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Rusticeanu MA, Zimmer V. Alterations in Intestinal Mucosal Barrier Visualized by Confocal Laser Endomicroscopy in Liver Cirrhosis: A Pilot Trial (AMBIC). Diagnostics (Basel) 2024; 14:1606. [PMID: 39125482 PMCID: PMC11311864 DOI: 10.3390/diagnostics14151606] [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: 06/07/2024] [Revised: 07/15/2024] [Accepted: 07/23/2024] [Indexed: 08/12/2024] Open
Abstract
BACKGROUND Chronic liver disease occurs throughout the world irrespective of region, age, sex, or race, and it is caused by a variety of liver conditions. One of the most frequent infectious complications in liver cirrhosis that severely reduces the median survival is spontaneous bacterial peritonitis. Current guidelines recommend a paracentesis before starting an antibiotic prophylaxis for this complication. METHODS Selective intestinal decontamination significantly lowers the rate of first or recurrent SBP in cirrhotic patients, so in this study we aimed to investigate and quantify the intestinal integrity of patients with liver cirrhosis and correlate a pathologically increased permeability with the incidence of SPB. We included 14 patients who met the inclusion criteria. No patient was excluded. For the CLE investigation, we use probe based confocal laser endomicroscopy techniques from Mauna Kea (Cellvizio), enabling in vivo surface imaging. The images (optical biopsies) were analyzed for functional and structural barrier defects after the procedure using Mauna Kea software (version 1.0.09). RESULTS Because of the small number of included patients and healthy controls, most results are lacking statistical relevance. We found that the CLE investigation showed an increased intestinal permeability in patients with liver cirrhosis, in concordance with previous published data, based on other assessment methods. CONCLUSIONS This study confirms that previously published permeability scores can be applied for patients with liver cirrhosis and is, to our knowledge, the first to investigate the intestinal permeability in vivo in patients with liver cirrhosis. Further data are needed to identify patients at risk and help develop new and less invasive diagnostic criteria for cirrhotic patients who may profit from a prophylactic antibiotic treatment.
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Affiliation(s)
- Monica Alexandrina Rusticeanu
- Department of Gastroenterology, Hospital Asklepios Klinikum Schwalmstadt, Krankenhausstraße 27, 34613 Schwalmstadt, Germany
- Department of Gastroenterology, University Hospital Berne, Freiburgstrasse 18, 3010 Bern, Switzerland
| | - Vincent Zimmer
- Department of Medicine, Hospital Knappschaftsklinikum Saar, In d. Humes 35, 66346 Püttlingen, Germany;
- Department of Medicine II, Saarland University Medical Center, Saarland University, 66421 Homburg, Germany
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2
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Pal P, Ramchandani M, Patel R, Banerjee R, Kanaganti S, Gupta R, Tandan M, Reddy DN. Role of ultra-high definition endoscopy (endomicroscopy and endocytoscopy) and real-time histologic examination in inflammatory bowel disease: Scoping review. Dig Endosc 2024; 36:274-289. [PMID: 37573562 DOI: 10.1111/den.14659] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 08/06/2023] [Indexed: 08/15/2023]
Abstract
OBJECTIVES Confocal laser endomicroscopy (CLE) and endocytoscopy (EC) are ultra-high definition (HD) imaging modalities that enable real-time histological assessment. Although existent for nearly two decades, their role in current clinical decision making in inflammatory bowel disease management is not well defined. METHODS We searched PubMed using keywords ("confocal" OR "CLE" OR "endocytoscopy") AND ("IBD" OR "inflammatory bowel" OR "Crohn*" OR "Crohn's" OR "colitis ulcerosa" OR "ulcerative colitis") between 2005 and March 2023. We identified 52 studies for detailed review. RESULTS Confocal laser endomicroscopy was useful in real-time assessment of histologic inflammation and dysplasia characterization in both ulcerative colitis (UC) and Crohn's disease. Although CLE was associated with higher per-biopsy yield for UC-associated neoplasia (UCAN), the benefit was offset by higher procedure time, frequent equipment failure, and conflicting results on incremental yield over chromoendoscopy. Assessment of barrier dysfunction by CLE did not correlate with disease/endoscopic activity but could predict major adverse outcomes. The implications of residual CLE abnormalities in endoscopic remission remain uncertain. Ex vivo binding of labeled biologics can help in predicting biologic response in UC. EC can discriminate mucosal inflammatory cells by morphology and allows assessment of histologic activity. EC combined with pit pattern was better than pit pattern alone for UCAN. Artificial intelligence-assisted EC in UCAN needs further study. CONCLUSION Ultra-HD imaging in inflammatory bowel disease can be useful in assessment of UCAN, barrier dysfunction, predicting histologic remission, and biologic response. Future controlled studies are warranted to define the role of these novel technologies in clinical decision making.
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Affiliation(s)
- Partha Pal
- Asian Institute of Gastroenterology, Hyderabad, India
| | | | | | - Rupa Banerjee
- Asian Institute of Gastroenterology, Hyderabad, India
| | | | - Rajesh Gupta
- Asian Institute of Gastroenterology, Hyderabad, India
| | - Manu Tandan
- Asian Institute of Gastroenterology, Hyderabad, India
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Quansah E, Gardey E, Ramoji A, Meyer-Zedler T, Goehrig B, Heutelbeck A, Hoeppener S, Schmitt M, Waldner M, Stallmach A, Popp J. Intestinal epithelial barrier integrity investigated by label-free techniques in ulcerative colitis patients. Sci Rep 2023; 13:2681. [PMID: 36792686 PMCID: PMC9931702 DOI: 10.1038/s41598-023-29649-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 02/08/2023] [Indexed: 02/17/2023] Open
Abstract
The intestinal epithelial barrier, among other compartments such as the mucosal immune system, contributes to the maintenance of intestinal homeostasis. Therefore, any disturbance within the epithelial layer could lead to intestinal permeability and promote mucosal inflammation. Considering that disintegration of the intestinal epithelial barrier is a key element in the etiology of ulcerative colitis, further assessment of barrier integrity could contribute to a better understanding of the role of epithelial barrier defects in ulcerative colitis (UC), one major form of chronic inflammatory bowel disease. Herein, we employ fast, non-destructive, and label-free non-linear methods, namely coherent anti-Stokes Raman scattering (CARS), second harmonic generation (SHG), two-photon excited fluorescence (TPEF), and two-photon fluorescence lifetime imaging (2P-FLIM), to assess the morpho-chemical contributions leading to the dysfunction of the epithelial barrier. For the first time, the formation of epithelial barrier gaps was directly visualized, without sophisticated data analysis procedures, by the 3D analysis of the colonic mucosa from severely inflamed UC patients. The results were compared with histopathological and immunofluorescence images and validated using transmission electron microscopy (TEM) to indicate structural alterations of the apical junction complex as the underlying cause for the formation of the epithelial barrier gaps. Our findings suggest the potential advantage of non-linear multimodal imaging is to give precise, detailed, and direct visualization of the epithelial barrier in the gastrointestinal tract, which can be combined with a fiber probe for future endomicroscopy measurements during real-time in vivo imaging.
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Affiliation(s)
- Elsie Quansah
- Institute of Physical Chemistry and Abbe Center of Photonics (IPC), Member of the Leibniz Centre for Photonics in Infection Research (LPI), Friedrich Schiller University Jena, Helmholtzweg 4, 07743, Jena, Germany
- Leibniz Institute of Photonic Technology (IPHT), Member of Leibniz Health Technologies, Member of the Leibniz Centre for Photonics in Infection Research (LPI), Albert-Einstein-Straße 9, 07745, Jena, Germany
| | - Elena Gardey
- Department of Internal Medicine IV (Gastroenterology, Hepatology, Infectious Diseases and Interdisciplinary Endoscopy), Jena University Hospital, Friedrich Schiller University Jena, Am Klinikum 1, 07747, Jena, Germany
- Friedrich Schiller University Jena, Jena Center for Soft Matter (JCSM), Philosophenweg 7, 07743, Jena, Germany
| | - Anuradha Ramoji
- Institute of Physical Chemistry and Abbe Center of Photonics (IPC), Member of the Leibniz Centre for Photonics in Infection Research (LPI), Friedrich Schiller University Jena, Helmholtzweg 4, 07743, Jena, Germany.
- Leibniz Institute of Photonic Technology (IPHT), Member of Leibniz Health Technologies, Member of the Leibniz Centre for Photonics in Infection Research (LPI), Albert-Einstein-Straße 9, 07745, Jena, Germany.
- Jena University Hospital, Center for Sepsis Control and Care (CSCC), Friedrich Schiller University Jena, Erlanger Allee 101, 07747, Jena, Germany.
| | - Tobias Meyer-Zedler
- Institute of Physical Chemistry and Abbe Center of Photonics (IPC), Member of the Leibniz Centre for Photonics in Infection Research (LPI), Friedrich Schiller University Jena, Helmholtzweg 4, 07743, Jena, Germany
- Leibniz Institute of Photonic Technology (IPHT), Member of Leibniz Health Technologies, Member of the Leibniz Centre for Photonics in Infection Research (LPI), Albert-Einstein-Straße 9, 07745, Jena, Germany
| | - Bianca Goehrig
- Institute for Occupational, Social, and Environmental Medicine, Jena University Hospital, Friedrich Schiller University Jena, Am Klinikum 1, 07747, Jena, Germany
| | - Astrid Heutelbeck
- Institute for Occupational, Social, and Environmental Medicine, Jena University Hospital, Friedrich Schiller University Jena, Am Klinikum 1, 07747, Jena, Germany
| | - Stephanie Hoeppener
- Friedrich Schiller University Jena, Jena Center for Soft Matter (JCSM), Philosophenweg 7, 07743, Jena, Germany
- Laboratory of Organic and Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena, Humboldtstraße 10, 07743, Jena, Germany
| | - Michael Schmitt
- Institute of Physical Chemistry and Abbe Center of Photonics (IPC), Member of the Leibniz Centre for Photonics in Infection Research (LPI), Friedrich Schiller University Jena, Helmholtzweg 4, 07743, Jena, Germany
- Leibniz Institute of Photonic Technology (IPHT), Member of Leibniz Health Technologies, Member of the Leibniz Centre for Photonics in Infection Research (LPI), Albert-Einstein-Straße 9, 07745, Jena, Germany
| | - Maximillian Waldner
- Department of Medicine, University of Erlangen-Nuremberg, 91054, Erlangen, Germany
| | - Andreas Stallmach
- Department of Internal Medicine IV (Gastroenterology, Hepatology, Infectious Diseases and Interdisciplinary Endoscopy), Jena University Hospital, Friedrich Schiller University Jena, Am Klinikum 1, 07747, Jena, Germany
- Friedrich Schiller University Jena, Jena Center for Soft Matter (JCSM), Philosophenweg 7, 07743, Jena, Germany
| | - Jürgen Popp
- Institute of Physical Chemistry and Abbe Center of Photonics (IPC), Member of the Leibniz Centre for Photonics in Infection Research (LPI), Friedrich Schiller University Jena, Helmholtzweg 4, 07743, Jena, Germany
- Leibniz Institute of Photonic Technology (IPHT), Member of Leibniz Health Technologies, Member of the Leibniz Centre for Photonics in Infection Research (LPI), Albert-Einstein-Straße 9, 07745, Jena, Germany
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Ngo PA, Neurath MF, López-Posadas R. Impact of Epithelial Cell Shedding on Intestinal Homeostasis. Int J Mol Sci 2022; 23:ijms23084160. [PMID: 35456978 PMCID: PMC9027054 DOI: 10.3390/ijms23084160] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Revised: 04/05/2022] [Accepted: 04/06/2022] [Indexed: 02/04/2023] Open
Abstract
The gut barrier acts as a first line of defense in the body, and plays a vital role in nutrition and immunoregulation. A layer of epithelial cells bound together via intercellular junction proteins maintains intestinal barrier integrity. Based on a tight equilibrium between cell extrusion and cell restitution, the renewal of the epithelium (epithelial turnover) permits the preservation of cell numbers. As the last step within the epithelial turnover, cell shedding occurs due to the pressure of cell division and migration from the base of the crypt. During this process, redistribution of tight junction proteins enables the sealing of the epithelial gap left by the extruded cell, and thereby maintains barrier function. Disturbance in cell shedding can create transient gaps (leaky gut) or cell accumulation in the epithelial layer. In fact, numerous studies have described the association between dysregulated cell shedding and infection, inflammation, and cancer; thus epithelial cell extrusion is considered a key defense mechanism. In the gastrointestinal tract, altered cell shedding has been observed in mouse models of intestinal inflammation and appears as a potential cause of barrier loss in human inflammatory bowel disease (IBD). Despite the relevance of this process, there are many unanswered questions regarding cell shedding. The investigation of those mechanisms controlling cell extrusion in the gut will definitely contribute to our understanding of intestinal homeostasis. In this review, we summarized the current knowledge about intestinal cell shedding under both physiological and pathological circumstances.
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Affiliation(s)
- Phuong A. Ngo
- Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; (P.A.N.); (M.F.N.)
- Deutsches Zentrum Immuntherapie (DZI), 91054 Erlangen, Germany
| | - Markus F. Neurath
- Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; (P.A.N.); (M.F.N.)
- Deutsches Zentrum Immuntherapie (DZI), 91054 Erlangen, Germany
| | - Rocío López-Posadas
- Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; (P.A.N.); (M.F.N.)
- Deutsches Zentrum Immuntherapie (DZI), 91054 Erlangen, Germany
- Correspondence:
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Hartwig O, Loretz B, Nougarede A, Jary D, Sulpice E, Gidrol X, Navarro F, Lehr CM. Leaky gut model of the human intestinal mucosa for testing siRNA-based nanomedicine targeting JAK1. J Control Release 2022; 345:646-660. [PMID: 35339579 PMCID: PMC9168449 DOI: 10.1016/j.jconrel.2022.03.037] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 03/11/2022] [Accepted: 03/20/2022] [Indexed: 02/07/2023]
Abstract
Complex in vitro models of human immune cells and intestinal mucosa may have a translation-assisting role in the assessment of anti-inflammatory compounds. Chronic inflammation of the gastrointestinal tract is a hallmark of inflammatory bowel diseases (IBD). In both IBD entities, Crohn's disease and ulcerative colitis, impaired immune cell activation and dysfunctional epithelial barrier are the common pathophysiology. Current therapeutic approaches are targeting single immune modulator molecules to stop disease progression and reduce adverse effects. Such molecular targets can be difficult to assess in experimental animal models of colitis, due to the disease complexity and species differences. Previously, a co-culture model based on human epithelial cells and monocytes arranged in a physiological microenvironment was used to mimic inflamed mucosa for toxicological and permeability studies. The leaky gut model described here, a co-culture of Caco-2, THP-1 and MUTZ-3 cells, was used to mimic IBD-related pathophysiology and for combined investigations of permeability and target engagement of two Janus kinase (JAK) inhibitors, tofacitinib (TOFA) and a JAK1-targeting siRNA nanomedicine. The co-culture just before reaching confluency of the epithelium was used to mimic the compromised intestinal barrier. Delivery efficacy and target engagement against JAK1 was quantified via downstream analysis of STAT1 protein phosphorylation after IFN-γ stimulation. Compared to a tight barrier, the leaky gut model showed 92 ± 5% confluence, a barrier function below 200 Ω*cm2, and enhanced immune response to bacteria-derived lipopolysaccharides. By confocal microscopy we observed an increased accumulation of siJAK1-nanoparticles within the sub-confluent regions leading to uptake into immune cells near the epithelium. A concentration-dependent downregulation of JAK/STAT pathway was observed for siJAK1-nanoparticles (10 ± 12% to 16 ± 12%), whereas TOFA inhibition was 86 ± 2%, compared to untreated cells. By mimicking the status of severely damaged epithelium, like in IBD, the leaky gut model holds promise as a human in vitro system to evaluate the efficacy of anti-inflammatory drugs and nanomedicines.
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Affiliation(s)
- Olga Hartwig
- Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), D-66123 Saarbrücken, Germany; Department of Pharmacy, Saarland University, D-66123 Saarbrücken, Germany
| | - Brigitta Loretz
- Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), D-66123 Saarbrücken, Germany.
| | - Adrien Nougarede
- University Grenoble Alpes, F-38000 Grenoble, France; CEA LETI, Minatec Campus, F-38054 Grenoble, France
| | - Dorothée Jary
- University Grenoble Alpes, F-38000 Grenoble, France; CEA LETI, Minatec Campus, F-38054 Grenoble, France
| | - Eric Sulpice
- University Grenoble Alpes, CEA, INSERM, IRIG, Biomics, F-38000 Grenoble, France
| | - Xavier Gidrol
- University Grenoble Alpes, CEA, INSERM, IRIG, Biomics, F-38000 Grenoble, France
| | - Fabrice Navarro
- University Grenoble Alpes, F-38000 Grenoble, France; CEA LETI, Minatec Campus, F-38054 Grenoble, France
| | - Claus-Michael Lehr
- Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), D-66123 Saarbrücken, Germany; Department of Pharmacy, Saarland University, D-66123 Saarbrücken, Germany
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6
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Pilonis ND, Januszewicz W, di Pietro M. Confocal laser endomicroscopy in gastro-intestinal endoscopy: technical aspects and clinical applications. Transl Gastroenterol Hepatol 2022; 7:7. [PMID: 35243116 PMCID: PMC8826043 DOI: 10.21037/tgh.2020.04.02] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2019] [Accepted: 03/30/2020] [Indexed: 08/24/2023] Open
Abstract
Confocal laser endomicroscopy (CLE) is an advanced endoscopic imaging technology that provides a magnified, cellular level view of gastrointestinal epithelia. In conjunction with topical or intravenous fluorescent dyes, CLE allows for an "optical biopsy" for real-time diagnosis. Two different CLE system have been used in clinical endoscopy, probe-based CLE (pCLE) and endoscope-based CLE (eCLE). Using pCLE, the device can be delivered: (I) into the luminal gastrointestinal tract through the working channel of standard endoscopes; (II) into extraluminal cystic and solid parenchymal lesions through an endoscopic ultrasound (EUS) needle; or (III) into the biliary system through an endoscopic retrograde cholangiopancreatography (ERCP) accessory channel. With eCLE, the probe is directly integrated into the tip of a conventional endoscope, however, these endoscopes are no longer commercially available. CLE has moderate to high diagnostic accuracy for neoplastic and inflammatory conditions through the gastrointestinal tract including: oesophageal, gastric and colonic neoplasia, pancreatic cysts and solid lesions, malignant pancreatobiliary strictures and inflammatory bowel disease. Some studies have demonstrated the diagnostic benefit of CLE imaging when combined with either conventional white light endoscopy or advanced imaging technologies. Therefore, optical biopsies using CLE can resolve diagnostic dilemmas in some cases where conventional imaging fails to achieve conclusive results. CLE could also reduce the requirement for extensive tissue sampling during surveillance procedures. In the future, CLE in combination with molecular probes, could allow for the molecular characterization of diseases and assess response to targeted therapy. However, the narrow field of view, high capital costs and specialized operator training requirements remain the main limitations. Future multi-center, randomized trials with a focus on conventional diagnostic applications, cost-effectiveness and standardized training will be required for definitive evidence. The objective of this review is to evaluate the technical aspects and current applications of CLE in patients with gastrointestinal and pancreatobiliary diseases and discuss future directions for this technique.
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Affiliation(s)
- Nastazja Dagny Pilonis
- MRC Cancer Unit at the University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
- Department of Gastroenterology, Hepatology and Clinical Oncology, Medical Centre for Postgraduate Education, Warsaw, Poland
- Department of Gastroenterological Oncology, the Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland
| | - Wladyslaw Januszewicz
- Department of Gastroenterology, Hepatology and Clinical Oncology, Medical Centre for Postgraduate Education, Warsaw, Poland
- Department of Gastroenterological Oncology, the Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland
| | - Massimiliano di Pietro
- MRC Cancer Unit at the University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
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Rusticeanu M, Zimmer V, Lammert F. Visualising and quantifying intestinal permeability -where do we stand. Ann Hepatol 2022; 23:100266. [PMID: 33045414 DOI: 10.1016/j.aohep.2020.09.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 09/20/2020] [Accepted: 09/20/2020] [Indexed: 02/04/2023]
Abstract
Intestinal permeability is getting more and more attention in gastrointestinal research. Although well recognized, its exact role in health and disease is yet to be defined. There are many methods of quantifying intestinal permeability, but most of them fail to deliver tangible information about the morphological integrity of the intestinal barrier. In this review we aim to describe imaging options for the assessment of intestinal barrier integrity and their potential relevance for clinical practice. Our focus is on confocal laser endomicroscopy, which is at this time the only method for visualizing not only functional but also morphological aspects of the gut barrier in vivo.
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Affiliation(s)
- Monica Rusticeanu
- Department of Medicine, Krankenhaus Vilshofen, Krankenhausstrasse 32, 94474 Vislhofen an der Donau, Germany.
| | - Vincent Zimmer
- Department of Medicine, Marienhausklinik St. Josef Kohlhof, Klinikweg 1-5, 66539 Neunkirchen, Germany; Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.
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Kociszewska D, Chan J, Thorne PR, Vlajkovic SM. The Link between Gut Dysbiosis Caused by a High-Fat Diet and Hearing Loss. Int J Mol Sci 2021; 22:13177. [PMID: 34947974 PMCID: PMC8708400 DOI: 10.3390/ijms222413177] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 12/02/2021] [Accepted: 12/06/2021] [Indexed: 12/17/2022] Open
Abstract
This review aims to provide a conceptual and theoretical overview of the association between gut dysbiosis and hearing loss. Hearing loss is a global health issue; the World Health Organisation (WHO) estimates that 2.5 billion people will be living with some degree of hearing loss by 2050. The aetiology of sensorineural hearing loss (SNHL) is complex and multifactorial, arising from congenital and acquired causes. Recent evidence suggests that impaired gut health may also be a risk factor for SNHL. Inflammatory bowel disease (IBD), type 2 diabetes, diet-induced obesity (DIO), and high-fat diet (HFD) all show links to hearing loss. Previous studies have shown that a HFD can result in microangiopathy, impaired insulin signalling, and oxidative stress in the inner ear. A HFD can also induce pathological shifts in gut microbiota and affect intestinal barrier (IB) integrity, leading to a leaky gut. A leaky gut can result in chronic systemic inflammation, which may affect extraintestinal organs. Here, we postulate that changes in gut microbiota resulting from a chronic HFD and DIO may cause a systemic inflammatory response that can compromise the permeability of the blood-labyrinth barrier (BLB) in the inner ear, thus inducing cochlear inflammation and hearing deficits.
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Affiliation(s)
| | | | | | - Srdjan M. Vlajkovic
- Department of Physiology and The Eisdell Moore Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag, Auckland 1142, New Zealand; (D.K.); (J.C.); (P.R.T.)
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Moriichi K, Fujiya M, Okumura T. The endoscopic diagnosis of mucosal healing and deep remission in inflammatory bowel disease. Dig Endosc 2021; 33:1008-1023. [PMID: 33020947 DOI: 10.1111/den.13863] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 09/24/2020] [Accepted: 09/28/2020] [Indexed: 12/13/2022]
Abstract
The therapeutic goal in inflammatory bowel disease (IBD) patients has shifted from controlling the clinical activity alone to managing other associated problems. The concept of mucosal healing (MH) and deep remission (DR) are advocated and regarded as new therapeutic goals in IBD. However, the definition of MH still remains controversial. It is unclear whether or not the histological structures or functional factors should be included in the definition of DR in addition to clinical remission and MH. The classifications of white-light imaging (e.g. Mayo endoscopic subscore, UCEIS, CD Endoscopic Index of Severity, simple Endoscopic Score-CD) have been proposed and are now widely used to assess the severity as well as the MH of inflammation in IBD. In ulcerative colitis, magnifying chromoendoscopy has been shown to be useful to assess the MH of inflammation while other types of image-enhanced endoscopy, such as narrow-band imaging, have not. Endocytoscopy and confocal laser endomicroscopy (CLE) are also applied to assess the activity in IBD. These endoscopic procedures can estimate MH with more precision through observing the details of superficial structures, such as crypt openings. In addition, CLE can partially assess the mucosal function by detecting fluorescence leakage. Molecular imaging can possibly detect the molecules associated with inflammation, intestinal regeneration and differentiation, and various functions including the intestinal barrier and mucus secretion. These novel procedures may improve the diagnosis strategy of DR through the assessment of DR-associated factors such as the histological structures and functional factors in the near future.
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Affiliation(s)
- Kentaro Moriichi
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Hokkaido, Japan
| | - Mikihiro Fujiya
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Hokkaido, Japan
| | - Toshikatsu Okumura
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Hokkaido, Japan
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Rahmi G, Coron E, Perrod G, Levy M, Moreau J, Moussata D, Perez-Cuadrado-Robles E, Chupin A, Quénéhervé L, Bourreille A, Marchal A, Cellier C, Peyrin-Biroulet L. Probe-based Confocal Laser Endomicroscopy for In Vivo Assessment of Histological Healing in Ulcerative Colitis: Development and Validation of the ENHANCE Index. J Crohns Colitis 2021; 15:994-999. [PMID: 33336249 DOI: 10.1093/ecco-jcc/jjaa255] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [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 Histological healing may represent the ultimate therapeutic goal in ulcerative colitis [UC], but it requires biopsies. Our aim was to develop a non-invasive index able to assess histological disease activity in ulcerative colitis, using probe-based confocal laser endomicroscopy [pCLE]. METHODS One hundred patients with quiescent UC were prospectively included in five French centres. After fluorescein intravenous injection, during colonoscopy, the colorectal mucosa was analysed by white light imaging and pCLE, and then biopsied in different locations. Five endoscopists performed central reading of pCLE images blinded to clinical, endoscopic, and histological data. One expert pathologist performed a central histological reading [Nancy index: gold standard]. Univariate and multivariate analyses were performed to identify the endomicroscopic items associated with the presence of histologically active disease. RESULTS Over 1000 pCLE videos sequences performed in 100 UC patients in endoscopic remission [Mayo 0 and 1] were evaluated. We observed that vessel diameter >20 µm, dilated crypt lumen, fluorescein leakage, and irregular crypt architecture were statistically associated with histologically proven inflammation according to the Nancy index. Hence, we built a pCLE index of mucosal inflammation with overall accuracy of 79.6% and overall sensitivity and specificity of, respectively, 57.8% and 82.8%. Negative predictive value, especially when a pCLE index ≤1 was observed, was high [93.1%]. CONCLUSIONS Using a robust methodology, large vessel diameter, dilated crypt lumen, fluorescein leakage,and irregular crypt architecture are reliable endomicroscopic items defining the ENHANCE index for real-time assessment of histological disease activity in UC.
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Affiliation(s)
- Gabriel Rahmi
- Hepato-Gastroenterology and Digestive Endoscopy Department, Georges Pompidou European Hospital, APHP Centre-Université de Paris, Paris, France
| | - Emmanuel Coron
- CHU Nantes, Institut des Maladies de l'Appareil Digestif [IMAD], University of Nantes, Nantes, France
| | - Guillaume Perrod
- Hepato-Gastroenterology and Digestive Endoscopy Department, Georges Pompidou European Hospital, APHP Centre-Université de Paris, Paris, France
| | - Michael Levy
- Department of Hepato-Gastroenterology, Henri Mondor Hospital, Université Paris Est, Paris, France
| | - Jacques Moreau
- Department of Hepato-Gastroenterology, Rangueil Hospital, CHU Toulouse, Toulouse, France
| | - Driffa Moussata
- Department of Hepato-Gastroenterology, CHU Tours, Tours, France
| | - Enrique Perez-Cuadrado-Robles
- Hepato-Gastroenterology and Digestive Endoscopy Department, Georges Pompidou European Hospital, APHP Centre-Université de Paris, Paris, France
| | - Antoine Chupin
- Hepato-Gastroenterology and Digestive Endoscopy Department, Georges Pompidou European Hospital, APHP Centre-Université de Paris, Paris, France
| | - Lucille Quénéhervé
- CHU Nantes, Institut des Maladies de l'Appareil Digestif [IMAD], University of Nantes, Nantes, France
| | - Arnaud Bourreille
- CHU Nantes, Institut des Maladies de l'Appareil Digestif [IMAD], University of Nantes, Nantes, France
| | - Aude Marchal
- Department of Pathology, CHU Reims, Reims, France
| | - Christophe Cellier
- Hepato-Gastroenterology and Digestive Endoscopy Department, Georges Pompidou European Hospital, APHP Centre-Université de Paris, Paris, France
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, University Hospital of Nancy-Brabois, Lorraine University, Vandœuvre-lès-Nancy, France
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11
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Tontini GE, Rimondi A, Vernero M, Neumann H, Vecchi M, Bezzio C, Cavallaro F. Artificial intelligence in gastrointestinal endoscopy for inflammatory bowel disease: a systematic review and new horizons. Therap Adv Gastroenterol 2021; 14:17562848211017730. [PMID: 34178115 PMCID: PMC8202249 DOI: 10.1177/17562848211017730] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Accepted: 04/26/2021] [Indexed: 02/04/2023] Open
Abstract
INTRODUCTION Since the advent of artificial intelligence (AI) in clinical studies, luminal gastrointestinal endoscopy has made great progress, especially in the detection and characterization of neoplastic and preneoplastic lesions. Several studies have recently shown the potential of AI-driven endoscopy for the investigation of inflammatory bowel disease (IBD). This systematic review provides an overview of the current position and future potential of AI in IBD endoscopy. METHODS A systematic search was carried out in PubMed and Scopus up to 2 December 2020 using the following search terms: artificial intelligence, machine learning, computer-aided, inflammatory bowel disease, ulcerative colitis (UC), Crohn's disease (CD). All studies on human digestive endoscopy were included. A qualitative analysis and a narrative description were performed for each selected record according to the Joanna Briggs Institute methodologies and the PRISMA statement. RESULTS Of 398 identified records, 18 were ultimately included. Two-thirds of these (12/18) were published in 2020 and most were cross-sectional studies (15/18). No relevant bias at the study level was reported, although the risk of publication bias across studies cannot be ruled out at this early stage. Eleven records dealt with UC, five with CD and two with both. Most of the AI systems involved convolutional neural network, random forest and deep neural network architecture. Most studies focused on capsule endoscopy readings in CD (n = 5) and on the AI-assisted assessment of mucosal activity in UC (n = 10) for automated endoscopic scoring or real-time prediction of histological disease. DISCUSSION AI-assisted endoscopy in IBD is a rapidly evolving research field with promising technical results and additional benefits when tested in an experimental clinical scenario. External validation studies being conducted in large and prospective cohorts in real-life clinical scenarios will help confirm the added value of AI in assessing UC mucosal activity and in CD capsule reading. PLAIN LANGUAGE SUMMARY Artificial intelligence for inflammatory bowel disease endoscopy Artificial intelligence (AI) is a promising technology in many areas of medicine. In recent years, AI-assisted endoscopy has been introduced into several research fields, including inflammatory bowel disease (IBD) endoscopy, with promising applications that have the potential to revolutionize clinical practice and gastrointestinal endoscopy.We have performed the first systematic review of AI and its application in the field of IBD and endoscopy.A formal process of paper selection and analysis resulted in the assessment of 18 records. Most of these (12/18) were published in 2020 and were cross-sectional studies (15/18). No relevant biases were reported. All studies showed positive results concerning the novel technology evaluated, so the risk of publication bias cannot be ruled out at this early stage.Eleven records dealt with UC, five with CD and two with both. Most studies focused on capsule endoscopy reading in CD patients (n = 5) and on AI-assisted assessment of mucosal activity in UC patients (n = 10) for automated endoscopic scoring and real-time prediction of histological disease.We found that AI-assisted endoscopy in IBD is a rapidly growing research field. All studies indicated promising technical results. When tested in an experimental clinical scenario, AI-assisted endoscopy showed it could potentially improve the management of patients with IBD.Confirmatory evidence from real-life clinical scenarios should be obtained to verify the added value of AI-assisted IBD endoscopy in assessing UC mucosal activity and in CD capsule reading.
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Affiliation(s)
- Gian Eugenio Tontini
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Alessandro Rimondi
- Department of Pathophysiology and Organ Transplantation, Università degli Studi di Milano, Via Francesco Sforza 35, Milano 20122, Italy
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Marta Vernero
- Gastroenterology Unit, Rho Hospital, ASST Rhodense, Milan, Italy
| | - Helmut Neumann
- Department of Interdisciplinary Endoscopy, University Hospital Mainz, Mainz, Germany
| | - Maurizio Vecchi
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Cristina Bezzio
- Gastroenterology Unit, Rho Hospital, ASST Rhodense, Milan, Italy
| | - Flaminia Cavallaro
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
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12
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Mathavarajah S, VanIderstine C, Dellaire G, Huber RJ. Cancer and the breakdown of multicellularity: What Dictyostelium discoideum, a social amoeba, can teach us. Bioessays 2021; 43:e2000156. [PMID: 33448043 DOI: 10.1002/bies.202000156] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 12/11/2020] [Accepted: 12/17/2020] [Indexed: 01/01/2023]
Abstract
Ancient pathways promoting unicellularity and multicellularity are associated with cancer, the former being pro-oncogenic and the latter acting to suppress oncogenesis. However, there are only a limited number of non-vertebrate models for studying these pathways. Here, we review Dictyostelium discoideum and describe how it can be used to understand these gene networks. D. discoideum has a unicellular and multicellular life cycle, making it possible to study orthologs of cancer-associated genes in both phases. During development, differentiated amoebae form a fruiting body composed of a mass of spores that are supported atop a stalk. A portion of the cells sacrifice themselves to become non-reproductive stalk cells. Cheating disrupts the principles of multicellularity, as cheater cells alter their cell fate to preferentially become spores. Importantly, D. discoideum has gene networks and several strategies for maintaining multicellularity. Therefore, D. discoideum can help us better understand how conserved genes and pathways involved in multicellularity also influence cancer development, potentially identifying new therapeutic avenues.
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Affiliation(s)
- Sabateeshan Mathavarajah
- Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Carter VanIderstine
- Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Graham Dellaire
- Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.,Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Robert J Huber
- Department of Biology, Trent University, Peterborough, Ontario, Canada
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13
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Hugenschmidt H, Labori KJ, Brunborg C, Verbeke CS, Seeberg LT, Bendigtsen Schirmer C, Renolen A, Borgen E, Naume B, Wiedswang G. Cytokeratin-positive cells in the bone marrow from patients with pancreatic, periampullary malignancy and benign pancreatic disease show no prognostic information. BMC Cancer 2020; 20:1107. [PMID: 33198661 PMCID: PMC7667773 DOI: 10.1186/s12885-020-07510-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 10/07/2020] [Indexed: 12/11/2022] Open
Abstract
Background Pancreatic and periampullary carcinoma are aggressive tumours where preoperative assessment is challenging. Disseminated tumour cells (DTC) in the bone marrow (BM) are associated with impaired prognosis in a variety of epithelial cancers. In a cohort of patients with presumed resectable pancreatic and periampullary carcinoma, we evaluated the frequency and the potential prognostic impact of the preoperative presence of DTC, defined as cytokeratin-positive cells detected by immunocytochemistry (ICC). Methods Preoperative BM samples from 242 patients selected for surgical resection of presumed resectable pancreatic and periampullary carcinoma from 09/2009 to 12/2014, were analysed for presence of CK-positive cells by ICC. The median observation time was 21.5 months. Overall survival (OS) and disease-free survival (DFS) were calculated by Kaplan-Meier and Cox regression analysis. Results Successful resections of malignant tumours were performed in 179 of the cases, 30 patients resected had benign pancreatic disease based on postoperative histology, and 33 were deemed inoperable intraoperatively due to advanced disease. Overall survival for patients with resected carcinoma was 21.1 months (95% CI: 18.0–24.1), for those with benign disease OS was 101 months (95% CI: 69.4–132) and for those with advanced disease OS was 8.8 months (95% CI: 4.3–13.3). The proportion of patients with detected CK-positive cells was 6/168 (3.6%) in resected malignant cases, 2/31 (6.5%) in advanced disease and 4/29 (13.8%) in benign disease. The presence of CK-positive cells was not correlated to OS or DFS, neither in the entire cohort nor in the subgroup negative for circulating tumour cells (CTC). Conclusions The results indicate that CK-positive cells may be present in both patients with malignant and benign diseases of the pancreas. Detection of CK-positive cells was not associated with differences in prognosis for the entire cohort or any of the subgroups analysed. Trial registration clinicaltrials.gov (NCT01919151).
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Affiliation(s)
- Harald Hugenschmidt
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway. .,Department of Transplantation Surgery, Oslo University Hospital, PO.Box 4950, NO-0424, Oslo, Nydalen, Norway. .,Department of Gastrointestinal Surgery, Oslo University Hospital, Oslo, Norway.
| | - Knut Jørgen Labori
- Department of Gastrointestinal Surgery, Oslo University Hospital, Oslo, Norway
| | - Cathrine Brunborg
- Oslo Centre for Biostatistics and Epidemiology, Oslo University Hospital, Oslo, Norway
| | - Caroline Sophie Verbeke
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Department of Pathology, Oslo University Hospital, Oslo, Norway
| | - Lars Thomas Seeberg
- Department of Gastrointestinal Surgery, Oslo University Hospital, Oslo, Norway.,Department of Gastrointestinal Surgery, Vestfold Hospital Trust, Tønsberg, Norway
| | | | - Anne Renolen
- Department of Pathology, Oslo University Hospital, Oslo, Norway
| | - Elin Borgen
- Department of Pathology, Oslo University Hospital, Oslo, Norway
| | - Bjørn Naume
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Deparment of Oncology, Oslo University Hospital, Oslo, Norway
| | - Gro Wiedswang
- Department of Gastrointestinal Surgery, Oslo University Hospital, Oslo, Norway
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14
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Limsrivilai J, Saleh ZM, Johnson LA, Stidham RW, Waljee AK, Govani SM, Gutermuth B, Brown AM, Briggs E, Rao K, Higgins PDR. Prevalence and Effect of Intestinal Infections Detected by a PCR-Based Stool Test in Patients with Inflammatory Bowel Disease. Dig Dis Sci 2020; 65:3287-3296. [PMID: 31981111 DOI: 10.1007/s10620-020-06071-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Accepted: 01/12/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND The advent of PCR-based stool testing has identified a greatly increased number of infectious agents in IBD, but their clinical significance is unknown. AIMS To determine the infectious agent prevalence and the clinical significance of these infectious agents in IBD patients. METHODS This cross-sectional study compared the prevalence of GI infections among IBD patients with active and quiescent disease versus healthy controls. Among actively inflamed patients, we compared clinical characteristics, medication use, and disease course between those with positive and negative tests. RESULTS Three hundred and thirty-three IBD patients and 52 healthy volunteers were included. The IBD group was divided into active Crohn's disease (CD, n = 113), inactive CD (n = 53), active ulcerative colitis (UC, n = 128), and inactive UC (n = 39). A significantly higher percentage of actively inflamed patients had positive stool tests (31.1%) compared to those with quiescent disease (7.6%, P = < 0.001) and healthy controls (13.5%, P = 0.01). In actively inflamed patients, shorter symptom duration and the use of multiple immunosuppressive agents were significantly associated with positive stool tests. Escalation of immunosuppressive therapy was less frequent in those with positive (61.3%) than with negative tests (77.7%, P = < 0.01). However, the need for surgery (13.3% vs. 18.7%, respectively, P = 0.31) and hospitalization (14.7% vs. 17.5%, respectively, P = 0.57) in 90 days was not significantly different. CONCLUSION GI infections are common in IBD patients with active disease. Evaluating patients for infection may help avoid unnecessary escalation of immunosuppressants, especially during an acute flare or combination immunosuppression.
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Affiliation(s)
- Julajak Limsrivilai
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
- Division of Gastroenterology, Department of Internal Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Zachary M Saleh
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Laura A Johnson
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Ryan W Stidham
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Akbar K Waljee
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
- VA Center for Clinical Management Research, VA Ann Arbor Healthcare System, Ann Arbor, MI, USA
- Institute for Healthcare Policy and Innovation, University of Michigan, Ann Arbor, MI, USA
| | - Shail M Govani
- Department of Internal Medicine, South Texas VA, San Antonio, TX, USA
| | - Brian Gutermuth
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Alexandra M Brown
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Emily Briggs
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Krishna Rao
- Division of Infectious Diseases, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Peter D R Higgins
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
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15
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Nojkov B, Zhou SY, Dolan RD, Davis EM, Appelman HD, Guo X, Jackson K, Sturm MB, Wang TD, Owyang C, Liu JJ, Chey WD. Evidence of Duodenal Epithelial Barrier Impairment and Increased Pyroptosis in Patients With Functional Dyspepsia on Confocal Laser Endomicroscopy and "Ex Vivo" Mucosa Analysis. Am J Gastroenterol 2020; 115:1891-1901. [PMID: 33156108 PMCID: PMC8409129 DOI: 10.14309/ajg.0000000000000827] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Duodenal epithelial barrier impairment and immune activation may play a role in the pathogenesis of functional dyspepsia (FD). This study was aimed to evaluate the duodenal epithelium of patients with FD and healthy individuals for detectable microscopic structural abnormalities. METHODS This is a prospective study using esophagogastroduodenoscopy enhanced with duodenal confocal laser endomicroscopy (CLE) and mucosal biopsies in patients with FD (n = 16) and healthy controls (n = 18). Blinded CLE images analysis evaluated the density of epithelial gaps (cell extrusion zones), a validated endoscopic measure of the intestinal barrier status. Analyses of the biopsied duodenal mucosa included standard histology, quantification of mucosal immune cells/cytokines, and immunohistochemistry for inflammatory epithelial cell death called pyroptosis. Transepithelial electrical resistance (TEER) was measured using Ussing chambers. Epithelial cell-to-cell adhesion proteins expression was assessed by real-time polymerase chain reaction. RESULTS Patients with FD had significantly higher epithelial gap density on CLE in the distal duodenum than that of controls (P = 0.002). These mucosal abnormalities corresponded to significant changes in the duodenal biopsy samples of patients with FD, compared with controls, including impaired mucosal integrity by TEER (P = 0.009) and increased number of epithelial cells undergoing pyroptosis (P = 0.04). Reduced TEER inversely correlated with the severity of certain dyspeptic symptoms. Furthermore, patients with FD demonstrated altered duodenal expression of claudin-1 and interleukin-6. No differences in standard histology were found between the groups. DISCUSSION This is the first report of duodenal CLE abnormalities in patients with FD, corroborated by biopsy findings of epithelial barrier impairment and increased cell death, implicating that duodenal barrier disruption is a pathogenesis factor in FD and introducing CLE a potential diagnostic biomarker in FD.
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Affiliation(s)
- Borko Nojkov
- Division of Gastroenterology and Hepatology, Michigan Medicine, Ann Arbor, Michigan, USA
| | - Shi-Yi Zhou
- Division of Gastroenterology and Hepatology, Michigan Medicine, Ann Arbor, Michigan, USA
| | - Russell D. Dolan
- Department of Internal Medicine, Michigan Medicine, Ann Arbor, Michigan, USA
| | - Elisabeth M. Davis
- Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Henry D. Appelman
- Department of Pathology, Michigan Medicine, Ann Arbor, Michigan, USA
| | - Xueyan Guo
- Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Kenya Jackson
- Division of Gastroenterology and Hepatology, Michigan Medicine, Ann Arbor, Michigan, USA
| | - Matthew B. Sturm
- Division of Gastroenterology and Hepatology, Michigan Medicine, Ann Arbor, Michigan, USA
| | - Thomas D. Wang
- Division of Gastroenterology and Hepatology, Michigan Medicine, Ann Arbor, Michigan, USA
| | - Chung Owyang
- Division of Gastroenterology and Hepatology, Michigan Medicine, Ann Arbor, Michigan, USA
| | - Julia J. Liu
- Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - William D. Chey
- Division of Gastroenterology and Hepatology, Michigan Medicine, Ann Arbor, Michigan, USA
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Stankovic B, Dragasevic S, Klaassen K, Kotur N, Srzentic Drazilov S, Zukic B, Sokic Milutinovic A, Milovanovic T, Lukic S, Popovic D, Pavlovic S, Nikcevic G. Exploring inflammatory and apoptotic signatures in distinct Crohn's disease phenotypes: Way towards molecular stratification of patients and targeted therapy. Pathol Res Pract 2020; 216:152945. [PMID: 32279918 DOI: 10.1016/j.prp.2020.152945] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 03/21/2020] [Accepted: 03/23/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND Crohn's disease (CD) is chronic inflammatory bowel disease with different phenotypic characteristics influencing disease prognosis and therapeutic strategies. The aim of this pilot study was to analyze selected inflammatory and apoptotic markers in non-inflamed and inflamed samples of ileal mucosa of non-stricturing/non-penetrating (NS/NP) and stricturing (S) CD mucosal phenotypes in order to characterize their distinct profiles. METHODS From twenty CD patients (9 NS/NP, 11 S) paired non-inflamed and inflamed ileal biopsies were collected and used for analysis of cytokine (TNF and IL6) and apoptotic (Bcl2, Bax, Fas and FasL) genes' expression levels by real-time PCR, while NFκB transcriptional potency was assessed by electromobility gel shift assay. RESULTS Our results demonstrated significant upregulation of TNF and IL6 in inflamed area of both NS/NP (p = 0.03, p = 0.01) and S phenotypes (p = 0.04, p = 0.04), respectively. However, TNF increase was more prominent in NS/NP compared to S inflamed mucosa (p = 0.02). Also, level of proapoptotic Bax was significantly higher in NS/NP compared to S inflamed mucosa (p = 0.01). Opposing transcription potency of NFκB has been detected between two phenotypes: being decreased in NS/NP (p = 0.07) and increased in S (p = 0.1) inflamed compared to non-inflamed mucosa, demonstrating trend towards statistical significance. CONCLUSIONS We found that two distinct CD phenotypes have specific molecular signatures. Obtained results could direct improvement of current and development of new therapeutic strategies based on more specific molecular stratification of CD patients.
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Affiliation(s)
- Biljana Stankovic
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11042 Belgrade, Serbia.
| | - Sanja Dragasevic
- Clinic for Gastroenterology and Hepatology, Clinical Center of Serbia, Koste Todorovica 2, 11000 Belgrade, Serbia; School of Medicine, University of Belgrade, Dr Subotica 8, 11000 Belgrade, Serbia.
| | - Kristel Klaassen
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11042 Belgrade, Serbia.
| | - Nikola Kotur
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11042 Belgrade, Serbia.
| | - Sanja Srzentic Drazilov
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11042 Belgrade, Serbia.
| | - Branka Zukic
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11042 Belgrade, Serbia.
| | - Aleksandra Sokic Milutinovic
- Clinic for Gastroenterology and Hepatology, Clinical Center of Serbia, Koste Todorovica 2, 11000 Belgrade, Serbia; School of Medicine, University of Belgrade, Dr Subotica 8, 11000 Belgrade, Serbia.
| | - Tamara Milovanovic
- Clinic for Gastroenterology and Hepatology, Clinical Center of Serbia, Koste Todorovica 2, 11000 Belgrade, Serbia; School of Medicine, University of Belgrade, Dr Subotica 8, 11000 Belgrade, Serbia.
| | - Snezana Lukic
- Clinic for Gastroenterology and Hepatology, Clinical Center of Serbia, Koste Todorovica 2, 11000 Belgrade, Serbia; School of Medicine, University of Belgrade, Dr Subotica 8, 11000 Belgrade, Serbia.
| | - Dragan Popovic
- Clinic for Gastroenterology and Hepatology, Clinical Center of Serbia, Koste Todorovica 2, 11000 Belgrade, Serbia; School of Medicine, University of Belgrade, Dr Subotica 8, 11000 Belgrade, Serbia.
| | - Sonja Pavlovic
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11042 Belgrade, Serbia.
| | - Gordana Nikcevic
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11042 Belgrade, Serbia.
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17
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Rohr MW, Narasimhulu CA, Rudeski-Rohr TA, Parthasarathy S. Negative Effects of a High-Fat Diet on Intestinal Permeability: A Review. Adv Nutr 2020; 11:77-91. [PMID: 31268137 PMCID: PMC7442371 DOI: 10.1093/advances/nmz061] [Citation(s) in RCA: 356] [Impact Index Per Article: 71.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Revised: 04/16/2019] [Accepted: 06/04/2019] [Indexed: 12/16/2022] Open
Abstract
The intestinal tract is the largest barrier between a person and the environment. In this role, the intestinal tract is responsible not only for absorbing essential dietary nutrients, but also for protecting the host from a variety of ingested toxins and microbes. The intestinal barrier system is composed of a mucus layer, intestinal epithelial cells (IECs), tight junctions (TJs), immune cells, and a gut microbiota, which are all susceptible to external factors such as dietary fats. When components of this barrier system are disrupted, intestinal permeability to luminal contents increases, which is implicated in intestinal pathologies such as inflammatory bowel disease, necrotizing enterocolitis, and celiac disease. Currently, there is mounting evidence that consumption of excess dietary fats can enhance intestinal permeability differentially. For example, dietary fat modulates the expression and distribution of TJs, stimulates a shift to barrier-disrupting hydrophobic bile acids, and even induces IEC oxidative stress and apoptosis. In addition, a high-fat diet (HFD) enhances intestinal permeability directly by stimulating proinflammatory signaling cascades and indirectly via increasing barrier-disrupting cytokines [TNFα, interleukin (IL) 1B, IL6, and interferon γ (IFNγ)] and decreasing barrier-forming cytokines (IL10, IL17, and IL22). Finally, an HFD negatively modulates the intestinal mucus composition and enriches the gut microflora with barrier-disrupting species. Although further research is necessary to understand the precise role HFDs play in intestinal permeability, current data suggest a stronger link between diet and intestinal disease than was first thought to exist. Therefore, this review seeks to highlight the various ways an HFD disrupts the gut barrier system and its many implications in human health.
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Affiliation(s)
- Michael W Rohr
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, USA
| | - Chandrakala A Narasimhulu
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, USA
| | - Trina A Rudeski-Rohr
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, USA
| | - Sampath Parthasarathy
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, USA
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18
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Taunk P, Atkinson CD, Lichtenstein D, Rodriguez-Diaz E, Singh SK. Computer-assisted assessment of colonic polyp histopathology using probe-based confocal laser endomicroscopy. Int J Colorectal Dis 2019; 34:2043-2051. [PMID: 31696259 DOI: 10.1007/s00384-019-03406-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/12/2019] [Indexed: 02/04/2023]
Abstract
INTRODUCTION Probe-based confocal laser endomicroscopy (pCLE) is a promising modality for classifying polyp histology in vivo, but decision making in real-time is hampered by high-magnification targeting and by the learning curve for image interpretation. The aim of this study is to test the feasibility of a system combining the use of a low-magnification, wider field-of-view pCLE probe and a computer-assisted diagnosis (CAD) algorithm that automatically classifies colonic polyps. METHODS This feasibility study utilized images of polyps from 26 patients who underwent colonoscopy with pCLE. The pCLE images were reviewed offline by two expert and five junior endoscopists blinded to index histopathology. A subset of images was used to train classification software based on the consensus of two GI histopathologists. Images were processed to extract image features as inputs to a linear support vector machine classifier. We compared the CAD algorithm's prediction accuracy against the classification accuracy of the endoscopists. RESULTS We utilized 96 neoplastic and 93 non-neoplastic confocal images from 27 neoplastic and 20 non-neoplastic polyps. The CAD algorithm had sensitivity of 95%, specificity of 94%, and accuracy of 94%. The expert endoscopists had sensitivities of 98% and 95%, specificities of 98% and 96%, and accuracies of 98% and 96%, while the junior endoscopists had, on average, a sensitivity of 60%, specificity of 85%, and accuracy of 73%. CONCLUSION The CAD algorithm showed comparable performance to offline review by expert endoscopists and improved performance when compared to junior endoscopists and may be useful for assisting clinical decision making in real time.
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Affiliation(s)
- Pushpak Taunk
- Division of Digestive Diseases and Nutrition, University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Christopher D Atkinson
- Department of Medicine, Section of Gastroenterology, VA Boston Healthcare System, Boston, MA, USA
| | - David Lichtenstein
- Boston Medical Center, Boston University School of Medicine, Boston, MA, USA
| | | | - Satish K Singh
- Department of Medicine, Section of Gastroenterology, VA Boston Healthcare System, Boston, MA, USA. .,Boston University School of Medicine & College of Engineering, Boston University, Boston, MA, USA.
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Buchner AM. Confocal Laser Endomicroscopy in the Evaluation of Inflammatory Bowel Disease. Inflamm Bowel Dis 2019; 25:1302-1312. [PMID: 30877772 DOI: 10.1093/ibd/izz021] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Indexed: 12/13/2022]
Abstract
Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, can be effectively monitored with the use of endoscopy. The additional application of small field imaging technology such as confocal laser endomicroscopy CLE during ongoing endoscopic evaluation has led to real-time visualization of mucosal abnormalities and thus in vivo histology. The endomicroscopy (CLE) can improve IBD endoscopic evaluation by identifying seemingly normal-appearing mucosa, assessing the function of the intestinal barrier of the epithelium and vascular permeability, and by characterizing any mucosal lesions, including dysplastic lesions. CLE used during conventional endoscopy could especially facilitate the evaluation of mucosal healing in IBD. In addition, future developments in molecular imaging in IBD may optimize therapeutic approaches by identifying mucosal targets for therapy and determining the reasons for lack of response to specific therapy or subsequent loss of the response.
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Affiliation(s)
- Anna M Buchner
- Division of Gastroenterology at University of Pennsylvania, Philadelphia, Pennsylvania
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20
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Tian Y, Zheng Y, Dong J, Zhang J, Wang H. Papaverine adjuvant therapy for microcirculatory disturbance in severe ulcerative colitis complicated with CMV infection: a case report. Clin J Gastroenterol 2019; 12:407-413. [PMID: 30945123 PMCID: PMC6763508 DOI: 10.1007/s12328-019-00974-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Accepted: 03/26/2019] [Indexed: 12/21/2022]
Abstract
Ulcerative colitis has hypercoagulable state and high risk of thrombosis; so mucosal disturbance of microcirculation may be mediate and amplify the inflammation of ulcerative colitis. A 56-year-old female patient was admitted in hospital for discontinuously mucous bloody stool for more than 1 year. Ulcerative colitis was determined after colonoscopy and pathologic examination. Mesalazine was effective during the year, but her symptoms recurred three times due to her bad compliance. One month before admission, the patient had severe recurrence after mesalazine withdrawal. At this time, the result of quantitative fluorescence PCR of colonic histic CMV-DNA was 1.6 × 104 copies/mL positive, CMV colitis was accompanied. After 4 weeks of ganciclovir and 6 weeks of mesalazine usage and nutrition support, the symptoms of diarrhea and abdominal cramp did not improve; stool frequency was more than twenty times a day. Probe-based confocal laser endomicroscopy revealed local microcirculation disturbance. Papaverine 90-mg slow drip for at least 10 h a day was added. The symptoms dramatically disappeared after 3 days of papaverine treatment. The patient had yellow mushy stool 2–3 times a day. Pathological findings showed diffuse submucosal hemorrhage and transparent thrombosis in capillaries. Treatment of microcirculatory disturbance in severe UC is a promising adjuvant therapy. Confocal laser endomicroscopy may be an effective method for microcirculation judgment.
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Affiliation(s)
- Yu Tian
- Gastroenterology Department of Peking, University First Hospital, Beijing, China
| | - Yue Zheng
- Gastroenterology Department of Peking, University First Hospital, Beijing, China
| | - Jinpei Dong
- Gastroenterology Department of Peking, University First Hospital, Beijing, China
| | - Jixin Zhang
- Pathology Department of Peking, University First Hospital, Beijing, China
| | - Huahong Wang
- Gastroenterology Department of Peking, University First Hospital, Beijing, China.
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21
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Tontini GE, Mudter J, Vieth M, Günther C, Milani V, Atreya R, Rath T, Nägel A, Hatem G, Sturniolo GC, Vecchi M, Neurath MF, Galle PR, Buda A, Neumann H. Prediction of clinical outcomes in Crohn's disease by using confocal laser endomicroscopy: results from a prospective multicenter study. Gastrointest Endosc 2018; 87:1505-1514.e3. [PMID: 29108979 DOI: 10.1016/j.gie.2017.10.033] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Accepted: 10/19/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Assessment of prognostic factors in patients with Crohn's disease (CD) is of pivotal importance for early intervention and "treat-to-target" strategies. Confocal laser endomicroscopy (CLE) enables on-demand in vivo characterization of mucosal inflammatory and architectural changes during endoscopy. We prospectively assessed the value of CLE for prediction of clinical outcome parameters in CD. METHODS Consecutive patients with CD undergoing colonoscopy were included in a multicenter study. Confocal imaging focused on 2 highly reproducible histologic hallmarks of active colonic inflammation: focal cryptitis and crypt architectural abnormality. We evaluated whether CLE, CD endoscopic index of severity (CDEIS), serum C-reactive protein (CRP), and CD activity index (CDAI) were associated with the risk of medical treatment escalation, transmural adverse events, and CD-related hospitalization or surgery during a 4-year follow-up. RESULTS Among 49 patients (53% men, median age, 39 years), baseline CRP was ≥5 mg/L in 47%, CDEIS ≥3 in 75%, and CDAI >150 in 51%. Focal cryptitis and crypt architectural abnormality were observed in 63% (CLE+ group). CLE+ patients showed an increased incidence of medical treatment escalation (P < .001; relative risk [RR] = 3.27) and transmural lesions (P = .025; RR = 1.70), whereas patients with CRP ≥5 mg/L had increased CD-related hospitalization and surgery (P = .020, RR = 2.71) at 1-year follow-up. No further association with prognostic clinical outcomes was found over the 1-year follow-up as well as for CDEIS and CDAI at any time. CONCLUSIONS CLE reveals CD-related features of mucosal inflammation and allows for early prediction of relevant clinical outcomes. Further studies should now address whether this promising prognostic tool could refine the timing of treatment strategies in patients with CD.
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Affiliation(s)
- Gian Eugenio Tontini
- Department of Medicine I, University of Erlangen-Nürnberg, Erlangen, Germany; Gastroenterology and Digestive Endoscopy Unit, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy
| | - Jonas Mudter
- Department of Medicine I, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Michael Vieth
- Institute of Pathology, Klinikum Bayreuth, Bayreuth, Germany
| | - Claudia Günther
- Department of Medicine I, University of Erlangen-Nürnberg, Erlangen, Germany
| | | | - Raja Atreya
- Department of Medicine I, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Timo Rath
- Department of Medicine I, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Andreas Nägel
- Department of Medicine I, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Giorgia Hatem
- Department of Surgical, Oncological, and Gastroenterological Sciences, University of Padua, Padua, Italy
| | - Giacomo Carlo Sturniolo
- Department of Surgical, Oncological, and Gastroenterological Sciences, University of Padua, Padua, Italy
| | - Maurizio Vecchi
- Gastroenterology and Digestive Endoscopy Unit, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy; Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
| | - Markus F Neurath
- Department of Medicine I, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Peter R Galle
- First Medical Department, University Medical Center Mainz, Mainz, Germany
| | - Andrea Buda
- Department of Surgical, Oncological, and Gastroenterological Sciences, University of Padua, Padua, Italy; Gastroenterology and Digestive Endoscopy Unit, Ospedale di Feltre, Feltre, Italy
| | - Helmut Neumann
- Department of Medicine I, University of Erlangen-Nürnberg, Erlangen, Germany; First Medical Department, University Medical Center Mainz, Mainz, Germany
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22
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Molecular Pathophysiology of Epithelial Barrier Dysfunction in Inflammatory Bowel Diseases. Proteomes 2018; 6:proteomes6020017. [PMID: 29614738 PMCID: PMC6027334 DOI: 10.3390/proteomes6020017] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Revised: 03/24/2018] [Accepted: 03/26/2018] [Indexed: 12/13/2022] Open
Abstract
Over the years, the scientific community has explored myriads of theories in search of the etiology and a cure for inflammatory bowel disease (IBD). The cumulative evidence has pointed to the key role of the intestinal barrier and the breakdown of these mechanisms in IBD. More and more scientists and clinicians are embracing the concept of the impaired intestinal epithelial barrier and its role in the pathogenesis and natural history of IBD. However, we are missing a key tool that bridges these scientific insights to clinical practice. Our goal is to overcome the limitations in understanding the molecular physiology of intestinal barrier function and develop a clinical tool to assess and quantify it. This review article explores the proteins in the intestinal tissue that are pivotal in regulating intestinal permeability. Understanding the molecular pathophysiology of impaired intestinal barrier function in IBD may lead to the development of a biochemical method of assessing intestinal tissue integrity which will have a significant impact on the development of novel therapies targeting the intestinal mucosa.
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23
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Kim ES. Role of Advanced Endoscopic Imaging Techniques in the Management of Inflammatory Bowel Disease. Clin Endosc 2017; 50:424-428. [PMID: 29017290 PMCID: PMC5642067 DOI: 10.5946/ce.2017.143] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Revised: 09/24/2017] [Accepted: 09/24/2017] [Indexed: 12/19/2022] Open
Abstract
Endoscopy plays a crucial role in the management of inflammatory bowel disease (IBD) in terms of diagnosis, monitoring of mucosal status, and surveillance of colitis-associated neoplasia. Mucosal healing evaluated by endoscopy has been recognized as the target of treatment in the era of powerful biologics therapy. The optimal modality for identifying dysplasia in IBD has yet to be well defined. Increasing progress has recently been made in endoscopic technologies to more accurately assess mucosal inflammation and more effectively detect dysplasia. Here we review the data of advanced endoscopic imaging techniques such as chromoendoscopy, virtual chromoendoscopy, endocytoscopy, and confocal laser endomicroscopy in the management of IBD.
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Affiliation(s)
- Eun Soo Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea
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24
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Kiesslich R, Neurath MF. Advanced endoscopy imaging in inflammatory bowel diseases. Gastrointest Endosc 2017; 85:496-508. [PMID: 27816496 DOI: 10.1016/j.gie.2016.10.034] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Accepted: 10/24/2016] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Rapid assessment of mucosal inflammation is of crucial importance for the initial diagnosis and the assessment of mucosal healing in inflammatory bowel disease (IBD). Moreover, the identification of intraepithelial neoplasias in IBD is of key relevance for clinical management. Here, we systematically analyzed the utility of advanced endoscopic imaging techniques for optimized diagnosis in IBD. METHODS PubMed/Medline, Web of Knowledge, and Cochrane library were searched twice for diagnostic studies on advanced endoscopic imaging in IBD. Clinical and technical information was retrieved and subsequently analyzed. Main outcome parameters consisted of the quality of the results, adverse events, and diagnostic yield. RESULTS Fifty-six clinical studies with a total of 3296 patients were selected for final analysis. Filter technologies permitted a more detailed analysis of mucosal inflammation in IBD. In spite of substantial heterogeneity across studies, dye-based chromoendoscopy with targeted biopsy sampling yielded higher detection rates of intraepithelial neoplasias in ulcerative colitis as compared with white-light endoscopy with random biopsy sampling. Moreover, endocytoscopy and endomicroscopy allowed subsurface imaging of inflamed or neoplastic mucosa in IBD at subcellular resolution. Finally, endomicroscopy-aided molecular imaging enabled the identification of membrane-bound tumor necrosis factor on mucosal cells as a potential driver of disease activity in Crohn's disease. No relevant adverse events were reported. CONCLUSIONS Advanced endoscopic imaging technologies are feasible, safe, and partially effective tools for detailed diagnosis of mucosal inflammation and detection of neoplasias in IBD. Results obtained from these advanced techniques may provide a rational basis for individualized, optimized therapy for IBD patients.
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Affiliation(s)
- Ralf Kiesslich
- Department of Medicine II, HELIOS Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Germany
| | - Markus F Neurath
- Medical Clinic 1, Department of Medicine, University Hospital Erlangen, University of Erlangen-Nürnberg, Nürnberg, Germany; Ludwig Demling Endoscopy Center of Excellence, Erlangen, Germany
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25
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Bertani H, Palazzo L, Mirante VG, Pigò F. Confocal Laser Endomicroscopy in GI Tract. DIAGNOSIS AND ENDOSCOPIC MANAGEMENT OF DIGESTIVE DISEASES 2017:1-20. [DOI: 10.1007/978-3-319-42358-6_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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26
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Enfermedad de Crohn: hemorragia fatal en paciente con 19.3 semanas de gestación. Reporte de un caso y revisión de la literatura mundial. CLINICA E INVESTIGACION EN GINECOLOGIA Y OBSTETRICIA 2017. [DOI: 10.1016/j.gine.2015.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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27
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Zaidi D, Bording-Jorgensen M, Huynh HQ, Carroll MW, Turcotte JF, Sergi C, Liu J, Wine E. Increased Epithelial Gap Density in the Noninflamed Duodenum of Children With Inflammatory Bowel Diseases. J Pediatr Gastroenterol Nutr 2016; 63:644-650. [PMID: 26933801 DOI: 10.1097/mpg.0000000000001182] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
OBJECTIVES Inflammatory bowel diseases (IBD) present commonly in childhood, with unknown etiology, but an important role for the epithelial lining is suggested. Epithelial cell extrusion, measured by counting gaps between epithelial cells, is higher in adult patients with Crohn disease (CD) than in controls. Our objectives were to compare epithelial gaps in the duodenum of IBD and non-IBD pediatric patients, to study the correlation between epithelial gaps, inflammation, and disease activity, and identify potential mechanisms. METHODS Epithelial gap density of the duodenum was evaluated using probe-based confocal laser endomicroscopy in 26 pediatric patients with IBD (16 CD, 10 ulcerative colitis [UC]) and 17 non-IBD controls during endoscopy. Epithelial gaps were correlated with serum inflammatory markers, disease activity indices, and intraepithelial lymphocytes. A panel of 10 inflammatory cytokines and expression of TNFAIP3 (A20; inhibits NF-κβ-induced inflammation) were analyzed in duodenal and ileal biopsies. RESULTS Confocal imaging showed significantly higher epithelial gap density in patients with IBD, including UC. Interleukin (IL)-2 and IL-8 were higher in duodenal but not ileal biopsies of patients with UC. No significant correlation was present between C-reactive protein, erythrocyte sedimentation rate, disease activity indices, and epithelial gaps in patients with UC. In patients with CD, C-reactive protein positively correlated with epithelial gaps. A20 expression in the duodenum was unchanged among non-IBD and IBD cases. CONCLUSIONS Duodenal epithelial gaps are increased in pediatric patients with IBD (including UC) but are unrelated to inflammation. This suggests that altered epithelial barrier is an important systemic feature of pediatric IBD and is not only secondary to inflammation.
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Affiliation(s)
- Deenaz Zaidi
- *Department of Pediatrics †Centre of Excellence for Gastrointestinal Inflammation and Immunity Research (CEGIIR) ‡Department of Physiology §Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada ||University of Arkansas for Medical Sciences, Little Rock, AR
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28
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Buchner AM, Wallace MB. Endomicroscopy and Molecular Tools to Evaluate Inflammatory Bowel Disease. Gastrointest Endosc Clin N Am 2016; 26:657-68. [PMID: 27633594 DOI: 10.1016/j.giec.2016.06.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Endoscopy is an essential tool for effective care of patients with inflammatory bowel disease (IBD), including Crohn disease and ulcerative colitis. The newest endoscopic small-field imaging technologies with confocal endomicroscopy have allowed real-time imaging of gastrointestinal mucosal during ongoing endoscopic evaluation and in vivo histology. Thus, endomicroscopy has a potential to further enhance the endoscopic evaluation of IBD. Advances in molecular in vivo imaging in IBD may be used not only to better understand the pathophysiology of IBD but also to guide optimized therapy and thus to allow a personalized, new approach to the IBD management.
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Affiliation(s)
- Anna M Buchner
- Division of Gastroenterology, University of Pennsylvania, 3400 Civic Center PCAM 7 South, Philadelphia, PA 19104, USA
| | - Michael B Wallace
- Division of Gastroenterology and Hepatology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
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29
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Tontini GE, Pastorelli L, Ishaq S, Neumann H. Advances in endoscopic imaging in ulcerative colitis. Expert Rev Gastroenterol Hepatol 2016; 9:1393-405. [PMID: 26365308 DOI: 10.1586/17474124.2015.1087848] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Modern strategies for the treatment of ulcerative colitis require more accurate tools for gastrointestinal imaging to better assess mucosal disease activity and long-term prognostic clinical outcomes. Recent advances in gastrointestinal luminal endoscopy are radically changing the role of endoscopy in every-day clinical practice and research trials. Advanced endoscopic imaging techniques including high-definition endoscopes, optical magnification endoscopy, and various chromoendoscopy techniques have remarkably improved endoscopic assessment of ulcerative colitis. More recently, optical biopsy techniques with either endocytoscopy or confocal laser endomicroscopy have shown great potential in predicting several histological changes in real time during ongoing endoscopy. Here, we review current applications of advanced endoscopic imaging techniques in ulcerative colitis and present the most promising upcoming headways in this field.
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Affiliation(s)
- Gian Eugenio Tontini
- a 1 Gastroenterology and Digestive Endoscopy Unit, IRCCS Policlinico San Donato, San Donato Milanese, Italy
| | - Luca Pastorelli
- a 1 Gastroenterology and Digestive Endoscopy Unit, IRCCS Policlinico San Donato, San Donato Milanese, Italy.,b 2 Department of Biomedical Sciences for Health, University of Milan, Milano, Italy
| | - Sauid Ishaq
- c 3 Department of Gastroenterology, Dudley Group Hospitals, Birmingham City University, Birmingham, UK.,d 4 Department of Medicine, St. George's University, Grenada, West Indies
| | - Helmut Neumann
- e 5 Department of Medicine I, University of Erlangen-Nuremberg, Erlangen, Germany
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30
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Confocal laser endomicroscopy in ulcerative colitis: a longitudinal study of endomicroscopic changes and response to medical therapy (with videos). Gastrointest Endosc 2016; 84:279-286.e1. [PMID: 26945556 DOI: 10.1016/j.gie.2016.01.069] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Accepted: 01/13/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Confocal laser endomicroscopy enables real-time in vivo microscopy during endoscopy and can predict relapse in patients with inflammatory bowel disease in remission. However, little is known about how endomicroscopic features change with time. The aim of this longitudinal study was to correlate colonic confocal laser endomicroscopy (CLE) in ulcerative colitis with histopathology and macroscopic appearance before and after intensification of medical treatment. METHODS Twenty-two patients with ulcerative colitis in clinical relapse and 7 control subjects referred for colonoscopy were enrolled. The colonic mucosa was examined with high-definition colonoscopy, histopathology, and CLE at 4 colonic sites. Subsequently, patients requiring medical treatment escalation were referred for repeat endoscopy with CLE after 6 to 8 weeks. RESULTS The baseline frequency of fluorescein leakage (P < .001), microerosions (P < .001), tortuosity of the crypts (P = .001), distortion of the crypts openings (P = .001), presence of inflammatory infiltrates (P < .001), and decreased crypt density (P < .001) were significantly higher in active ulcerative colitis compared with inactive ulcerative colitis and control subjects. A decrease in histopathologic score after medical treatment escalation was correlated with improvement in crypt tortuosity (rs = .35, P = .016), distortion of crypt openings (rs = .30, P = .045), and decreased crypt density (rs = .33, P = .026) but not in other features. CONCLUSIONS CLE is an emerging endoscopic technique that reproducibly identifies mucosal changes in ulcerative colitis. With the exception of crypt changes, endomicroscopic features appear to improve slowly with time after medical treatment. ( CLINICAL TRIAL REGISTRATION NUMBER NCT01684514.).
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31
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Liu JJ, Kay TM, Davis EM, Lou Y, Kao D, Claggett B, Fedorak RN, Irvin RT. Epithelial Cell Extrusion Zones Observed on Confocal Laser Endomicroscopy Correlates with Immunohistochemical Staining of Mucosal Biopsy Samples. Dig Dis Sci 2016; 61:1895-902. [PMID: 27098414 PMCID: PMC5896752 DOI: 10.1007/s10620-016-4154-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Accepted: 03/31/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS The density of epithelial cell extrusion zones in the intestinal lining, also known as gap density (number of gaps/1000 epithelial cells counted), can be quantitated using probe-based confocal laser endomicroscopy (pCLE). Gap density has been reported to be higher than normal in both inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) patients. Epithelial cells destined for extrusion from the intestinal surface would stain positive for either activated caspase-1 or caspase-3 on mucosal biopsy samples. The aim of this study was to determine whether epithelial gap density on pCLE correlates with quantitative analysis of activated caspase staining of mucosal biopsy samples from patients. METHODS We obtained pCLE images and biopsy samples of the terminal ileum during colonoscopies of healthy controls and patients with either IBD or IBS. The pCLE images and biopsy samples were blindly analyzed for gap density and for cells staining positive for activated caspases, respectively. The degree of correlation was determined using nonparametric statistical tests. RESULTS The median results were 10 gaps/1000 cells counted for controls versus 33 gaps/1000 cells counted for chronic intestinal disorder patients (p = 0.02). Activated caspase staining showed 13 positive cells/1000 epithelial cells counted versus 26 positive cells/1000 epithelial cells counted, respectively (p = 0.02), thus showing a strong correlation with a Spearman's coefficient ρ of 0.61 (strong correlation for ρ = 0.4-0.75, p = 0.01). CONCLUSIONS Intestinal epithelial gap density via pCLE correlated strongly with quantitative analysis of immunohistochemical staining of mucosal biopsy samples.
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Affiliation(s)
- Julia J Liu
- Division of Gastroenterology, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.
- Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Shorey S8/62, Little Rock, AR, 72205, USA.
| | - Theresa M Kay
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA
| | - Elisabeth M Davis
- Division of Gastroenterology, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR, USA
| | - Yuefei Lou
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, AB, Canada
| | - Dina Kao
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, AB, Canada
| | - Brian Claggett
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Richard N Fedorak
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, AB, Canada
| | - Randall T Irvin
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada
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32
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A Pilot Study of Confocal Laser Endomicroscopy to Predict Barrier Dysfunction and Relapse in Pediatric Inflammatory Bowel Disease. J Pediatr Gastroenterol Nutr 2016; 62:873-8. [PMID: 26513619 PMCID: PMC5854472 DOI: 10.1097/mpg.0000000000001022] [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] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Probe-based confocal laser endomicroscopy (pCLE) is a novel imaging modality that enables virtual optical biopsy in vivo. Loss of barrier function of the small bowel observed via pCLE as increased density of epithelial gaps (extrusion zones left in the intestinal lining after cells are shed) is predictive of relapse in adult patients with inflammatory bowel disease (IBD). This study aims to determine whether such observations on pCLE are similarly predictive of disease relapse in pediatric patients with IBD. METHODS Pediatric patients with biopsy-proven IBD underwent pCLE during colonoscopy and subsequent clinical follow-up every 6 months. Relapse was defined as moderate to severe flare with endoscopic evidence of inflammation during the follow-up period. The relations between epithelial gap density, disease relapse, and imaging parameters were determined using Cox models. RESULTS Twenty-four patients with IBD (13 with Crohn disease, 11 with ulcerative colitis) with a median age of 14 years (range 10-21) were studied for a median of 13 (4-33) months. The median duration of disease was 2.9 years (range 0-9). Increased epithelial gap density in the terminal ileum on pCLE of normal endoscopic appearing terminal ileum mucosa (N = 19) was predictive of disease relapse when 3 or more areas were imaged (N = 6, log-rank P = 0.02, C-statistic = 0.94). CONCLUSIONS In pediatric patients with IBD, barrier dysfunction observed on pCLE imaging of the small bowel was predictive of disease relapse.
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33
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Miguel JC, Maxwell AA, Hsieh JJ, Harnisch LC, Al Alam D, Polk DB, Lien CL, Watson AJM, Frey MR. Epidermal growth factor suppresses intestinal epithelial cell shedding through a MAPK-dependent pathway. J Cell Sci 2016; 130:90-96. [PMID: 27026527 DOI: 10.1242/jcs.182584] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Accepted: 03/18/2016] [Indexed: 12/27/2022] Open
Abstract
Cell shedding from the intestinal villus is a key element of tissue turnover that is essential to maintain health and homeostasis. However, the signals regulating this process are not well understood. We asked whether shedding is controlled by epidermal growth factor receptor (EGFR), an important driver of intestinal growth and differentiation. In 3D ileal enteroid culture and cell culture models (MDCK, IEC-6 and IPEC-J2 cells), extrusion events were suppressed by EGF, as determined by direct counting of released cells or rhodamine-phalloidin labeling of condensed actin rings. Blockade of the MEK-ERK pathway, but not other downstream pathways such as phosphoinositide 3-kinase (PI3K) or protein kinase C (PKC), reversed EGF inhibition of shedding. These effects were not due to a change in cell viability. Furthermore, EGF-driven MAPK signaling inhibited both caspase-independent and -dependent shedding pathways. Similar results were found in vivo, in a novel zebrafish model for intestinal epithelial shedding. Taken together, the data show that EGF suppresses cell shedding in the intestinal epithelium through a selective MAPK-dependent pathway affecting multiple extrusion mechanisms. EGFR signaling might be a therapeutic target for disorders featuring excessive cell turnover, such as inflammatory bowel diseases.
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Affiliation(s)
- Jennifer C Miguel
- Department of Pediatrics, University of Southern California Keck School of Medicine and The Saban Research Institute at Children's Hospital Los Angeles, Los Angeles, CA 90027, USA
| | - Adrienne A Maxwell
- Department of Pediatrics, University of Southern California Keck School of Medicine and The Saban Research Institute at Children's Hospital Los Angeles, Los Angeles, CA 90027, USA
| | - Jonathan J Hsieh
- Department of Pediatrics, University of Southern California Keck School of Medicine and The Saban Research Institute at Children's Hospital Los Angeles, Los Angeles, CA 90027, USA
| | - Lukas C Harnisch
- Department of Medicine, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7UQ, UK
| | - Denise Al Alam
- Department of Surgery, University of Southern California Keck School of Medicine and The Saban Research Institute at Children's Hospital Los Angeles, Los Angeles, CA 90027, USA
| | - D Brent Polk
- Department of Pediatrics, University of Southern California Keck School of Medicine and The Saban Research Institute at Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.,Department of Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine, Los Angeles, CA 90089, USA
| | - Ching-Ling Lien
- Department of Surgery, University of Southern California Keck School of Medicine and The Saban Research Institute at Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.,Department of Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine, Los Angeles, CA 90089, USA
| | - Alastair J M Watson
- Department of Medicine, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7UQ, UK
| | - Mark R Frey
- Department of Pediatrics, University of Southern California Keck School of Medicine and The Saban Research Institute at Children's Hospital Los Angeles, Los Angeles, CA 90027, USA .,Department of Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine, Los Angeles, CA 90089, USA
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Wang AH, Li M, Li CQ, Kou GJ, Zuo XL, Li YQ. Human colorectal mucosal microbiota correlates with its host niche physiology revealed by endomicroscopy. Sci Rep 2016; 6:21952. [PMID: 26916597 PMCID: PMC4768150 DOI: 10.1038/srep21952] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2015] [Accepted: 01/26/2016] [Indexed: 01/05/2023] Open
Abstract
The human gut microbiota plays a pivotal role in the maintenance of health, but how the microbiota interacts with the host at the colorectal mucosa is poorly understood. We proposed that confocal laser endomicroscopy (CLE) might help to untangle this relationship by providing in vivo physiological information of the mucosa. We used CLE to evaluate the in vivo physiology of human colorectal mucosa, and the mucosal microbiota was quantified using 16 s rDNA pyrosequencing. The human mucosal microbiota agglomerated to three major clusters dominated by Prevotella, Bacteroides and Lactococcus. The mucosal microbiota clusters did not significantly correlate with the disease status or biopsy sites but closely correlated with the mucosal niche physiology, which was non-invasively revealed by CLE. Inflammation tilted two subnetworks within the mucosal microbiota. Infiltration of inflammatory cells significantly correlated with multiple components in the predicted metagenome, such as the VirD2 component of the type IV secretory pathway. Our data suggest that a close correlation exists between the mucosal microbiota and the colorectal mucosal physiology, and CLE is a clinically available tool that can be used to facilitate the study of the in vivo correlation between colorectal mucosal physiology and the mucosal microbiota.
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Affiliation(s)
- Ai-Hua Wang
- Department of Gastroenterology, Shandong University, Qilu Hospital, Jinan, 250012, China.,Department of Gastroenterology, Shandong Rongjun General Hospital, Jinan, 250013, China
| | - Ming Li
- Department of Gastroenterology, Shandong University, Qilu Hospital, Jinan, 250012, China
| | - Chang-Qing Li
- Department of Gastroenterology, Shandong University, Qilu Hospital, Jinan, 250012, China
| | - Guan-Jun Kou
- Department of Gastroenterology, Shandong University, Qilu Hospital, Jinan, 250012, China
| | - Xiu-Li Zuo
- Department of Gastroenterology, Shandong University, Qilu Hospital, Jinan, 250012, China
| | - Yan-Qing Li
- Department of Gastroenterology, Shandong University, Qilu Hospital, Jinan, 250012, China
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Confocal Laser Endomicroscopy in Gastrointestinal and Pancreatobiliary Diseases: A Systematic Review and Meta-Analysis. BIOMED RESEARCH INTERNATIONAL 2016; 2016:4638683. [PMID: 26989684 PMCID: PMC4773527 DOI: 10.1155/2016/4638683] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/06/2015] [Accepted: 12/31/2015] [Indexed: 12/15/2022]
Abstract
Confocal laser endomicroscopy (CLE) is an endoscopic-assisted technique developed to obtain histopathological diagnoses of gastrointestinal and pancreatobiliary diseases in real time. The objective of this systematic review is to analyze the current literature on CLE and to evaluate the applicability and diagnostic yield of CLE in patients with gastrointestinal and pancreatobiliary diseases. A literature search was performed on MEDLINE, EMBASE, Scopus, and Cochrane Oral Health Group Specialized Register, using pertinent keywords without time limitations. Both prospective and retrospective clinical studies that evaluated the sensitivity, specificity, or accuracy of CLE were eligible for inclusion. Of 662 articles identified, 102 studies were included in the systematic review. The studies were conducted between 2004 and 2015 in 16 different countries. CLE demonstrated high sensitivity and specificity in the detection of dysplasia in Barrett's esophagus, gastric neoplasms and polyps, colorectal cancers in inflammatory bowel disease, malignant pancreatobiliary strictures, and pancreatic cysts. Although CLE has several promising applications, its use has been limited by its low availability, high cost, and need of specific operator training. Further clinical trials with a particular focus on cost-effectiveness and medicoeconomic analyses, as well as standardized institutional training, are advocated to implement CLE in routine clinical practice.
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Rodriguez-Diaz E, Baffy G, Singh SK. Probe-based confocal laser endomicroscopy quantitative morphometric markers associated with portal hypertension in duodenal mucosa. Liver Int 2016; 36:223-31. [PMID: 26133980 DOI: 10.1111/liv.12906] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2015] [Accepted: 06/27/2015] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Early detection of portal hypertension (PH) may help to prevent the morbidity of late-stage cirrhosis by stratifying disease severity and enabling disease-modifying interventions in potentially reversible conditions like non-alcoholic fatty liver disease and alcoholic hepatitis. This study seeks to correlate morphometric features by confocal endomicroscopy with established surrogate clinical markers of PH. METHODS Patients with and without PH scheduled for upper endoscopy at VA Boston participated in this IRB-approved study. Real-time probe-based confocal endomicroscopy (pCLE) was performed in the duodenum. Vascular and epithelial morphometry was performed off-line, in a blinded manner, using image-processing software. RESULTS Morphometric analysis of pCLE images from 16 patients with PH and 15 control patients was performed. Statistically significant differences were observed among control and PH patients for average vessel diameter (AVD: 11.7 μm vs. 17.1 μm), average vessel branching (AVB: 0.11 vs. 0.31 bifurcations per image frame), and average columnar cell height (ACCH: 40.0 μm vs. 52.0 μm). Spearman correlations comparing AVD, AVB and ACCH to portal gastropathy scores (0.86, 0.44 and 0.70) and to grade of oesophageal varices (0.88, 0.41 and 0.66) were statistically significant. Similarly, Pearson correlations of AVD and ACCH to spleen size (0.72 and 0.57), platelet count (-0.69 and -0.40) and the platelet count/spleen size ratio (-0.69 and -0.41) were also found to be statistically significant. CONCLUSIONS Duodenal pCLE reveals microvascular dilatation and altered epithelial cell volume/morphology in PH. These morphometric pCLE markers correlate with surrogate markers of PH. Additional studies will define the correlation between microscopic vascular patterns, epithelial cell volume and the hepatic venous pressure gradient.
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Affiliation(s)
- Eladio Rodriguez-Diaz
- Department of Medicine, Section of Gastroenterology, Boston University School of Medicine, Boston, MA, USA.,Section of Gastroenterology, VA Boston Healthcare System, Boston, MA, USA
| | - György Baffy
- Section of Gastroenterology, VA Boston Healthcare System, Boston, MA, USA.,Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA
| | - Satish K Singh
- Department of Medicine, Section of Gastroenterology, Boston University School of Medicine, Boston, MA, USA.,Section of Gastroenterology, VA Boston Healthcare System, Boston, MA, USA.,Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA.,Department of Biomedical Engineering, College of Engineering, Boston University, Boston, MA, USA
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Atkinson CD, Singh SK. Luminal Confocal Laser Endomicroscopy. ENDOSCOPIC IMAGING TECHNIQUES AND TOOLS 2016:83-114. [DOI: 10.1007/978-3-319-30053-5_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Rasmussen DN, Karstensen JG, Riis LB, Brynskov J, Vilmann P. Confocal Laser Endomicroscopy in Inflammatory Bowel Disease--A Systematic Review. J Crohns Colitis 2015. [PMID: 26209861 DOI: 10.1093/ecco-jcc/jjv131] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Confocal laser endomicroscopy is an endoscopic method that provides in vivo real-time imaging of the mucosa at a cellular level, elucidating mucosal changes that are undetectable by white light endoscopy. This paper systematically reviews current indications and perspectives of confocal laser endomicroscopy for inflammatory bowel disease. METHODS Available literature was searched systematically for studies applying confocal laser endomicroscopy in Crohn's disease or ulcerative colitis. Relevant literature was reviewed and only studies reporting original clinical data were included. Next, eligible studies were analysed with respect to several parameters, such as technique and clinical aim and definitions of outcomes. RESULTS Confocal laser endomicroscopy has been used for a wide range of purposes in inflammatory bowel disease, covering assessment of inflammatory severity, prediction of therapeutic response and relapse and adenoma surveillance in patients with ulcerative colitis. Methods for measurement of the histological changes ranged from subjective grading to objective quantification analysed by computer-aided models. The studies derived their conclusions from assessment of histological features such as colonic crypts, epithelial gaps and epithelial leakiness to fluorescein. CONCLUSIONS Confocal laser endomicroscopy remains an experimental but emerging tool for assessment of inflammatory bowel disease. It is the only method that enables in vivo functional assessment of intestinal barrier function. There is great heterogeneity in the literature and no single approach has been validated and reproduced to the level of general acceptance.
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Affiliation(s)
- Ditlev Nytoft Rasmussen
- Department of Gastroenterology and Gastrointestinal Surgery, Copenhagen University Hospital Hvidovre, Copenhagen, Denmark
| | - John Gásdal Karstensen
- Gastro Unit, Division of Endoscopy, Copenhagen University Hospital Herlev, Copenhagen, Denmark
| | - Lene Buhl Riis
- Department of Pathology, Copenhagen University Hospital Herlev, Copenhagen, Denmark
| | - Jørn Brynskov
- Gastro Unit, Division of Endoscopy, Copenhagen University Hospital Herlev, Copenhagen, Denmark
| | - Peter Vilmann
- Gastro Unit, Division of Endoscopy, Copenhagen University Hospital Herlev, Copenhagen, Denmark
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Wang KK, Carr-Locke DL, Singh SK, Neumann H, Bertani H, Galmiche JP, Arsenescu RI, Caillol F, Chang KJ, Chaussade S, Coron E, Costamagna G, Dlugosz A, Ian Gan S, Giovannini M, Gress FG, Haluszka O, Ho KY, Kahaleh M, Konda VJ, Prat F, Shah RJ, Sharma P, Slivka A, Wolfsen HC, Zfass A. Use of probe-based confocal laser endomicroscopy (pCLE) in gastrointestinal applications. A consensus report based on clinical evidence. United European Gastroenterol J 2015; 3:230-54. [PMID: 26137298 DOI: 10.1177/2050640614566066] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Accepted: 11/17/2014] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Probe-based confocal laser endomicroscopy (pCLE) provides microscopic imaging during an endoscopic procedure. Its introduction as a standard modality in gastroenterology has brought significant progress in management strategies, affecting many aspects of clinical care and requiring standardisation of practice and training. OBJECTIVE This study aimed to provide guidance on the standardisation of its practice and training in Barrett's oesophagus, biliary strictures, colorectal lesions and inflammatory bowel diseases. METHODS Initial statements were developed by five group leaders, based on the available clinical evidence. These statements were then voted and edited by the 26 participants, using a modified Delphi approach. After two rounds of votes, statements were validated if the threshold of agreement was higher than 75%. RESULTS Twenty-six experts participated and, among a total of 77 statements, 61 were adopted (79%) and 16 were rejected (21%). The adoption of each statement was justified by the grade of evidence. CONCLUSION pCLE should be used to enhance the diagnostic arsenal in the evaluation of these indications, by providing microscopic information which improves the diagnostic performance of the physician. In order actually to implement this technology in the clinical routine, and to ensure good practice, standardised initial and continuing institutional training programmes should be established.
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Affiliation(s)
- Kenneth K Wang
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - David L Carr-Locke
- Division of Digestive Diseases, Beth Israel Medical Center, New York City, NY, USA
| | - Satish K Singh
- Department of Medicine, Boston University School of Medicine, Boston, MA, USA
| | - Helmut Neumann
- The Ludwig Demling Endoscopy Center of Excellence, Erlangen, Germany
| | - Helga Bertani
- Endoscopy Unit, Nuovo Ospedale Civile S. Agostino Estense, Modena, Italy
| | | | | | - Fabrice Caillol
- Endoscopy Unit, Paoli-Calmettes Institute, Marseille, France
| | - Kenneth J Chang
- H.H. Chao Comprehensive Digestive Disease Center, University of California, Irvine, CA, USA
| | - Stanislas Chaussade
- Division of Gastroenterology, Hopital Cochin and Paris-Descartes University, Paris, France
| | - Emmanuel Coron
- Division of Gastroenterology and Hepatology, Nantes CHU, Rouen, France
| | | | - Aldona Dlugosz
- Karolinska Institutet, Department of Medicine, Division of Gastroenterology and Hepatology, Karolinska University Hospital, Stockholm, Sweden
| | - S Ian Gan
- Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA, USA
| | - Marc Giovannini
- Endoscopy Unit, Paoli-Calmettes Institute, Marseille, France
| | - Frank G Gress
- Division of Digestive and Liver disease, Columbia University Medical Center, New York City, NY, USA
| | - Oleh Haluszka
- Department of Medicine, Temple University School of Medicine, Philadelphia, PA, USA
| | - Khek Y Ho
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Michel Kahaleh
- Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York City, NY, USA
| | - Vani J Konda
- Center for Endoscopic Research and Therapeutics, Department of Medicine, University of Chicago Medicine, Chicago, IL, USA
| | - Frederic Prat
- Division of Gastroenterology, Hopital Cochin and Paris-Descartes University, Paris, France
| | - Raj J Shah
- University of Colorado School of Medicine, Aurora, CO, USA
| | - Prateek Sharma
- Department of Gastroenterology and Hepatology, Veterans Affairs Medical Center, Kansas City, MI, USA ; Department of Gastroenterology and Hepatology, The University of Kansas Medical Center, Kansas City, KS, USA
| | - Adam Slivka
- Division of Gastroenterology & Hepatology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | | | - Alvin Zfass
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University Medical Center, Richmond, VA, USA
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Tontini GE, Vecchi M, Pastorelli L, Neurath MF, Neumann H. Differential diagnosis in inflammatory bowel disease colitis: State of the art and future perspectives. World J Gastroenterol 2015; 21:21-46. [PMID: 25574078 PMCID: PMC4284336 DOI: 10.3748/wjg.v21.i1.21] [Citation(s) in RCA: 138] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2014] [Revised: 07/31/2014] [Accepted: 09/16/2014] [Indexed: 02/06/2023] Open
Abstract
Distinction between Crohn’s disease of the colon-rectum and ulcerative colitis or inflammatory bowel disease (IBD) type unclassified can be of pivotal importance for a tailored clinical management, as each entity often involves specific therapeutic strategies and prognosis. Nonetheless, no gold standard is available and the uncertainty of diagnosis may frequently lead to misclassification or repeated examinations. Hence, we have performed a literature search to address the problem of differential diagnosis in IBD colitis, revised current and emerging diagnostic tools and refined disease classification strategies. Nowadays, the differential diagnosis is an untangled issue, and the proper diagnosis cannot be reached in up to 10% of patients presenting with IBD colitis. This topic is receiving emerging attention, as medical therapies, surgical approaches and leading prognostic outcomes require more and more disease-specific strategies in IBD patients. The optimization of standard diagnostic approaches based on clinical features, biomarkers, radiology, endoscopy and histopathology appears to provide only marginal benefits. Conversely, emerging diagnostic techniques in the field of gastrointestinal endoscopy, molecular pathology, genetics, epigenetics, metabolomics and proteomics have already shown promising results. Novel advanced endoscopic imaging techniques and biomarkers can shed new light for the differential diagnosis of IBD, better reflecting diverse disease behaviors based on specific pathogenic pathways.
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Abstract
IBS is estimated to have a prevalence of up to 20% in Western populations and results in substantial costs to health-care services worldwide, estimated to be US$1 billion per year in the USA. IBS remains difficult to diagnose due to its multifactorial aetiology, heterogeneous nature and overlap of symptoms with organic pathologies, such as coeliac disease and IBD. As a result, IBS often continues to be a diagnosis of exclusion, resulting in unnecessary investigations. Available methods for the diagnosis of IBS-including the current gold standard, the Rome III criteria-perform only moderately well. Visceral hypersensitivity and altered pain perception do not discriminate between IBS and other functional gastrointestinal diseases or health with any great accuracy. Attention has now turned to developing novel biomarkers and using psychological markers (so-called psychomarkers) to aid the diagnosis of IBS. This Review describes how useful symptoms, symptom-based criteria, biomarkers and psychomarkers, and indeed combinations of all these approaches, are in the diagnosis of IBS. Future directions in diagnosing IBS could include combining demographic data, gastrointestinal symptoms, biomarkers and psychomarkers using statistical methods. Latent class analysis to distinguish between IBS and non-IBS symptom profiles might also represent a promising avenue for future research.
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Fritscher-Ravens A, Schuppan D, Ellrichmann M, Schoch S, Röcken C, Brasch J, Bethge J, Böttner M, Klose J, Milla PJ. Confocal endomicroscopy shows food-associated changes in the intestinal mucosa of patients with irritable bowel syndrome. Gastroenterology 2014; 147:1012-20.e4. [PMID: 25083606 DOI: 10.1053/j.gastro.2014.07.046] [Citation(s) in RCA: 232] [Impact Index Per Article: 21.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2014] [Revised: 07/06/2014] [Accepted: 07/22/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS We investigated suspected food intolerances in patients with irritable bowel syndrome (IBS) using confocal laser endomicroscopy (CLE) for real-time visualization of structural/functional changes in the intestinal mucosa after food challenge. Patients with functional changes after food challenge (CLE+) were placed on personalized exclusion diets and followed up for long-term symptom relief. METHODS Thirty-six IBS patients with suspected food intolerance and 10 patients with Barrett's esophagus (controls) without IBS symptoms were examined by CLE at University Hospital Schleswig-Holstein (Kiel, Germany). Diluted food antigens were administered directly to the duodenal mucosa through the working channel of the endoscope. Epithelial breaks, intervillous spaces, and the number of intraepithelial lymphocytes (IEL) were measured before and after the food challenge. CLE+ patients were placed on exclusion diets, given symptom score questionnaires, and followed up for 1 year; controls resumed their previous diet. RESULTS CLE showed a real-time response to food antigens in 22 of 36 patients; no responses were observed in 14 of 36 patients (CLE-) or any of the controls. Baseline IELs were significantly higher in CLE+ than CLE- subjects (P = .004); numbers increased significantly after food challenge (P = .0008). Within 5 minutes of exposure of CLE+ patients to food antigens, IELs increased, epithelial leaks/gaps formed, and intervillous spaces widened. Epithelial leaks and intervillous spaces also increased significantly in CLE+ vs baseline (both P < .001). The concordance of IELs measured by CLE and conventional histology was 70.6%; they did not correlate (P = .89; r(2) = 0.027). Symptom scores improved more than 50% in CLE+ patients after a 4-week exclusion diet and increased to 74% at 12 months; symptoms continued in CLE- patients. CONCLUSIONS Based on CLE analysis of IBS patients with a suspected food intolerance, exposure to candidate food antigens caused immediate breaks, increased intervillous spaces, and increased IELs in the intestinal mucosa. These changes are associated with patient responses to exclusion diets. Registered at clinicaltrials.gov (registration number: NCT01692613).
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Affiliation(s)
- Annette Fritscher-Ravens
- Unit of Experimental Endoscopy, Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany.
| | - Detlef Schuppan
- Institute of Translational Immunology, Department of Medicine I, University of Mainz, Mainz, Germany; Research Center for Immunology, University of Mainz, Mainz, Germany; Division of Gastroenterology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts
| | - Mark Ellrichmann
- Unit of Experimental Endoscopy, Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Stefan Schoch
- Unit of Experimental Endoscopy, Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Christoph Röcken
- Department of Pathology, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Jochen Brasch
- Department of Dermatology, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Johannes Bethge
- Unit of Experimental Endoscopy, Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Martina Böttner
- Department of Anatomy, Christian Albrecht University, Kiel, Germany
| | - Julius Klose
- Unit of Experimental Endoscopy, Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Peter J Milla
- University College London Institute of Child Health, University College London, London, United Kingdom
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Shi S, Wang H, Gao H, Li Z, Chen FX, Zuo XL, Li YQ. Increased gap density predicts weakness of the epithelial barrier in vivo by confocal laser endomicroscopy in indomethacin-induced enteropathy. Dig Dis Sci 2014; 59:1398-405. [PMID: 24573719 DOI: 10.1007/s10620-014-3076-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2013] [Accepted: 02/11/2014] [Indexed: 01/26/2023]
Abstract
BACKGROUND AND AIMS The intestinal epithelial barrier plays an important role in the pathogenesis of non-steroidal anti-inflammatory drug-induced enteropathy, and its disruption is often associated with increased cell shedding. The purpose of this report is to observe the gap density in indomethacin-induced small intestinal damage by confocal laser endomicroscopy (CLE) and to investigate the mechanisms involved in this process and how mucosal protectants improve intestinal epithelial barrier dysfunction. CLE is expected to provide a new way for evaluating non-steroidal anti-inflammatory drugs-induced enteropathy in humans and assessing drug efficacy. METHODS Using the new technique of CLE, we established a method to evaluate, in real time, intestinal damage after the administration of indomethacin in Wistar rats by investigating the gap density in the small intestine. The mucosal protectant teprenone and acid-suppressant rabeprazole were then given by gavage before and after the administration of indomethacin, and the mechanisms affecting the intestinal epithelial barrier were investigated. RESULTS Using CLE, gaps could be clearly observed and easily distinguished from goblet cells. Gap density was increased after the administration of indomethacin. During this process, the expression of tumor necrosis factor-α, nuclear factor-κB, and caspase-3 was up-regulated and the expression of tight junctions was down-regulated, which led to the damage of the epithelial barrier. Teprenone and rabeprazole could intervene in this pathway and protect the integrity of the epithelial barrier. CONCLUSIONS CLE can be objective, accurate, and real time in investigating gap density. Teprenone and rabeprazole can prevent indomethacin-induced intestinal lesions and protect the epithelial barrier by intervening in the tumor necrosis factor-α pathway. Gap density was expected to be an indicator of evaluating intestinal inflammation and drug efficacy.
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Affiliation(s)
- Sha Shi
- Department of Gastroenterology, Qilu Hospital, Shandong University, No. 107, Wenhuaxi Road, Jinan, 250012, People's Republic of China,
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Li CQ, Liu J, Ji R, Li Z, Xie XJ, Li YQ. Use of confocal laser endomicroscopy to predict relapse of ulcerative colitis. BMC Gastroenterol 2014; 14:45. [PMID: 24618122 PMCID: PMC3975275 DOI: 10.1186/1471-230x-14-45] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2013] [Accepted: 02/24/2014] [Indexed: 12/13/2022] Open
Abstract
Background Assessment of inflammatory activity in patients with ulcerative colitis (UC) is crucial to the prediction of relapse. Confocal laser endomicroscopy (CLE) is an accurate tool for assessing inflammatory activity in UC patients. This study aimed to evaluate whether CLE could be used to predict UC relapse reliably. Methods In total, forty-three patients with documented UC were analyzed in this study. Patients identified as having obvious active inflammation by conventional colonoscopy were excluded. The mucosa of each patient’s sigmoid colon and rectum was assessed by CLE before targeted biopsies were taken. The patients were then followed up for at least 12 months to evaluate relapse according to the Simple Clinical Colitis Activity Index. The correlation between CLE classification and UC relapse was evaluated. Results Seventeen of 20 patients with histologically confirmed normal or chronic inflammation were diagnosed as having non-active inflammation by real-time CLE and 22 of 23 patients with histologically confirmed acute inflammation were diagnosed as having active inflammation by CLE. The sensitivity, specificity, and accuracy of CLE in real-time diagnosis of active inflammation were 95.7%, 85%, and 90.7%, respectively. The agreement between CLE and conventional histology was excellent (kappa value = 0.812). Two of 18 (11.1%) patients who were classified as having non-active inflammation by CLE relapsed, while 16 of 25 (64%) patients classified as having as active inflammation relapsed. The relapse rate of patients with active inflammation was significantly higher than of those with non-active inflammation (P < 0.001). Conclusions CLE is comparable to conventional histology in predicting relapse in patients with UC.
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Affiliation(s)
| | | | | | | | | | - Yan-Qing Li
- Department of Gastroenterology, Laboratory of Translational Gastroenterology, Shandong University Qilu Hospital, No, 107, Wenhuaxi Road, Jinan, Shandong 250012, China.
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Abstract
Performing real-time microscopy has been a vision of endoscopists since the very early phases of gastrointestinal endoscopy. Confocal endomicroscopy, an adaption of confocal laser scanning microscopy, and endocytoscopy, an adaption of white-light microscopy, have been introduced into the endoscopic armamentarium in the past decade. Both techniques yield on-site histological information. Multiple trials have demonstrated the ability of gastroenterologists to obtain and interpret microscopic images from the upper and lower gastrointestinal tract, and also the hepatobiliary-pancreatic system, during endoscopy. Such microscopic information has been successfully used in expert hands to minimize sampling error by 'smart', microscopically targeted biopsies and to guide endoscopic interventions. However, endomicroscopy is also unique in its ability to dynamically visualize cellular processes in their native environment free of artefacts. This ability enables fundamental insights into mechanisms of human diseases in clinical and translational science.
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Palma GDD, Rispo A. Confocal laser endomicroscopy in inflammatory bowel diseases: Dream or reality? World J Gastroenterol 2013; 19:5593-5597. [PMID: 24039350 PMCID: PMC3769894 DOI: 10.3748/wjg.v19.i34.5593] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2013] [Accepted: 08/06/2013] [Indexed: 02/06/2023] Open
Abstract
Confocal laser endomicroscopy (CLE) is a newly introduced procedure that provide real-time, high-resolution imaging of the gastrointestinal mucosa during endoscopy, allowing the visualization of the pathology of the mucosal epithelium with its cellular and subcellular structures. Recently, the use of CLE was reported in the study of colonic mucosa in patients with inflammatory bowel diseases and in particular in patients affected by ulcerative colitis. CLE has the potential to have an important role in management of inflammatory bowel diseases (IBD) patients as it can be used to assess the grading of colitis and in detection of microscopic colitis in endoscopically silent segments. Moreover, CLE can be used in surveillance programs especially in high-risk patients. Finally, CLE has been effectively used in diagnosing a biliary dysplasia/neoplasia in patients with primary sclerosing cholangitis, a pathological condition frequently associated with IBD, with a coexisting bile duct stricture.
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Abstract
Two types of endomicroscopy systems exist. One is integrated into a standard, high-resolution endoscope and one is probe-based, capable of passage through the working channel of a standard endoscope. Endocytoscopy allows visualization of the superficial mucosal layer. Endoscope-integrated and probe-based devices allow magnification of the mucosa up to 1400-fold. Endomicroscopy can differentiate histologic changes of Crohn disease and ulcerative colitis in vivo in real time. Endocytoscopy can discriminate mucosal inflammatory cells, allowing determination of histopathologic activity of ulcerative colitis. Molecular imaging with fluorescence-labeled probes against disease-specific receptors will enable individualized management of inflammatory bowel diseases.
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Affiliation(s)
- Helmut Neumann
- Interdisciplinary Endoscopy, Department of Medicine I, University of Erlangen-Nuremberg, Ulmenweg 18, Erlangen 91054, Germany.
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Musquer N, Coquenlorge S, Bourreille A, Aubert P, Matysiak-Budnik T, des Varannes SB, Lauwers G, Neunlist M, Coron E. Probe-based confocal laser endomicroscopy: a new method for quantitative analysis of pit structure in healthy and Crohn's disease patients. Dig Liver Dis 2013; 45:487-92. [PMID: 23466186 DOI: 10.1016/j.dld.2013.01.018] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2012] [Revised: 01/02/2013] [Accepted: 01/06/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND Probe-based confocal laser endomicroscopy enables microscopic examination of the digestive mucosa. AIMS (1) To identify and validate quantitative endomicroscopic criteria for evaluation of the colonic mucosa and (2) to compare these criteria between healthy and Crohn's disease patients in clinical remission. METHODS Six healthy controls and ten Crohn's disease patients in clinical remission were included in this prospective study. Methylene blue-stained biopsies of the right colon and corresponding endomicroscopic images were analyzed. Major axis, minor axis, and major axis/minor axis ratio of crypt lumens were quantified. RESULTS Quantitative assessment was performed on 21 ± 4 crypt lumens per patient. Major axis/minor axis ratio values measured with endomicroscopy or methylene blue-stained biopsies were linearly correlated (r=0.63, p=0.01). All macroscopically inflamed mucosa had values of major axis/minor axis ratio higher than the median of controls. Interestingly, 50% (3/6) of Crohn's disease patients with macroscopically normal mucosa had also a higher ratio than pooled controls. Histological analysis showed that 6/7 patients with major axis/minor axis ratio superior to 1.7 had microscopic inflammation. CONCLUSION Probe-based confocal laser endomicroscopy allows quantitative analysis of colonic pit structure. Endomicroscopic analysis of major axis/minor axis ratio allows the detection of microscopic residual inflammation with greater accuracy than standard endoscopy in Crohn's disease patients in clinical remission.
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Affiliation(s)
- Nicolas Musquer
- Digestive Diseases Institute, Nantes University Hospital, F-44093, France
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Breaks in the wall: increased gaps in the intestinal epithelium of irritable bowel syndrome patients identified by confocal laser endomicroscopy (with videos). Gastrointest Endosc 2013; 77:624-30. [PMID: 23357497 DOI: 10.1016/j.gie.2012.11.006] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2012] [Accepted: 11/05/2012] [Indexed: 02/08/2023]
Abstract
BACKGROUND Altered intestinal permeability and mucosal inflammation have been reported in irritable bowel syndrome (IBS) patients. Increased cell extrusion in the epithelium as measured by epithelial gaps may be associated with barrier dysfunction and may lead to mucosal inflammation. Confocal laser endomicroscopy can be used to identify and quantitate epithelial gaps in the small intestine. OBJECTIVE To determine the epithelial gap density in IBS and healthy control patients. DESIGN Prospective, controlled cohort study. SETTING A tertiary referral center. PATIENTS In IBS and control patients undergoing routine colonoscopy, probe-based confocal laser endomicroscopy was used to image the terminal ileum. MAIN OUTCOME MEASUREMENTS The primary outcome was the density of epithelial gaps (gaps/cells counted) in adequately imaged villi using pCLE. Images were reviewed by 2 blinded reviewers. RESULTS We recruited 18 healthy controls and 16 IBS patients. The median epithelial gap densities for control and IBS patients were 6 and 32 gaps per 1000 cells, respectively (P < .001). There was a trend toward higher gap density in female (P = .07) and younger (ρ = -0.43, P = .07) patients. Using 3% (90% of the control population) as the cutoff for abnormal gap density, we found the diagnostic accuracy for IBS to be as follows: 62% sensitivity, 89% specificity, 83% positive predictive value, and 73% negative predictive value. LIMITATIONS A single-center study, small number of patients. CONCLUSIONS IBS patients have significantly more epithelial gaps in their small intestine compared with healthy controls, which suggests that increased epithelial cell extrusion may be a cause of altered intestinal permeability observed in IBS.
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Neumann H, Günther C, Vieth M, Grauer M, Wittkopf N, Mudter J, Becker C, Schoerner C, Atreya R, Neurath MF. Confocal laser endomicroscopy for in vivo diagnosis of Clostridium difficile associated colitis - a pilot study. PLoS One 2013; 8:e58753. [PMID: 23527018 PMCID: PMC3602426 DOI: 10.1371/journal.pone.0058753] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2012] [Accepted: 02/06/2013] [Indexed: 12/26/2022] Open
Abstract
Background Clostridium difficile infection (CDI) is one of the most dreaded causes of hospital-acquired diarrhea. Main objective was to investigate whether confocal laser endomicroscopy (CLE) has the capability for in vivo diagnosis of C. difficile associated histological changes. Second objective was to prove the presence of intramucosal bacteria using CLE. Methods 80 patients were prospectively included, 10 patients were diagnosed with CDI based on toxigenic culture. To validate the presence of intramucosal bacteria ex vivo, CLE was performed in pure C. difficile culture; additionally fluorescence in situ hybridization (FISH) was performed. Finally, CLE with fluorescence labelled oligonucleotide probe specific for C. difficile was performed ex vivo in order to prove the presence of bacteria. Results CLE identified CDI-associated histological changes in vivo (sensitivity and accuracy of 88.9% and 96.3%). In addition, intramucosal bacteria were visualized. The presence of these bacteria could be proven by CLE with labeled, specific molecular C. difficile probe and FISH-technique. Based on comparison between CLE and FISH analyses, sensitivity and specificity for the presence of intramucosal bacteria were 100%. Conclusion CLE has the potential for in vivo diagnosis of CDI associated colitis. In addition, CLE allowed the detection of intramucosal bacteria in vivo.
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Affiliation(s)
- Helmut Neumann
- Department of Medicine I, University of Erlangen-Nuremberg, Erlangen, Germany.
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