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Dudzińska E, Grabrucker AM, Kwiatkowski P, Sitarz R, Sienkiewicz M. The Importance of Visceral Hypersensitivity in Irritable Bowel Syndrome-Plant Metabolites in IBS Treatment. Pharmaceuticals (Basel) 2023; 16:1405. [PMID: 37895876 PMCID: PMC10609912 DOI: 10.3390/ph16101405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 09/28/2023] [Accepted: 10/02/2023] [Indexed: 10/29/2023] Open
Abstract
The visceral stimuli from the digestive tract are transmitted via afferent nerves through the spinal cord to the brain, where they are felt as pain. The overreaction observed in the brain of irritable bowel syndrome (IBS) patients may be due to increased peripheral sensitivity to stimuli from the gastrointestinal tract. Although the exact pathway is uncertain, attenuation of visceral hypersensitivity is still of interest in treating IBS. It has been shown that stress stimulates the sympathetic nervous system while inhibiting the vagus nerve (VN). In addition, stress factors lead to dysbiosis and chronic low-grade inflammation of the intestinal mucosa, which can lead to lower gastrointestinal visceral hypersensitivity. Therefore, an important goal in the treatment of IBS is the normalization of the intestinal microflora. An interesting option seems to be nutraceuticals, including Terminalia chebula, which has antibacterial and antimicrobial activity against various pathogenic Gram-positive and Gram-negative bacteria. Additionally, short-term transcutaneous vagus nerve stimulation can reduce the stress-induced increase in intestinal permeability, thereby reducing inflammation. The conducted studies also indicate a relationship between the stimulation of the vagus nerve (VN) and the activation of neuromodulatory networks in the central nervous system. Therefore, it seems reasonable to conclude that a two-way action through stimulating the VN and using nutraceuticals may become an effective therapy in treating IBS.
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Affiliation(s)
- Ewa Dudzińska
- Department of Dietetics and Nutrition Education, Medical University of Lublin, 20-093 Lublin, Poland
| | - Andreas M. Grabrucker
- Department of Biological Sciences, University of Limerick, V94 PH61 Limerick, Ireland;
- Bernal Institute, University of Limerick, V94 PH61 Limerick, Ireland
- Health Research Institute (HRI), University of Limerick, V94 PH61 Limerick, Ireland
| | - Paweł Kwiatkowski
- Department of Diagnostic Immunology, Pomeranian Medical University in Szczecin, Al. Powstancow Wlkp. 72, 70-111 Szczecin, Poland;
| | - Robert Sitarz
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland;
- First Department of Surgical Oncology, St. John’s Cancer Center, 20-090 Lublin, Poland
| | - Monika Sienkiewicz
- Department of Pharmaceutical Microbiology and Microbiological Diagnostic, Medical University of Lodz, Muszynskiego 1, 90-151 Lodz, Poland;
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Phylogenetic analyses of 5-hydroxytryptamine 3 (5-HT3) receptors in Metazoa. PLoS One 2023; 18:e0281507. [PMID: 36857360 PMCID: PMC9977066 DOI: 10.1371/journal.pone.0281507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 01/24/2023] [Indexed: 03/02/2023] Open
Abstract
The 5-hydroxytrptamine 3 (5-HT3) receptor is a member of the 'Cys-loop' family and the only pentameric ligand gated ion channel among the serotonin receptors. 5-HT3 receptors play an important role in controlling growth, development, and behaviour in animals. Several 5-HT3 receptor antagonists are used to treat diseases (e.g., irritable bowel syndrome, nausea and emesis). Humans express five different subunits (A-E) enabling a variety of heteromeric receptors to form but all contain 5HT3A subunits. However, the information available about the 5-HT3 receptor subunit occurrence among the metazoan lineages is minimal. In the present article we searched for 5-HT3 receptor subunit homologs from different phyla in Metazoa. We identified more than 1000 5-HT3 receptor subunits in Metazoa in different phyla and undertook simultaneous phylogenetic analysis of 526 5HT3A, 358 5HT3B, 239 5HT3C, 70 5HT3D, and 173 5HT3E sequences. 5-HT3 receptor subunits were present in species belonging to 11 phyla: Annelida, Arthropoda, Chordata, Cnidaria, Echinodermata, Mollusca, Nematoda, Orthonectida, Platyhelminthes, Rotifera and Tardigrada. All subunits were most often identified in Chordata phylum which was strongly represented in searches. Using multiple sequence alignment, we investigated variations in the ligand binding region of the 5HT3A subunit protein sequences in the metazoan lineage. Several critical amino acid residues important for ligand binding (common structural features) are commonly present in species from Nematoda and Platyhelminth gut parasites through to Chordata. Collectively, this better understanding of the 5-HT3 receptor evolutionary patterns raises possibilities of future pharmacological challenges facing Metazoa including effects on parasitic and other species in ecosystems that contain 5-HT3 receptor ligands.
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Teng M, Zhao X, Wang C, Wang C, White JC, Zhao W, Zhou L, Duan M, Wu F. Polystyrene Nanoplastics Toxicity to Zebrafish: Dysregulation of the Brain-Intestine-Microbiota Axis. ACS NANO 2022; 16:8190-8204. [PMID: 35507640 DOI: 10.1021/acsnano.2c01872] [Citation(s) in RCA: 129] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
In animal species, the brain-gut axis is a complex bidirectional network between the gastrointestinal (GI) tract and the central nervous system (CNS) consisting of numerous microbial, immune, neuronal, and hormonal pathways that profoundly impact organism development and health. Although nanoplastics (NPs) have been shown to cause intestinal and neural toxicity in fish, the role of the neurotransmitter and intestinal microbiota interactions in the underlying mechanism of toxicity, particularly at environmentally relevant contaminant concentrations, remains unknown. Here, the effect of 44 nm polystyrene nanoplastics (PS-NPs) on the brain-intestine-microbe axis and embryo-larval development in zebrafish (Danio rerio) was investigated. Exposure to 1, 10, and 100 μg/L PS-NPs for 30 days inhibited growth and adversely affected inflammatory responses and intestinal permeability. Targeted metabolomics analysis revealed an alteration of 42 metabolites involved in neurotransmission. The content of 3,4-dihydroxyphenylacetic acid (DOPAC; dopamine metabolite formed by monoamine oxidase activity) was significantly decreased in a dose-dependent manner after PS-NP exposure. Changes in the 14 metabolites correlated with changes to 3 microbial groups, including Proteobacteria, Firmicutes, and Bacteroidetes, as compared to the control group. A significant relationship between Firmicutes and homovanillic acid (0.466, Pearson correlation coefficient) was evident. Eight altered metabolites (l-glutamine (Gln), 5-hydroxyindoleacetic acid (5-HIAA), serotonin, 5-hydroxytryptophan (5-HTP), l-cysteine (Cys), l-glutamic acid (Glu), norepinephrine (NE), and l-tryptophan (l-Trp)) had a negative relationship with Proteobacteria although histamine (His) and acetylcholine chloride (ACh chloride) levels were positively correlated with Proteobacteria. An Associated Network analysis showed that Firmicutes and Bacteroidetes were highly correlated (0.969). Furthermore, PS-NPs accumulated in the gastrointestinal tract of offspring and impaired development of F1 (2 h post-fertilization) embryos, including reduced spontaneous movements, hatching rate, and length. This demonstration of transgenerational deficits is of particular concern. These findings suggest that PS-NPs cause intestinal inflammation, growth inhibition, and restricted development of zebrafish, which are strongly linked to the disrupted regulation within the brain-intestine-microbiota axis. Our study provides insights into how xenobiotics can disrupt the regulation of brain-intestine-microbiota and suggests that these end points should be taken into account when assessing environmental health risks of PS-NPs to aquatic organisms.
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Affiliation(s)
- Miaomiao Teng
- State Key Laboratory of Environmental Criteria and Risk Assessment, Chinese Research Academy of Environmental Sciences, Beijing 100012, China
| | - Xiaoli Zhao
- State Key Laboratory of Environmental Criteria and Risk Assessment, Chinese Research Academy of Environmental Sciences, Beijing 100012, China
| | - Chengju Wang
- Innovation Center of Pesticide Research, Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, China
| | - Chen Wang
- State Key Laboratory of Environmental Criteria and Risk Assessment, Chinese Research Academy of Environmental Sciences, Beijing 100012, China
| | - Jason C White
- The Connecticut Agricultural Experiment Station, New Haven, Connecticut 06511, United States
| | - Wentian Zhao
- Innovation Center of Pesticide Research, Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, China
| | - Lingfeng Zhou
- State Key Laboratory of Environmental Criteria and Risk Assessment, Chinese Research Academy of Environmental Sciences, Beijing 100012, China
| | - Manman Duan
- Innovation Center of Pesticide Research, Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, China
| | - Fengchang Wu
- State Key Laboratory of Environmental Criteria and Risk Assessment, Chinese Research Academy of Environmental Sciences, Beijing 100012, China
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Caffaratti C, Plazy C, Mery G, Tidjani AR, Fiorini F, Thiroux S, Toussaint B, Hannani D, Le Gouellec A. What We Know So Far about the Metabolite-Mediated Microbiota-Intestinal Immunity Dialogue and How to Hear the Sound of This Crosstalk. Metabolites 2021; 11:406. [PMID: 34205653 PMCID: PMC8234899 DOI: 10.3390/metabo11060406] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 06/15/2021] [Accepted: 06/16/2021] [Indexed: 12/25/2022] Open
Abstract
Trillions of microorganisms, termed the "microbiota", reside in the mammalian gastrointestinal tract, and collectively participate in regulating the host phenotype. It is now clear that the gut microbiota, metabolites, and intestinal immune function are correlated, and that alterations of the complex and dynamic host-microbiota interactions can have deep consequences for host health. However, the mechanisms by which the immune system regulates the microbiota and by which the microbiota shapes host immunity are still not fully understood. This article discusses the contribution of metabolites in the crosstalk between gut microbiota and immune cells. The identification of key metabolites having a causal effect on immune responses and of the mechanisms involved can contribute to a deeper insight into host-microorganism relationships. This will allow a better understanding of the correlation between dysbiosis, microbial-based dysmetabolism, and pathogenesis, thus creating opportunities to develop microbiota-based therapeutics to improve human health. In particular, we systematically review the role of soluble and membrane-bound microbial metabolites in modulating host immunity in the gut, and of immune cells-derived metabolites affecting the microbiota, while discussing evidence of the bidirectional impact of this crosstalk. Furthermore, we discuss the potential strategies to hear the sound of such metabolite-mediated crosstalk.
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Affiliation(s)
- Clément Caffaratti
- Faculty of Medicine, CNRS, Grenoble INP, CHU Grenoble-Alpes, University Grenoble Alpes, TIMC (UMR5525), 38000 Grenoble, France; (C.C.); (C.P.); (G.M.); (A.-R.T.); (S.T.); (B.T.)
| | - Caroline Plazy
- Faculty of Medicine, CNRS, Grenoble INP, CHU Grenoble-Alpes, University Grenoble Alpes, TIMC (UMR5525), 38000 Grenoble, France; (C.C.); (C.P.); (G.M.); (A.-R.T.); (S.T.); (B.T.)
- Service de Biochimie Biologie Moléculaire Toxicologie Environnementale, UM Biochimie des Enzymes et des Protéines, Institut de Biologie et Pathologie, CHU Grenoble-Alpes, 38000 Grenoble, France
- Plateforme de Métabolomique GEMELI-GExiM, Institut de Biologie et Pathologie, CHU Grenoble-Alpes, 38000 Grenoble, France;
| | - Geoffroy Mery
- Faculty of Medicine, CNRS, Grenoble INP, CHU Grenoble-Alpes, University Grenoble Alpes, TIMC (UMR5525), 38000 Grenoble, France; (C.C.); (C.P.); (G.M.); (A.-R.T.); (S.T.); (B.T.)
- Department of Infectiology-Pneumology, CHU Grenoble-Alpes, 38000 Grenoble, France
| | - Abdoul-Razak Tidjani
- Faculty of Medicine, CNRS, Grenoble INP, CHU Grenoble-Alpes, University Grenoble Alpes, TIMC (UMR5525), 38000 Grenoble, France; (C.C.); (C.P.); (G.M.); (A.-R.T.); (S.T.); (B.T.)
| | - Federica Fiorini
- Plateforme de Métabolomique GEMELI-GExiM, Institut de Biologie et Pathologie, CHU Grenoble-Alpes, 38000 Grenoble, France;
| | - Sarah Thiroux
- Faculty of Medicine, CNRS, Grenoble INP, CHU Grenoble-Alpes, University Grenoble Alpes, TIMC (UMR5525), 38000 Grenoble, France; (C.C.); (C.P.); (G.M.); (A.-R.T.); (S.T.); (B.T.)
| | - Bertrand Toussaint
- Faculty of Medicine, CNRS, Grenoble INP, CHU Grenoble-Alpes, University Grenoble Alpes, TIMC (UMR5525), 38000 Grenoble, France; (C.C.); (C.P.); (G.M.); (A.-R.T.); (S.T.); (B.T.)
- Service de Biochimie Biologie Moléculaire Toxicologie Environnementale, UM Biochimie des Enzymes et des Protéines, Institut de Biologie et Pathologie, CHU Grenoble-Alpes, 38000 Grenoble, France
- Plateforme de Métabolomique GEMELI-GExiM, Institut de Biologie et Pathologie, CHU Grenoble-Alpes, 38000 Grenoble, France;
| | - Dalil Hannani
- Faculty of Medicine, CNRS, Grenoble INP, CHU Grenoble-Alpes, University Grenoble Alpes, TIMC (UMR5525), 38000 Grenoble, France; (C.C.); (C.P.); (G.M.); (A.-R.T.); (S.T.); (B.T.)
| | - Audrey Le Gouellec
- Faculty of Medicine, CNRS, Grenoble INP, CHU Grenoble-Alpes, University Grenoble Alpes, TIMC (UMR5525), 38000 Grenoble, France; (C.C.); (C.P.); (G.M.); (A.-R.T.); (S.T.); (B.T.)
- Service de Biochimie Biologie Moléculaire Toxicologie Environnementale, UM Biochimie des Enzymes et des Protéines, Institut de Biologie et Pathologie, CHU Grenoble-Alpes, 38000 Grenoble, France
- Plateforme de Métabolomique GEMELI-GExiM, Institut de Biologie et Pathologie, CHU Grenoble-Alpes, 38000 Grenoble, France;
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Shi H, Zhu X, Cui Y, Qin Y, Yang L, Deng X. Analgesic activity of cynaropicrinon on post-inflammatory irritable bowel syndrome visceral hypersensitivity in a rat model. Exp Ther Med 2017; 14:4476-4482. [PMID: 29067122 DOI: 10.3892/etm.2017.5037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Accepted: 08/10/2017] [Indexed: 11/05/2022] Open
Abstract
Visceral hypersensitivity is one of the most common symptoms in patients with post-inflammatory-irritable bowel syndrome (PI-IBS). Enterochromaffin (EC) cells and 5-hydroxytryptamine (5-HT) are important in the development of visceral hyperalgesia, and EC cells are influenced by helper T-cell subtype 1 or 2 cytokine predominant environments. In the present study, the analgesic effect of cynaropicrin and its underlying mechanism on the treatment of trinitrobenzene sulfonic (TNBS)-induced PI-IBS visceral hyperalgesia rats was investigated. The results from the abdominal withdrawal reflex tests and electromyography recordings indicated that treatment with cynaropicrin significantly and dose-dependently alleviated the visceral hyperalgesia of PI-IBS rats (P<0.05). In addition, the increased colonic 5-HT content, colonic tryptophan hydroxylase expression, EC cell number and the cytokine levels, including tumor necrosis factor-α and interleukin-6 in PI-IBS rats were significantly alleviated by cynaropicrin (P<0.05). These data demonstrate that the analgesic activity of cynaropicrin on TNBS-induced PI-IBS visceral hypersensitive rats was mediated via reduction of cytokines levels. Thus, cynaropicrin as a bioactive natural product may offer promising therapeutic avenues for visceral hypersensitivity in IBS.
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Affiliation(s)
- Hailong Shi
- Laboratory for Functional Glycomics, College of Life Sciences, Northwest University, Xi'an Shaanxi 710069, P.R. China.,College of Basic Medicine, Shaanxi University of Chinese Medicine, Xi'an-Xianyang New Economic Zone, Xianyang Shaanxi 712046, P.R. China
| | - Xianwei Zhu
- College of Basic Medicine, Shaanxi University of Chinese Medicine, Xi'an-Xianyang New Economic Zone, Xianyang Shaanxi 712046, P.R. China.,Innovation Research Centre of Acupuncture Combined with Medicine, Shaanxi University of Chinese Medicine, Xi'an-Xianyang New Economic Zone, Shaanxi 712046, P.R. China.,Graduate School of Innovative Life Science for Education, University of Toyama, Toyama 930-8555, Japan
| | - Yaya Cui
- College of Basic Medicine, Shaanxi University of Chinese Medicine, Xi'an-Xianyang New Economic Zone, Xianyang Shaanxi 712046, P.R. China
| | - Yifei Qin
- The Second Clinical Medical College, Shaanxi University of Chinese Medicine, Xi'an-Xianyang New Economic Zone, Xianyang Shaanxi 712046, P.R. China
| | - Lin Yang
- Graduate School of Innovative Life Science for Education, University of Toyama, Toyama 930-8555, Japan
| | - Xu Deng
- College of Basic Medicine, Shaanxi University of Chinese Medicine, Xi'an-Xianyang New Economic Zone, Xianyang Shaanxi 712046, P.R. China
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6
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Shi H, Cui Y, Qin Y. Discovery and characterization of a novel tryptophan hydroxylase 1 inhibitor as a prodrug. Chem Biol Drug Des 2017; 91:202-212. [DOI: 10.1111/cbdd.13071] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2016] [Revised: 05/31/2017] [Accepted: 06/24/2017] [Indexed: 01/05/2023]
Affiliation(s)
- Hailong Shi
- Laboratory for Functional Glycomics; College of Life Sciences; Northwest University; Xi'an City Shaanxi Province China
- College of Basic Medicine; Shaanxi University of Chinese Medicine; Xi'an-Xianyang New Economic Zone; Xianyang City Shaanxi Province China
| | - Yaya Cui
- College of Basic Medicine; Shaanxi University of Chinese Medicine; Xi'an-Xianyang New Economic Zone; Xianyang City Shaanxi Province China
| | - Yifei Qin
- The Second Clinical Medical College; Shaanxi University of Chinese Medicine; Xi'an-Xianyang New Economic Zone; Xianyang City Shaanxi Province China
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Roohafza H, Bidaki EZ, Hasanzadeh-Keshteli A, Daghaghzade H, Afshar H, Adibi P. Anxiety, depression and distress among irritable bowel syndrome and their subtypes: An epidemiological population based study. Adv Biomed Res 2016; 5:183. [PMID: 28028523 PMCID: PMC5156966 DOI: 10.4103/2277-9175.190938] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2015] [Accepted: 10/05/2015] [Indexed: 12/13/2022] Open
Abstract
Background: Psychiatric disorders are common in irritable bowel syndrome (IBS). We conducted this study to investigate the relationship of IBS and their subtypes with some of psychological factors. Materials and Methods: A cross-sectional study was performed among 4763 staff of Isfahan University of Medical Sciences in 2011. Modified ROME III questionnaire and Talley Bowel Disease Questionnaire were used to evaluate IBS symptoms. Hospital Anxiety and Depression Scale and 12-item General Health Questionnaire were utilized to assess anxiety, depression and psychological distress. Logistic regression analysis was used to determine the association of psychological states and IBS in the total subject and both genders. Results: About, 4763 participants with mean age 36/58 ± 8/09 were included the 2106 males and 2657 females. Three thousand and seven hundred and seventy-six (81.2%) and 2650 (57.2%) participants were married and graduated respectively. Subtype analysis of IBS and its relationship with anxiety, depression and distress comparing the two genders can be observed that: IBS and clinically-significant IBS have higher anxiety, depression symptoms, and distress than the subject without IBS (P < 0.001). Women with IBS, have higher scores than men (P < 0.001). Compared to other subtypes, mixed IBS subtype has a higher anxiety, depression, and distress score. Conclusion: A high prevalence of anxiety, depression symptoms and distress in our subjects emphasize the importance of the psychological evaluation of the patients with IBS, in order to better management of the patients and may also help to reduce the burden of health care costs.
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Affiliation(s)
- Hamidreza Roohafza
- Cardiac Rehabilitation Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Ehsan Zare Bidaki
- Integrative Functional Gastroenterology Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Ammar Hasanzadeh-Keshteli
- CEGIIR-Division of Gastroenterology, Department of Medicine, University of Alberta 7-142 Katz Group Centre for Pharmacy and Health Research Edmonton, Alberta, Canada
| | - Hamed Daghaghzade
- Integrative Functional Gastroenterology Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Hamid Afshar
- Psychosomatic Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Peyman Adibi
- Psychosomatic Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
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8
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Chandler JD, Hu X, Ko EJ, Park S, Lee YT, Orr M, Fernandes J, Uppal K, Kang SM, Jones DP, Go YM. Metabolic pathways of lung inflammation revealed by high-resolution metabolomics (HRM) of H1N1 influenza virus infection in mice. Am J Physiol Regul Integr Comp Physiol 2016; 311:R906-R916. [PMID: 27558316 DOI: 10.1152/ajpregu.00298.2016] [Citation(s) in RCA: 88] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Accepted: 08/19/2016] [Indexed: 12/21/2022]
Abstract
Influenza is a significant health concern worldwide. Viral infection induces local and systemic activation of the immune system causing attendant changes in metabolism. High-resolution metabolomics (HRM) uses advanced mass spectrometry and computational methods to measure thousands of metabolites inclusive of most metabolic pathways. We used HRM to identify metabolic pathways and clusters of association related to inflammatory cytokines in lungs of mice with H1N1 influenza virus infection. Infected mice showed progressive weight loss, decreased lung function, and severe lung inflammation with elevated cytokines [interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ] and increased oxidative stress via cysteine oxidation. HRM showed prominent effects of influenza virus infection on tryptophan and other amino acids, and widespread effects on pathways including purines, pyrimidines, fatty acids, and glycerophospholipids. A metabolome-wide association study (MWAS) of the aforementioned inflammatory cytokines was used to determine the relationship of metabolic responses to inflammation during infection. This cytokine-MWAS (cMWAS) showed that metabolic associations consisted of distinct and shared clusters of 396 metabolites highly correlated with inflammatory cytokines. Strong negative associations of selected glycosphingolipid, linoleate, and tryptophan metabolites with IFN-γ contrasted strong positive associations of glycosphingolipid and bile acid metabolites with IL-1β, TNF-α, and IL-10. Anti-inflammatory cytokine IL-10 had strong positive associations with vitamin D, purine, and vitamin E metabolism. The detailed metabolic interactions with cytokines indicate that targeted metabolic interventions may be useful during life-threatening crises related to severe acute infection and inflammation.
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Affiliation(s)
- Joshua D Chandler
- Division of Pulmonary Medicine, Department of Medicine, Emory University, Atlanta, Georgia; and
| | - Xin Hu
- Division of Pulmonary Medicine, Department of Medicine, Emory University, Atlanta, Georgia; and
| | - Eun-Ju Ko
- Georgia State University, Atlanta, Georgia
| | | | | | - Michael Orr
- Division of Pulmonary Medicine, Department of Medicine, Emory University, Atlanta, Georgia; and
| | - Jolyn Fernandes
- Division of Pulmonary Medicine, Department of Medicine, Emory University, Atlanta, Georgia; and
| | - Karan Uppal
- Division of Pulmonary Medicine, Department of Medicine, Emory University, Atlanta, Georgia; and
| | | | - Dean P Jones
- Division of Pulmonary Medicine, Department of Medicine, Emory University, Atlanta, Georgia; and
| | - Young-Mi Go
- Division of Pulmonary Medicine, Department of Medicine, Emory University, Atlanta, Georgia; and
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Abstract
Rotavirus (RV) has been shown to infect and stimulate secretion of serotonin from human enterochromaffin (EC) cells and to infect EC cells in the small intestine of mice. It remains to identify which intracellularly expressed viral protein(s) is responsible for this novel property and to further establish the clinical role of serotonin in RV infection. First, we found that siRNA specifically silencing NSP4 (siRNANSP4) significantly attenuated secretion of serotonin from Rhesus rotavirus (RRV) infected EC tumor cells compared to siRNAVP4, siRNAVP6 and siRNAVP7. Second, intracellular calcium mobilization and diarrhoeal capacity from virulent and avirulent porcine viruses correlated with the capacity to release serotonin from EC tumor cells. Third, following administration of serotonin, all (10/10) infants, but no (0/8) adult mice, responded with diarrhoea. Finally, blocking of serotonin receptors using Ondansetron significantly attenuated murine RV (strain EDIM) diarrhoea in infant mice (2.9 vs 4.5 days). Ondansetron-treated mice (n = 11) had significantly (p < 0.05) less diarrhoea, lower diarrhoea severity score and lower total diarrhoea output as compared to mock-treated mice (n = 9). Similarly, Ondansetron-treated mice had better weight gain than mock-treated animals (p < 0.05). A most surprising finding was that the serotonin receptor antagonist significantly (p < 0.05) also attenuated total viral shedding. In summary, we show that intracellularly expressed NSP4 stimulates release of serotonin from human EC tumor cells and that serotonin participates in RV diarrhoea, which can be attenuated by Ondansetron.
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Terry N, Margolis KG. Serotonergic Mechanisms Regulating the GI Tract: Experimental Evidence and Therapeutic Relevance. Handb Exp Pharmacol 2016; 239:319-342. [PMID: 28035530 DOI: 10.1007/164_2016_103] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Serotonin (5-hydroxytryptamine; 5-HT) is best known as a neurotransmitter critical for central nervous system (CNS) development and function. 95% of the body's serotonin, however, is produced in the intestine where it has been increasingly recognized for its hormonal, autocrine, paracrine, and endocrine actions. This chapter provides the most current knowledge of the critical autocrine and paracrine roles of 5-HT in intestinal motility and inflammation as well as its function as a hormone in osteocyte homeostasis. Therapeutic applications in each of these areas are also discussed.
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Affiliation(s)
- Natalie Terry
- Division of Pediatric Gastroenterology, Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Kara Gross Margolis
- Division of Pediatric Gastroenterology, Department of Pediatrics, Morgan Stanley Children's Hospital, Columbia University Medical Center, New York, NY, USA.
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11
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Goldner D, Margolis KG. Association of Serotonin Transporter Promoter Polymorphism (5HTTLPR) with Microscopic Colitis and Ulcerative Colitis: Time to Be AsSERTive? Dig Dis Sci 2015; 60:819-21. [PMID: 25732715 PMCID: PMC4459509 DOI: 10.1007/s10620-015-3598-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2015] [Accepted: 02/17/2015] [Indexed: 12/12/2022]
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12
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Nabatov AA. The vesicle-associated function of NOD2 as a link between Crohn's disease and mycobacterial infection. Gut Pathog 2015; 7:1. [PMID: 25653718 PMCID: PMC4316803 DOI: 10.1186/s13099-015-0049-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2014] [Accepted: 01/03/2015] [Indexed: 12/18/2022] Open
Abstract
Although Crohn’s disease (CD) etiology remains unclear, a growing body of evidence suggests that CD may include an infectious component, with Mycobacterium avium subsp. paratuberculosis (MAP) being the most likely candidate for this role. However, the molecular mechanism of the MAP involvement in CD pathogenesis remains unclear. The polymorphism of the NOD2 gene, coding for an intracellular pattern recognition receptor, is a factor of predisposition to mycobacterial infections and CD. Recent findings on NOD2 interactions and functions provide the missing pieces in the puzzle of a NOD2-mediated mechanism common for mycobacterial infections and CD. Implications of these new findings for the development of a better understanding and treatments of CD and mycobacterial infections are discussed.
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Affiliation(s)
- Alexey A Nabatov
- Maastricht Radiation Oncology, MAASTRO/GROW Maastricht University Medical Center+, PO Box 616, 6200 MD Maastricht, The Netherlands ; Science Center, Volga Region State Academy of Physical Culture, Sport and Tourism, 33, Universiade Village, Kazan, 420138 Russia
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Serotonin, tryptophan metabolism and the brain-gut-microbiome axis. Behav Brain Res 2014; 277:32-48. [PMID: 25078296 DOI: 10.1016/j.bbr.2014.07.027] [Citation(s) in RCA: 1253] [Impact Index Per Article: 113.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2014] [Revised: 07/08/2014] [Accepted: 07/16/2014] [Indexed: 12/14/2022]
Abstract
The brain-gut axis is a bidirectional communication system between the central nervous system and the gastrointestinal tract. Serotonin functions as a key neurotransmitter at both terminals of this network. Accumulating evidence points to a critical role for the gut microbiome in regulating normal functioning of this axis. In particular, it is becoming clear that the microbial influence on tryptophan metabolism and the serotonergic system may be an important node in such regulation. There is also substantial overlap between behaviours influenced by the gut microbiota and those which rely on intact serotonergic neurotransmission. The developing serotonergic system may be vulnerable to differential microbial colonisation patterns prior to the emergence of a stable adult-like gut microbiota. At the other extreme of life, the decreased diversity and stability of the gut microbiota may dictate serotonin-related health problems in the elderly. The mechanisms underpinning this crosstalk require further elaboration but may be related to the ability of the gut microbiota to control host tryptophan metabolism along the kynurenine pathway, thereby simultaneously reducing the fraction available for serotonin synthesis and increasing the production of neuroactive metabolites. The enzymes of this pathway are immune and stress-responsive, both systems which buttress the brain-gut axis. In addition, there are neural processes in the gastrointestinal tract which can be influenced by local alterations in serotonin concentrations with subsequent relay of signals along the scaffolding of the brain-gut axis to influence CNS neurotransmission. Therapeutic targeting of the gut microbiota might be a viable treatment strategy for serotonin-related brain-gut axis disorders.
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Fukuba N, Ishihara S, Tada Y, Oshima N, Moriyama I, Yuki T, Kawashima K, Kushiyama Y, Fujishiro H, Kinoshita Y. Prevalence of irritable bowel syndrome-like symptoms in ulcerative colitis patients with clinical and endoscopic evidence of remission: prospective multicenter study. Scand J Gastroenterol 2014; 49:674-680. [PMID: 24646420 DOI: 10.3109/00365521.2014.898084] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Irritable bowel syndrome (IBS)-like symptoms are often found in ulcerative colitis (UC) patients in remission. However, the prevalence of those symptoms in UC patients with endoscopic evidence of remission shown by mucosal healing remains unknown. MATERIAL AND METHODS IBS diagnosis was evaluated by questionnaire results according to the Rome III criteria. Clinical remission was assessed by clinical activity index (CAI), whereas endoscopic remission was evaluated by endoscopic index (Matts grade). RESULTS We enrolled 172 patients in clinical remission (CAI ≤ 4), after excluding 36 for incomplete questionnaire results or nonremission findings, as well as 330 control subjects. Of the 172 UC patients, 46 (26.7%) met the Rome III criteria, which was a significantly higher rate as compared with the controls (4.8%). The prevalence rate of IBS-like symptoms in UC patients with endoscopic remission findings (Matts grade ≤2) was 25.6%, which was similar to that of those with clinical remission. When endoscopic remission was defined as Matts grade 1, the prevalence rate of IBS-like symptoms was decreased to 15.4%, although the prevalence rate remained higher than that of the control subjects. CONCLUSIONS The prevalence of IBS-like symptoms in UC patients with clinical and endoscopic remission findings was significantly higher than that of control subjects. Furthermore, the prevalence rate in patients with complete endoscopic remission was decreased. These findings suggest that residual low-grade inflammation may influence the presence of IBS-like symptoms in UC patients in remission.
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Affiliation(s)
- Nobuhiko Fukuba
- Department of Internal Medicine II, Shimane University School of Medicine , Shimane , Japan
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El-Salhy M, Hatlebakk JG, Gilja OH, Hausken T. Irritable bowel syndrome: recent developments in diagnosis, pathophysiology, and treatment. Expert Rev Gastroenterol Hepatol 2014; 8:435-43. [PMID: 24580043 DOI: 10.1586/17474124.2014.888952] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The diagnosis of irritable bowel syndrome (IBS) remains a diagnosis of exclusion, whereby an extensive investigation is performed to exclude other organic diseases that may explain the symptoms of patients. Attempts to have a positive diagnosis based on symptom assessments failed to achieve widely use in clinical practice. Abnormalities in the gastrointestinal endocrine cells in IBS patients have been reported recently, providing evidence that IBS is an organic disorder, and opening the door to the use of these abnormalities as markers for a positive diagnosis of IBS. New and promising drugs for the treatment of IBS with constipation as the predominant symptom are currently on the market, and the treatment results have been satisfactory thus far.
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Affiliation(s)
- Magdy El-Salhy
- Department of Medicine, Section for Gastroenterology, Stord Hospital, Stord, Norway
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Lee YJ, Park KS. Irritable bowel syndrome: Emerging paradigm in pathophysiology. World J Gastroenterol 2014; 20:2456-2469. [PMID: 24627583 PMCID: PMC3949256 DOI: 10.3748/wjg.v20.i10.2456] [Citation(s) in RCA: 106] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 12/01/2013] [Accepted: 02/20/2014] [Indexed: 02/06/2023] Open
Abstract
Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorders, characterized by abdominal pain, bloating, and changes in bowel habits. These symptoms cannot be explained by structural abnormalities and there is no specific laboratory test or biomarker for IBS. Therefore, IBS is classified as a functional disorder with diagnosis dependent on the history taking about manifested symptoms and careful physical examination. Although a great deal of research has been carried out in this area, the pathophysiology of IBS is complex and not completely understood. Multiple factors are thought to contribute to the symptoms in IBS patients; altered gastrointestinal motility, visceral hypersensitivity, and the brain-gut interaction are important classical concepts in IBS pathophysiology. New areas of research in this arena include inflammation, postinfectious low-grade inflammation, genetic and immunologic factors, an altered microbiota, dietary factors, and enteroendocrine cells. These emerging studies have not shown consistent results, provoking controversy in the IBS field. However, certain lines of evidence suggest that these mechanisms are important at least a subset of IBS patients, confirming that IBS symptoms cannot be explained by a single etiological mechanism. Therefore, it is important to keep in mind that IBS requires a more holistic approach to determining effective treatment and understanding the underlying mechanisms.
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El-Salhy M, Gundersen D, Gilja OH, Hatlebakk JG, Hausken T. Is irritable bowel syndrome an organic disorder? World J Gastroenterol 2014; 20:384-400. [PMID: 24574708 PMCID: PMC3923014 DOI: 10.3748/wjg.v20.i2.384] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 11/05/2013] [Accepted: 11/13/2013] [Indexed: 02/06/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a common gastrointestinal disorder that is generally considered to be functional because there appears to be no associated anatomical defect. Stress and psychological factors are thought to play an important role in IBS. The gut neuroendocrine system (NES), which regulates all functions of the gastrointestinal tract, consists of endocrine cells that are scattered among the epithelial cells of the mucosa, and the enteric nervous system. Although it is capable of operating independently from the central nervous system (CNS), the gut NES is connected to and modulated by the CNS. This review presents evidence for the presence of an anatomical defect in IBS patients, namely in the gastrointestinal endocrine cells. These cells have specialized microvilli that project into the lumen and function as sensors for the luminal content and respond to luminal stimuli by releasing hormones into the lamina propria, which starts a chain reaction that progresses throughout the entire NES. The changes in the gastrointestinal endocrine cells observed in IBS patients are highly consistent with the other abnormalities reported in IBS patients, such as visceral hypersensitivity, dysmotility, and abnormal secretion.
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Albayrak A, Halici Z, Cadirci E, Polat B, Karakus E, Bayir Y, Unal D, Atasoy M, Dogrul A. Inflammation and peripheral 5-HT7 receptors: The role of 5-HT7 receptors in carrageenan induced inflammation in rats. Eur J Pharmacol 2013; 715:270-9. [DOI: 10.1016/j.ejphar.2013.05.010] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2013] [Revised: 04/30/2013] [Accepted: 05/11/2013] [Indexed: 12/21/2022]
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O' Mahony SM, Clarke G, McKernan DP, Bravo JA, Dinan TG, Cryan JF. Differential visceral nociceptive, behavioural and neurochemical responses to an immune challenge in the stress-sensitive Wistar Kyoto rat strain. Behav Brain Res 2013; 253:310-7. [PMID: 23872358 DOI: 10.1016/j.bbr.2013.07.023] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2013] [Revised: 07/11/2013] [Accepted: 07/14/2013] [Indexed: 01/08/2023]
Abstract
A highly regulated crosstalk exists between the immune and neuroendocrine systems with the altered immune responses in stress-related disorders being a valid example of this interaction. The Wister Kyoto (WKY) rat is an animal model with a genetic predisposition towards an exaggerated stress response and is used to study disorders such as depression and irritable bowel syndrome (IBS), where stress plays a substantial role. The impact of a lipopolysaccride (LPS) immune challenge has not yet been investigated in this animal model to date. Hence our aim was to assess if the stress susceptible genetic background of the WKY rat was associated with a differential response to an acute immune challenge. Central and peripheral parameters previously shown to be altered by LPS administration were assessed. Under baseline conditions, WKY rats displayed visceral hypersensitivity compared to Sprague Dawley (SD) control rats. However, only SD rats showed an increase in visceral sensitivity following endotoxin administration. The peripheral immune response to the LPS was similar in both strains whilst the central neurochemistry was blunted in the WKY rats. Sickness behaviour was also abrogated in the WKY rats. Taken together, these data indicate that the genetic background of the WKY rat mitigates the response to infection centrally, but not peripherally. This implies that heightened stress-susceptibility in vulnerable populations may compromise the coordinated CNS response to peripheral immune activation.
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Essien B, Grasberger H, Romain RD, Law DJ, Veniaminova NA, Saqui-Salces M, El-Zaatari M, Tessier A, Hayes MM, Yang AC, Merchant JL. ZBP-89 regulates expression of tryptophan hydroxylase I and mucosal defense against Salmonella typhimurium in mice. Gastroenterology 2013; 144:1466-77, 1477.e1-9. [PMID: 23395646 PMCID: PMC3665710 DOI: 10.1053/j.gastro.2013.01.057] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2012] [Revised: 01/28/2013] [Accepted: 01/31/2013] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS ZBP-89 (also ZNF148 or Zfp148) is a butyrate-inducible zinc finger transcription factor that binds to GC-rich DNA elements. Deletion of the N-terminal domain is sufficient to increase mucosal susceptibility to chemical injury and inflammation. We investigated whether conditional deletion of ZBP-89 from the intestinal and colonic epithelium of mice increases their susceptibility to pathogens such as Salmonella typhimurium. METHODS We generated mice with a conditional null allele of Zfp148 (ZBP-89(FL/FL)) using homologous recombination to flank Zfp148 with LoxP sites (ZBP-89(FL/FL)), and then bred the resulting mice with those that express VillinCre. We used microarray analysis to compare gene expression patterns in colonic mucosa between ZBP-89(ΔInt) and C57BL/6 wild-type mice (controls). Mice were gavaged with 2 isogenic strains of S. typhimurium after administration of streptomycin. RESULTS Microarray analysis revealed that the colonic mucosa of ZBP-89(ΔInt) mice had reduced levels of tryptophan hydroxylase 1 (Tph1) messenger RNA, encoding the rate-limiting enzyme in enterochromaffin cell serotonin (5-hydroxytryptamine [5HT]) biosynthesis. DNA affinity precipitation demonstrated direct binding of ZBP-89 to the mouse Tph1 promoter, which was required for its basal and butyrate-inducible expression. ZBP-89(ΔInt) mice did not increase mucosal levels of 5HT in response to S. typhimurium infection, and succumbed to the infection 2 days before control mice. The ΔhilA isogenic mutant of S. typhimurium lacks this butyrate-regulated locus and stimulated, rather than suppressed, expression of Tph1 approximately 50-fold in control, but not ZBP-89(ΔInt), mice, correlating with fecal levels of butyrate. CONCLUSIONS ZBP-89 is required for butyrate-induced expression of the Tph1 gene and subsequent production of 5HT in response to bacterial infection in mice. Reductions in epithelial ZBP-89 increase susceptibility to colitis and sepsis after infection with S. typhimurium, partly because of reduced induction of 5HT production in response to butyrate and decreased secretion of antimicrobial peptides.
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Affiliation(s)
- Bryan Essien
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI
| | - Helmut Grasberger
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI
| | - Rachael D. Romain
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI
| | - David J. Law
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI
| | - Natalia A. Veniaminova
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI
| | - Milena Saqui-Salces
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI
| | - Mohamad El-Zaatari
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI
| | - Arthur Tessier
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI
| | - Michael M. Hayes
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI
| | - Alexander C. Yang
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI
| | - Juanita L. Merchant
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI,Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI
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El-Salhy M, Mazzawi T, Gundersen D, Hatlebakk JG, Hausken T. The role of peptide YY in gastrointestinal diseases and disorders (review). Int J Mol Med 2013; 31:275-82. [PMID: 23292145 PMCID: PMC4042877 DOI: 10.3892/ijmm.2012.1222] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2012] [Accepted: 11/09/2012] [Indexed: 12/13/2022] Open
Abstract
Peptide YY (PYY) is affected in several gastrointestinal diseases and disorders. Changes in PYY appear to be an adaptive response to alterations in pathophysiological conditions caused by the disease. This applies to gastrointestinal diseases/disorders such as irritable bowel syndrome, inflammatory bowel disease, celiac disease, systemic sclerosis, and post-intestinal resection. By contrast, the changes in PYY in chronic idiopathic slow transit constipation (CST) seem to be of a primary nature, and may be one etiological factor of the disease. Abnormalities in PYY seem to contribute to the development of symptoms present in irritable bowel syndrome, inflammatory bowel disease, gastroenteropathy in long-standing diabetes and CST. The changes in PYY could, however, be favorable in some gastrointestinal disorders such as celiac disease, systemic sclerosis and post-intestinal resection state. Investigating changes in PYY in gastrointestinal diseases/disorders could be beneficial in clinical practice, where a receptor agonist or an antagonist can be used as a drug, depending on the condition. Similar to other neuroendocrine peptides/amines of the gut, PYY has broad physiological/pharmacological effects: it can bind to and activate several receptors with independent actions. Thus, in order to use PYY as a drug, receptor-specific agonists or antagonists need to be developed.
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Affiliation(s)
- Magdy El-Salhy
- Section for Gastroenterology, Department of Medicine, Stord Helse-Fonna Hospital, Stord, Norway.
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El-Salhy M, Gundersen D, Hatlebakk JG, Hausken T. High densities of serotonin and peptide YY cells in the colon of patients with lymphocytic colitis. World J Gastroenterol 2012; 18:6070-5. [PMID: 23155335 PMCID: PMC3496883 DOI: 10.3748/wjg.v18.i42.6070] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2012] [Revised: 07/26/2012] [Accepted: 07/29/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate colonic endocrine cells in lymphocytic colitis (LC) patients.
METHODS: Fifty-seven patients with LC were included. These patients were 41 females and 16 males, with an average age of 49 years (range 19-84 years). Twenty-seven subjects that underwent colonoscopy with biopsies were used as controls. These subjects underwent colonoscopy because of gastrointestinal bleeding or health worries, where the source of bleeding was identified as haemorrhoids or angiodysplasia. They were 19 females and 8 males with an average age of 49 years (range 18-67 years). Biopsies from the right and left colon were obtained from both patients and controls during colonoscopy. Biopsies were fixed in 4% buffered paraformaldehyde, embedded in paraffin and cut into 5 μm-thick sections. The sections immunostained by the avidin-biotin-complex method for serotonin, peptide YY (PYY), pancreatic polypeptide (PP) enteroglucagon and somatostatin cells. The cell densities were quantified by computerised image analysis using Olympus software.
RESULTS: The colon of both the patient and the control subjects were macroscopically normal. Histopathological examination of colon biopsies from controls revealed normal histology. All patients fulfilled the diagnosis criteria required for of LC: an increase in intraepithelial lymphocytes (> 20 lymphocytes/100 epithelial cells) and surface epithelial damage with increased lamina propria plasma cells and absent or minimal crypt architectural distribution. In the colon of both patients and control subjects, serotonin-, PYY-, PP-, enteroglucagon- and somatostatin-immunoreactive cells were primarily located in the upper part of the crypts of Lieberkühn. These cells were basket- or flask-shaped. There was no statistically significant difference between the right and left colon in controls with regards to the densities of serotonin- and PYY-immunoreactive cells (P = 0.9 and 0.1, respectively). Serotonin cell density in the right colon in controls was 28.9 ± 1.8 and in LC patients 41.6 ± 2.6 (P = 0.008). In the left colon, the corresponding figures were 28.5 ± 1.9 and 42.4 ± 2.9, respectively (P = 0.009). PYY cell density in the right colon of the controls was 10.1 ± 1 and of LC patients 41 ± 4 (P = 0.00006). In the left colon, PYY cell density in controls was 6.6 ± 1.2 and in LC patients 53.3 ± 4.6 (P = 0.00007).
CONCLUSION: The change in serotonin cells could be caused by an interaction between immune cells and serotonin cells, and that of PYY density might be secondary.
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El-Salhy M. Irritable bowel syndrome: Diagnosis and pathogenesis. World J Gastroenterol 2012; 18:5151-63. [PMID: 23066308 PMCID: PMC3468846 DOI: 10.3748/wjg.v18.i37.5151] [Citation(s) in RCA: 125] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2012] [Revised: 06/18/2012] [Accepted: 07/18/2012] [Indexed: 02/06/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a common gastrointestinal (GI) disorder that considerably reduces the quality of life. It further represents an economic burden on society due to the high consumption of healthcare resources and the non-productivity of IBS patients. The diagnosis of IBS is based on symptom assessment and the Rome III criteria. A combination of the Rome III criteria, a physical examination, blood tests, gastroscopy and colonoscopy with biopsies is believed to be necessary for diagnosis. Duodenal chromogranin A cell density is a promising biomarker for the diagnosis of IBS. The pathogenesis of IBS seems to be multifactorial, with the following factors playing a central role in the pathogenesis of IBS: heritability and genetics, dietary/intestinal microbiota, low-grade inflammation, and disturbances in the neuroendocrine system (NES) of the gut. One hypothesis proposes that the cause of IBS is an altered NES, which would cause abnormal GI motility, secretions and sensation. All of these abnormalities are characteristic of IBS. Alterations in the NES could be the result of one or more of the following: genetic factors, dietary intake, intestinal flora, or low-grade inflammation. Post-infectious IBS (PI-IBS) and inflammatory bowel disease-associated IBS (IBD-IBS) represent a considerable subset of IBS cases. Patients with PI- and IBD-IBS exhibit low-grade mucosal inflammation, as well as abnormalities in the NES of the gut.
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De Silva AP, Nandasiri SD, Hewavisenthi J, Manamperi A, Ariyasinghe MP, Dassanayake AS, Jewell DP, de Silva HJ. Subclinical mucosal inflammation in diarrhea-predominant irritable bowel syndrome (IBS) in a tropical setting. Scand J Gastroenterol 2012; 47:619-24. [PMID: 22486731 DOI: 10.3109/00365521.2012.666672] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS There is evidence for low-grade inflammation in the pathophysiology of post-infectious irritable bowel syndrome (IBS). We assessed the degree of subclinical intestinal mucosal inflammation in diarrhea-predominant IBS (IBS-D) in a tropical setting. MATERIAL AND METHODS In a prospective study over 1 year, we investigated 49 patients with IBS-D (cases; median age 34 years (range 18-59); M:F 36:13), diagnosed on Rome III criteria. 14 individuals with a family history of colon cancer (median age 46.5 years (range 23-56); M:F 6:8) were selected as controls. Stools of cases and controls were tested for calprotectin. During colonoileoscopy, serial biopsies were obtained. Mucosal mast cells, neutrophils, eosinophils and lymphocytes/plasma cell infiltrate were quantified. Tissue expression of IL-8 and IL-10 was assessed in biopsies by semi-quantitative RT-PCR. RESULTS A history suggestive of an episode of infectious diarrhea (ID) was present in 16/49 cases and 0/14 controls (p = 0.013). In cases, there were significantly more mucosal mast cells in the ileum and all segments of colon and significantly more eosinophils in the cecum. Tissue expression of IL-8 was significantly higher and IL-10 significantly lower in cases compared with controls (target/standard cDNA ratio, median (range) IL-8: 1.25 (0.75-2) vs. 0.85 (0.63-1.3), p < 0.0001, Mann-Whitney U test; IL-10: 0.33 (0-0.63) vs. 0.55 (0.5-0.7), p < 0.0001). There was a significant inverse correlation between IL-8 and IL-10 expression (Pearson correlation, (-) 0.509; p < 0.01). CONCLUSION There was evidence of subclinical intestinal mucosal inflammation in patients with IBS-D. The finding of increased eosinophils is novel, and may be of special relevance to IBS-D in the tropics.
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Abstract
The gastrointestinal (GI) tract is the largest producer of serotonin (5-hydroxytryptamine (5-HT)) in the body, and as such it is intimately connected with GI function and physiology. 5-HT produced by enterochromaffin (EC) cells is an important enteric mucosal signaling molecule and has been implicated in a number of GI diseases, including inflammatory bowel disease and functional disorders such as irritable bowel syndrome. This review will focus on what is known of basic 5-HT physiology and also on the emerging evidence for its novel role in activation of immune response and inflammation in the gut. Utilizing pubmed.gov, search terms such as “5-HT,” “EC cell,” and “colitis,” as well as pertinent reviews, were used to develop a brief overview of EC cell biology and the association between 5-HT and various GI disorders. It is the aim of this review to provide the readers with an update on EC cell biology and current understanding on the role of 5-HT in GI disorders specifically in inflammatory conditions.
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El-Salhy M, Gundersen D, Ostgaard H, Lomholt-Beck B, Hatlebakk JG, Hausken T. Low densities of serotonin and peptide YY cells in the colon of patients with irritable bowel syndrome. Dig Dis Sci 2012; 57:873-8. [PMID: 22057239 PMCID: PMC3306780 DOI: 10.1007/s10620-011-1948-8] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2011] [Accepted: 10/12/2011] [Indexed: 12/11/2022]
Abstract
BACKGROUND The gut hormones are important in regulating gastrointestinal motility. Disturbances in gastrointestinal motility have been reported in patients with irritable bowel syndrome (IBS). Reduced endocrine cell density, as revealed by chromogranin A, has been reported in the colon of IBS patients. AIMS To investigate a possible abnormality in the colonic endocrine cells of IBS patients. METHODS A total of 41 patients with IBS according to Rome Criteria III and 20 controls were included in the study. Biopsies from the right and left colon were obtained from both patients and controls during colonoscopy. The biopsies were immunostained for serotonin, peptide YY (PYY), pancreatic polypeptide (PP), entroglucagon, and somatostatin cells. Cell densities were quantified by computerized image analysis. RESULTS Serotonin and PYY cell densities were reduced in the colon of IBS patients. PP, entroglucagon, and somatostatin-immunoreactive cells were too few to enable reliable quantification. CONCLUSION The cause of these observations could be primary genetic defect(s), secondary to altered serotonin and/or PYY signaling systems and/or subclinical inflammation. Serotonin activates the submucosal sensory branch of the enteric nervous system and controls gastrointestinal motility and chloride secretion via interneurons and motor neurons. PYY stimulates absorption of water and electrolytes, and inhibits prostaglandin (PG) E2, and vasoactive intestinal peptide, which stimulates intestinal fluid secretion and is a major regulator of the "ileal brake". Although the cause and effect relationship of these findings is difficult to elucidate, the abnormalities reported here might contribute to the symptoms associated with IBS.
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Affiliation(s)
- M El-Salhy
- Section for Gastroenterology, Department of Medicine, Stord Helse-Fonna Hospital, Box 4000, 54 09 Stord, Norway.
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Brown PM, Drossman DA, Wood AJJ, Cline GA, Frazier KS, Jackson JI, Bronner J, Freiman J, Zambrowicz B, Sands A, Gershon MD. The tryptophan hydroxylase inhibitor LX1031 shows clinical benefit in patients with nonconstipating irritable bowel syndrome. Gastroenterology 2011; 141:507-16. [PMID: 21684281 PMCID: PMC4905727 DOI: 10.1053/j.gastro.2011.05.005] [Citation(s) in RCA: 85] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2010] [Revised: 03/21/2011] [Accepted: 05/05/2011] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Serotonin (5-hydroxytryptamine [5-HT]) has an important role in gastrointestinal function. LX1031 is an oral, locally acting, small molecule inhibitor of tryptophan hydroxylase (TPH). Local inhibition of TPH in the gastrointestinal tract might reduce mucosal production of serotonin (5-HT) and be used to treat patients with nonconstipating irritable bowel syndrome (IBS). METHODS We evaluated 2 dose levels of LX1031 (250 mg or 1000 mg, given 4 times/day) in a 28-day, multicenter, randomized, double-blind, placebo-controlled study of 155 patients with nonconstipating IBS. 5-hydroxyindoleacetic acid (5-HIAA), a biomarker of pharmacodynamic activity, was measured in urine samples at baseline (24 hours after LX1031 administration), and at weeks 4 and 6 (n = 76). RESULTS Each dose of LX1031 was safe and well-tolerated. The primary efficacy end point, relief of IBS pain and discomfort, improved significantly in patients given 1000 mg LX1031 (25.5%), compared with those given placebo, at week 1 (P = .018); with nonsignificant improvements at weeks 2, 3, and 4 (17.9%, 16.3%, and 11.6%, respectively). Symptom improvement correlated with a dose-dependent reduction in 5-HIAA, a marker for TPH inhibition, from baseline until week 4. This suggests the efficacy of LX1031 is related to the extent of inhibition of 5-HT biosynthesis. Stool consistency significantly improved, compared with the group given placebo, at weeks 1 and 4 (P < .01) and at week 2 (P < .001). CONCLUSIONS In a phase 2 study, LX1031 was well tolerated, relieving symptoms and increasing stool consistency in patients with nonconstipating IBS. Symptom relief was associated with reduced levels of 5-HIAA in urine samples. This marker might be used to identify patients with nonconstipating IBS who respond to inhibitors of 5-HT synthesis.
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Affiliation(s)
| | - Douglas A. Drossman
- UNC Center for Functional GI and Motility Disorders, University of North Carolina School of Medicine, Division of Gastroenterology and Hepatology, Chapel Hill, North Carolina
| | - Alastair J. J. Wood
- Symphony Capital, Weill Cornell Medical College, Department of Medicine, Department of Pharmacology
| | - Gary A. Cline
- Icon Clinical Research, Department of Biostatistics, North Wales, Pennsylvania
| | | | | | | | - Joel Freiman
- Lexicon Pharmaceuticals, Inc, The Woodlands, Texas
| | | | - Arthur Sands
- Lexicon Pharmaceuticals, Inc, The Woodlands, Texas
| | - Michael D. Gershon
- Department of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, New York
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Abstract
INTRODUCTION Rifaximin is increasingly being used to treat acute and chronic gastrointestinal infections and disorders. The drug exerts its beneficial effect through a variety of gut-selective mechanisms involving the host intestinal microbiota. AREAS COVERED Abstracts of all publications listed in PubMed on the topic of rifaximin are reviewed to determine their potential value in the understanding of mechanisms of rifaximin activity. The author's extensive file on the drug is also used in the review. EXPERT OPINION Rifaximin inhibits a broad spectrum of bacteria in the bile-rich small bowel and susceptible bacteria in the aqueous colon, and alters microbial virulence and epithelial cell function. The different mechanisms of action of rifaximin potentially explain the use of the drug in widely varied diseases and syndromes.
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Affiliation(s)
- Herbert L DuPont
- The University of Texas School of Public Health, Baylor College of Medicine, St. Luke's Episcopal Hospital, Kelsey Research Foundation, 1200 Herman Pressler, Houston, TX 77030, USA.
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Katiraei P, Bultron G. Need for a comprehensive medical approach to the neuro-immuno-gastroenterology of irritable bowel syndrome. World J Gastroenterol 2011; 17:2791-800. [PMID: 21734786 PMCID: PMC3120938 DOI: 10.3748/wjg.v17.i23.2791] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2010] [Revised: 03/08/2011] [Accepted: 03/15/2011] [Indexed: 02/06/2023] Open
Abstract
Irritable bowel syndrome (IBS) is defined by the Rome III criteria as symptoms of recurrent abdominal pain or discomfort with the onset of a marked change in bowel habits with no evidence of an inflammatory, anatomic, metabolic, or neoplastic process. As such, many clinicians regard IBS as a central nervous system problem of altered pain perception. Here, we review the recent literature and discuss the evidence that supports an organic based model, which views IBS as a complex, heterogeneous, inter-dependent, and multi-variable inflammatory process along the neuronal-gut axis. We delineate the organic pathophysiology of IBS, demonstrate the role of inflammation in IBS, review the possible differences between adult and pediatric IBS, discuss the merits of a comprehensive treatment model as taught by the Institute of Functional Medicine, and describe the potential for future research for this syndrome.
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Depression, anxiety and anger in subtypes of irritable bowel syndrome patients. J Clin Psychol Med Settings 2010; 17:64-70. [PMID: 20094761 DOI: 10.1007/s10880-009-9182-7] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The present study aimed to elucidate the differences in depression, anxiety, anger, and quality of life in a sample of non-psychiatric IBS patients, starting from the hypothesis that IBS subtypes may have different symptomatic expressions of negative emotions with different outcomes on quality of life measures. Forty-two constipation-predominant IBS (C-IBS) subjects and 44 diarrhea-predominant IBS (D-IBS) subjects, after an examination by a gastroenterologist and a total colonoscopy, underwent a clinical interview and psychometric examination for the assessment of depression, anxiety, anger and quality of life. IBS subtypes showed different symptomatic profiles in depression, anxiety and anger, with C-IBS patients more psychologically distressed than D-IBS subjects. Affective and emotional symptoms should be considered as specific and integral to the syndrome, and recognizing the differences between IBS subtypes may have relevant implications for treatment options and clinical outcome.
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Abstract
Gut inflammation is characterized by mucosal recruitment of activated cells from both the innate and adaptive immune systems. In addition to immune cells, inflammation in the gut is associated with an alteration in enteric endocrine cells and various biologically active compounds produced by these cells. Although the change in enteric endocrine cells or their products is considered to be important in regulating gut physiology (motility and secretion), it is not clear whether the change plays any role in immune activation and in the regulation of gut inflammation. Due to the strategic location of enteric endocrine cells in gut mucosa, these gut hormones may play an important role in immune activation and promotion of inflammation in the gut. This review addresses the research on the interface between immune and endocrine systems in gastrointestinal (GI) pathophysiology, specifically in the context of two major products of enteric endocrine systems, namely serotonin (5-hydroxytryptamine: 5-HT) and chromogranins (Cgs), in relation to immune activation and generation of inflammation. The studies reviewed in this paper demonstrate that 5-HT activates the immune cells to produce proinflammatory mediators and by manipulating the 5-HT system it is possible to modulate gut inflammation. In the case of Cgs the scenario is more complex, as this hormone has been shown to play both proinflammatory and anti-inflammatory functions. It is also possible that interaction between 5-HT and Cgs may play a role in the modulation of immune and inflammatory responses. In addition to enhancing our understanding of immunoendocrine interaction in the gut, the data generated from the these studies may have implications in understanding the role of gut hormone in the pathogenesis of both GI and non-GI inflammatory diseases which may lead ultimately to improved therapeutic strategies in inflammatory disorders.
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Affiliation(s)
- W I Khan
- Farncombe Family Digestive Health Research Institute, Department of Pathology and Molecular Medicine, McMaster University, ON, Canada.
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Mawe GM, Strong DS, Sharkey KA. Plasticity of enteric nerve functions in the inflamed and postinflamed gut. Neurogastroenterol Motil 2009; 21:481-91. [PMID: 19368664 PMCID: PMC2717558 DOI: 10.1111/j.1365-2982.2009.01291.x] [Citation(s) in RCA: 70] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Inflammation of the gut alters the properties of the intrinsic and extrinsic neurons that innervate it. While the mechanisms of neuroplasticity differ amongst the inflammatory models that have been used, amongst various regions of the gut, and between intrinsic vs extrinsic neurons, a number of consistent features have been observed. For example, intrinsic and extrinsic primary afferent neurons become hyperexcitable in response to inflammation, and interneuronal synaptic transmission is facilitated in the enteric circuitry. These changes contribute to alterations in gut function and sensation in the inflamed bowel as well as functional disorders, and these changes persist for weeks beyond the point at which detectable inflammation has subsided. Thus, gaining a more thorough understanding of the mechanisms responsible for inflammation-induced neuroplasticity, and strategies to reverse these changes are clinically relevant goals. The purpose of this review is to summarize our current knowledge regarding neurophysiological changes that occur during and following intestinal inflammation, and to identify and address gaps in our knowledge regarding the role of enteric neuroplasticity in inflammatory and functional gastrointestinal disorders.
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Affiliation(s)
- Gary M. Mawe
- Department of Anatomy and Neurobiology, The University of Vermont College of Medicine, Burlington, VT, USA, Hotchkiss Brain Institute and Snyder Institute of Infection, Immunity and Inflammation, Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada
| | - Derek S. Strong
- Department of Anatomy and Neurobiology, The University of Vermont College of Medicine, Burlington, VT, USA
| | - Keith A. Sharkey
- Department of Anatomy and Neurobiology, The University of Vermont College of Medicine, Burlington, VT, USA, Hotchkiss Brain Institute and Snyder Institute of Infection, Immunity and Inflammation, Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada
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Bischoff SC, Mailer R, Pabst O, Weier G, Sedlik W, Li Z, Chen JJ, Murphy DL, Gershon MD. Role of serotonin in intestinal inflammation: knockout of serotonin reuptake transporter exacerbates 2,4,6-trinitrobenzene sulfonic acid colitis in mice. Am J Physiol Gastrointest Liver Physiol 2009; 296:G685-95. [PMID: 19095763 DOI: 10.1152/ajpgi.90685.2008] [Citation(s) in RCA: 147] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Serotonin (5-HT) regulates peristaltic and secretory reflexes in the gut. The serotonin reuptake transporter (SERT; SLC6A4), which inactivates 5-HT, is expressed in the intestinal mucosa and the enteric nervous system. Stool water content is increased and colonic motility is irregular in mice with a targeted deletion of SERT. We tested the hypotheses that 5-HT plays a role in regulating intestinal inflammation and that the potentiation of serotonergic signaling that results from SERT deletion is proinflammatory. Rectal installation of 2,4,6-trinitrobenzene sulfonic acid (TNBS) was used to induce an immune-mediated colitis, which was compared in SERT knockout mice and littermate controls. Intestinal myeloperoxidase and histamine levels were significantly increased, whereas the survival rate and state of health were significantly decreased in TNBS-treated mice that lacked SERT. Deletion of SERT thus increases the severity of TNBS colitis. These data suggest that 5-HT and its SERT-mediated termination play roles in intestinal immune/inflammatory responses in mice.
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Affiliation(s)
- Stephan C Bischoff
- Department of Nutritional Medicine and Immunology, University of Hohenheim, D-70593 Stuttgart, Germany.
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Colucci R, Blandizzi C, Bellini M, Ghisu N, Tonini M, Del Tacca M. The genetics of the serotonin transporter and irritable bowel syndrome. Trends Mol Med 2008; 14:295-304. [PMID: 18550438 DOI: 10.1016/j.molmed.2008.05.001] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2008] [Revised: 04/15/2008] [Accepted: 05/07/2008] [Indexed: 12/12/2022]
Abstract
Serotonin transporter (SERT) mediates the intracellular reuptake of released serotonin, thus regulating its biological functions. Abnormalities in serotonin reuptake can alter enteric serotonergic signalling, leading to sensory, motor and secretory gut dysfunctions, which contribute to the pathophysiology of irritable bowel syndrome (IBS). This relationship has fostered the use of selective serotonin reuptake inhibitors (SSRIs) in the treatment of IBS. Current data on the efficacy of SSRIs in IBS, association of the SERT gene promoter polymorphism 5-HTTLPR with IBS and the expression pattern of SERT in the intestinal mucosa of IBS patients are conflicting. Recent molecular studies have raised critical questions about multiple SERT mRNA transcripts in the human gut, the role of polymorphic SERT promoter in the regulation of enteric SERT expression and the ability of 5-HTTLPR to affect human SERT gene transcription. The present review highlights recent advances in SERT genetics, discusses their implications for potential therapeutic applications of SSRIs in IBS and presents original suggestions for future investigations.
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Affiliation(s)
- Rocchina Colucci
- Division of Pharmacology and Chemotherapy, Department of Internal Medicine, University of Pisa, Via Roma 55, I-56126, Pisa, Italy
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