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1
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Lundquist P, Hagforsen E, Wagner M, Alimohammadi M, Melo FR, Pejler G, Artursson P, Carlson M, Rollman O, Lampinen M. Mild-to-moderate psoriasis is associated with subclinical inflammation in the duodenum and a tendency of disturbed intestinal barrier. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167634. [PMID: 39706352 DOI: 10.1016/j.bbadis.2024.167634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 11/01/2024] [Accepted: 12/15/2024] [Indexed: 12/23/2024]
Abstract
Psoriasis is a chronic skin disease occasionally associated with abdominal symptoms and IBD. We aimed to characterize intestinal immune cells and the integrity of the intestinal barrier in psoriasis. Biopsies from the duodenum and colon were analyzed by flow cytometry and immunohistochemistry for the presence and activation status of different immune cell populations. Intestinal permeability was measured using Ussing chambers. Proinflammatory markers were analyzed in fecal and blood samples using ELISA. The intestinal level of inflammatory mediators was assessed using a multiplex proximity extension assay. We found an increased density of intestinal eosinophils, mast cells, macrophages, and CD8+ T-cells in psoriasis; eosinophils, macrophages, and CD8+ T-cells expressed activation markers. Half of the psoriasis patients showed increased permeability across the duodenum, correlating with increased mucosal IL-17A, IL-13, IL-2, and IL-20, and with gastrointestinal symptoms. Our findings reveal that psoriasis is associated with low-grade intestinal inflammation, which may contribute to abdominal symptoms in these patients and possibly set the stage for the development of intestinal disease.
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Affiliation(s)
- Patrik Lundquist
- Department of Pharmacy, Uppsala University, Box 580, SE-751 23 Uppsala, Sweden
| | - Eva Hagforsen
- Dermatology and Venereology, Department of Medical Sciences, Uppsala University Hospital, SE-751 85 Uppsala, Sweden
| | - Michael Wagner
- Gastroenterology Research Group, Department of Medical Sciences, Uppsala University Hospital, SE-751 85 Uppsala, Sweden
| | - Mohammad Alimohammadi
- Dermatology and Venereology, Department of Medical Sciences, Uppsala University Hospital, SE-751 85 Uppsala, Sweden
| | - Fabio Rabelo Melo
- Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, SE-751 23 Uppsala, Sweden
| | - Gunnar Pejler
- Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, SE-751 23 Uppsala, Sweden
| | - Per Artursson
- Department of Pharmacy, Uppsala University, Box 580, SE-751 23 Uppsala, Sweden
| | - Marie Carlson
- Gastroenterology Research Group, Department of Medical Sciences, Uppsala University Hospital, SE-751 85 Uppsala, Sweden
| | - Ola Rollman
- Dermatology and Venereology, Department of Medical Sciences, Uppsala University Hospital, SE-751 85 Uppsala, Sweden
| | - Maria Lampinen
- Department of Pharmacy, Uppsala University, Box 580, SE-751 23 Uppsala, Sweden; Gastroenterology Research Group, Department of Medical Sciences, Uppsala University Hospital, SE-751 85 Uppsala, Sweden.
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2
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Grover M, Vanuytsel T, Chang L. Intestinal Permeability in Disorders of Gut-Brain Interaction: From Bench to Bedside. Gastroenterology 2025; 168:480-495. [PMID: 39236897 DOI: 10.1053/j.gastro.2024.08.033] [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: 02/15/2024] [Revised: 06/27/2024] [Accepted: 08/20/2024] [Indexed: 09/07/2024]
Abstract
Intestinal barrier function lies at a critical interface of a range of peripheral and central processes that influence disorders of gut-brain interactions (DGBI). Although rigorously tested, the role of barrier dysfunction in driving clinical phenotype of DGBI remains to be fully elucidated. In vitro, in vivo, and ex vivo strategies can test various aspects of the broader permeability and barrier mechanisms in the gut. Luminal mediators of host, bacterial, and dietary origin can influence the barrier function and a disrupted barrier can also influence the luminal milieu. Critical to our understanding is how barrier dysfunction is influenced by stress and other comorbidities that associate with DGBI and the crosstalk between barrier and neural, hormonal, and immune responses. Additionally, the microbiome's significant role in the communication between the brain and gut has led to the integrative model of a microbiome gut-brain axis with reciprocal interactions between brain networks and networks composed of multiple cells in the gut, including immune cells, enterochromaffin cells, gut microbiota and the derived luminal mediators. This review highlights the techniques for assessment of barrier function, appraises evidence for barrier dysfunction in DGBI including mechanistic studies in humans, as well as provides an overview of therapeutic strategies that can be used to directly or indirectly restore barrier function in DGBI patients.
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Affiliation(s)
- Madhusudan Grover
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Tim Vanuytsel
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism (ChroMeta), KULeuven, Leuven, Belgium
| | - Lin Chang
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, University of California, Los Angeles, California.
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3
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Li J, Ng W, Liu Y, Fang X, Wang Z, Pei L, Wei X. Neuroplasticity of the white matter tracts underlying recovery of diarrhea-predominant irritable bowel syndrome following acupuncture treatment. Front Neurosci 2024; 18:1383041. [PMID: 39364438 PMCID: PMC11447489 DOI: 10.3389/fnins.2024.1383041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Accepted: 07/30/2024] [Indexed: 10/05/2024] Open
Abstract
Irritable bowel syndrome (IBS) is a functional bowel disorder frequently associated with other pain syndromes and psychiatric conditions, including depression and anxiety. These abnormalities coincide with alterations in the brain's structure, particularly in the thalamus and cingulate system. Acupuncture has been demonstrated to be highly effective in treating IBS. However, it remains unclear how white matter (WM) tracts change after acupuncture treatment, and whether the neuroplasticity of these tracts can serve as a neural marker to assist in the development of novel treatments. In this study, we aim to answer these questions by investigating longitudinal changes in the WM of the thalamus and cingulate system in a group of diarrhea-predominant irritable bowel syndrome (IBS-D) patients before and after acupuncture treatment. We found that after acupuncture treatment, as IBS symptoms improved, there were significant changes in the microstructure of the right thalamus radiation (TR) (p < 0.05) and the right cingulum hippocampus (CH) (p < 0.05). At the same time, patients with reduced IBS symptom severity scores (SSSs) were associated with the change of the right CH (p = 0.015, r = -0.491), while reduced depressive conditions correlated with the change of the left TR (p = 0.019, r = 0.418). In addition, the consequences for the quality of life (QOL) showed a correlation with the right cingulum [cingulate cortex (CC)] (p = 0.012, r = 0.504) and left TR (p = 0.027, r = -0.397). Our study highlighted the potential implications of neuroplasticity in WM tracts for IBS. Furthermore, these findings suggested that the right CH, TR, and right CC can serve as potential "biomarkers" of IBS-D recovery under acupuncture treatments.
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Affiliation(s)
- Jing Li
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
| | - WingYi Ng
- Department of Acupuncture-Moxibustion and Rehabilitation, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
| | - YongKang Liu
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
| | - XiaoKun Fang
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
| | - ZhongQiu Wang
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
| | - LiXia Pei
- Department of Acupuncture-Moxibustion and Rehabilitation, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
| | - XueHu Wei
- McLean Imaging Center, McLean Hospital, Harvard Medical School, Belmont, MA, United States
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
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4
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Han L, Xu Q, Meng P, Xu R, Nan J. Brain identification of IBS patients based on GBDT and multiple imaging techniques. Phys Eng Sci Med 2024; 47:651-662. [PMID: 38416373 DOI: 10.1007/s13246-024-01394-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 01/16/2024] [Indexed: 02/29/2024]
Abstract
The brain biomarker of irritable bowel syndrome (IBS) patients is still lacking. The study aims to explore a new technology studying the brain alterations of IBS patients based on multi-source brain data. In the study, a decision-level fusion method based on gradient boosting decision tree (GBDT) was proposed. Next, 100 healthy subjects were used to validate the effectiveness of the method. Finally, the identification of brain alterations and the pain evaluation in IBS patients were carried out by the fusion method based on the resting-state fMRI and DWI for 46 patients and 46 controls selected randomly from 100 healthy subjects. The results showed that the method can achieve good classification between IBS patients and controls (accuracy = 95%) and pain evaluation of IBS patients (mean absolute error = 0.1977). Moreover, both the gain-based and the permutation-based evaluation instead of statistical analysis showed that left cingulum bundle contributed most significantly to the classification, and right precuneus contributed most significantly to the evaluation of abdominal pain intensity in the IBS patients. The differences seem to suggest a probable but unexplored separation about the central regions between the identification and progression of IBS. This finding may provide one new thought and technology for brain alteration related to IBS.
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Affiliation(s)
- Li Han
- School of Computer and Communication Engineering, Zhengzhou University of Light Industry, 136 Science Avenue, Zhengzhou, 450000, Henan, China
| | - Qian Xu
- School of Computer and Communication Engineering, Zhengzhou University of Light Industry, 136 Science Avenue, Zhengzhou, 450000, Henan, China
| | - Panting Meng
- School of Computer and Communication Engineering, Zhengzhou University of Light Industry, 136 Science Avenue, Zhengzhou, 450000, Henan, China
| | - Ruyun Xu
- School of Computer and Communication Engineering, Zhengzhou University of Light Industry, 136 Science Avenue, Zhengzhou, 450000, Henan, China
| | - Jiaofen Nan
- School of Computer and Communication Engineering, Zhengzhou University of Light Industry, 136 Science Avenue, Zhengzhou, 450000, Henan, China.
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Doney E, Dion-Albert L, Coulombe-Rozon F, Osborne N, Bernatchez R, Paton SE, Kaufmann FN, Agomma RO, Solano JL, Gaumond R, Dudek KA, Szyszkowicz JK, Lebel M, Doyen A, Durand A, Lavoie-Cardinal F, Audet MC, Menard C. Chronic Stress Exposure Alters the Gut Barrier: Sex-Specific Effects on Microbiota and Jejunum Tight Junctions. BIOLOGICAL PSYCHIATRY GLOBAL OPEN SCIENCE 2024; 4:213-228. [PMID: 38306213 PMCID: PMC10829561 DOI: 10.1016/j.bpsgos.2023.04.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 04/04/2023] [Accepted: 04/06/2023] [Indexed: 02/04/2024] Open
Abstract
Background Major depressive disorder (MDD) is the leading cause of disability worldwide. Of individuals with MDD, 30% to 50% are unresponsive to common antidepressants, highlighting untapped causal biological mechanisms. Dysfunction in the microbiota-gut-brain axis has been implicated in MDD pathogenesis. Exposure to chronic stress disrupts blood-brain barrier integrity; still, little is known about intestinal barrier function in these conditions, particularly for the small intestine, where absorption of most foods and drugs takes place. Methods We investigated how chronic social or variable stress, two mouse models of depression, impact the jejunum intestinal barrier in males and females. Mice were subjected to stress paradigms followed by analysis of gene expression profiles of intestinal barrier-related targets, fecal microbial composition, and blood-based markers. Results Altered microbial populations and changes in gene expression of jejunum tight junctions were observed depending on the type and duration of stress, with sex-specific effects. We used machine learning to characterize in detail morphological tight junction properties, identifying a cluster of ruffled junctions in stressed animals. Junctional ruffling is associated with inflammation, so we evaluated whether lipopolysaccharide injection recapitulates stress-induced changes in the jejunum and observed profound sex differences. Finally, lipopolysaccharide-binding protein, a marker of gut barrier leakiness, was associated with stress vulnerability in mice, and translational value was confirmed on blood samples from women with MDD. Conclusions Our results provide evidence that chronic stress disrupts intestinal barrier homeostasis in conjunction with the manifestation of depressive-like behaviors in a sex-specific manner in mice and, possibly, in human depression.
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Affiliation(s)
- Ellen Doney
- Department of Psychiatry and Neuroscience, Faculty of Medicine and CERVO Brain Research Center, Université Laval, Québec City, Québec, Canada
| | - Laurence Dion-Albert
- Department of Psychiatry and Neuroscience, Faculty of Medicine and CERVO Brain Research Center, Université Laval, Québec City, Québec, Canada
| | - Francois Coulombe-Rozon
- Department of Psychiatry and Neuroscience, Faculty of Medicine and CERVO Brain Research Center, Université Laval, Québec City, Québec, Canada
| | - Natasha Osborne
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Renaud Bernatchez
- Department of Computer Science and Software Engineering and Department of Electrical and Computer Engineering, Université Laval, Québec City, Québec, Canada
| | - Sam E.J. Paton
- Department of Psychiatry and Neuroscience, Faculty of Medicine and CERVO Brain Research Center, Université Laval, Québec City, Québec, Canada
| | - Fernanda Neutzling Kaufmann
- Department of Psychiatry and Neuroscience, Faculty of Medicine and CERVO Brain Research Center, Université Laval, Québec City, Québec, Canada
| | - Roseline Olory Agomma
- Department of Computer Science and Software Engineering and Department of Electrical and Computer Engineering, Université Laval, Québec City, Québec, Canada
| | - José L. Solano
- Department of Psychiatry and Neuroscience, Faculty of Medicine and CERVO Brain Research Center, Université Laval, Québec City, Québec, Canada
| | - Raphael Gaumond
- Department of Psychiatry and Neuroscience, Faculty of Medicine and CERVO Brain Research Center, Université Laval, Québec City, Québec, Canada
| | - Katarzyna A. Dudek
- Department of Psychiatry and Neuroscience, Faculty of Medicine and CERVO Brain Research Center, Université Laval, Québec City, Québec, Canada
| | - Joanna Kasia Szyszkowicz
- Douglas Mental Health University Institute and Department of Psychiatry, McGill University, Montréal, Québec, Canada
| | - Manon Lebel
- Department of Psychiatry and Neuroscience, Faculty of Medicine and CERVO Brain Research Center, Université Laval, Québec City, Québec, Canada
| | - Alain Doyen
- Department of Food Science, Institute of Nutrition and Functional Foods, Université Laval, Québec City, Québec, Canada
| | - Audrey Durand
- Department of Computer Science and Software Engineering and Department of Electrical and Computer Engineering, Université Laval, Québec City, Québec, Canada
| | - Flavie Lavoie-Cardinal
- Department of Psychiatry and Neuroscience, Faculty of Medicine and CERVO Brain Research Center, Université Laval, Québec City, Québec, Canada
| | - Marie-Claude Audet
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
- School of Nutrition Sciences, University of Ottawa, Ottawa, Ontario, Canada
| | - Caroline Menard
- Department of Psychiatry and Neuroscience, Faculty of Medicine and CERVO Brain Research Center, Université Laval, Québec City, Québec, Canada
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6
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Öhlmann H, Lanters LR, Theysohn N, Langhorst J, Engler H, Icenhour A, Elsenbruch S. Distinct Alterations in Central Pain Processing of Visceral and Somatic Pain in Quiescent Ulcerative Colitis Compared to Irritable Bowel Syndrome and Health. J Crohns Colitis 2023; 17:1639-1651. [PMID: 37161902 PMCID: PMC10637045 DOI: 10.1093/ecco-jcc/jjad080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Indexed: 05/11/2023]
Abstract
BACKGROUND AND AIMS Despite relevance to pain chronicity, disease burden, and treatment, mechanisms of pain perception for different types of acute pain remain incompletely understood in patients with inflammatory bowel disease [IBD]. Building on experimental research across pain modalities, we herein addressed behavioural and neural correlates of visceral versus somatic pain processing in women with quiescent ulcerative colitis [UC] compared to irritable bowel syndrome [IBS] as a patient control group and healthy women [HC]. METHODS Thresholds for visceral and somatic pain were assessed with rectal distensions and cutaneous thermal pain, respectively. Using functional magnetic resonance imaging, neural and behavioural responses to individually calibrated and intensity-matched painful stimuli from both modalities were compared. RESULTS Pain thresholds were comparable across groups, but visceral thresholds correlated with gastrointestinal symptom severity and chronic stress burden exclusively within UC. Upon experience of visceral and somatic pain, both control groups demonstrated enhanced visceral pain-induced neural activation and greater perceived pain intensity, whereas UC patients failed to differentiate between pain modalities at both behavioural and neural levels. CONCLUSIONS When confronted with acute pain from multiple bodily sites, UC patients' responses are distinctly altered. Their failure to prioritise pain arising from the viscera may reflect a lack of adaptive behavioural flexibility, possibly resulting from long-lasting central effects of repeated intestinal inflammatory insults persisting during remission. The role of psychological factors, particularly chronic stress, in visceral sensitivity and disease-specific alterations in the response to acute pain call for dedicated mechanistic research as a basis for tailoring interventions for intestinal and extraintestinal pain symptoms in IBD.
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Affiliation(s)
- Hanna Öhlmann
- Department of Medical Psychology and Medical Sociology, Ruhr University Bochum, Bochum, Germany
| | - Laura Ricarda Lanters
- Department of Neurology, Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Nina Theysohn
- Institute of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Jost Langhorst
- Department for Internal and Integrative Medicine, Sozialstiftung Bamberg, Bamberg, Germany
- Department for Integrative Medicine, Medical Faculty, University of Duisburg-Essen, Essen, Germany
| | - Harald Engler
- Institute of Medical Psychology and Behavioral Immunobiology, Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Adriane Icenhour
- Department of Medical Psychology and Medical Sociology, Ruhr University Bochum, Bochum, Germany
| | - Sigrid Elsenbruch
- Department of Medical Psychology and Medical Sociology, Ruhr University Bochum, Bochum, Germany
- Department of Neurology, Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
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7
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Wan C, Kong X, Liao Y, Chen Q, Chen M, Ding Q, Liu X, Zhong W, Xu C, Liu W, Wang B. Bibliometric analysis of the 100 most-cited papers about the role of gut microbiota in irritable bowel syndrome from 2000 to 2021. Clin Exp Med 2023; 23:2759-2772. [PMID: 36522553 DOI: 10.1007/s10238-022-00971-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 12/01/2022] [Indexed: 12/23/2022]
Abstract
AIM Over the last few decades, gut microbiota research has been the focus of intense research and this field has become particularly important. This research aimed to provide a quantitative evaluation of the 100 most-cited articles on gut microbiota and IBS and highlight the most important advances in this field. METHODS The database Web of Science Core Collection was used to download the bibliometric information the top 100 most-cited papers. Microsoft Excel 2021, CiteSpace, VOSviewer, R software, and an online analytical platform ( https://bibliometric.com/ ) were was applied to perform bibliometric analysis of these papers. RESULTS The total citation frequency in the top 100 article ranged from 274 to 2324, with an average citation of 556.57. A total of 24 countries/regions made contributions to the top 100 cited papers, and USA, Ireland, and China were the most top three productive countries. Cryan JF was the most frequently nominated author, and of the top 100 articles, 20 listed his name. Top-cited papers mainly came from the Gastroenterology (n = 13, citations = 6373) and Gut (n = 9, citations = 3903). There was a significant citation path, indicating publications in molecular/biology/immunology primarily cited journals in molecular/biology/genetics fields. Keywords analysis suggested that the main topics on gut microbiota and IBS were mechanisms of microbiome in brain-gut axis." Behavior" was the keyword with the strongest burst strength (2.36), followed by "anxiety like behavior" (2.24), "intestinal microbiota" (2.19), and "chain fatty acid" (1.99), and "maternal separation" (1.95). CONCLUSION This study identified and provided the bibliometric information of the top 100 cited publications related to gut microbiota and IBS. The results provided a general overview of this topic and might help researchers to better understand the evolution, Influential findings and hotspots in researching gut microbiota and IBS, thus providing new perspectives and novel research ideas in this specific area.
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Affiliation(s)
- Changshan Wan
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, 300052, China
| | - Xiangxu Kong
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, 300052, China
| | - Yusheng Liao
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, 300052, China
- Department of Gastroenterology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430014, China
| | - Qiuyu Chen
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, 300052, China
| | - Mengshi Chen
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, 300052, China
| | - Qian Ding
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, 300052, China
| | - Xiaotong Liu
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, 300052, China
| | - Weilong Zhong
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, 300052, China
| | - Chen Xu
- Department of Colorectal Surgery, Tianjin Union Medical Center, No. 190, Jieyuan Road, Hongqiao District, Tianjin, 300121, China.
| | - Wentian Liu
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, 300052, China.
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, 300052, China.
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8
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Horowitz A, Chanez-Paredes SD, Haest X, Turner JR. Paracellular permeability and tight junction regulation in gut health and disease. Nat Rev Gastroenterol Hepatol 2023:10.1038/s41575-023-00766-3. [PMID: 37186118 PMCID: PMC10127193 DOI: 10.1038/s41575-023-00766-3] [Citation(s) in RCA: 261] [Impact Index Per Article: 130.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/03/2023] [Indexed: 05/17/2023]
Abstract
Epithelial tight junctions define the paracellular permeability of the intestinal barrier. Molecules can cross the tight junctions via two distinct size-selective and charge-selective paracellular pathways: the pore pathway and the leak pathway. These can be distinguished by their selectivities and differential regulation by immune cells. However, permeability increases measured in most studies are secondary to epithelial damage, which allows non-selective flux via the unrestricted pathway. Restoration of increased unrestricted pathway permeability requires mucosal healing. By contrast, tight junction barrier loss can be reversed by targeted interventions. Specific approaches are needed to restore pore pathway or leak pathway permeability increases. Recent studies have used preclinical disease models to demonstrate the potential of pore pathway or leak pathway barrier restoration in disease. In this Review, we focus on the two paracellular flux pathways that are dependent on the tight junction. We discuss the latest evidence that highlights tight junction components, structures and regulatory mechanisms, their impact on gut health and disease, and opportunities for therapeutic intervention.
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Affiliation(s)
- Arie Horowitz
- UNIROUEN, INSERM U1245, Normandy Centre for Genomic and Personalized Medicine, Normandie University, Rouen, France
| | - Sandra D Chanez-Paredes
- Laboratory of Mucosal Barrier Pathobiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Xenia Haest
- Laboratory of Mucosal Barrier Pathobiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Jerrold R Turner
- Laboratory of Mucosal Barrier Pathobiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
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9
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Vanuytsel T, Bercik P, Boeckxstaens G. Understanding neuroimmune interactions in disorders of gut-brain interaction: from functional to immune-mediated disorders. Gut 2023; 72:787-798. [PMID: 36657961 PMCID: PMC10086308 DOI: 10.1136/gutjnl-2020-320633] [Citation(s) in RCA: 59] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 12/08/2022] [Indexed: 01/21/2023]
Abstract
Functional gastrointestinal disorders-recently renamed into disorders of gut-brain interaction-such as irritable bowel syndrome and functional dyspepsia are highly prevalent conditions with bothersome abdominal symptoms in the absence of structural abnormalities. While traditionally considered as motility disorders or even psychosomatic conditions, our understanding of the pathophysiology has evolved significantly over the last two decades. Initial observations of subtle mucosal infiltration with immune cells, especially mast cells and eosinophils, are since recently being backed up by mechanistic evidence demonstrating increased release of nociceptive mediators by immune cells and the intestinal epithelium. These mediators can activate sensitised neurons leading to visceral hypersensitivity with bothersome symptoms. The interaction between immune activation and an impaired barrier function of the gut is most likely a bidirectional one with alterations in the microbiota, psychological stress and food components as upstream players in the pathophysiology. Only few immune-targeting treatments are currently available, but an improved understanding through a multidisciplinary scientific approach will hopefully identify novel, more precise treatment targets with ultimately better outcomes.
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Affiliation(s)
- Tim Vanuytsel
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism (ChroMeta), KU Leuven, Leuven, Belgium.,Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - Premysl Bercik
- Faculty of Health Sciences, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Guy Boeckxstaens
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism (ChroMeta), KU Leuven, Leuven, Belgium .,Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
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10
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Hu C, Yan C, Wu Y, Tao E, Guo R, Zhu Z, Chen X, Fang M, Jiang M. Low FODMAP Diet Relieves Visceral Hypersensitivity and Is Associated with Changes in Colonic Microcirculation in Water Avoidance Mice Model. Nutrients 2023; 15:1155. [PMID: 36904154 PMCID: PMC10004816 DOI: 10.3390/nu15051155] [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: 01/12/2023] [Revised: 02/20/2023] [Accepted: 02/22/2023] [Indexed: 03/02/2023] Open
Abstract
(1) Background: Irritable bowel syndrome (IBS) is a global public health problem, the pathogenesis of which has not been fully explored. Limiting fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) can relieve symptoms in some patients with IBS. Studies have shown that normal microcirculation perfusion is necessary to maintain the primary function of the gastrointestinal system. Here, we hypothesized that IBS pathogenesis might be related to abnormalities in colonic microcirculation. A low-FODMAP diet could alleviate visceral hypersensitivity (VH) by improving colonic microcirculation; (2) Methods: C57BL/6 mice were raised to establish an IBS-like rodent model using water avoidance (WA) stress or SHAM-WA as a control, one hour per day for ten days. The mice in the WA group were administered different levels of the FODMAP diet: 2.1% regular FODMAP (WA-RF), 10% high FODMAP diet (WA-HF), 5% medium FODMAP diet (WA-MF), and 0% low FODMAP diet (WA-LF) for the following 14 days. The body weight and food consumption of the mice were recorded. Visceral sensitivity was measured as colorectal distention (CRD) using the abdominal withdrawal reflex (AWR) score. Colonic microcirculation was assessed using laser speckle contrast imaging (LCSI). Vascular endothelial-derived growth factor (VEGF) was detected using immunofluorescence staining; (3) Results: The threshold values of CRD pressure in the WA-RF, WA-HF, and WA-MF groups were significantly lower than those in the SHAM-WA group. Moreover, we observed that colonic microcirculation perfusion decreased, and the expression of VEGF protein increased in these three groups of mice. Interestingly, a low-FODMAP dietary intervention could reverse this situation. Specifically, a low-FODMAP diet increased colonic microcirculation perfusion, reduced VEGF protein expression in mice, and increased the threshold of VH. There was a significant positive correlation between colonic microcirculation and threshold for VH; (4) Conclusions: These results demonstrate that a low-FODMAP diet can alter VH by affecting colonic microcirculation. Changes in intestinal microcirculation may be related to VEGF expression.
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Affiliation(s)
- Chenmin Hu
- Endoscopy Center and Gastrointestinal Laboratory, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou 310052, China
- Department of Pediatrics, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Chenxi Yan
- Endoscopy Center and Gastrointestinal Laboratory, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou 310052, China
| | - Yuhao Wu
- Endoscopy Center and Gastrointestinal Laboratory, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou 310052, China
| | - Enfu Tao
- Endoscopy Center and Gastrointestinal Laboratory, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou 310052, China
| | - Rui Guo
- Endoscopy Center and Gastrointestinal Laboratory, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou 310052, China
| | - Zhenya Zhu
- Endoscopy Center and Gastrointestinal Laboratory, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou 310052, China
| | - Xiaolong Chen
- Endoscopy Center and Gastrointestinal Laboratory, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou 310052, China
| | - Marong Fang
- Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China
- Institute of System Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Mizu Jiang
- Endoscopy Center and Gastrointestinal Laboratory, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou 310052, China
- Department of Gastroenterology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou 310052, China
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11
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Labus JS, Wang C, Mayer EA, Gupta A, Oughourlian T, Kilpatrick L, Tillisch K, Chang L, Naliboff B, Ellingson BM. Sex-specific brain microstructural reorganization in irritable bowel syndrome. Pain 2023; 164:292-304. [PMID: 35639426 PMCID: PMC9691795 DOI: 10.1097/j.pain.0000000000002699] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 05/17/2022] [Indexed: 02/06/2023]
Abstract
ABSTRACT Preliminary evidence suggests that there are sex differences in microstructural brain organization among individuals with irritable bowel syndrome (IBS). The aim of this study was to further investigate sex-dependent differences in brain microstructure and organization in a large sample of well-phenotyped participants with IBS compared with healthy controls. We hypothesized that female patients with IBS would show evidence for increased axonal strength and myelination within and between brain regions concerned with pain and sensory processing, when compared with males with IBS. We also hypothesized that female compared with male IBS subjects show greater levels of somatic awareness and sensory sensitivity consistent with multisystem sensory sensitivity. Diffusion tensor images and clinical assessments were obtained in 100 healthy controls (61 females) and 152 IBS (107 females) on a 3T Siemens Trio. Whole brain voxel-wise differences in fractional anisotropy, mean, radial and axial diffusivity, and track density as differences in somatic awareness and sensory sensitivity were assessed using the general linear model. Female compared with male IBS participants showed extensive microstructural alterations in sensorimotor, corticothalamic, and basal ganglia circuits involved in pain processing and integration of sensorimotor information. Together with the observed increases in symptom severity, somatic awareness, and sensory sensitivity, the findings support the hypotheses that the etiology and maintenance of symptoms in females with IBS may be driven by greater central sensitivity for multiple sensory stimuli.
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Affiliation(s)
- Jennifer S. Labus
- Oppenheimer Center for the Neurobiology of Stress and Resilience, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA
| | - Chencai Wang
- Department of Radiological Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA
| | - Emeran A Mayer
- Oppenheimer Center for the Neurobiology of Stress and Resilience, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA
| | - Arpana Gupta
- Oppenheimer Center for the Neurobiology of Stress and Resilience, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA
| | - Talia Oughourlian
- Department of Radiological Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA
| | - Lisa Kilpatrick
- Oppenheimer Center for the Neurobiology of Stress and Resilience, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA
| | - Kirsten Tillisch
- Oppenheimer Center for the Neurobiology of Stress and Resilience, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA
| | - Lin Chang
- Oppenheimer Center for the Neurobiology of Stress and Resilience, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA
| | - Bruce Naliboff
- Oppenheimer Center for the Neurobiology of Stress and Resilience, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA
| | - Benjamin M. Ellingson
- Oppenheimer Center for the Neurobiology of Stress and Resilience, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA
- Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA
- Department of Radiological Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA
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12
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Kindt S, Louis H, De Schepper H, Arts J, Caenepeel P, De Looze D, Gerkens A, Holvoet T, Latour P, Mahler T, Mokaddem F, Nullens S, Piessevaux H, Poortmans P, Rasschaert G, Surmont M, Vafa H, Van Malderen K, Vanuytsel T, Wuestenberghs F, Tack J. Belgian consensus on irritable bowel syndrome. Acta Gastroenterol Belg 2022; 85:360-382. [PMID: 35709780 DOI: 10.51821/85.2.10100] [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] [Indexed: 11/11/2022]
Abstract
BACKGROUND Irritable bowel syndrome (IBS) is characterised by recurrent abdominal pain related to defaecation or associated with altered stool frequency or consistency. Despite its prevalence, major uncertainties in the diagnostic and therapeutic management persist in clinical practice. METHODS A Delphi consensus was conducted by 20 experts from Belgium, and consisted of literature review and voting process on 78 statements. Grading of recommendations, assessment, development and evaluation criteria were applied to evaluate the quality of evidence. Consensus was defined as > 80 % agreement. RESULTS Consensus was reached for 50 statements. The Belgian consensus agreed as to the multifactorial aetiology of IBS. According to the consensus abdominal discomfort also represents a cardinal symptom, while bloating and abdominal distension often coexist. IBS needs subtyping based on stool pattern. The importance of a positive diagnosis, relying on history and clinical examination is underlined, while additional testing should remain limited, except when alarm features are present. Explanation of IBS represents a crucial part of patient management. Lifestyle modification, spasmolytics and water-solube fibres are considered first-line agents. The low FODMAP diet, selected probiotics, cognitive behavioural therapy and specific treatments targeting diarrhoea and constipation are considered appropriate. There is a consensus to restrict faecal microbiota transplantation and gluten-free diet, while other treatments are strongly discouraged. CONCLUSIONS A panel of Belgian gastroenterologists summarised the current evidence on the aetiology, symptoms, diagnosis and treatment of IBS with attention for the specificities of the Belgian healthcare system.
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Affiliation(s)
- S Kindt
- Department of gastroenterology and Hepatology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussel, Belgium
| | - H Louis
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme University Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070 Brussels, Belgium
| | - H De Schepper
- Department of Gastroenterology and Hepatology, University Hospital Antwerp, Antwerp, Belgium
| | - J Arts
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
- Department of Gastroenterology, AZ Sint-Lucas, Brugge, Belgium
| | - P Caenepeel
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
- Department of Gastroenterology, Ziekenhuis Oost-Limburg, Campus Sint-Jan, Genk, Belgium
- UHasselt, Hasselt, Belgium
| | - D De Looze
- Department of Gastroenterology and Hepatology, University Hospital Ghent, Gent, Belgium
| | - A Gerkens
- Boitsfort Medical Center, Brussels, Belgium
| | - T Holvoet
- Department of Gastroenterology and Hepatology, University Hospital Ghent, Gent, Belgium
- Department of Gastroenterology, AZ Nikolaas, Sint Niklaas, Belgium
| | - P Latour
- Department of Gastroenterology, Hepatology and Digestive Oncology, Centre Hospitalier Universitaire de Liège, Liège, Belgium
| | - T Mahler
- Department of Pediatrics, Universitair Ziekenuis Brussel, Brussel, Belgium
| | - F Mokaddem
- Department of Gastroenterology and Hepatology, Vivalia-Centre Sud Luxembourg, Arlon, Belgium
| | - S Nullens
- Department of Gastroenterology and Hepatology, University Hospital Antwerp, Antwerp, Belgium
| | - H Piessevaux
- Department of Hepato-gastroenterology, Cliniques universitaires St-Luc, Université catholique de Louvain, Brussels, Belgium
| | - P Poortmans
- Department of gastroenterology and Hepatology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussel, Belgium
| | - G Rasschaert
- Department of gastroenterology and Hepatology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussel, Belgium
| | - M Surmont
- Department of gastroenterology and Hepatology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussel, Belgium
| | - H Vafa
- Department of Gastroenterology and Hepatology, Chirec-Site Delta, Brussels, Belgium
| | - K Van Malderen
- Department of Gastroenterology and Hepatology, University Hospital Antwerp, Antwerp, Belgium
| | - T Vanuytsel
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - F Wuestenberghs
- Department of Gastroenterology and Hepatology, CHU UCL Namur, Université catholique de Louvain, Yvoir, Belgium
| | - J Tack
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
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13
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Wauters L, Ceulemans M, Schol J, Farré R, Tack J, Vanuytsel T. The Role of Leaky Gut in Functional Dyspepsia. Front Neurosci 2022; 16:851012. [PMID: 35422683 PMCID: PMC9002356 DOI: 10.3389/fnins.2022.851012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Accepted: 03/07/2022] [Indexed: 12/12/2022] Open
Abstract
Patients with functional dyspepsia (FD) complain of epigastric symptoms with no identifiable cause. Increased intestinal permeability has been described in these patients, especially in the proximal small bowel or duodenum, and was associated with mucosal immune activation and symptoms. In this review, we discuss duodenal barrier function, including techniques currently applied in FD research. We summarize the available data on duodenal permeability in FD and factors associated to increased permeability, including mucosal eosinophils, mast cells, luminal and systemic factors. While the increased influx of antigens into the duodenal mucosa could result in local immune activation, clinical evidence for a causal role of permeability is lacking in the absence of specific barrier-protective treatments. As both existing and novel treatments, including proton pump inhibitors (PPI) and pre- or probiotics may impact duodenal barrier function, it is important to recognize and study these alterations to improve the knowledge and management of FD.
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Affiliation(s)
- Lucas Wauters
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
- *Correspondence: Lucas Wauters,
| | - Matthias Ceulemans
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
| | - Jolien Schol
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
| | - Ricard Farré
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
| | - Jan Tack
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
| | - Tim Vanuytsel
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
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14
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Nisticò V, Rossi RE, D'Arrigo AM, Priori A, Gambini O, Demartini B. Functional neuroimaging in Irritable Bowel Syndrome: a systematic review highlights common brain alterations with Functional Movement Disorders. J Neurogastroenterol Motil 2022; 28:185-203. [PMID: 35189600 PMCID: PMC8978134 DOI: 10.5056/jnm21079] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 09/03/2021] [Accepted: 11/24/2021] [Indexed: 12/02/2022] Open
Abstract
Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder characterized by recurring abdominal pain and altered bowel habits without detectable organic causes. This study aims to provide a comprehensive overview of the literature on functional neuroimaging in IBS and to highlight brain alterations similarities with other functional disorders - functional movement disorders in particular. We conducted the bibliographic search via PubMed in August 2020 and included 50 studies following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines for systematic reviews. Overall, our findings showed an aberrant activation and functional connectivity of the insular, cingulate, sensorimotor and frontal cortices, the amygdala and the hippocampus, suggesting an altered activity of the homeostatic and salience network and of the autonomous nervous system. Moreover, glutamatergic dysfunction in the anterior insula and hypothalamic pituitary axis dysregulation were often reported. These alterations seem to be very similar to those observed in patients with functional movement disorders. Hence, we speculate that different functional disturbances might share a common pathophysiology and we discussed our findings in the light of a Bayesian model framework.
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Affiliation(s)
- Veronica Nisticò
- Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milan, Italy.,"Aldo Ravelli" Research Center for Neurotechnology and Experimental Brain Therapeutics, Università degli Studi di Milano, Milan, Italy.,Department of Psychology, University of Milan-Bicocca, Milan, Italy
| | - Roberta E Rossi
- Gastro-intestinal Surgery and Liver Transplantation Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.,Department of Pathophysiology and Organ Transplant, Università degli Studi di Milano, Milan, Italy
| | - Andrea M D'Arrigo
- Department of Neurology, ASST Fatebenefratelli Sacco, Ospedale Fatebenefratelli, Milan, Italy
| | - Alberto Priori
- Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milan, Italy.,"Aldo Ravelli" Research Center for Neurotechnology and Experimental Brain Therapeutics, Università degli Studi di Milano, Milan, Italy.,III Clinica Neurologica, ASST Santi Paolo e Carlo, Presidio San Paolo, Milan, Italy
| | - Orsola Gambini
- Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milan, Italy.,"Aldo Ravelli" Research Center for Neurotechnology and Experimental Brain Therapeutics, Università degli Studi di Milano, Milan, Italy.,Unità di Psichiatria 52, ASST Santi Paolo e Carlo, Presidio San Paolo, Milan, Italy
| | - Benedetta Demartini
- Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milan, Italy.,"Aldo Ravelli" Research Center for Neurotechnology and Experimental Brain Therapeutics, Università degli Studi di Milano, Milan, Italy.,Unità di Psichiatria 52, ASST Santi Paolo e Carlo, Presidio San Paolo, Milan, Italy
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15
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Shulman RJ, Devaraj S, Heitkemper M. Activation of the Innate Immune System in Children With Irritable Bowel Syndrome Evidenced by Increased Fecal Human β-Defensin-2. Clin Gastroenterol Hepatol 2021; 19:2121-2127. [PMID: 32961343 PMCID: PMC8041153 DOI: 10.1016/j.cgh.2020.09.034] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Revised: 09/14/2020] [Accepted: 09/16/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS The role of the innate immune system in functional gastrointestinal pain disorders is unclear. We investigated the role of β-defensin-2 and gut permeability in childhood irritable bowel syndrome (IBS) and functional abdominal pain (FAP) symptom generation. METHODS Fecal β-defensin-2 (and in a subset, gut permeability) was measured in children with IBS (n = 116), FAP (n = 33), and healthy control (HC) children (n = 72). IBS and FAP patients were recruited from tertiary and primary care, and HCs were recruited from primary care. RESULTS β-defensin-2 concentration was greater in children with IBS (P = .003) and FAP (P = .03) than in HCs. β-defensin-2 was greater in girls with IBS than female HCs (P = .007) and in girls with IBS vs boys with IBS (P = .036). There was no difference by sex in the FAP and HC groups. For the entire cohort, β-defensin-2 correlated with multiple pain symptoms. In the IBS group, β-defensin-2 correlated with pain interference (P = .014). No correlation with pain was found in the FAP or HC group. Gut permeability was greater in the IBS vs the FAP and HC groups (P = .038). For the entire cohort, permeability correlated with the number of pain episodes (P = .041) and interfering pain episodes (P = .049). For the entire cohort there was a correlation between β-defensin-2 and permeability (P = .003), with borderline correlation in the IBS group (P = .086). For the cohort and IBS and HC groups, the number of bowel movements was modestly inversely related to fecal β-defensin-2 concentrations. CONCLUSIONS Increased fecal β-defensin-2 concentration in children with IBS suggests activation of the innate immune system in some, which, along with increased gut permeability, appears related to abdominal pain symptoms. Sex is an important variable in interpreting β-defensin-2 concentration in children with IBS.
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Affiliation(s)
- Robert J Shulman
- Department of Pediatrics; Children's Nutrition Research Center; Texas Children's Hospital; Baylor College of Medicine, Houston, Texas.
| | - Sridevi Devaraj
- Texas Children's Hospital; Baylor College of Medicine, Houston, Texas; Department of Pathology and Immunology
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16
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Tang HY, Jiang AJ, Wang XY, Wang H, Guan YY, Li F, Shen GM. Uncovering the pathophysiology of irritable bowel syndrome by exploring the gut-brain axis: a narrative review. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1187. [PMID: 34430628 PMCID: PMC8350700 DOI: 10.21037/atm-21-2779] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 07/14/2021] [Indexed: 12/12/2022]
Abstract
Objective To improve the pathophysiological understanding of irritable bowel syndrome (IBS) by exploring the gut-brain axis. Background Disorders of gut-brain interaction (DGBIs) are gastrointestinal (GI) disorders in which alterations in bowel functions occur. IBS, which is one of the most studied DGBIs, is linked with abdominal distress or pain without obvious structural or biochemical anomalies. Methods The etiology of IBS has not been clearly described but is known to be multifactorial, involving GI motility changes, post-infectious reactivity, visceral hypersensitivity, gut-brain interactions, microbiota dysbiosis, small intestinal bacterial overgrowth, food sensitivity, carbohydrate malabsorption, and intestinal inflammation. Conclusions One of the main features of IBS is the occurrence of structural and functional disruptions in the gut-brain axis, which alter reflective and perceptual nervous system reactions. Herein, we provide a brief summary of this topic. Furthermore, we discuss animal models, which are important in the study of IBS, especially as it is linked with stressors. These animal models cannot fully represent the human disease but serve as important tools for understanding this complicated disorder. In the future, technologies, such as organ-on-a-chip models and metabolomics, will provide novel information regarding the pathophysiology of IBS, which will play an important role in treatment development. Finally, we take a brief glance at how acupuncture treatments may hold potential for patients with IBS.
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Affiliation(s)
- He-Yong Tang
- Graduate School of Anhui University of Chinese Medicine, Hefei, China
| | - Ai-Juan Jiang
- School of Integrated Traditional Chinese and Western Medicine, Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Xi-Yang Wang
- Graduate School of Anhui University of Chinese Medicine, Hefei, China
| | - Hao Wang
- School of Integrated Traditional Chinese and Western Medicine, Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Yuan-Yuan Guan
- Department of Acupuncture and Moxibustion, The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Fei Li
- Department of Rehabilitation, Second Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
| | - Guo-Ming Shen
- School of Integrated Traditional Chinese and Western Medicine, Anhui University of Traditional Chinese Medicine, Hefei, China
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17
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Elbadawi M, Ammar RM, Aziz-Kalbhenn H, Rabini S, Klauck SM, Dawood M, Saeed MEM, Kampf CJ, Efferth T. Anti-inflammatory and tight junction protective activity of the herbal preparation STW 5-II on mouse intestinal organoids. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2021; 88:153589. [PMID: 34111617 DOI: 10.1016/j.phymed.2021.153589] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 04/17/2021] [Accepted: 04/29/2021] [Indexed: 06/12/2023]
Abstract
BACKGROUND Irritable bowel syndrome (IBS) is a functional bowel disorder, in which recurrent abdominal pain is associated with defecation or a change in bowel habits. STW 5-II is a combination of six medicinal herbs with a clinically proven efficacy in managing IBS. AIM This study aims to establish an in vitro IBS model using mouse intestinal organoids and to explore the anti-inflammatory and tight junction protective activities of the multi-herbal preparation STW 5-II. METHODS Intestinal organoids were cultured in 1:1 Matrigel™ and medium domes. Inflammation and tight junction disruption were induced by a cocktail of cytokines (TNFα, IFNγ, IL-1β, IL-6) and bacterial proteins (LPS, flagellin). Organoids were treated with different concentrations of STW 5-II, and its multi-target activity was assessed using microarray analyses, RT-qPCR, immunofluorescence, western blot, immunohistochemistry, and a FITC permeability assay. In addition, we analyzed the expression of pNF-κB, pSTAT1, iNOS and ZO-1. In silico analyses were conducted to predict and identify the active components that may be responsible in mediating the multi-target anti-inflammatory activity of STW 5-II. RESULTS An organoid based IBS model was successfully established. STW 5-II effectively reduced the cytokines-induced overexpression of the pro-inflammatory mediators pNF-κB, pSTAT1 and iNOS. Moreover, STW 5-II attenuated cytokine-mediated downregulation of the tight junction protein, ZO-1. This finding was confirmed by a FITC permeability assay. In silico analyses revealed a promising inhibitory activity of some isolated compounds from STW 5-II against NF-κB, STAT1 and iNOS. CONCLUSION STW 5-II possesses multiple anti-inflammatory as well as tight junction protective activities that could explain its clinically proven efficacy in managing IBS symptoms.
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Affiliation(s)
- Mohamed Elbadawi
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany
| | - Ramy M Ammar
- Bayer Consumer Health, Steigerwald Arzneimittelwerk GmbH, Darmstadt, Germany
| | - Heba Aziz-Kalbhenn
- Bayer Consumer Health, Steigerwald Arzneimittelwerk GmbH, Darmstadt, Germany
| | - Sabine Rabini
- Bayer Consumer Health, Steigerwald Arzneimittelwerk GmbH, Darmstadt, Germany
| | - Sabine M Klauck
- Division of Cancer Genome Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - Mona Dawood
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany; Department of Molecular Biology, Faculty of Medical Laboratory Science, Al-Neelain University, Khartoum, Sudan
| | - Mohamed E M Saeed
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany
| | | | - Thomas Efferth
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany.
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18
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Casado-Bedmar M, de-Faria FM, Biskou O, Lindqvist CM, Ranasinghe PD, Bednarska O, Peterson C, Walter SA, Carlson M, Keita ÅV. Elevated F-EDN correlates with mucosal eosinophil degranulation in patients with IBS-A possible association with microbiota? J Leukoc Biol 2021; 111:655-665. [PMID: 34151454 DOI: 10.1002/jlb.4a0521-228r] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Eosinophils have been linked to functional dyspepsia; however, less is known about their role in irritable bowel syndrome (IBS). This study tested the hypothesis of alterations in levels of fecal eosinophil-derived neurotoxin (F-EDN) and eosinophil density and degranulation within the colonic mucosa of IBS patients compared with healthy controls (HC). Colonic biopsies were collected from 37 IBS patients and 20 HC and analyzed for eosinophil numbers and local degranulation of eosinophil cationic protein (ECP) by histologic procedures. Fecal samples were collected for F-EDN and microbiota analysis. Differentiated 15HL-60 cells were used in vitro to investigate the direct effect of live bacteria on eosinophil activation measured by a colorimetric assay with o-phenylenediamine (OPD) substrate. We observed a higher number of eosinophils and increased extracellular ECP in the mucosa of IBS patients compared with HC. Moreover, F-EDN levels in IBS samples were elevated compared with HC and positively correlated to extracellular ECP. Metagenomic analysis showed significant correlations between bacterial composition and eosinophil measurements in both HC and IBS patients. In vitro experiments revealed an increased degranulation of 15HL-60 after stimulation with Salmonella typhimurium, Salmonella enterica, and Yersinia enterocolitica. To conclude, we could demonstrate alterations related to eosinophils in IBS, and, for the first time, a positive correlation between F-EDN levels and degranulated eosinophils in the colonic mucosa of IBS patients. Together our results suggest that eosinophils play a role in the pathophysiology of IBS and the mechanisms might be linked to an altered microbiota.
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Affiliation(s)
- Maite Casado-Bedmar
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Felipe Meira de-Faria
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Olga Biskou
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | | | - Purnika Damindi Ranasinghe
- Institute of Global Food Security, School of Biological Sciences, Queen's University Belfast, Belfast, UK
| | - Olga Bednarska
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.,Department of Gastroenterology, Linköping, Sweden
| | - Christer Peterson
- Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden and Diagnostics Development, Uppsala, Sweden
| | - Susanna A Walter
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.,Department of Gastroenterology, Linköping, Sweden
| | - Marie Carlson
- Department of Medical Sciences, Gastroenterology Research Group, Uppsala University, Uppsala, Sweden
| | - Åsa V Keita
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
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19
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Ortega VA, Mercer EM, Giesbrecht GF, Arrieta MC. Evolutionary Significance of the Neuroendocrine Stress Axis on Vertebrate Immunity and the Influence of the Microbiome on Early-Life Stress Regulation and Health Outcomes. Front Microbiol 2021; 12:634539. [PMID: 33897639 PMCID: PMC8058197 DOI: 10.3389/fmicb.2021.634539] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Accepted: 03/15/2021] [Indexed: 12/12/2022] Open
Abstract
Stress is broadly defined as the non-specific biological response to changes in homeostatic demands and is mediated by the evolutionarily conserved neuroendocrine networks of the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic nervous system. Activation of these networks results in transient release of glucocorticoids (cortisol) and catecholamines (epinephrine) into circulation, as well as activation of sympathetic fibers innervating end organs. These interventions thus regulate numerous physiological processes, including energy metabolism, cardiovascular physiology, and immunity, thereby adapting to cope with the perceived stressors. The developmental trajectory of the stress-axis is influenced by a number of factors, including the gut microbiome, which is the community of microbes that colonizes the gastrointestinal tract immediately following birth. The gut microbiome communicates with the brain through the production of metabolites and microbially derived signals, which are essential to human stress response network development. Ecological perturbations to the gut microbiome during early life may result in the alteration of signals implicated in developmental programming during this critical window, predisposing individuals to numerous diseases later in life. The vulnerability of stress response networks to maladaptive development has been exemplified through animal models determining a causal role for gut microbial ecosystems in HPA axis activity, stress reactivity, and brain development. In this review, we explore the evolutionary significance of the stress-axis system for health maintenance and review recent findings that connect early-life microbiome disturbances to alterations in the development of stress response networks.
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Affiliation(s)
- Van A Ortega
- Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada.,International Microbiome Centre, Cumming School of Medicine, Health Sciences Centre, University of Calgary, Calgary, AB, Canada
| | - Emily M Mercer
- Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada.,International Microbiome Centre, Cumming School of Medicine, Health Sciences Centre, University of Calgary, Calgary, AB, Canada.,Department of Pediatrics, University of Calgary, Calgary, AB, Canada
| | - Gerald F Giesbrecht
- Department of Pediatrics, University of Calgary, Calgary, AB, Canada.,Department of Community Health Sciences, University of Calgary, Calgary, AB, Canada.,Owerko Centre, The Alberta Children's Hospital Research Institute, Calgary, AB, Canada
| | - Marie-Claire Arrieta
- Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada.,International Microbiome Centre, Cumming School of Medicine, Health Sciences Centre, University of Calgary, Calgary, AB, Canada.,Department of Pediatrics, University of Calgary, Calgary, AB, Canada
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20
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Meira de-Faria F, Bednarska O, Ström M, Söderholm JD, Walter SA, Keita ÅV. Colonic paracellular permeability and circulating zonulin-related proteins. Scand J Gastroenterol 2021; 56:424-431. [PMID: 33535002 DOI: 10.1080/00365521.2021.1879247] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 01/14/2021] [Accepted: 01/16/2021] [Indexed: 02/08/2023]
Abstract
OBJECTIVE Irritable bowel syndrome (IBS) is a gut-brain disorder associated with increased gut permeability. Zonulin has been suggested to regulate the gut barrier and claimed to be pre-haptoglobin 2 (pre-HP2) and circulating zonulin is often used as a proxy for gastrointestinal permeability. This study investigated the correlation between colonic paracellular permeability and levels of circulating zonulin and pre-HP2. MATERIALS AND METHODS Colonic biopsies from 32 patients with IBS and 15 healthy controls (HC) were used to measure permeability in Ussing chambers and levels of zonulin (Cusabio ELISA). Zonulin was also measured in blood samples from 40 HC, 78 patients with IBS and 20 patients with celiac disease (CeD), before and after a gluten-free diet. In addition, we verified HP genotype and circulating pre-HP2 using a monoclonal pre-HP2 antibody (Bio-Rad) by ELISA. RESULTS Increased colonic paracellular permeability correlated positively with zonulin levels in IBS biopsies, but negatively with plasma zonulin. We found no agreement between circulating zonulin and pre-HP2. Genotyping revealed non-specificity of the zonulin kit, as all pre-HP2 non-producers presented detectable levels. Patients with CeD displayed higher pre-HP2 and zonulin levels compared to HC. A gluten-free diet in patients with CeD led to lower serum zonulin and pre-HP2 concentrations. CONCLUSIONS Our study suggests that neither circulating zonulin nor pre-HP2 mirror colonic permeability. Our data corroborate previous reports showing the inability of the Cusabio zonulin kit to target zonulin and highlights that the results of studies using this kit must be re-examined with caution.
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Affiliation(s)
- Felipe Meira de-Faria
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Olga Bednarska
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
- Department of Gastroenterology, Linköping University, Linköping, Sweden
| | - Magnus Ström
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
- Department of Gastroenterology, Linköping University, Linköping, Sweden
| | - Johan D Söderholm
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
- Department of Surgery, Linköping University, Linköping, Sweden
| | - Susanna A Walter
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
- Department of Gastroenterology, Linköping University, Linköping, Sweden
| | - Åsa V Keita
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
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21
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Hanning N, Edwinson AL, Ceuleers H, Peters SA, De Man JG, Hassett LC, De Winter BY, Grover M. Intestinal barrier dysfunction in irritable bowel syndrome: a systematic review. Therap Adv Gastroenterol 2021; 14:1756284821993586. [PMID: 33717210 PMCID: PMC7925957 DOI: 10.1177/1756284821993586] [Citation(s) in RCA: 114] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 01/19/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND AND AIM Irritable bowel syndrome (IBS) is a complex and heterogeneous disorder. Sensory, motor and barrier dysfunctions are the key physiological endophenotypes of IBS. Our aim is to review studies evaluating barrier dysfunction in adults and children with IBS, as well as to link those changes with IBS symptomatology and quality of life. METHODS A comprehensive and systematic review of multiple databases was performed up to March 2020 to identify studies comparing intestinal permeability in IBS patients with healthy controls. Both in vivo and in vitro studies were considered. RESULTS We identified 66 studies, of which 27 used intestinal probes to quantify barrier function. The prevalence of barrier dysfunction differed between PI-IBS (17-50%), IBS-D (37-62%) and IBS-C (4-25%). At a group level, permeability was increased compared with healthy controls in IBS-D (9/13 studies) and PI-IBS (4/4 studies), but only a minority of IBS-C (2/7 studies) and not in the only IBS-M study. All four studies in children with IBS demonstrated loss of barrier function. A heterogeneous set of tight junction genes were found to be altered in small and large intestines of adults with IBS, but these have not been evaluated in children. Positive associations were identified between barrier dysfunction and bowel disturbances (6/9 studies), abdominal pain (9/13 studies), overall symptom severity (1/6 studies), depression and anxiety (1/1 study) and quality of life (1/4 studies). Fecal slurry or supernatants of IBS patients were found to induce barrier disruption in animal models (5/6 studies). CONCLUSIONS Barrier dysfunction is present in a significant proportion of adult and all pediatric IBS studies, especially in the IBS-D and PI-IBS subtype. The majority of studies indicated a positive association between loss of barrier function and symptoms such as abdominal pain and changes in the bowel function.
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Affiliation(s)
- Nikita Hanning
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
- Laboratory of Experimental Medicine and Pediatrics (LEMP) and Infla-Med, research consortium of excellence, University of Antwerp, Antwerp, Belgium
| | - Adam L. Edwinson
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Hannah Ceuleers
- Laboratory of Experimental Medicine and Pediatrics (LEMP) and Infla-Med, research consortium of excellence, University of Antwerp, Antwerp, Belgium
| | - Stephanie A. Peters
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Joris G. De Man
- Laboratory of Experimental Medicine and Pediatrics (LEMP) and Infla-Med, research consortium of excellence, University of Antwerp, Antwerp, Belgium
| | | | - Benedicte Y. De Winter
- Division of Gastroenterology, Laboratory of Experimental Medicine and Pediatrics, Universiteitsplein 1, Antwerp, 2610, Belgium
- Department of Gastroenterology and Hepatology, Antwerp University Hospital (UZA), Antwerp, Belgium
| | - Madhusudan Grover
- Department of Medicine and Physiology, Enteric NeuroScience Program, 200 First St SW, Rochester, MN 55905, USA
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22
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Berentsen B, Nagaraja BH, Teige EP, Lied GA, Lundervold AJ, Lundervold K, Steinsvik EK, Hillestad ER, Valeur J, Brønstad I, Gilja OH, Osnes B, Hatlebakk JG, Haász J, Labus J, Gupta A, Mayer EA, Benitez-Páez A, Sanz Y, Lundervold A, Hausken T. Study protocol of the Bergen brain-gut-microbiota-axis study: A prospective case-report characterization and dietary intervention study to evaluate the effects of microbiota alterations on cognition and anatomical and functional brain connectivity in patients with irritable bowel syndrome. Medicine (Baltimore) 2020; 99:e21950. [PMID: 32925728 PMCID: PMC7489588 DOI: 10.1097/md.0000000000021950] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
INTRODUCTION Irritable bowel syndrome (IBS) is a common clinical label for medically unexplained gastrointestinal (GI) symptoms, recently described as a disturbance of the brain-gut-microbiota (BGM) axis. To gain a better understanding of the mechanisms underlying the poorly understood etiology of IBS, we have designed a multifaceted study that aim to stratify the complex interaction and dysfunction between the brain, the gut, and the microbiota in patients with IBS. METHODS Deep phenotyping data from patients with IBS (n = 100) and healthy age- (between 18 and 65) and gender-matched controls (n = 40) will be collected between May 2019 and December 2021. Psychometric tests, questionnaires, human biological tissue/samples (blood, faeces, saliva, and GI biopsies from antrum, duodenum, and sigmoid colon), assessment of gastric accommodation and emptying using transabdominal ultrasound, vagal activity, and functional and structural magnetic resonance imaging (MRI) of the brain, are included in the investigation of each participant. A subgroup of 60 patients with IBS-D will be further included in a 12-week low FODMAP dietary intervention-study to determine short and long-term effects of diet on GI symptoms, microbiota composition and functions, molecular GI signatures, cognitive, emotional and social functions, and structural and functional brain signatures. Deep machine learning, prediction tools, and big data analyses will be used for multivariate analyses allowing disease stratification and diagnostic biomarker detection. DISCUSSION To our knowledge, this is the first study to employ unsupervised machine learning techniques and incorporate systems-based interactions between the central and the peripheral components of the brain-gut-microbiota axis at the levels of the multiomics, microbiota profiles, and brain connectome of a cohort of 100 patients with IBS and matched controls; study long-term safety and efficacy of the low-FODMAP diet on changes in nutritional status, gut microbiota composition, and metabolites; and to investigate changes in the brain and gut connectome after 12 weeks strict low-FODMAP-diet in patients with IBS. However, there are also limitations to the study. As a restrictive diet, the low-FODMAP diet carries risks of nutritional inadequacy and may foster disordered eating patterns. Strict FODMAP restriction induces a potentially unfavourable gut microbiota, although the health effects are unknown. TRIAL REGISTRATION NUMBER NCT04296552 (ClinicalTrials.gov).
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Affiliation(s)
- Birgitte Berentsen
- National Center for Functional Gastrointestinal Disorders, Haukeland University Hospital, Bergen, Norway
- Center for Nutrition, Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | | | - Erica Pearson Teige
- National Center for Functional Gastrointestinal Disorders, Haukeland University Hospital, Bergen, Norway
- Center for Nutrition, Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Gülen Arslan Lied
- National Center for Functional Gastrointestinal Disorders, Haukeland University Hospital, Bergen, Norway
- Center for Nutrition, Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Astri J. Lundervold
- Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway
| | - Katarina Lundervold
- National Center for Functional Gastrointestinal Disorders, Haukeland University Hospital, Bergen, Norway
- National Center for Ultrasound in Gastroenterology, Medical Department, Haukeland University Hospital, Bergen, Norway
| | - Elisabeth Kjelsvik Steinsvik
- National Center for Functional Gastrointestinal Disorders, Haukeland University Hospital, Bergen, Norway
- National Center for Ultrasound in Gastroenterology, Medical Department, Haukeland University Hospital, Bergen, Norway
| | - Eline Randulff Hillestad
- National Center for Functional Gastrointestinal Disorders, Haukeland University Hospital, Bergen, Norway
| | - Jørgen Valeur
- Unger-Vetlesen Institute, Lovisenberg Diaconal Hospital, Oslo, Norway
| | - Ingeborg Brønstad
- National Center for Functional Gastrointestinal Disorders, Haukeland University Hospital, Bergen, Norway
- National Center for Ultrasound in Gastroenterology, Medical Department, Haukeland University Hospital, Bergen, Norway
| | - Odd Helge Gilja
- National Center for Functional Gastrointestinal Disorders, Haukeland University Hospital, Bergen, Norway
- National Center for Ultrasound in Gastroenterology, Medical Department, Haukeland University Hospital, Bergen, Norway
| | - Berge Osnes
- Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway
| | - Jan Gunnar Hatlebakk
- National Center for Functional Gastrointestinal Disorders, Haukeland University Hospital, Bergen, Norway
| | - Judit Haász
- Department of Radiology, Haukeland University Hospital, Bergen, Norway
| | - Jennifer Labus
- G. Oppenheimer Center for Neurobiology of Stress and Resilience, UCLA Vatche and Tamar Manoukian Division of Digestive Diseases, and UCLA Microbiome Center, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Arpana Gupta
- G. Oppenheimer Center for Neurobiology of Stress and Resilience, UCLA Vatche and Tamar Manoukian Division of Digestive Diseases, and UCLA Microbiome Center, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Emeran A. Mayer
- G. Oppenheimer Center for Neurobiology of Stress and Resilience, UCLA Vatche and Tamar Manoukian Division of Digestive Diseases, and UCLA Microbiome Center, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Alfonso Benitez-Páez
- Microbial Ecology, Nutrition & Health Research Unit, Institute of Agrochemistry and Food Technology, National Research Council (IATA-CSIC), Valencia, Spain
| | - Yolanda Sanz
- Microbial Ecology, Nutrition & Health Research Unit, Institute of Agrochemistry and Food Technology, National Research Council (IATA-CSIC), Valencia, Spain
| | - Arvid Lundervold
- Mohn Medical Imaging and Visualization Center, Haukeland University Hospital, Bergen, Norway
| | - Trygve Hausken
- National Center for Functional Gastrointestinal Disorders, Haukeland University Hospital, Bergen, Norway
- Center for Nutrition, Department of Clinical Medicine, University of Bergen, Bergen, Norway
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23
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Kano M, Grinsvall C, Ran Q, Dupont P, Morishita J, Muratsubaki T, Mugikura S, Ly HG, Törnblom H, Ljungberg M, Takase K, Simrén M, Van Oudenhove L, Fukudo S. Resting state functional connectivity of the pain matrix and default mode network in irritable bowel syndrome: a graph theoretical analysis. Sci Rep 2020; 10:11015. [PMID: 32620938 PMCID: PMC7335204 DOI: 10.1038/s41598-020-67048-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 05/27/2020] [Indexed: 01/14/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a functional disorder of brain-gut interactions. Differential brain responses to rectal distention between IBS and healthy controls (HCs) have been demonstrated, particularly in the pain matrix and the default mode network. This study aims to compare resting-state functional properties of these networks between IBS patients and HCs using graph analysis in two independent cohorts. We used a weighted graph analysis of the adjacency matrix based on partial correlations between time series in the different regions in each subject to determine subject specific graph measures. These graph measures were normalized by values obtained in equivalent random networks. We did not find any significant differences between IBS patients and controls in global normalized graph measures, hubs, or modularity structure of the pain matrix and the DMN in any of our two independent cohorts. Furthermore, we did not find consistent associations between these global network measures and IBS symptom severity or GI-specific anxiety but we found a significant difference in the relationship between measures of psychological distress (anxiety and/or depressive symptoms) and normalized characteristic path length. The responses of these networks to visceral stimulation rather than their organisation at rest may be primarily disturbed in IBS.
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Affiliation(s)
- Michiko Kano
- Sukawa clinic, Kirari health coop, Fukushima, Japan.
- Behavioral Medicine, Graduate School of Medicine, Tohoku University, Sendai, Japan.
- Psychosomatic Medicine, Tohoku University Hospital, Sendai, Japan.
| | - Cecilia Grinsvall
- Department of Internal Medicine & Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Qian Ran
- Laboratory for Cognitive Neurology, KU Leuven, Leuven, Belgium
| | - Patrick Dupont
- Laboratory for Cognitive Neurology, KU Leuven, Leuven, Belgium
| | - Joe Morishita
- Behavioral Medicine, Graduate School of Medicine, Tohoku University, Sendai, Japan
| | - Tomohiko Muratsubaki
- Behavioral Medicine, Graduate School of Medicine, Tohoku University, Sendai, Japan
| | - Shunji Mugikura
- Diagnostic Radiology, Tohoku University Hospital, Sendai, Japan
| | - Huynh Giao Ly
- Laboratory for Brain-Gut Axis Studies (LaBGAS), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - Hans Törnblom
- Department of Internal Medicine & Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Maria Ljungberg
- Department of Radiation Physics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Medical Physics and Biomedical Engineering, Diagnostic Imaging, Sahlgrenska University Hospital, MR Centre, Gothenburg, Sweden
| | - Kei Takase
- Diagnostic Radiology, Tohoku University Hospital, Sendai, Japan
| | - Magnus Simrén
- Department of Internal Medicine & Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Lukas Van Oudenhove
- Laboratory for Brain-Gut Axis Studies (LaBGAS), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
- Cognitive and Affective Neuroscience Lab, Department of Psychological & Brain Sciences, Dartmouth College, Hanover, NH, USA
| | - Shin Fukudo
- Behavioral Medicine, Graduate School of Medicine, Tohoku University, Sendai, Japan
- Psychosomatic Medicine, Tohoku University Hospital, Sendai, Japan
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24
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Inczefi O, Bacquié V, Olier-Pierre M, Rincel M, Ringot-Destrez B, Ellero-Simatos S, Eutamène H, Bétoulières C, Thomas J, Lainé J, Gros L, Lévêque M, Leonard R, Harkat C, Robbe-Masselot C, Róka R, Mercier-Bonin M, Theodorou V, Darnaudéry M, Turner JR, Ferrier L. Targeted Intestinal Tight Junction Hyperpermeability Alters the Microbiome, Behavior, and Visceromotor Responses. Cell Mol Gastroenterol Hepatol 2020; 10:206-208.e3. [PMID: 32147490 PMCID: PMC7296230 DOI: 10.1016/j.jcmgh.2020.02.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 02/26/2020] [Accepted: 02/27/2020] [Indexed: 12/18/2022]
Affiliation(s)
- O Inczefi
- UMR 1331 ToxAlim, French National Institute for Agriculture, Food, and Environment, Toulouse, France; First Department of Medicine, University of Szeged, Szeged, Hungary
| | - V Bacquié
- UMR 1331 ToxAlim, French National Institute for Agriculture, Food, and Environment, Toulouse, France
| | - M Olier-Pierre
- UMR 1331 ToxAlim, French National Institute for Agriculture, Food, and Environment, Toulouse, France
| | - M Rincel
- UMR 1286, Nutrition and Integrative Neurobiology, University of Bordeaux, French National Institute for Agriculture, Food, and Environment, Bordeaux, France
| | - B Ringot-Destrez
- Unité de Glycobiologie Structurale et Fonctionnelle, Université de Lille, Villeneuve d'Ascq, France
| | - S Ellero-Simatos
- UMR 1331 ToxAlim, French National Institute for Agriculture, Food, and Environment, Toulouse, France
| | - H Eutamène
- UMR 1331 ToxAlim, French National Institute for Agriculture, Food, and Environment, Toulouse, France
| | - C Bétoulières
- UMR 1331 ToxAlim, French National Institute for Agriculture, Food, and Environment, Toulouse, France
| | - J Thomas
- UMR 1286, Nutrition and Integrative Neurobiology, University of Bordeaux, French National Institute for Agriculture, Food, and Environment, Bordeaux, France
| | - J Lainé
- UMR 1286, Nutrition and Integrative Neurobiology, University of Bordeaux, French National Institute for Agriculture, Food, and Environment, Bordeaux, France
| | - L Gros
- UMR 1286, Nutrition and Integrative Neurobiology, University of Bordeaux, French National Institute for Agriculture, Food, and Environment, Bordeaux, France
| | - M Lévêque
- UMR 1331 ToxAlim, French National Institute for Agriculture, Food, and Environment, Toulouse, France
| | - R Leonard
- Unité de Glycobiologie Structurale et Fonctionnelle, Université de Lille, Villeneuve d'Ascq, France
| | - C Harkat
- UMR 1331 ToxAlim, French National Institute for Agriculture, Food, and Environment, Toulouse, France
| | - C Robbe-Masselot
- Unité de Glycobiologie Structurale et Fonctionnelle, Université de Lille, Villeneuve d'Ascq, France
| | - R Róka
- First Department of Medicine, University of Szeged, Szeged, Hungary
| | - M Mercier-Bonin
- UMR 1331 ToxAlim, French National Institute for Agriculture, Food, and Environment, Toulouse, France
| | - V Theodorou
- UMR 1331 ToxAlim, French National Institute for Agriculture, Food, and Environment, Toulouse, France
| | - M Darnaudéry
- UMR 1286, Nutrition and Integrative Neurobiology, University of Bordeaux, French National Institute for Agriculture, Food, and Environment, Bordeaux, France
| | - J R Turner
- Laboratory of Mucosal Barrier Pathobiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
| | - L Ferrier
- UMR 1331 ToxAlim, French National Institute for Agriculture, Food, and Environment, Toulouse, France.
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25
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Gastrointestinal disorders-induced pain. GENE REPORTS 2020. [DOI: 10.1016/j.genrep.2019.100580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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26
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Labanski A, Langhorst J, Engler H, Elsenbruch S. Stress and the brain-gut axis in functional and chronic-inflammatory gastrointestinal diseases: A transdisciplinary challenge. Psychoneuroendocrinology 2020; 111:104501. [PMID: 31715444 DOI: 10.1016/j.psyneuen.2019.104501] [Citation(s) in RCA: 113] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Revised: 10/17/2019] [Accepted: 10/29/2019] [Indexed: 12/18/2022]
Abstract
The broad role of stress in the brain-gut axis is widely acknowledged, with implications for multiple prevalent health conditions that are characterized by chronic gastrointestinal symptoms. These include the functional gastrointestinal disorders (FGID), such as irritable bowel syndrome and functional dyspepsia, as well as inflammatory bowel diseases (IBD) like ulcerative colitis and Crohn's disease. Although the afferent and efferent pathways linking the gut and the brain are modulated by stress, the fields of neurogastroenterology and psychoneuroendocrinology (PNE)/ psychoneuroimmunology (PNI) remain only loosely connected. We aim to contribute to bringing these fields closer together by drawing attention to a fascinating, evolving research area, targeting an audience with a strong interest in the role of stress in health and disease. To this end, this review introduces the concept of the brain-gut axis and its major pathways, and provides a brief introduction to epidemiological and clinical aspects of FGIDs and IBD. From an interdisciplinary PNE/PNI perspective, we then detail current knowledge regarding the role of chronic and acute stress in the pathophysiology of FGID and IBD. We provide an overview of evidence regarding non-pharmacological treatment approaches that target central or peripheral stress mechanisms, and conclude with future directions, particularly those arising from recent advances in the neurosciences and discoveries surrounding the gut microbiota.
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Affiliation(s)
- Alexandra Labanski
- Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Jost Langhorst
- Chair for Integrative Medicine, University of Duisburg-Essen, Essen, Germany; Clinic for Internal and Integrative Medicine, Klinikum Bamberg, Bamberg, Germany
| | - Harald Engler
- Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Sigrid Elsenbruch
- Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
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The Role of Descending Pain Modulation in Chronic Primary Pain: Potential Application of Drugs Targeting Serotonergic System. Neural Plast 2019; 2019:1389296. [PMID: 31933624 PMCID: PMC6942873 DOI: 10.1155/2019/1389296] [Citation(s) in RCA: 100] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 11/02/2019] [Accepted: 11/27/2019] [Indexed: 11/24/2022] Open
Abstract
Chronic primary pain (CPP) is a group of diseases with long-term pain and functional disorders but without structural or specific tissue pathologies. CPP is becoming a serious health problem in clinical practice due to the unknown cause of intractable pain and high cost of health care yet has not been satisfactorily addressed. During the past decades, a significant role for the descending pain modulation and alterations due to specific diseases of CPP has been emphasized. It has been widely established that central sensitization and alterations in neuroplasticity induced by the enhancement of descending pain facilitation and/or the impairment of descending pain inhibition can explain many chronic pain states including CPP. The descending serotonergic neurons in the raphe nuclei target receptors along the descending pain circuits and exert either pro- or antinociceptive effects in different pain conditions. In this review, we summarize the possible underlying descending pain regulation mechanisms in CPP and the role of serotonin, thus providing evidence for potential application of analgesic medications based on the serotonergic system in CPP patients.
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Wang XJ, Camilleri M. Personalized medicine in functional gastrointestinal disorders: Understanding pathogenesis to increase diagnostic and treatment efficacy. World J Gastroenterol 2019; 25:1185-1196. [PMID: 30886502 PMCID: PMC6421234 DOI: 10.3748/wjg.v25.i10.1185] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Revised: 02/04/2019] [Accepted: 02/23/2019] [Indexed: 02/06/2023] Open
Abstract
There is overwhelming evidence that functional gastrointestinal disorders (FGIDs) are associated with specific mechanisms that constitute important targets for personalized treatment. There are specific mechanisms in patients presenting with functional upper gastrointestinal symptoms (UGI Sx). Among patients with UGI Sx, approximately equal proportions (25%) of patients have delayed gastric emptying (GE), reduced gastric accommodation (GA), both impaired GE and GA, or neither, presumably due to increased gastric or duodenal sensitivity. Treatments targeted to the underlying pathophysiology utilize prokinetics, gastric relaxants, or central neuromodulators. Similarly, specific mechanisms in patients presenting with functional lower gastrointestinal symptoms, especially with diarrhea or constipation, are recognized, including at least 30% of patients with functional constipation pelvic floor dyssynergia and 5% has colonic inertia (with neural or interstitial cells of Cajal loss in myenteric plexus); 25% of patients with diarrhea-predominant irritable bowel syndrome (IBSD) has evidence of bile acid diarrhea; and, depending on ethnicity, a varying proportion of patients has disaccharidase deficiency, and less often sucrose-isomaltase deficiency. Among patients with predominant pain or bloating, the role of fermentable oligosaccharides, disaccharides, monosaccharides and polyols should be considered. Personalization is applied through pharmacogenomics related to drug pharmacokinetics, specifically the role of CYP2D6, 2C19 and 3A4 in the use of drugs for treatment of patients with FGIDs. Single mutations or multiple genetic variants are relatively rare, with limited impact to date on the understanding or treatment of FGIDs. The role of mucosal gene expression in FGIDs, particularly in IBS-D, is the subject of ongoing research. In summary, the time for personalization of FGIDs, based on deep phenotyping, is here; pharmacogenomics is relevant in the use of central neuromodulators. There is still unclear impact of the role of genetics in the management of FGIDs.
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Affiliation(s)
- Xiao Jing Wang
- Division of Gastroenterology and Hepatology, Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, MN 55905, United States
| | - Michael Camilleri
- Division of Gastroenterology and Hepatology, Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, MN 55905, United States
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