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Fakhri Bafghi MS, Khoshnam Rad N, Roostaei G, Nikfar S, Abdollahi M. The reality of modeling irritable bowel syndrome: progress and challenges. Expert Opin Drug Discov 2025; 20:433-445. [PMID: 40162721 DOI: 10.1080/17460441.2025.2481264] [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: 06/03/2024] [Accepted: 03/14/2025] [Indexed: 04/02/2025]
Abstract
INTRODUCTION Irritable bowel syndrome (IBS) is a common gastrointestinal disorder that is often therapeutically challenging. While research has advanced our understanding of IBS pathophysiology, developing precise models to predict drug response and treatment outcomes remains a significant hurdle. AREAS COVERED This perspective provides an overview of the use of animal models alongside cutting-edge technologies used to bring drugs from bench to bedside.Furthermore, the authors examine the progress and limitations of IBS modeling. The authors further discuss the challenges of traditional animal models and gives a spotlight to the potential of innovative technologies, such as organ-on-chip systems, computational models, and artificial intelligence (AI). These approaches intend to enhance both the understanding and treatment of IBS. EXPERT OPINION Although animal models have been central to understanding IBS research, they have limitations. The future of IBS research resides in integrating organ-on-chip systems and utilizing modern technological developments, such as AI. These tools will enable the design of more effective treatment strategies and improve patients' overall well-being. To achieve this, collaboration between experts from various disciplines is essential to improve these models and guarantee their clinical application and reliability.
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Affiliation(s)
- Maryam S Fakhri Bafghi
- Department of Internal Medicine, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Niloofar Khoshnam Rad
- Thoracic Research Center, Imam Khomeini Hospital Complex, Tehran, Iran
- Department of Toxicology and Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences Research Center (PSRC), Tehran University of Medical Sciences, Tehran, Iran
| | - Ghazal Roostaei
- Thoracic Research Center, Imam Khomeini Hospital Complex, Tehran, Iran
- Rasoul Akram Hospital Clinical Research Development Center, School of Medicine, Rasool Akram Medical Complex, Iran University of Medical Sciences, Tehran, Iran
| | - Shekoufeh Nikfar
- Department of Toxicology and Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences Research Center (PSRC), Tehran University of Medical Sciences, Tehran, Iran
- Personalized Medicine Research Center, Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Mohammad Abdollahi
- Department of Toxicology and Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences Research Center (PSRC), Tehran University of Medical Sciences, Tehran, Iran
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Jeong ES, Jung HK, Choi E, Yun K, Lee A, Kim YS. Characterization of post-inflammatory irritable bowel syndrome animal model following acute colitis recovery. Sci Rep 2025; 15:8512. [PMID: 40075091 PMCID: PMC11904205 DOI: 10.1038/s41598-025-88981-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Accepted: 02/03/2025] [Indexed: 03/14/2025] Open
Abstract
Irritable bowel syndrome (IBS) is a prevalent disorder with an unclear pathophysiology. This study aimed to investigate the features of dextran sulfate sodium (DSS)-induced low-grade inflammation using murine models of acute severe colitis (acute model) and chronic mild repeated colitis (chronic model), with potential implications for IBS research. The acute model was induced with 3% DSS for 5 days, followed by a 12-week recovery period. The chronic model involved administration of 0.5% DSS for 5 days, followed by a 5-day resting period, repeated thrice. We conducted comparative analyses to assess inflammation severity, intestinal motility, permeability, visceral hypersensitivity, and microbiome composition. In the acute model, mild leukocyte infiltration was observed, colonic transit time shortened at 12 weeks (P < 0.001), occludin expression decreased (P = 0.041), inflammatory cytokines, and transient receptor potential vanilloid 1 was upregulated in colonic mucosa (P < 0.050). In the chronic model, only mild inflammatory changes were noted. Microbiota analysis in the acute model revealed differences in microbial abundance and compositions (P = 0.001). The acute model demonstrated low-grade inflammation that caused gut dysmotility, altered permeability, and increased visceral hypersensitivity with notable microbial composition changes, potentially relevant to IBS phenotypes.
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Affiliation(s)
- Eui Sun Jeong
- Department of Internal Medicine, College of Medicine, Ewha Womans University, Seoul, Korea
| | - Hye-Kyung Jung
- Department of Internal Medicine, College of Medicine, Ewha Womans University, Seoul, Korea.
| | - Euno Choi
- Department of Pathology, College of Medicine, Ewha Womans University, Seoul, Korea
| | | | - Ayoung Lee
- Department of Internal Medicine, College of Medicine, Korea University, Ansan, Gyeonggi-do, Korea
| | - Yong Sung Kim
- Digestive Disease Research Institute, College of Medicine, Wonkwang University, Iksan, Jeonlabuk-do, Korea
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Serrafi A, Chegdani F, Bennis F, Kepinska M. The Importance of Argan Oil in Medicine and Cosmetology. Nutrients 2024; 16:3573. [PMID: 39458566 PMCID: PMC11510224 DOI: 10.3390/nu16203573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 10/07/2024] [Accepted: 10/17/2024] [Indexed: 10/28/2024] Open
Abstract
Argan oil, rich in unsaturated fatty acids and polyphenols, exerts beneficial effects on both the intestinal and skin microbiotas. In the gut, it promotes the growth of beneficial bacteria, such as lactobacilli, while reducing pathogenic bacteria, due to its anti-inflammatory properties that help maintain microbial balance. Additionally, it improves the integrity of the intestinal mucosa, reducing the risk of dysbiosis. On the skin, argan oil hydrates and balances the lipid environment, creating a favorable setting for beneficial microorganisms, while also possessing antimicrobial and anti-inflammatory properties that soothe conditions like eczema and acne. Thus, argan oil is valuable for overall health, supporting digestion and skin health. The objective of this review is to provide a summary of the benefits of argan oil for alternative and complementary medicine. An exhaustive search of the literature was carried out using targeted keywords. A set of 83 articles were selected and analyzed. As the mechanisms of action of argan oil are not completely understood, this work highlighted the benefits of this oil by analyzing its nutritional properties and its beneficial effects on the intestinal and skin microbiotas. Indeed, argan oil is valuable for overall health.
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Affiliation(s)
- Agata Serrafi
- Department of Immunochemistry and Chemistry, Wroclaw Medical University, ul. M. Skłodowskiej-Curie 48/50, 50-369 Wroclaw, Poland;
| | - Fatima Chegdani
- Laboratory of Immunology and Biodiversity, Department of Biology, Faculty of Sciences Aïn Chock, Hassan II University of Casablanca, Route El Jadida, BP 5366 Maarif, Casablanca 20100, Morocco; (F.C.); (F.B.)
| | - Faïza Bennis
- Laboratory of Immunology and Biodiversity, Department of Biology, Faculty of Sciences Aïn Chock, Hassan II University of Casablanca, Route El Jadida, BP 5366 Maarif, Casablanca 20100, Morocco; (F.C.); (F.B.)
| | - Marta Kepinska
- Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211a, 50-556 Wroclaw, Poland
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Ke W, Wu J, Li H, Huang S, Li H, Wang Y, Wu Y, Yuan J, Zhang S, Tang H, Lei K. Network pharmacology and experimental validation to explore the mechanism of Changji'an formula against irritable bowel syndrome with predominant diarrhea. Heliyon 2024; 10:e33102. [PMID: 39005919 PMCID: PMC11239594 DOI: 10.1016/j.heliyon.2024.e33102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Revised: 06/13/2024] [Accepted: 06/13/2024] [Indexed: 07/16/2024] Open
Abstract
Changji'an Formula (CJAF) is a Chinese herbal compound, which is effective against irritable bowel syndrome with predominant diarrhea (IBS-D) in clinic. However, the molecular mechanism has not been well defined. In the current study, the potential targets and signaling pathways of CJAF against IBS-D were predicted using network pharmacology analysis. The pharmacological mechanisms of CJAF against IBS-D and the potential mechanism were validated by using an IBS-D mouse model induced by enema with trinitrobenzene-sulfonic acid (TNBS) plus with restraint stress and further intervened with CJAF. A total of 232 active compounds of CJAF were obtained, a total of 397 potential targets for the active ingredients were retrieved and a total of 219 common targets were obtained as the potential targets of CJAF against IBS-D. GO and KEGG enrichment analyses showed that multiple targets were enriched and could be experimentally validated in a mouse model of IBS-D. The mechanisms were mainly converged on the immune and inflammatory pathways, especially the NF-κB, TNF and IL-17 signaling pathway, which were closely involved in the treatment of CJAF against IBS-D. Animal experiment showed that CJAF alleviated visceral hypersensitivity and diarrhea symptom of IBS-D. CJAF also restored the histological and ultrastructure damage of IBS-D. The result of Western blot showed that CJAF upregulated colonic tight junction proteins of ZO-1, Occludin and Claudin-1. Further results demonstrated that CJAF inhibited the protein expression of NF-κB/NLRP3 inflammasome pathway targets and downregulated proinflammatory mediators of IL-1β, IL-18, TNF-α. In conclusion, CJAF could effectively reduce inflammatory response and alleviate visceral hypersensitivity as well as diarrhea symptom of IBS-D by inhibiting the NF-κB/NLRP3 signaling pathway. This study not only reveals the mechanism of CJAF against IBS-D, but also provides a novel therapeutic strategy for IBS-D.
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Affiliation(s)
- Wei Ke
- Foshan Hospital of Traditional Chinese Medicine, Foshan, 528000, Guangdong, China
- The Eighth Clinical Medical College of Guangzhou University of Chinese Medicine, Foshan, 528000, Guangdong, China
| | - Jinjun Wu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, Guangdong, China
| | - Hongbin Li
- The First Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China
| | - Siyu Huang
- Guangdong Provincial Key Laboratory of Advanced Drug Delivery Systems and Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, Guangzhou, 510006, Guangdong, China
| | - Huibiao Li
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China
| | - Yongfu Wang
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Yingxiu Wu
- Foshan Hospital of Traditional Chinese Medicine, Foshan, 528000, Guangdong, China
| | - Jie Yuan
- Foshan Clinical Medical School, Guangzhou University of Chinese Medicine, Foshan, 528000, Guangdong, China
| | - Shuncong Zhang
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China
| | - Hongmei Tang
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China
| | - Kaijun Lei
- Foshan Hospital of Traditional Chinese Medicine, Foshan, 528000, Guangdong, China
- The Eighth Clinical Medical College of Guangzhou University of Chinese Medicine, Foshan, 528000, Guangdong, China
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Zhou Q, Yang L, Verne ML, Zhang BB, Fields J, Verne GN. Catechol-O-Methyltransferase Loss Drives Cell-Specific Nociceptive Signaling via the Enteric Catechol-O-Methyltransferase/microRNA-155/Tumor Necrosis Factor α Axis. Gastroenterology 2023; 164:630-641.e34. [PMID: 36623778 PMCID: PMC10038873 DOI: 10.1053/j.gastro.2022.12.041] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Revised: 12/21/2022] [Accepted: 12/27/2022] [Indexed: 01/11/2023]
Abstract
BACKGROUND & AIMS The etiology of abdominal pain in postinfectious, diarrhea-predominant irritable bowel syndrome (PI-IBS-D) is unknown, and few treatment options exist. Catechol-O-methyltransferase (COMT), an enzyme that inactivates and degrades biologically active catecholamines, plays an important role in numerous physiologic processes, including modulation of pain perception. Our objective was to determine the mechanism(s) of how decreased colonic COMT in PI-IBS-D patients contributes to the chronic abdominal pain phenotype after enteric infections. METHODS Colon neurons, epithelial cells, and macrophages were procured with laser capture microdissection from PI-IBS-D patients to evaluate cell-specific colonic COMT, microRNA-155 (miR-155), and tumor necrosis factor (TNF) α expression levels compared to recovered patients (infection cleared: did not develop PI-IBS-D) and control individuals. COMT-/-, colon-specific COMT-/-, and miR-155-/- mice and human colonoids were used to model phenotypic expression of COMT in PI-IBS-D patients and to investigate signaling pathways linking abdominal pain. Citrobacter rodentium and trinitrobenzene sulfonic acid animal models were used to model postinflammatory changes seen in PI-IBS-D patients. RESULTS Colonic COMT levels were significantly decreased and correlated with increased visual analog scale abdominal pain ratings in PI-IBS-D patients compared to recovered patients and control individuals. Colonic miR-155 and TNF-α were increased in PI-IBS-D patients with diminished colonic COMT. COMT-/- mice had significantly increased expression of miR-155 and TNF-α in both colon tissues and dorsal root ganglia. Introduction of cV1q antibody (anti-TNF-α) into mice reversed visceral hypersensitivity after C rodentium and trinitrobenzene sulfonic acid. CONCLUSIONS Decreased colonic COMT in PI-IBS-D patients drives abdominal pain phenotypes via the COMT/miR-155/TNF-α axis. These important findings will allow new treatment paradigms and more targeted and personalized medicine approaches for gastrointestinal disorders after enteric infections.
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Affiliation(s)
- QiQi Zhou
- Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee; Memphis Veterans Affairs Medical Center, Research Service, Memphis, Tennessee
| | - Liuqing Yang
- Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee
| | - Meghan L Verne
- Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee
| | - Benjamin B Zhang
- Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee
| | - Jeremy Fields
- Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee
| | - George Nicholas Verne
- Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee; Memphis Veterans Affairs Medical Center, Research Service, Memphis, Tennessee.
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Di Nardo G, Cremon C, Staiano A, Stanghellini V, Borrelli O, Strisciuglio C, Romano C, Mallardo S, Scarpato E, Marasco G, Salvatore S, Zenzeri L, Felici E, Pensabene L, Sestito S, Francavilla R, Quitadamo P, Baldassarre M, Giorgio V, Tambucci R, Ziparo C, Parisi P, Barbaro MR, Barbara G. Role of inflammation in pediatric irritable bowel syndrome. Neurogastroenterol Motil 2023; 35:e14365. [PMID: 35340083 DOI: 10.1111/nmo.14365] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 02/09/2022] [Accepted: 03/15/2022] [Indexed: 12/14/2022]
Abstract
BACKGROUND IBS affects a large number of children throughout the world and is thought to be the result of disturbed neuroimmune function along with the brain-gut axis. Although the underlying pathophysiologic mechanisms are not clear, the role of low-grade inflammation and mucosal immune activation in IBS symptom generation has become evident also in subsets of pediatric patients. Animal models provided meaningful insight in the causal relationship between abnormal mucosal immune activation and changes in gastrointestinal (GI) sensory-motor function. Likewise, the development of long-standing GI symptoms fulfilling the current criteria for functional GI disorders after infection gastroenteritis and in patients with IBD or celiac disease in remission further supports this hypothesis. Immune activation, its impact on gut sensory-motor function, and potential implications for symptom generation emerged in both children and adults with IBS. PURPOSE The aim of this review is to summarize the main evidence on the presence of low-grade inflammation and immune activation in children with IBS, its possible role in symptom generation, and its potential implication for new therapeutic strategies.
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Affiliation(s)
- Giovanni Di Nardo
- NESMOS Department, Faculty of Medicine and Psychology, Sant'Andrea University Hospital, Sapienza University of Rome, Rome, Italy
| | - Cesare Cremon
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Annamaria Staiano
- Department of Translational Medical Science, "Federico II", University of Naples, Naples, Italy
| | | | - Osvaldo Borrelli
- Division of Neurogastroenterology and Motility, Department of Paediatric Gastroenterology, UCL Institute of Child Health and Great Ormond Street Hospital, London, UK
| | - Caterina Strisciuglio
- Department of Woman, Child and General and Specialistic Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Claudio Romano
- Pediatric Gastroenterology Unit, Department of Human Pathology in Adulthood and Childhood "G. Barresi", University of Messina, Messina, Italy
| | - Saverio Mallardo
- Pediatric Department, Santa Maria Goretti Hospital, Sapienza University of Rome, Latina, Italy
| | - Elena Scarpato
- Department of Translational Medical Science, "Federico II", University of Naples, Naples, Italy
| | - Giovanni Marasco
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Silvia Salvatore
- Pediatric Department, Ospedale "F. Del Ponte", University of Insubria, Varese, Italy
| | - Letizia Zenzeri
- NESMOS Department, Faculty of Medicine and Psychology, Sant'Andrea University Hospital, Sapienza University of Rome, Rome, Italy
- Pediatric Emergency Unit, Santobono-Pausilipon Children's Hospital, Naples, Italy
| | - Enrico Felici
- Pediatric and Pediatric Emergency Unit, "Umberto Bosio" Center for Digestive Diseases, The Children Hospital, AO SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy
| | - Licia Pensabene
- Department of Medical and Surgical Sciences, Pediatric Unit, University "Magna Graecia" of Catanzaro, Catanzaro, Italy
| | - Simona Sestito
- Department of Medical and Surgical Sciences, Pediatric Unit, University "Magna Graecia" of Catanzaro, Catanzaro, Italy
| | - Ruggiero Francavilla
- Pediatric Section, Department of Interdisciplinary Medicine, University of Bari "Aldo Moro", Bari, Italy
| | - Paolo Quitadamo
- Department of Pediatrics, A.O.R.N. Santobono-Pausilipon, Naples, Italy
| | - Mariella Baldassarre
- Neonatology and Neonatal Intensive Care Unit, Department of Biomedical Science and Human Oncology, University of Bari "Aldo Moro", Bari, Italy
| | | | - Renato Tambucci
- Digestive Endoscopy and Surgery Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Chiara Ziparo
- NESMOS Department, Faculty of Medicine and Psychology, Sant'Andrea University Hospital, Sapienza University of Rome, Rome, Italy
| | - Pasquale Parisi
- NESMOS Department, Faculty of Medicine and Psychology, Sant'Andrea University Hospital, Sapienza University of Rome, Rome, Italy
| | | | - Giovanni Barbara
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
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Chen Q, Zhang H, Sun CY, He QY, Zhang RR, Luo BF, Zhou ZH, Chen XF. Evaluation of two laboratory model methods for diarrheal irritable bowel syndrome. Mol Med 2023; 29:5. [PMID: 36635623 PMCID: PMC9837933 DOI: 10.1186/s10020-022-00599-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 12/27/2022] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND Diarrheal irritable bowel syndrome (IBS-D) is a common chronic functional gastrointestinal disorder, and the underlying pathogenic mechanism is still unclear. Animal models that mimic the pathological state of IBS-D patients were constructed to provide a reference for later drug research and model development. METHODS The IBS-D model was induced using restraint stress and chemical stimulation (rhubarb), and rats were divided into normal control group (NC), chemically stimulated group (CS), and restraint stress group (RS). Visceral motility responses to Colorectal Balloon Dilation (CRD) were measured by Abdominal Withdrawal Reflex (AWR); evaluation of faecal properties and water content; determination of colonic tissue tight junction (TJ) mRNA expression by RT-PCR; measurement of inflammatory cytokines by ELISA; and intestinal flora and short chain fatty acids. RESULTS Compared to NC group, CS and RS group rats showed increased intestinal sensitivity and Bristol stool score, significant diarrheal symptoms and weight loss. Mucin 2, ZO-1, OCLN, CLDN4 mRNA expression was reduced and the intestinal mucosal barrier function was diminished. In addition, the levels of inflammatory factors IL-1β, IL-6, IL-8, IL-10 and TNF-α increased, the abundance and diversity of intestinal flora decreased, the content of beneficial bacteria such as Bifidobacteria decreased, and SCFAs such as acetic acid, propionic acid and butyric acid decreased to different degrees. Although, no significant difference was observed for any molecular and inflammatory marker, but compared to CS group, RS group had less water in the stool, higher visceral sensitivity, and higher relative abundance of beneficial intestinal bacteria such as Actinobacteria. CONCLUSION In conclusion, restraint stress combined with chemical stimulation can mimic the pathological state of diarrhoea symptoms, visceral hypersensitivity, reduced intestinal mucosal barrier permeability, immune regulatory dysfunction and dysbiosis in IBS-D patients. However, herbs with antibacterial effects such as rhubarb and senna, for example, are not suitable as the first choice for chemical stimulation, as they may lead to a decrease in harmful bacteria and an increase in beneficial bacteria in the intestinal fraction and do not perfectly mimic the imbalanced state of intestinal flora in IBS-D patients, while restraint stress may be a key factor in modelling.
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Affiliation(s)
- Qian Chen
- Evidence-Based Medicine Research Centre, Jiangxi University of Chinese Medicine, Nanchang, 330004 Jiangxi China
| | - Hua Zhang
- Department of Food Nutrition and Safety, College of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang, 330004 Jiangxi China
| | - Chang-Yue Sun
- Evidence-Based Medicine Research Centre, Jiangxi University of Chinese Medicine, Nanchang, 330004 Jiangxi China
| | - Qing-Ying He
- grid.411304.30000 0001 0376 205XChengdu University of Traditional Chinese Medicine, Chengdu, 611137 China
| | - Rui-Rong Zhang
- Department of Food Nutrition and Safety, College of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang, 330004 Jiangxi China
| | - Bin-Fei Luo
- Evidence-Based Medicine Research Centre, Jiangxi University of Chinese Medicine, Nanchang, 330004 Jiangxi China
| | - Zi-Hao Zhou
- Evidence-Based Medicine Research Centre, Jiangxi University of Chinese Medicine, Nanchang, 330004 Jiangxi China
| | - Xiao-Fan Chen
- Evidence-Based Medicine Research Centre, Jiangxi University of Chinese Medicine, Nanchang, 330004 Jiangxi China
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Yoshioka T, Ohashi M, Matsumoto K, Omata T, Hamano T, Yamazaki M, Kimiki S, Okano K, Kobayashi R, Yamada D, Hada N, Kato S, Saitoh A. Repeated psychological stress, chronic vicarious social defeat stress, evokes irritable bowel syndrome-like symptoms in mice. Front Neurosci 2022; 16:993132. [PMID: 36277999 PMCID: PMC9582264 DOI: 10.3389/fnins.2022.993132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Accepted: 09/06/2022] [Indexed: 11/13/2022] Open
Abstract
Increasing evidence has demonstrated that emotional states and intestinal conditions are inter-connected in so-called “brain–gut interactions.” Indeed, many psychiatric disorders are accompanied by gastrointestinal symptoms, such as the irritable bowel syndrome (IBS). However, the functional connection remains elusive, partly because there are few useful experimental animal models. Here, we focused on a highly validated animal model of stress-induced psychiatric disorders, such as depression, known as the chronic vicarious social defeat stress (cVSDS) model mice, which we prepared using exposure to repeated psychological stress, thereafter examining their intestinal conditions. In the charcoal meal test and the capsaicin-induced hyperalgesia test, cVSDS model mice showed a significantly higher intestinal transit ratio and increased visceral pain-related behaviors, respectively. These changes persisted over one month after the stress session. On the other hand, the pathological evaluations of the histological and inflammatory scores of naive and cVSDS model mice did not differ. Furthermore, keishikashakuyakuto—a kampo medicine clinically used for the treatment of IBS—normalized the intestinal motility change in cVSDS model mice. Our results indicate that cVSDS model mice present IBS-like symptoms such as chronic intestinal peristaltic changes and abdominal hyperalgesia without organic lesion. We therefore propose the cVSDS paradigm as a novel animal model of IBS with wide validity, elucidating the correlation between depressive states and intestinal abnormalities.
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Affiliation(s)
- Toshinori Yoshioka
- Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan
| | - Misaki Ohashi
- Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan
| | - Kenjiro Matsumoto
- Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Tomoki Omata
- Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan
| | - Takumi Hamano
- Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan
| | - Mayuna Yamazaki
- Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan
| | - Sayaka Kimiki
- Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan
| | - Kotaro Okano
- Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan
| | - Riho Kobayashi
- Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan
| | - Daisuke Yamada
- Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan
| | - Noriyasu Hada
- Laboratory of Pharmacognosy, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan
| | - Shinichi Kato
- Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Akiyoshi Saitoh
- Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan
- *Correspondence: Akiyoshi Saitoh,
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Liu A, Gao W, Zhu Y, Hou X, Chu H. Gut Non-Bacterial Microbiota: Emerging Link to Irritable Bowel Syndrome. Toxins (Basel) 2022; 14:596. [PMID: 36136534 PMCID: PMC9503233 DOI: 10.3390/toxins14090596] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 08/18/2022] [Accepted: 08/25/2022] [Indexed: 11/20/2022] Open
Abstract
As a common functional gastrointestinal disorder, irritable bowel syndrome (IBS) significantly affects personal health and imposes a substantial economic burden on society, but the current understanding of its occurrence and treatment is still inadequate. Emerging evidence suggests that IBS is associated with gut microbial dysbiosis, but most studies focus on the bacteria and neglect other communities of the microbiota, including fungi, viruses, archaea, and other parasitic microorganisms. This review summarizes the latest findings that link the nonbacterial microbiota with IBS. IBS patients show less fungal and viral diversity but some alterations in mycobiome, virome, and archaeome, such as an increased abundance of Candida albicans. Moreover, fungi and methanogens can aid in diagnosis. Fungi are related to distinct IBS symptoms and induce immune responses, intestinal barrier disruption, and visceral hypersensitivity via specific receptors, cells, and metabolites. Novel therapeutic methods for IBS include fungicides, inhibitors targeting fungal pathogenic pathways, probiotic fungi, prebiotics, and fecal microbiota transplantation. Additionally, viruses, methanogens, and parasitic microorganisms are also involved in the pathophysiology and treatment. Therefore, the gut nonbacterial microbiota is involved in the pathogenesis of IBS, which provides a novel perspective on the noninvasive diagnosis and precise treatment of this disease.
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Affiliation(s)
- Ao Liu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China
| | - Wenkang Gao
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China
| | - Yixin Zhu
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
| | - Xiaohua Hou
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China
| | - Huikuan Chu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China
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10
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Chemically Induced Colitis-Associated Cancer Models in Rodents for Pharmacological Modulation: A Systematic Review. J Clin Med 2022; 11:jcm11102739. [PMID: 35628865 PMCID: PMC9146029 DOI: 10.3390/jcm11102739] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 04/29/2022] [Accepted: 05/10/2022] [Indexed: 02/01/2023] Open
Abstract
Animal models for colitis-associated colorectal cancer (CACC) represent an important tool to explore the mechanistic basis of cancer-related inflammation, providing important evidence that several inflammatory mediators play specific roles in the initiation and perpetuation of colitis and CACC. Although several original articles have been published describing the CACC model in rodents, there is no consensus about the induction method. This review aims to identify, summarize, compare, and discuss the chemical methods for the induction of CACC through the PRISMA methodology. METHODS We searched MEDLINE via the Pubmed platform for studies published through March 2021, using a highly sensitive search expression. The inclusion criteria were only original articles, articles where a chemically-induced animal model of CACC is described, preclinical studies in vivo with rodents, and articles published in English. RESULTS Chemically inducible models typically begin with the administration of a carcinogenic compound (as azoxymethane (AOM) or 1,2-dimethylhydrazine (DMH)), and inflammation is caused by repeated cycles of colitis-inducing agents (such as 2,4,6-trinitrobenzenesulfonic acid (TNBS) or dextran sulfate sodium (DSS)). The strains mostly used are C57BL/6 and Balb/c with 5-6 weeks. To characterize the preclinical model, the parameters more used include body weight, stool consistency and morbidity, inflammatory biomarkers such as tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β, angiogenesis markers such as proliferating cell nuclear antigen (PCNA), marker of proliferation Ki-67, and caspase 3, the presence of ulcers, thickness or hyperemia in the colon, and histological evaluation of inflammation. CONCLUSION The AOM administration seems to be important to the CACC induction method, since the carcinogenic effect is achieved with just one administration. DSS has been the more used inflammatory agent; however, the TNBS contribution should be more studied, since it allows a reliable, robust, and a highly reproducible animal model of intestinal inflammation.
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11
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Wu H, Zhan K, Rao K, Zheng H, Qin S, Tang X, Huang S. Comparison of five diarrhea-predominant irritable bowel syndrome (IBS-D) rat models in the brain-gut-microbiota axis. Biomed Pharmacother 2022; 149:112811. [PMID: 35303570 DOI: 10.1016/j.biopha.2022.112811] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 03/06/2022] [Accepted: 03/08/2022] [Indexed: 11/20/2022] Open
Abstract
The brain-gut-microbiota (BGM) axis is known to be essential for diarrhea-predominant irritable bowel syndrome (IBS-D). In order to evaluate the effects of IBS-D rat models (the central sensitization model, the peripheral sensitization model and the compound model) on the BGM axis, five models were induced in Wistar rats with 4% acetic acid (AD, dissolved 0.4 ml of AD in 9.6 ml of ultrapure water) + wrap restrain stress (WRS), 4% AD, colorectal distention (CRD), WRS, and neonatal maternal separation (NMS). Abdominal withdrawal reflex (AWR) scale scores and the moisture content of feces (MCF) were evaluated on the day of completing modeling. Body weight was measured every 7 days during modeling. Brain gut peptides, cytokine levels, the activity of spinal cord neurons, intestinal mucosal barrier function, and gut microbiota were determined after induction of IBS-D. We found intervention with 4% AD + WRS, 4% AD, CRD, WRS, and NMS induced a similar course of effects on the BGM axis. Among the five models, AWR scores (60 mmHg, 80 mmHg) were all increased. The levels of 5-hydroxytryptamine, corticotropin-releasing factor, substance P, and calcitonin gene-related protein in serum rapidly increased, whereas that of neuropeptide Y decreased. C-fos in the spinal cord showed increased neuronal activity. The intestinal permeability was increased and the composition and structure of gut microbiota were changed. In conclusion, the five models could cause changes in BGM axis, but the 4% AD + WRS model was closer to the changes BGM axis of post-inflammatory models of IBS-D.
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Affiliation(s)
- Haomeng Wu
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China; The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou 510120, China; State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510120, China; Collaborative Innovation Team of Traditional Chinese Medicine in Prevention and Treatment of Functional Gastrointestinal Diseases, Guangzhou 510120, China
| | - Kai Zhan
- The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou 510120, China
| | - Kehan Rao
- The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou 510120, China
| | - Huan Zheng
- The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou 510120, China; Collaborative Innovation Team of Traditional Chinese Medicine in Prevention and Treatment of Functional Gastrointestinal Diseases, Guangzhou 510120, China
| | - Shumin Qin
- The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou 510120, China; State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510120, China; Collaborative Innovation Team of Traditional Chinese Medicine in Prevention and Treatment of Functional Gastrointestinal Diseases, Guangzhou 510120, China
| | - Xudong Tang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China.
| | - Shaogang Huang
- The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou 510120, China; State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510120, China; Collaborative Innovation Team of Traditional Chinese Medicine in Prevention and Treatment of Functional Gastrointestinal Diseases, Guangzhou 510120, China; Dongguan Hospital of Guangzhou University of Chinese Medicine, Dongguan 523000, China.
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12
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Malik A, Brudvig JM, Gadsden BJ, Ethridge AD, Mansfield LS. Campylobacter jejuni induces autoimmune peripheral neuropathy via Sialoadhesin and Interleukin-4 axes. Gut Microbes 2022; 14:2064706. [PMID: 35442154 PMCID: PMC9037470 DOI: 10.1080/19490976.2022.2064706] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 03/29/2022] [Indexed: 02/04/2023] Open
Abstract
Campylobacter jejuni is a leading cause of gastroenteritis that has been causally linked with development of the autoimmune peripheral neuropathy Guillain Barré Syndrome (GBS). Previously, we showed that C. jejuni isolates from human enteritis patients induced Type1/17-cytokine dependent colitis in interleukin-10 (IL-10)-/- mice, while isolates from GBS patients colonized these mice without colitis but instead induced autoantibodies that cross-reacted with the sialylated oligosaccharide motifs on the LOS of GBS-associated C. jejuni and the peripheral nerve gangliosides. We show here that infection of IL-10-/- mice with the GBS but not the colitis isolate led to sciatic nerve inflammation and abnormal gait and hind limb movements, with character and timing consistent with this syndrome in humans. Autoantibody responses and associated nerve histologic changes were dependent on IL-4 production by CD4 T cells. We further show that Siglec-1 served as a central antigen presenting cell receptor mediating the uptake of the GBS isolates via interaction with the sialylated oligosaccharide motifs found specifically on the LOS of GBS-associated C. jejuni, and the ensuing T cell differentiation and autoantibody elicitation. Sialylated oligosaccharide motifs on the LOS of GBS-associated C. jejuni therefore acted as both the Siglec-1-ligand for phagocytosis, as well as the epitope for autoimmunity. Overall, we present a mouse model of an autoimmune disease induced directly by a bacterium that is dependent upon Siglec-1 and IL-4. We also demonstrate the negative regulatory role of IL-10 in C. jejuni induced autoimmunity and provide IL-4 and Siglec-1 blockade as potential therapeutic interventions against GBS.
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Affiliation(s)
- Ankit Malik
- Department of Large Animal Clinical Sciences, Michigan State University, East Lansing, MI, USA
- Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, USA
| | - Jean M. Brudvig
- Department of Large Animal Clinical Sciences, Michigan State University, East Lansing, MI, USA
- Comparative Medicine and Integrative Biology Program, Michigan State University, East Lansing, MIUSA
| | - Barbie J. Gadsden
- Department of Large Animal Clinical Sciences, Michigan State University, East Lansing, MI, USA
- Comparative Medicine and Integrative Biology Program, Michigan State University, East Lansing, MIUSA
| | - Alexander D. Ethridge
- Department of Large Animal Clinical Sciences, Michigan State University, East Lansing, MI, USA
- Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, USA
| | - Linda S. Mansfield
- Department of Large Animal Clinical Sciences, Michigan State University, East Lansing, MI, USA
- Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, USA
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13
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An Update of Research Animal Models of Inflammatory Bowel Disease. ScientificWorldJournal 2021; 2021:7479540. [PMID: 34938152 PMCID: PMC8687830 DOI: 10.1155/2021/7479540] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Accepted: 11/28/2021] [Indexed: 12/14/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a group of chronic disorders that includes two main disease forms, Crohn's disease, and ulcerative colitis. The understanding of the intestinal inflammation occurring in IBD has been immeasurably advanced by the development of the now numerous murine models of intestinal inflammation. The usefulness of this research tool in IBD arises from a convergence of underlying genetic susceptibility, immune system dysfunction, environmental factors, and shifts in gut microbiota. Due to the multifactorial feature of these diseases, different animal models have been used to investigate the underlying mechanisms and develop potential therapeutic strategies. The results of preclinical efficacy studies often inform the progression of therapeutic strategies. This review describes the distinct feature and limitations of each murine IBD model and discusses the previous and current lessons from the IBD models.
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14
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Enteric Microbiota-Mediated Serotonergic Signaling in Pathogenesis of Irritable Bowel Syndrome. Int J Mol Sci 2021; 22:ijms221910235. [PMID: 34638577 PMCID: PMC8508930 DOI: 10.3390/ijms221910235] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 09/18/2021] [Accepted: 09/19/2021] [Indexed: 12/12/2022] Open
Abstract
Irritable bowel syndrome (IBS) is a chronic functional disorder that affects the gastrointestinal tract. Details regarding the pathogenesis of IBS remain largely unknown, though the dysfunction of the brain-gut-microbiome (BGM) axis is a major etiological factor, in which neurotransmitters serve as a key communication tool between enteric microbiota and the brain. One of the most important neurotransmitters in the pathology of IBS is serotonin (5-HT), as it influences gastrointestinal motility, pain sensation, mucosal inflammation, immune responses, and brain activity, all of which shape IBS features. Genome-wide association studies discovered susceptible genes for IBS in serotonergic signaling pathways. In clinical practice, treatment strategies targeting 5-HT were effective for a certain portion of IBS cases. The synthesis of 5-HT in intestinal enterochromaffin cells and host serotonergic signaling is regulated by enteric resident microbiota. Dysbiosis can trigger IBS development, potentially through aberrant 5-HT signaling in the BGM axis; thus, the manipulation of the gut microbiota may be an alternative treatment strategy. However, precise information regarding the mechanisms underlying the microbiota-mediated intestinal serotonergic pathway related to the pathogenesis of IBS remains unclear. The present review summarizes current knowledge and recent progress in understanding microbiome–serotonin interaction in IBS cases.
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15
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Safety Profile, In Vitro Anti-Inflammatory Activity, and In Vivo Antiulcerogenic Potential of Root Barks from Annona senegalensis Pers. (Annonaceae). EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:4441375. [PMID: 34527060 PMCID: PMC8437626 DOI: 10.1155/2021/4441375] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 07/18/2021] [Accepted: 08/17/2021] [Indexed: 01/11/2023]
Abstract
Annona senegalensis (Annonaceae) is a tropical shrub widely distributed in Burkina Faso. This plant is traditionally used as a medicine against many pathologies including typhoid fever, gastrointestinal disorders, ulcers, and inflammatory and infectious diseases. The present study was conducted to evaluate the anti-inflammatory and antiulcer properties of Annona senegalensis root bark extracts. Therefore, toxicity tests were first performed, followed by other biological tests. For this purpose, we first undertook to evaluate the toxicity tests before considering the other biological tests in a second step. The results showed that the extracted fractions had a significant effect for the different methods used (protein denaturation inhibition activity, hyaluronidase inhibition activity, and xanthine oxidase inhibition activity). However, of the extracted fractions used, the ethyl acetate fraction was the most anti-inflammatory fraction. The antiulcer activity was evaluated using the best bioactive fraction. The antiulcer effect of the ethyl acetate fraction may be due to both the reduction of gastric acid secretion and gastric cytoprotection. The results of this study also showed that the bioactive fraction reduced ethanol-induced ulceration and pyloric ligation in a dose-dependent manner, and at the highest dose (200 mg/kg), the effect was similar to that of the reference drug. In summary, the ethyl acetate fraction was found to have the best anti-inflammatory and antiulcerogenic activities. The ethyl acetate fraction at a dose of 200 mg/kg also showed a rather interesting level of cytoprotection. The anti-inflammatory and antiulcer activities could be due to the different secondary metabolites contained in the fractions extracted from Annona senegalensis, notably flavonoids, triterpenoids, steroids, saponins, and tannins. As the mechanisms of action are still little or not understood, we will consider in the future identifying the phytoconstituents and the mechanisms of action involved in the results.
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16
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West C, McVey Neufeld KA. Animal models of visceral pain and the role of the microbiome. NEUROBIOLOGY OF PAIN (CAMBRIDGE, MASS.) 2021; 10:100064. [PMID: 34151049 PMCID: PMC8190503 DOI: 10.1016/j.ynpai.2021.100064] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 05/16/2021] [Accepted: 05/24/2021] [Indexed: 02/06/2023]
Abstract
Visceral pain refers to pain arising from the internal organs and is distinctly different from the expression and mechanisms of somatic pain. Diseases and disorders with increased visceral pain are associated with significantly reduced quality of life and incur large financial costs due to medical visits and lost work productivity. In spite of the notable burden of illness associated with those disorders involving increased visceral pain, and some knowledge regarding etiology, few successful therapeutics have emerged, and thus increased attention to animal models of visceral hypersensitivity is warranted in order to elucidate new treatment opportunities. Altered microbiota-gut-brain (MGB) axis communication is central to the comorbid gastrointestinal/psychiatric diseases of which increased visceral (intestinal) sensitivity is a hallmark. This has led to a particular focus on intestinal microbiome disruption and its potential role in the etiology of heightened visceral pain. Here we provide a review of studies examining models of heightened visceral pain due to altered bidirectional communication of the MGB axis, many of which are conducted on a background of stress exposure. We discuss work in which the intestinal microbiota has either been directly manipulated (as with germ-free, antibiotic, and fecal microbial transplantation studies) or indirectly affected through early life or adult stress, inflammation, and infection. Animal models of visceral pain alterations with accompanying changes to the intestinal microbiome have the highest face and construct validity to the human condition and are the focus of the current review.
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Affiliation(s)
- Christine West
- McMaster Brain-Body Institute at St Joseph’s Healthcare, Hamilton, Ontario, Canada
| | - Karen-Anne McVey Neufeld
- McMaster Brain-Body Institute at St Joseph’s Healthcare, Hamilton, Ontario, Canada
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
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17
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Parisio C, Lucarini E, Micheli L, Toti A, Bellumori M, Cecchi L, Calosi L, Bani D, Di Cesare Mannelli L, Mulinacci N, Ghelardini C. Extra virgin olive oil and related by-products (Olea europaea L.) as natural sources of phenolic compounds for abdominal pain relief in gastrointestinal disorders in rats. Food Funct 2020; 11:10423-10435. [PMID: 33237043 DOI: 10.1039/d0fo02293d] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Management of abdominal pain, a common symptom of IBDs and IBS, is still a clinical problem. Extra virgin olive oil (EVOO), a main component of the Mediterranean diet, shows positive effects on chronic inflammation in IBDs. In this study, the effect of the oral administration of EVOO (3 mL) and two olive milling by-products, DPA (300 mg kg-1) and DRF (300 mg kg-1), on preventing the development of abdominal pain in a DNBS-induced colitis model in rats was evaluated. The doses were chosen with the aim of simulating a plausible daily intake in humans. DPA and EVOO treatments significantly reduced the abdominal viscero-motor response to colon-rectal distension at 2 and 3 mL of balloon distension volume, both 7 and 14 days after the DNBS-injection. DRF showed efficacy in the reduction of visceral hypersensitivity only with 3 mL balloon inflation. In awake animals, DPA and DRF reduced pain perception (evaluated as abdominal withdrawal reflex) with all balloon distension volumes, while EVOO was effective only with higher distension volumes. Fourteen days after the DNBS-injection, all samples reduced the macroscopic intestinal damage (quantified as the macroscopic damage score) also showing, at the microscopic level, a reduction of the inflammatory infiltrate (quantified by hematoxylin and eosin analysis), fibrosis (highlighted by picrosirius red staining), the increase in mast cells and their degranulation (analyzed by triptase immunohistochemistry). This is the first report on the promotion of abdominal pain relief in a rat model obtained administering EVOO and two derived by-products. Our results suggest a protective role of phenol-rich EVOO and milling by-products, which may be proposed as food ingredients for novel functional foods.
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Affiliation(s)
- Carmen Parisio
- Department of Neuroscience, Psychology, Drug Research and Child Health - NEUROFARBA - Pharmacology and Toxicology Section, University of Florence, Viale Pieraccini 6, 50139, Florence, Italy.
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18
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Mishima Y, Ishihara S. Molecular Mechanisms of Microbiota-Mediated Pathology in Irritable Bowel Syndrome. Int J Mol Sci 2020; 21:ijms21228664. [PMID: 33212919 PMCID: PMC7698457 DOI: 10.3390/ijms21228664] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Revised: 11/12/2020] [Accepted: 11/13/2020] [Indexed: 02/07/2023] Open
Abstract
Irritable bowel syndrome (IBS) is one of the most prevalent functional gastrointestinal disorders, and accumulating evidence gained in both preclinical and clinical studies indicate the involvement of enteric microbiota in its pathogenesis. Gut resident microbiota appear to influence brain activity through the enteric nervous system, while their composition and function are affected by the central nervous system. Based on these results, the term “brain–gut–microbiome axis” has been proposed and enteric microbiota have become a potential therapeutic target in IBS cases. However, details regarding the microbe-related pathophysiology of IBS remain elusive. This review summarizes the existing knowledge of molecular mechanisms in the pathogenesis of IBS as well as recent progress related to microbiome-derived neurotransmitters, compounds, metabolites, neuroendocrine factors, and enzymes.
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19
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Morales W, Triantafyllou K, Parodi G, Weitsman S, Park SC, Rezaie A, Pichetshote N, Lin E, Pimentel M. Immunization with cytolethal distending toxin B produces autoantibodies to vinculin and small bowel bacterial changes in a rat model of postinfectious irritable bowel syndrome. Neurogastroenterol Motil 2020; 32:e13875. [PMID: 32436301 DOI: 10.1111/nmo.13875] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 03/25/2020] [Accepted: 04/17/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND Recent data substantiate the importance of acute gastroenteritis in the development of irritable bowel syndrome (IBS). An animal model of postinfectious IBS determined the importance of cytolethal distending toxin B (CdtB) during live Campylobacter jejuni infection and its development of autoimmunity to vinculin. In this study, we examine whether subcutaneous exposure to CdtB alone is sufficient to produce the postinfectious IBS effect and autoimmunity. METHODS Sixty adult Sprague Dawley rats were randomized into 2 groups to receive subcutaneous injection of either CdtB or vehicle and administered a booster injection of the same product 3 weeks later. Serum was collected for anti-CdtB and anti-vinculin titers. Duodenal and ileal luminal contents for total eubacterial qPCR, and ileal bowel segments were harvested for vinculin and ileal expression. In a second experiment, 4 adult, Sprague Dawley rats were injected with either Cy7-labeled anti-CdtB and anti-vinculin antibodies were injected into the tail vein and imaged to determine organ localization of the antibodies. KEY RESULTS Rats that received CdtB increased in serum anti-CdtB after injection. CdtB exposure also precipitated significant elevation in anti-vinculin antibodies (P < .001). This was associated with a reduction in intestinal vinculin expression (P < .001) that negatively correlated with serum anti-CdtB levels. CdtB exposure was also associated with greater levels of duodenal (P < .001) and ileal (P < .01) bacteria by qPCR that positively correlated with anti-CdtB levels. CONCLUSIONS AND INFERENCES Rats injected with CdtB developed a postinfectious IBS-like phenotype and autoimmunity to vinculin with corresponding reduction in intestinal vinculin expression.
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Affiliation(s)
- Walter Morales
- Medically Associated Science and Technology (MAST) Program, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Konstantinos Triantafyllou
- Hepatogastroenterology Unit, 2nd Department of Internal Medicine - Propaedeutic, Research Institute and Diabetes Center, Medical School, Attikon University General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Gonzalo Parodi
- Medically Associated Science and Technology (MAST) Program, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Stacy Weitsman
- Medically Associated Science and Technology (MAST) Program, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Sung Chul Park
- Medically Associated Science and Technology (MAST) Program, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, South Korea
| | - Ali Rezaie
- Medically Associated Science and Technology (MAST) Program, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Nipaporn Pichetshote
- Medically Associated Science and Technology (MAST) Program, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Eugenia Lin
- Medically Associated Science and Technology (MAST) Program, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Mark Pimentel
- Medically Associated Science and Technology (MAST) Program, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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20
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Gomes Júnior A, Islam MT, Nicolau LAD, de Souza LKM, Araújo TDS, Lopes de Oliveira GA, de Melo Nogueira K, da Silva Lopes L, Medeiros JVR, Mubarak MS, Melo-Cavalcante AAC. Anti-Inflammatory, Antinociceptive, and Antioxidant Properties of Anacardic Acid in Experimental Models. ACS OMEGA 2020; 5:19506-19515. [PMID: 32803044 PMCID: PMC7424580 DOI: 10.1021/acsomega.0c01775] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 07/09/2020] [Indexed: 06/11/2023]
Abstract
Anacardic acid (AA), a compound extracted from cashew nut liquid, exhibits numerous pharmacological activities. The aim of the current investigation was to assess the anti-inflammatory, antinociceptive, and antioxidant activities of AA in mouse models. For this, Swiss albino mice were pretreated with AA (10, 25, 50 mg/kg, intraperitoneally, ip) 30 min prior to the administration of carrageenan, as well as 25 mg/kg of prostaglandin E2, dextran, histamine, and compound 48/80. The antinociceptive activity was evaluated by formalin, abdominal, and hot plate tests, using antagonist of opioid receptors (naloxene, 3 mg/kg, ip) to identify antinociceptive mechanisms. Results from this study revealed that AA at 25 mg/kg inhibits carrageenan-induced edema. In addition, AA at 25 mg/kg reduced edema and leukocyte and neutrophilic migration to the intraperitoneal cavity, diminished myeloperoxidase activity and malondialdehyde concentration, and increased the levels of reduced glutathione. In nociceptive tests, it also decreased licking, abdominal writhing, and latency to thermal stimulation, possibly via interaction with opioid receptors. Taken together, these results indicate that AA exhibits anti-inflammatory and antinociceptive actions and also reduces oxidative stress in acute experimental models, suggesting AA as a promising compound in the pharmaceutical arena.
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Affiliation(s)
- Antonio
Luiz Gomes Júnior
- RENORBIO
- Post-Graduation Program in Biotechnology, Federal University of Piauí, Teresina 64049-550, Piauí, Brazil
- LAPNEX
- Laboratory of Research in Experimental Neurochemistry of Post-Graduation
Program in Pharmaceutical Sciences, Federal
University of Piauí, Teresina CEP 64049-550, Piauí, Brazil
- LAPGENIC
- Laboratory of Research in Genetic Toxicology of Post-Graduation
Program in Pharmaceutical Sciences, Federal
University of Piauí, Teresina 64049-550, Piauí, Brazil
| | - Muhammad Torequl Islam
- Laboratory
of Theoretical and Computational Biophysics, Ton Duc Thang University, Ho Chi Minh City 700000, Vietnam
- Faculty
of Pharmacy, Ton Duc Thang University, Ho Chi Minh City 700000, Vietnam
| | - Lucas Antonio Duarte Nicolau
- LAFFEX -
Laboratory of Experimental Physiopharmacology in Biotechnology and
Biodiversity Center Research (BIOTEC), Federal
University of Piauí-CMRV, Parnaíba 64202-020, Piauí, Brazil
| | - Luan Kevin Miranda de Souza
- RENORBIO
- Post-Graduation Program in Biotechnology, Federal University of Piauí, Teresina 64049-550, Piauí, Brazil
- LAFFEX -
Laboratory of Experimental Physiopharmacology in Biotechnology and
Biodiversity Center Research (BIOTEC), Federal
University of Piauí-CMRV, Parnaíba 64202-020, Piauí, Brazil
| | - Tiago de Souza
Lopes Araújo
- RENORBIO
- Post-Graduation Program in Biotechnology, Federal University of Piauí, Teresina 64049-550, Piauí, Brazil
- LAFFEX -
Laboratory of Experimental Physiopharmacology in Biotechnology and
Biodiversity Center Research (BIOTEC), Federal
University of Piauí-CMRV, Parnaíba 64202-020, Piauí, Brazil
| | - Guilherme Antônio Lopes de Oliveira
- RENORBIO
- Post-Graduation Program in Biotechnology, Federal University of Piauí, Teresina 64049-550, Piauí, Brazil
- LAPNEX
- Laboratory of Research in Experimental Neurochemistry of Post-Graduation
Program in Pharmaceutical Sciences, Federal
University of Piauí, Teresina CEP 64049-550, Piauí, Brazil
- LAFFEX -
Laboratory of Experimental Physiopharmacology in Biotechnology and
Biodiversity Center Research (BIOTEC), Federal
University of Piauí-CMRV, Parnaíba 64202-020, Piauí, Brazil
| | - Kerolayne de Melo Nogueira
- LAFFEX -
Laboratory of Experimental Physiopharmacology in Biotechnology and
Biodiversity Center Research (BIOTEC), Federal
University of Piauí-CMRV, Parnaíba 64202-020, Piauí, Brazil
| | - Luciano da Silva Lopes
- LAPNEX
- Laboratory of Research in Experimental Neurochemistry of Post-Graduation
Program in Pharmaceutical Sciences, Federal
University of Piauí, Teresina CEP 64049-550, Piauí, Brazil
| | - Jand-Venes Rolim Medeiros
- RENORBIO
- Post-Graduation Program in Biotechnology, Federal University of Piauí, Teresina 64049-550, Piauí, Brazil
- LAFFEX -
Laboratory of Experimental Physiopharmacology in Biotechnology and
Biodiversity Center Research (BIOTEC), Federal
University of Piauí-CMRV, Parnaíba 64202-020, Piauí, Brazil
| | | | - Ana Amélia
de Carvalho Melo-Cavalcante
- RENORBIO
- Post-Graduation Program in Biotechnology, Federal University of Piauí, Teresina 64049-550, Piauí, Brazil
- LAPGENIC
- Laboratory of Research in Genetic Toxicology of Post-Graduation
Program in Pharmaceutical Sciences, Federal
University of Piauí, Teresina 64049-550, Piauí, Brazil
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21
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Lucarini E, Parisio C, Branca JJV, Segnani C, Ippolito C, Pellegrini C, Antonioli L, Fornai M, Micheli L, Pacini A, Bernardini N, Blandizzi C, Ghelardini C, Di Cesare Mannelli L. Deepening the Mechanisms of Visceral Pain Persistence: An Evaluation of the Gut-Spinal Cord Relationship. Cells 2020; 9:cells9081772. [PMID: 32722246 PMCID: PMC7464824 DOI: 10.3390/cells9081772] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 07/11/2020] [Accepted: 07/20/2020] [Indexed: 12/11/2022] Open
Abstract
The management of visceral pain is a major clinical problem in patients affected by gastrointestinal disorders. The poor knowledge about pain chronicization mechanisms prompted us to study the functional and morphological alterations of the gut and nervous system in the animal model of persistent visceral pain caused by 2,4-dinitrobenzenesulfonic acid (DNBS). This agent, injected intrarectally, induced a colonic inflammation peaking on day 3 and remitting progressively from day 7. In concomitance with bowel inflammation, the animals developed visceral hypersensitivity, which persisted after colitis remission for up to three months. On day 14, the administration of pain-relieving drugs (injected intraperitoneally and intrathecally) revealed a mixed nociceptive, inflammatory and neuropathic pain originating from both the peripheral and central nervous system. At this time point, the colonic histological analysis highlighted a partial restitution of the tunica mucosa, transmural collagen deposition, infiltration of mast cells and eosinophils, and upregulation of substance P (SP)-positive nerve fibers, which were surrounded by eosinophils and MHC-II-positive macrophages. A significant activation of microglia and astrocytes was observed in the dorsal and ventral horns of spinal cord. These results suggest that the persistence of visceral pain induced by colitis results from maladaptive plasticity of the enteric, peripheral and central nervous systems.
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Affiliation(s)
- Elena Lucarini
- Department of Neuroscience, Psychology, Drug Research and Child Health, Neurofarba, Pharmacology and Toxicology Section, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy; (E.L.); (C.P.); (L.M.); (C.G.)
| | - Carmen Parisio
- Department of Neuroscience, Psychology, Drug Research and Child Health, Neurofarba, Pharmacology and Toxicology Section, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy; (E.L.); (C.P.); (L.M.); (C.G.)
| | - Jacopo J. V. Branca
- Department of Experimental and Clinical Medicine—DMSC, Anatomy and Histology Section, University of Florence, L. go Brambilla 3, 50134 Florence, Italy; (J.J.V.B.); (A.P.)
| | - Cristina Segnani
- Department of Clinical and Experimental Medicine, Unit of Histology, University of Pisa, 56126 Pisa, Italy; (C.S.); (C.I.); (N.B.)
| | - Chiara Ippolito
- Department of Clinical and Experimental Medicine, Unit of Histology, University of Pisa, 56126 Pisa, Italy; (C.S.); (C.I.); (N.B.)
| | - Carolina Pellegrini
- Department of Pharmacy, Unit of Pharmacology, University of Pisa, 56126 Pisa, Italy;
| | - Luca Antonioli
- Department of Clinical and Experimental Medicine, Unit of Pharmacology and Pharmacovigilance, University of Pisa, 56126 Pisa, Italy; (L.A.); (M.F.); (C.B.)
| | - Matteo Fornai
- Department of Clinical and Experimental Medicine, Unit of Pharmacology and Pharmacovigilance, University of Pisa, 56126 Pisa, Italy; (L.A.); (M.F.); (C.B.)
| | - Laura Micheli
- Department of Neuroscience, Psychology, Drug Research and Child Health, Neurofarba, Pharmacology and Toxicology Section, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy; (E.L.); (C.P.); (L.M.); (C.G.)
| | - Alessandra Pacini
- Department of Experimental and Clinical Medicine—DMSC, Anatomy and Histology Section, University of Florence, L. go Brambilla 3, 50134 Florence, Italy; (J.J.V.B.); (A.P.)
| | - Nunzia Bernardini
- Department of Clinical and Experimental Medicine, Unit of Histology, University of Pisa, 56126 Pisa, Italy; (C.S.); (C.I.); (N.B.)
- Interdepartmental Research Center “Nutraceuticals and Food for Health”, University of Pisa, 56126 Pisa, Italy
| | - Corrado Blandizzi
- Department of Clinical and Experimental Medicine, Unit of Pharmacology and Pharmacovigilance, University of Pisa, 56126 Pisa, Italy; (L.A.); (M.F.); (C.B.)
| | - Carla Ghelardini
- Department of Neuroscience, Psychology, Drug Research and Child Health, Neurofarba, Pharmacology and Toxicology Section, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy; (E.L.); (C.P.); (L.M.); (C.G.)
| | - Lorenzo Di Cesare Mannelli
- Department of Neuroscience, Psychology, Drug Research and Child Health, Neurofarba, Pharmacology and Toxicology Section, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy; (E.L.); (C.P.); (L.M.); (C.G.)
- Correspondence:
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22
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Rossi G, Gioacchini G, Pengo G, Suchodolski JS, Jergens AE, Allenspach K, Gavazza A, Scarpona S, Berardi S, Galosi L, Bassotti G, Cerquetella M. Enterocolic increase of cannabinoid receptor type 1 and type 2 and clinical improvement after probiotic administration in dogs with chronic signs of colonic dysmotility without mucosal inflammatory changes. Neurogastroenterol Motil 2020; 32:e13717. [PMID: 31495983 DOI: 10.1111/nmo.13717] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 08/20/2019] [Accepted: 08/20/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND Colonic dysmotility in dogs can cause different GI signs. Sometimes, histology of enterocolic biopsies does not reveal inflammatory infiltrates or mucosal lesions that are typically associated with clinical disease activity. It is speculated that, similarly to humans, colonic dysmotility may be anxiety-based, although recent data demonstrate that irritable bowel syndrome (IBS) could result from acute infectious enteritis. Specific Lactobacillus spp. strains administered orally in humans induced the expression of μ-opioid and cannabinoid receptors in mucosal enterocytes, modulating intestinal morphine-like analgesic functions. We investigated the potential association of GI signs caused by colonic dysmotility and mucosal expression of cannabinoid receptors in intestinal epithelial cells and the number of mucosal mast cells. METHODS Ten to 15 endoscopic biopsies were collected from colonic mucosa of 20 dogs diagnosed with dysmotility disturbances before and after probiotic (Slab51 bacterial blend; Sivoy® ) administration (3-month period). Number and distribution of mast cells (MCs), and cannabinoid receptor type 1 (CB1) and type 2 (CB2) were evaluated by immunohistochemistry and PCR. Results were compared to data obtained from five clinically healthy dogs (archive samples). KEY RESULTS Decreased numbers of MCs (P < .0001) and increased CB1- and CB2-positive epithelial cells (P < .0001) in diseased dogs were positively associated with post-treatment CCECAI scores (P < .0001). CONCLUSIONS AND INFERENCES Our results suggest that probiotic administration can reduce signs of colonic dysmotility, possibly due to microbiota modulation and epithelial cell receptor-mediated signaling in intestinal mucosa.
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Affiliation(s)
- Giacomo Rossi
- School of Biosciences and Veterinary Medicine, University of Camerino, Matelica, Italy
| | - Giorgia Gioacchini
- Department of Life and Environmental Sciences, Polytechnic University of Marche, Ancona, Italy
| | | | - Jan S Suchodolski
- Gastrointestinal Laboratory, Department of Small Animal Clinical Sciences, Texas A&M University, College Station, TX, USA
| | - Albert E Jergens
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, USA
| | - Karin Allenspach
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, USA
| | - Alessandra Gavazza
- School of Biosciences and Veterinary Medicine, University of Camerino, Matelica, Italy
| | - Silvia Scarpona
- School of Biosciences and Veterinary Medicine, University of Camerino, Matelica, Italy
| | - Sara Berardi
- School of Biosciences and Veterinary Medicine, University of Camerino, Matelica, Italy
| | - Livio Galosi
- School of Biosciences and Veterinary Medicine, University of Camerino, Matelica, Italy
| | - Gabrio Bassotti
- Gastroenterology and Hepatology Section, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy
| | - Matteo Cerquetella
- School of Biosciences and Veterinary Medicine, University of Camerino, Matelica, Italy
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23
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Accarie A, Vanuytsel T. Animal Models for Functional Gastrointestinal Disorders. Front Psychiatry 2020; 11:509681. [PMID: 33262709 PMCID: PMC7685985 DOI: 10.3389/fpsyt.2020.509681] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Accepted: 10/22/2020] [Indexed: 12/12/2022] Open
Abstract
Functional gastrointestinal disorders (FGID), such as functional dyspepsia (FD) and irritable bowel syndrome (IBS) are characterized by chronic abdominal symptoms in the absence of an organic, metabolic or systemic cause that readily explains these complaints. Their pathophysiology is still not fully elucidated and animal models have been of great value to improve the understanding of the complex biological mechanisms. Over the last decades, many animal models have been developed to further unravel FGID pathophysiology and test drug efficacy. In the first part of this review, we focus on stress-related models, starting with the different perinatal stress models, including the stress of the dam, followed by a discussion on neonatal stress such as the maternal separation model. We also describe the most commonly used stress models in adult animals which brought valuable insights on the brain-gut axis in stress-related disorders. In the second part, we focus more on models studying peripheral, i.e., gastrointestinal, mechanisms, either induced by an infection or another inflammatory trigger. In this section, we also introduce more recent models developed around food-related metabolic disorders or food hypersensitivity and allergy. Finally, we introduce models mimicking FGID as a secondary effect of medical interventions and spontaneous models sharing characteristics of GI and anxiety-related disorders. The latter are powerful models for brain-gut axis dysfunction and bring new insights about FGID and their comorbidities such as anxiety and depression.
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Affiliation(s)
- Alison Accarie
- Department of Chronic Diseases, Metabolism and Ageing (ChroMetA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - Tim Vanuytsel
- Department of Chronic Diseases, Metabolism and Ageing (ChroMetA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium.,Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
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24
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Silva I, Pinto R, Mateus V. Preclinical Study in Vivo for New Pharmacological Approaches in Inflammatory Bowel Disease: A Systematic Review of Chronic Model of TNBS-Induced Colitis. J Clin Med 2019; 8:jcm8101574. [PMID: 31581545 PMCID: PMC6832474 DOI: 10.3390/jcm8101574] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 09/19/2019] [Accepted: 09/25/2019] [Indexed: 12/14/2022] Open
Abstract
The preclinical studies in vivo provide means of characterizing physiologic interactions when our understanding of such processes is insufficient to allow replacement with in vitro systems and play a pivotal role in the development of a novel therapeutic drug cure. Chemically induced colitis models are relatively easy and rapid to develop. The 2,4,6-trinitrobenzenesulfonic acid (TNBS) colitis model is one of the main models in the experimental studies of inflammatory bowel disease (IBD) since inflammation induced by TNBS mimics several features of Crohn’s disease. This review aims to summarize the existing literature and discuss different protocols for the induction of chronic model of TNBS-induced colitis. We searched MEDLINE via Pubmed platform for studies published through December 2018, using MeSH terms (Crohn Disease.kw) OR (Inflammatory Bowel Diseases.kw) OR (Colitis, Ulcerative.kw) AND (trinitrobenzenesulfonic acid.kw) AND (disease models, animal.kw) AND (mice.all). The inclusion criteria were original articles, preclinical studies in vivo using mice, chronic model of colitis, and TNBS as the inducer of colitis and articles published in English. Chronic TNBS-induced colitis is made with multiple TNBS intrarectal administrations in an average dose of 1.2 mg using a volume lower than 150 μL in 50% ethanol. The strains mostly used are Balb/c and C57BL/6 with 5–6 weeks. To characterize the preclinical model the parameters more used include body weight, stool consistency and morbidity, inflammatory biomarkers like interferon (IFN)-γ, myeloperoxidase (MPO), tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-10, presence of ulcers, thickness or hyperemia in the colon, and histological evaluation of the inflammation. Experimental chronic colitis is induced by multiple rectal instillations of TNBS increasing doses in ethanol using Balb/c and C57BL/6 mice.
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Affiliation(s)
- Inês Silva
- H&TRC–Health and Technology Research Center, ESTeSL–Lisbon School of Health Technology, Instituto Politécnico de Lisboa, 1990-096 Lisbon, Portugal;
- iMed.ULisboa, Faculdade de Farmácia, Universidade de Lisboa, 1990-096 Lisboa, Portugal;
| | - Rui Pinto
- iMed.ULisboa, Faculdade de Farmácia, Universidade de Lisboa, 1990-096 Lisboa, Portugal;
- JCS, Dr. Joaquim Chaves, Laboratório de Análises Clínicas, Miraflores, 1495-069 Algés, Portugal
| | - Vanessa Mateus
- H&TRC–Health and Technology Research Center, ESTeSL–Lisbon School of Health Technology, Instituto Politécnico de Lisboa, 1990-096 Lisbon, Portugal;
- iMed.ULisboa, Faculdade de Farmácia, Universidade de Lisboa, 1990-096 Lisboa, Portugal;
- Correspondence: ; Tel.: +351-218-980-400; Fax: +351-218-980-460
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25
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Effects of probiotic supplementation on post-infectious irritable bowel syndrome in rodent model. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2019; 19:195. [PMID: 31366385 PMCID: PMC6668102 DOI: 10.1186/s12906-019-2610-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Accepted: 07/23/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND Probiotics have been reported to be the active component used in the treatment of many functional gastrointestinal symptoms and syndromes. Lactobacillus and yeast culture are extensively used in probiotic supplements and traditional treatments for irritable bowel syndrome (IBS). The aim of this study was to investigate the effects of probiotic treatments (Lactobacillus acidophilus LA5, Bifidobacterium animalis subsp. lactis BB12 and Saccharomyces cerevisiae var. boulardii) on the behavioral response, targeted gene expression and pro-inflammatory cytokine levels of Pi (Post infectious)-IBS -induced mice. METHODS Pathogen-free male C57L/B6 mice and the Trichinella-infected mice were used to measure the score of abdominal withdrawal reflex (AWR). To compare molecular, biological and biochemical evidences of given probiotics with normal and positive control groups in mice, we conducted quantitative reverse transcription polymerase chain reaction (RT-qPCR), western blotting, and cytokine analysis. RESULTS Pi-IBS-induced immune response was confirmed that PAR-2 mRNA level was significantly increased by Trichinella infection (P < 0.05). The reduction of Pi-IBS symptoms through Trichinella infection and the effects of given probiotics were confirmed by a change in the protein levels of cytokines (P < 0.05). In addition, the administration of DW (Daewon) probiotics significantly decreased serum levels of IL-1 and IL-6 (P < 0.05). CONCLUSIONS We have demonstrated that the given probiotics decreased pro-inflammatory cytokine levels in both the control and Pi-IBS induced mice. Taken all the results together, the results support that DW probiotics has a potential as a probiotic medication for patient with IBS via regulating TNF-α and IL-6 protein levels and serum IL-1 and IL-6 levels.
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26
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Wang XS, Yue J, Hu LN, Tian Z, Yang LK, Lu L, Zhao MG, Liu SB. Effects of CPEB1 in the anterior cingulate cortex on visceral pain in mice. Brain Res 2019; 1712:55-62. [DOI: 10.1016/j.brainres.2019.02.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 12/28/2018] [Accepted: 02/03/2019] [Indexed: 02/07/2023]
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27
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Barbara G, Grover M, Bercik P, Corsetti M, Ghoshal UC, Ohman L, Rajilić-Stojanović M. Rome Foundation Working Team Report on Post-Infection Irritable Bowel Syndrome. Gastroenterology 2019; 156:46-58.e7. [PMID: 30009817 PMCID: PMC6309514 DOI: 10.1053/j.gastro.2018.07.011] [Citation(s) in RCA: 143] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Revised: 07/03/2018] [Accepted: 07/05/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS The existence of postinfection irritable bowel syndrome (PI-IBS) has been substantiated by epidemiology studies conducted in diverse geographic and clinical settings. However, the available evidence has not been well summarized, and there is little guidance for diagnosis and treatment of PI-IBS. The ROME Foundation has produced a working team report to summarize the available evidence on the pathophysiology of PI-IBS and provide guidance for diagnosis and treatment, based on findings reported in the literature and clinical experience. METHODS The working team conducted an evidence-based review of publication databases for articles describing the clinical features (diagnosis), pathophysiology (intestinal sensorimotor function, microbiota, immune dysregulation, barrier dysfunction, enteroendocrine pathways, and genetics), and animal models of PI-IBS. We used a Delphi-based consensus system to create guidelines for management of PI-IBS and a developed treatment algorithm based on published findings and experiences of team members. RESULTS PI-IBS develops in about 10% of patients with infectious enteritis. Risk factors include female sex, younger age, psychological distress during or before acute gastroenteritis, and severity of the acute episode. The pathogenesis of PI-PBS appears to involve changes in the intestinal microbiome as well as epithelial, serotonergic, and immune system factors. However, these mechanisms are incompletely understood. There are no evidence-based, effective pharmacologic strategies for treatment of PI-IBS. We provide a consensus-based treatment algorithm, based on clinical presentation and potential disease mechanisms. CONCLUSIONS Based on a systematic review of the literature and team experience, we summarize the clinical features, pathophysiology (from animal models and human studies), and progression of PI-IBS. Based on these findings, we present an algorithm for diagnosis and treatment of PI-IBS based on team consensus. We also propose areas for future investigation.
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Affiliation(s)
- Giovanni Barbara
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
| | - Madhusudan Grover
- Enteric NeuroScience Program, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Premysl Bercik
- Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Maura Corsetti
- Nottingham Digestive Diseases Biomedical Research Centre, National Institute for Health Research, Nottingham University Hospitals NHS Trust, University of Nottingham, UK
| | - Uday C Ghoshal
- Department of Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Lena Ohman
- Department of Microbiology and Immunology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Mirjana Rajilić-Stojanović
- Department of Biochemical Engineering and Biotechnology, Faculty of Technology and Metallurgy, University of Belgrade, Belgrade, Serbia
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28
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Moulahoum H, Boumaza BMA, Ferrat M, Bounaama A, Djerdjouri B. Arsenic trioxide ameliorates murine colon inflammation through inflammatory cell enzymatic modulation. Naunyn Schmiedebergs Arch Pharmacol 2018; 392:259-270. [PMID: 30415273 DOI: 10.1007/s00210-018-1578-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Accepted: 11/02/2018] [Indexed: 12/20/2022]
Abstract
Arsenic trioxide (As2O3) is a trending subject in recent therapy approaches despite its described toxicity. In this work, we have investigated the use of arsenic trioxide in a murine model of chemically induced inflammatory bowel disease "colitis." Male mice were randomly separated into four different groups. Controls received vehicle, arsenic group had a daily injection of As2O3 (2.5 mg/kg, i.p.) for 2 days. Colitis was induced through intra-rectal instillation of 4% (v/v) solution of acetic acid in the second day. The treatment group (As2O3 + acetic acid) received the same treatment as the two previous groups. Twenty-four hours after colitis challenge, animals were sacrificed and organs (colons, livers, and kidneys) were taken for analysis. Disease-related macroscopic and microscopic symptoms, as well as histologic observations, showed a high index in the colitis group, which was greatly reduced by the As2O3 pretreatment. Similarly, colon length was reduced during colon inflammation, which was prevented in the presence of As2O3. Inflammatory cells and oxidative stress markers significantly increased during inflammation accompanied by a considerable reduction of antioxidants. As2O3 treatment managed to reverse these observations to normal levels. Mitochondrial implication was observed through mPTP opening phenomena and semi-quantitative cell death estimation. Low-dose As2O3 use as a mean of preventing the acute phase of colitis can be seen as an interesting approach which counts as a great addition to IBD available treatments.
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Affiliation(s)
- Hichem Moulahoum
- Laboratory of Cell and Molecular Biology, Faculty of Biological Sciences, University of Sciences and Technology Houari Boumediene (USTHB), Algiers, Algeria. .,Faculty of Science, Biochemistry Department, Ege University, Bornova, 35100, İzmir, Turkey.
| | - Belkacem Mohamed Amine Boumaza
- Laboratory of Cell and Molecular Biology, Faculty of Biological Sciences, University of Sciences and Technology Houari Boumediene (USTHB), Algiers, Algeria
| | - Meriem Ferrat
- Laboratory of Cell and Molecular Biology, Faculty of Biological Sciences, University of Sciences and Technology Houari Boumediene (USTHB), Algiers, Algeria
| | - Abdelkader Bounaama
- Laboratory of Cell and Molecular Biology, Faculty of Biological Sciences, University of Sciences and Technology Houari Boumediene (USTHB), Algiers, Algeria
| | - Bahia Djerdjouri
- Laboratory of Cell and Molecular Biology, Faculty of Biological Sciences, University of Sciences and Technology Houari Boumediene (USTHB), Algiers, Algeria
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Zhang F, Weng ZJ, Wu LY, Bao CH, Yang L, Zhao M, Wu HZ, Liu HR, Zhou CL. Etiology related irritable bowel syndrome animal models. Shijie Huaren Xiaohua Zazhi 2018; 26:1772-1777. [DOI: 10.11569/wcjd.v26.i30.1772] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a common chronic functional disease of the gastrointestinal tract. Its incidence is increasing worldwide. However, its etiology and pathogenesis are not clear yet, although some factors, such as visceral hypersensitivity, intestinal infection, mental state, gastrointestinal hormones, intestinal flora, and genetic factors, are widely accepted. Great progress has been made in the study of animal models related to the etiology and pathogenesis of IBS. This article summarizes the domestic and international etiology related animal models of IBS, in order to provide reference for choosing appropriate animal models in the basic research of IBS.
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Affiliation(s)
- Fang Zhang
- Department of Acupuncture and Immunity, Shanghai Institute of Acupuncture and Moxibustion, Shanghai 200030, China
| | - Zhi-Jun Weng
- Department of Acupuncture and Immunity, Shanghai Institute of Acupuncture and Moxibustion, Shanghai 200030, China
| | - Lu-Yi Wu
- Shanghai Qigong Research Institute, Shanghai 200030, China
| | - Chun-Hui Bao
- Department of Acupuncture and Immunity, Shanghai Institute of Acupuncture and Moxibustion, Shanghai 200030, China
| | - Ling Yang
- Department of Acupuncture and Immunity, Shanghai Institute of Acupuncture and Moxibustion, Shanghai 200030, China
| | - Min Zhao
- Department of Acupuncture and Immunity, Shanghai Institute of Acupuncture and Moxibustion, Shanghai 200030, China
| | - Huan-Zhen Wu
- Department of Acupuncture and Immunity, Shanghai Institute of Acupuncture and Moxibustion, Shanghai 200030, China
| | - Hui-Rong Liu
- Department of Acupuncture and Immunity, Shanghai Institute of Acupuncture and Moxibustion, Shanghai 200030, China
| | - Ci-Li Zhou
- Department of Acupuncture and Immunity, Shanghai Institute of Acupuncture and Moxibustion, Shanghai 200030, China
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30
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Zhu X, Liu Z, Qin Y, Niu W, Wang Q, Li L, Zhou J. Analgesic Effects of Electroacupuncture at St25 and Cv12 in a Rat Model of Postinflammatory Irritable Bowel Syndrome Visceral Pain. Acupunct Med 2018; 36:240-246. [DOI: 10.1136/acupmed-2016-011320] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/21/2017] [Indexed: 12/20/2022]
Abstract
Background Treatment with electroacupuncture (EA) at ST25 and CV12 has a significant analgesic effect on postinflammatory irritable bowel syndrome (PI-IBS) visceral pain. Enterochromaffin (EC) cells and serotonin (5-hydroxytryptamine (5-HT)) are important in the development of visceral hyperalgesia. Objective To investigate the analgesic effect and underlying mechanisms of EA at ST25 and CV12 on the treatment of trinitrobenzene sulfonic acid (TNBS)-induced PI-IBS visceral hyperalgesia in rats. Methods After EA at ST25 and CV12, changes in abdominal withdrawal reflex (AWR), electromyography (EMG) recordings, colonic EC cell numbers, and expression of tryptophan hydroxylase (TPH), 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) of TNBS-induced PI-IBS visceral hyperalgesia in rats were examined. Results The results of AWR tests and EMG recordings indicated a significant analgesic effect of EA stimulation at ST25 and CV12on PI-IBS visceral hyperalgesia (p<0.05). In addition, the increased EC cell numbers and colonic expression of TPH and 5-HT in rats with TNBS-induced PI-IBS visceral hyperalgesia were significantly reduced by EA (p<0.05). Conclusions EA stimulation at ST25 and CV12 can attenuate visceral hyperalgesia. This analgesic effect may be mediated via reduction of both colonic EC cell number and 5-HT concentration.
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Affiliation(s)
- Xianwei Zhu
- Innovation Research Centre of Acupuncture combined with Medicine, Shaanxi University of Chinese Medicine, Xi'an-Xianyang New Economic Zone, Shaanxi Province, China
| | - Zhibin Liu
- Innovation Research Centre of Acupuncture combined with Medicine, Shaanxi University of Chinese Medicine, Xi'an-Xianyang New Economic Zone, Shaanxi Province, China
- Department of Acupuncture and Moxibustion, Shaanxi University of Chinese Medicine, Xi'an-Xianyang New Economic Zone, Shaanxi Province, China
| | - Yifei Qin
- Innovation Research Centre of Acupuncture combined with Medicine, Shaanxi University of Chinese Medicine, Xi'an-Xianyang New Economic Zone, Shaanxi Province, China
| | - Wenmin Niu
- Innovation Research Centre of Acupuncture combined with Medicine, Shaanxi University of Chinese Medicine, Xi'an-Xianyang New Economic Zone, Shaanxi Province, China
- Department of Acupuncture and Moxibustion, Shaanxi University of Chinese Medicine, Xi'an-Xianyang New Economic Zone, Shaanxi Province, China
| | - Qiang Wang
- Innovation Research Centre of Acupuncture combined with Medicine, Shaanxi University of Chinese Medicine, Xi'an-Xianyang New Economic Zone, Shaanxi Province, China
| | - Lu Li
- Department of Acupuncture and Moxibustion, Shaanxi University of Chinese Medicine, Xi'an-Xianyang New Economic Zone, Shaanxi Province, China
| | - Jing Zhou
- College of Public Hygiene, Shaanxi University of Chinese Medicine, Xi'an-Xianyang New Economic Zone, Shaanxi Province, China
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Lefter R, Ciobica A, Guenné S, Compaoré M, Kiendrebéogo M, Stanciu C, Trifan A. Complex Neurobehavioral Testing of a Rat Model of the Irritable Bowel Syndrome. NEUROPHYSIOLOGY+ 2018; 50:266-277. [DOI: 10.1007/s11062-018-9748-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Indexed: 02/05/2023]
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Dolatabadi F, Abdolghaffari AH, Farzaei MH, Baeeri M, Ziarani FS, Eslami M, Abdollahi M, Rahimi R. The Protective Effect of Melissa officinalis L. in Visceral Hypersensitivity in Rat Using 2 Models of Acid-induced Colitis and Stress-induced Irritable Bowel Syndrome: A Possible Role of Nitric Oxide Pathway. J Neurogastroenterol Motil 2018; 24:490-501. [PMID: 29879761 PMCID: PMC6034661 DOI: 10.5056/jnm17035] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Revised: 11/25/2017] [Accepted: 01/21/2018] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND/AIMS The aim of present study is to estimate the effects of Melissa officinalis L. (MO) on visceral hypersensitivity (VH), defecation pattern and biochemical factors in 2 experimental models of irritable bowel syndrome (IBS) and the possible role of nitric oxide. METHODS Two individual models of IBS were induced in male Wistar-albino rats. In the acetic acid model, the animals were exposed to rectal distension and abdominal withdrawal reflex, and the defecation patterns were determined. In the restraint stress model, the levels of TNF-α, myeloperoxidase, lipid peroxidation, and antioxidant powers were determined in the (removed) colon. Rats had been treated with MO, L-NG-nitroarginine methyl ester (L-NAME), aminoguanidine (AG), MO + AG, or MO + L-NAME in the mentioned experimental models. RESULTS Hypersensitive response to rectal distension and more stool defecation in control rats have been observed in comparison to shams. MO-300 significantly reduced VH and defecation frequency in comparison to controls. VH and defecation pattern did not show significant change in AG + MO and L-NAME + MO groups compared to controls. Also, significant reduction in TNF-α, myeloperoxidase, thiobarbituric acid reactive substances (TBARS), and an increase in antioxidant power in MO-300 group was recorded compared to controls. AG + MO and L-NAME + MO groups showed a reverse pattern compared to MO-300 group. CONCLUSIONS MO can ameliorate IBS by modulating VH and defecation patterns. Antioxidant and anti-inflammatory properties along with its effect on the nitrergic pathway seem to play important roles in its pharmacological activity.
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Affiliation(s)
- Fatemeh Dolatabadi
- Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran,
Iran
| | - Amir H Abdolghaffari
- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Karaj,
Iran
- Department of Pharmacology and Toxicology and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran,
Iran
- Gastrointestinal Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran,
Iran
| | - Mohammad H Farzaei
- Pharmaceutical Sciences Research Center, Kermanshah University of Medical Sciences, Kermanshah,
Iran
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah,
Iran
| | - Maryam Baeeri
- Department of Pharmacology and Toxicology and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran,
Iran
| | - Fatemeh S Ziarani
- Department of Anatomy, School of Medicine, Ghazvin University of Medical Sciences, Ghazvin,
Iran
| | - Majid Eslami
- Department of Pharmacology and Toxicology and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran,
Iran
| | - Mohammad Abdollahi
- Department of Pharmacology and Toxicology and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran,
Iran
| | - Roja Rahimi
- Department of Traditional Pharmacy, School of Traditional Medicine, Tehran University of Medical Sciences, Tehran,
Iran
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Su T, Liu R, Lee A, Long Y, Du L, Lai S, Chen X, Wang L, Si J, Owyang C, Chen S. Altered Intestinal Microbiota with Increased Abundance of Prevotella Is Associated with High Risk of Diarrhea-Predominant Irritable Bowel Syndrome. Gastroenterol Res Pract 2018; 2018:6961783. [PMID: 29967640 PMCID: PMC6008816 DOI: 10.1155/2018/6961783] [Citation(s) in RCA: 78] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Accepted: 05/10/2018] [Indexed: 02/06/2023] Open
Abstract
Alterations in gut microbiota are postulated to be an etiologic factor in the pathogenesis of irritable bowel syndrome (IBS). To determine whether IBS patients in China exhibited differences in their gut microbial composition, fecal samples were collected from diarrhea-predominant IBS (IBS-D) and healthy controls and evaluated by 16S ribosomal RNA gene sequence and quantitative real-time PCR. A mouse model of postinfectious IBS (PI-IBS) was established to determine whether the altered gut microbiota was associated with increased visceral hypersensitivity. The results indicated that there were significant differences in the bacterial community profiles between IBS-D patients and healthy controls. Prevotella was more abundant in fecal samples from IBS-D patients compared with healthy controls (p < 0.05). Meanwhile, there were significant reductions in the quantity of Bacteroides, Bifidobacteria, and Lactobacillus in IBS-D patients compared with healthy controls (p < 0.05). Animal models similarly showed an increased abundance of Prevotella in fecal samples compared with control mice (p < 0.05). Finally, after the PI-IBS mice were cohoused with control mice, both the relative abundance of Prevotella and visceral hypersensitivity of PI-IBS mice were decreased. In conclusion, the altered intestinal microbiota is associated with increased visceral hypersensitivity and enterotype enriched with Prevotella may be positively associated with high risk of IBS-D.
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Affiliation(s)
- Tingting Su
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Institute of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang, China
| | - Rongbei Liu
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Institute of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang, China
| | - Allen Lee
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA
| | - Yanqin Long
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Lijun Du
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Sanchuan Lai
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Institute of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xueqin Chen
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Institute of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang, China
| | - Lan Wang
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Institute of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jianmin Si
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Institute of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang, China
| | - Chung Owyang
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA
| | - Shujie Chen
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Institute of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang, China
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Jin Y, Ren X, Li G, Li Y, Zhang L, Wang H, Qian W, Hou X. Beneficial effects of Rifaximin in post-infectious irritable bowel syndrome mouse model beyond gut microbiota. J Gastroenterol Hepatol 2018; 33:443-452. [PMID: 28573746 DOI: 10.1111/jgh.13841] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Revised: 05/23/2017] [Accepted: 05/30/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Rifaximin is a minimally absorbed antibiotic, which has shown efficacy in irritable bowel syndrome (IBS) patients. However, the mechanism on how it effects in IBS is still incompletely defined. In this study, Trichinella spiralis-infected post-infectious (PI) IBS mouse model was used, to assess the action of rifaximin on visceral hypersensitivity, barrier function, gut inflammation, and microbiota. METHODS Post-infectious IBS model was established by T. spiralis infection in mice. Rifaximin were administered to PI-IBS mice for seven consecutive days. The abdominal withdrawal reflex and threshold of colorectal distention were employed to evaluate visceral sensitivity. Smooth muscle contractile response was recorded in the organ bath. Intestinal permeability was measured by Ussing chamber. Expression of tight junction protein and cytokines were measured by Western blotting. Ilumina miseq platform was used to analyze bacterial 16S ribosomal RNA. RESULTS Post-infectious IBS mice treated with rifaximin exhibited decreased abdominal withdrawal reflex score, increased threshold, reduced contractile response, and intestinal permeability. Rifaximin also suppressed the expression of interleukin-12 and interleukin-17 and promoted the expression of the major tight junction protein occludin. Furthermore, rifaximin did not change the composition and diversity, and the study reavealed that rifaximin had a tiny effect on the relative abundance of Lactobacillus and Bifidobacterium in this PI-IBS model. CONCLUSIONS Rifaximin alleviated visceral hypersensitivity, recovered intestinal barrier function, and inhibited low-grade inflammation in colon and ileum of PI-IBS mouse model. Moreover, rifaximin exerts anti-inflammatory effects with only a minimal effect on the overall composition and diversity of the gut microbiota in this model.
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Affiliation(s)
- Yu Jin
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoyang Ren
- The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Gangping Li
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ying Li
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lei Zhang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huan Wang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Qian
- 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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Arendt‐Nielsen L, Morlion B, Perrot S, Dahan A, Dickenson A, Kress H, Wells C, Bouhassira D, Drewes AM. Assessment and manifestation of central sensitisation across different chronic pain conditions. Eur J Pain 2018; 22:216-241. [DOI: 10.1002/ejp.1140] [Citation(s) in RCA: 435] [Impact Index Per Article: 62.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Abstract
AbstractDifferent neuroplastic processes can occur along the nociceptive pathways and may be important in the transition from acute to chronic pain and for diagnosis and development of optimal management strategies. The neuroplastic processes may result in gain (sensitisation) or loss (desensitisation) of function in relation to the incoming nociceptive signals. Such processes play important roles in chronic pain, and although the clinical manifestations differ across condition processes, they share some common mechanistic features. The fundamental understanding and quantitative assessment of particularly some of the central sensitisation mechanisms can be translated from preclinical studies into the clinic. The clinical perspectives are implementation of such novel information into diagnostics, mechanistic phenotyping, prevention, personalised treatment, and drug development. The aims of this paper are to introduce and discuss (1) some common fundamental central pain mechanisms, (2) how they may translate into the clinical signs and symptoms across different chronic pain conditions, (3) how to evaluate gain and loss of function using quantitative pain assessment tools, and (4) the implications for optimising prevention and management of pain. The chronic pain conditions selected for the paper are neuropathic pain in general, musculoskeletal pain (chronic low back pain and osteoarthritic pain in particular), and visceral pain (irritable bowel syndrome in particular). The translational mechanisms addressed are local and widespread sensitisation, central summation, and descending pain modulation.SignificanceCentral sensitisation is an important manifestation involved in many different chronic pain conditions. Central sensitisation can be different to assess and evaluate as the manifestations vary from pain condition to pain condition. Understanding central sensitisation may promote better profiling and diagnosis of pain patients and development of new regimes for mechanism based therapy. Some of the mechanisms underlying central sensitisation can be translated from animals to humans providing new options in development of therapies and profiling drugs under development.
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Affiliation(s)
| | - B. Morlion
- The Leuven Centre for Algology University Hospitals Leuven University of Leuven Belgium
| | - S. Perrot
- INSERM U987 Pain Center Cochin Hospital Paris Descartes University Paris France
| | - A. Dahan
- Department of Anesthesiology Leiden University Medical Center Leiden The Netherlands
| | - A. Dickenson
- Neuroscience Physiology & Pharmacology University College London UK
| | - H.G. Kress
- Department of Special Anaesthesia and Pain Therapy Medizinische Universität/AKH Wien Vienna Austria
| | | | - D. Bouhassira
- INSERM U987 Centre d'Evaluation et de Traitement de la Douleur Hôpital Ambroise Paré Boulogne Billancourt France
| | - A. Mohr Drewes
- Mech‐Sense Department of Gastroenterology and Hepatology Clinical Institute Aalborg University Hospital Aalborg Denmark
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Blitz J, Riddle MS, Porter CK. The Risk of Chronic Gastrointestinal Disorders Following Acute Infection with Intestinal Parasites. Front Microbiol 2018; 9:17. [PMID: 29410653 PMCID: PMC5787065 DOI: 10.3389/fmicb.2018.00017] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Accepted: 01/05/2018] [Indexed: 12/12/2022] Open
Abstract
Background: Infectious gastroenteritis (IGE) is caused by numerous bacterial, viral, and parasitic pathogens. A history of IGE has been shown in previous studies to increase the risk of developing chronic gastrointestinal disorders and other chronic conditions. As bacteria and viruses represent the majority of pathogen-specific causes of IGE, post-infectious studies have primarily focused on these organisms. The objective of this study was to investigate an association between a history of parasite-associated IGE and the subsequent development of chronic post-infectious gastrointestinal and non-gastrointestinal disorders in a military population. Methods: International Classification of Diseases, 9th Revision Clinical Modification (ICD-9-CM) diagnostic coding data for primary exposures and outcomes were obtained for a retrospective cohort study of active component military personnel from 1998 to 2013. Exposed subjects consisted of individuals with documented infection with one of ten parasitic pathogens. Unexposed subjects were matched to exposed subjects on demographic and operational deployment history parameters. Adjusted odds ratios (aORs) were estimated using logistic regression for several chronic disorders previously shown to be associated with a history of IGE. Results: A total of 896 subjects with a parasitic exposure were matched to 3681 unexposed subjects for multivariate regression analysis. Individuals infected with Balantidium coli, Ascaris lumbricoides, Strongyloides stercoralis, Necator americanus/Ancylostoma duodenale, and Taenia spp. had higher aOR for development of several chronic gastrointestinal disorders when compared with unexposed subjects after controlling for various covariates. Conclusion: We found that parasite-associated enteric infection increases the risk of development of post-infectious chronic gastrointestinal disorders in a military population. These results require confirmation in similar populations and in the developing world where infection with these parasites is endemic. Further understanding of disease burden and causal mechanisms should direct primary prevention and potential disease interception strategies.
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Affiliation(s)
- Jason Blitz
- Navy Environmental and Preventive Medicine Unit Six, Pearl Harbor, HI, United States
| | - Mark S Riddle
- Department of Preventive and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda, MD, United States.,Naval Medical Research Center, Silver Spring, MD, United States
| | - Chad K Porter
- Naval Medical Research Center, Silver Spring, MD, United States
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Fuke N, Aizawa K, Suganuma H, Takagi T, Naito Y. Effect of combined consumption of Lactobacillus brevis KB290 and β-carotene on minor diarrhoea-predominant irritable bowel syndrome-like symptoms in healthy subjects: a randomised, double-blind, placebo-controlled, parallel-group trial. Int J Food Sci Nutr 2017; 68:973-986. [PMID: 28391736 DOI: 10.1080/09637486.2017.1311843] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
People with non-pathological diarrhoea-predominant irritable bowel syndrome (IBS-D)-like symptoms are present at a significant level even in healthy populations, but established prophylaxis is lacking. Previously, we have found that co-administration of Lactobacillus brevis KB290 (KB290) and β-carotene (βC) attenuated murine colitis (potential cause of IBS-D-like symptoms) significantly. Here, we investigated the effect of KB290 and βC on minor IBS-D-like symptoms in healthy volunteers. After a 4-week run-in period, subjects received a KB290 + βC or placebo capsule for 12 weeks, followed by a 4-week washout period. The KB290 + βC group showed a significant improvement in intensity of abdominal pain and stool frequency compared with the placebo group. The KB290 + βC group showed a significantly higher serum concentration of anti-inflammatory cytokine, interleukin-10, compared with the placebo group. In conclusion, we demonstrated that consumption of KB290 + βC improves minor IBS-D-like symptoms and inflammatory status in healthy volunteers. (UMIN000018002).
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Affiliation(s)
- Nobuo Fuke
- a Nature & Wellness Research Department , Innovation Division, KAGOME CO., LTD , Nasushiobara , Tochigi , Japan
| | - Koichi Aizawa
- a Nature & Wellness Research Department , Innovation Division, KAGOME CO., LTD , Nasushiobara , Tochigi , Japan
| | - Hiroyuki Suganuma
- a Nature & Wellness Research Department , Innovation Division, KAGOME CO., LTD , Nasushiobara , Tochigi , Japan
| | - Tomohisa Takagi
- b Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science , Kyoto Prefectural University of Medicine , Kamigyo-ku , Kyoto , Japan
| | - Yuji Naito
- b Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science , Kyoto Prefectural University of Medicine , Kamigyo-ku , Kyoto , Japan
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Lashermes A, Boudieu L, Barbier J, Sion B, Gelot A, Barnich N, Ardid D, Carvalho FA. Adherent-Invasive E. coli enhances colonic hypersensitivity and P2X receptors expression during post-infectious period. Gut Microbes 2017; 9:26-37. [PMID: 28806140 PMCID: PMC5914911 DOI: 10.1080/19490976.2017.1361091] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Irritable Bowel Syndrome (IBS) and Inflammatory Bowel Disease (IBD) are related gastrointestinal disorders characterized by abdominal pain associated with colonic hypersensitivity (CHS). Studies in humans have reported an abnormal colonization of Adherent-Invasive E. coli (AIEC) in the ileum of Crohn's disease (CD) patients associated with overexpression of the bacterial colonizing receptor CEACAM6. The aim of the present study was to investigate whether AIEC reference strain LF82 could induce intestinal impairment during infectious and/or post-infectious periods and subsequently the development of CHS. Transgenic mice overexpressing human CEACAM6 protein (TG) and their wild-type littermates were gavaged by CD-associated AIEC bacteria (reference strain LF82) or PBS for 3 d. Colonic hypersensitivity was assessed by colorectal distension (CRD) test during infectious (D4) and post-infectious periods (D21). Several markers of intestinal inflammation were monitored and the colonic expression of purinergic P2X receptors was quantified. At D4, an increased visceromotor response (VMR) to the CRD test was observed in TG mice infected with CD-associated AIEC LF82 in comparison with non-infected TG mice and persisted in a subgroup of infected animals at D21 after bacteria clearance. Increased VMR was associated with low-grade intestinal inflammation, increased intestinal permeability and expression of P2X 3, 4 and 7. This study shows that certain susceptible hosts infected with CD-associated AIEC bacteria can develop persistent CHS associated with low-grade inflammation and increased P2X receptors expression. Thus, CD-associated AIEC infection in CEACAM6 transgenic mice could be used as a novel post-infectious mouse model mimicking quiescent IBD with IBS-like symptoms such as visceral pain.
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Affiliation(s)
- Amandine Lashermes
- Université Clermont Auvergne, Inserm U1107, NeuroDol, CHRN Auvergne, Clermont-Ferrand, France
| | - Ludivine Boudieu
- Université Clermont Auvergne, Inserm U1107, NeuroDol, CHRN Auvergne, Clermont-Ferrand, France
| | - Julie Barbier
- Université Clermont Auvergne, Inserm U1107, NeuroDol, CHRN Auvergne, Clermont-Ferrand, France
| | - Benoit Sion
- Université Clermont Auvergne, Inserm U1107, NeuroDol, CHRN Auvergne, Clermont-Ferrand, France
| | - Agathe Gelot
- Université Clermont Auvergne, Inserm U1107, NeuroDol, CHRN Auvergne, Clermont-Ferrand, France
| | - Nicolas Barnich
- Université Clermont Auvergne, Inserm U1071, M2iSH, USC-INRA 2018, Clermont-Ferrand, France
| | - Denis Ardid
- Université Clermont Auvergne, Inserm U1107, NeuroDol, CHRN Auvergne, Clermont-Ferrand, France
| | - Frédéric Antonio Carvalho
- Université Clermont Auvergne, Inserm U1107, NeuroDol, CHRN Auvergne, Clermont-Ferrand, France,CONTACT Frédéric A. Carvalho, PhD Université d'Auvergne, INSERM 1107 NeuroDol, 28 place Henri Dunant, BP38, F-63001 Clermont-Ferrand, France
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The Anti-Inflammatory Effect of Guchangzhixie-Pill by Reducing Colonic EC Cell Hyperplasia and Serotonin Availability in an Ulcerative Colitis Rat Model. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2017; 2017:8547257. [PMID: 28845184 PMCID: PMC5563416 DOI: 10.1155/2017/8547257] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/18/2016] [Revised: 04/05/2017] [Accepted: 06/05/2017] [Indexed: 12/12/2022]
Abstract
Ulcerative colitis (UC) is one of the major types of inflammatory bowel diseases (IBD). Abnormal colonic enterochromaffin (EC) cell hyperplasia and serotonin availability have been described in UC. Guchangzhixie-pill (GCZX-pill), a Chinese herbal formula composed of six herbs, is modified based on a traditional formula (Jiechangyan-pill) for inflammatory and ulcerative gastrointestinal disorders. This study aims to investigate the anti-inflammatory effect and the underlying mechanisms of GCZX-pill on trinitrobenzene sulfonic acid- (TNBS-) induced UC in rats. After orally administrating a GCZX-pill to UC rats for 14 days, the results of the inflammation evaluation, such as disease activity index (DAI), macroscopic score (MS), myeloperoxidase (MPO) activity, and other methods, suggested that the GCZX-pill showed remarkable anti-inflammatory results in UC rats. In addition, the abnormal EC cell numbers, colonic tryptophan hydroxylase (TPH) expression, and serotonin (5-HT) contents in TNBS-induced UC rats were significantly reduced by the GCZX-pill. This data demonstrates that the GCZX-pill can attenuate the inflammation in UC rats and the anti-inflammatory effect of the GCZX-pill may be medicated by reducing colonic EC cell hyperplasia and 5-HT availability.
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Naz R, Ayub H, Nawaz S, Islam ZU, Yasmin T, Bano A, Wakeel A, Zia S, Roberts TH. Antimicrobial activity, toxicity and anti-inflammatory potential of methanolic extracts of four ethnomedicinal plant species from Punjab, Pakistan. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2017; 17:302. [PMID: 28595608 PMCID: PMC5465528 DOI: 10.1186/s12906-017-1815-z] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Accepted: 05/31/2017] [Indexed: 02/01/2023]
Abstract
Background The plant species Aristolochia indica (AI), Melilotus indicus (MI), Tribulus terrestris (TT) and Cuscuta pedicellata (CP) are widely used in folk medicine in the villages around Chowk Azam, South Punjab, Pakistan. The aim of this study was to evaluate the antioxidant activity, phytochemical composition, and the antibacterial, antifungal, cytotoxic and anti-inflammatory potential of the four medicinal plants listed above. For CP stem, this study represents (to the best of our knowledge) the first time phytochemicals have been identified and the antioxidant and anti-inflammatory potential determined. Methods Phytochemicals were analyzed through chemical tests, thin layer chromatography (TLC) and spectrophotometric methods. Antioxidant activities (DPPH and H2O2) were also determined through spectrophotometric methods. Extracts were evaluated for antibacterial potential via the agar well diffusion method against Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumonia and Acinetobacter baumannii. The minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) were determined by the microdilution method. Antifungal activities were tested using the agar tube dilution method against three species: Aspergillus fumigatus, Aspergillus flavus and Rhizopus oryzae. The cytotoxic potential of the plant extracts was checked using the brine shrimp assay. In vitro anti-inflammatory activity of the selected plant extracts was evaluated using albumin denaturation, membrane stabilization and proteinase inhibitory assays. Results Of all the methanolic extracts tested, those from CP (stem) and TTF (T. terrestris fruit) had the highest phenolic, flavonoid and flavonol contents (497±4 mg GAE/g, 385±8 mg QE/g and 139±4 mg QE/g; 426±5 mg GAE/g, 371±8 mg QE/g and 138±6 mg QE/g, respectively) and also exhibited strong antioxidant potential in scavenging DPPH and hydrogen peroxide (IC50 values; 20±1 and 18±0.7 μg/mL; 92±2 and 26±2 μg/mL, respectively). CP, TTF and TTL (T. terrestris leaf) extracts substantially inhibited the growth of the bacteria A. baumannii, S. aureus, and K. pneumonia and also exhibited the highest antifungal potential. The ranking of the plant extracts for cytotoxicity was TTF > TTL > AI > CP > MI, while the ranking for in vitro anti-inflammatory potential at a concentration of 200 μg/mL of the selected plant extracts was CP > TTL, TTF > AI > MI. The lowest IC50 (28 μg/mL) observed in the albumin denaturation assay was for CP. Positive correlations were observed between total phenolics, antioxidants, antibacterial, antifungal and anti-inflammatory potential of the selected plant extracts, indicating a significant contribution of phenolic compounds in the plant extracts to these activities. Conclusions This study revealed the strong antimicrobial, antioxidant, cytotoxic and anti-inflammatory potential of the plant species CP and TT used in folk medicine.
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Boeckxstaens GE, Wouters MM. Neuroimmune factors in functional gastrointestinal disorders: A focus on irritable bowel syndrome. Neurogastroenterol Motil 2017; 29. [PMID: 28027594 DOI: 10.1111/nmo.13007] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Accepted: 11/11/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND Abnormal abdominal pain perception is the most bothersome and difficult to treat symptom of functional gastrointestinal disorders (FGIDs). Visceral pain stimuli are perceived and transmitted by afferent neurons residing in the dorsal root ganglia that have sensory nerve endings in the gut wall and mesentery. Accumulating evidence indicates that peripheral activation and sensitization of these sensory nerve endings by bioactive mediators released by activated immune cells, in particular mast cells, can lead to aberrant neuroimmune interactions and the development and maintenance of visceral hypersensitivity. Besides direct neuronal activation, low concentrations of proteases, histamine, and serotonin can chronically sensitize nociceptors, such as TRP channels, leading to persistent aberrant pain perception. PURPOSE This review discusses the potential mechanisms underlying aberrant neuroimmune interactions in peripheral sensitization of sensory nerves. A better understanding of the cells, mediators, and molecular mechanisms triggering persistent aberrant neuroimmune interactions brings new insights into their contribution to the physiology and pathophysiology of visceral pain perception and provides novel opportunities for more efficient therapeutic treatments for these disorders.
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Affiliation(s)
- G E Boeckxstaens
- Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven University, Leuven, Belgium
| | - M M Wouters
- Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven University, Leuven, Belgium
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Sharman SK, Islam BN, Hou Y, Usry M, Bridges A, Singh N, Sridhar S, Rao S, Browning DD. Sildenafil normalizes bowel transit in preclinical models of constipation. PLoS One 2017; 12:e0176673. [PMID: 28448580 PMCID: PMC5407793 DOI: 10.1371/journal.pone.0176673] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2016] [Accepted: 04/16/2017] [Indexed: 12/12/2022] Open
Abstract
Guanylyl cyclase-C (GC-C) agonists increase cGMP levels in the intestinal epithelium to promote secretion. This process underlies the utility of exogenous GC-C agonists such as linaclotide for the treatment of chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C). Because GC-C agonists have limited use in pediatric patients, there is a need for alternative cGMP-elevating agents that are effective in the intestine. The present study aimed to determine whether the PDE-5 inhibitor sildenafil has similar effects as linaclotide on preclinical models of constipation. Oral administration of sildenafil caused increased cGMP levels in mouse intestinal epithelium demonstrating that blocking cGMP-breakdown is an alternative approach to increase cGMP in the gut. Both linaclotide and sildenafil reduced proliferation and increased differentiation in colon mucosa, indicating common target pathways. The homeostatic effects of cGMP required gut turnover since maximal effects were observed after 3 days of treatment. Neither linaclotide nor sildenafil treatment affected intestinal transit or water content of fecal pellets in healthy mice. To test the effectiveness of cGMP elevation in a functional motility disorder model, mice were treated with dextran sulfate sodium (DSS) to induce colitis and were allowed to recover for several weeks. The recovered animals exhibited slower transit, but increased fecal water content. An acute dose of sildenafil was able to normalize transit and fecal water content in the DSS-recovery animal model, and also in loperamide-induced constipation. The higher fecal water content in the recovered animals was due to a compromised epithelial barrier, which was normalized by sildenafil treatment. Taken together our results show that sildenafil can have similar effects as linaclotide on the intestine, and may have therapeutic benefit to patients with CIC, IBS-C, and post-infectious IBS.
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Affiliation(s)
- Sarah K. Sharman
- Department of Biochemistry and Molecular Biology, Cancer Research Center, Augusta University, Augusta, Georgia, United States of America
| | - Bianca N. Islam
- Department of Biochemistry and Molecular Biology, Cancer Research Center, Augusta University, Augusta, Georgia, United States of America
| | - Yali Hou
- Department of Biochemistry and Molecular Biology, Cancer Research Center, Augusta University, Augusta, Georgia, United States of America
| | - Margaux Usry
- Department of Biochemistry and Molecular Biology, Cancer Research Center, Augusta University, Augusta, Georgia, United States of America
| | - Allison Bridges
- Department of Biochemistry and Molecular Biology, Cancer Research Center, Augusta University, Augusta, Georgia, United States of America
| | - Nagendra Singh
- Department of Biochemistry and Molecular Biology, Cancer Research Center, Augusta University, Augusta, Georgia, United States of America
| | - Subbaramiah Sridhar
- Department of Medicine, Division of Gastroenterology and Hepatology, Augusta University, Augusta, Georgia, United States of America
| | - Satish Rao
- Department of Medicine, Division of Gastroenterology and Hepatology, Augusta University, Augusta, Georgia, United States of America
| | - Darren D. Browning
- Department of Biochemistry and Molecular Biology, Cancer Research Center, Augusta University, Augusta, Georgia, United States of America
- * E-mail:
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Yu YB, Zhao DY, Qi QQ, Long X, Li X, Chen FX, Zuo XL. BDNF modulates intestinal barrier integrity through regulating the expression of tight junction proteins. Neurogastroenterol Motil 2017; 29. [PMID: 27747999 DOI: 10.1111/nmo.12967] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2016] [Accepted: 09/03/2016] [Indexed: 12/22/2022]
Abstract
BACKGROUND Brain-derived neurotrophic factor (BDNF) may play a vital role in the homeostatic regulation of intestinal barrier integrity. We aimed to investigate the physiological role of BDNF in maintaining the intestinal epithelial barrier using postinflammatory irritable bowel syndrome (PI-IBS) mice and explore the underlying molecular mechanisms using intestinal epithelial cells in vitro. METHODS Postinflammatory-IBS mice were induced by intrarectal administration of trinitrobenzene sulfonic acid and allowed to recover for 28 days. Frequency of defecation, fecal water content, colonic epithelial integrity and expressions of BDNF and tight junction (TJ) proteins (occludin, ZO-1, claudin-1, claudin-2) of the PI-IBS mice were investigated. Based on the results of animal studies, we further performed RT-PCR and Western blots to assess how BDNF stimulation and BDNF knockdown impacted TJ proteins in the ht-29 intestinal epithelial cells. KEY RESULTS Water content of stools was significantly increased in the PI-IBS mice compared with controls. Colonic mucosa from the PI-IBS mice displayed epithelial barrier defects and exhibited increased protein expressions of BDNF and claudin-2 and decreased protein expressions of occludin, ZO-1 and claudin-1. Furthermore, a siRNA against BDNF in the ht-29 cells could effectively suppress BDNF gene and protein expressions, and subsequently reduce TJ gene and protein levels. When the ht-29 cells were incubated with different doses of exogenous BDNF, significant increases of occludin, ZO-1 and claudin-1 and decreases of claudin-2 protein were observed. CONCLUSIONS & INFERENCES BDNF may play a role in regulating intestinal epithelial barrier via affecting the expression of TJ proteins.
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Affiliation(s)
- Y-B Yu
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
| | - D-Y Zhao
- Laboratory of Translational Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
- Department of Gastroenterology, General Hospital of Puyang Oilfield, Puyang, China
| | - Q-Q Qi
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
| | - X Long
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
| | - X Li
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
| | - F-X Chen
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
| | - X-L Zuo
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
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Tsang SW, Auyeung KKW, Bian ZX, Ko JKS. Pathogenesis, Experimental Models and Contemporary Pharmacotherapy of Irritable Bowel Syndrome: Story About the Brain-Gut Axis. Curr Neuropharmacol 2017; 14:842-856. [PMID: 27009115 PMCID: PMC5333584 DOI: 10.2174/1570159x14666160324144154] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Revised: 02/07/2016] [Accepted: 03/22/2016] [Indexed: 11/22/2022] Open
Abstract
Background Although the precise pathophysiology of irritable bowel syndrome (IBS) remains unknown, it is generally considered to be a disorder of the brain-gut axis, representing the disruption of communication between the brain and the digestive system. The present review describes advances in understanding the pathophysiology and experimental approaches in studying IBS, as well as providing an update of the therapies targeting brain-gut axis in the treatment of the disease. Methods Causal factors of IBS are reviewed. Following this, the preclinical experimental models of IBS will be introduced. Besides, both current and future therapeutic approaches of IBS will be discussed. Results When signal of the brain-gut axis becomes misinterpreted, it may lead to dysregulation of both central and enteric nervous systems, altered intestinal motility, increased visceral sensitivity and consequently contributing to the development of IBS. Interference of the brain-gut axis can be modulated by various psychological and environmental factors. Although there is no existing animal experiment that can represent this complex multifactorial disease, these in vivo models are clinically relevant readouts of gastrointestinal functions being essential to the identification of effective treatments of IBS symptoms as well as their molecular targets. Understanding the brain-gut axis is essential in developing the effective therapy for IBS. Therapies include improvement of GI motor functions, relief of visceral hypersensitivity and pain, attenuation of autonomic dysfunctions and suppression of mucosal immune activation. Conclusion Target-oriented therapies that provide symptomatic, psychological and physiological benefits could surely help to improve the quality of life of IBS patients.
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Affiliation(s)
| | | | | | - J K S Ko
- Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, 7 Baptist University Road, Kowloon Tong, Hong Kong SAR, China
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Antoniou E, Margonis GA, Angelou A, Pikouli A, Argiri P, Karavokyros I, Papalois A, Pikoulis E. The TNBS-induced colitis animal model: An overview. Ann Med Surg (Lond) 2016; 11:9-15. [PMID: 27656280 PMCID: PMC5021709 DOI: 10.1016/j.amsu.2016.07.019] [Citation(s) in RCA: 232] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2016] [Revised: 07/21/2016] [Accepted: 07/21/2016] [Indexed: 02/06/2023] Open
Abstract
Background Despite recent advances the pathogenesis of Crohn's disease remains incompletely understood. A variety of animal models have been utilized in an effort to provide further insights and develop more therapeutic options. In order to simulate, to an extent, the pathogenesis and the clinical course of the disease, TNBS induced colitis is often used. Various approaches for inducing TNBS -colitis have been described in the literature. Methods/results In this review, we sought to present the animal model of TNBS induced colitis and outline the pathogenesis, pathophysiology, clinical course and pathological characteristics of the model. Furthermore, we describe the differences among those protocols regarding types of animals and colitis induction. Data sources The MEDLINE database was thoroughly searched using the keywords: TNBS, colitis, Crohn's disease, animal model. Two investigators independently reviewed the abstracts and appropriate articles were included in this review. Additional articles were gathered and evaluated. Conclusion The aim of this study was to thoroughly present an updated review of the TNBS-induced colitis protocols that are implemented by researchers.
We sought to present the animal model of TNBS induced colitis and outline the pathogenesis, pathophysiology, clinical course and pathological characteristics of the model. Furthermore, we describe the differences among those protocols regarding types of animals and colitis induction. The MEDLINE database was thoroughly searched using the keywords: TNBS, colitis, Crohn's disease, animal model. Two investigators independently reviewed the abstracts and appropriate articles were included in this review. The aim of this study was to thoroughly present an updated review of the TNBS-induced colitis protocols that are implemented by researchers.
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Affiliation(s)
- Efstathios Antoniou
- 2nd Department of Propaedeutic Surgery, Laiko Hospital, University of Athens, School of Medicine, Athens, Greece
| | - Georgios Antonios Margonis
- 2nd Department of Propaedeutic Surgery, Laiko Hospital, University of Athens, School of Medicine, Athens, Greece
| | - Anastasios Angelou
- 1st Department of Surgery, Laiko Hospital, University of Athens, School of Medicine, Athens, Greece
| | - Anastasia Pikouli
- 1st Department of Surgery, Laiko Hospital, University of Athens, School of Medicine, Athens, Greece
| | - Paraskevi Argiri
- CT-MRI Department, Larissa General Hospital, Larissa, 41221, Greece
| | - Ioannis Karavokyros
- 1st Department of Surgery, Laiko Hospital, University of Athens, School of Medicine, Athens, Greece
| | | | - Emmanouil Pikoulis
- 1st Department of Surgery, Laiko Hospital, University of Athens, School of Medicine, Athens, Greece
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Zhang Y, Li F, Wang H, Yin C, Huang J, Mahavadi S, Murthy KS, Hu W. Immune/Inflammatory Response and Hypocontractility of Rabbit Colonic Smooth Muscle After TNBS-Induced Colitis. Dig Dis Sci 2016; 61:1925-40. [PMID: 26879904 PMCID: PMC4920730 DOI: 10.1007/s10620-016-4078-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Accepted: 02/03/2016] [Indexed: 12/13/2022]
Abstract
BACKGROUND The contractility of colonic smooth muscle is dysregulated due to immune/inflammatory responses in inflammatory bowel diseases. Inflammation in vitro induces up-regulation of regulator of G-protein signaling 4 (RGS4) expression in colonic smooth muscle cells. AIMS To characterize the immune/inflammatory responses and RGS4 expression pattern in colonic smooth muscle after induction of colitis. METHODS Colitis was induced in rabbits by intrarectal instillation of 2,4,6-trinitrobenzene sulfonic acid (TNBS). Innate/adaptive immune response RT-qPCR array was performed using colonic circular muscle strips. At 1-9 weeks after colonic intramuscular microinjection of lentivirus, the distal and proximal colons were collected, and muscle strips and dispersed muscle cells were prepared from circular muscle layer. Expression levels of RGS4 and NFκB signaling components were determined by Western blot analysis. The biological consequences of RGS4 knockdown were assessed by measurement of muscle contraction and phospholipase C (PLC)-β activity in response to acetylcholine (ACh). RESULTS Contraction in response to ACh was significantly inhibited in the inflamed colonic circular smooth muscle cells. RGS4, IL-1, IL-6, IL-8, CCL3, CD1D, and ITGB2 were significantly up-regulated, while IL-18, CXCR4, CD86, and C3 were significantly down-regulated in the inflamed muscle strips. RGS4 protein expression in the inflamed smooth muscles was dramatically increased. RGS4 stable knockdown in vivo augmented ACh-stimulated PLC-β activity and contraction in colonic smooth muscle cells. CONCLUSION Inflamed smooth muscle exhibits up-regulation of IL-1-related signaling components, Th1 cytokines and RGS4, and inhibition of contraction. Stable knockdown of endogenous RGS4 in colonic smooth muscle increases PLC-β activity and contractile responses.
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Affiliation(s)
- Yonggang Zhang
- Department of Neuroscience, Temple University School of Medicine, 3500 N Broad Street, Philadelphia, PA 19140, USA
| | - Fang Li
- Department of Neuroscience, Temple University School of Medicine, 3500 N Broad Street, Philadelphia, PA 19140, USA
| | - Hong Wang
- Department of Neuroscience, Temple University School of Medicine, 3500 N Broad Street, Philadelphia, PA 19140, USA
| | - Chaoran Yin
- Department of Neuroscience, Temple University School of Medicine, 3500 N Broad Street, Philadelphia, PA 19140, USA
| | - JieAn Huang
- Department of Gastroenterology, First Affiliated Hospital, Guangxi Medical University, No. 6 Shuangyong Rd, Nanning 530021, Guangxi, China
| | - Sunila Mahavadi
- Department of Physiology and Biophysics, Medical College of Virginia Campus, Virginia Commonwealth University, 1101 East Marshall Street, Richmond, VA 23298, USA
| | - Karnam S. Murthy
- Department of Physiology and Biophysics, Medical College of Virginia Campus, Virginia Commonwealth University, 1101 East Marshall Street, Richmond, VA 23298, USA
| | - Wenhui Hu
- Department of Neuroscience, Temple University School of Medicine, 3500 N Broad Street, Philadelphia, PA 19140, USA
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Zhou XY, Li M, Li X, Long X, Zuo XL, Hou XH, Cong YZ, Li YQ. Visceral hypersensitive rats share common dysbiosis features with irritable bowel syndrome patients. World J Gastroenterol 2016; 22:5211-5227. [PMID: 27298564 PMCID: PMC4893468 DOI: 10.3748/wjg.v22.i22.5211] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Revised: 03/01/2016] [Accepted: 03/18/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate gut microbial dysbiosis in two visceral hypersensitive models in comparison with irritable bowel syndrome (IBS) patients and to explore the extent to which these models capture the dysbiosis of IBS patients. METHODS Visceral hypersensitivity was developed using the maternal separation (MS) rat model and post-inflammatory rat model. The visceral sensitivity of the model groups and control group was evaluated using the abdominal withdraw reflex score and electromyography in response to graded colorectal distention. The 16S ribosomal RNA gene from fecal samples was pyrosequenced and analyzed. The correlation between dysbiosis in the microbiota and visceral hypersensitivity was calculated. Positive findings were compared to sequencing data from a published human IBS cohort. RESULTS Dysbiosis triggered by neonatal maternal separation was lasting but not static. Both MS and post-inflammatory rat fecal microbiota deviated from that of the control rats to an extent that was larger than the co-housing effect. Two short chain fatty acid producing genera, Fusobacterium and Clostridium XI, were shared by the human IBS cohort and by the maternal separation rats and post-inflammatory rats, respectively, to different extents. Fusobacterium was significantly increased in the MS group, and its abundance positively correlated with the degree of visceral hypersensitivity. Porphyromonadaceae was a protective biomarker for both the rat control group and healthy human controls. CONCLUSION The dysbiosis MS rat model and the post-inflammatory rat model captured some of the dysbiosis features of IBS patients. Fusobacterium, Clostridium XI and Porphyromonadaceae were identified as targets for future mechanistic research.
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Mechanically evoked cortical potentials: A physiological approach to assessment of anorectal sensory pathways. J Neurosci Methods 2015; 256:198-202. [DOI: 10.1016/j.jneumeth.2015.09.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Revised: 08/14/2015] [Accepted: 09/04/2015] [Indexed: 11/24/2022]
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Litleskare S, Wensaas KA, Eide GE, Hanevik K, Kahrs GE, Langeland N, Rortveit G. Perceived food intolerance and irritable bowel syndrome in a population 3 years after a giardiasis-outbreak: a historical cohort study. BMC Gastroenterol 2015; 15:164. [PMID: 26585714 PMCID: PMC4653841 DOI: 10.1186/s12876-015-0393-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2015] [Accepted: 11/10/2015] [Indexed: 02/08/2023] Open
Abstract
Background Studies have shown an increased prevalence of irritable bowel syndrome (IBS) after acute gastroenteritis. Food as a precipitating and perpetuating factor in IBS has gained recent interest, but food intolerance following gastroenteritis is less investigated. The aims of this study were firstly, to compare perceived food intolerance in a group previously exposed to Giardia lamblia with a control group; secondly, to explore the relation with IBS status; and thirdly, to investigate associations with content of fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) in foods reported. Methods This is a historical cohort study with mailed questionnaire to 1252 Giardia exposed and a control cohort matched by gender and age. Differences between groups were investigated using bivariate and multivariate analyses. Results The questionnaire response rate in the exposed group was 65.3 % (817/1252) and in the control group 31.4 % (1128/3598). The adjusted odds ratio (OR) for perceived food intolerance for the exposed group was 2.00 with 95 % confidence interval (CI): 1.65 to 2.42, as compared with the control group. Perceived intolerance for dairy products was the most frequently reported intolerance, with an adjusted OR for the exposed of 1.95 (95 % CI: 1.51 to 2.51). Perceived intolerance for fatty foods, vegetables, fruit, cereals and alcohol was also significantly higher in the exposed group. The groups did not differ in perceived intolerance to spicy foods, coffee or soda. The association between exposure to Giardia infection and perceived food intolerance differed between the IBS group and the no-IBS group, but IBS was not a significant effect modifier for the association. Perceived intolerance for high FODMAP foods (adjusted OR 1.91) and low FODMAP foods (adjusted OR 1.55) was significantly associated with exposure status. Conclusion Exposure to Giardia infection was associated with perceived food intolerance 3 years after giardiasis. IBS status did not alter the association between exposure status and perceived food intolerance. Perceived intolerance to high FODMAP foods and low FODMAP foods were both statistically significantly associated with exposure to Giardia infection. Electronic supplementary material The online version of this article (doi:10.1186/s12876-015-0393-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Sverre Litleskare
- Research Unit for General Practice, Uni Research Health, Kalfarveien 31, N-5018, Bergen, Norway.
| | - Knut-Arne Wensaas
- Research Unit for General Practice, Uni Research Health, Kalfarveien 31, N-5018, Bergen, Norway.
| | - Geir Egil Eide
- Centre for Clinical Research, Haukeland University Hospital, Bergen, Norway. .,Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway.
| | - Kurt Hanevik
- National Centre for Tropical Infectious Diseases, Haukeland University Hospital, Bergen, Norway. .,Department of Clinical Science, University of Bergen, Bergen, Norway.
| | - Gudrun Elise Kahrs
- Department of Clinical Nutrition, Haukeland University Hospital, Bergen, Norway.
| | - Nina Langeland
- Department of Clinical Science, University of Bergen, Bergen, Norway.
| | - Guri Rortveit
- Research Unit for General Practice, Uni Research Health, Kalfarveien 31, N-5018, Bergen, Norway. .,Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway.
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