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Pallotta L, Pisano A, Vona R, Cappelletti M, Pignataro MG, Tattoli I, Maselli MA, Tarallo M, Casella G, Caronna R, Tancredi A, Scotti GB, Scalese G, Matarrese P, Giordano C, Severi C. From diverticulosis to complicated diverticular disease: Progression of myogenic alterations and oxidative imbalance. Neurogastroenterol Motil 2024; 36:e14850. [PMID: 38924329 DOI: 10.1111/nmo.14850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Revised: 04/12/2024] [Accepted: 06/04/2024] [Indexed: 06/28/2024]
Abstract
BACKGROUND The natural history and pathophysiology of diverticular disease (DD) are still uncertain. An ex-vivo human complicated DD (cDD) model has recently shown a predominant transmural oxidative imbalance. The present study aims to evaluate whether the previously described alterations may precede the symptomatic form of the disease. METHODS Colonic surgical samples obtained from patients with asymptomatic diverticulosis (DIV), complicated DD, and controls were systematically and detailed morphologically and molecularly analyzed. Therefore, histologic, histomorphometric, immunohistochemical evaluation, and gene and protein expression analysis were performed to characterize colonic muscle changes and evaluate chronic inflammation, oxidative imbalance, and hypoxia. Functional muscle activity was tested on strips and isolated cells in response to contractile and relaxant agents. KEY RESULTS Compared with controls, DD showed a marketed increase in muscle layer thickness, smooth muscle cell syncytium disarray, and increased interstitial fibrosis; moreover, the observed features were more evident in the cDD group. These changes mainly affected longitudinal muscle and were associated with altered contraction-relaxation dynamics and fibrogenic switch of smooth muscle cells. Chronic lymphoplasmacytic inflammation was primarily evident in the mucosa and spared the muscle. A transmural increase in carbonylated and nitrated proteins, with loss of antioxidant molecules, characterized both stages of DD, suggesting early oxidative stress probably triggered by recurrent ischemic events, more pronounced in cDD, where HIF-1 was detected in both muscle and mucosa. CONCLUSION & INFERENCES The different DD clinical scenarios are part of a progressive process, with oxidative imbalance representing a new target in the management of DD.
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Affiliation(s)
- Lucia Pallotta
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Annalinda Pisano
- Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, Rome, Italy
| | - Rosa Vona
- Center for Gender-Specific Medicine, Italian National Institute of Health, Rome, Italy
| | - Martina Cappelletti
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Maria Gemma Pignataro
- Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, Rome, Italy
| | - Ivan Tattoli
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Maria Antonietta Maselli
- Experimental Pharmacology Laboratory, National Institute of Gastroenterology "S. de Bellis", Research Hospital, Castellana Grotte, Bari, Italy
| | - Mariarita Tarallo
- Department of Surgical Science, Sapienza University of Rome, Rome, Italy
| | - Giovanni Casella
- Department of Surgical Science, Sapienza University of Rome, Rome, Italy
| | - Roberto Caronna
- Department of Surgical Science, Sapienza University of Rome, Rome, Italy
| | - Andrea Tancredi
- Department of Methods and Models for Economy, Territory and Finance, Sapienza University of Rome, Rome, Italy
| | | | - Giulia Scalese
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Paola Matarrese
- Center for Gender-Specific Medicine, Italian National Institute of Health, Rome, Italy
| | - Carla Giordano
- Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, Rome, Italy
| | - Carola Severi
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
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Ariam E, Richter V, Bermont A, Sandler Y, Cohen DL, Shirin H. Prior abdominal surgery as a potential risk factor for colonic diverticulosis or diverticulitis. World J Clin Cases 2023; 11:8320-8329. [PMID: 38130607 PMCID: PMC10731208 DOI: 10.12998/wjcc.v11.i35.8320] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 11/15/2023] [Accepted: 12/04/2023] [Indexed: 12/14/2023] Open
Abstract
BACKGROUND Abnormal colonic pressure profiles have been associated with an increased risk of colonic diverticulosis. A surgical history is a known risk factor for abdominal adhesions and these may lead to increased intraluminal colonic pressure. AIM To assess whether previous abdominal surgery is associated with colonic diverticulosis or diverticulitis. METHODS We analyzed data from a study of patients undergoing colonoscopy for different indications from 2020 through 2021. Patients completed a structured questionnaire concerning previous abdominal surgeries, dietary and lifestyle exposures including smoking, alcohol use and co-morbidities. RESULTS Three hundred and fifty-nine patients were included in the study. The mean age was 67.6 and 46% were females. Diabetes mellitus, hypertension, ischemic heart disease, chronic obstructive pulmonary disease, chronic renal failure, and body mass index were similar in the diverticulosis and control groups. The overall prevalence of colonic diverticulosis was 25% (91/359) and 48% of the patients had previous abdominal surgery. As expected, the prevalence of diverticulosis increased with age. There was no difference in the rate of previous abdominal surgery between patients with or without diverticulosis (49% vs 47%, P = 0.78). In regards to specific surgeries, inguinal hernia repair was significantly associated with diverticulosis (52% vs 20%, P = 0.001), but not diverticulitis. In contrast, appendectomy was not associated with diverticulosis (6% vs 14%, P = 0.048). CONCLUSION These findings suggest that post-operative abdominal adhesions inducing high colonic intraluminal pressures do not appear to be the mechanism for diverticula formation. Rather, inguinal hernia and diverticulosis may share similar connective tissue pathologies with no causative relationship between them.
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Affiliation(s)
- Eran Ariam
- Department of Gastroenterology, Kaplan Medical Center, Rehovot 76100, Israel
| | - Vered Richter
- The Gonczarowski Family Institute of Gastroenterology and Liver Diseases, Shamir Medical Center, Zerifin 70300, Israel and the Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Anton Bermont
- The Gonczarowski Family Institute of Gastroenterology and Liver Diseases, Shamir Medical Center, Zerifin 70300, Israel and the Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Yael Sandler
- Department of Surgery Division, Shamir Medical Center, Zerifin 70300, Israel
| | - Daniel L Cohen
- The Gonczarowski Family Institute of Gastroenterology and Liver Diseases, Shamir Medical Center, Zerifin 70300, Israel and the Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Haim Shirin
- The Gonczarowski Family Institute of Gastroenterology and Liver Diseases, Shamir Medical Center, Zerifin 70300, Israel and the Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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Tanjore Ramanathan J, Zárybnický T, Filppu P, Monzo HJ, Monni O, Tervonen TA, Klefström J, Kerosuo L, Kuure S, Laakkonen P. Immunoglobulin superfamily member 3 is required for the vagal neural crest cell migration and enteric neuronal network organization. Sci Rep 2023; 13:17162. [PMID: 37821496 PMCID: PMC10567708 DOI: 10.1038/s41598-023-44093-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 10/03/2023] [Indexed: 10/13/2023] Open
Abstract
The immunoglobulin (Ig) superfamily members are involved in cell adhesion and migration, complex multistep processes that play critical roles in embryogenesis, wound healing, tissue formation, and many other processes, but their specific functions during embryonic development remain unclear. Here, we have studied the function of the immunoglobulin superfamily member 3 (IGSF3) by generating an Igsf3 knockout (KO) mouse model with CRISPR/Cas9-mediated genome engineering. By combining RNA and protein detection methodology, we show that during development, IGSF3 localizes to the neural crest and a subset of its derivatives, suggesting a role in normal embryonic and early postnatal development. Indeed, inactivation of Igsf3 impairs the ability of the vagal neural crest cells to migrate and normally innervate the intestine. The small intestine of Igsf3 KO mice shows reduced thickness of the muscularis externa and diminished number of enteric neurons. Also, misalignment of neurons and smooth muscle cells in the developing intestinal villi is detected. Taken together, our results suggest that IGSF3 functions contribute to the formation of the enteric nervous system. Given the essential role of the enteric nervous system in maintaining normal gastrointestinal function, our study adds to the pool of information required for further understanding the mechanisms of gut innervation and etiology behind bowel motility disorders.
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Affiliation(s)
| | - Tomáš Zárybnický
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Pauliina Filppu
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Hector J Monzo
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Outi Monni
- Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Topi A Tervonen
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Finnish genome editing center (FinGEEC), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland
| | - Juha Klefström
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Finnish Cancer Institute & FICAN South, Helsinki University Hospital (HUS), Helsinki, Finland
| | - Laura Kerosuo
- Neural Crest Development and Disease Unit, Department of Health and Human Services, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, 20892, USA.
| | - Satu Kuure
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
- GM-unit, Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland.
| | - Pirjo Laakkonen
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
- iCAN Flagship Program, University of Helsinki, Helsinki, Finland.
- Laboratory Animal Centre, Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland.
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Wu Y, Goleva SB, Breidenbach LB, Kim M, MacGregor S, Gandal MJ, Davis LK, Wray NR. 150 risk variants for diverticular disease of intestine prioritize cell types and enable polygenic prediction of disease susceptibility. CELL GENOMICS 2023; 3:100326. [PMID: 37492107 PMCID: PMC10363821 DOI: 10.1016/j.xgen.2023.100326] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 03/11/2023] [Accepted: 04/20/2023] [Indexed: 07/27/2023]
Abstract
We conducted a genome-wide association study (GWAS) analysis of diverticular disease (DivD) of intestine within 724,372 individuals and identified 150 independent genome-wide significant DNA variants. Integration of the GWAS results with human gut single-cell RNA sequencing data implicated gut myocyte, mesothelial and stromal cells, and enteric neurons and glia in DivD development. Ninety-five genes were prioritized based on multiple lines of evidence, including SLC9A3, a drug target gene of tenapanor used for the treatment of the constipation subtype of irritable bowel syndrome. A DivD polygenic score (PGS) enables effective risk prediction (area under the curve [AUC], 0.688; 95% confidence interval [CI], 0.645-0.732) and the top 20% PGS was associated with ∼3.6-fold increased DivD risk relative to the remaining population. Our statistical and bioinformatic analyses suggest that the mechanism of DivD is through colon structure, gut motility, gastrointestinal mucus, and ionic homeostasis. Our analyses reinforce the link between gastrointestinal disorders and the enteric nervous system through genetics.
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Affiliation(s)
- Yeda Wu
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia
- QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia
| | - Slavina B. Goleva
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Lindsay B. Breidenbach
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Minsoo Kim
- Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
- Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
- Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Stuart MacGregor
- QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia
| | - Michael J. Gandal
- Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
- Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
- Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Lea K. Davis
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Department of Psychiatry and Behavioural Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Departments of Medicine and Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Division of Genetic Medicine, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University, 511-A Light Hall, 2215 Garland Avenue, Nashville, TN 37232, USA
| | - Naomi R. Wray
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia
- Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia
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Pallotta L, Vona R, Maselli MA, Cicenia A, Bella A, Ignazzi A, Carabotti M, Cappelletti M, Gioia A, Tarallo M, Tellan G, Fiori E, Pezzolla F, Matarrese P, Severi C. Oxidative imbalance and muscular alterations in diverticular disease. Dig Liver Dis 2022; 54:1186-1194. [PMID: 35232677 DOI: 10.1016/j.dld.2022.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 12/20/2021] [Accepted: 02/02/2022] [Indexed: 12/14/2022]
Abstract
BACKGROUND It is still a matter of debate if neuromuscular alterations reflect a primary event in diverticular disease (DD). AIMS This study aimed to assess colonic wall layers from both stenotic and non-stenotic complicated DD, bio-phenotypic alterations, inflammatory and oxidative status. METHODS A systematic analysis of colonic specimens obtained from stenotic and non-stenotic DD specimens was conducted and compared with controls. Biological activity and qPCR analysis were performed on longitudinal and circular muscles. Western blot analysis was performed throughout colonic wall layers to quantify oxidative and inflammatory markers. RESULTS A homogenous increase in oxidative stress was observed through all the layers, which were more sharpened in the longitudinal muscle for a loss in antioxidant defenses. In both stenotic and non-stenotic colon, the longitudinal muscle presented an impaired relaxation and a cellular phenotypic switch driven by transforming growth factor-β with an increase in mRNA expression of collagen Iα and a decrease in myosin heavy chain. The circular muscle, as the mucosa, was less affected by molecular alterations. No peculiar increase in inflammatory markers was observed. CONCLUSION A longitudinal colonic myopathy is present in DD, independently from the disease stage associated with an oxidative imbalance that could suggest new therapeutic strategies.
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Affiliation(s)
- Lucia Pallotta
- Department of Translational and Precision Medicine, Sapienza University of Rome, Italy.
| | - Rosa Vona
- Center for Gender-Specific Medicine, Italian National Institute of Health, Rome, Italy
| | - Maria Antonietta Maselli
- Experimental Pharmacology Laboratory, National Institute of Gastroenterology "S. de Bellis", Research Hospital, Castellana Grotte, BA, USA
| | - Alessia Cicenia
- Department of Translational and Precision Medicine, Sapienza University of Rome, Italy
| | - Antonino Bella
- Department of Infectious Diseases, Italian National Institute of Health, Rome, Italy
| | - Antonia Ignazzi
- Experimental Pharmacology Laboratory, National Institute of Gastroenterology "S. de Bellis", Research Hospital, Castellana Grotte, BA, USA
| | - Marilia Carabotti
- Medical-Surgical Department of Clinical Sciences and Translational Medicine, Sapienza University of Rome, Italy
| | - Martina Cappelletti
- Department of Translational and Precision Medicine, Sapienza University of Rome, Italy
| | - Alessia Gioia
- Department of Translational and Precision Medicine, Sapienza University of Rome, Italy
| | - Mariarita Tarallo
- Department of Surgery "P. Valdoni", Sapienza University of Rome, Italy
| | - Guglielmo Tellan
- Department of Internistic, Anaesthetic and Cardiovascular Clinical Sciences, Sapienza University of Rome, Italy
| | - Enrico Fiori
- Department of Surgery "P. Valdoni", Sapienza University of Rome, Italy
| | - Francesco Pezzolla
- Experimental Pharmacology Laboratory, National Institute of Gastroenterology "S. de Bellis", Research Hospital, Castellana Grotte, BA, USA
| | - Paola Matarrese
- Center for Gender-Specific Medicine, Italian National Institute of Health, Rome, Italy
| | - Carola Severi
- Department of Translational and Precision Medicine, Sapienza University of Rome, Italy
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Zeng J, Wang X, Pan F, Mao Z. The relationship between Parkinson's disease and gastrointestinal diseases. Front Aging Neurosci 2022; 14:955919. [PMID: 36034146 PMCID: PMC9399652 DOI: 10.3389/fnagi.2022.955919] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Accepted: 07/25/2022] [Indexed: 01/03/2023] Open
Abstract
An increasing number of studies have provided evidence for the hypothesis that the pathogenesis of Parkinson's disease (PD) may derive from the gut. Firstly, Lewy pathology can be induced in the enteric nervous system (ENS) and be transported to the central nervous system (CNS) via the vagal nerve. Secondly, the altered composition of gut microbiota causes an imbalance between beneficial and deleterious microbial metabolites which interacts with the increased gut permeability and the gut inflammation as well as the systemic inflammation. The activated inflammatory status then affects the CNS and promotes the pathology of PD. Given the above-mentioned findings, researchers start to pay attention to the connection between PD and gastrointestinal diseases including irritable bowel syndrome, inflammatory bowel disease (IBD), microscopic colitis (MC), gastrointestinal infections, gastrointestinal neoplasms, and colonic diverticular disease (CDD). This review focuses on the association between PD and gastrointestinal diseases as well as the pathogenesis of PD from the gut.
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Affiliation(s)
- Jiaqi Zeng
- Department of Gastroenterology and Hepatology, First Medical Center, Chinese PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
| | - Xinchan Wang
- Department of Gastroenterology and Hepatology, First Medical Center, Chinese PLA General Hospital, Beijing, China
- Medical School of Nankai University, Tianjin, China
| | - Fei Pan
- Department of Gastroenterology and Hepatology, First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Zhiqi Mao
- Department of Neurosurgery, First Medical Center, Chinese PLA General Hospital, Beijing, China
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7
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Pathophysiology of Diverticular Disease: From Diverticula Formation to Symptom Generation. Int J Mol Sci 2022; 23:ijms23126698. [PMID: 35743141 PMCID: PMC9223421 DOI: 10.3390/ijms23126698] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 06/13/2022] [Accepted: 06/13/2022] [Indexed: 01/04/2023] Open
Abstract
Diverticular disease is a common clinical problem, particularly in industrialized countries. In most cases, colonic diverticula remain asymptomatic throughout life and sometimes are found incidentally during colonic imaging in colorectal cancer screening programs in otherwise healthy subjects. Nonetheless, roughly 25% of patients bearing colonic diverticula develop clinical manifestations. Abdominal symptoms associated with diverticula in the absence of inflammation or complications are termed symptomatic uncomplicated diverticular disease (SUDD). The pathophysiology of diverticular disease as well as the mechanisms involved in the shift from an asymptomatic condition to a symptomatic one is still poorly understood. It is accepted that both genetic factors and environment, as well as intestinal microenvironment alterations, have a role in diverticula development and in the different phenotypic expressions of diverticular disease. In the present review, we will summarize the up-to-date knowledge on the pathophysiology of diverticula and their different clinical setting, including diverticulosis and SUDD.
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8
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Leifeld L, Kruis W, Germer CT. Divertikelkrankheit. DER GASTROENTEROLOGE 2022; 17:189-197. [DOI: 10.1007/s11377-022-00608-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 03/22/2022] [Indexed: 01/05/2025]
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9
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Leifeld L, Germer CT, Böhm S, Dumoulin FL, Frieling T, Kreis M, Meining A, Labenz J, Lock JF, Ritz JP, Schreyer A, Kruis W. S3-Leitlinie Divertikelkrankheit/Divertikulitis – Gemeinsame Leitlinie der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) und der Deutschen Gesellschaft für Allgemein- und Viszeralchirurgie (DGAV). ZEITSCHRIFT FUR GASTROENTEROLOGIE 2022; 60:613-688. [PMID: 35388437 DOI: 10.1055/a-1741-5724] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Ludger Leifeld
- Medizinische Klinik 3 - Gastroenterologie und Allgemeine Innere Medizin, St. Bernward Krankenhaus, Hildesheim, apl. Professur an der Medizinischen Hochschule Hannover
| | - Christoph-Thomas Germer
- Klinik und Poliklinik für Allgemein-, Viszeral-, Transplantations-, Gefäß- und Kinderchirurgie, Zentrum für Operative Medizin, Universitätsklinikum Würzburg, Würzburg
| | - Stephan Böhm
- Spital Bülach, Spitalstrasse 24, 8180 Bülach, Schweiz
| | | | - Thomas Frieling
- Medizinische Klinik II, Klinik für Gastroenterologie, Hepatologie, Infektiologie, Neurogastroenterologie, Hämatologie, Onkologie und Palliativmedizin HELIOS Klinikum Krefeld
| | - Martin Kreis
- Klinik für Allgemein-, Viszeral- und Gefäßchirurgie, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
| | - Alexander Meining
- Medizinische Klinik und Poliklinik 2, Zentrum für Innere Medizin (ZIM), Universitätsklinikum Würzburg, Würzburg
| | - Joachim Labenz
- Abteilung für Innere Medizin, Evang. Jung-Stilling-Krankenhaus, Siegen
| | - Johan Friso Lock
- Klinik und Poliklinik für Allgemein-, Viszeral-, Transplantations-, Gefäß- und Kinderchirurgie, Zentrum für Operative Medizin, Universitätsklinikum Würzburg, Würzburg
| | - Jörg-Peter Ritz
- Klinik für Allgemein- und Viszeralchirurgie, Helios Klinikum Schwerin
| | - Andreas Schreyer
- Institut für diagnostische und interventionelle Radiologie, Medizinische Hochschule Brandenburg Theodor Fontane Klinikum Brandenburg, Brandenburg, Deutschland
| | - Wolfgang Kruis
- Medizinische Fakultät, Universität Köln, Köln, Deutschland
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Bhattarai C, Poudel PP, Ghosh A, Kalthur SG. Histomorphology of enteric neurons and enteric ganglia in different layers of human fetal colon. J Taibah Univ Med Sci 2022; 17:556-563. [PMID: 35983451 PMCID: PMC9356345 DOI: 10.1016/j.jtumed.2022.01.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 01/11/2022] [Accepted: 01/22/2022] [Indexed: 11/28/2022] Open
Abstract
Objective Methods Results Conclusion
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Affiliation(s)
- Chacchu Bhattarai
- Department of Anatomy, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Karnataka, India
- Department of Anatomy, Manipal College of Medical Sciences, Pokhara, Nepal
| | - Phanindra P. Poudel
- Department of Anatomy, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Karnataka, India
- Department of Anatomy, Manipal College of Medical Sciences, Pokhara, Nepal
| | - Arnab Ghosh
- Department of Pathology, Manipal College of Medical Sciences, Pokhara, Nepal
| | - Sneha G. Kalthur
- Department of Anatomy, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Karnataka, India
- Corresponding address: Department of Anatomy, Kasturba Medical College, Manipal, Manipal Academy of Higher Education (MAHE), Karnataka, 576104, India.
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11
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Bassotti G, Pellegrini C, Bernardini N. Neuromuscular Function Abnormalities. COLONIC DIVERTICULAR DISEASE 2022:31-39. [DOI: 10.1007/978-3-030-93761-4_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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12
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Vayzband V, Ashraf H, Esparragoza P. Surgically Managed Perforated Jejunal Diverticulitis. Cureus 2021; 13:e15930. [PMID: 34336432 PMCID: PMC8313005 DOI: 10.7759/cureus.15930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/25/2021] [Indexed: 11/26/2022] Open
Abstract
A 71-year-old male with a past medical history significant for chronic constipation presented to the emergency department for acute onset of severe abdominal pain. On presentation, the patient appeared to be in distress, exemplifying signs of peritonitis despite vital signs being grossly benign. CT scan established the diagnosis of a perforated jejunal diverticulitis. Initially, the patient was managed conservatively with IV fluids, antibiotics, and pain control medications. Diagnostic imaging in tandem with the patient's failure to improve incited surgical intervention with a jejunal resection and establishment of a primary anastomosis. This case illustrates additional differential diagnoses necessary for consideration in an elderly patient presenting with an acute abdomen.
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Affiliation(s)
- Vlad Vayzband
- Internal Medicine, Saint Peter's University Hospital, New Brunswick, USA
| | - Hamza Ashraf
- Internal Medicine, Saint Peter's University Hospital, New Brunswick, USA
| | - Paola Esparragoza
- Gastroenterology and Hepatology, Saint Peter's University Hospital, New Brunswick, USA
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Evaluation of molecular and genetic predisposing parameters at diverticular disease of the colon. Int J Colorectal Dis 2021; 36:903-910. [PMID: 33409567 DOI: 10.1007/s00384-020-03812-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/25/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Diverticular disease (DD) refers to the presence of diverticula throughout the gastrointestinal (GI) tract, mainly along colon. DD might evolve into diverticulitis that is accompanied by severe clinical presentation, which includes abscess formation, perforation, stricture, obstruction and/or fistula. AIM The aim of the present review is to summarize the role of molecular and genetic factors in DD development, as well as their possible contribution towards new prognostic indicators, diagnostic algorithms and new therapeutic approaches. METHODS AND RESULTS Except from common predisposing parameters, several genetic mutations, immune factors, neurotransmitters, hormones and protein dysfunctions have been associated to the early onset of DD symptoms, pathogenesis and prognosis of the disease. Specific structural changes in the colonic wall, altered matrix composition and compromised motility have been verified as possible pathogenic factors for the development of DD. Dysregulation in peristaltic activity and reduced ability of the longitudinal muscle to relax following contraction has been also associated with DD evolution. In addition, it has been suspected that genetic defects combined with alterations in intestinal microbiota might play an important role in diverticulitis presentation.
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14
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Abstract
Left sided colonic diverticulitis is a common and costly gastrointestinal disease in Western countries, characterized by acute onset of often severe abdominal pain. Imaging is necessary to make an initial diagnosis and determine disease severity. Colonoscopy should be done six to eight weeks after diagnosis to rule out a missed colon malignancy. Antibiotic treatment is used selectively in immunocompetent patients with mild acute uncomplicated diverticulitis. The clinical course of diverticulitis commonly includes unpredictable recurrences and chronic gastrointestinal symptoms, which are a detriment to quality of life. A better understanding of prognosis has prompted a shift toward non-operative approaches. The decision to undergo prophylactic colon resection should be individualized to consider the severity of diverticulitis, the patient's health and immune status, and the patient's preferences and values, as well as benefits and risks. Because only a section of colon is removed, recurrent diverticulitis remains a risk. Acute diverticulitis with an abscess is treated with antibiotics that cover Gram negative and anaerobic bacteria, with or without percutaneous drainage. Acute diverticulitis with purulent or feculent contamination of the peritoneal cavity is managed with surgery; primary resection and anastomosis is the procedure of choice in stable patients.
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Affiliation(s)
- Anne F Peery
- University of North Carolina School of Medicine, Chapel Hill, NC 27599-7555, USA
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15
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D’Antongiovanni V, Pellegrini C, Fornai M, Colucci R, Blandizzi C, Antonioli L, Bernardini N. Intestinal epithelial barrier and neuromuscular compartment in health and disease. World J Gastroenterol 2020; 26:1564-1579. [PMID: 32327906 PMCID: PMC7167418 DOI: 10.3748/wjg.v26.i14.1564] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 03/04/2020] [Accepted: 03/09/2020] [Indexed: 02/06/2023] Open
Abstract
A number of digestive and extra-digestive disorders, including inflammatory bowel diseases, irritable bowel syndrome, intestinal infections, metabolic syndrome and neuropsychiatric disorders, share a set of clinical features at gastrointestinal level, such as infrequent bowel movements, abdominal distension, constipation and secretory dysfunctions. Several lines of evidence indicate that morphological and molecular changes in intestinal epithelial barrier and enteric neuromuscular compartment contribute to alterations of both bowel motor and secretory functions in digestive and extra-digestive diseases. The present review has been conceived to provide a comprehensive and critical overview of the available knowledge on the morphological and molecular changes occurring in intestinal epithelial barrier and enteric neuromuscular compartment in both digestive and extra-digestive diseases. In addition, our intent was to highlight whether these morphological and molecular alterations could represent a common path (or share some common features) driving the pathophysiology of bowel motor dysfunctions and related symptoms associated with digestive and extra-digestive disorders. This assessment might help to identify novel targets of potential usefulness to develop original pharmacological approaches for the therapeutic management of such disturbances.
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Affiliation(s)
| | | | - Matteo Fornai
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa 56126, Italy
| | - Rocchina Colucci
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova 35131, Italy
| | - Corrado Blandizzi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa 56126, Italy
| | - Luca Antonioli
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa 56126, Italy
| | - Nunzia Bernardini
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa 56126, Italy
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16
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Involvement of Enteric Glia in Small Intestine Neuromuscular Dysfunction of Toll-Like Receptor 4-Deficient Mice. Cells 2020; 9:cells9040838. [PMID: 32244316 PMCID: PMC7226836 DOI: 10.3390/cells9040838] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 03/26/2020] [Accepted: 03/27/2020] [Indexed: 12/16/2022] Open
Abstract
Enteric glial cells (EGCs) influence nitric oxide (NO)− and adenosine diphosphate (ADP)− mediated signaling in the enteric nervous system (ENS). Since Toll-like receptor 4 (TLR4) participates to EGC homoeostasis, this study aimed to evaluate the possible involvement of EGCs in the alterations of the inhibitory neurotransmission in TLR4−/− mice. Ileal segments from male TLR4−/− and wild-type (WT) C57BL/6J mice were incubated with the gliotoxin fluoroacetate (FA). Alterations in ENS morphology and neurochemical coding were investigated by immunohistochemistry whereas neuromuscular responses were determined by recording non-adrenergic non-cholinergic (NANC) relaxations in isometrically suspended isolated ileal preparations. TLR4−/− ileal segments showed increased iNOS immunoreactivity associated with enhanced NANC relaxation, mediated by iNOS-derived NO and sensitive to P2Y1 inhibition. Treatment with FA diminished iNOS immunoreactivity and partially abolished NO− and ADP− mediated relaxation in the TLR4−/− mouse ileum, with no changes of P2Y1 and connexin-43 immunofluorescence distribution in the ENS. After FA treatment, S100β and GFAP immunoreactivity in TLR4−/− myenteric plexus was reduced to levels comparable to those observed in WT. Our findings show the involvement of EGCs in the alterations of ENS architecture and in the increased purinergic and nitrergic-mediated relaxation, determining gut dysmotility in TLR4−/− mice.
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17
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Tursi A, Scarpignato C, Strate LL, Lanas A, Kruis W, Lahat A, Danese S. Colonic diverticular disease. Nat Rev Dis Primers 2020; 6:20. [PMID: 32218442 PMCID: PMC7486966 DOI: 10.1038/s41572-020-0153-5] [Citation(s) in RCA: 139] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/11/2020] [Indexed: 12/12/2022]
Abstract
Diverticula are outpouchings of the intestinal wall and are common anatomical alterations detected in the human colon. Colonic diverticulosis (the presence of diverticula in the colon; referred to as diverticulosis) remains asymptomatic in most individuals but ~25% of individuals will develop symptomatic diverticulosis, termed colonic diverticular disease (also known as diverticular disease). Diverticular disease can range in severity from symptomatic uncomplicated diverticular disease (SUDD) to symptomatic disease with complications such as acute diverticulitis or diverticular haemorrhage. Since the early 2000s, a greater understanding of the pathophysiology of diverticulosis and diverticular disease, which encompasses genetic alterations, chronic low-grade inflammation and gut dysbiosis, has led to improvements in diagnosis and management. Diagnosis of diverticular disease relies on imaging approaches, such as ultrasonography, CT and MRI, as biomarkers alone are insufficient to establish a diagnosis despite their role in determining disease severity and progression as well as in differential diagnosis. Treatments for diverticular disease include dietary fibre, pharmacological treatments such as antibiotics (rifaximin), anti-inflammatory drugs (mesalazine) and probiotics, alone or in combination, and eventually surgery. Despite being effective in treating primary disease, their effectiveness in primary and secondary prevention of complications is still uncertain.
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Affiliation(s)
- Antonio Tursi
- Territorial Gastroenterology Service, Azienda Sanitaria Locale Barletta-Andria-Trani, Andria, Italy.
| | - Carmelo Scarpignato
- Faculty of Health Sciences, LUdeS Lugano Campus, Lugano, Switzerland
- United Campus of Malta, Birkirkara, Msida, Malta
| | - Lisa L Strate
- Division of Gastroenterology, Department of Medicine, Harborview Medical Center, University of Washington Medical School, Seattle, WA, USA
| | - Angel Lanas
- Service of Digestive Diseases, University Clinic Hospital Lozano Blesa, University of Zaragoza, IIS Aragón (CIBERehd), Zaragoza, Spain
| | | | - Adi Lahat
- Department of Gastroenterology, Sheba Medical Center, Tel Hashomer, affiliated with Sackler School of Medicine, Tel Aviv University, Ramat Gan, Israel
| | - Silvio Danese
- IBD Center, Department of Gastroenterology, Humanitas Clinical and Research Center - IRCCS -, Rozzano, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
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18
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Barrenschee M, Cossais F, Böttner M, Egberts JH, Becker T, Wedel T. Impaired Expression of Neuregulin 1 and Nicotinic Acetylcholine Receptor β4 Subunit in Diverticular Disease. Front Cell Neurosci 2019; 13:563. [PMID: 31920561 PMCID: PMC6930903 DOI: 10.3389/fncel.2019.00563] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Accepted: 12/05/2019] [Indexed: 12/15/2022] Open
Abstract
Neuregulin 1 (NRG1) regulates the expression of the nicotinic acetylcholine receptor (nAChR) and is suggested to promote the survival and maintenance of the enteric nervous system (ENS), since deficiency of its corresponding receptor complex ErbB2/ErbB3 leads to postnatal colonic aganglionosis. As diverticular disease (DD) is associated with intestinal hypoganglionosis, the NRG1-ErbB2/ErbB3 system and the nAChR were studied in patients with DD and controls. Samples of tunica muscularis of the sigmoid colon from patients with DD (n = 8) and controls (n = 11) were assessed for mRNA expression of NRG1, ErbB2, and ErbB3 and the nAChR subunits α3, α5, α7, β2, and β4. Site-specific gene expression levels of the NRG1-ErbB2/3 system were determined in myenteric ganglia harvested by laser microdissection (LMD). Localization studies were performed by immunohistochemistry for the NRG1-ErbB2/3 system and nAChR subunit β4. Rat enteric nerve cell cultures were stimulated with NRG1 or glial-cell line derived neurotrophic factor (GDNF) for 6 days and mRNA expression of the aforementioned nAchR was measured. NRG1, ErbB3, and nAChR subunit β4 expression was significantly down-regulated in both the tunica muscularis and myenteric ganglia of patients with DD compared to controls, whereas mRNA expression of ErbB3 and nAChR subunits β2, α3, α5, and α7 remained unaltered. NRG1, ErbB3, and nAChR subunit β4 immunoreactive signals were reduced in neuronal somata and the neuropil of myenteric ganglia from patients with DD compared to control. nAChR subunit β4 exhibited also weaker immunoreactive signals in the tunica muscularis of patients with DD. NRG1 treatment but not GDNF treatment of enteric nerve cell cultures significantly enhanced mRNA expression of nAchR β4. The down-regulation of NRG1 and ErbB3 in myenteric ganglia of patients with DD supports the hypothesis that intestinal hypoganglionosis observed in DD may be attributed to a lack of neurotrophic factors. Regulation of nAChR subunit β4 by NRG1 and decreased nAChR β4 in patients with DD provide evidence that a lack of NRG1 may affect the composition of enteric neurotransmitter receptor subunits thus contributing to the intestinal motility disorders previously reported in DD.
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Affiliation(s)
- Martina Barrenschee
- Neurogastroenterology, Institute of Anatomy, Christian-Albrechts University of Kiel, Kiel, Germany
| | - François Cossais
- Neurogastroenterology, Institute of Anatomy, Christian-Albrechts University of Kiel, Kiel, Germany
| | - Martina Böttner
- Neurogastroenterology, Institute of Anatomy, Christian-Albrechts University of Kiel, Kiel, Germany
| | - Jan-Hendrik Egberts
- Department of General, Visceral-, Thoracic-, Transplantation-, and Pediatric Surgery, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Thomas Becker
- Department of General, Visceral-, Thoracic-, Transplantation-, and Pediatric Surgery, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Thilo Wedel
- Neurogastroenterology, Institute of Anatomy, Christian-Albrechts University of Kiel, Kiel, Germany
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19
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Camilleri M, Sandler RS, Peery AF. Etiopathogenetic Mechanisms in Diverticular Disease of the Colon. Cell Mol Gastroenterol Hepatol 2019; 9:15-32. [PMID: 31351939 PMCID: PMC6881605 DOI: 10.1016/j.jcmgh.2019.07.007] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 07/17/2019] [Accepted: 07/18/2019] [Indexed: 02/08/2023]
Abstract
This article reviews epidemiological evidence of heritability and putative mechanisms in diverticular disease, with greatest attention to 3 recent studies of genetic associations with diverticular disease based on genome-wide or whole-genome sequencing studies in large patient cohorts. We provide an analysis of the biological plausibility of the significant associations with gene variants reported and highlight the relevance of ANO1, CPI-17 (aka PPP1R14A), COLQ6, COL6A1, CALCB or CALCA, COL6A1, ARHGAP15, and S100A10 to colonic neuromuscular function and tissue properties that may result in altered compliance and predispose to the development of diverticular disease. Such studies also identify candidate genes for future studies.
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Affiliation(s)
- Michael Camilleri
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Robert S Sandler
- Center for Gastrointestinal Biology and Disease, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Anne F Peery
- Center for Gastrointestinal Biology and Disease, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
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20
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Persistent Increased Enteric Glial Expression of S100β is Associated With Low-grade Inflammation in Patients With Diverticular Disease. J Clin Gastroenterol 2019. [PMID: 29517710 DOI: 10.1097/mcg.0000000000001011] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Diverticular disease (DD) is a common gastrointestinal inflammatory disorder associated with an enteric neuropathy. Although enteric glial cells (EGCs) are essential regulators of intestinal inflammation and motility functions, their contribution to the pathophysiology of DD remains unclear. Therefore, we analyzed the expression of specific EGC markers in patients with DD. MATERIALS AND METHODS Expression of the glial markers S100β, GFAP, Sox10, and Connexin 43 was analyzed by real-time quantitative PCR in colonic specimens of patients with DD and in that of controls. Protein expression levels of S100β, GFAP, and Connexin 43 were further analyzed using immunohistochemistry in the submucosal and myenteric plexus of patients with DD and in that of controls. Expression of the inflammatory cytokines tumor necrosis factor-α and interleukin-6 was quantified using qPCR, and infiltration of CD3+ lymphocytes was determined using immunohistochemistry. RESULTS Expression of S100β was increased in the submucosal and myenteric plexus of patients with DD compared with that in controls, whereas expression of other glial factors remained unchanged. This increased expression of S100β was correlated to CD3+ lymphocytic infiltrates in patients with DD, whereas no correlation was observed in controls. CONCLUSIONS DD is associated with limited but significant alterations of the enteric glial network. The increased expression of S100β is associated with a persistent low-grade inflammation reported in patients with DD, further emphasizing the role of EGCs in intestinal inflammation.
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21
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Alaburda P, Lukosiene JI, Pauza AG, Rysevaite-Kyguoliene K, Kupcinskas J, Saladzinskas Z, Tamelis A, Pauziene N. Ultrastructural changes of the human enteric nervous system and interstitial cells of Cajal in diverticular disease. Histol Histopathol 2019; 35:147-157. [PMID: 31187871 DOI: 10.14670/hh-18-136] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
BACKGROUND In spite of numerous advances in understanding diverticular disease, its pathogenesis remains one of the main problems to be solved. We aimed to investigate the ultrastructural changes of the enteric nervous system in unaffected individuals, in asymptomatic patients with diverticulosis and in patients with diverticular disease. METHODS Transmission electron microscopy was used to analyse samples of the myenteric, outer submucosal and inner submucosal plexuses from patients without diverticula (n=9), asymptomatic patients with diverticulosis (n=7) and in patients with complicated diverticular disease (n=9). We described the structure of ganglia, interstitial cells of Cajal and enteric nerves, as well as their relationship with each other. The distribution and size of nerve processes were analysed quantitatively. RESULTS In complicated diverticular disease, neurons exhibited larger lipofuscin-like inclusions, their membranous organelles had larger cisterns and the nucleus showed deeper indentations. Nerve remodeling occurred in every plexus, characterised by an increased percentage of swollen and fine neurites. Interstitial cells of Cajal had looser contacts with the surrounding cells and showed cytoplasmic depletion and proliferation of the rough endoplasmic reticulum. In asymptomatic patients with diverticulosis, alterations of enteric nerves and ICC were less pronounced. CONCLUSIONS In conclusion, the present findings suggest that most ultrastructural changes of the enteric nervous system occur in complicated diverticular disease. The changes are compatible with damage to the enteric nervous system and reactive remodeling of enteric ganglia, nerves and interstitial cells of Cajal. Disrupted architecture of enteric plexuses might explain clinical and pathophysiological changes associated with diverticular disease.
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Affiliation(s)
- Paulius Alaburda
- Institute of Anatomy, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Jaune I Lukosiene
- Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Audrys G Pauza
- Institute of Anatomy, Lithuanian University of Health Sciences, Kaunas, Lithuania.,Present address: Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, United Kingdom
| | | | - Juozas Kupcinskas
- Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania.,Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | | | - Algimantas Tamelis
- Department of Surgery, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Neringa Pauziene
- Institute of Anatomy, Lithuanian University of Health Sciences, Kaunas, Lithuania.
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22
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Abstract
Diverticulitis was thought to be a simple complication of an even simpler disease (diverticulosis), but may in fact result from an entirely new set of complex pathologies. Considering diverticulitis is increasing in annual incidence and becoming more prevalent in younger populations, the implications of appropriate management become more vital than ever. This article reviews old and new understandings of diverticulitis and current recommendations for prevention and clinical management.
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23
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Role of Inflammation in the Pathogenesis of Diverticular Disease. Mediators Inflamm 2019; 2019:8328490. [PMID: 31001067 PMCID: PMC6437747 DOI: 10.1155/2019/8328490] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Revised: 01/13/2019] [Accepted: 02/04/2019] [Indexed: 12/19/2022] Open
Abstract
Diverticulosis of the colon is the most common condition in Western societies and it is the most common anatomic alteration of the human colon. Recurrent abdominal pain is experienced by about 20% of patients with diverticulosis, but the pathophysiologic mechanisms of its occurrence are not completely understood. In the last years, several fine papers have showed clearly the role of low-grade inflammation both in the occurrence of symptoms in people having diverticulosis, both in symptom persistence following acute diverticulitis, even if the evidence available is not so strong. We do not know yet what the trigger of this low-grade inflammation occurrence is. However, some preliminary evidence found colonic dysbiosis linked to low-grade inflammation and therefore to symptom occurrence in those patients. The aim of this paper is to summarize current evidences about the role of inflammation in symptom occurrence in symptomatic uncomplicated diverticular disease and in symptom persistence after an episode of acute diverticulitis.
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24
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Cossais F, Lange C, Barrenschee M, Möding M, Ebsen M, Vogel I, Böttner M, Wedel T. Altered enteric expression of the homeobox transcription factor Phox2b in patients with diverticular disease. United European Gastroenterol J 2019; 7:349-357. [PMID: 31019703 DOI: 10.1177/2050640618824913] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Accepted: 12/22/2018] [Indexed: 12/17/2022] Open
Abstract
Background Diverticular disease, a major gastrointestinal disorder, is associated with modifications of the enteric nervous system, encompassing alterations of neurochemical coding and of the tyrosine receptor kinase Ret/GDNF pathway. However, molecular factors underlying these changes remain to be determined. Objectives We aimed to characterise the expression of Phox2b, an essential regulator of Ret and of neuronal subtype development, in the adult human enteric nervous system, and to evaluate its potential involvement in acute diverticulitis. Methods Site-specific gene expression of Phox2b in the adult colon was analysed by quantitative polymerase chain reaction. Colonic specimens of adult controls and patients with diverticulitis were subjected to quantitative polymerase chain reaction for Phox2b and dual-label immunochemistry for Phox2b and the neuronal markers RET and tyrosine hydroxylase or the glial marker S100β. Results The results indicate that Phox2b is physiologically expressed in myenteric neuronal and glial subpopulations in the adult enteric nervous system. Messenger RNA expression of Phox2b was increased in patients with diverticulitis and both neuronal, and glial protein expression of Phox2b were altered in these patients. Conclusions Alterations of Phox2b expression may contribute to the enteric neuropathy observed in diverticular disease. Future studies are required to characterise the functions of Phox2b in the adult enteric nervous system and to determine its potential as a therapeutic target in gastrointestinal disorders.
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Affiliation(s)
- François Cossais
- Institute of Anatomy, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Christina Lange
- Institute of Anatomy, Christian-Albrechts-University of Kiel, Kiel, Germany
| | | | - Marie Möding
- Institute of Anatomy, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Michael Ebsen
- Department of Pathology, Städtisches Krankenhaus Kiel, Kiel, Germany
| | - Ilka Vogel
- Department of Surgery, Städtisches Krankenhaus Kiel, Kiel, Germany
| | - Martina Böttner
- Institute of Anatomy, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Thilo Wedel
- Institute of Anatomy, Christian-Albrechts-University of Kiel, Kiel, Germany
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25
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Violi A, Cambiè G, Miraglia C, Barchi A, Nouvenne A, Capasso M, Leandro G, Meschi T, De' Angelis GL, Di Mario F. Epidemiology and risk factors for diverticular disease. ACTA BIO-MEDICA : ATENEI PARMENSIS 2018; 89:107-112. [PMID: 30561403 PMCID: PMC6502189 DOI: 10.23750/abm.v89i9-s.7924] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Indexed: 02/06/2023]
Abstract
Diverticulosis of the colon is the most frequent anatomical alteration diagnosed at colonoscopy. The prevalence of the disease is higher in elderly patients over 65 years old, recent studies show an increment also in youngers over 40 years old. Even its large prevalence in the population, its pathophysiology still remain poorly understood. It’s widely accepted that diverticula are likely to be the result of complex interactions among genetic factors, alteration of colonic motility, lifestyle conditions such as smoking, obesity, alcohol consumption, fiber and meat intake with diet. Recently many authors considered also alterations in colonic microbiota composition, co-morbidity with diabetes and hypertension and the chronic assumption of certain medications like PPI, ARB and aspirin, as important risk factors for the development of diverticulosis. The aim of this narrative review is to summarise current knowledges on this topic. (www.actabiomedica.it)
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Affiliation(s)
- Alessandra Violi
- Department of Medicine and Surgery, University of Parma, Parma, Italy.
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26
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27
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Pauza AG, Rysevaite-Kyguoliene K, Malinauskas M, Lukosiene JI, Alaburda P, Stankevicius E, Kupcinskas J, Saladzinskas Z, Tamelis A, Pauziene N. Alterations in enteric calcitonin gene-related peptide in patients with colonic diverticular disease: CGRP in diverticular disease. Auton Neurosci 2018; 216:63-71. [PMID: 30274796 DOI: 10.1016/j.autneu.2018.09.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Revised: 08/04/2018] [Accepted: 09/16/2018] [Indexed: 02/06/2023]
Abstract
Diverticular disease (DD) is one of the most prevalent diseases of the large bowel. Lately, imbalance of neuro-muscular transmission has been recognized as a major etiological factor for DD. Neuronal calcitonin gene-related peptide (CGRP) is a potent gastrointestinal smooth muscle relaxant shown to have a widespread effect within the alimentary tract. Nevertheless, CGRPergic innervation of the enteric ganglia has never been considered in the context of motility impairment observed in DD patients. Changes in CGRP and calcitonin receptor-like receptor (CRLR) abundance within enteric ganglia were investigated in sigmoid samples from symptomatic and asymptomatic DD patients using quantitative fluorescence microscopy. CGRP effect on gastrointestinal smooth muscle was investigated using organ bath technique. We found CGRP levels within the enteric ganglia to be declined by up to 52% in symptomatic DD patients. Conversely, CRLR within the enteric ganglia was upregulated by 41% in symptomatic DD. Longitudinal smooth muscle displayed an elevated (+10.5%) relaxant effect to the exogenous application of CGRP in colonic strips from symptomatic DD patients. Samples from asymptomatic DD patients consistently showed intermediate values across different experiments. In conclusion, the present study demonstrates that CGRPergic signaling is subject to alteration in DD. Our results suggest that a hypersensitization mechanism to gradually decreasing levels of CGRP-IR nerve fibers takes place during DD progression. Alterations to CGRPergic signaling in DD disease may have implications for physiological abnormalities associated with colonic DD.
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Affiliation(s)
- A G Pauza
- Institute of Anatomy, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | | | - M Malinauskas
- Institute of Physiology and Pharmacology, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - J I Lukosiene
- Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - P Alaburda
- Institute of Anatomy, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - E Stankevicius
- Institute of Physiology and Pharmacology, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - J Kupcinskas
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania; Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Z Saladzinskas
- Department of Surgery, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - A Tamelis
- Department of Surgery, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - N Pauziene
- Institute of Anatomy, Lithuanian University of Health Sciences, Kaunas, Lithuania.
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28
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Abstract
Inflammation of diverticula, or outpouchings of the colonic mucosa and submucosa through the muscularis layer, leads to diverticulitis. The development of diverticular disease, encompassing both diverticulosis and diverticulitis, is a result of genetic predisposition, lifestyle, and environmental factors, including the microbiome. Areas covered: Previous reports implicated genetic predisposition, environmental factors, and colonic dysmotility in diverticular disease. Recent studies have associated specific host immune responses and the microbiome as contributors to diverticulitis. To review pertinent literature describing pathophysiological factors associated with diverticulosis or diverticulitis, we searched the PubMed database (March 2018) for articles considering the role of colonic architecture, genetic predisposition, environment, colonic motility, immune response, and the microbiome. Expert commentary: In the recent years, research into the molecular underpinnings of diverticular disease has enhanced our understanding of diverticular disease pathogenesis. Although acute uncomplicated diverticulitis is treated with broad spectrum antibiotics, evaluation of the microbiome has been limited and requires further comprehensive studies. Evidence suggests that a deregulation of the host immune response is associated with both diverticulosis and diverticulitis. Further examining these pathways may reveal proteins that can be therapeutic targets or aid in identifying biological determinants of clinical or surgical decision making.
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Affiliation(s)
- Kathleen M Schieffer
- a Department of Surgery, Division of Colon and Rectal Surgery , The Pennsylvania State University, College of Medicine , Hershey , PA , USA
| | - Bryan P Kline
- a Department of Surgery, Division of Colon and Rectal Surgery , The Pennsylvania State University, College of Medicine , Hershey , PA , USA
| | - Gregory S Yochum
- a Department of Surgery, Division of Colon and Rectal Surgery , The Pennsylvania State University, College of Medicine , Hershey , PA , USA.,b Department of Biochemistry & Molecular Biology , The Pennsylvania State University, College of Medicine , Hershey , PA , USA
| | - Walter A Koltun
- a Department of Surgery, Division of Colon and Rectal Surgery , The Pennsylvania State University, College of Medicine , Hershey , PA , USA
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29
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Ng KS, Montes-Adrian NA, Mahns DA, Gladman MA. Quantification and neurochemical coding of the myenteric plexus in humans: No regional variation between the distal colon and rectum. Neurogastroenterol Motil 2018; 30. [PMID: 28836741 DOI: 10.1111/nmo.13193] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Accepted: 07/28/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND It remains unclear whether regional variation exists in the human enteric nervous system (ENS) ie, whether intrinsic innervation varies along the gut. Recent classification of gastrointestinal neuropathies has highlighted inadequacies in the quantification of the human ENS. This study used paired wholemounts to accurately quantify and neurochemically code the hindgut myenteric plexus, comparing human distal colon and rectum. METHODS Paired human descending colonic/rectal specimens were procured from 15 patients undergoing anterior resection. Wholemounts of myenteric plexi were triple-immunostained with anti-Hu/NOS/ChAT antibodies. Images were acquired by motorized epifluorescence microscopy, allowing assessment of ganglionic density/size, ganglionic area density, and neuronal density. 'Stretch-corrected' values were calculated using stretched/relaxed tissue dimensions. KEY RESULTS Tile-stitching created a collage with average area 99 300 000 μm2 . Stretch-corrected ganglionic densities were similar (colon: median 510 ganglia/100 mm2 [range 386-1170], rectum: 585 [307-923]; P = .99), as were average ganglionic sizes (colon: 57 593 μm2 [40 301-126 579], rectum: 54 901 [38 701-90 211], P = .36). Ganglionic area density (colon: 11.92 mm2 per 100 mm2 [7.53-18.64], rectum: 9.84 [5.80-17.19], P = .10) and stretch-corrected neuronal densities (colon: 189 neurons/mm2 [117-388], rectum: 182 [89-361], P = .31) were also similar, as were the neurochemical profiles of myenteric ganglia, with comparable proportions of NOS+ and ChAT+ neurons (P > .10). CONCLUSIONS AND INFERENCES This study has revealed similar neuronal and ganglionic densities and neurochemical profiles in human distal colon and rectum. Further investigation of other components of the ENS, incorporating additional immunohistochemical markers are required to confirm that there is no regional variation in the human hindgut ENS.
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Affiliation(s)
- K-S Ng
- Academic Colorectal Unit, Sydney Medical School - Concord, University of Sydney, Concord, New South Wales, Australia
| | - N A Montes-Adrian
- Academic Colorectal Unit, Sydney Medical School - Concord, University of Sydney, Concord, New South Wales, Australia
| | - D A Mahns
- Department of Integrative Physiology, School of Medicine, University of Western Sydney, Campbelltown, New South Wales, Australia
| | - M A Gladman
- Academic Colorectal Unit, Sydney Medical School - Concord, University of Sydney, Concord, New South Wales, Australia.,Enteric Neuroscience and Gastrointestinal Research Group, Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia
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30
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Coble JL, Sheldon KE, Yue F, Salameh TJ, Harris LR, Deiling S, Ruggiero FM, Eshelman MA, Yochum GS, Koltun WA, Gerhard GS, Broach JR. Identification of a rare LAMB4 variant associated with familial diverticulitis through exome sequencing. Hum Mol Genet 2018; 26:3212-3220. [PMID: 28595269 DOI: 10.1093/hmg/ddx204] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2017] [Accepted: 05/23/2017] [Indexed: 12/13/2022] Open
Abstract
Diverticulitis is a chronic disease of the colon in which diverticuli, or outpouching through the colonic wall, become inflamed. Although recent observations suggest that genetic factors may play a significant role in diverticulitis, few genes have yet been implicated in disease pathogenesis and familial cases are uncommon. Here, we report results of whole exome sequencing performed on members from a single multi-generational family with early onset diverticulitis in order to identify a genetic component of the disease. We identified a rare single nucleotide variant in the laminin β 4 gene (LAMB4) that segregated with disease in a dominant pattern and causes a damaging missense substitution (D435N). Targeted sequencing of LAMB4 in 148 non-familial and unrelated sporadic diverticulitis patients identified two additional rare variants in the gene. Immunohistochemistry indicated that LAMB4 localizes to the myenteric plexus of colonic tissue and patients harboring LAMB4 variants exhibited reduced LAMB4 protein levels relative to controls. Laminins are constituents of the extracellular matrix and play a major role in regulating the development and function of the enteric nervous system. Reduced LAMB4 levels may therefore alter innervation and morphology of the enteric nervous system, which may contribute to colonic dysmotility associated with diverticulitis.
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Affiliation(s)
- Joel L Coble
- Department of Biochemistry and Molecular Biology
| | | | - Feng Yue
- Department of Biochemistry and Molecular Biology
| | | | | | - Sue Deiling
- Department of Surgery, Division of Colon and Rectal Surgery
| | - Francesca M Ruggiero
- Division of Anatomical Pathology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | | | - Gregory S Yochum
- Department of Biochemistry and Molecular Biology.,Department of Surgery, Division of Colon and Rectal Surgery
| | | | - Glenn S Gerhard
- Department of Medical Genetics and Molecular Biochemistry, Temple University College of Medicine, Philadelphia, PA 19140, USA
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Severi C, Carabotti M, Cicenia A, Pallotta L, Annibale B. Recent advances in understanding and managing diverticulitis. F1000Res 2018; 7:F1000 Faculty Rev-971. [PMID: 30026920 PMCID: PMC6039950 DOI: 10.12688/f1000research.14299.1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/21/2018] [Indexed: 02/05/2023] Open
Abstract
In the past few decades, the increasing socioeconomic burden of acute diverticulitis (AD) has become evident, and with the growth of the population age, this significant economic impact will likely continue to rise. Furthermore, recent evidence showed an increased rate of hospital admissions especially evident among women and younger individuals. The natural history and pathophysiology of this clinical condition is still to be fully defined, and efforts continue to be made in the identification of risk factors and the establishment of relative preventive strategies. The actual therapeutic strategies aimed to modulate gut microbiota, such as rifaximin or probiotics, or to reduce mucosal inflammation, such as mesalazine, present a relatively poor efficacy for both the prevention of the first AD episode (primary prevention) and its recurrence (secondary prevention). In the last few years, the main goal achieved has been in the management of AD in that uncomplicated AD can, to a larger extent, be managed in an outpatient setting with no or little supportive therapy, a strategy that will certainly impact on the health costs of this disease. The problem of AD recurrence remains a topic of debate. The aim of this review is to present updated evidence on AD epidemiology and relative open clinical questions and to analyze in detail predisposing and protective factors with an attempt to integrate their possible modes of action into the several pathogenic mechanisms that have been suggested to contribute to this multifactorial disease. A unifying hypothesis dealing with the colonic luminal and extra-luminal microenvironments separately is provided. Finally, evidence-based changes in therapeutic management will be summarized. Because of an ascertained multifactorial pathogenesis of uncomplicated and complicated AD, it is probable that a single 'causa prima' will not be identifiable, and a better stratification of patients could allow one to pursue tailored therapeutic algorithm strategies.
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Affiliation(s)
- Carola Severi
- Department of Internal Medicine and Medical Specialties, University Sapienza of Rome, Viale del Policlinico 155, 00161 Rome, Italy
| | - Marilia Carabotti
- Medical-Surgical Department of Clinical Sciences and Translational Medicine, University Hospital S. Andrea, University Sapienza of Rome, Via di Grottarossa 1035-1039, 00189 Roma, Italy
| | - Alessia Cicenia
- Department of Internal Medicine and Medical Specialties, University Sapienza of Rome, Viale del Policlinico 155, 00161 Rome, Italy
| | - Lucia Pallotta
- Department of Internal Medicine and Medical Specialties, University Sapienza of Rome, Viale del Policlinico 155, 00161 Rome, Italy
| | - Bruno Annibale
- Medical-Surgical Department of Clinical Sciences and Translational Medicine, University Hospital S. Andrea, University Sapienza of Rome, Via di Grottarossa 1035-1039, 00189 Roma, Italy
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Barbara G, Scaioli E, Barbaro MR, Biagi E, Laghi L, Cremon C, Marasco G, Colecchia A, Picone G, Salfi N, Capozzi F, Brigidi P, Festi D. Gut microbiota, metabolome and immune signatures in patients with uncomplicated diverticular disease. Gut 2017; 66:1252-1261. [PMID: 27618836 DOI: 10.1136/gutjnl-2016-312377] [Citation(s) in RCA: 143] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2016] [Revised: 08/19/2016] [Accepted: 08/20/2016] [Indexed: 12/18/2022]
Abstract
OBJECTIVE The engagement of the gut microbiota in the development of symptoms and complications of diverticular disease has been frequently hypothesised. Our aim was to explore colonic immunocytes, gut microbiota and the metabolome in patients with diverticular disease in a descriptive, cross-sectional, pilot study. DESIGN Following colonoscopy with biopsy and questionnaire phenotyping, patients were classified into diverticulosis or symptomatic uncomplicated diverticular disease; asymptomatic subjects served as controls. Mucosal immunocytes, in the diverticular region and in unaffected sites, were quantified with immunohistochemistry. Mucosa and faecal microbiota were analysed by the phylogenetic platform high taxonomic fingerprint (HTF)-Microbi.Array, while the metabolome was assessed by 1H nuclear magnetic resonance. RESULTS Compared with controls, patients with diverticula, regardless of symptoms, had a >70% increase in colonic macrophages. Their faecal microbiota showed depletion of Clostridium cluster IV. Clostridium cluster IX, Fusobacterium and Lactobacillaceae were reduced in symptomatic versus asymptomatic patients. A negative correlation was found between macrophages and mucosal Clostridium cluster IV and Akkermansia. Urinary and faecal metabolome changes in diverticular disease involved the hippurate and kynurenine pathways. Six urinary molecules allowed to discriminate diverticular disease and control groups with >95% accuracy. CONCLUSIONS Patients with colonic diverticular disease show depletion of microbiota members with anti-inflammatory activity associated with mucosal macrophage infiltration. Metabolome profiles were linked to inflammatory pathways and gut neuromotor dysfunction and showed the ability to discriminate diverticular subgroups and controls. These data pave the way for further large-scale studies specifically aimed at identifying microbiota signatures with a potential diagnostic value in patients with diverticular disease.
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Affiliation(s)
- Giovanni Barbara
- Department of Medical and Surgical Sciences, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Eleonora Scaioli
- Department of Medical and Surgical Sciences, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Maria Raffaella Barbaro
- Department of Medical and Surgical Sciences, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Elena Biagi
- Department of Pharmacy and Biotechnology, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Luca Laghi
- Department of Agri-Food Sciences and Technologies, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Cesare Cremon
- Department of Medical and Surgical Sciences, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Giovanni Marasco
- Department of Medical and Surgical Sciences, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Antonio Colecchia
- Department of Medical and Surgical Sciences, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Gianfranco Picone
- Department of Agri-Food Sciences and Technologies, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Nunzio Salfi
- Pathology Unit, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Francesco Capozzi
- Department of Agri-Food Sciences and Technologies, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Patrizia Brigidi
- Department of Pharmacy and Biotechnology, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Davide Festi
- Department of Medical and Surgical Sciences, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
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Barrenschee M, Wedel T, Lange C, Hohmeier I, Cossais F, Ebsen M, Vogel I, Böttner M. No neuronal loss, but alterations of the GDNF system in asymptomatic diverticulosis. PLoS One 2017; 12:e0171416. [PMID: 28152033 PMCID: PMC5289619 DOI: 10.1371/journal.pone.0171416] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Accepted: 01/20/2017] [Indexed: 12/15/2022] Open
Abstract
Background Glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor known to promote the survival and maintenance of neurons not only in the developing but also in the adult enteric nervous system. As diverticular disease (DD) is associated with reduced myenteric neurons, alterations of the GDNF system were studied in asymptomatic diverticulosis (diverticulosis) and DD. Methods Morphometric analysis for quantifying myenteric ganglia and neurons were assessed in colonic full-thickness sections of patients with diverticulosis and controls. Samples of tunica muscularis (TM) and laser-microdissected myenteric ganglia from patients with diverticulosis, DD and controls were analyzed for mRNA expression levels of GDNF, GFRA1, and RET by RT-qPCR. Myenteric protein expression of both receptors was quantified by fluorescence-immunohistochemistry of patients with diverticulosis, DD, and controls. Results Although no myenteric morphometric alterations were found in patients with diverticulosis, GDNF, GFRA1 and RET mRNA expression was down-regulated in the TM of patients with diverticulosis as well as DD. Furthermore GFRA1 and RET myenteric plexus mRNA expression of patients with diverticulosis and DD was down-regulated, whereas GDNF remained unaltered. Myenteric immunoreactivity of the receptors GFRα1 and RET was decreased in both asymptomatic diverticulosis and DD patients. Conclusion Our data provide evidence for an impaired GDNF system at gene and protein level not only in DD but also during early stages of diverticula formation. Thus, the results strengthen the idea of a disturbed GDNF-responsiveness as contributive factor for a primary enteric neuropathy involved in the pathogenesis and disturbed intestinal motility observed in DD.
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Affiliation(s)
| | - Thilo Wedel
- Institute of Anatomy, Kiel University, Kiel, Germany
| | | | - Ines Hohmeier
- Institute of Anatomy, Kiel University, Kiel, Germany
| | | | - Michael Ebsen
- Department of Pathology, Städtisches Krankenhaus Kiel, Kiel, Germany
| | - Ilka Vogel
- Department of Surgery, Städtisches Krankenhaus Kiel, Kiel, Germany
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Abstract
BACKGROUND Diverticulosis and redundant colon are colonic conditions for which underlying pathophysiology, management and prevention are poorly understood. Historical papers suggest an inverse relationship between these two conditions. However, no further attempt has been made to validate this relationship. This study set out to assess the correlation between diverticulosis and colonic redundancy. METHODS Redundant colon, diverticulosis and patient demographics were recorded during colonoscopy. Multivariate binary logistic regression was performed with redundant colon as the dependent variable and age, gender and diverticulosis as independent variables. Nagelkerke R 2 and a receiver operator curve were calculated to assess goodness of fit and internally validate the multivariate model. RESULTS Redundant colon and diverticulosis were diagnosed in 31 and 113 patients, respectively. The probability of redundant colon was increased by female gender odds ratio (OR) 8.4 (95% CI 2.7-26, p = 0.00020) and increasing age OR 1.7 (95% CI 1.1-2.6, p = 0.017). Paradoxically, diverticulosis strongly reduced the probability of redundant colon with OR of 0.12 (95% CI 0.42-0.32, p = 0.000039). The Nagelkerke R 2 for the multivariate model was 0.29 and the area under the curve at ROC analysis was 0.81 (95% CI 0.73-0.90 p-value 3.1 × 10-8). CONCLUSIONS This study found an inverse correlation between redundant colon and diverticulosis, supporting the historical suggestion that the two conditions rarely occur concurrently. The underlying principle for this relationship remains to be found. However, it may contribute to the understanding of the aetiology and pathophysiology of these colonic conditions.
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35
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Turco F, Andreozzi P, Palumbo I, Zito FP, Cargiolli M, Fiore W, Gennarelli N, De Palma GD, Sarnelli G, Cuomo R. Bacterial stimuli activate nitric oxide colonic mucosal production in diverticular disease. Protective effects of L. casei DG® ( Lactobacillus paracasei CNCM I-1572). United European Gastroenterol J 2016; 5:715-724. [PMID: 28815036 DOI: 10.1177/2050640616684398] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Accepted: 11/13/2016] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Micro-inflammation and changes in gut microbiota may play a role in the pathogenesis of diverticular disease (DD). OBJECTIVE The objective of this article is to evaluate the expression of nitric oxide (NO)-related mediators and S100B in colonic mucosa of patients with DD in an ex vivo model of bacterial infection. METHODS Intestinal biopsies obtained from patients with diverticulosis, symptomatic uncomplicated diverticular disease (SUDD) and SUDD with previous acute diverticulitis (SUDD+AD) were stimulated with the probiotic L. casei DG® (LCDG) and/or the pathogen enteroinvasive Escherichia coli (EIEC). S100B, NO release and iNOS expression were then evaluated. RESULTS Basal iNOS expression was significantly increased in SUDD and SUDD+AD patients. Basal NO expression was significantly increased in SUDD+AD. No differences in S100B release were found. In all groups, iNOS expression was significantly increased by EIEC and reduced by LCDG. In all groups, except for SUDD+AD, EIEC significantly increased NO release, whereas no increase was observed when LCDG was added to biopsies. EIEC did not induce significant changes in S100B release. CONCLUSIONS Colonic mucosa of patients with DD is characterized by a different reactivity toward pathogenic stimuli. LCDG plays a role in counteracting the pro-inflammatory effects exerted by EIEC, suggesting a beneficial role of this probiotic in DD.
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Affiliation(s)
- Fabio Turco
- Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy
| | - Paolo Andreozzi
- Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy
| | - Ilaria Palumbo
- Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy
| | - Francesco Paolo Zito
- Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy
| | - Martina Cargiolli
- Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy
| | | | - Nicola Gennarelli
- Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy
| | | | - Giovanni Sarnelli
- Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy
| | - Rosario Cuomo
- Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy
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36
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Feuerstein JD, Falchuk KR. Diverticulosis and Diverticulitis. Mayo Clin Proc 2016; 91:1094-104. [PMID: 27156370 DOI: 10.1016/j.mayocp.2016.03.012] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Revised: 02/12/2016] [Accepted: 03/14/2016] [Indexed: 02/08/2023]
Abstract
Diverticular disease is a common condition that is associated with variable presentations. For this review article, we performed a review of articles in PubMed through February 1, 2016, by using the following MeSH terms: colon diverticula, colonic diverticulitis, colonic diverticulosis, colonic diverticulum, colonic diverticula, and diverticula. Diverticula are structural alterations within the colonic wall that classically form "pockets" referred to as diverticula. Diverticula form from herniation of the colonic mucosa and submucosa through defects in the circular muscle layers within the colonic wall. Often this is at the sites of penetrating blood vessels in the colon. Diverticular disease is extremely common, which resulted in 2,682,168 outpatient visits and 283,355 hospitalization discharges for diverticulitis or diverticulosis in 2009. Diverticulosis is one of the most common detected conditions found incidentally on colonoscopy. Risk factors for the development of diverticulitis include obesity, smoking, nonsteroidal anti-inflammatory drugs, corticosteroids, and opiates. In contrast, fiber may be protective, but recent studies have questioned the role of fiber in developing diverticular disease. Most patients with diverticulosis will be asymptomatic, but a subset of patients may develop nonspecific abdominal pain (isolated or recurrent), diverticulitis, or segmental colitis associated with diverticulosis. Classically, the treatment of diverticulitis has included antibiotics for all patients. More recent evidence indicates that in mild to even moderate uncomplicated diverticulitis, antibiotics may not be as necessary as initially believed. In more complicated diverticulitis, intravenous antibiotics and surgery may be necessary. Once a patient has had an attack of diverticulitis, increasing fiber may help prevent future attacks. Other modalities such as 5-aminosalicylate products, antibiotics, and probiotics are still of unclear benefit in preventing future episodes of diverticulitis. Similarly, even when patients develop recurrent episodes of diverticulitis, surgery may not be necessary as a prophylactic treatment.
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MESH Headings
- Adult
- Age Distribution
- Aged
- Aged, 80 and over
- Diagnosis, Differential
- Dietary Fiber/standards
- Diverticulitis, Colonic/diagnosis
- Diverticulitis, Colonic/epidemiology
- Diverticulitis, Colonic/etiology
- Diverticulitis, Colonic/therapy
- Diverticulosis, Colonic/diagnosis
- Diverticulosis, Colonic/epidemiology
- Diverticulosis, Colonic/etiology
- Diverticulosis, Colonic/therapy
- Female
- Geography
- Humans
- Male
- Middle Aged
- Prevalence
- Protective Factors
- Risk Factors
- Sex Distribution
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Affiliation(s)
- Joseph D Feuerstein
- Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
| | - Kenneth R Falchuk
- Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
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Abstract
Acute diverticulitis, defined as acute inflammation of a colonic diverticulum, is a common emergency presentation managed by both surgeons and physicians. There have been advances in the medical treatments offered to patients in recent years. Factors predisposing individuals to the development of acute diverticulitis include obesity, smoking, lack of physical activity and medication use, such as NSAIDs. Although widely used, there is limited evidence on the efficacy of individual antibiotic regimens and antibiotic treatment may not be required in all patients. Mesalazine seems to be the only effective treatment for the primary prevention of acute diverticulitis. Finally, evidence of effective measures for the prevention of recurrence is lacking. Furthermore, high-quality randomized controlled trials are required for medical treatments in patients with acute diverticulitis, if management is to be evidence based.
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Affiliation(s)
- Antonio Tursi
- a Gastroenterology Service, ASL BAT, Andria, BT, Italy
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38
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Dréanic J, Sion E, Dhooge M, Dousset B, Camus M, Chaussade S, Coriat R. Traitement de la diverticulite aiguë sigmoïdienne : revue de la littérature. JOURNAL EUROPÉEN DES URGENCES ET DE RÉANIMATION 2016; 28:26-38. [DOI: 10.1016/j.jeurea.2016.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Abstract
Diverticulosis of the colon is a widespread disease, and its prevalence is increasing especially in the developing world. The underlying pathological mechanisms that cause the formation of colonic diverticula remain unclear but are likely to be the result of complex interactions among age, diet, genetic factors, colonic motility, and changes in colonic structure. The large majority of patients remain asymptomatic throughout their life, one fifth of them become symptomatic (developing the so-called 'diverticular disease') while only a minority of these will develop acute diverticulitis. The factors predicting the development of symptoms remain to be identified. Again, it is generally recognized that diverticular disease occurrence is probably related to complex interactions among colonic motility, diet, lifestyle, and genetic features. Changes in intestinal microflora due to low-fiber diet and consequent low-grade inflammation are thought to be one of the mechanisms responsible for symptoms occurrence of both diverticular disease and acute diverticulitis. Current therapeutic approaches with rifaximin and mesalazine to treat the symptoms seem to be promising. Antibiotic treatment is currently advised only in acute complicated diverticulitis, and no treatment has currently proven effective in preventing the recurrence of acute diverticulitis. Further studies are required in order to clarify the reasons why diverticulosis occurs and the factors triggering occurrence of symptoms. Moreover, the reasons why rifaximin and mesalazine work in symptomatic diverticular disease but not in acute diverticulitis are yet to be elucidated.
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Affiliation(s)
- Antonio Tursi
- Gastroenterology Service, ASL BAT, Via Torino, 49, 76123 Andria (BT), Italy
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40
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Bassotti G, Villanacci V, Sidoni A, Nascimbeni R, Dore MP, Binda GA, Bandelloni R, Salemme M, Del Sordo R, Cadei M, Manca A, Bernardini N, Maurer CA, Cathomas G. Myenteric plexitis: A frequent feature in patients undergoing surgery for colonic diverticular disease. United European Gastroenterol J 2015; 3:523-8. [PMID: 26668745 DOI: 10.1177/2050640614563822] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND Diverticular disease of the colon is frequent in clinical practice, and a large number of patients each year undergo surgical procedures worldwide for their symptoms. Thus, there is a need for better knowledge of the basic pathophysiologic mechanisms of this disease entity. OBJECTIVES Because patients with colonic diverticular disease have been shown to display abnormalities of the enteric nervous system, we assessed the frequency of myenteric plexitis (i.e. the infiltration of myenteric ganglions by inflammatory cells) in patients undergoing surgery for this condition. METHODS We analyzed archival resection samples from the proximal resection margins of 165 patients undergoing left hemicolectomy (60 emergency and 105 elective surgeries) for colonic diverticulitis, by histology and immunochemistry. RESULTS Overall, plexitis was present in almost 40% of patients. It was subdivided into an eosinophilic (48%) and a lymphocytic (52%) subtype. Plexitis was more frequent in younger patients; and it was more frequent in those undergoing emergency surgery (50%), compared to elective (28%) surgery (p = 0.007). All the severe cases of plexitis displayed the lymphocytic subtype. CONCLUSIONS In conclusion, myenteric plexitis is frequent in patients with colonic diverticular disease needing surgery, and it might be implicated in the pathogenesis of the disease.
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Affiliation(s)
- Gabrio Bassotti
- Department of Medicine, University of Perugia School of Medicine, Perugia, Italy
| | | | - Angelo Sidoni
- Department of Experimental Medicine, University of Perugia School of Medicine, Perugia, Italy
| | - Riccardo Nascimbeni
- Department of Medical and Surgical Sciences, University of Brescia School of Medicine, Brescia, Italy
| | - Maria P Dore
- Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy ; Baylor College of Medicine, Houston, TX, USA
| | - Gian A Binda
- Department of General Surgery, Galliera Hospital, Genova, Italy
| | | | | | - Rachele Del Sordo
- Department of Experimental Medicine, University of Perugia School of Medicine, Perugia, Italy
| | - Moris Cadei
- Pathology Institute, Spedali Civili, Brescia, Italy
| | - Alessandra Manca
- Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy
| | - Nunzia Bernardini
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | | | - Gieri Cathomas
- Hospital of Baselland, University of Basel, Liestal, Switzerland
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Gargallo Puyuelo CJ, Sopeña F, Lanas Arbeloa A. Colonic diverticular disease. Treatment and prevention. GASTROENTEROLOGIA Y HEPATOLOGIA 2015; 38:590-9. [PMID: 25979437 DOI: 10.1016/j.gastrohep.2015.03.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Revised: 03/06/2015] [Accepted: 03/11/2015] [Indexed: 02/07/2023]
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Abstract
Diverticular disease is a common condition in Western countries and the incidence and prevalence of the disease is increasing. The pathogenetic factors involved include structural changes in the gut that increase with age, a diet low in fibre and rich in meat, changes in intestinal motility, the concept of enteric neuropathy and an underlying genetic background. Current treatment strategies are hampered by insufficient options to stratify patients according to individual risk. One of the main reasons is the lack of an all-encompassing classification system of diverticular disease. In response, the German Society for Gastroenterology and Digestive Diseases (DGVS) has proposed a classification system as part of its new guideline for the diagnosis and management of diverticular disease. The classification system includes five main types of disease: asymptomatic diverticulosis, acute uncomplicated and complicated diverticulitis, as well as chronic diverticular disease and diverticular bleeding. Here, we review prevention and treatment strategies stratified by these five main types of disease, from prevention of the first attack of diverticulitis to the management of chronic complications and diverticular bleeding.
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Barrenschee M, Lange C, Cossais F, Egberts JH, Becker T, Wedel T, Böttner M. Expression and function of Neuregulin 1 and its signaling system ERBB2/3 in the enteric nervous system. Front Cell Neurosci 2015; 9:360. [PMID: 26441531 PMCID: PMC4585281 DOI: 10.3389/fncel.2015.00360] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2015] [Accepted: 08/28/2015] [Indexed: 12/12/2022] Open
Abstract
Neuregulin 1 (NRG1) is suggested to promote the survival and maintenance of the enteric nervous system (ENS). As deficiency in its corresponding receptor signaling complex ERBB2/ERBB3 leads to postnatal colonic hypo/aganglionosis we assessed the distributional and expressional pattern of the NRG1-ERBB2/ERBB3 system in the human colon and explored the neurotrophic capacity of NRG1 on cultured enteric neurons. Site-specific mRNA expression of the NRG1-ERBB2/3 system was determined in microdissected samples harvested from enteric musculature and ganglia. Localization of NRG1, ERBB2 and ERBB3 was determined by dual-label-immunohistochemistry using pan-neuronal and pan-glial markers. Morphometric analysis was performed on NRG1-stimulated rat enteric nerve cultures to evaluate neurotrophic effects. mRNA expression of the NRG1-ERBB2/3 system was determined by qPCR. Co-localization of NRG1 with neuronal or synaptic markers was analyzed in enteric nerve cultures stimulated with glial cell line-derived neurotrophic factor (GDNF). The NRG1 system was expressed in both neurons and glial cells of enteric ganglia and in nerve fibers. NRG1 significantly enhanced growth parameters in enteric nerve cell cultures and ErB3 mRNA expression was down-regulated upon NRG1 stimulation. GDNF negatively regulates ErbB2 and ErbB3 mRNA expression. The NRG1-ERBB2/3 system is physiologically present in the human ENS and NRG1 acts as a neurotrophic factor for the ENS. The down-regulation of ErbB3/ErbB2 in GDNF stimulated nerve cell cultures points to an interaction of both neurotrophic factors. Thus, the data may provide a basis to assess disturbed signaling components of the NRG1 system in enteric neuropathies.
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Affiliation(s)
- Martina Barrenschee
- Neurogastroenterology, Institute of Anatomy, Christian-Albrechts-University of Kiel Kiel, Germany
| | - Christina Lange
- Neurogastroenterology, Institute of Anatomy, Christian-Albrechts-University of Kiel Kiel, Germany
| | - François Cossais
- Neurogastroenterology, Institute of Anatomy, Christian-Albrechts-University of Kiel Kiel, Germany
| | - Jan-Hendrik Egberts
- Department of General, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein, Campus Kiel Kiel, Germany
| | - Thomas Becker
- Department of General, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein, Campus Kiel Kiel, Germany
| | - Thilo Wedel
- Neurogastroenterology, Institute of Anatomy, Christian-Albrechts-University of Kiel Kiel, Germany
| | - Martina Böttner
- Neurogastroenterology, Institute of Anatomy, Christian-Albrechts-University of Kiel Kiel, Germany
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[Treatment of the acute diverticulitis: A systematic review]. Presse Med 2015; 44:1113-25. [PMID: 26358668 DOI: 10.1016/j.lpm.2015.08.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2015] [Revised: 07/23/2015] [Accepted: 08/03/2015] [Indexed: 01/04/2023] Open
Abstract
Acute diverticulitis is a common disease with increasing incidence. In most of cases, diagnosis is made at an uncomplicated stage offering a curative attempt under medical treatment and use of antibiotics. There is a risk of diverticulitis recurrence. Uncomplicated diverticulitis is opposed to complicated forms (perforation, abscess or fistula). Recent insights in the pathophysiology of diverticulitis, the natural history, and treatments have permitted to identify new treatment strategies. For example, the use of antibiotics tends to decrease; surgery is now less invasive, percutaneous drainage is preferred, peritoneal lavage is encouraged. Treatments of the diverticulitis are constantly evolving. In this review, we remind the pathophysiology and natural history, and summarize new recommendations for the medical and surgical treatment of acute diverticulitis.
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Tursi A, Papa A, Danese S. Review article: the pathophysiology and medical management of diverticulosis and diverticular disease of the colon. Aliment Pharmacol Ther 2015. [PMID: 26202723 DOI: 10.1111/apt.13322] [Citation(s) in RCA: 72] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND The incidence of diverticulosis and diverticular disease of the colon, including diverticulitis, is increasing worldwide, and becoming a significant burden on national health systems. Treatment of patients with diverticulosis and DD is generally based on high-fibre diet and antibiotics, respectively. However, new pathophysiological knowledge suggests that further treatment may be useful. AIM To review the current treatment of diverticulosis and diverticular disease. METHODS A search of PubMed and Medline databases was performed to identify articles relevant to the management of diverticulosis and diverticular disease. Major international conferences were also reviewed. RESULTS Two randomised controlled trials (RCT) found the role of antibiotics in managing acute diverticulitis to be questionable, particularly in patients with no complicating comorbidities. One RCT found mesalazine to be effective in preventing acute diverticulitis in patients with symptomatic uncomplicated diverticular disease. The role of rifaximin or mesalazine in preventing diverticulitis recurrence, based on the results of 1 and 4 RCTs, respectively, remains unclear. RCTs found rifaximin and mesalazine to be effective in treating symptomatic uncomplicated diverticular disease. The use of probiotics in diverticular disease and in preventing acute diverticulitis occurrence/recurrence appears promising but unconclusive. Finally, the role of fibre in treating diverticulosis remains unclear. CONCLUSIONS Available evidence suggests that antibiotics have a role only in the treatment of complicated diverticulitis. It appears to be some evidence for a role for rifaximin and mesalazine in treating symptomatic uncomplicated diverticular disease. Finally, there is not currently adequate evidence to recommend any medical treatment for the prevention of diverticulitis recurrence.
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Affiliation(s)
- A Tursi
- Gastroenterology Service, ASL BAT, Andria, BT, Italy
| | - A Papa
- Division of Internal Medicine and Gastroenterology, Complesso Integrato "Columbus", Catholic University, Rome, Italy
| | - S Danese
- IBD Unit, IRCCS "Humanitas", Rozzano, MI, Italy
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Kruis W, Germer CT, Leifeld L. Diverticular disease: guidelines of the german society for gastroenterology, digestive and metabolic diseases and the german society for general and visceral surgery. Digestion 2015; 90:190-207. [PMID: 25413249 DOI: 10.1159/000367625] [Citation(s) in RCA: 102] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Diverticular disease is one of the most common disorders of the gastrointestinal tract. 28-45% of the population develop colonic diverticula, while about 25% suffer symptoms and about 5% complications. AIM To create formal guidelines for diagnosis and management. METHODS Six working groups with 44 participants analyzed key questions in subject areas assigned to them. Following a systematic literature search, 451 publications were included. Consensus was obtained by agreement within the working groups, two Delphi processes and a guideline conference. RESULTS Targeted management of diverticular disease requires a classificatory diagnosis. A new classification was created. In addition to the clinical examination, intestinal ultrasound or computed tomography is the determining factor. Interval colonoscopy is recommended to exclude comorbidities. A low-fiber diet, obesity, lack of exercise, smoking and immunosuppression have an adverse impact on diverticulosis. This can lead to diverticulitis. Antibiotics are no longer recommended in uncomplicated diverticulitis if no risk factors such as immunosuppression are present. If close monitoring is ensured, uncomplicated diverticulitis can be treated on an outpatient basis. Complicated diverticulitis should be treated in hospital, involving broad-spectrum antibiotic therapy, where necessary abscess drainage, and surgery, if possible laparoscopically. In the case of chronic relapsing diverticulitis, the risk of perforation decreases with each episode, so that surgery is no longer recommended after the second episode but only following individual assessment. CONCLUSIONS New findings on diverticular disease call into question the overuse of antibiotics and excessive indications for surgery. Targeted treatment requires a precise diagnosis and intensive interdisciplinary cooperation.
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Wedel T, Barrenschee M, Lange C, Cossais F, Böttner M. Morphologic Basis for Developing Diverticular Disease, Diverticulitis, and Diverticular Bleeding. VISZERALMEDIZIN 2015; 31:76-82. [PMID: 26989376 PMCID: PMC4789973 DOI: 10.1159/000381431] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Diverticula of the colon are pseudodiverticula defined by multiple outpouchings of the mucosal and submucosal layers penetrating through weak spots of the muscle coat along intramural blood vessels. A complete prolapse consists of a diverticular opening, a narrowed neck, and a thinned diverticular dome underneath the serosal covering. The susceptibility of diverticula to inflammation is explained by local ischemia, translocation of pathogens due to retained stool, stercoral trauma by fecaliths, and microperforations. Local inflammation may lead to phlegmonous diverticulitis, paracolic/mesocolic abscess, bowel perforation, peritonitis, fistula formation, and stenotic strictures. Diverticular bleeding is due to an asymmetric rupture of distended vasa recta at the diverticular dome and not primarily linked to inflammation. Structural and functional changes of the bowel wall in diverticular disease comprise: i) Altered amount, composition, and metabolism of connective tissue; ii) Enteric myopathy with muscular thickening, deranged architecture, and altered myofilament composition; iii) Enteric neuropathy with hypoganglionosis, neurotransmitter imbalance, deficiency of neurotrophic factors and nerve fiber remodeling; and iv) Disturbed intestinal motility both in vivo (increased intraluminal pressure, motility index, high-amplitude propagated contractions) and in vitro (altered spontaneous and pharmacologically triggered contractility). Besides established etiologic factors, recent studies suggest that novel pathophysiologic concepts should be considered in the pathogenesis of diverticular disease.
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Affiliation(s)
- Thilo Wedel
- Institute of Anatomy, Christian-Albrechts-University of Kiel, Kiel, Germany
| | | | - Christina Lange
- Institute of Anatomy, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - François Cossais
- Institute of Anatomy, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Martina Böttner
- Institute of Anatomy, Christian-Albrechts-University of Kiel, Kiel, Germany
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Shin JE. Are there any association between colonic diverticula and bowel symptoms?(neurogastroenterol motil 2015;27:333-338). J Neurogastroenterol Motil 2015; 21:290-1. [PMID: 25843081 PMCID: PMC4398231 DOI: 10.5056/jnm15051] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2015] [Revised: 03/24/2015] [Accepted: 03/25/2015] [Indexed: 12/16/2022] Open
Affiliation(s)
- Jeong Eun Shin
- Department of Internal Medicine, Dankook University College of Medicine, Cheonan, Korea
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Spiller RC. Changing views on diverticular disease: impact of aging, obesity, diet, and microbiota. Neurogastroenterol Motil 2015; 27:305-12. [PMID: 25703217 DOI: 10.1111/nmo.12526] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Accepted: 01/15/2015] [Indexed: 12/13/2022]
Abstract
The development of colonic diverticulosis is a common aging change in industrialized nations. While most patients have asymptomatic diverticulosis, around one in five develops symptomatic diverticular disease. This is characterized by recurrent abdominal pain and disturbed bowel habit. Some of the pain episodes are prolonged and are due to acute diverticulitis, which itself may be complicated by abscess, perforation, fistulation, or stricture formation. Risk factors favouring the development of symptomatic diverticular disease include obesity, smoking and diets low in fiber but high in red meat and animal fat. What determines the transition from asymptomatic diverticulosis to symptomatic diverticular disease is unclear but neuromuscular changes following acute diverticulitis may be responsible in some cases. The severity of symptoms generated depends on cerebral pain processing which is influenced by psychosocial factors. These are important considerations in deciding optimal patient management. Prior theories of the cause of diverticulosis suggested that constipation was an important cause, but new data challenge this and has provoked new ideas. Underlying mechanisms causing diverticulosis include weakening of the colonic wall and/or degenerative changes in the enteric nerves. Dietary induced changes in microbiota and the host inflammatory response may underlie the subsequent development of acute/chronic diverticulitis and its sequela.
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Affiliation(s)
- R C Spiller
- Nottingham Digestive Diseases Centre, University of Nottingham, Queens Medical Centre, Nottingham, UK
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