial cells can play a role in the myofibroblastic differentiation. CONCLUSIONS The development of CD fibrotic strictures could involve epithelial ER stress and particularly the secretion of AGR2.
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Affiliation(s)
- Sophie Vieujean
- Corresponding author: Sophie Vieujean, MD, Laboratory of Translational Gastroenterology, University of Liège, GIGA-Research, +2, B34, Avenue de l’hôpital 1, 4000 Liège, Belgium. Tel.: +32-4-3667256; fax: +32-4-3667889; mail:
| | | | - Emeline Bequet
- Laboratory of Translational Gastroenterology, University of Liège, Liège, Belgium,Division of Hepato-Gastroenterology, Department of Paediatrics, University Hospital of Liège, Liège, Belgium
| | - Catherine Salee
- Laboratory of Translational Gastroenterology, University of Liège, Liège, Belgium
| | - Charlotte Massot
- Laboratory of Translational Gastroenterology, University of Liège, Liège, Belgium
| | - Noëlla Bletard
- Pathological Anatomy and Cytology, University Hospital CHU of Liège, Liège, Belgium
| | - Nicolas Pierre
- Laboratory of Translational Gastroenterology, University of Liège, Liège, Belgium
| | | | | | - Gabriel Mazzucchelli
- MolSys Research Unit, Laboratory of Mass Spectrometry, University of Liège, Liège, Belgium
| | - Edwin De Pauw
- MolSys Research Unit, Laboratory of Mass Spectrometry, University of Liège, Liège, Belgium
| | | | - Philippe Delvenne
- Pathological Anatomy and Cytology, University Hospital CHU of Liège, Liège, Belgium
| | - Florian Rieder
- Gastroenterology, Hepatology & Nutrition, Cleveland Clinic, Cleveland, OH, USA
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27
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Bruckner RS, Spalinger MR, Barnhoorn MC, Feakins R, Fuerst A, Jehle EC, Rickenbacher A, Turina M, Niechcial A, Lang S, Hawinkels LJAC, van der Meulen-de Jong AE, Verspaget HW, Rogler G, Scharl M. Contribution of CD3+CD8- and CD3+CD8+ T Cells to TNF-α Overexpression in Crohn Disease-Associated Perianal Fistulas and Induction of Epithelial-Mesenchymal Transition in HT-29 Cells. Inflamm Bowel Dis 2021; 27:538-549. [PMID: 33146394 DOI: 10.1093/ibd/izaa240] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Fistulas represent a frequent and severe complication in patients with Crohn disease (CD). Tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta, and interleukin (IL)-13 are known to trigger epithelial-mesenchymal transition (EMT), promoting fistula formation. Here, we investigated the role of T-lymphocytes (T cells) in fistula pathogenesis. METHODS CD3+CD8-, CD3+CD8+, or CD45+CD3- cells from healthy volunteers, patients with CD, and patients with CD with perianal fistula were co-cultured with HT-29 cells. The EMT, cytokine production, and mRNA expression were analyzed. Perianal CD fistula specimens were immunohistochemically stained for cytokines and their receptors. The effect of cytokines on EMT induction was investigated using an EMT spheroid model. RESULTS Patients with CD with fistula revealed more CD3+CD8- and less CD3+CD8+ T cells in blood than healthy control patients and patients with CD without fistula. In perianal fistula specimens, CD4+ cells-and to a lesser extent CD8+ cells-were highly present around fistula tracts. When co-cultured with HT-29 cells, both cell subsets promoted EMT-related gene expression and TNF-α production in a time-dependent manner. The CD3+CD8- T cells from patients with CD with fistula also produced higher amounts of IL-13 than cells from healthy control patients or patients with CD without a fistula. We found that IL-22 and IL-22Rα1 were highly expressed in perianal CD fistula specimens and that IL-22 cotreatment potentiated TNF-α-induced EMT in HT-29 spheroids. CONCLUSIONS Our data indicate that both CD3+CD8- and CD3+CD8+ T cells play an important role in the pathogenesis of perianal CD fistulas by the secretion of TNF-α. Our data support clinical evidence indicating that anti-TNF-α therapy is effective in fistula treatment and identify IL-13 and IL-22 as possible novel therapeutic targets for fistula therapy.
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Affiliation(s)
- Ramona S Bruckner
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.,Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Marianne R Spalinger
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Marieke C Barnhoorn
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Roger Feakins
- Department of Histopathology, Royal Free Hospital, London, United Kingdom
| | - Alois Fuerst
- Department of Surgery, Caritas-Krankenhaus St. Josef, Regensburg, Germany
| | | | - Andreas Rickenbacher
- Department of Surgery, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Matthias Turina
- Department of Surgery, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Anna Niechcial
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Silvia Lang
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Lukas J A C Hawinkels
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | | | - Hein W Verspaget
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.,Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Michael Scharl
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.,Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
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28
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Lightner AL, Ashburn JH, Brar MS, Carvello M, Chandrasinghe P, van Overstraeten ADB, Fleshner PR, Gallo G, Kotze PG, Holubar SD, Reza LM, Spinelli A, Strong SA, Tozer PJ, Truong A, Warusavitarne J, Yamamoto T, Zaghiyan K. Fistulizing Crohn's disease. Curr Probl Surg 2020; 57:100808. [PMID: 33187597 DOI: 10.1016/j.cpsurg.2020.100808] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 04/22/2020] [Indexed: 02/06/2023]
Affiliation(s)
- Amy L Lightner
- Department of Colorectal Surgery, Digestive Disease Surgical Institute, Cleveland Clinic, OH.
| | - Jean H Ashburn
- Department of Surgery, Wake Forest University Baptist Medical Center, Winston-Salem, NC
| | - Mantaj S Brar
- Department of Surgery, Mount Sinai Hospital, Toronto, ON; Zane Cohen Center for Digestive Diseases, Toronto, ON; Department of Surgery, University of Toronto, ON
| | - Michele Carvello
- Department of Medical and Surgical Sciences, University of Catanzaro, Catanzaro, Italy
| | | | - Anthony de Buck van Overstraeten
- Department of Surgery, Mount Sinai Hospital, Toronto, ON; Zane Cohen Center for Digestive Diseases, Toronto, ON; Department of Surgery, University of Toronto, ON
| | | | - Gaetano Gallo
- Department of Medical and Surgical Sciences, University of Catanzaro, Catanzaro, Italy
| | - Paulo Gustavo Kotze
- IBD Outpatient Clinics, Colorectal Surgery Unit, Catholic University of Parana (PUCPR), Curitiba, Brazil
| | - Stefan D Holubar
- Department of Colorectal Surgery, Digestive Disease Surgical Institute, Cleveland Clinic, OH
| | - Lillian M Reza
- Fistula research Unit, St Mark's Hospital and academic institute, London, UK
| | - Antonino Spinelli
- Humanitas Clinical and Research Center, Colon and Rectal Surgery Unit, Italy; Humanitas University, Department of Biomedical Sciences, Italy
| | - Scott A Strong
- Department of Gastrointestinal Surgery, Northwestern University, Chicago, IL
| | - Philip J Tozer
- Fistula research Unit, St Mark's Hospital and academic institute, London, UK
| | - Adam Truong
- Department of Surgery, Cedars Sinai, Los Angeles, CA
| | | | - Takayuki Yamamoto
- Inflammatory Bowel Disease Center & Department of Surgery, Yokkaichi Hazu Medical Center, Yokkaichi, Japan
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Gallo G, Tiesi V, Fulginiti S, De Paola G, Vescio G, Sammarco G. Mesenchymal Stromal Cell Therapy in the Management of Perianal Fistulas in Crohn's Disease: An Up-To-Date Review. MEDICINA (KAUNAS, LITHUANIA) 2020; 56:563. [PMID: 33121049 PMCID: PMC7692376 DOI: 10.3390/medicina56110563] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 10/19/2020] [Accepted: 10/26/2020] [Indexed: 12/12/2022]
Abstract
Crohn's Disease (CD) is a chronic inflammatory disorder that potentially involves the entire gastrointestinal tract. Perianal fistulizing CD (pCD) is a serious and frequent complication associated with significant morbidities and a heavy negative impact on quality of life. The aim of CD treatment is to induce and maintain disease remission and to promote mucosal repair. Unfortunately, even the best therapeutic regimens in pCD do not have long-term efficacy and cause a significant number of side effects. Therefore, it is mandatory to study new therapeutical options such as the use of mesenchymal stromal cells (MSCs). These cells promote tissue repair via the induction of immunomodulation. The present review aims to analyze the existing updated scientific literature on MSCs adoption in the treatment of pCD to evaluate its efficacy and safety and to compare the use of bone marrow and adipose tissue derived MSCs, type of administration, and dose required for recovery.
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Affiliation(s)
- Gaetano Gallo
- Department of Medical and Surgical Sciences, University of Catanzaro, Viale Europa, 88100 Catanzaro, Italy; (V.T.); (S.F.); (G.D.P.); (G.V.)
| | - Vincenzo Tiesi
- Department of Medical and Surgical Sciences, University of Catanzaro, Viale Europa, 88100 Catanzaro, Italy; (V.T.); (S.F.); (G.D.P.); (G.V.)
| | - Serena Fulginiti
- Department of Medical and Surgical Sciences, University of Catanzaro, Viale Europa, 88100 Catanzaro, Italy; (V.T.); (S.F.); (G.D.P.); (G.V.)
| | - Gilda De Paola
- Department of Medical and Surgical Sciences, University of Catanzaro, Viale Europa, 88100 Catanzaro, Italy; (V.T.); (S.F.); (G.D.P.); (G.V.)
| | - Giuseppina Vescio
- Department of Medical and Surgical Sciences, University of Catanzaro, Viale Europa, 88100 Catanzaro, Italy; (V.T.); (S.F.); (G.D.P.); (G.V.)
| | - Giuseppe Sammarco
- Department of Health Sciences, University of Catanzaro, Viale Europa, 88100 Catanzaro, Italy;
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30
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Angus HCK, Butt AG, Schultz M, Kemp RA. Intestinal Organoids as a Tool for Inflammatory Bowel Disease Research. Front Med (Lausanne) 2020; 6:334. [PMID: 32010704 PMCID: PMC6978713 DOI: 10.3389/fmed.2019.00334] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Accepted: 12/23/2019] [Indexed: 12/26/2022] Open
Abstract
Inflammatory Bowel Diseases (IBD) are difficult to model as freshly acquired tissues are short-lived, provide data as a snapshot in time, and are not always accessible. Many patients with IBD are non-responders to first-line treatments, and responders are prone to developing resistance to treatment over time—resulting in reduced patient quality of life, increased time to remission, and potential relapse. IBD is heterogenous and we are yet to fully understand the mechanisms of disease; thus, our ability to diagnose and prescribe optimal treatment remains ineffective. Intestinal organoids are derived from patient tissues expanded in vitro. Organoids offer unique insight into individual patient disease and are a potential route to personalized treatments. However, organoid models do not contain functional microbial and immune cell components. In this review, we discuss immune cell subsets in the context of IBD, and the requirement of immune cell and microbial components in organoid models for IBD research.
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Affiliation(s)
- Hamish C K Angus
- Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand
| | - A Grant Butt
- Department of Physiology, University of Otago, Dunedin, New Zealand
| | - Michael Schultz
- Department of Medicine, University of Otago, Dunedin, New Zealand
| | - Roslyn A Kemp
- Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand
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31
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Haddow JB, Musbahi O, MacDonald TT, Knowles CH. Comparison of cytokine and phosphoprotein profiles in idiopathic and Crohn’s disease-related perianal fistula. World J Gastrointest Pathophysiol 2019; 10:42-53. [PMID: 31750007 PMCID: PMC6854389 DOI: 10.4291/wjgp.v10.i4.42] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 09/28/2019] [Accepted: 10/18/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Perianal fistulae are either primary (idiopathic) or secondary [commonly associated with Crohn’s disease, (CD)]. It is assumed, although not proven, that the pathophysiology differs.
AIM To systematically compare the clinical phenotypes, cytokine and phosphoprotein profiles of idiopathic and CD-related perianal fistulae.
METHODS Sixty-one patients undergoing surgery for perianal fistula were prospectively recruited (48 idiopathic, 13 CD) into a cohort study. Clinical data, including the Perineal Disease Activity Index (PDAI) and EQ-5D-5L were collected. Biopsies of the fistula tract, granulation tissue, internal opening mucosa and rectal mucosa were obtained at surgery. Concentrations of 30 cytokines and 39 phosphoproteins were measured in each biopsy using a magnetic bead multiplexing instrument and a chemiluminescent antibody array respectively. Over 12000 clinical and 23500 laboratory measurements were made.
RESULTS The PDAI was significantly higher (indicating more active disease) in the CD group with a mean difference of 2.40 (95%CI: 0.52-4.28, P = 0.01). Complex pathoanatomy was more prevalent in the CD group, namely more multiple fistulae, supralevator extensions, collections and rectal thickening. The IL-12p70 concentration at the internal opening specimen site was significantly higher (median difference 19.7 pg/mL, 99%CI: 0.2-40.4, P = 0.008) and the IL-1RA/IL-1β ratio was significantly lower in the CD group at the internal opening specimen site (median difference 15.0, 99%CI = 0.4-50.5, P = 0.008). However in the remaining 27 cytokines and all 39 of the phosphoproteins across the four biopsy sites, no significant differences were found between the groups.
CONCLUSION CD-related perianal fistulae are more clinically severe and anatomically complex than idiopathic perianal fistulae. However, overall there are no major differences in cytokine and phosphoprotein profiles.
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Affiliation(s)
- James B Haddow
- Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 5AT, United Kingdom
| | - Omar Musbahi
- Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 5AT, United Kingdom
| | - Thomas T MacDonald
- Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 5AT, United Kingdom
| | - Charles H Knowles
- Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 5AT, United Kingdom
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32
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Jørgensen AHR, Thomsen SF, Karmisholt KE, Ring HC. Clinical, microbiological, immunological and imaging characteristics of tunnels and fistulas in hidradenitis suppurativa and Crohn's disease. Exp Dermatol 2019; 29:118-123. [PMID: 31519056 DOI: 10.1111/exd.14036] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 08/19/2019] [Accepted: 09/09/2019] [Indexed: 12/20/2022]
Abstract
Hidradenitis suppurativa (HS) tunnels and Crohn's disease (CD) fistulas are a challenge to treat. Although pathogenic similarities have been described between HS and CD, recent studies indicate that clinical, microbiological, immunological and imaging characteristics differ between these diseases. This review highlights the differences between HS tunnels and CD fistulas. Next-generation sequencing studies demonstrate a microbiome in HS tunnels dominated by Porphyromonas spp., Prevotella spp. whereas no specific bacteria have been associated with cutaneous CD. Immunologically, TNF has been found upregulated in HS tunnels along with various interleukins (IL-8, IL-16, IL-1α and IL-1β). In CD fistulas, Th1, Th17, IL-17, IFN-ɤ, TNF and IL-23 are increased. US imaging is an important tool in HS. US of HS tunnels depict hypoechoic band-like structure across skin layers in the dermis and/or hypodermis connected to the base of a widened hair follicle. In CD, MR imaging of simple perianal fistulas illustrates a linear, non-branching inflammatory tract relating to an internal opening in the anus or low rectum and an external opening to the skin surface. An increased awareness of the immediate potential differences between HS tunnels and CD fistulas may optimize treatment regimens of these intractable skin manifestations.
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Affiliation(s)
| | - Simon Francis Thomsen
- Department of Dermato-Venereology & Wound Healing Centre, Bispebjerg Hospital, Copenhagen, Denmark.,Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | | | - Hans Christian Ring
- Department of Dermato-Venereology & Wound Healing Centre, Bispebjerg Hospital, Copenhagen, Denmark
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33
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Bislenghi G, Wolthuis A, Van Assche G, Vermeire S, Ferrante M, D'Hoore A. Cx601 (darvadstrocel) for the treatment of perianal fistulizing Crohn's disease. Expert Opin Biol Ther 2019; 19:607-616. [PMID: 31121104 DOI: 10.1080/14712598.2019.1623876] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Introduction: Given the well-documented difficulty to treat perianal fistulizing Crohn's disease (pCD), with 40% of patients experiencing recurrence even after reiterative surgery and advanced medical therapy, research in this field has focused on the role of mesenchymal stem cells (MSC). Areas covered: The aim of this article is to furnish an overview of the pathogenetic mechanisms, clinical applications and evidences for the use of MSC for pCD with particular focus on adipose-derived allogenic MSC including darvadstrocel. Expert Opinion: The effect of MSC on fistula healing is probably mediated by their anti-inflammatory properties more than by their ability to engraft and trans-differentiate in the healthy tissue. A holistic treatment of pCD, addressing different pathophysiological factors, may represent the key for an improvement in the healing rate. In this setting, MSC might play a role as 'augmentation' therapy in combination with more conventional treatments. Whether MSC have benefit in non-complex fistula in biological naïve patients, in complex fistula with many tracts and/or in rectovaginal fistulas, are unexplored fields that need further investigation. A central registry of pCD patients undergoing treatment with MSC should be created in order to elucidate the efficacy, safety and costs of stem cells treatment on long term follow up.
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Affiliation(s)
- G Bislenghi
- a Department of Abdominal Surgery , University Hospitals Leuven, KU Leuven , Leuven , Belgium
| | - A Wolthuis
- a Department of Abdominal Surgery , University Hospitals Leuven, KU Leuven , Leuven , Belgium
| | - G Van Assche
- b Department of Gastroenterology and Hepatology , University Hospitals Leuven, KU Leuven , Leuven , Belgium
| | - S Vermeire
- b Department of Gastroenterology and Hepatology , University Hospitals Leuven, KU Leuven , Leuven , Belgium
| | - M Ferrante
- b Department of Gastroenterology and Hepatology , University Hospitals Leuven, KU Leuven , Leuven , Belgium
| | - A D'Hoore
- a Department of Abdominal Surgery , University Hospitals Leuven, KU Leuven , Leuven , Belgium
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34
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Transperineal ultrasound for assessment of fistulas and abscesses: a pictorial essay. J Ultrasound 2019; 22:241-249. [PMID: 31066004 DOI: 10.1007/s40477-019-00381-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2019] [Accepted: 04/22/2019] [Indexed: 02/07/2023] Open
Abstract
Perianal fistulas and abscesses may be cryptogenetic or associated with inflammatory bowel disease (IBD), specifically Crohn's disease. Proper identification and classification of these lesions are paramount for correct therapeutic management. Current diagnostic modalities include MRI (magnetic resonance imaging), EUS (endoscopic ultrasound), EUA (exam under anaesthesia) and recently, transperineal ultrasound (TPUS). The latter has been proposed as a noninvasive, easily available and cost-effective technique to diagnose, assess and follow up perianal disease particularly in IBD patients. This pictorial review focuses on the role of TPUS in clinical practice, highlighting the features of fistulas and abscesses.
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35
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Lovisa S, Genovese G, Danese S. Role of Epithelial-to-Mesenchymal Transition in Inflammatory Bowel Disease. J Crohns Colitis 2019; 13:659-668. [PMID: 30520951 DOI: 10.1093/ecco-jcc/jjy201] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Intestinal fibrosis is an inevitable complication in patients with inflammatory bowel disease [IBD], occurring in its two major clinical manifestations: ulcerative colitis and Crohn's disease. Fibrosis represents the final outcome of the host reaction to persistent inflammation, which triggers a prolonged wound healing response resulting in the excessive deposition of extracellular matrix, eventually leading to intestinal dysfunction. The process of epithelial-to-mesenchymal transition [EMT] represents an embryonic program relaunched during wound healing, fibrosis and cancer. Here we discuss the initial observations and the most recent findings highlighting the role of EMT in IBD-associated intestinal fibrosis and fistulae formation. In addition, we briefly review knowledge on the cognate process of endothelial-to-mesenchymal transition [EndMT]. Understanding EMT functionality and the molecular mechanisms underlying the activation of this mesenchymal programme will permit designing new therapeutic strategies to halt the fibrogenic response in the intestine.
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Affiliation(s)
- Sara Lovisa
- Department of Cancer Biology, Metastasis Research Center, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
| | - Giannicola Genovese
- Department of Genomic Medicine, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.,Department of Genitourinary Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
| | - Silvio Danese
- IBD Center, Department of Gastroenterology, Humanitas Research Hospital, Rozzano, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, Italy
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36
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Treatments for Crohn's Disease-Associated Bowel Damage: A Systematic Review. Clin Gastroenterol Hepatol 2019; 17:847-856. [PMID: 30012430 DOI: 10.1016/j.cgh.2018.06.043] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Revised: 06/25/2018] [Accepted: 06/26/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Despite significant advances in the treatment of Crohn's disease (CD), most patients still develop stricturing or penetrating complications that require surgical resections. We performed a systematic review of mechanisms and potential treatments for tissue damage lesions in CD patients. METHODS We searched the PubMed, MBASE, and Cochrane databases from January 1960 to July 2017 for full-length articles on CD, fibrosis, damage lesions, mesenchymal stem cells, and/or treatment. We also searched published conference abstracts and performed manual searches of all reference lists of relevant articles. RESULTS Mechanisms of intestinal damage in patients with CD include fibroblast proliferation and migration, activation of stellate cells, recruitment of intestinal or extra-intestinal fibroblast, and cell trans-differentiation. An altered balance of metalloproteinases and tissue inhibitors of metalloproteinases might contribute to fistula formation. Treatment approaches that reduce excessive transforming growth factor beta (TGFB) activation might be effective in treating established intestinal damage. Stem cell therapies have been effective in tissue damage lesions in CD. Particularly, randomized controlled trials have shown local injections of mesenchymal stem cells to heal perianal fistulas. CONCLUSION In a systematic review of mechanisms and treatments of bowel wall damage in patients with CD, we found a need to test drugs that reduce TGFB and increase healing of transmural damage lesions and to pursue research on local injection of mesenchymal stem cells.
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37
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Tozer PJ, Lung P, Lobo AJ, Sebastian S, Brown SR, Hart AL, Fearnhead N. Review article: pathogenesis of Crohn's perianal fistula-understanding factors impacting on success and failure of treatment strategies. Aliment Pharmacol Ther 2018; 48:260-269. [PMID: 29920706 DOI: 10.1111/apt.14814] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2017] [Revised: 01/22/2018] [Accepted: 04/30/2018] [Indexed: 12/14/2022]
Abstract
BACKGROUND Evidence from groups who have studied fistula aetiology and extrapolation from interventional studies supports a multifactorial hypothesis of Crohn's perianal fistula, with several pathophysiological elements that may contribute to fistula formation, persistence and resistance to treatment. AIM An evidence synthesis of current understanding of pathophysiological factors underlying Crohn's perianal fistula is presented, exploring the fundamental reasons why some treatments succeed and others fail, as a means of focussing clinical knowledge on improving treatment of Crohn's perianal fistula. METHODS Evidence to support this review was gathered via the Pubmed database. Studies discussing pathophysiological factors underpinning perianal fistula, particularly in Crohn's disease, were reviewed and cross-referenced for additional reports. RESULTS Pathophysiological factors that impact on success or failure of interventions for Crohn's perianal fistulae include the high-pressure zone, obliterating the dead space, disconnecting the track from the anus, removing epithelialisation, eradicating sepsis and by-products of bacterial colonisation, correcting abnormalities in wound repair and removing the pro-inflammatory environment which allows fistula persistence. Most current interventions for Crohn's perianal fistulae tend to focus on a single, or at best two, aspects of the pathophysiology of Crohn's anal fistulae; as a result, failure to heal fully is common. CONCLUSIONS For an intervention or combination of interventions to succeed, multiple factors must be addressed. We hypothesise that correct, timely and complete attention to all of these factors in a multimodal approach represents a new direction that may enable the creation of an effective treatment algorithm for Crohn's anal fistula.
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Affiliation(s)
- P J Tozer
- St Mark's Hospital and Imperial College London, London, UK
| | - P Lung
- St Mark's Hospital and Imperial College London, London, UK
| | - A J Lobo
- Academic Unit of Gastroenterology, University of Sheffield, Sheffield, UK
| | - S Sebastian
- IBD Unit, Hull and East Yorkshire Hospitals NHS Trust, Hull, UK
| | - S R Brown
- Sheffield Teaching Hospitals, Sheffield, UK
| | - A L Hart
- St Mark's Hospital and Imperial College London, London, UK
| | - N Fearnhead
- Addenbrookes Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
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38
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Leutenegger M, Bruckner R, Spalinger MR, Lang S, Rogler G, Scharl M. Eribulin Does Not Prevent Epithelial-to-Mesenchymal Transition in HT-29 Intestinal Epithelial Cells. Inflamm Intest Dis 2018; 2:211-218. [PMID: 30221148 DOI: 10.1159/000490052] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Accepted: 05/10/2018] [Indexed: 12/19/2022] Open
Abstract
Background Fistula formation affects up to 50$ of Crohn's disease (CD) patients and causes considerable morbidity. Current pharmacological management mainly includes antibiotics, immunosuppressives, and anti-TNF antibodies. CD fistulas develop from intestinal epithelial cells undergoing epithelial-to-mesenchymal transition (EMT). TGFβ, the most important inducer of EMT, is detectable around CD fistula tracts and induces expression of the EMT-associated transcription factors SNAIL1 and SLUG as well as of IL-13. Conversely, together with TNF, IL-13 induces the expression of the transcription factor Ets-1 and β6-integrin, which are associated with cell invasiveness. Eribulin is a synthetic derivative of halichondrin B, a large polyether macrolide, which reverses EMT in triple-negative breast cancer (TNBC) cells. Here, we investigated whether Eribulin might be a potential therapeutic option for CD fistulas via the inhibition of EMT. Summary Chronic treatment with high concentrations of Eribulin (> 5 ng/ml) is toxic for intestinal epithelial cells (IEC), and Eribulin treatment does not decrease the mRNA expression of EMT markers in HT-29 monolayers nor prevent EMT in HT-29 spheroids. Together with TNF, Eribulin induces the expression of vimentin and SLUG mRNA in HT-29 spheroids but concomitantly also promotes E-cadherin expression. Key Messages Our data suggest that the previously reported antimetastatic effect of Eribulin in TNBC by reversing EMT does not apply to IEC. Interestingly, Eribulin promotes E-cadherin expression, suggesting an additional mechanism. The increase of E-cadherin might point towards the described role for Eribulin in reversing EMT. Taken together, our data do not support a role for Eribulin as treatment option for CD-associated fistulas.
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Affiliation(s)
- Martin Leutenegger
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Ramona Bruckner
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Marianne R Spalinger
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Silvia Lang
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.,Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Michael Scharl
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.,Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
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39
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Epithelial-mesenchymal transition in Crohn's disease. Mucosal Immunol 2018; 11:294-303. [PMID: 29346350 DOI: 10.1038/mi.2017.107] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Accepted: 11/06/2017] [Indexed: 02/06/2023]
Abstract
Crohn's disease (CD) is often accompanied by the complications of intestinal strictures and fistulas. These complications remain obstacles in CD treatment. In recent years, the importance of epithelial-mesenchymal transition in the pathogenesis of CD-associated fistulas and intestinal fibrosis has become apparent. Epithelial-mesenchymal transition refers to a dynamic change, wherein epithelial cells lose their polarity and adherence and acquire migratory function and fibroblast features. During formation of CD-associated fistulas, intestinal epithelial cells dislocate from the basement membrane and migrate to the lining of the fistula tracts, where they convert into transitional cells as a compensatory response under the insufficient wound healing condition. In CD-associated intestinal fibrosis, epithelial-mesenchymal transition may serve as a source of new fibroblasts and consequently lead to overproduction of extracellular matrix. In this review, we present current knowledge of epithelial-mesenchymal transition and its role in the pathogenesis of CD in order to highlight new therapy targets for the associated complications.
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40
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Ibraheim H, Giacomini C, Kassam Z, Dazzi F, Powell N. Advances in mesenchymal stromal cell therapy in the management of Crohn's disease. Expert Rev Gastroenterol Hepatol 2018; 12:141-153. [PMID: 29096549 DOI: 10.1080/17474124.2018.1393332] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The aim of therapy in Crohn's disease (CD) is induction and maintenance of remission, promotion of mucosal healing and restoration of quality of life. Even the best treatment regimes, including combinations of biologics and immunomodulators lack durable efficacy and have well documented side effects. Accordingly, there is an unmet need for novel therapies. Mesenchymal stromal cells (MSCs) are a subset of non-hematopoietic stem cells that home to sites of inflammation where they exert potent immunomodulatory effects and contribute to tissue repair. Their utility is being explored in several inflammatory and immune mediated disorders including CD, where they have demonstrated favourable safety, feasibility and efficacy profiles. Areas covered: This review highlights current knowledge on MSC therapy and critically evaluates their safety, efficacy and potential mechanisms of action in CD. Expert commentary: Building on positive early phase clinical trials and a recent phase 3 trial in perianal CD, there is considerable optimism for the possibility of MSCs changing the treatment landscape in complicated CD. Although important questions remain unanswered, including the safety and durability of MSC therapy, optimal adjunctive therapies and their sourcing and manufacturing, it is anticipated that MSCs are likely to enter mainstream treatment algorithms in the near future.
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Affiliation(s)
- Hajir Ibraheim
- a Department of Gastroenterology , Guy's and St Thomas' Hospital , London , UK
| | - Chiara Giacomini
- b School of Immunology and Microbial Sciences , King's College London , London , UK
| | - Zain Kassam
- b School of Immunology and Microbial Sciences , King's College London , London , UK
| | - Francesco Dazzi
- b School of Immunology and Microbial Sciences , King's College London , London , UK
| | - Nick Powell
- a Department of Gastroenterology , Guy's and St Thomas' Hospital , London , UK.,b School of Immunology and Microbial Sciences , King's College London , London , UK
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41
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Abstract
Fistulas still represent one of the most important complications in patients with Crohn’s disease (CD). At least one third of CD patients suffer from fistulas during their disease course and amongst them longstanding remission of complex fistulas occurs only in about one third. So far, fistula pathogenesis is only partially understood. From a histopathological view, a fistula is a tube covered by flat epithelial cells. Current research suggests that the driving force for fistula development is epithelial-to-mesenchymal transition (EMT). Around the fistula, high levels of tumor necrosis factor (TNF), IL-13, and TGFβ can be detected and recent studies indicated an involvement of the intestinal microbiota. Fistula diagnosis requires clinical and surgical assessment, radiologic investigations, e.g., magnet resonance imaging and endoscopy. Routine medical treatment of fistulas includes antibiotics, immunosuppressives, and anti-TNF antibodies. There is no well-established role for calcineurin inhibitors in fistula treatment, corticosteroids appear to be even contra-productive. A promising novel approach might be the application of adipose tissue-derived or bone marrow-derived mesenchymal stem cells that have been studied recently. Due to insufficient efficacy of medical treatment and recurrence of fistulas, surgical interventions are frequently necessary. Further research is needed to better understand fistula pathogenesis aiming to develop novel treatment option for our patients.
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42
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van Haaften WT, Mortensen JH, Karsdal MA, Bay‐Jensen AC, Dijkstra G, Olinga P. Misbalance in type III collagen formation/degradation as a novel serological biomarker for penetrating (Montreal B3) Crohn's disease. Aliment Pharmacol Ther 2017; 46:26-39. [PMID: 28481042 PMCID: PMC6221070 DOI: 10.1111/apt.14092] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Revised: 08/28/2016] [Accepted: 03/21/2017] [Indexed: 12/14/2022]
Abstract
BACKGROUND Misbalances in extracellular matrix turnover are key factors in the development of stricturing (Montreal B2) and penetrating (Montreal B3) Crohn's disease. AIM To determine whether serological markers for collagen formation and degradation could serve as biomarkers for complications of Crohn's disease. METHODS Serum biomarkers for type I, III, V and VI collagen formation (P1NP, Pro-C3, Pro-C5, Pro-C6) and matrix metalloproteinase mediated degradation (C1M, C3M, C5M and C6M) were measured in a retrospective, single centre cohort of 112 patients with Crohn's disease in the terminal ileum (nonstricturing/nonpenetrating: n=40, stricturing: n=55, penetrating: n=17) and 24 healthy controls. Active inflammation was defined as CRP >5 mg/L. RESULTS C3M and Pro-C5 levels were higher in penetrating vs nonpenetrating/nonstricturing and stricturing disease (33.6±5 vs 25.8±2.2 [P=.004] and 27.2±2.3 [P=.018] nmol/L C3M, 1262.7±259.4 vs 902.9±109.9 [P=.005] and 953.0±106.4 [P=.015] nmol/L Pro-C5). C1M (71.2±26.1 vs 46.2±6.2 nmol/L [P<.001]), C3M (31.6±3.9 vs 26.1±1.6 nmol/L [P=.002] and Pro-C5 levels (1171.7±171.5 vs 909.6±80.4 nmol/L [P=.002]) were higher in patients with active inflammation vs without active inflammation. Pro-C3/C3M-ratios were best to differentiate between penetrating vs nonstricturing/nonpenetrating and stricturing disease with area under the curves of 0.815±0.109 (P<.001) and 0.746±0.114 (P=.002) respectively. CONCLUSIONS Serological biomarkers show that penetrating Crohn's disease is characterised by increased matrix metalloproteinase-9 degraded type III collagen and formation of type V collagen. Active inflammation in Crohn's disease is characterised by increased formation of type V collagen and increased matrix metalloproteinase mediated breakdown of type I, III collagen. Pro-C3/C3M ratios are superior in differentiating between penetrating Crohn's disease vs inflammatory and stricturing Crohn's disease.
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Affiliation(s)
- W. T. van Haaften
- Department of Gastroenterology and HepatologyUniversity Medical Center GroningenUniversity of GroningenGroningenThe Netherlands
- Department of Pharmaceutical Technology and BiopharmacyGroningen Research Institute of PharmacyUniversity of GroningenGroningenThe Netherlands
| | | | - M. A. Karsdal
- Biomarkers and ResearchNordic BioscienceHerlevDenmark
| | | | - G. Dijkstra
- Department of Gastroenterology and HepatologyUniversity Medical Center GroningenUniversity of GroningenGroningenThe Netherlands
| | - P. Olinga
- Department of Pharmaceutical Technology and BiopharmacyGroningen Research Institute of PharmacyUniversity of GroningenGroningenThe Netherlands
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Zeitz J, Fournier N, Labenz C, Biedermann L, Frei P, Misselwitz B, Scharl S, Vavricka SR, Sulz MC, Fried M, Rogler G, Scharl M. Risk Factors for the Development of Fistulae and Stenoses in Crohn Disease Patients in the Swiss Inflammatory Bowel Disease Cohort. Inflamm Intest Dis 2017; 1:172-181. [PMID: 29922674 DOI: 10.1159/000458144] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Accepted: 01/19/2017] [Indexed: 12/14/2022] Open
Abstract
Background Fistulae and stenoses represent frequent and severe complications in patients with Crohn disease (CD). Our study aimed to identify risk factors for fistula and stenosis formation in CD patients. Summary We retrieved data of 1,600 CD patients from the nationwide Swiss Inflammatory Bowel Disease Cohort Study (SIBDCS). The risk for fistulae and stenoses in relation to gender, age at diagnosis, smoking status at diagnosis, and ileal involvement at diagnosis were analyzed. In the multivariate analysis, female gender showed a lower risk for developing perianal and any fistula (risk ratio [RR] 0.721, 95% confidence interval [CI] 0.582-0.893, p = 0.003 and RR 0.717, 95% CI 0.580-0.888, p = 0.002, respectively), and older age at diagnosis showed a lower risk for developing perianal fistula (RR 0.661, 95% CI 0.439-0.995, p = 0.047). Furthermore, ileal involvement was associated with a lower risk for perianal fistula (RR 0.713, 95% CI 0.561-0.906, p = 0.006), a lower risk for any fistula (RR 0.709, 95% CI 0.558-0.901, p = 0.005), and a higher risk for stenosis (RR 2.170, 95% CI 1.728-2.725, p < 0.001). Key Messages In the nationwide SIBDCS, younger age at diagnosis and male gender were risk factors for developing perianal and nonperianal fistulae. Additionally, ileal involvement was revealed to be a potent risk factor (RR 2.170) for developing a stenosis.
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Affiliation(s)
- Jonas Zeitz
- Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Nicolas Fournier
- Institute of Social and Preventive Medicine, Université de Lausanne, Lausanne, Switzerland
| | - Christian Labenz
- Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.,Department of Internal Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Luc Biedermann
- Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Pascal Frei
- Department of Gastroenterology, Gastroenterology Bethanien, University of Zurich, Zurich, Switzerland
| | - Benjamin Misselwitz
- Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Sylvie Scharl
- Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Stephan R Vavricka
- Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.,Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.,Department of Gastroenterology, Triemli Spital, Zurich, Switzerland
| | - Michael C Sulz
- Department of Gastroenterology and Hepatology, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Michael Fried
- Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.,Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Gerhard Rogler
- Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.,Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Michael Scharl
- Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.,Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
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44
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Scharl M, Bruckner RS, Rogler G. The two sides of the coin: Similarities and differences in the pathomechanisms of fistulas and stricture formations in irritable bowel disease. United European Gastroenterol J 2016; 4:506-14. [PMID: 27536360 PMCID: PMC4971795 DOI: 10.1177/2050640616635957] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2015] [Accepted: 01/27/2016] [Indexed: 12/11/2022] Open
Abstract
Fistulas and fibrosis or strictures represent frequent complications in irritable bowel disease (IBD) patients. To date, treatment options for fistulas are limited and surgery is often required. Similarly, no preventive treatment for fibrosis and stricture formation has been established. Frequently, stricture formation and fibrosis precede fistula formation, indicating that both processes may be connected or interrelated. Knowledge about the pathology of both processes is limited. A crucial role for the epithelial-to-mesenchymal transition (EMT) in fistula development has been demonstrated. Of note, EMT also plays a major role in the pathogenesis of fibrosis in many organs, and most likely also plays that role in the intestine. In addition, aberrant matrix remodeling, as well as soluble factors such as tumor necrosis factor (TNF), interleukin 13 (IL-13) and tumor growth factor beta (TGFβ) were involved, both in the onset of the fistula and fibrosis formation. Both fistulas and fibrosis may occur due to deregulated wound healing mechanisms from chronic and severe intestinal inflammation; however, further research is required to obtain a better understanding of the complex pathophysiology of fistula and intestinal fibrosis formation, to allow the development of new and more effective preventive treatment options for those important disease complications.
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Affiliation(s)
- Michael Scharl
- Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Ramona S Bruckner
- Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Gerhard Rogler
- Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
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45
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Siegmund B, Feakins RM, Barmias G, Ludvig JC, Teixeira FV, Rogler G, Scharl M. Results of the Fifth Scientific Workshop of the ECCO (II): Pathophysiology of Perianal Fistulizing Disease. J Crohns Colitis 2016; 10:377-386. [PMID: 26681764 PMCID: PMC4946764 DOI: 10.1093/ecco-jcc/jjv228] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Accepted: 12/08/2015] [Indexed: 12/19/2022]
Abstract
The fifth scientific workshop of the European Crohn's and Colitis Organization (ECCO) focused on the relevance of fistulas to the disease course of patients with Crohn's disease (CD). The objectives were to reach a better understanding of the pathophysiological mechanisms underlying the formation of CD fistulas; to identify future topics in fistula research that could provide insights into pathogenesis; to develop novel therapeutic approaches; and to review current therapeutic strategies (with clarification of existing approaches to prevention, diagnosis and treatment). The results of the workshop are presented in two separate manuscripts. This manuscript describes current state-of-the-art knowledge about fistula pathogenesis, including the roles of epithelial-to-mesenchymal transition and cytokine matrix remodelling enzymes, and highlights the common association between fistulas and stenosis in CD. The review also considers the possible roles that genetic predisposition and intestinal microbiota play in fistula development. Finally, it proposes future directions and needs for fistula research that might substantially increase our understanding of this complex condition and help unravel novel therapeutic strategies and specific targets for treatment. Overall, it aims to highlight unanswered questions in fistula research and to provide a framework for future research work.
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Affiliation(s)
- Britta Siegmund
- Department of Medicine (Gastroenterology, Infectious Diseases, Rheumatology), Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Roger M Feakins
- Department of Histopathology, Royal London Hospital, London, UK
| | - Giorgos Barmias
- Academic Department of Gastroenterology, Ethnikon and Kapodistriakon University of Athens, Laikon Hospital, Athens, Greece
| | - Juliano Coelho Ludvig
- ESADI Clinic and Gastroenterology Unit, Santa Isabel Hospital, Blumenau, Santa Catarina, Brazil
| | - Fabio Vieira Teixeira
- Colorectal Unit, Gastrosaude Clinic, Marilia, Sao Paulo, Brazil Department of Surgery, UNESP Botucatu, Sao Paulo, Brazil
| | - Gerhard Rogler
- Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Michael Scharl
- Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
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46
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Manieri NA, Mack MR, Himmelrich MD, Worthley DL, Hanson EM, Eckmann L, Wang TC, Stappenbeck TS. Mucosally transplanted mesenchymal stem cells stimulate intestinal healing by promoting angiogenesis. J Clin Invest 2015; 125:3606-18. [PMID: 26280574 DOI: 10.1172/jci81423] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2015] [Accepted: 07/08/2015] [Indexed: 12/16/2022] Open
Abstract
Mesenchymal stem cell (MSC) therapy is an emerging field of regenerative medicine; however, it is often unclear how these cells mediate repair. Here, we investigated the use of MSCs in the treatment of intestinal disease and modeled abnormal repair by creating focal wounds in the colonic mucosa of prostaglandin-deficient mice. These wounds developed into ulcers that infiltrated the outer intestinal wall. We determined that penetrating ulcer formation in this model resulted from increased hypoxia and smooth muscle wall necrosis. Prostaglandin I₂ (PGI₂) stimulated VEGF-dependent angiogenesis to prevent penetrating ulcers. Treatment of mucosally injured WT mice with a VEGFR inhibitor resulted in the development of penetrating ulcers, further demonstrating that VEGF is critical for mucosal repair. We next used this model to address the role of transplanted colonic MSCs (cMSCs) in intestinal repair. Compared with intravenously injected cMSCs, mucosally injected cMSCs more effectively prevented the development of penetrating ulcers, as they were more efficiently recruited to colonic wounds. Importantly, mucosally injected cMSCs stimulated angiogenesis in a VEGF-dependent manner. Together, our results reveal that penetrating ulcer formation results from a reduction of local angiogenesis and targeted injection of MSCs can optimize transplantation therapy. Moreover, local MSC injection has potential for treating diseases with features of abnormal angiogenesis and repair.
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47
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Klag T, Goetz M, Stange EF, Wehkamp J. Medical Therapy of Perianal Crohn's Disease. VISZERALMEDIZIN 2015; 31:265-72. [PMID: 26557835 PMCID: PMC4608613 DOI: 10.1159/000434664] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Background Development of perianal fistulas are a common feature of Crohn's disease (CD). Consequences are severe impairment of quality of life as well as potentially life-threatening complications like abscess formation or bacterial sepsis. Therefore, appropriate treatment is an important task in the management of CD. Methods This review describes the epidemiology, pathogenesis, diagnosis, and conservative medical treatment of perianal CD with regard to the available literature. In February 2015, a PubMed search was performed with the following terms (combined and separate): ‘Crohn's disease management’, ‘Crohn's disease complications’, ‘perianal Crohn's disease’, ‘fistulizing Crohn's disease’, ‘perianal fistulas’, ‘fistula healing’, ‘fistula closure’. From the search results, 36 articles were chosen as core elements of this review. Results Pelvic magnetic resonance imaging and rectal endosonography are established diagnostic approaches to evaluate perianal fistulas in conjunction with endoscopy. Antibiotics, thiopurines, and calcineurin inhibitors are useful agents in the management of perianal CD. The availability of anti-TNF-alpha therapies has substantially changed the prospects and goals of medical treatment, and fistula healing seems to be possible in a substantial proportion of patients. Conclusion Antibiotics and several immunosuppressive drugs have improved the treatment of fistulizing CD and should be combined with surgical measures.
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Affiliation(s)
- Thomas Klag
- Department of Internal Medicine I, University of Tübingen, Tübingen, Germany
| | - Martin Goetz
- Department of Internal Medicine I, University of Tübingen, Tübingen, Germany
| | - Eduard F Stange
- Department of Internal Medicine I, Robert-Bosch-Hospital, Stuttgart, Germany
| | - Jan Wehkamp
- Department of Internal Medicine I, University of Tübingen, Tübingen, Germany
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Scharl M, Huber N, Lang S, Fürst A, Jehle E, Rogler G. Hallmarks of epithelial to mesenchymal transition are detectable in Crohn's disease associated intestinal fibrosis. Clin Transl Med 2015; 4:1. [PMID: 25852817 PMCID: PMC4384762 DOI: 10.1186/s40169-015-0046-5] [Citation(s) in RCA: 101] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2014] [Accepted: 01/05/2015] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Intestinal fibrosis and subsequent stricture formation represent frequent complications of Crohn's disease (CD). In many organs, fibrosis develops as a result of epithelial to mesenchymal transition (EMT). Recent studies suggested that EMT could be involved in intestinal fibrosis as a result of chronic inflammation. Here, we investigated whether EMT might be involved in stricture formation in CD patients. METHODS Human colonic tissue specimens from fibrotic areas of 18 CD and 10 non-IBD control patients were studied. Immunohistochemical staining of CD68 (marker for monocytes/macrophages), transforming growth factor-β1 (TGFβ1), β-catenin, SLUG, E-.cadherin, α-smooth muscle actin and fibroblast activation protein (FAP) were performed using standard techniques. RESULTS In fibrotic areas in the intestine of CD patients, a large number of CD68-positive mononuclear cells was detectable suggesting an inflammatory character of the fibrosis. We found stronger expression of TGFβ1, the most powerful driving force for EMT, in and around the fibrotic lesions of CD patients than in non-IBD control patients. In CD patients membrane staining of β-catenin was generally weaker than in control patients and more cells featured nuclear staining indicating transcriptionally active β-catenin, in fibrotic areas. In these regions we also detected nuclear localisation of the transcription factor, SLUG, which has also been implicated in EMT pathogenesis. Adjacent to the fibrotic tissue regions, we observed high levels of FAP, a marker of reactive fibroblasts. CONCLUSIONS We demonstrate the presence of EMT-associated molecules in fibrotic lesions of CD patients. These findings support the hypothesis that EMT might play a role for the development of CD-associated intestinal fibrosis.
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Affiliation(s)
- Michael Scharl
| | - Nicole Huber
| | - Silvia Lang
| | - Alois Fürst
| | - Ekkehard Jehle
| | - Gerhard Rogler
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49
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Marzo M, Felice C, Pugliese D, Andrisani G, Mocci G, Armuzzi A, Guidi L. Management of perianal fistulas in Crohn’s disease: An up-to-date review. World J Gastroenterol 2015; 21:1394-1403. [PMID: 25663759 PMCID: PMC4316082 DOI: 10.3748/wjg.v21.i5.1394] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2014] [Revised: 11/17/2014] [Accepted: 12/16/2014] [Indexed: 02/06/2023] Open
Abstract
Perianal disease is one of the most disabling manifestations of Crohn’s disease. A multidisciplinary approach of gastroenterologist, colorectal surgeon and radiologist is necessary for its management. A correct diagnosis, based on endoscopy, magnetic resonance imaging, endoanal ultrasound and examination under anesthesia, is crucial for perianal fistula treatment. Available medical and surgical therapies are discussed in this review, including new local treatment modalities that are under investigation.
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50
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Abstract
An international consensus on the classification, diagnosis and multidisciplinary treatment of perianal fistulising Crohn's disease has recently been published. The statement is an important starting point to address the many problems we still have with the clinical classification and treatment of fistulising Crohn's disease.
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