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Halder N, Yadav S, Lal G. Neuroimmune communication of the cholinergic system in gut inflammation and autoimmunity. Autoimmun Rev 2024; 23:103678. [PMID: 39500481 DOI: 10.1016/j.autrev.2024.103678] [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: 10/01/2024] [Revised: 11/01/2024] [Accepted: 11/01/2024] [Indexed: 11/08/2024]
Abstract
Neuroimmune communication in the body forms a bridge between two central regulatory systems of the body, i.e., nervous and immune systems. The cholinergic system is a crucial modulatory neurotransmitter in the central and peripheral nervous system. It includes the neurotransmitter acetylcholine (ACh), the enzyme required for the synthesis of ACh (choline acetyltransferase, ChAT), the enzyme required for its degradation (acetylcholinesterase, AChE), and cholinergic receptors (Nicotinic acetylcholine receptors and muscarinic acetylcholine receptors). The cholinergic system in neurons is well known for its role in cognitive function, sensory perception, motor control, learning, and memory processes. It has been shown that the non-neuronal cholinergic system (NNCS) is present in various tissues and immune cells and forms a neuroimmune communications system. In the present review, we discussed the NNCS on immune cells, its role in homeostasis and inflammatory reactions in the gut, and how it can be exploited in treating inflammatory responses.
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Affiliation(s)
- Namrita Halder
- Biotechnology Research and Innovation Council-National Centre for Cell Science (BRIC-NCCS), SPPU campus, Ganeshkhind, Pune, MH-411007, India
| | - Sourabh Yadav
- Biotechnology Research and Innovation Council-National Centre for Cell Science (BRIC-NCCS), SPPU campus, Ganeshkhind, Pune, MH-411007, India
| | - Girdhari Lal
- Biotechnology Research and Innovation Council-National Centre for Cell Science (BRIC-NCCS), SPPU campus, Ganeshkhind, Pune, MH-411007, India.
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Mizoguchi A, Higashiyama M, Wada A, Nishimura H, Tomioka A, Ito S, Tanemoto R, Nishii S, Inaba K, Sugihara N, Hanawa Y, Horiuchi K, Okada Y, Kurihara C, Akita Y, Narimatu K, Komoto S, Tomita K, Kawauchi S, Sato S, Hokari R. Visceral hypersensitivity induced by mild traumatic brain injury via the corticotropin-releasing hormone receptor: An animal model. Neurogastroenterol Motil 2023; 35:e14634. [PMID: 37357384 DOI: 10.1111/nmo.14634] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 03/30/2023] [Accepted: 06/12/2023] [Indexed: 06/27/2023]
Abstract
BACKGROUND Mild blast-induced traumatic brain injury (bTBI) induces various gut symptoms resembling human irritable bowel syndrome (IBS) as one of mental and behavioral disorders. However, the underlying mechanisms remain unclear. We investigated whether the extremely localized brain impact extracranially induced by laser-induced shock wave (LISW) evoked IBS-like phenomenon including visceral hypersensitivity and intestinal hyperpermeability in rats. METHODS The rats were subjected to LISW on the scalp to shock the entire brain. Visceral hypersensitivity was evaluated by the threshold pressure of abdominal withdrawal reflex (AWR) using a colorectal distension test. Permeability was evaluated by the concentration of penetrating FITC-dextran from intestine and the mRNA expression levels of tight junction family proteins. Involvement of corticotropin-releasing factor receptor (CRFR) 1 and 2 was examined by evaluating mRNA expression and modulating CRFR function with agonist, recombinant CRF (10 μg/kg), and antagonist, astressin (33 μg/kg). High-throughput sequencing of the gut microbiota was performed by MiSeqIII instrument and QIIME tool. KEY RESULTS The thresholds of the AWR were significantly lowered after LISW. Permeability was increased in small intestine by LISW along with decreased expression of tight junction ZO-1. LISW significantly increased CRFR1 expression and decreased CRFR2 expression. Visceral hypersensitivity was significantly aggravated by CRFR agonist and suppressed by CRFR antagonist. The α- and β-diversity of the fecal microbiota was altered after LISW. CONCLUSIONS AND INFERENCES LISW provoked visceral hypersensitivity, small intestinal hyperpermeability, altered expression of CRFRs and changes in the microbiota, suggesting that genuine bTBI caused by LISW can induce a pathophysiology comparable to that of human IBS.
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Affiliation(s)
- Akinori Mizoguchi
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Masaaki Higashiyama
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Akinori Wada
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Hiroyuki Nishimura
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Akira Tomioka
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Suguru Ito
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Rina Tanemoto
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Shin Nishii
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Kenichi Inaba
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Nao Sugihara
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Yoshinori Hanawa
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Kazuki Horiuchi
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Yoshikiyo Okada
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Chie Kurihara
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Yoshihiro Akita
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Kazuyuki Narimatu
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Shunsuke Komoto
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Kengo Tomita
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
| | - Satoko Kawauchi
- Division of Bioinformation and Therapeutic Systems, National Defense Medical College Research Institute, Saitama, Japan
| | - Shunichi Sato
- Division of Bioinformation and Therapeutic Systems, National Defense Medical College Research Institute, Saitama, Japan
| | - Ryota Hokari
- Department of Internal Medicine, National Defense Medical College, Saitama, Japan
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Fujikawa Y, Tominaga K. Enhanced neuron-glia network in the submucosa and increased neuron outgrowth into the mucosa are associated with distinctive expressions of neuronal factors in the colon of rat IBS model. Neurogastroenterol Motil 2023; 35:e14595. [PMID: 37170695 DOI: 10.1111/nmo.14595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 01/16/2023] [Accepted: 04/03/2023] [Indexed: 05/13/2023]
Abstract
BACKGROUND Neuronal attraction and repulsion factors regulate neuron network formation. In the colon of irritable bowel syndrome (IBS), neuron network and enteric glial cells (EGCs) in the submucosa, neuronal outgrowth in the mucosa, and expressions of neuronal factors remain unknown. METHODS IBS models were prepared by intracolonic injections of acetic acid to Wistar Kyoto (WKY) rats. Using whole-mount submucosal plexus tissue stripped from the distal colon, we examined neuron network, EGC morphology, and localization of both attraction factor (nerve growth factor: NGF) and repulsion factor (semaphorin3A: Sema3A). We evaluated mRNA expressions of NGF and Sema3A in the mucosa and submucosa and neuron outgrowth into the mucosa. KEY RESULTS In IBS models, nerve fibers were thickened and densely increased in the submucosa remarkably from the outer toward the inner plexus. Submucosal EGCs exhibited process hyperplasia and bulbous swelling of terminals. NGF was predominantly expressed in EGCs than neurons in the submucosa. NGF mRNA expressions were increased in the submucosa in WKY, and their expressions were increased in the mucosa after the injection. Sema3A mRNA expressions were increased in both layers of WKY but tended to be decreased in the mucosa alone after the injection. Neuron outgrowth was increased into the mucosa. NGF was localized at EGCs in the lamina propria mucosae but not mucosal mast cells. CONCLUSIONS & INFERENCES Neuron network enhancement in the submucosa and neuron outgrowth into the mucosa may be associated with axon guidance factors expressed in hyperplastic EGCs in the colonic submucosa of IBS models.
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Ma T, Xue X, Tian H, Zhou X, Wang J, Zhao Z, Wang M, Song J, Feng R, Li L, Jing C, Tian F. Effect of the gut microbiota and their metabolites on postoperative intestinal motility and its underlying mechanisms. J Transl Med 2023; 21:349. [PMID: 37237321 DOI: 10.1186/s12967-023-04215-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Accepted: 05/19/2023] [Indexed: 05/28/2023] Open
Abstract
Gut microbiota is closely related to human health and disease because, together with their metabolites, gut microbiota maintain normal intestinal peristalsis. The use of antibiotics or opioid anesthetics, or both, during surgical procedures can lead to dysbiosis and affect intestinal motility; however, the underlying mechanisms are not fully known. This review aims to discuss the effect of gut microbiota and their metabolites on postoperative intestinal motility, focusing on regulating the enteric nervous system, 5-hydroxytryptamine neurotransmitter, and aryl hydrocarbon receptor.
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Affiliation(s)
- TianRong Ma
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
| | - XiaoLei Xue
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
- Department of Pharmacy, The Second Affiliated Hospital of Shandong First Medical University, Taian, 271000, China
| | - Hui Tian
- Department of Gastroenterology, Liaocheng People's Hospital, Shandong First Medical University, Liaocheng, 252000, China
| | - XinXiu Zhou
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
| | - JunKe Wang
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
| | - ZhiWen Zhao
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
| | - MingFei Wang
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, China
| | - JiYuan Song
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, China
| | - RenXiang Feng
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, China
| | - Leping Li
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, China
| | - Changqing Jing
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China.
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, China.
| | - Feng Tian
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China.
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, China.
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Traini C, Idrizaj E, Biagioni C, Baccari MC, Vannucchi MG. Otilonium Bromide Prevents Cholinergic Changes in the Distal Colon Induced by Chronic Water Avoidance Stress, a Rat Model of Irritable Bowel Syndrome. Int J Mol Sci 2023; 24:ijms24087440. [PMID: 37108603 PMCID: PMC10139220 DOI: 10.3390/ijms24087440] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 04/12/2023] [Accepted: 04/13/2023] [Indexed: 04/29/2023] Open
Abstract
Irritable Bowel syndrome (IBS) is a highly widespread gastrointestinal disorder whose symptomatology mainly affect the large intestine. Among the risk factors, psychosocial stress is the most acknowledged. The repeated water avoidance stress (rWAS) is considered an animal model of psychosocial stress that is capable of mimicking IBS. Otilonium bromide (OB), which is orally administered, concentrates in the large bowel and controls most of the IBS symptoms in humans. Several reports have shown that OB has multiple mechanisms of action and cellular targets. We investigated whether the application of rWAS to rats induced morphological and functional alterations of the cholinergic neurotransmission in the distal colon and whether OB prevented them. The results demonstrated that rWAS affects cholinergic neurotransmission by causing an increase in acid mucin secretion, in the amplitude of electrically evoked contractile responses, abolished by atropine, and in the number of myenteric neurons expressing choline acetyltransferase. OB counteracted these changes and also showed an intrinsic antimuscarinic effect on the post-synaptic muscular receptors. We assume that the rWAS consequences on the cholinergic system are linked to corticotrophin-releasing factor-1 (CRF1) receptor activation by the CRF hypothalamic hormone. OB, by interfering with the CFR/CRFr activation, interrupted the cascade events responsible for the changes affecting the rWAS rat colon.
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Affiliation(s)
- Chiara Traini
- Histology and Embryology Research Unit, Department of Experimental and Clinical Medicine, University of Florence, 50139 Florence, Italy
| | - Eglantina Idrizaj
- Section of Physiological Sciences, Department of Experimental and Clinical Medicine, University of Florence, 50139 Florence, Italy
| | - Cristina Biagioni
- Histology and Embryology Research Unit, Department of Experimental and Clinical Medicine, University of Florence, 50139 Florence, Italy
| | - Maria Caterina Baccari
- Section of Physiological Sciences, Department of Experimental and Clinical Medicine, University of Florence, 50139 Florence, Italy
| | - Maria Giuliana Vannucchi
- Histology and Embryology Research Unit, Department of Experimental and Clinical Medicine, University of Florence, 50139 Florence, Italy
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Tryptase activates enteric glial cells followed by affecting neuronal properties possibly via the stimuli-associated mediators. J Pharmacol Sci 2023; 151:163-170. [PMID: 36925214 DOI: 10.1016/j.jphs.2023.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 02/01/2023] [Accepted: 02/03/2023] [Indexed: 02/10/2023] Open
Abstract
OBJECTIVES Mast cell-derived tryptase causes neuronal elongation/sensitization leading to visceral hypersensitivity. However, effects of tryptase on enteric glial cells (EGCs) and subsequent interaction between EGCs and neurons remain unknown. METHODS We evaluated proteins and mRNA expressions in EGC (CRL-2690, ATCC) after tryptase stimulation: nerve growth factor (NGF), netrin-1, and glial cell-derived neurotrophic factor (GDNF). We examined morphological changes in neurons (PC12 cells, CRL-1721.1) by co-incubation with the conditioned medium of EGCs after tryptase stimulation. RESULTS EGC was activated by tryptase, and proliferated (by 1.8-fold) with cytoplasmic expansion and process elongation. Intercellular connections of EGC were more complexed. Tryptase induced mRNA expression (2.5-fold) and protein expression of NGF. Netrin-1 (3-fold) and GDNF (3-fold) mRNA expressions were increased at 30 min. Increase in netrin-1 continued until 6 h, whereas the latter decreased by 3 h. The conditioned medium of EGC after tryptase stimulation expanded neuronal cytoplasm (round or ramified shapes) and neurite outgrowth with elongation of cytoskeletal filaments in time-dependent and dose-dependent manners. These changes were similar to those after NGF stimulation. Growth cone proteins of neurons were also increased by the conditioned medium. CONCLUSION EGC activated by tryptase changes neuronal morphology (process elongation and cytoplasm expansion) possibly via the stimuli-associated mediators.
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Mantel M, Derkinderen P, Bach-Ngohou K, Neunlist M, Rolli-Derkinderen M. Crosstalk between omega-6 oxylipins and the enteric nervous system: Implications for gut disorders? Front Med (Lausanne) 2023; 10:1083351. [PMID: 37056732 PMCID: PMC10086145 DOI: 10.3389/fmed.2023.1083351] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 03/03/2023] [Indexed: 03/30/2023] Open
Abstract
The enteric nervous system (ENS) continues to dazzle scientists with its ability to integrate signals, from the outside as well as from the host, to accurately regulate digestive functions. Composed of neurons and enteric glial cells, the ENS interplays with numerous neighboring cells through the reception and/or the production of several types of mediators. In particular, ENS can produce and release n-6 oxylipins. These lipid mediators, derived from arachidonic acid, play a major role in inflammatory and allergic processes, but can also regulate immune and nervous system functions. As such, the study of these n-6 oxylipins on the digestive functions, their cross talk with the ENS and their implication in pathophysiological processes is in full expansion and will be discussed in this review.
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Affiliation(s)
- Marine Mantel
- Nantes Université, Inserm, The Enteric Nervous System in Gut and Brain Disorders, Nantes, France
| | - Pascal Derkinderen
- CHU Nantes, Inserm, Nantes Université, The Enteric Nervous System in Gut and Brain Disorders, Nantes, France
| | - Kalyane Bach-Ngohou
- CHU Nantes, Inserm, Nantes Université, The Enteric Nervous System in Gut and Brain Disorders, Nantes, France
| | - Michel Neunlist
- Nantes Université, Inserm, The Enteric Nervous System in Gut and Brain Disorders, Nantes, France
| | - Malvyne Rolli-Derkinderen
- Nantes Université, Inserm, The Enteric Nervous System in Gut and Brain Disorders, Nantes, France
- *Correspondence: Malvyne Rolli-Derkinderen,
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Sun Z, Wang X, Feng S, Xie C, Xing Y, Guo L, Zhao J, Ji C. A review of neuroendocrine immune system abnormalities in IBS based on the brain–gut axis and research progress of acupuncture intervention. Front Neurosci 2023; 17:934341. [PMID: 36968497 PMCID: PMC10034060 DOI: 10.3389/fnins.2023.934341] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 02/07/2023] [Indexed: 03/11/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a common digestive disorder observed in clinics. Current studies suggest that the pathogenesis of the disease is closely related to abnormal brain–gut interactions, hypokinesia, visceral sensory hypersensitivity in the gastrointestinal tract, and alterations in the intestinal microenvironment. However, it is difficult for a single factor to explain the heterogeneity of symptoms. The Rome IV criteria emphasized the holistic biologic-psycho-social model of IBS, suggesting that symptoms of the disease are closely related to neurogastroenterology and various abnormalities in brain–gut interaction. This study comprehensively reviewed the relationship between the brain–gut axis and IBS, the structure of the brain–gut axis, and the relationship between the brain–gut axis and intestinal microenvironment, and discussed the relationship between the abnormal regulation of the nervous system, endocrine system, and immune system and the incidence of IBS on the basis of brain–gut axis. In terms of treatment, acupuncture therapy can regulate the neuroendocrine-immune system of the body and improve the intestinal microenvironment, and it has the advantages of safety, economy, and effectiveness. We study the pathogenesis of IBS from local to global and micro to macro, and review the use of acupuncture to treat the disease as a whole so as to provide new ideas for the treatment of the disease.
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Affiliation(s)
- Zhangyin Sun
- College of Acupuncture and Moxibustion, Shaanxi University of Traditional Chinese Medicine, Xianyang, China
- Department of Acupuncture and Moxibustion, Shaanxi Hospital of Traditional Chinese Medicine, Xi'an, China
| | - Xuejiao Wang
- College of Acupuncture and Moxibustion, Shaanxi University of Traditional Chinese Medicine, Xianyang, China
- Department of Acupuncture and Moxibustion, Shaanxi Hospital of Traditional Chinese Medicine, Xi'an, China
| | - Shangsheng Feng
- MOE Key Laboratory of Biomedical Information Engineering, Xi'an Jiaotong University, Xi'an, China
| | - Chaoju Xie
- College of Acupuncture and Moxibustion, Shaanxi University of Traditional Chinese Medicine, Xianyang, China
- Department of Acupuncture and Moxibustion, Shaanxi Hospital of Traditional Chinese Medicine, Xi'an, China
| | - Yu Xing
- College of Acupuncture and Moxibustion, Shaanxi University of Traditional Chinese Medicine, Xianyang, China
- Department of Acupuncture and Moxibustion, Shaanxi Hospital of Traditional Chinese Medicine, Xi'an, China
| | - Liang Guo
- College of Acupuncture and Moxibustion, Shaanxi University of Traditional Chinese Medicine, Xianyang, China
- Department of Acupuncture and Moxibustion, Shaanxi Hospital of Traditional Chinese Medicine, Xi'an, China
| | - Jingyu Zhao
- Department of Acupuncture and Moxibustion, Xi'an Hospital of Traditional Chinese Medicine, Xi'an, China
- *Correspondence: Jingyu Zhao
| | - Changchun Ji
- Department of Acupuncture and Moxibustion, Shaanxi Hospital of Traditional Chinese Medicine, Xi'an, China
- Department of Acupuncture and Moxibustion, Shaanxi Provincial Institute of Traditional Chinese Medicine, Xi'an, China
- Changchun Ji
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Namakin K, Moghaddam MH, Sadeghzadeh S, Mehranpour M, Vakili K, Fathi M, Golshan A, Bayat AH, Tajik AH, Eskandari N, Mohammadzadeh I, Benisi SZ, Aliaghaei A, Abdollahifar MA. Elderberry diet improves gut-brain axis dysfunction, neuroinflammation, and cognitive impairment in the rat model of irritable bowel syndrome. Metab Brain Dis 2023; 38:1555-1572. [PMID: 36877342 DOI: 10.1007/s11011-023-01187-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 02/13/2023] [Indexed: 03/07/2023]
Abstract
Irritable bowel syndrome (IBS) is related to a problem in the gut-brain axis. This experimental research aimed to shed light on the potential therapeutic application of elderberry (EB), which can work on the axis and get better the IBS symptoms. There were three groups (36 Sprague-Dawley rats) in this experiment, including control, IBS, and IBS with EB diet (IBS + EB). Making use of intracolonic instillation of 1 ml of 4% acetic acid for 30 s, IBS was induced. 7 days later, the EB extract (2%) was added to the diets of all animals for 8 weeks. Some histological, behavioral, and stereological techniques were used to detect the effects of EB on the gut and brain tissues. The findings showed that the EB diet improved locomotion and decreased anxiety-like behavior in the rat models of IBS. Moreover, the diet dropped the expression of TNF-α and increased mucosal layer thickness and the number of goblet and mast cells in colon tissue samples. In the hippocampal samples, administration of EB prevented astrogliosis and astrocyte reactivity. Although hippocampal and cortical neurons decreased markedly in the IBS group, EB prevented the drop in the number of neurons. Although lots of research is needed to elucidate the effectiveness of EB in IBS and its exact molecular mechanism, the result of this study showed that EB as an antioxidant and immune-modulatory agent could be a promising research target to prevent the impairment in the gut-brain axis, and could ameliorative classic IBS symptoms.
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Affiliation(s)
- Kosar Namakin
- Hearing Disorders Research Center, Loghman-Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Meysam Hassani Moghaddam
- Department of Anatomical Sciences, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran
| | - Sara Sadeghzadeh
- Hearing Disorders Research Center, Loghman-Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Mehranpour
- Department of Genetics, Faculty of Biological Sciences, North Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Kimia Vakili
- Student Research Committee, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mobina Fathi
- Student Research Committee, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ahmadreza Golshan
- Hearing Disorders Research Center, Loghman-Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amir-Hossein Bayat
- Department of Neuroscience, School of Sciences and Advanced Technology in Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Amir-Hossein Tajik
- Hearing Disorders Research Center, Loghman-Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Neda Eskandari
- Department of Anatomical Sciences, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran
| | - Ibrahim Mohammadzadeh
- Hearing Disorders Research Center, Loghman-Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Soheila Zamanlui Benisi
- Stem Cell Research Center, Tissue Engineering and Regenerative Medicine Institute, Central Tehran Branch, Islamic Azad University, 1385/768, Tehran, Iran
| | - Abbas Aliaghaei
- Hearing Disorders Research Center, Loghman-Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Mohammad-Amin Abdollahifar
- Hearing Disorders Research Center, Loghman-Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Identifying Mast Cells in Gastrointestinal Biopsies in Pediatric Irritable Bowel Patients. J Pediatr Gastroenterol Nutr 2022; 75:572-577. [PMID: 35976360 PMCID: PMC9584038 DOI: 10.1097/mpg.0000000000003588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVES Mast cells (MCs) have been proposed to be involved in the pathophysiology of irritable bowel syndrome (IBS). Nonetheless, the quantity and distribution of MCs in the gastrointestinal tract of pediatric patients with IBS are not well defined. This study aimed to compare the number of MCs in children with and without IBS and to establish histopathological reference values in pediatrics. METHODS Forty-nine participants with IBS were prospectively enrolled and classified into IBS with atopy (n = 29) and IBS without atopy (n = 20). As our retrospective control group, we selected 42 individuals with a history of polyposis syndrome or gastroesophageal reflux disease with normal histopathology. Retrospective selection of the control cohort was performed in a manner similar to previously published adult and pediatric studies. MCs were prospectively stained immunohistochemically on specimens from the stomach, duodenum, terminal ileum, and descending colon of both groups. RESULTS The IBS group showed significantly more MCs per high-power field (MCs/HPF) in the stomach, duodenum, terminal ileum, and descending colon ( P < 0.001), irrespective of their atopic status. Optimal MC cutoff values for IBS are ≥20.5 MCs/HPF in the stomach (area under the curve [AUC] = 0.84); ≥23.0 MCs/HPF in the duodenum (AUC = 0.79); ≥33.5 MCs/HPF in the terminal ileum (AUC = 0.82); and ≥22.5 MCs/HPF in the descending colon (AUC = 0.86). CONCLUSIONS Pediatric patients with IBS showed increased numbers of MCs in the stomach, duodenum, terminal ileum, and descending colon when compared with controls. Further trials are needed to explain the role of MCs in pediatric IBS, which might facilitate the development of targeted therapeutic interventions.
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11
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Lee KN, Lee J, Hwang J, Lee C, Kim JS, Song SH, Lee OY, Lee KG. Association Between Visceral Hypersensitivity in Irritable Bowel Syndrome, Intestinal Microbiota, and Mast Cells: How to Detect Mast Cells Using Confocal Microscopy. J Neurogastroenterol Motil 2021; 27:657-659. [PMID: 34642288 PMCID: PMC8521466 DOI: 10.5056/jnm21132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Affiliation(s)
- Kang Nyeong Lee
- Department of Internal Medicine, Hanyang University Hospital, Seoul, Korea
| | - Jiwon Lee
- Department of Physics, Hanyang University, Seoul, Korea
| | - Juil Hwang
- Department of Physics, Hanyang University, Seoul, Korea
| | - Chungha Lee
- Department of Physics, Hanyang University, Seoul, Korea
| | - Ji Sook Kim
- Department of Pathology, Hanyang University Hospital, Seoul, Korea
| | - Seok Ho Song
- Department of Physics, Hanyang University, Seoul, Korea
| | - Oh Young Lee
- Department of Internal Medicine, Hanyang University Hospital, Seoul, Korea
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12
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Lu Y, Huang J, Zhang Y, Huang Z, Yan W, Zhou T, Wang Z, Liao L, Cao H, Tan B. Therapeutic Effects of Berberine Hydrochloride on Stress-Induced Diarrhea-Predominant Irritable Bowel Syndrome Rats by Inhibiting Neurotransmission in Colonic Smooth Muscle. Front Pharmacol 2021; 12:596686. [PMID: 34594213 PMCID: PMC8476869 DOI: 10.3389/fphar.2021.596686] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 09/01/2021] [Indexed: 11/13/2022] Open
Abstract
The etiology of diarrhea-predominant irritable bowel syndrome (IBS-D) is complicated and closely related to neurotransmission in the gastrointestinal (GI) tract. Developing new strategies for treating this disease is a major challenge for IBS-D research. Berberine hydrochloride (BBH), the derivative of berberine, is a herbal constituent used to treat IBS. Previous studies have shown that BBH has potential anti-inflammatory, antibacterial, analgesic, and antidiarrheal effects and a wide range of biological activities, especially in regulating the release of some neurotransmitters. A modified IBS-D rat model induced by chronic restraint stress was used in all experiments to study the effects of BBH on the GI tract. This study measured the abdominal withdrawal reflex (AWR) response to graded colorectal distention (CRD; 20, 40, 60, and 80 mmHg) and observed the fecal areas of stress-induced IBS-D model. Experiments were conducted using organ bath techniques, which were performed in vitro using strips of colonic longitudinal smooth muscle. Inhibitory and excitatory neurotransmitter agents were added to each organ bath to observe contractile responses on the strips and the treatment effect exerted by BBH. The IBS-D rat model was successfully induced by chronic restraint stress, which resulted in an increased defecation frequency and visceral hypersensitivity similar to that of humans. BBH could reduce 4-h fecal areas and AWR response to CRD in IBS-D. The stress-induced IBS-D model showed upregulated colonic mRNA expression levels of 5-hydroxytryptamine-3A receptor and downregulated expression levels of neuronal nitric oxide synthase. Meanwhile, BBH could reverse this outcome. The responses of substances that regulate the contraction induced by related neurotransmission in the longitudinal smooth muscle of IBS-D colon (including the agonist of acetylcholine, carbachol; NOS inhibitor, L-NAME; and P2Y1 receptor antagonist, MRS2500) can be inhibited by BBH. In summary, BBH promotes defecation frequency and visceral hypersensitivity in IBS-D and exerts inhibitory effects on contractile responses in colonic longitudinal smooth muscle. Thus, BBH may represent a new therapeutic approach for treating IBS-D.
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Affiliation(s)
- Yulin Lu
- Research Center for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jingjing Huang
- Research Center for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yao Zhang
- School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zitong Huang
- Research Center for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Weiming Yan
- The Third Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Tianran Zhou
- The Fourth Clinical Medical College, Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Zhesheng Wang
- Research Center for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Lu Liao
- Research Center for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Hongying Cao
- School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Bo Tan
- Research Center for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
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A Survey of Methodologies for Assessing Mast Cell Density and Activation in Patients with Functional Abdominal Pain Disorders. GASTROINTESTINAL DISORDERS 2021. [DOI: 10.3390/gidisord3040016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The aim was to assess methods utilized in assessing mast cell involvement in functional abdominal pain disorders (FAPDs), specifically to describe variability in methods utilized to assess both mast cell density and activation and determine if a consensus exists. After a literature search identified 70 manuscripts assessing mast cell density, data were extracted including FAPD diagnosis, site of biopsy, selection of microscopic fields analyzed, selection of mucosal region analyzed, method of mast cell identification, method to assess mast cell density, and if performed, method to assess mast cell activation. There appears to be some consensus favoring inmmunohistochemical stains over histochemical stains for identifying mast cells. Otherwise, considerable variability exists in methodology for assessing mast cell density and activation. Regardless of method, approximately 80% of studies found increased mast cell density and/or activation in comparison to controls with no method being superior. A wide variety of methods have been employed to assess mast cell density and activation with no well-established consensus and inadequate data to recommend specific approaches. The current methodology providing physiologic information needs to be translated to a standard methodology providing clinical information with the development of criteria establishing abnormal density and/or activation, and more importantly, predicting treatment response.
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14
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Gros M, Gros B, Mesonero JE, Latorre E. Neurotransmitter Dysfunction in Irritable Bowel Syndrome: Emerging Approaches for Management. J Clin Med 2021; 10:jcm10153429. [PMID: 34362210 PMCID: PMC8347293 DOI: 10.3390/jcm10153429] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/13/2021] [Accepted: 07/28/2021] [Indexed: 02/06/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder whose aetiology is still unknown. Most hypotheses point out the gut-brain axis as a key factor for IBS. The axis is composed of different anatomic and functional structures intercommunicated through neurotransmitters. However, the implications of key neurotransmitters such as norepinephrine, serotonin, glutamate, GABA or acetylcholine in IBS are poorly studied. The aim of this review is to evaluate the current evidence about neurotransmitter dysfunction in IBS and explore the potential therapeutic approaches. IBS patients with altered colorectal motility show augmented norepinephrine and acetylcholine levels in plasma and an increased sensitivity of central serotonin receptors. A decrease of colonic mucosal serotonin transporter and a downregulation of α2 adrenoceptors are also correlated with visceral hypersensitivity and an increase of 5-hydroxyindole acetic acid levels, enhanced expression of high affinity choline transporter and lower levels of GABA. Given these neurotransmitter dysfunctions, novel pharmacological approaches such as 5-HT3 receptor antagonists and 5-HT4 receptor agonists are being explored for IBS management, for their antiemetic and prokinetic effects. GABA-analogous medications are being considered to reduce visceral pain. Moreover, agonists and antagonists of muscarinic receptors are under clinical trials. Targeting neurotransmitter dysfunction could provide promising new approaches for IBS management.
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Affiliation(s)
- Mónica Gros
- Centro de Salud Univérsitas, Hospital Clínico Universitario Lozano Blesa, 50009 Zaragoza, Spain;
- Instituto de Investigación Sanitaria de Aragón (IIS Aragón), 50009 Zaragoza, Spain; (B.G.); (J.E.M.)
| | - Belén Gros
- Instituto de Investigación Sanitaria de Aragón (IIS Aragón), 50009 Zaragoza, Spain; (B.G.); (J.E.M.)
- Servicio de Urgencias, Hospital Universitario Miguel Servet, 50009 Zaragoza, Spain
| | - José Emilio Mesonero
- Instituto de Investigación Sanitaria de Aragón (IIS Aragón), 50009 Zaragoza, Spain; (B.G.); (J.E.M.)
- Departamento de Farmacología, Fisiología y Medicina Legal y Forense, Facultad de Veterinaria, Universidad de Zaragoza, 50009 Zaragoza, Spain
- Instituto Agroalimentario de Aragón—IA2—(Universidad de Zaragoza—CITA), 50013 Zaragoza, Spain
| | - Eva Latorre
- Instituto de Investigación Sanitaria de Aragón (IIS Aragón), 50009 Zaragoza, Spain; (B.G.); (J.E.M.)
- Instituto Agroalimentario de Aragón—IA2—(Universidad de Zaragoza—CITA), 50013 Zaragoza, Spain
- Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, 50009 Zaragoza, Spain
- Correspondence:
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15
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Wang C, Fang X. Inflammation and Overlap of Irritable Bowel Syndrome and Functional Dyspepsia. J Neurogastroenterol Motil 2021; 27:153-164. [PMID: 33795538 PMCID: PMC8026374 DOI: 10.5056/jnm20175] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 11/23/2020] [Accepted: 11/29/2020] [Indexed: 12/13/2022] Open
Abstract
Irritable bowel syndrome (IBS) and functional dyspepsia (FD) are common functional gastrointestinal disorders (FGIDs) and account for a large proportion of consulting patients. These 2 disorders overlap with each other frequently. The pathogenesis of IBS or FD is complicated and multi-factors related, in which infectious or non-infectious inflammation and local or systemic immune response play significant roles. There are few studies focusing on the mechanism of inflammation in patients with overlap syndrome of irritable bowel syndrome and functional dyspepsia (IBS-FD). This review focuses on current advances about the role of inflammation in the pathogenesis of IBS and FD and the possible mechanism of inflammation in IBS-FD.
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Affiliation(s)
- Congzhen Wang
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiucai Fang
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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16
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Cheng L, Luo QQ, Chen SL. The role of intestinal mast cell infiltration in irritable bowel syndrome. J Dig Dis 2021; 22:143-151. [PMID: 33511763 DOI: 10.1111/1751-2980.12971] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Revised: 01/17/2021] [Accepted: 01/25/2021] [Indexed: 12/11/2022]
Abstract
As an essential part of the immune system, mast cells (MCs) play an important role in the pathogenesis of irritable bowel syndrome (IBS). Accumulating evidence has identified altered MC count and density in intestinal mucosa of patients with IBS; however, conflicting findings yield inconsistent conclusions. Currently, most studies have suggested intestinal MC infiltration in IBS patients. Considering the pivotal role of MCs in IBS, it is necessary to achieve a better understanding about the pathological changes in the intestine. The risk factors for IBS, including dietary habits, psychological factors, infection, and dysbiosis, are implicated to induce intestinal MC infiltration. Mechanistically, food may trigger immune-related allergic reactions and affect the intestinal microbiota activity. Some exogenous pathogens and altered profile of commensal bacteria promote intestinal MC recruitment through promoted release of chemokines from epithelial cells or direct activation of the immune system. In addition, psychological factors may affect the microenvironment where MCs live. MCs have been proven to interact with the enteric neurons and other immunocytes, evidenced by the close proximity of MCs to neurons and regional altered immune system components. A variety of mediators released by the enteric neurons, immunocytes, and MCs per se, such as neurotrophins, neuropeptides, cytokines, and chemokines, may have stimulant effects on MCs by modulating the survival, proliferation, and recruitment process of MCs in the intestine. In this review, the associations between IBS and intestinal MC density and the underlying mechanisms are discussed.
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Affiliation(s)
- Li Cheng
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Qing Qing Luo
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Sheng Liang Chen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
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17
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Mast Cell Regulation and Irritable Bowel Syndrome: Effects of Food Components with Potential Nutraceutical Use. Molecules 2020; 25:molecules25184314. [PMID: 32962285 PMCID: PMC7570512 DOI: 10.3390/molecules25184314] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 09/12/2020] [Accepted: 09/17/2020] [Indexed: 12/12/2022] Open
Abstract
Mast cells are key actors in inflammatory reactions. Upon activation, they release histamine, heparin and nerve growth factor, among many other mediators that modulate immune response and neuron sensitization. One important feature of mast cells is that their population is usually increased in animal models and biopsies from patients with irritable bowel syndrome (IBS). Therefore, mast cells and mast cell mediators are regarded as key components in IBS pathophysiology. IBS is a common functional gastrointestinal disorder affecting the quality of life of up to 20% of the population worldwide. It is characterized by abdominal pain and altered bowel habits, with heterogeneous phenotypes ranging from constipation to diarrhea, with a mixed subtype and even an unclassified form. Nutrient intake is one of the triggering factors of IBS. In this respect, certain components of the daily food, such as fatty acids, amino acids or plant-derived substances like flavonoids, have been described to modulate mast cells' activity. In this review, we will focus on the effect of these molecules, either stimulatory or inhibitory, on mast cell degranulation, looking for a nutraceutical capable of decreasing IBS symptoms.
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18
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Robles A, Perez Ingles D, Myneedu K, Deoker A, Sarosiek I, Zuckerman MJ, Schmulson MJ, Bashashati M. Mast cells are increased in the small intestinal mucosa of patients with irritable bowel syndrome: A systematic review and meta-analysis. Neurogastroenterol Motil 2019; 31:e13718. [PMID: 31498961 DOI: 10.1111/nmo.13718] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 08/05/2019] [Accepted: 08/20/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND Colonic mast cells have been proposed to be related to the pathophysiology of irritable bowel syndrome (IBS). Whether mast cell counts are altered in the small intestine, a less-explored region in patients with IBS is not completely clear. METHODS PubMed and EMBASE were searched for case-control studies on mast cell count/density in the small intestine of patients with IBS vs controls through February 2019. Mast cell counts were separately analyzed in the duodenum, jejunum, and ileum. Data were pooled using the standardized mean difference (SMD) method. When zero was not within the 95% confidence interval (CI), the SMD was considered significant. KEY RESULTS Data from 344 patients with IBS and 229 healthy controls from three studies in the duodenum, six in the jejunum, and five in the ileum were pooled in this meta-analysis. The number of mast cells was significantly higher in the ileum (SMD: 1.78 [95% CI: 0.89, 2.66]) of patients with IBS. Mast cell counts were not significantly different in the duodenum (SMD: 0.81 [-0.06, 1.67]) or the jejunum (SMD: 0.58 [-0.03, 1.19]) of patients with IBS vs healthy controls. CONCLUSIONS AND INFERENCES Mast cells are increased in the small intestine of IBS vs controls, mainly in the ileum. Future studies should address whether such findings are IBS subtype or gender-dependent. Methodological variations, single-center bias, and the limited number of studies included in this meta-analysis may affect the final results.
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Affiliation(s)
- Alejandro Robles
- Department of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, USA
| | - David Perez Ingles
- Department of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, USA
| | - Kanchana Myneedu
- Department of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, USA
| | - Abhizith Deoker
- Department of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, USA
| | - Irene Sarosiek
- Division of Gastroenterology, Department of Medicine, Texas Tech University Health Sciences Center/Paul L. Foster School of Medicine, El Paso, TX, USA
| | - Marc J Zuckerman
- Division of Gastroenterology, Department of Medicine, Texas Tech University Health Sciences Center/Paul L. Foster School of Medicine, El Paso, TX, USA
| | - Max J Schmulson
- Laboratorio de Hígado, Páncreas y Motilidad (HIPAM)-Unidad de Investigación en Medicina Experimental, Facultad de Medicina-Universidad Nacional Autónoma de México (UNAM), Hospital General de México Dr. Eduardo Liceaga, Mexico City, Mexico
| | - Mohammad Bashashati
- Division of Gastroenterology, Department of Medicine, Texas Tech University Health Sciences Center/Paul L. Foster School of Medicine, El Paso, TX, USA
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19
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Aguilera-Lizarraga J, Florens MV, Van Brussel T, Clevers E, Van Oudenhove L, Lambrechts D, Wouters MM, Boeckxstaens GE. Expression of immune-related genes in rectum and colon descendens of Irritable Bowel Syndrome patients is unrelated to clinical symptoms. Neurogastroenterol Motil 2019; 31:e13579. [PMID: 30854791 DOI: 10.1111/nmo.13579] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Revised: 02/06/2019] [Accepted: 02/07/2019] [Indexed: 12/18/2022]
Abstract
BACKGROUND Mucosal immune activation has been postulated to play an important role in the pathogenesis of irritable bowel syndrome (IBS). However, data are conflicting and often based on small patient cohorts. Here, we aimed to evaluate the gene expression of a large set of immune-related genes in mucosal biopsies from IBS patients and healthy volunteers (HV). METHODS A total of 171 IBS patients and 127 HV were included in the study. Rectum biopsies were collected from a cohort of 70 HV and 77 IBS patients (Rome III) and colon descendens biopsies from another cohort of 57 HV and 94 IBS patients (Rome II). Gene expression was assessed using OpenArray technology, and validated questionnaires were used to evaluate clinical characteristics (GI symptoms, somatization, anxiety, and depression). KEY RESULTS A subset of IBS patients (33%) with increased immune activation in the colon descendens was identified using multivariate analysis and displayed increased gene expression of IL1B (3-fold change), prostaglandin synthase PTGS2 (2.1-fold change), and the G-protein-coupled receptor MRGPRX2 (10.7-fold change). Clinical characteristics in this subgroup were however similar to the rest of the patient cohort. Analysis of rectal biopsies failed to identify such subgroup of "immuno-active" IBS patients in the other patient cohort. CONCLUSION A subset of IBS patients reveals evidence of immune activation in the colon descendens, but not in the rectum; however, gene expression is unrelated to clinical symptoms. To what extent this subgroup might however respond to anti-inflammatory therapy remains to be investigated.
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Affiliation(s)
- Javier Aguilera-Lizarraga
- Laboratory of Intestinal Neuroimmune Interactions, Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium
| | - Morgane V Florens
- Laboratory of Intestinal Neuroimmune Interactions, Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium
| | - Thomas Van Brussel
- Laboratory of Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium.,Laboratory of Translational Genetics, Vesalius Research Center, VIB, Leuven, Belgium
| | - Egbert Clevers
- Laboratory of Brain-Gut Axis Studies, Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium.,Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Lukas Van Oudenhove
- Laboratory of Brain-Gut Axis Studies, Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium
| | - Diether Lambrechts
- Laboratory of Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium.,Laboratory of Translational Genetics, Vesalius Research Center, VIB, Leuven, Belgium
| | - Mira M Wouters
- Laboratory of Intestinal Neuroimmune Interactions, Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium
| | - Guy E Boeckxstaens
- Laboratory of Intestinal Neuroimmune Interactions, Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium
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20
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Blockage of High-Affinity Choline Transporter Increases Visceral Hypersensitivity in Rats with Chronic Stress. Gastroenterol Res Pract 2018; 2018:9252984. [PMID: 29849603 PMCID: PMC5904806 DOI: 10.1155/2018/9252984] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Accepted: 03/14/2018] [Indexed: 12/19/2022] Open
Abstract
Background Visceral hypersensitivity is a common feature of irritable bowel syndrome. Cholinergic system involves in the development of visceral hypersensitivity, and high-affinity choline transporter (CHT1) is of crucial importance in choline uptake system. However, involvement of CHT1 in visceral hypersensitivity remains unknown. The research aimed to study the CHT1 expression in dorsal root ganglions (DRGs) and the role of CHT1 in visceral hypersensitivity. Methods Repetitive water avoidance stress (WAS) was used to induce visceral hypersensitivity in rats. Colorectal distension (CRD) was determined, and the abdominal withdrawal reflex (AWR) and threshold intensity data were recorded to measure the visceral sensitivity. After intraperitoneal injection of hemicholinium-3 (HC-3), the specific inhibitor of CHT1, CRD data were also recorded. The CHT1 expression of DRGs was investigated by Western blotting, immunohistochemistry, and quantitative RT-PCR. Acetylcholine levels in the DRGs were detected by the assay kit. Results Repetitive WAS increased the AWR score of CRD at high distension pressure and decreased the mean threshold of rats. The CHT1 expression and acetylcholine concentration of DRG were significantly increased in WAS rats. After the administration of HC-3, the AWR score in WAS group was significantly increased at higher distension pressure while the threshold intensity was significantly reduced compared to the normal saline group. Acetylcholine concentration was significantly lower than the normal saline rats. Conclusion Our research firstly reports that CHT1 is overexpressed in noninflammatory visceral hypersensitivity, and blockage of CHT1 can enhance the visceral hypersensitivity. CHT1 may play an inhibitory role in visceral hypersensitivity.
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Dothel G, Barbaro MR, Raschi E, Barbara G, De Ponti F. Advancements in drug development for diarrhea-predominant irritable bowel syndrome. Expert Opin Investig Drugs 2018; 27:251-263. [PMID: 29451407 DOI: 10.1080/13543784.2018.1442434] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Diarrhea-predominant irritable bowel syndrome (IBS-D) is a common disorder characterized by a complex pathophysiology hampering optimal targeted drug development. Recent advances in our understanding of key underlying mechanisms prompted novel therapeutics including novel pharmacological approaches. AREAS COVERED This review summarizes the latest advancements in the pipeline of IBS-D drugs focusing on new pharmacological targets, efficacy and safety of medicinal products considering the recent harmonization of regulatory requirements by the FDA and the EMA. EXPERT OPINION The new 5-HT3 receptor antagonist ramosetron appears a promising therapeutic approach devoid of significant adverse events, although it is presently unavailable in Western countries, most likely because of the precautionary approach taken by regulatory agencies with this drug class. New pharmacological concepts on full agonists/antagonists, mixed-receptor activity and novel drug targets may streamline the present drug pipeline along with the adherence on new regulatory guidelines on outcome measures. Eluxadoline can be taken as an example of this paradigm shift. It has now been granted marketing authorization for IBS-D on both sides of the Atlantic, but it is still considered as a second-line agent by the NICE. There is still much work to be done to fully cover clinical needs of patients with IBS-D.
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Affiliation(s)
- Giovanni Dothel
- a Department of Medical and Surgical Sciences , University of Bologna , Bologna , Italy
| | | | - Emanuel Raschi
- a Department of Medical and Surgical Sciences , University of Bologna , Bologna , Italy
| | - Giovanni Barbara
- a Department of Medical and Surgical Sciences , University of Bologna , Bologna , Italy
| | - Fabrizio De Ponti
- a Department of Medical and Surgical Sciences , University of Bologna , Bologna , Italy
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Lazaridis N, Germanidis G. Current insights into the innate immune system dysfunction in irritable bowel syndrome. Ann Gastroenterol 2018; 31:171-187. [PMID: 29507464 PMCID: PMC5825947 DOI: 10.20524/aog.2018.0229] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Accepted: 11/22/2017] [Indexed: 12/12/2022] Open
Abstract
Irritable bowel syndrome (IBS) is a functional bowel disorder associated with abdominal pain and alterations in bowel habits. The presence of IBS greatly impairs patients' quality of life and imposes a high economic burden on the community; thus, there is intense pressure to reveal its elusive pathogenesis. Many etiological mechanisms have been implicated, but the pathophysiology of the syndrome remains unclear. As a result, novel drug development has been slow and no pharmacological intervention is universally accepted. A growing evidence implicates the role of low-grade inflammation and innate immune system dysfunction, although contradictory results have frequently been presented. Mast cells (MC), eosinophils and other key immune cells together with their mediators seem to play an important role, at least in subgroups of IBS patients. Cytokine imbalance in the systematic circulation and in the intestinal mucosa may also characterize IBS presentation. Toll-like receptors and their emerging role in pathogen recognition have also been highlighted recently, as dysregulation has been reported to occur in patients with IBS. This review summarizes the current knowledge regarding the involvement of any immunological alteration in the development of IBS. There is substantial evidence to support innate immune system dysfunction in several IBS phenotypes, but additional studies are required to better clarify the underlying pathogenetic pathways. IBS heterogeneity could potentially be attributed to multiple causes that lead to different disease phenotypes, thus explaining the variability found between study results.
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Affiliation(s)
- Nikolaos Lazaridis
- Gastroenterology Department, AHEPA University General Hospital of Thessaloniki, Thessaloniki, Greece
| | - Georgios Germanidis
- Gastroenterology Department, AHEPA University General Hospital of Thessaloniki, Thessaloniki, Greece
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Mast cell-nerve interaction in the colon of Trypanosoma cruzi-infected individuals with chagasic megacolon. Parasitol Res 2018; 117:1147-1158. [PMID: 29470711 DOI: 10.1007/s00436-018-5792-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Accepted: 01/29/2018] [Indexed: 12/16/2022]
Abstract
Chagas disease is an infection caused by the parasite Trypanosoma cruzi that affects millions of people worldwide and is endemic in Latin America. Megacolon is the most frequent complication of the digestive chronic form and happens due to lesions of the enteric nervous system. The neuronal lesions seem to initiate in the acute phase and persist during the chronic phase, albeit the mechanisms involved in this process are still debated. Among the cells of the immune system possibly involved in this pathological process is the mast cell (MC) due to its well-known role in the bi-directional communication between the immune and nervous systems. Using ultrastructural analysis, we found an increased number of degranulated MCs in close proximity to nerve fibers in infected patients when compared with uninfected controls. We also immunostained MCs for the two pro-inflammatory molecules tryptase and chymase, the first being also important in neuronal death. The number of MCs immunostained for tryptase or chymase was increased in patients with megacolon, whereas increased tryptase staining was additionally observed in patients without megacolon. Moreover, we detected the expression of the tryptase receptor PAR2 in neurons of the enteric nervous system, which correlated to the tryptase staining results. Altogether, the data presented herein point to the participation of MCs on the denervation process that occurs in the development of T. cruzi-induced megacolon.
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Hoffman JM, Sideri A, Ruiz JJ, Stavrakis D, Shih DQ, Turner JR, Pothoulakis C, Karagiannides I. Mesenteric Adipose-derived Stromal Cells From Crohn's Disease Patients Induce Protective Effects in Colonic Epithelial Cells and Mice With Colitis. Cell Mol Gastroenterol Hepatol 2018; 6:1-16. [PMID: 29928668 PMCID: PMC6008259 DOI: 10.1016/j.jcmgh.2018.02.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Accepted: 02/01/2018] [Indexed: 12/14/2022]
Abstract
Mesenteric adipose tissue hyperplasia is a hallmark of Crohn's disease (CD). Recently, we showed that mesenteric adipose-derived stromal cells (ADSCs) from CD, ulcerative colitis, and control patients synthesize and release adipokines in a disease-dependent manner. Here we examined the expression profiles of CD and control patient-derived mesenteric ADSCs and studied the effects of their extracellular mediators on colonocyte signaling in vitro and experimental colitis in vivo. ADSCs were isolated from mesenteric fat of control and CD patients. Microarray profiling and network analysis were performed in ADSCs and human colonocytes treated with conditioned media from cultured ADSCs. Mice with acute colitis received daily injections of conditioned media from patient-derived ADSCs, vehicle, or apolactoferrin. Proliferative responses were evaluated in conditioned media-treated colonocytes and mouse colonic epithelium. Total protein was isolated from cultured colonocytes after treatment with apolactoferrin for Western blot analysis of phosphorylated intracellular signaling kinases. Microarray profiling revealed differential mRNA expression in CD patient-derived ADSCs compared with controls, including lactoferrin. Administration of CD patient-derived medium or apolactoferrin increased colonocyte proliferation compared with controls. Conditioned media from CD patient-derived ADSCs or apolactoferrin attenuated colitis severity in mice and enhanced colonocyte proliferation in vivo. ADSCs from control and CD patients show disease-dependent inflammatory responses and alter colonic epithelial cell signaling in vitro and in vivo. Furthermore, we demonstrate lactoferrin production by adipose tissue, specifically mesenteric ADSCs. We suggest that mesenteric ADSC-derived lactoferrin may mediate protective effects and participate in the pathophysiology of CD by promoting colonocyte proliferation and the resolution of inflammation.
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Key Words
- ADSC, adipose-derived stromal cell
- CD, Crohn’s disease
- DSS, dextran sodium sulfate
- IBD, inflammatory bowel disease
- IBS, irritable bowel syndrome
- IL, interleukin
- Inflammatory Bowel Disease
- Intestinal Epithelium
- Mesenteric Adipose Tissue
- PCR, polymerase chain reaction
- Preadipocytes
- RT, reverse-transcriptase
- TNBS, trinitrobenzenesulfonic acid
- VEGF, vascular endothelial growth factor
- i.c., intracolonic
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Affiliation(s)
- Jill M. Hoffman
- Center for Inflammatory Bowel Diseases, Division of Digestive Diseases, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California,Jill Hoffman, PhD, Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine, University of California at Los Angeles, 675 Charles E. Young Drive South, MRL Building 1220, Los Angeles, California 90095. fax: (310) 825-3542
| | - Aristea Sideri
- Center for Inflammatory Bowel Diseases, Division of Digestive Diseases, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California
| | - Jonathan J. Ruiz
- Center for Inflammatory Bowel Diseases, Division of Digestive Diseases, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California
| | - Dimitris Stavrakis
- Center for Inflammatory Bowel Diseases, Division of Digestive Diseases, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California
| | - David Q. Shih
- Inflammatory Bowel and Immunobiology Research Institute, Cedars Sinai Medical Center, Los Angeles, California
| | - Jerrold R. Turner
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts,Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Charalabos Pothoulakis
- Center for Inflammatory Bowel Diseases, Division of Digestive Diseases, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California
| | - Iordanes Karagiannides
- Center for Inflammatory Bowel Diseases, Division of Digestive Diseases, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California,Correspondence Address correspondence to: Iordanes Karagiannides, PhD, Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine, University of California at Los Angeles, 675 Charles E. Young Drive South, MRL Building 1220, Los Angeles, California 90095. fax: (310) 825-3542.
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25
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Bashashati M, Moossavi S, Cremon C, Barbaro MR, Moraveji S, Talmon G, Rezaei N, Hughes PA, Bian ZX, Choi CH, Lee OY, Coëffier M, Chang L, Ohman L, Schmulson MJ, McCallum RW, Simren M, Sharkey KA, Barbara G. Colonic immune cells in irritable bowel syndrome: A systematic review and meta-analysis. Neurogastroenterol Motil 2018; 30. [PMID: 28851005 DOI: 10.1111/nmo.13192] [Citation(s) in RCA: 115] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Accepted: 07/26/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Increases in mucosal immune cells have frequently been observed in irritable bowel syndrome (IBS) patients. However, this finding is not completely consistent between studies, possibly due to a combination of methodological variability, population differences and small sample sizes. We performed a meta-analysis of case-control studies that compared immune cell counts in colonic biopsies of IBS patients and controls. METHODS PubMed and Embase were searched in February 2017. Results were pooled using standardized mean difference (SMD) and were considered significant when zero was not within the 95% confidence interval (CI). Heterogeneity was assessed based on I2 statistics where I2 ≤ 50% and I2 > 50% indicated fixed and random effect models, respectively. KEY RESULTS Twenty-two studies on 706 IBS patients and 401 controls were included. Mast cells were increased in the rectosigmoid (SMD: 0.38 [95% CI: 0.06-0.71]; P = .02) and descending colon (SMD: 1.69 [95% CI: 0.65-2.73]; P = .001) of IBS patients. Increased mast cells were observed in both constipation (IBS-C) and diarrhea predominant IBS (IBS-D). CD3+ T cells were increased in the rectosigmoid (SMD: 0.53 [95% CI: 0.21-0.85]; P = .001) and the descending colon of the IBS patients (SMD: 0.79, 95% CI [0.28-1.30]; P = .002). This was possibly in relation to higher CD4+ T cells in IBS (SMD: 0.33 [95% CI: 0.01-0.65]; P = .04) as there were no differences in CD8+ T cells. CONCLUSIONS & INFERENCES Mast cells and CD3+ T cells are increased in colonic biopsies of patients with IBS vs non-inflamed controls. These changes are segmental and sometimes IBS-subtype dependent. The diagnostic value of the quantification of colonic mucosal cells in IBS requires further investigation.
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Affiliation(s)
- M Bashashati
- Division of Gastroenterology, Department of Internal Medicine, Texas Tech University Health Sciences Center/Paul L. Foster School of Medicine, El Paso, TX, USA
| | - S Moossavi
- Digestive Oncology Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
- Department of Medical Microbiology, University of Manitoba, Winnipeg, MB, Canada
| | - C Cremon
- Department of Medical and Surgical Sciences, Centre for Applied Biomedical Research, University of Bologna, Bologna, Italy
| | - M R Barbaro
- Department of Medical and Surgical Sciences, Centre for Applied Biomedical Research, University of Bologna, Bologna, Italy
| | - S Moraveji
- Division of Gastroenterology, Department of Internal Medicine, Texas Tech University Health Sciences Center/Paul L. Foster School of Medicine, El Paso, TX, USA
| | - G Talmon
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
- Fred and Pamela Buffet Cancer Center, Omaha, NE, USA
| | - N Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - P A Hughes
- Centre for Nutritional and Gastrointestinal Diseases, Department of Medicine, University of Adelaide and South Australian Health Medical Health Research Institute, Adelaide, SA, Australia
| | - Z X Bian
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China
| | - C H Choi
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - O Y Lee
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
| | - M Coëffier
- Normandie Univ, INSERM unit 1073 "Nutrition, inflammation and brain-gut axis", Institute for Research and Innovation in Biomedicine, Rouen Medical University and Rouen University Hospital, Rouen, France
| | - L Chang
- G Oppenheimer Center of Neurobiology of Stress and Resilience, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - L Ohman
- Departments of Internal Medicine and Clinical Nutrition and Microbiology and Immunology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - M J Schmulson
- Laboratorio de Hígado, Páncreas y Motilidad (HIPAM), Unidad de Investigación en Medicina Experimental, Facultad de Medicina-Universidad Nacional Autónoma de México (UNAM), Hospital General de México, Mexico City, Mexico
| | - R W McCallum
- Division of Gastroenterology, Department of Internal Medicine, Texas Tech University Health Sciences Center/Paul L. Foster School of Medicine, El Paso, TX, USA
| | - M Simren
- Department of Internal Medicine & Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Center for Functional GI and Motility Disorders, University of North Carolina, Chapel Hill, NC, USA
| | - K A Sharkey
- Hotchkiss Brain Institute and Snyder Institute for Chronic Diseases, Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada
| | - G Barbara
- Department of Medical and Surgical Sciences, Centre for Applied Biomedical Research, University of Bologna, Bologna, Italy
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Kaji I, Akiba Y, Furuyama T, Adelson DW, Iwamoto K, Watanabe M, Kuwahara A, Kaunitz JD. Free fatty acid receptor 3 activation suppresses neurogenic motility in rat proximal colon. Neurogastroenterol Motil 2018; 30:10.1111/nmo.13157. [PMID: 28714277 PMCID: PMC5739952 DOI: 10.1111/nmo.13157] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Accepted: 06/14/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND Short-chain fatty acids (SCFA) are microbial fermentation products absorbed by the colon. We recently reported that activation of the SCFA receptor termed free fatty acid receptor 3 (FFA3), expressed on cholinergic nerves, suppresses nicotinic acetylcholine receptor (nAChR)-mediated transepithelial anion secretion. This study aimed to clarify how activation of neurally expressed FFA3 affects colonic motor function. METHODS FFA3-expressing myenteric neurons were identified by immunostaining; contractions of isolated circular muscle strips obtained from rat proximal colon were measured by isometric transducers. The effect of FFA3 agonists on defecation in vivo was examined in an exogenous serotonin-induced defecation model. KEY RESULTS FFA3 immunoreactivity was located in nitrergic and cholinergic neurons in the myenteric plexus. In isolated circular muscle strips without mucosa and submucosa, the addition of nicotine (10 μM) or serotonin transiently relaxed the muscle through nitrergic neurons, whereas high concentrations of nicotine (100 μM) induced large-amplitude contractions that were mediated by cholinergic neurons. Pretreatment with FFA3 agonists inhibited nicotine- or serotonin-induced motility changes but had no effect on bethanechol-induced direct muscle contractions. The Gi/o inhibitor pertussis toxin reversed the inhibitory effect of an FFA3 agonist AR420626 on nicotine-evoked contractions, suggesting that FFA3 activation suppresses nAChR-mediated neural activity in myenteric neurons, consistent with an FFA3-mediated antisecretory effect. In conscious rats, exogenous serotonin increased the volume of fecal output, compared with the vehicle- or AR420626-treated groups. Pretreatment with AR420626 significantly suppressed serotonin-induced fecal output. CONCLUSION AND INFERENCES FFA3 is a promising target for the treatment of neurogenic diarrheal disorders by suppressing nAChR-mediated neural pathways.
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Affiliation(s)
- Izumi Kaji
- Department of Medicine, University of California Los Angeles,Greater Los Angeles VA Healthcare System
| | - Yasutada Akiba
- Department of Medicine, University of California Los Angeles,Greater Los Angeles VA Healthcare System
| | - Takafumi Furuyama
- Neuroethology & Bioengineering, Graduate School of Life & Medical Sciences, Doshisha University,Japan Society for the Promotion of Science
| | | | - Kenichi Iwamoto
- Graduate School of Integrated Pharmaceutical and Nutritional Sciences, University of Shizuoka
| | - Masahiko Watanabe
- Department of Anatomy, Graduate School of Medicine, Hokkaido University
| | - Atsukazu Kuwahara
- Graduate School of Integrated Pharmaceutical and Nutritional Sciences, University of Shizuoka
| | - Jonathan D. Kaunitz
- Department of Medicine, University of California Los Angeles,Department of Surgery, University of California Los Angeles,Greater Los Angeles VA Healthcare System
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McIntosh K, Reed DE, Schneider T, Dang F, Keshteli AH, De Palma G, Madsen K, Bercik P, Vanner S. FODMAPs alter symptoms and the metabolome of patients with IBS: a randomised controlled trial. Gut 2017; 66:1241-1251. [PMID: 26976734 DOI: 10.1136/gutjnl-2015-311339] [Citation(s) in RCA: 317] [Impact Index Per Article: 39.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Revised: 02/04/2016] [Accepted: 02/17/2016] [Indexed: 12/12/2022]
Abstract
OBJECTIVE To gain mechanistic insights, we compared effects of low fermentable oligosaccharides, disaccharides and monosaccharides and polyols (FODMAP) and high FODMAP diets on symptoms, the metabolome and the microbiome of patients with IBS. DESIGN We performed a controlled, single blind study of patients with IBS (Rome III criteria) randomised to a low (n=20) or high (n=20) FODMAP diet for 3 weeks. Symptoms were assessed using the IBS symptom severity scoring (IBS-SSS). The metabolome was evaluated using the lactulose breath test (LBT) and metabolic profiling in urine using mass spectrometry. Stool microbiota composition was analysed by 16S rRNA gene profiling. RESULTS Thirty-seven patients (19 low FODMAP; 18 high FODMAP) completed the 3-week diet. The IBS-SSS was reduced in the low FODMAP diet group (p<0.001) but not the high FODMAP group. LBTs showed a minor decrease in H2 production in the low FODMAP compared with the high FODMAP group. Metabolic profiling of urine showed groups of patients with IBS differed significantly after the diet (p<0.01), with three metabolites (histamine, p-hydroxybenzoic acid, azelaic acid) being primarily responsible for discrimination between the two groups. Histamine, a measure of immune activation, was reduced eightfold in the low FODMAP group (p<0.05). Low FODMAP diet increased Actinobacteria richness and diversity, and high FODMAP diet decreased the relative abundance of bacteria involved in gas consumption. CONCLUSIONS IBS symptoms are linked to FODMAP content and associated with alterations in the metabolome. In subsets of patients, FODMAPs modulate histamine levels and the microbiota, both of which could alter symptoms. TRIAL REGISTRATION NUMBER NCT01829932.
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Affiliation(s)
- Keith McIntosh
- GI Diseases Research Unit, Queen's University, Kingston General Hospital, Kingston, Ontario, Canada
- St. Joseph's Hospital, Western University, London, Ontario, Canada
| | - David E Reed
- GI Diseases Research Unit, Queen's University, Kingston General Hospital, Kingston, Ontario, Canada
| | - Theresa Schneider
- GI Diseases Research Unit, Queen's University, Kingston General Hospital, Kingston, Ontario, Canada
| | - Frances Dang
- GI Diseases Research Unit, Queen's University, Kingston General Hospital, Kingston, Ontario, Canada
| | | | - Giada De Palma
- Farmcombe Institute, McMaster University, Hamilton, Ontario, Canada
| | - Karen Madsen
- University of Alberta, Edmonton, Alberta, Canada
| | - Premysl Bercik
- Farmcombe Institute, McMaster University, Hamilton, Ontario, Canada
| | - Stephen Vanner
- GI Diseases Research Unit, Queen's University, Kingston General Hospital, Kingston, Ontario, Canada
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28
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Purinergic Signalling in the Gut. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 891:91-112. [PMID: 27379638 DOI: 10.1007/978-3-319-27592-5_10] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The article will begin with the discovery of purinergic inhibitory neuromuscular transmission in the 1960s/1970s, the proposal for purinergic cotransmission in 1976 and the recognition that sympathetic nerves release adenosine 5'-triphosphate (ATP), noradrenaline and neuropeptide Y, while non-adrenergic, non-cholinergic inhibitory nerve cotransmitters are ATP, nitric oxide and vasoactive intestinal polypeptide in variable proportions in different regions of the gut. Later, purinergic synaptic transmission in the myenteric and submucosal plexuses was established and purinergic receptors expressed by both glial and interstitial cells. The focus will then be on purinergic mechanosensory transduction involving release of ATP from mucosal epithelial cells during distension to activate P2X3 receptors on submucosal sensory nerve endings. The responses of low threshold fibres mediate enteric reflex activity via intrinsic sensory nerves, while high threshold fibres initiate pain via extrinsic sensory nerves. Finally, the involvement of purinergic signalling in an animal model of colitis will be presented, showing that during distension there is increased ATP release, increased P2X3 receptor expression on calcitonin gene-related peptide-labelled sensory neurons and increased sensory nerve activity.
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29
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Guarino MP, Barbara G, Cicenia A, Altomare A, Barbaro MR, Cocca S, Scirocco A, Cremon C, Emerenziani S, Stanghellini V, Cicala M, Severi C. Supernatants of irritable bowel syndrome mucosal biopsies impair human colonic smooth muscle contractility. Neurogastroenterol Motil 2017; 29. [PMID: 27619727 DOI: 10.1111/nmo.12928] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2015] [Accepted: 07/27/2016] [Indexed: 12/20/2022]
Abstract
BACKGROUND Changes in intestinal motility are likely to contribute to irritable bowel syndrome (IBS) pathophysiology. The aim of the study was to investigate the effects of IBS mucosal supernatants on human colonic muscle contractility. METHODS Supernatants were obtained from biopsies of 18 IBS patients-nine with constipation (IBS-C) and nine with diarrhea-predominant IBS (IBS-D)-and nine asymptomatic subjects, used as controls. Colonic circular smooth muscle strips or isolated cells (SMC) were exposed to control or IBS supernatants. Spontaneous phasic contractions on strips and morphofunctional parameters on cells were evaluated in basal conditions and in response to acetylcholine (Ach). Incubation with IBS supernatants was also conducted in the presence of antagonists and inhibitors (namely histamine, protease and prostaglandin antagonists, nuclear factor-kappa B inhibitor, catalase, NADPH oxidase inhibitor, and the cAMP- and/or cGMP-cyclase inhibitors). KEY RESULTS Exposure to IBS-C and IBS-D supernatants induced a significant reduction in basal tone and Ach-elicited contraction of muscle strips and a significant shortening and impairment of Ach contraction of SMCs. The NADPH oxidase inhibitor prevented the effect of supernatants, while the protease antagonist only IBS-C effect. No effect was observed with the other antagonists and inhibitors. Dilution of IBS-D supernatants partially restored the effects only on SMCs, whereas dilution of IBS-C supernatants significantly reverted the effects on muscle strips and Ach-elicited response on SMC. CONCLUSIONS & INFERENCES Supernatants from mucosal biopsies of IBS patients reduce colonic contractility. The observed impairment was concentration dependent, likely occurring through intracellular oxidative stress damage, involving different neuromotor mechanisms depending on the IBS subtype.
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Affiliation(s)
- M P Guarino
- Gastroenterology Department, University Campus Bio-medico, Rome, Italy
| | - G Barbara
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - A Cicenia
- Department of Internal Medicine and Medical Specialties, University Sapienza, Rome, Italy
| | - A Altomare
- Gastroenterology Department, University Campus Bio-medico, Rome, Italy
| | - M R Barbaro
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - S Cocca
- Gastroenterology Department, University Campus Bio-medico, Rome, Italy
| | - A Scirocco
- Department of Internal Medicine and Medical Specialties, University Sapienza, Rome, Italy
| | - C Cremon
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - S Emerenziani
- Gastroenterology Department, University Campus Bio-medico, Rome, Italy
| | - V Stanghellini
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - M Cicala
- Gastroenterology Department, University Campus Bio-medico, Rome, Italy
| | - C Severi
- Department of Internal Medicine and Medical Specialties, University Sapienza, Rome, Italy
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30
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Lee KN, Lee OY. The Role of Mast Cells in Irritable Bowel Syndrome. Gastroenterol Res Pract 2016; 2016:2031480. [PMID: 28115927 PMCID: PMC5225338 DOI: 10.1155/2016/2031480] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2016] [Revised: 11/18/2016] [Accepted: 12/05/2016] [Indexed: 12/20/2022] Open
Abstract
Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders, but its treatment is unsatisfactory as its pathophysiology is multifactorial. The putative factors of IBS pathophysiology are visceral hypersensitivity and intestinal dysmotility, also including psychological factors, dysregulated gut-brain axis, intestinal microbiota alterations, impaired intestinal permeability, and mucosal immune alterations. Recently, mucosal immune alterations have received much attention with the role of mast cells in IBS. Mast cells are abundant in the intestines and function as intestinal gatekeepers at the interface between the luminal environment in the intestine and the internal milieu under the intestinal epithelium. As a gatekeeper at the interface, mast cells communicate with the adjacent cells such as epithelial, neuronal, and other immune cells throughout the mediators released when they themselves are activated. Many studies have suggested that mast cells play a role in the pathophysiology of IBS. This review will focus on studies of the role of mast cell in IBS and the limitations of studies and will also consider future directions.
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Affiliation(s)
- Kang Nyeong Lee
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea
| | - Oh Young Lee
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea
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31
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Piscaglia AC, Laterza L, Cesario V, Gerardi V, Landi R, Lopetuso LR, Calò G, Fabbretti G, Brisigotti M, Stefanelli ML, Gasbarrini A. Nodular lymphoid hyperplasia: A marker of low-grade inflammation in irritable bowel syndrome? World J Gastroenterol 2016; 22:10198-10209. [PMID: 28028368 PMCID: PMC5155179 DOI: 10.3748/wjg.v22.i46.10198] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2016] [Revised: 10/25/2016] [Accepted: 11/16/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the prevalence of nodular lymphoid hyperplasia (NLH) in adult patients undergoing colonoscopy and its association with known diseases.
METHODS We selected all cases showing NLH at colonoscopy in a three-year timeframe, and stratified them into symptomatic patients with irritable bowel syndrome (IBS)-type symptoms or suspected inflammatory bowel disease (IBD), and asymptomatic individuals undergoing endoscopy for colorectal cancer screening. Data collection included medical history and final diagnosis. As controls, we considered all colonoscopies performed for the aforementioned indications during the same period.
RESULTS One thousand and one hundred fifty colonoscopies were selected. NLH was rare in asymptomatic individuals (only 3%), while it was significantly more prevalent in symptomatic cases (32%). Among organic conditions associated with NLH, the most frequent was IBD, followed by infections and diverticular disease. Interestingly, 31% of IBS patients presented diffuse colonic NLH. NLH cases shared some distinctive clinical features among IBS patients: they were younger, more often female, and had a higher frequency of abdominal pain, bloating, diarrhoea, unspecific inflammation, self-reported lactose intolerance and metal contact dermatitis.
CONCLUSION About 1/3 of patients with IBS-type symptoms or suspected IBD presented diffuse colonic NLH, which could be a marker of low-grade inflammation in a conspicuous subset of IBS patients.
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Guarino MPL, Cicala M, Putignani L, Severi C. Gastrointestinal neuromuscular apparatus: An underestimated target of gut microbiota. World J Gastroenterol 2016; 22:9871-9879. [PMID: 28018095 PMCID: PMC5143755 DOI: 10.3748/wjg.v22.i45.9871] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Revised: 10/13/2016] [Accepted: 11/16/2016] [Indexed: 02/06/2023] Open
Abstract
Over the last few years, the importance of the resident intestinal microbiota in the pathogenesis of several gastro-intestinal diseases has been largely investigated. Growing evidence suggest that microbiota can influence gastro-intestinal motility. The current working hypothesis is that dysbiosis-driven mucosal alterations induce the production of several inflammatory/immune mediators which affect gut neuro-muscular functions. Besides these indirect mucosal-mediated effects, the present review highlights that recent evidence suggests that microbiota can directly affect enteric nerves and smooth muscle cells functions through its metabolic products or bacterial molecular components translocated from the intestinal lumen. Toll-like receptors, the bacterial recognition receptors, are expressed both on enteric nerves and smooth muscle and are emerging as potential mediators between microbiota and the enteric neuromuscular apparatus. Furthermore, the ongoing studies on probiotics support the hypothesis that the neuromuscular apparatus may represent a target of intervention, thus opening new physiopathological and therapeutic scenarios.
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Abstract
Amyotrophic lateral sclerosis is a complex neurodegenerative disease. Limitations in animal models have impeded progress in studying disease pathology and potential drug discovery. Here, we will review recent advances in the development of stem cell models for the study of ALS. Additionally, we will discuss the progress toward therapeutic development derived from these stem cell based assays.
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Affiliation(s)
- A Sophie de Boer
- a The Howard Hughes Medical Institute; The Harvard Stem Cell Institute; The Stanley Center for Psychiatric Research ; The Department of Stem Cell and Regenerative Biology ; Harvard University ; Cambridge , MA USA.,b Department of Anatomy & Embryology ; Leiden University Medical Center ; The Netherlands
| | - Kevin Eggan
- a The Howard Hughes Medical Institute; The Harvard Stem Cell Institute; The Stanley Center for Psychiatric Research ; The Department of Stem Cell and Regenerative Biology ; Harvard University ; Cambridge , MA USA
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34
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Martin-Viñas JJ, Quigley EMM. Immune response in irritable bowel syndrome: A systematic review of systemic and mucosal inflammatory mediators. J Dig Dis 2016; 17:572-581. [PMID: 27426409 DOI: 10.1111/1751-2980.12379] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Revised: 06/21/2016] [Accepted: 07/04/2016] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To systematically review the available data on cytokine and immune cells in the peripheral blood and mucosal biopsy samples from patients with irritable bowel syndrome (IBS). METHODS From a review of the literature, data on cytokines and immune cells that had been assayed in at least three independent studies were collated and trends examined. RESULTS Levels of interleukin (IL)-10 tended to be decreased and those of IL-6, IL-8, tumor necrosis factor-α and IL-1β increased in the systemic circulation in IBS, while in the mucosa, IL-10 was decreased and IL-8, mast cells, enterochromaffin cells and CD3+ T lymphocytes were increased. However, these findings were not consistent across all studies and, in some instances, were limited to certain IBS sub-populations. CONCLUSIONS The interpretation of this literature is limited by several factors, such as the intrinsic heterogeneity of IBS and a lack of standardization in study design. While a number of intriguing immunological observations have been made in IBS, more work is needed before a compelling case can be made for a role for immune-mediated events in the etiology of IBS.
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Affiliation(s)
- Juan J Martin-Viñas
- Lynda K and David M Underwood Center for Digestive Disorders, Division of Gastroenterology and Hepatology, Houston Methodist Hospital and Weill Cornell Medical College, Houston, Texas, USA
| | - Eamonn M M Quigley
- Lynda K and David M Underwood Center for Digestive Disorders, Division of Gastroenterology and Hepatology, Houston Methodist Hospital and Weill Cornell Medical College, Houston, Texas, USA
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Coquenlorge S, Van Landeghem L, Jaulin J, Cenac N, Vergnolle N, Duchalais E, Neunlist M, Rolli-Derkinderen M. The arachidonic acid metabolite 11β-ProstaglandinF2α controls intestinal epithelial healing: deficiency in patients with Crohn's disease. Sci Rep 2016; 6:25203. [PMID: 27140063 PMCID: PMC4853710 DOI: 10.1038/srep25203] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Accepted: 03/15/2016] [Indexed: 02/07/2023] Open
Abstract
In healthy gut enteric glial cells (EGC) are essential to intestinal epithelial barrier (IEB) functions. In Crohn's Disease (CD), both EGC phenotype and IEB functions are altered, but putative involvement of EGC in CD pathogenesis remains unknown and study of human EGC are lacking. EGC isolated from CD and control patients showed similar expression of glial markers and EGC-derived soluble factors (IL6, TGF-β, proEGF, GSH) but CD EGC failed to increase IEB resistance and healing. Lipid profiling showed that CD EGC produced decreased amounts of 15-HETE, 18-HEPE, 15dPGJ2 and 11βPGF2α as compared to healthy EGC. They also had reduced expression of the L-PGDS and AKR1C3 enzymes. Produced by healthy EGC, the 11βPGF2 activated PPARγ receptor of intestinal epithelial cells to induce cell spreading and IEB wound repair. In addition to this novel healing mechanism our data show that CD EGC presented impaired ability to promote IEB functions through defect in L-PGDS-AKR1C3-11βPGF2α dependent pathway.
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Affiliation(s)
- Sabrina Coquenlorge
- INSERM, UMR913, Nantes, F-44093, France
- Université Nantes, Nantes, F-44093, France
- Institut des Maladies de l’Appareil Digestif, CHU Nantes, Hôpital Hôtel-Dieu, Nantes, F-44093, France
- Centre de Recherche en Nutrition Humaine, Nantes, F-44093, France
| | - Laurianne Van Landeghem
- INSERM, UMR913, Nantes, F-44093, France
- Université Nantes, Nantes, F-44093, France
- Institut des Maladies de l’Appareil Digestif, CHU Nantes, Hôpital Hôtel-Dieu, Nantes, F-44093, France
- Centre de Recherche en Nutrition Humaine, Nantes, F-44093, France
| | - Julie Jaulin
- INSERM, UMR913, Nantes, F-44093, France
- Université Nantes, Nantes, F-44093, France
- Institut des Maladies de l’Appareil Digestif, CHU Nantes, Hôpital Hôtel-Dieu, Nantes, F-44093, France
- Centre de Recherche en Nutrition Humaine, Nantes, F-44093, France
| | - Nicolas Cenac
- Centre de Pathophysiologie, CHU Purpan, Toulouse, France
- INSERM UMR-1043 CNRS UMR-5282, Toulouse, France
| | - Nathalie Vergnolle
- Centre de Pathophysiologie, CHU Purpan, Toulouse, France
- INSERM UMR-1043 CNRS UMR-5282, Toulouse, France
| | - Emilie Duchalais
- INSERM, UMR913, Nantes, F-44093, France
- Université Nantes, Nantes, F-44093, France
- Institut des Maladies de l’Appareil Digestif, CHU Nantes, Hôpital Hôtel-Dieu, Nantes, F-44093, France
- Centre de Recherche en Nutrition Humaine, Nantes, F-44093, France
| | - Michel Neunlist
- INSERM, UMR913, Nantes, F-44093, France
- Université Nantes, Nantes, F-44093, France
- Institut des Maladies de l’Appareil Digestif, CHU Nantes, Hôpital Hôtel-Dieu, Nantes, F-44093, France
- Centre de Recherche en Nutrition Humaine, Nantes, F-44093, France
| | - Malvyne Rolli-Derkinderen
- INSERM, UMR913, Nantes, F-44093, France
- Université Nantes, Nantes, F-44093, France
- Institut des Maladies de l’Appareil Digestif, CHU Nantes, Hôpital Hôtel-Dieu, Nantes, F-44093, France
- Centre de Recherche en Nutrition Humaine, Nantes, F-44093, France
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Halliez MCM, Motta JP, Feener TD, Guérin G, LeGoff L, François A, Colasse E, Favennec L, Gargala G, Lapointe TK, Altier C, Buret AG. Giardia duodenalis induces paracellular bacterial translocation and causes postinfectious visceral hypersensitivity. Am J Physiol Gastrointest Liver Physiol 2016; 310:G574-85. [PMID: 26744469 PMCID: PMC4836132 DOI: 10.1152/ajpgi.00144.2015] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2015] [Accepted: 01/04/2016] [Indexed: 02/07/2023]
Abstract
Irritable bowel syndrome (IBS) is the most frequent functional gastrointestinal disorder. It is characterized by abdominal hypersensitivity, leading to discomfort and pain, as well as altered bowel habits. While it is common for IBS to develop following the resolution of infectious gastroenteritis [then termed postinfectious IBS (PI-IBS)], the mechanisms remain incompletely understood. Giardia duodenalis is a cosmopolitan water-borne enteropathogen that causes intestinal malabsorption, diarrhea, and postinfectious complications. Cause-and-effect studies using a human enteropathogen to help investigate the mechanisms of PI-IBS are sorely lacking. In an attempt to establish causality between giardiasis and postinfectious visceral hypersensitivity, this study describes a new model of PI-IBS in neonatal rats infected with G. duodenalis At 50 days postinfection with G. duodenalis (assemblage A or B), long after the parasite was cleared, rats developed visceral hypersensitivity to luminal balloon distension in the jejunum and rectum, activation of the nociceptive signaling pathway (increased c-fos expression), histological modifications (villus atrophy and crypt hyperplasia), and proliferation of mucosal intraepithelial lymphocytes and mast cells in the jejunum, but not in the rectum. G. duodenalis infection also disrupted the intestinal barrier, in vivo and in vitro, which in turn promoted the translocation of commensal bacteria. Giardia-induced bacterial paracellular translocation in vitro correlated with degradation of the tight junction proteins occludin and claudin-4. The extensive observations associated with gut hypersensitivity described here demonstrate that, indeed, in this new model of postgiardiasis IBS, alterations to the gut mucosa and c-fos are consistent with those associated with PI-IBS and, hence, offer avenues for new mechanistic research in the field.
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Affiliation(s)
- Marie C. M. Halliez
- 1Protozooses transmises par l'alimentation, Rouen University Hospital, University of Rouen and University of Reims Champagne-Ardennes, and Institute for Biomedical Research, Rouen and Reims, France; ,2Department of Biological Sciences, Inflammation Research Network, Host-Parasite Interaction NSERC-CREATE, University of Calgary, Calgary, Alberta, Canada;
| | - Jean-Paul Motta
- 2Department of Biological Sciences, Inflammation Research Network, Host-Parasite Interaction NSERC-CREATE, University of Calgary, Calgary, Alberta, Canada;
| | - Troy D. Feener
- 2Department of Biological Sciences, Inflammation Research Network, Host-Parasite Interaction NSERC-CREATE, University of Calgary, Calgary, Alberta, Canada;
| | - Gaetan Guérin
- 1Protozooses transmises par l'alimentation, Rouen University Hospital, University of Rouen and University of Reims Champagne-Ardennes, and Institute for Biomedical Research, Rouen and Reims, France;
| | - Laetitia LeGoff
- 1Protozooses transmises par l'alimentation, Rouen University Hospital, University of Rouen and University of Reims Champagne-Ardennes, and Institute for Biomedical Research, Rouen and Reims, France;
| | - Arnaud François
- 1Protozooses transmises par l'alimentation, Rouen University Hospital, University of Rouen and University of Reims Champagne-Ardennes, and Institute for Biomedical Research, Rouen and Reims, France; ,3Service d'Anatomie et de Cytologie Pathologique CHU Rouen, Rouen cedex, France; and
| | - Elodie Colasse
- 3Service d'Anatomie et de Cytologie Pathologique CHU Rouen, Rouen cedex, France; and
| | - Loic Favennec
- 1Protozooses transmises par l'alimentation, Rouen University Hospital, University of Rouen and University of Reims Champagne-Ardennes, and Institute for Biomedical Research, Rouen and Reims, France;
| | - Gilles Gargala
- 1Protozooses transmises par l'alimentation, Rouen University Hospital, University of Rouen and University of Reims Champagne-Ardennes, and Institute for Biomedical Research, Rouen and Reims, France;
| | - Tamia K. Lapointe
- 4Snyder Institute for Chronic Diseases, Inflammation Research Network, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada
| | - Christophe Altier
- 4Snyder Institute for Chronic Diseases, Inflammation Research Network, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada
| | - André G. Buret
- 2Department of Biological Sciences, Inflammation Research Network, Host-Parasite Interaction NSERC-CREATE, University of Calgary, Calgary, Alberta, Canada;
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Zhang L, Song J, Hou X. Mast Cells and Irritable Bowel Syndrome: From the Bench to the Bedside. J Neurogastroenterol Motil 2016; 22:181-92. [PMID: 26755686 PMCID: PMC4819856 DOI: 10.5056/jnm15137] [Citation(s) in RCA: 85] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Revised: 12/07/2015] [Accepted: 12/26/2015] [Indexed: 12/11/2022] Open
Abstract
Irritable bowel syndrome (IBS) is traditionally defined as a functional disorder since it lacks demonstrable pathological abnormalities. However, in recent years, low grade inflammatory infiltration, often rich in mast cells, in both the small and large bowel, has been observed in some patients with IBS. The close association of mast cells with major intestinal functions, such as epithelial secretion and permeability, neuroimmune interactions, visceral sensation, and peristalsis, makes researchers and gastroenterologists to focus attention on the key roles of mast cells in the pathogenesis of IBS. Numerous studies have been carried out to identify the mechanisms in the development, infiltration, activation, and degranulation of intestinal mast cells, as well as the actions of mast cells in the processes of mucosal barrier disruption, mucosal immune dysregulation, visceral hypersensitivity, dysmotility, and local and central stress in IBS. Moreover, therapies targeting mast cells, such as mast cell stabilizers (cromoglycate and ketotifen) and antagonists of histamine and serotonin receptors, have been tried in IBS patients, and have partially exhibited considerable efficacy. This review focuses on recent advances in the role of mast cells in IBS, with particular emphasis on bridging experimental data with clinical therapeutics for IBS patients.
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Affiliation(s)
- Lei Zhang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jun Song
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaohua Hou
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Barbara G, Cremon C, Annese V, Basilisco G, Bazzoli F, Bellini M, Benedetti A, Benini L, Bossa F, Buldrini P, Cicala M, Cuomo R, Germanà B, Molteni P, Neri M, Rodi M, Saggioro A, Scribano ML, Vecchi M, Zoli G, Corinaldesi R, Stanghellini V. Randomised controlled trial of mesalazine in IBS. Gut 2016; 65:82-90. [PMID: 25533646 PMCID: PMC4717362 DOI: 10.1136/gutjnl-2014-308188] [Citation(s) in RCA: 81] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2014] [Accepted: 11/20/2014] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Low-grade intestinal inflammation plays a role in the pathophysiology of IBS. In this trial, we aimed at evaluating the efficacy and safety of mesalazine in patients with IBS. DESIGN We conducted a phase 3, multicentre, tertiary setting, randomised, double-blind, placebo-controlled trial in patients with Rome III confirmed IBS. Patients were randomly assigned to either mesalazine, 800 mg, or placebo, three times daily for 12 weeks, and were followed for additional 12 weeks. The primary efficacy endpoint was satisfactory relief of abdominal pain/discomfort for at least half of the weeks of the treatment period. The key secondary endpoint was satisfactory relief of overall IBS symptoms. Supportive analyses were also performed classifying as responders patients with a percentage of affirmative answers of at least 75% or >75% of time. RESULTS A total of 185 patients with IBS were enrolled from 21 centres. For the primary endpoint, the responder patients were 68.6% in the mesalazine group versus 67.4% in the placebo group (p=0.870; 95% CI -12.8 to 15.1). In explorative analyses, with the 75% rule or >75% rule, the percentage of responders was greater in the mesalazine group with a difference over placebo of 11.6% (p=0.115; 95% CI -2.7% to 26.0%) and 5.9% (p=0.404; 95% CI -7.8% to 19.4%), respectively, although these differences were not significant. For the key secondary endpoint, overall symptoms improved in the mesalazine group and reached a significant difference of 15.1% versus placebo (p=0.032; 95% CI 1.5% to 28.7%) with the >75% rule. CONCLUSIONS Mesalazine treatment was not superior than placebo on the study primary endpoint. However, a subgroup of patients with IBS showed a sustained therapy response and benefits from a mesalazine therapy. TRIAL REGISTRATION NUMBER ClincialTrials.gov number, NCT00626288.
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Affiliation(s)
- Giovanni Barbara
- Department of Medical and Surgical Sciences, Centre for Applied Biomedical Research, University of Bologna, Bologna, Italy
| | - Cesare Cremon
- Department of Medical and Surgical Sciences, Centre for Applied Biomedical Research, University of Bologna, Bologna, Italy
| | - Vito Annese
- Division of Gastroenterology SOD2, University Hospital Careggi, Florence, Italy
| | - Guido Basilisco
- Gastroenterology Unit, Ospedale Maggiore, Policlinico, Milan, Italy
| | - Franco Bazzoli
- Gastroenterology Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Massimo Bellini
- Gastroenterology Unit, Department of Gastroenterology, University of Pisa, Pisa, Italy
| | - Antonio Benedetti
- Department of Gastroenterology and Hepatology, Università Politecnica delle Marche, Ancona, Italy
| | - Luigi Benini
- Gastroenterology Unit, University of Verona, Verona, Italy
| | - Fabrizio Bossa
- Division of Gastroenterology, Casa Sollievo Sofferenza Hospital, IRCCS, San Giovanni Rotondo, Italy
| | - Paola Buldrini
- Gastroenterology Unit of Comacchio/Lagosanto, Ferrara, Italy
| | - Michele Cicala
- Gastroenterology Unit, University Campus Bio-Medico of Rome, Rome, Italy
| | - Rosario Cuomo
- Digestive Motility Diseases, Department of Clinical Medicine and Surgery, Federico II University Hospital, Naples, Italy
| | | | - Paola Molteni
- Gastroenterology Unit, Department of Clinical Science, "L. Sacco" University Hospital, Milan, Italy
| | - Matteo Neri
- Department of Medicine and Aging Sciences and CESI, G. D'Annunzio University and Foundation, Chieti, Italy
| | - Marcello Rodi
- Gastroenterology Unit, St. Andrea Hospital, Vercelli, Italy
| | - Alfredo Saggioro
- Department of Digestive Diseases, Hepatology and Clinical Nutrition, Dell'Angelo Hospital, Venice, Italy
| | | | - Maurizio Vecchi
- Gastroenterology and Digestive Endoscopy Unit, IRCCS Policlinico San Donato, San Donato Milanese, Italy
| | | | - Roberto Corinaldesi
- Department of Medical and Surgical Sciences, Centre for Applied Biomedical Research, University of Bologna, Bologna, Italy
| | - Vincenzo Stanghellini
- Department of Medical and Surgical Sciences, Centre for Applied Biomedical Research, University of Bologna, Bologna, Italy
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Wouters MM, Vicario M, Santos J. The role of mast cells in functional GI disorders. Gut 2016; 65:155-68. [PMID: 26194403 DOI: 10.1136/gutjnl-2015-309151] [Citation(s) in RCA: 228] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2015] [Accepted: 06/30/2015] [Indexed: 02/06/2023]
Abstract
Functional gastrointestinal disorders (FGIDs) are characterized by chronic complaints arising from disorganized brain-gut interactions leading to dysmotility and hypersensitivity. The two most prevalent FGIDs, affecting up to 16-26% of worldwide population, are functional dyspepsia and irritable bowel syndrome. Their etiopathogenic mechanisms remain unclear, however, recent observations reveal low-grade mucosal inflammation and immune activation, in association with impaired epithelial barrier function and aberrant neuronal sensitivity. These findings come to challenge the traditional view of FGIDs as pure functional disorders, and relate the origin to a tangible organic substrate. The mucosal inflammatory infiltrate is dominated by mast cells, eosinophils and intraepithelial lymphocytes in the intestine of FGIDs. It is well established that mast cell activation can generate epithelial and neuro-muscular dysfunction and promote visceral hypersensitivity and altered motility patterns in FGIDs, postoperative ileus, food allergy and inflammatory bowel disease. This review will discuss the role of mucosal mast cells in the gastrointestinal tract with a specific focus on recent advances in disease mechanisms and clinical management in irritable bowel syndrome and functional dyspepsia.
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Affiliation(s)
- Mira M Wouters
- Translational Research Center for Gastrointestinal Disorders (TARGID), University Hospital Leuven, Leuven, Belgium
| | - Maria Vicario
- Neuro-immuno-gastroenterology Laboratory, Digestive Diseases Research Unit. Vall d'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitari Vall d'Hebron & Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Javier Santos
- Neuro-immuno-gastroenterology Laboratory, Digestive Diseases Research Unit. Vall d'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitari Vall d'Hebron & Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
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Halliez MCM, Buret AG. Gastrointestinal Parasites and the Neural Control of Gut Functions. Front Cell Neurosci 2015; 9:452. [PMID: 26635531 PMCID: PMC4658430 DOI: 10.3389/fncel.2015.00452] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Accepted: 11/02/2015] [Indexed: 12/30/2022] Open
Abstract
Gastrointestinal motility and transport of water and electrolytes play key roles in the pathophysiology of diarrhea upon exposure to enteric parasites. These processes are actively modulated by the enteric nervous system (ENS), which includes efferent, and afferent neurons, as well as interneurons. ENS integrity is essential to the maintenance of homeostatic gut responses. A number of gastrointestinal parasites are known to cause disease by altering the ENS. The mechanisms remain incompletely understood. Cryptosporidium parvum, Giardia duodenalis (syn. Giardia intestinalis, Giardia lamblia), Trypanosoma cruzi, Schistosoma species and others alter gastrointestinal motility, absorption, or secretion at least in part via effects on the ENS. Recent findings also implicate enteric parasites such as C. parvum and G. duodenalis in the development of post-infectious complications such as irritable bowel syndrome, which further underscores their effects on the gut-brain axis. This article critically reviews recent advances and the current state of knowledge on the impact of enteric parasitism on the neural control of gut functions, and provides insights into mechanisms underlying these abnormalities.
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Affiliation(s)
- Marie C M Halliez
- Department of Biological Sciences, Inflammation Research Network, Host-Parasite Interaction NSERC-CREATE, University of Calgary Calgary, AB, Canada ; Protozooses transmises par l'alimentation, Rouen University Hospital, University of Rouen and Institute for Biomedical Research, University of Reims Champagne-Ardennes Rouen and Reims, France
| | - André G Buret
- Department of Biological Sciences, Inflammation Research Network, Host-Parasite Interaction NSERC-CREATE, University of Calgary Calgary, AB, Canada
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Sood R, Gracie DJ, Law GR, Ford AC. Systematic review with meta-analysis: the accuracy of diagnosing irritable bowel syndrome with symptoms, biomarkers and/or psychological markers. Aliment Pharmacol Ther 2015; 42:491-503. [PMID: 26076071 DOI: 10.1111/apt.13283] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2015] [Revised: 05/14/2015] [Accepted: 05/30/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Irritable bowel syndrome (IBS) is a complex, heterogeneous disease which can be challenging to diagnose. No study has identified and assessed the accuracy of all available methods of diagnosing IBS. AIM To conduct a systematic review of the literature to identify and assess accuracy of symptom-based diagnostic criteria, biomarkers, psychological markers or combinations thereof. METHODS MEDLINE, EMBASE and EMBASE Classic were searched (until April 2015) to identify studies reporting accuracy of available methods to diagnose IBS in adult populations. Eligible studies assessed accuracy of these diagnostic tests against an accepted reference standard. Data were extracted to calculate positive and negative likelihood ratios, with 95% confidence intervals (CIs), of the diagnostic test utilised. Where more than one study used the same test, data were pooled in a meta-analysis. RESULTS Twenty-two studies (7106 patients) were eligible. Positive and negative likelihood ratios of the current gold standard, the Rome III criteria, were 3.35 (95% CI: 2.97-3.79) and 0.39 (95% CI: 0.34-0.46), similar to other symptom-based criteria. Eleven biomarkers performed no better than symptom-based criteria. Psychological markers performed well in one study. Five different combinations were assessed. The best in terms of positive likelihood ratio was faecal calprotectin, intestinal permeability and Rome I criteria (26.4; 95% CI: 11.4-61.9), and in terms of negative likelihood ratio serum-based biomarkers and psychological markers (0.18; 95% CI: 0.12-0.25). CONCLUSIONS Symptom-based diagnostic criteria, biomarkers and psychological markers performed modestly in predicting IBS. Combining symptoms with markers appears more effective, and may represent the way forward in the diagnosis of IBS.
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Affiliation(s)
- R Sood
- Leeds Gastroenterology Institute, St. James's University Hospital, Leeds, UK.,Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds, UK
| | - D J Gracie
- Leeds Gastroenterology Institute, St. James's University Hospital, Leeds, UK.,Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds, UK
| | - G R Law
- Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK
| | - A C Ford
- Leeds Gastroenterology Institute, St. James's University Hospital, Leeds, UK.,Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds, UK
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Evidence for neuronal and structural changes in submucous ganglia of patients with functional dyspepsia. Am J Gastroenterol 2015; 110:1205-15. [PMID: 26077177 DOI: 10.1038/ajg.2015.158] [Citation(s) in RCA: 119] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2014] [Accepted: 04/02/2015] [Indexed: 02/07/2023]
Abstract
OBJECTIVES An intact and well-functioning enteric nervous system is necessary to efficiently organize gut function. Functional gastrointestinal disorders are pathological entities in which gut function is impaired without a clearly established pathophysiology. On the basis of the relative ease with which intestinal biopsies can be obtained, and taking advantage of a recently developed optical recording technique, we evaluated whether functional neuronal defects exist in enteric nerves of patients with functional dyspepsia (FD). METHODS The submucous plexus isolated from duodenal biopsies taken from FD patients and control subjects was used to functionally and morphologically examine nerves and ganglionic architecture (neurons and glial cells). In light of previous studies reporting eosinophil and mast cell infiltration in the gut mucosa of FD patients, we also examined whether these cells infiltrated the submucous plexus and whether this correlated with neuronal activity and specific clinical symptoms. RESULTS We demonstrate that neuronal functioning is impaired in the submucous plexus of FD patients, as shown by decreased calcium responses to depolarization and electrical stimulation. Glial (S100) and neuronal (HuCD) markers show signs of gliosis, altered ganglionic architecture, and neuronal abnormalities in the submucous plexus of FD patients. We found that eosinophils and mast cells infiltrated the submucous layer of FD patients to a much larger extent than in controls. A significant correlation was found between the number of these cells and the calcium transient amplitudes measured in submucous ganglia. CONCLUSIONS We provide the first direct evidence that FD is characterized by functional and structural abnormalities within the submucous ganglion plexus, which may be of future predictive and diagnostic value in the treatment of FD patients.
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Berdún S, Bombuy E, Estrada O, Mans E, Rychter J, Clavé P, Vergara P. Peritoneal mast cell degranulation and gastrointestinal recovery in patients undergoing colorectal surgery. Neurogastroenterol Motil 2015; 27:764-74. [PMID: 25677271 DOI: 10.1111/nmo.12525] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Accepted: 01/14/2015] [Indexed: 02/08/2023]
Abstract
BACKGROUND Degranulation of peritoneal mast cells (MCs) induced by intestinal manipulation has been proposed as a pathophysiological factor in postoperative ileus (POI). We aimed to explore the relationship between peritoneal and colonic MC degranulation and gastrointestinal (GI) recovery following colectomy. METHODS Patients undergoing elective laparoscopic cholecystectomy (using a laparoscope and small abdominal incisions, n = 14), and elective laparoscopic (n = 32) or open partial colectomy (through a large abdominal incision, n = 10) were studied. MC protease tryptase and chymase were studied in peritoneal fluid at the beginning, middle, and end of each surgical intervention. Density of MCs in colectomy samples were examined and oro-caecal transit time by breath test, GI function recovery by clinical composite endpoint GI-2 and association between MC proteases and clinical recovery. KEY RESULTS Open and laparoscopic colectomy caused greater peritoneal release of tryptase and chymase (323.0 ng/mL [IQR: 53.05-381.4] and 118.6 ng/mL [IQR: 53.60-240.3]), than cholecystectomy (41.64 ng/mL [IQR: 11.17-90.93]) at the end of the surgical intervention. However, there were no differences between laparoscopic and open colectomy. Increased peritoneal protease release during surgery was observed in patients who developed POI after colectomy. CONCLUSIONS & INFERENCES Colorectal surgery causes protease release from peritoneal MCs. Protease release does not differ between both types of colectomy (laparoscopy vs laparotomy). However, MC activation is increased in colectomy patients developing POI. Therefore, degranulation of peritoneal MCs as a factor contributing to human POI after colectomy might be considered in future studies as a target to avoid POI.
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Affiliation(s)
- S Berdún
- Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - E Bombuy
- Department of Surgery, Consorci Sanitari del Maresme (CSdM) - Hospital de Mataró, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - O Estrada
- Department of Surgery, Consorci Sanitari del Maresme (CSdM) - Hospital de Mataró, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - E Mans
- Department of Surgery, Consorci Sanitari del Maresme (CSdM) - Hospital de Mataró, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - J Rychter
- Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain
| | - P Clavé
- Department of Surgery, Consorci Sanitari del Maresme (CSdM) - Hospital de Mataró, Universitat Autònoma de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain
| | - P Vergara
- Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain
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Deiteren A, De Man JG, Pelckmans PA, De Winter BY. Histamine H₄ receptors in the gastrointestinal tract. Br J Pharmacol 2015; 172:1165-78. [PMID: 25363289 DOI: 10.1111/bph.12989] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Revised: 09/28/2014] [Accepted: 10/20/2014] [Indexed: 12/13/2022] Open
Abstract
Histamine is a well-established mediator involved in a variety of physiological and pathophysiological mechanisms and exerts its effect through activation of four histamine receptors (H1-H₄). The histamine H₄ receptor is the newest member of this histamine receptor family, and is expressed throughout the gastrointestinal tract as well as in the liver, pancreas and bile ducts. Functional studies using a combination of selective and non-selective H₄ receptor ligands have rapidly increased our knowledge of H₄ receptor involvement in gastrointestinal processes both under physiological conditions and in models of disease. Strong evidence points towards a role for H₄ receptors in the modulation of immune-mediated responses in gut inflammation such as in colitis, ischaemia/reperfusion injury, radiation-induced enteropathy and allergic gut reactions. In addition, data have emerged implicating H₄ receptors in gastrointestinal cancerogenesis, sensory signalling, and visceral pain as well as in gastric ulceration. These studies highlight the potential of H₄ receptor targeted therapy in the treatment of various gastrointestinal disorders such as inflammatory bowel disease, irritable bowel syndrome and cancer.
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Affiliation(s)
- A Deiteren
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, Antwerp, Belgium
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Ostertag D, Buhner S, Michel K, Pehl C, Kurjak M, Götzberger M, Schulte-Frohlinde E, Frieling T, Enck P, Phillip J, Schemann M. Reduced Responses of Submucous Neurons from Irritable Bowel Syndrome Patients to a Cocktail Containing Histamine, Serotonin, TNFα, and Tryptase (IBS-Cocktail). Front Neurosci 2015; 9:465. [PMID: 26733780 PMCID: PMC4679876 DOI: 10.3389/fnins.2015.00465] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Accepted: 11/23/2015] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND AND AIMS Malfunctions of enteric neurons are believed to play an important role in the pathophysiology of irritable bowel syndrome (IBS). Our aim was to investigate whether neuronal activity in biopsies from IBS patients is altered in comparison to healthy controls (HC). METHODS Activity of human submucous neurons in response to electrical nerve stimulation and local application of nicotine or a mixture of histamine, serotonin, tryptase, and TNF-α (IBS-cocktail) was recorded in biopsies from 17 HC and 35 IBS patients with the calcium-sensitive-dye Fluo-4 AM. The concentrations of the mediators resembeled those found in biopsy supernatants or blood. Neuronal activity in guinea-pig submucous neurons was studied with the voltage-sensitive-dye di-8-ANEPPS. RESULTS Activity in submucous ganglia in response to nicotine or electrical nerve stimulation was not different between HC and IBS patients (P = 0.097 or P = 0.448). However, the neuronal response after application of the IBS-cocktail was significantly decreased (P = 0.039) independent of whether diarrhea (n = 12), constipation (n = 5) or bloating (n = 5) was the predominant symptom. In agreement with this we found that responses of submucous ganglia conditioned by overnight incubation with IBS mucosal biopsy supernatant to spritz application of this supernatant was significantly reduced (P = 0.019) when compared to incubation with HC supernatant. CONCLUSION We demonstrated for the first time reduced neuronal responses in mucosal IBS biopsies to an IBS mediator cocktail. While excitability to classical stimuli of enteric neurons was comparable to HC, the activation by the IBS-cocktail was decreased. This was very likely due to desensitization to mediators constantly released by mucosal and immune cells in the gut wall of IBS patients.
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Affiliation(s)
| | - Sabine Buhner
- Human Biology, Technische Universität MünchenFreising, Germany
| | - Klaus Michel
- Human Biology, Technische Universität MünchenFreising, Germany
| | | | | | | | | | | | - Paul Enck
- Academic Hospital TübingenTübingen, Germany
| | | | - Michael Schemann
- Human Biology, Technische Universität MünchenFreising, Germany
- *Correspondence: Michael Schemann
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Abstract
The aetiology and pathology of IBS, a functional bowel disorder thought to lack an organic cause, is largely unknown. However, studies suggest that various features, such as altered composition of the gut microbiota, together with increased intestinal permeability, a changed balance in the enteroendocrine system and a dysregulated immune system in the gut, most likely have an important role in IBS. Exactly how these entities act together and give rise to symptoms is still unknown, but an altered gut microbiota composition could lead to dysregulation of the intestinal barrier as well as the enteroendocrine and the immune systems, which (through interactions with the nervous system) might generate symptoms. This Review highlights the crosstalk between the gut microbiota, the enteroendocrine system, the immune system and the role of intestinal permeability in patients with IBS.
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Medani M, Collins D, Mohan HM, Walsh E, Winter DC, Baird AW. Prostaglandin D2 regulates human colonic ion transport via the DP1 receptor. Life Sci 2014; 122:87-91. [PMID: 25534438 DOI: 10.1016/j.lfs.2014.12.017] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2014] [Revised: 11/20/2014] [Accepted: 12/09/2014] [Indexed: 01/07/2023]
Abstract
AIMS Prostaglandin D2 is released by mast cells and is important in allergies. Its role in gastrointestinal function is not clearly defined. This study aimed to determine the effect of exogenous PGD2 on ion transport in ex vivo normal human colonic mucosa. MATERIALS AND METHODS Mucosal sheets were mounted in Ussing chambers and voltage clamped to zero electric potential. Ion transport was quantified as changes in short-circuit current. In separate experiments epithelial monolayers or colonic crypts, isolated by calcium chelation, were treated with PGD2 and cAMP levels determined by ELISA or calcium levels were determined by fluorimetry. KEY FINDINGS PGD2 caused a sustained, concentration-dependent rise in short-circuit current by increasing chloride secretion (EC50=376nM). This effect of PGD2 is mediated by the DP1 receptor, as the selective DP1 receptor antagonist BW A686C inhibited PGD2-induced but not PGE2-induced rise in short-circuit current. PGD2 also increased intracellular cAMP in isolated colonic crypts with no measurable influence on cytosolic calcium. PGD2 induces chloride secretion in isolated human colonic mucosa in a concentration-dependent manner with concomitant elevation of cytoplasmic cAMP in epithelial cells. SIGNIFICANCE The involvement of DP2 receptor subtypes has not previously been considered in regulation of ion transport in human intestine. Since inflammatory stimuli may induce production of eicosanoids, selective regulation of these pathways may be pivotal in determining therapeutic strategies and in understanding disease.
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Affiliation(s)
- M Medani
- Department of Surgery, St Vincent's University Hospital, Elm Park, Dublin 4, Ireland; UCD School of Veterinary Medicine, University College Dublin, Belfield, Dublin 4, Ireland; Conway Institute of Biomolecular & Biomedical Science, University College Dublin, Belfield, Dublin 4, Ireland; UCD School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland
| | - D Collins
- Department of Surgery, St Vincent's University Hospital, Elm Park, Dublin 4, Ireland; UCD School of Veterinary Medicine, University College Dublin, Belfield, Dublin 4, Ireland; Conway Institute of Biomolecular & Biomedical Science, University College Dublin, Belfield, Dublin 4, Ireland; UCD School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland
| | - H M Mohan
- Department of Surgery, St Vincent's University Hospital, Elm Park, Dublin 4, Ireland; UCD School of Veterinary Medicine, University College Dublin, Belfield, Dublin 4, Ireland; Conway Institute of Biomolecular & Biomedical Science, University College Dublin, Belfield, Dublin 4, Ireland; UCD School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland
| | - E Walsh
- UCD School of Veterinary Medicine, University College Dublin, Belfield, Dublin 4, Ireland; Conway Institute of Biomolecular & Biomedical Science, University College Dublin, Belfield, Dublin 4, Ireland
| | - D C Winter
- Department of Surgery, St Vincent's University Hospital, Elm Park, Dublin 4, Ireland; UCD School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland
| | - A W Baird
- UCD School of Veterinary Medicine, University College Dublin, Belfield, Dublin 4, Ireland; Conway Institute of Biomolecular & Biomedical Science, University College Dublin, Belfield, Dublin 4, Ireland.
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Abstract
IBS is estimated to have a prevalence of up to 20% in Western populations and results in substantial costs to health-care services worldwide, estimated to be US$1 billion per year in the USA. IBS remains difficult to diagnose due to its multifactorial aetiology, heterogeneous nature and overlap of symptoms with organic pathologies, such as coeliac disease and IBD. As a result, IBS often continues to be a diagnosis of exclusion, resulting in unnecessary investigations. Available methods for the diagnosis of IBS-including the current gold standard, the Rome III criteria-perform only moderately well. Visceral hypersensitivity and altered pain perception do not discriminate between IBS and other functional gastrointestinal diseases or health with any great accuracy. Attention has now turned to developing novel biomarkers and using psychological markers (so-called psychomarkers) to aid the diagnosis of IBS. This Review describes how useful symptoms, symptom-based criteria, biomarkers and psychomarkers, and indeed combinations of all these approaches, are in the diagnosis of IBS. Future directions in diagnosing IBS could include combining demographic data, gastrointestinal symptoms, biomarkers and psychomarkers using statistical methods. Latent class analysis to distinguish between IBS and non-IBS symptom profiles might also represent a promising avenue for future research.
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Abstract
PURPOSE OF REVIEW Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) are classically viewed as dichotomous conditions. The former is perceived as a typical organic disease, and the latter is regarded as a disorder of gut function driven by mood. Recent research identified some shared contributing factors, which will be discussed here. RECENT FINDINGS Mounting evidence shows the importance in both IBD and IBS of genetic, microbiological, epithelial, and immunological factors. In some instances, these factors overlap in the two conditions as shown by: involvement of brain-gut axis dysfunction in IBD, implication of TNFSF gene in Crohn's disease and IBS, evidence of abnormal microbiota and its impact on host functions, identification of low-grade inflammation in subsets of IBS patients, and development of IBS symptoms in patients with IBD in remission. SUMMARY IBD and IBS remain separate conditions although there are some overlapping mechanisms. Both research and clinical management would benefit from considering a functional approach for certain manifestations of IBD and accepting an organic view in subsets of IBS patients.
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Vivinus-Nébot M, Frin-Mathy G, Bzioueche H, Dainese R, Bernard G, Anty R, Filippi J, Saint-Paul MC, Tulic MK, Verhasselt V, Hébuterne X, Piche T. Functional bowel symptoms in quiescent inflammatory bowel diseases: role of epithelial barrier disruption and low-grade inflammation. Gut 2014; 63:744-52. [PMID: 23878165 DOI: 10.1136/gutjnl-2012-304066] [Citation(s) in RCA: 283] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE To determine the role of colonic barrier defects and low-grade inflammation in irritable bowel syndrome (IBS)-like symptoms in quiescent inflammatory bowel disease (IBD). DESIGN Caecal biopsies were collected from 51 IBS, 49 quiescent IBD (31 Crohn's disease (CD) and 18 ulcerative colitis (UC)) patients and 27 controls. IBS was assessed using the Rome III criteria and the IBS severity score. Epithelial barrier integrity was evaluated by determining the paracellular permeability of biopsies mounted in Ussing chambers and the mRNA expression of tight junction proteins (ZO-1, α-catenin and occludin). Low-grade inflammation was evaluated by counting cells, including intraepithelial lymphocytes (IELs), eosinophils and mast cells, and by determining the mRNA and protein expression of tumour necrosis factor (TNF)-α in biopsies and culture supernatants. RESULTS IBS-like symptoms were present in 35.4 and 38% of CD and UC patients, respectively. Paracellular permeability was significantly increased in both quiescent IBD with IBS-like symptoms and IBS compared with quiescent IBD without IBS-like symptoms (p<0.01, respectively) or controls (p<0.01, respectively). Significantly lower expression of ZO-1 and α-catenin was detected in IBS and quiescent IBD with IBS-like symptoms. IELs and TNF-α were significantly increased in quiescent IBD with IBS-like symptoms, but not in IBS. CONCLUSIONS In quiescent IBD, IBS-like symptoms related to persistent subclinical inflammation associated with increased colonic paracellular permeability. A persistent increase in TNF-α in colonic mucosa may contribute to the epithelial barrier defects associated with abdominal pain in quiescent IBD, but not in IBS. Optimisation of anti-inflammatory therapy may be considered in quiescent IBD with IBS-like symptoms.
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Affiliation(s)
- M Vivinus-Nébot
- Department of Immunology, Pole of Biology, Hôpital Archet 1, CHU de Nice, Université de Nice Sophia-Antipolis, Nice, France
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