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Tao E, Long G, Yang T, Chen B, Guo R, Ye D, Fang M, Jiang M. Maternal Separation Induced Visceral Hypersensitivity Evaluated via Novel and Small Size Distention Balloon in Post-weaning Mice. Front Neurosci 2022; 15:803957. [PMID: 35153662 PMCID: PMC8831756 DOI: 10.3389/fnins.2021.803957] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 12/20/2021] [Indexed: 11/29/2022] Open
Abstract
Early life stress (ELS) disposes to functional gastrointestinal diseases in adult, such as irritable bowel syndrome (IBS). Maternal separation (MS) is a well-known animal model of IBS and has been shown to induce visceral hypersensitivity in adult rats and mice. However, to the best of our knowledge, it has not been reported whether MS induces visceral hypersensitivity in young mice, such as the post-weaning mice. Moreover, the method for evaluation of visceral sensitivity also has not been described. Accordingly, the present study aims to evaluate the visceral sensitivity caused by MS in post-weaning mice and develop a novel and small size distention balloon for assessment of visceral sensitivity of such mice. Male pups of C57BL/6 mice were randomly divided into two groups, MS (n = 12) and non-separation (NS) (n = 10). MS pups were separated from the dams through postnatal days (PND) 2 to 14, while NS pups were undisturbed. After, all pups stayed with respective dams and were weaned at PND 22. Visceral sensitivity was evaluated by colorectal distention (CRD) with a novel and small size distention balloon at PND 25. The threshold of abdominal withdrawal reflex (AWR) scores were significantly lower in MS than NS. In addition, AWR scores at different pressures of CRD were significantly higher in MS than NS. The results demonstrate that MS induced visceral hypersensitivity in post-weaning mice. The designed small size distention balloon for evaluation of visceral sensitivity is of significance to further study the pathophysiology of IBS from early life to adulthood.
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Affiliation(s)
- Enfu Tao
- Endoscopy Center and Gastrointestinal Laboratory, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou, China
- Department of Pediatrics, Wenling Maternal and Child Health Care Hospital, Wenling, China
| | - Gao Long
- Endoscopy Center and Gastrointestinal Laboratory, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou, China
| | - Ting Yang
- Endoscopy Center and Gastrointestinal Laboratory, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou, China
| | - Bo Chen
- Endoscopy Center and Gastrointestinal Laboratory, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou, China
| | - Rui Guo
- Endoscopy Center and Gastrointestinal Laboratory, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou, China
| | - Diya Ye
- Endoscopy Center and Gastrointestinal Laboratory, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou, China
| | - Marong Fang
- Institute of Neuroscience and Gastrointestinal Laboratory, Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Mizu Jiang
- Endoscopy Center and Gastrointestinal Laboratory, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, National Children’s Regional Medical Center, Hangzhou, China
- *Correspondence: Mizu Jiang,
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Melchior M, Kuhn P, Poisbeau P. The burden of early life stress on the nociceptive system development and pain responses. Eur J Neurosci 2021; 55:2216-2241. [PMID: 33615576 DOI: 10.1111/ejn.15153] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 01/27/2021] [Accepted: 02/12/2021] [Indexed: 02/07/2023]
Abstract
For a long time, the capacity of the newborn infant to feel pain was denied. Today it is clear that the nociceptive system, even if still immature, is functional enough in the newborn infant to elicit pain responses. Unfortunately, pain is often present in the neonatal period, in particular in the case of premature infants which are subjected to a high number of painful procedures during care. These are accompanied by a variety of environmental stressors, which could impact the maturation of the nociceptive system. Therefore, the question of the long-term consequences of early life stress is a critical question. Early stressful experience, both painful and non-painful, can imprint the nociceptive system and induce long-term alteration in brain function and nociceptive behavior, often leading to an increase sensitivity and higher susceptibility to chronic pain. Different animal models have been developed to understand the mechanisms underlying the long-term effects of different early life stressful procedures, including pain and maternal separation. This review will focus on the clinical and preclinical data about early life stress and its consequence on the nociceptive system.
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Affiliation(s)
- Meggane Melchior
- Centre National de la Recherche Scientifique and University of Strasbourg, Institut des Neurosciences Cellulaires et Intégratives, Strasbourg, France
| | - Pierre Kuhn
- Centre National de la Recherche Scientifique and University of Strasbourg, Institut des Neurosciences Cellulaires et Intégratives, Strasbourg, France.,Service de Médecine et Réanimation du Nouveau-né, Hôpital de Hautepierre, Centre Hospitalier Universitaire de Strasbourg, Strasbourg, France
| | - Pierrick Poisbeau
- Centre National de la Recherche Scientifique and University of Strasbourg, Institut des Neurosciences Cellulaires et Intégratives, Strasbourg, France
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3
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Abstract
The developmental period constitutes a critical window of sensitivity to stress. Indeed, early-life adversity increases the risk to develop psychiatric diseases, but also gastrointestinal disorders such as the irritable bowel syndrome at adulthood. In the past decade, there has been huge interest in the gut-brain axis, especially as regards stress-related emotional behaviours. Animal models of early-life adversity, in particular, maternal separation (MS) in rodents, demonstrate lasting deleterious effects on both the gut and the brain. Here, we review the effects of MS on both systems with a focus on stress-related behaviours. In addition, we discuss more recent findings showing the impact of gut-directed interventions, including nutrition with pre- and probiotics, illustrating the role played by gut microbiota in mediating the long-term effects of MS. Overall, preclinical studies suggest that nutritional approaches with pro- and prebiotics may constitute safe and efficient strategies to attenuate the effects of early-life stress on the gut-brain axis. Further research is required to understand the complex mechanisms underlying gut-brain interaction dysfunctions after early-life stress as well as to determine the beneficial impact of gut-directed strategies in a context of early-life adversity in human subjects.
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Rationale of Probiotic Supplementation during Pregnancy and Neonatal Period. Nutrients 2018; 10:nu10111693. [PMID: 30404227 PMCID: PMC6267579 DOI: 10.3390/nu10111693] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Revised: 10/31/2018] [Accepted: 11/03/2018] [Indexed: 02/07/2023] Open
Abstract
Probiotics are living microorganisms that confer a health benefit when administered in adequate amounts. It has been speculated that probiotics supplementation during pregnancy and in the neonatal period might reduce some maternal and neonatal adverse outcomes. In this narrative review, we describe the rationale behind probiotic supplementation and its possible role in preventing preterm delivery, perinatal infections, functional gastrointestinal diseases, and atopic disorders during early life.
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Felice VD, O'Mahony SM. The microbiome and disorders of the central nervous system. Pharmacol Biochem Behav 2017; 160:1-13. [PMID: 28666895 DOI: 10.1016/j.pbb.2017.06.016] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Revised: 06/12/2017] [Accepted: 06/26/2017] [Indexed: 02/07/2023]
Abstract
Alterations of the gut microbiota have been associated with stress-related disorders including depression and anxiety and irritable bowel syndrome (IBS). More recently, researchers have started investigating the implication of perturbation of the microbiota composition in neurodevelopmental disorders including autism spectrum disorders and Attention-Deficit Hypersensitivity Disorder (ADHD). In this review we will discuss how the microbiota is established and its functions in maintaining health. We also summarize both pre and post-natal factors that shape the developing neonatal microbiota and how they may impact on health outcomes with relevance to disorders of the central nervous system. Finally, we discuss potential therapeutic approaches based on the manipulation of the gut bacterial composition.
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Affiliation(s)
- Valeria D Felice
- Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland
| | - Siobhain M O'Mahony
- APC Microbiome Institute, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.
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6
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Lee KN, Lee OY. The Role of Mast Cells in Irritable Bowel Syndrome. Gastroenterol Res Pract 2016; 2016:2031480. [PMID: 28115927 PMCID: PMC5225338 DOI: 10.1155/2016/2031480] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2016] [Revised: 11/18/2016] [Accepted: 12/05/2016] [Indexed: 12/20/2022] Open
Abstract
Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders, but its treatment is unsatisfactory as its pathophysiology is multifactorial. The putative factors of IBS pathophysiology are visceral hypersensitivity and intestinal dysmotility, also including psychological factors, dysregulated gut-brain axis, intestinal microbiota alterations, impaired intestinal permeability, and mucosal immune alterations. Recently, mucosal immune alterations have received much attention with the role of mast cells in IBS. Mast cells are abundant in the intestines and function as intestinal gatekeepers at the interface between the luminal environment in the intestine and the internal milieu under the intestinal epithelium. As a gatekeeper at the interface, mast cells communicate with the adjacent cells such as epithelial, neuronal, and other immune cells throughout the mediators released when they themselves are activated. Many studies have suggested that mast cells play a role in the pathophysiology of IBS. This review will focus on studies of the role of mast cell in IBS and the limitations of studies and will also consider future directions.
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Affiliation(s)
- Kang Nyeong Lee
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea
| | - Oh Young Lee
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea
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Moloney RD, Johnson AC, O'Mahony SM, Dinan TG, Greenwood‐Van Meerveld B, Cryan JF. Stress and the Microbiota-Gut-Brain Axis in Visceral Pain: Relevance to Irritable Bowel Syndrome. CNS Neurosci Ther 2016; 22:102-17. [PMID: 26662472 PMCID: PMC6492884 DOI: 10.1111/cns.12490] [Citation(s) in RCA: 253] [Impact Index Per Article: 28.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Revised: 11/05/2015] [Accepted: 11/05/2015] [Indexed: 02/06/2023] Open
Abstract
Visceral pain is a global term used to describe pain originating from the internal organs of the body, which affects a significant proportion of the population and is a common feature of functional gastrointestinal disorders (FGIDs) such as irritable bowel syndrome (IBS). While IBS is multifactorial, with no single etiology to completely explain the disorder, many patients also experience comorbid behavioral disorders, such as anxiety or depression; thus, IBS is described as a disorder of the gut-brain axis. Stress is implicated in the development and exacerbation of visceral pain disorders. Chronic stress can modify central pain circuitry, as well as change motility and permeability throughout the gastrointestinal (GI) tract. More recently, the role of the gut microbiota in the bidirectional communication along the gut-brain axis, and subsequent changes in behavior, has emerged. Thus, stress and the gut microbiota can interact through complementary or opposing factors to influence visceral nociceptive behaviors. This review will highlight the evidence by which stress and the gut microbiota interact in the regulation of visceral nociception. We will focus on the influence of stress on the microbiota and the mechanisms by which microbiota can affect the stress response and behavioral outcomes with an emphasis on visceral pain.
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Affiliation(s)
- Rachel D. Moloney
- Laboratory of NeurogastroenterologyAPC Microbiome InstituteUniversity College CorkCorkIreland
- Present address:
Oklahoma Center for NeuroscienceUniversity of Oklahoma Health Science CenterOklahoma CityOKUSA
| | - Anthony C. Johnson
- Oklahoma Center for NeuroscienceUniversity of Oklahoma Health Science CenterOklahoma CityOKUSA
| | - Siobhain M. O'Mahony
- Laboratory of NeurogastroenterologyAPC Microbiome InstituteUniversity College CorkCorkIreland
- Department of Anatomy and NeuroscienceUniversity College CorkCorkIreland
| | - Timothy G. Dinan
- Laboratory of NeurogastroenterologyAPC Microbiome InstituteUniversity College CorkCorkIreland
- Department of Psychiatry and Neurobehavioural ScienceUniversity College CorkCorkIreland
| | - Beverley Greenwood‐Van Meerveld
- Oklahoma Center for NeuroscienceUniversity of Oklahoma Health Science CenterOklahoma CityOKUSA
- V.A. Medical CenterOklahoma CityOKUSA
| | - John F. Cryan
- Laboratory of NeurogastroenterologyAPC Microbiome InstituteUniversity College CorkCorkIreland
- Department of Anatomy and NeuroscienceUniversity College CorkCorkIreland
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8
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De Palma G, Blennerhassett P, Lu J, Deng Y, Park AJ, Green W, Denou E, Silva MA, Santacruz A, Sanz Y, Surette MG, Verdu EF, Collins SM, Bercik P. Microbiota and host determinants of behavioural phenotype in maternally separated mice. Nat Commun 2015. [DOI: 10.1038/ncomms8735] [Citation(s) in RCA: 299] [Impact Index Per Article: 29.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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9
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Fernández-Blanco JA, Estévez J, Shea-Donohue T, Martínez V, Vergara P. Changes in Epithelial Barrier Function in Response to Parasitic Infection: Implications for IBD Pathogenesis. J Crohns Colitis 2015; 9:463-76. [PMID: 25820018 PMCID: PMC4817368 DOI: 10.1093/ecco-jcc/jjv056] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2015] [Accepted: 03/19/2015] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIMS Mast cells [MCs] are implicated in epithelial barrier alterations that characterize inflammatory and functional bowel disorders. In this study, we describe mast cell proteinases [chymases and tryptases] and tight junction [TJ] proteins kinetics in a rat model of postinfectious gut dysfunction. METHODS Jejunal tissues of control and -infected rats were used. Inflammation-related changes in MCs and the expression of TJ-related proteins were evaluated by immunostaining and reverse transcription-quantitative polymerase chain reaction. Epithelial barrier function was assessed in vitro (Ussing chambers) and in vivo. RESULTS After infection, intestinal inflammation was associated with a generalized overexpression of MC chymases, peaking between Days 6 and 14. Thereafter, a mucosal MC hyperplasia and a late increase in connective tissue MC counts were observed. From Day 2 post-infection, TJ proteins occludin and claudin-3 expression was down-regulated whereas the pore-forming protein claudin-2 was overexpressed. The expression of proglucagon, precursor of the barrier-enhancing factor glucagon-like peptide-2, was reduced. These changes were associated with an increase in epithelial permeability, both in vitro and in vivo. CONCLUSIONS Proteinases expression and location of mucosal and connective tissue MCs indicate a time-related pattern in the maturation of intestinal MCs following infection. Altered expression of TJ-related proteins is consistent with a loss of epithelial tightness, and provides a molecular mechanism for the enhanced epithelial permeability observed in inflammatory conditions of the gut.
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Affiliation(s)
| | - Javier Estévez
- Department of Cell Biology, Physiology and Immunology, Universitat
Autònoma de Barcelona, Barcelona,
Spain
| | - Terez Shea-Donohue
- University of Maryland School of Medicine, Division of Gastroenterology
& Hepatology and Mucosal Biology Research Center,
Baltimore, MD, USA
| | - Vicente Martínez
- Department of Cell Biology, Physiology and Immunology, Universitat
Autònoma de Barcelona, Barcelona,
Spain,Instituto de Neurociencias, Universitat Autònoma de
Barcelona, Barcelona,
Spain,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y
Digestivas [CIBERehd], Instituto de Salud Carlos III,
Madrid, Spain
| | - Patri Vergara
- Department of Cell Biology, Physiology and Immunology, Universitat
Autònoma de Barcelona, Barcelona,
Spain,Instituto de Neurociencias, Universitat Autònoma de
Barcelona, Barcelona,
Spain,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y
Digestivas [CIBERehd], Instituto de Salud Carlos III,
Madrid, Spain
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10
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Kennedy PJ, Cryan JF, Dinan TG, Clarke G. Irritable bowel syndrome: A microbiome-gut-brain axis disorder? World J Gastroenterol 2014; 20:14105-14125. [PMID: 25339800 PMCID: PMC4202342 DOI: 10.3748/wjg.v20.i39.14105] [Citation(s) in RCA: 214] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Revised: 04/18/2014] [Accepted: 05/26/2014] [Indexed: 02/07/2023] Open
Abstract
Irritable bowel syndrome (IBS) is an extremely prevalent but poorly understood gastrointestinal disorder. Consequently, there are no clear diagnostic markers to help diagnose the disorder and treatment options are limited to management of the symptoms. The concept of a dysregulated gut-brain axis has been adopted as a suitable model for the disorder. The gut microbiome may play an important role in the onset and exacerbation of symptoms in the disorder and has been extensively studied in this context. Although a causal role cannot yet be inferred from the clinical studies which have attempted to characterise the gut microbiota in IBS, they do confirm alterations in both community stability and diversity. Moreover, it has been reliably demonstrated that manipulation of the microbiota can influence the key symptoms, including abdominal pain and bowel habit, and other prominent features of IBS. A variety of strategies have been taken to study these interactions, including probiotics, antibiotics, faecal transplantations and the use of germ-free animals. There are clear mechanisms through which the microbiota can produce these effects, both humoral and neural. Taken together, these findings firmly establish the microbiota as a critical node in the gut-brain axis and one which is amenable to therapeutic interventions.
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11
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O'Mahony SM, Felice VD, Nally K, Savignac HM, Claesson MJ, Scully P, Woznicki J, Hyland NP, Shanahan F, Quigley EM, Marchesi JR, O'Toole PW, Dinan TG, Cryan JF. Disturbance of the gut microbiota in early-life selectively affects visceral pain in adulthood without impacting cognitive or anxiety-related behaviors in male rats. Neuroscience 2014; 277:885-901. [PMID: 25088912 DOI: 10.1016/j.neuroscience.2014.07.054] [Citation(s) in RCA: 194] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2014] [Revised: 06/19/2014] [Accepted: 07/15/2014] [Indexed: 02/08/2023]
Abstract
Disruption of bacterial colonization during the early postnatal period is increasingly being linked to adverse health outcomes. Indeed, there is a growing appreciation that the gut microbiota plays a role in neurodevelopment. However, there is a paucity of information on the consequences of early-life manipulations of the gut microbiota on behavior. To this end we administered an antibiotic (vancomycin) from postnatal days 4-13 to male rat pups and assessed behavioral and physiological measures across all aspects of the brain-gut axis. In addition, we sought to confirm and expand the effects of early-life antibiotic treatment using a different antibiotic strategy (a cocktail of pimaricin, bacitracin, neomycin; orally) during the same time period in both female and male rat pups. Vancomycin significantly altered the microbiota, which was restored to control levels by 8 weeks of age. Notably, vancomycin-treated animals displayed visceral hypersensitivity in adulthood without any significant effect on anxiety responses as assessed in the elevated plus maze or open field tests. Moreover, cognitive performance in the Morris water maze was not affected by early-life dysbiosis. Immune and stress-related physiological responses were equally unaffected. The early-life antibiotic-induced visceral hypersensitivity was also observed in male rats given the antibiotic cocktail. Both treatments did not alter visceral pain perception in female rats. Changes in visceral pain perception in males were paralleled by distinct decreases in the transient receptor potential cation channel subfamily V member 1, the α-2A adrenergic receptor and cholecystokinin B receptor. In conclusion, a temporary disruption of the gut microbiota in early-life results in very specific and long-lasting changes in visceral sensitivity in male rats, a hallmark of stress-related functional disorders of the brain-gut axis such as irritable bowel disorder.
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Affiliation(s)
- S M O'Mahony
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
| | - V D Felice
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
| | - K Nally
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Department of Biochemistry, University College Cork, Cork, Ireland
| | - H M Savignac
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
| | - M J Claesson
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Department of Microbiology, University College Cork, Cork, Ireland
| | - P Scully
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
| | - J Woznicki
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
| | - N P Hyland
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Department of Pharmacology & Therapeutics, University College Cork, Cork, Ireland
| | - F Shanahan
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Department of Medicine, University College Cork, Cork, Ireland
| | - E M Quigley
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
| | - J R Marchesi
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
| | - P W O'Toole
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Department of Microbiology, University College Cork, Cork, Ireland
| | - T G Dinan
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Department of Psychiatry, University College Cork, Cork, Ireland
| | - J F Cryan
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
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12
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Bravo JA, Dinan TG, Cryan JF. Early-life stress induces persistent alterations in 5-HT1A receptor and serotonin transporter mRNA expression in the adult rat brain. Front Mol Neurosci 2014; 7:24. [PMID: 24782706 PMCID: PMC3989758 DOI: 10.3389/fnmol.2014.00024] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2014] [Accepted: 03/19/2014] [Indexed: 11/13/2022] Open
Abstract
Early-life experience plays a major role in the stress response throughout life. Neonatal maternal separation (MS) is an animal model of depression with an altered serotonergic response. We hypothesize that this alteration may be caused by differences in 5-HT1A receptor and serotonin transporter (SERT) mRNA expression in brain areas involved in the control of emotions, memory, and fear as well as in regions controlling the central serotonergic tone. To test this, Sprague-Dawley rats were subjected to MS for 3 h daily during postnatal days 2-12. As control, age matched rats were non-separated (NS) from their dams. When animals reached adulthood (11-13 weeks) brain was extracted and mRNA expression of 5-HT1A receptor in amygdala, hippocampus and dorsal raphé nucleus (DRN) and SERT in the DRN was analyzed through in situ hybridisation. Densitometric analysis revealed that MS increased 5-HT1A receptor mRNA expression in the amygdala, and reduced its expression in the DRN, but no changes were observed in the hippocampus in comparison to NS controls. Also, MS reduced SERT mRNA expression in the DRN when compared to NS rats. These results suggest that early-life stress induces persistent changes in 5-HT1A receptor and SERT mRNA expression in key brain regions involved in the development of stress-related psychiatric disorders. The reduction in SERT mRNA indicates an alteration that is in line with clinical findings such as polymorphic variants in individuals with higher risk of depression. These data may help to understand how early-life stress contributes to the development of mood disorders in adulthood.
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Affiliation(s)
- Javier A Bravo
- Grupo de NeuroGastroBioquímica, Laboratorio de Química Biológica, Instituto de Química, Facultad de Ciencias, Pontificia Universidad Católica de Valparaíso Valparaíso, Chile
| | - Timothy G Dinan
- Department of Psychiatry, University College Cork Cork, Ireland ; Laboratory of Neurogastroenterology, Alimentary Pharmabiotic Centre, University College Cork Cork, Ireland
| | - John F Cryan
- Laboratory of Neurogastroenterology, Alimentary Pharmabiotic Centre, University College Cork Cork, Ireland ; Department of Anatomy, University College Cork Cork, Ireland
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13
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Felice VD, Gibney SM, Gosselin RD, Dinan TG, O'Mahony SM, Cryan JF. Differential activation of the prefrontal cortex and amygdala following psychological stress and colorectal distension in the maternally separated rat. Neuroscience 2014; 267:252-62. [PMID: 24513388 DOI: 10.1016/j.neuroscience.2014.01.064] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Revised: 01/29/2014] [Accepted: 01/30/2014] [Indexed: 12/17/2022]
Abstract
Visceral hypersensitivity is a hallmark of many clinical conditions and remains an ongoing medical challenge. Although the central neural mechanisms that regulate visceral hypersensitivity are incompletely understood, it has been suggested that stress and anxiety often act as initiating or exacerbating factors. Dysfunctional corticolimbic structures have been implicated in disorders of visceral hypersensitivity such as irritable bowel syndrome (IBS). Moreover, the pattern of altered physiological responses to psychological and visceral stressors reported in IBS patients is also observed in the maternally separated (MS) rat model of IBS. However, the relative contribution of various divisions within the cortex to the altered stress responsivity of MS rats remains unknown. The aim of this study was to analyze the cellular activation pattern of the prefrontal cortex and amygdala in response to an acute psychological stressor (open field) and colorectal distension (CRD) using c-fos immunohistochemistry. Several corticoamygdalar structures were analyzed for the presence of c-fos-positive immunoreactivity including the prelimbic cortex, infralimbic cortex, the anterior cingulate cortex (both rostral and caudal) and the amygdala. Our data demonstrate distinct activation patterns within these corticoamygdalar regions including differential activation in basolateral versus central amygdala following exposure to CRD but not the open field stress. The identification of this neuronal activation pattern may provide further insight into the neurochemical pathways through which therapeutic strategies for IBS could be derived.
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Affiliation(s)
- V D Felice
- Department of Anatomy and Neuroscience, University College Cork, Ireland; Laboratory of Neurogastroenterology, Alimentary Pharmabiotic Centre, University College Cork, Ireland
| | - S M Gibney
- Laboratory of Neurogastroenterology, Alimentary Pharmabiotic Centre, University College Cork, Ireland
| | - R D Gosselin
- Laboratory of Neurogastroenterology, Alimentary Pharmabiotic Centre, University College Cork, Ireland
| | - T G Dinan
- Department of Anatomy and Neuroscience, University College Cork, Ireland; Department of Psychiatry, University College Cork, Ireland
| | - S M O'Mahony
- Department of Anatomy and Neuroscience, University College Cork, Ireland; Laboratory of Neurogastroenterology, Alimentary Pharmabiotic Centre, University College Cork, Ireland.
| | - J F Cryan
- Department of Anatomy and Neuroscience, University College Cork, Ireland; Laboratory of Neurogastroenterology, Alimentary Pharmabiotic Centre, University College Cork, Ireland
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14
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Carroll SY, O’Mahony SM, Grenham S, Cryan JF, Hyland NP. Disodium cromoglycate reverses colonic visceral hypersensitivity and influences colonic ion transport in a stress-sensitive rat strain. PLoS One 2013; 8:e84718. [PMID: 24367692 PMCID: PMC3867510 DOI: 10.1371/journal.pone.0084718] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2013] [Accepted: 11/18/2013] [Indexed: 01/05/2023] Open
Abstract
The interface between psychiatry and stress-related gastrointestinal disorders (GI), such as irritable bowel syndrome (IBS), is well established, with anxiety and depression the most frequently occurring comorbid conditions. Moreover, stress-sensitive Wistar Kyoto (WKY) rats, which display anxiety- and depressive-like behaviors, exhibit GI disturbances akin to those observed in stress-related GI disorders. Additionally, there is mounting preclinical and clinical evidence implicating mast cells as significant contributors to the development of abdominal visceral pain in IBS. In this study we examined the effects of the rat connective tissue mast cell (CTMC) stabiliser, disodium cromoglycate (DSCG) on visceral hypersensitivity and colonic ion transport, and examined both colonic and peritoneal mast cells from stress-sensitive WKY rats. DSCG significantly decreased abdominal pain behaviors induced by colorectal distension in WKY animals independent of a reduction in colonic rat mast cell mediator release. We further demonstrated that mast cell-stimulated colonic ion transport was sensitive to inhibition by the mast cell stabiliser DSCG, an effect only observed in stress-sensitive rats. Moreover, CTMC-like mast cells were significantly increased in the colonic submucosa of WKY animals, and we observed a significant increase in the proportion of intermediate, or immature, peritoneal mast cells relative to control animals. Collectively our data further support a role for mast cells in the pathogenesis of stress-related GI disorders.
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Affiliation(s)
- Siobhan Yvonne Carroll
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
- Department of Pharmacology & Therapeutics, University College Cork, Cork, Ireland
| | - Siobhain Mary O’Mahony
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
- Department of Anatomy & Neuroscience, University College Cork, Cork, Ireland
| | - Susan Grenham
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
- Department of Anatomy & Neuroscience, University College Cork, Cork, Ireland
| | - John Francis Cryan
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
- Department of Anatomy & Neuroscience, University College Cork, Cork, Ireland
| | - Niall Patrick Hyland
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
- Department of Pharmacology & Therapeutics, University College Cork, Cork, Ireland
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15
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Heuston S, Hyland NP. Chymase inhibition as a pharmacological target: a role in inflammatory and functional gastrointestinal disorders? Br J Pharmacol 2013; 167:732-40. [PMID: 22646261 DOI: 10.1111/j.1476-5381.2012.02055.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Chymase has been extensively studied with respect to its role in the pathophysiology of cardiovascular disease, and is notable for its role in the generation of angiotensin II, a mediator crucial in vascular remodelling. However, in more recent years, an association between chymase and several inflammatory diseases, including gastrointestinal (GI) disorders such as inflammatory bowel diseases (IBD) have been described. Such studies, to date, with respect to IBD at least, are descriptive in the clinical context; nonetheless, preclinical studies implicate chymase in the pathogenesis of gut inflammation. However, studies to elucidate the role of chymase in functional bowel disease are in their infancy, but suggest a plausible role for chymase in contributing to some of the phenotypic changes observed in such disorders, namely increased epithelial permeability. In this short review, we have summarized the current knowledge on the pathophysiological role of chymase and its inhibition with reference to inflammation and tissue injury outside of the GI tract and discussed its potential role in GI disorders. We speculate that chymase may be a novel therapeutic target in the GI tract, and as such, inhibitors of chymase warrant preclinical investigation in GI diseases.
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Affiliation(s)
- S Heuston
- Department of Pharmacology and Therapeutics, University College Cork, Ireland Alimentary Pharmabiotic Centre, University College Cork, Ireland
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16
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Lopes LV, Kussmann M. Proteomics at the interface of psychology, gut physiology and dysfunction: an underexploited approach that deserves expansion. Expert Rev Proteomics 2012; 8:605-14. [PMID: 21999831 DOI: 10.1586/epr.11.50] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Gut functions such as digestion and absorption are essential to life and the emerging insights into the gut-brain axis - that is, the cross talk between the enteric and CNS - point towards critical links between (eating) behavior, psychology, whole body and gut physiology, and digestive and overall health. While proteomics is ideally positioned to shed more light on these interactions, be it applied to the periphery (e.g., blood) or the locus of action (i.e., the gut), it is to date largely underexploited, mainly because of challenging sampling and tissue complexity. In view of the contrast between potential and current delivery of proteomics in the context of intestinal health, this article briefs the reader on the state-of-the-art of molecular intestinal research, reviews current proteomic studies (explicitly focusing on the most recent ones that target inflammatory bowel disease patient samples) and argues for an expansion of this research field.
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Affiliation(s)
- Luísa V Lopes
- Neurosciences Unit, Instituto de Medicina Molecular, Av. Prof. Egas Moniz, 1640-028 Lisboa, Portugal.
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17
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Kennedy PJ, Clarke G, Quigley EMM, Groeger JA, Dinan TG, Cryan JF. Gut memories: towards a cognitive neurobiology of irritable bowel syndrome. Neurosci Biobehav Rev 2012; 36:310-40. [PMID: 21777613 DOI: 10.1016/j.neubiorev.2011.07.001] [Citation(s) in RCA: 124] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2011] [Revised: 06/30/2011] [Accepted: 07/04/2011] [Indexed: 01/06/2023]
Abstract
The brain and the gut are engaged in continual crosstalk along a number of pathways collectively termed the 'brain-gut axis'. Over recent years it has become increasingly clear that dysregulation of the axis at a number of levels can result in disorders such as irritable bowel syndrome (IBS). With recent advances in neuroimaging technologies, insights into the neurobiology of IBS are beginning to emerge. However the cognitive neurobiology of IBS has remained relatively unexplored to date. In this review we summarise the available data on cognitive function in IBS. Moreover, we specifically address three key pathophysiological factors, namely; stress, immune activation and chronic pain, together with other factors involved in the manifestation of IBS, and explore how each of these components may impact centrally, what neurobiological mechanisms might be involved, and consider the implications for cognitive functioning in IBS. We conclude that each factor addressed could significantly impinge on central nervous system function, supporting the view that future research efforts must be directed towards a detailed assessment of cognitive function in IBS.
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Affiliation(s)
- Paul J Kennedy
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
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18
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Alterations in the central CRF system of two different rat models of comorbid depression and functional gastrointestinal disorders. Int J Neuropsychopharmacol 2011; 14:666-83. [PMID: 20860876 DOI: 10.1017/s1461145710000994] [Citation(s) in RCA: 83] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Clinical evidence suggests comorbidity between depression and irritable bowel syndrome (IBS). Early-life stress and genetic predisposition are key factors in the pathophysiology of both IBS and depression. Thus, neonatal maternal separation (MS), and the Wistar-Kyoto (WKY) rat, a genetically stress-sensitive rat strain, are two animal models of depression that display increased visceral hypersensitivity and alterations in the hypothalamic-pituitary-adrenal axis. Corticotrophin-releasing factor (CRF) is the primary peptide regulating this axis, acting through two receptors: CRF1 and CRF2. The central CRF system is also a key regulator in the stress response. However, there is a paucity of studies investigating alterations in the central CRF system of adult MS or WKY animals. Using in-situ hybridization we demonstrate that CRF mRNA is increased in the paraventricular nucleus (PVN) of WKY rats and the dorsal raphé nucleus (DRN) of MS animals, compared to Sprague-Dawley and non-separated controls, respectively. Additionally, CRF1 mRNA was higher in the PVN, amygdala and DRN of both animal models, along with high levels of CRF1 mRNA in the hippocampus of WKY animals compared to control animals. Finally, CRF2 mRNA was lower in the DRN of MS and WKY rats compared to control animals, and in the hippocampus and amygdala of MS rats. These results show that the central CRF system is altered in both animal models. Such alterations may affect HPA axis regulation, contribute to behavioural changes associated with stress-related disorders, and alter the affective component of visceral pain modulation, which is enhanced in IBS patients.
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O'Malley D, Dinan TG, Cryan JF. Altered expression and secretion of colonic interleukin-6 in a stress-sensitive animal model of brain-gut axis dysfunction. J Neuroimmunol 2011; 235:48-55. [PMID: 21565410 DOI: 10.1016/j.jneuroim.2011.04.003] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2011] [Revised: 04/06/2011] [Accepted: 04/13/2011] [Indexed: 12/21/2022]
Abstract
Interleukin-6 (IL-6) can activate gastrointestinal submucosal neurons, with associated implications for motility and secretory function. Patients with irritable bowel syndrome (IBS) have elevated levels of circulating IL-6. Colons from the Wistar Kyoto (WKY) rat model of IBS secrete more IL-6 (12.84 pg/ml) than control Sprague Dawley (SD) colons (5.55 pg/ml) and WKY secretions stimulated calcium responses in naïve submucosal neurons of greater amplitude. Recombinant IL-6 activated more submucosal neurons in WKY tissue preparations (p<0.05). These data demonstrate that WKY colonic supernatants activate submucosal neurons using an IL-6-dependent mechanism, thereby providing a link between gastrointestinal dysfunction and alterations in IL-6 levels.
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Affiliation(s)
- Dervla O'Malley
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
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20
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O'Malley D, Dinan TG, Cryan JF. Neonatal maternal separation in the rat impacts on the stress responsivity of central corticotropin-releasing factor receptors in adulthood. Psychopharmacology (Berl) 2011; 214:221-229. [PMID: 20499051 DOI: 10.1007/s00213-010-1885-9] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2010] [Accepted: 05/07/2010] [Indexed: 12/30/2022]
Abstract
RATIONALE Adverse events during early developmental stages can induce persistent changes in central stress circuits, leading to increased stress sensitivity in adulthood, as is apparent in the maternally separated (MS) rat model. It is widely accepted that the stress peptide corticotropin-releasing factor (CRF) by binding to CRF1 and 2 receptors (CRFR1 and CRFR2) is key to these phenotypic changes. OBJECTIVES These studies aim to investigate the effects of maternal separation on central expression of CRFR1 and CRFR2 under basal conditions and following an acute psychological stressor in adulthood. METHODS Western blotting techniques were employed to examine changes in receptor expression in the hypothalamus, pre-frontal and frontal cortices, amygdala and hippocampus of MS rats as compared to controls. Additionally, the effects of an acute psychological stressor (open field exposure) on these changes were assessed. RESULTS Under basal conditions, CRFR1 was elevated in the hypothalamus of MS rats. Exposure to an acute stress had limited effects in non-separated animals but induced significant changes in CRFR1 in the hypothalamus, pre-frontal cortex and hippocampus of MS rats. Additionally, stress-induced increases in CRFR2 were observed in the amygdala of MS rats. CONCLUSIONS These data demonstrate the discrete and significant alterations in how the brain CRF system responds to acute stress following maternal separation. These studies illustrate that early life perturbations induce persistent changes in central CRF receptor expression and increased sensitivity to stress, which may contribute to the stress-related behavioural changes observed in these animals.
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Affiliation(s)
- Dervla O'Malley
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
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21
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Maternal separation as a model of brain-gut axis dysfunction. Psychopharmacology (Berl) 2011; 214:71-88. [PMID: 20886335 DOI: 10.1007/s00213-010-2010-9] [Citation(s) in RCA: 288] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2010] [Accepted: 08/28/2010] [Indexed: 12/13/2022]
Abstract
RATIONALE Early life stress has been implicated in many psychiatric disorders ranging from depression to anxiety. Maternal separation in rodents is a well-studied model of early life stress. However, stress during this critical period also induces alterations in many systems throughout the body. Thus, a variety of other disorders that are associated with adverse early life events are often comorbid with psychiatric illnesses, suggesting a common underlying aetiology. Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder that is thought to involve a dysfunctional interaction between the brain and the gut. Essential aspects of the brain-gut axis include spinal pathways, the hypothalamic pituitary adrenal axis, the immune system, as well as the enteric microbiota. Accumulating evidence suggest that stress, especially in early life, is a predisposing factor to IBS. OBJECTIVE The objective of this review was to assess and compile the most relevant data on early life stress and alterations at all levels of the brain gut axis. RESULTS In this review, we describe the components of the brain-gut axis individually and how they are altered by maternal separation. The separated phenotype is characterised by alterations of the intestinal barrier function, altered balance in enteric microflora, exaggerated stress response and visceral hypersensitivity, which are all evident in IBS. CONCLUSION Thus, maternally separated animals are an excellent model of brain-gut axis dysfunction for the study of disorders such as IBS and for the development of novel therapeutic interventions.
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22
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O'Mahony CM, Bravo JA, Dinan TG, Cryan JF. Comparison of hippocampal metabotropic glutamate receptor 7 (mGlu7) mRNA levels in two animal models of depression. Neurosci Lett 2010; 482:137-41. [PMID: 20638442 DOI: 10.1016/j.neulet.2010.07.018] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2010] [Revised: 07/02/2010] [Accepted: 07/09/2010] [Indexed: 12/16/2022]
Abstract
There is increasing evidence to suggest that metabotropic glutamate (mGlu) receptors including mGlu(7) receptor are important in the pathophysiology of stress-related psychiatric disorders such as anxiety and major depression. mGlu(7) receptor is highly expressed in the hippocampus, a key region involved in the modulation of depression-related behaviour. Moreover, mice deficient in mGlu(7) receptor have an antidepressant-like behaviour and altered stress response. To our knowledge there is little information as to whether stressful phenotypes can influence hippocampal mGlu(7) receptor levels. To this end, we examined hippocampal mGlu(7) receptor mRNA expression in two models of depression, the stress-sensitive Wistar Kyoto (WKY) and the maternally separated model of early-life stress. In situ hybridization analysis revealed that the WKY, but not the maternally separated (MS) rats displayed selective increases in mGlu(7) receptor mRNA expression in subregions of the hippocampus compared to relevant controls. These data suggest that higher levels of this receptor could affect the behaviour in response to stressful conditions and may play a role in WKY animal's susceptibility to stress-related disorders. However, the data in maternally separated animals confirm that whilst hippocampal mGlu(7) receptors maybe involved in certain aspects of stress biology, an increased expression is not necessary for the manifestation of depression-related phenotype per se.
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Affiliation(s)
- Cliona M O'Mahony
- NeuroPharmacology Research Group, Dept of Pharmacology and Therapeutics, University College Cork, Ireland
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23
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Gosselin RD, O'Connor RM, Tramullas M, Julio-Pieper M, Dinan TG, Cryan JF. Riluzole normalizes early-life stress-induced visceral hypersensitivity in rats: role of spinal glutamate reuptake mechanisms. Gastroenterology 2010; 138:2418-25. [PMID: 20226190 DOI: 10.1053/j.gastro.2010.03.003] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2009] [Revised: 02/23/2010] [Accepted: 03/04/2010] [Indexed: 12/30/2022]
Abstract
BACKGROUND & AIMS The molecular basis underlying visceral hypersensitivity in functional irritable bowel syndrome remains elusive, resulting in poor treatment effectiveness. Because alterations in spinal non-neuronal (astrocytic) glutamate reuptake are suspected to participate in chronic pain, we asked whether such processes occur in visceral hypersensitivity. METHODS Visceral hypersensitivity was induced in Sprague-Dawley rats by maternal separation. Separated adults were given a systemic administration of riluzole (5 mg/kg), an approved neuroprotective agent activating glutamate reuptake. Visceral hypersensitivity was assessed using colorectal distension (40 mm Hg). Somatic nociception was quantified using Hot Plate, Randall-Sellito, and Hargreaves tests. Spinal proteins were quantified using immunofluorescence and Western blot. The dependence of visceral sensory function upon spinal glutamate transport was evaluated by intrathecal injection of glutamate transport antagonist DL-threo-beta-benzyloxyaspartate (TBOA). For in vitro testing of riluzole and TBOA, primary cultures of astrocytes were used. RESULTS We show that riluzole counteracts stress-induced visceral hypersensitivity without affecting visceral response in nonseparated rats or altering nociceptive responses to somatic pain stimulation. In addition, maternal separation produces a reduction in glial excitatory amino acid transporter (EAAT)-1 with no change in EAAT-2 or gamma-amino butyric acid transporters. Stress was not associated with changes in glial fibrillary acidic protein or astrocytic morphology per se. Furthermore, visceral normosensitivity relies on spinal EAAT, as intrathecal TBOA is sufficient to induce hypersensitivity in normal rats. CONCLUSIONS We identify spinal EAAT as a therapeutic target, and establish riluzole as a candidate to counteract gastrointestinal hypersensitivity in disorders such as irritable bowel syndrome.
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Affiliation(s)
- Romain-Daniel Gosselin
- Laboratory of Neurogastroenterology, Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
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O'Malley D, Dinan TG, Cryan JF. Alterations in colonic corticotropin-releasing factor receptors in the maternally separated rat model of irritable bowel syndrome: differential effects of acute psychological and physical stressors. Peptides 2010; 31:662-670. [PMID: 20096320 DOI: 10.1016/j.peptides.2010.01.004] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2009] [Revised: 01/13/2010] [Accepted: 01/13/2010] [Indexed: 12/21/2022]
Abstract
Early-life stress is a key predisposing factor to the development of functional gastrointestinal (GI) disorders. Thus, changes in stress-related molecular substrates which influence colonic function may be important in understanding the pathophysiology of such disorders. Activation of peripheral corticotropin-releasing factor (CRF) receptors is thought to be important in the maintenance of GI function homeostasis. Therefore, immunofluorescent and Western blotting techniques were utilized to investigate colonic expression of CRF receptors in the maternal separation (MS) model as compared to non-separated (NS) rats. Receptor expression was also assessed following exposure to two different acute stressors, the open field (OF) and colorectal distension (CRD). Immunofluorescent dual-labeling demonstrated increased activation of both CRFR1 (MS: 79.6+/-4.4% vs. NS: 43.8+/-6.8%, p<0.001) and CRFR2 (MS: 65.9+/-3.2% vs. NS: 51.6+/-5.8%, p<0.05) positive cells in MS rats. Protein expression of CRFR1 and CRFR2 in the proximal colon was similar under baseline conditions and not affected by exposure to an OF stressor in either cohort. In contrast, distal CRFR1 and CRFR2 levels were higher in MS rats but were significantly reduced post OF stress. Moreover, decreases in expression of CRFR1 in the proximal and distal colon of NS rats following exposure to CRD were blunted in MS rats. CRD also caused an increase in the functional isoform of CRFR2 in the distal colon of MS rats with no effect in NS colons. This study demonstrates that acute stressors alter colonic CRF receptor expression in a manner that is determined by the underlying stress sensitivity of the subject.
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Affiliation(s)
- Dervla O'Malley
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
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O'Malley D, Julio-Pieper M, Gibney SM, Dinan TG, Cryan JF. Distinct alterations in colonic morphology and physiology in two rat models of enhanced stress-induced anxiety and depression-like behaviour. Stress 2010; 13:114-122. [PMID: 20214436 DOI: 10.3109/10253890903067418] [Citation(s) in RCA: 95] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Stress and anxiety are important causal and exacerbating factors in functional gastro-intestinal (GI) disorders such as irritable bowel syndrome. Stress affects GI motility, faecal transit and visceral pain sensitivity. Additionally, permeability and function of the gut epithelium, which acts as a barrier between the external environment and the body's internal milieu is altered by stress. However, the effects of an enhanced stress response on colonic morphology require further investigation. We have used two animal models of stress and anxiety, the maternally separated (MS) and Wistar Kyoto (WKY) rats to examine colonic morphology. These rats exhibit increased anxiety behaviours, visceral hypersensitivity and increased stress-induced defecation in the open field arena. At a morphological level, increased mucus secretion and an associated elevation in the number of mucosal goblet cells was observed in the high anxiety rats. Additionally, the mucosal layer was flattened in MS and WKY rats, a finding indicative of mild mucosal damage. Furthermore, the muscular layer of the distal colon in these animals was thickened, an observation that may have implications for faecal transit and visceral pain perception. This study provides evidence of altered colonic function and morphology in two animal models with a heightened response to stress.
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Affiliation(s)
- Dervla O'Malley
- Laboratory of Neurogastroenterology, Alimentary Pharmabiotic Centre, BioSciences Institute, University College Cork, Cork, Ireland
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McKernan DP, Nolan A, Brint EK, O'Mahony SM, Hyland NP, Cryan JF, Dinan TG. Toll-like receptor mRNA expression is selectively increased in the colonic mucosa of two animal models relevant to irritable bowel syndrome. PLoS One 2009; 4:e8226. [PMID: 20011045 PMCID: PMC2785428 DOI: 10.1371/journal.pone.0008226] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2009] [Accepted: 11/11/2009] [Indexed: 02/06/2023] Open
Abstract
Background Irritable bowel syndrome (IBS) is largely viewed as a stress-related disorder caused by aberrant brain-gut–immune communication and altered gastrointestinal (GI) homeostasis. Accumulating evidence demonstrates that stress modulates innate immune responses; however, very little is known on the immunological effects of stress on the GI tract. Toll-like receptors (TLRs) are critical pattern recognition molecules of the innate immune system. Activation of TLRs by bacterial and viral molecules leads to activation of NF-kB and an increase in inflammatory cytokine expression. It was our hypothesis that innate immune receptor expression may be changed in the gastrointestinal tract of animals with stress-induced IBS-like symptoms. Methodology/Principal Findings In this study, our objective was to evaluate the TLR expression profile in the colonic mucosa of two rat strains that display colonic visceral hypersensivity; the stress-sensitive Wistar-Kyoto (WKY) rat and the maternally separated (MS) rat. Quantitative PCR of TLR2-10 mRNA in both the proximal and distal colonic mucosae was carried out in adulthood. Significant increases are seen in the mRNA levels of TLR3, 4 & 5 in both the distal and proximal colonic mucosa of MS rats compared with controls. No significant differences were noted for TLR 2, 7, 9 & 10 while TLR 6 could not be detected in any samples in both rat strains. The WKY strain have increased levels of mRNA expression of TLR3, 4, 5, 7, 8, 9 & 10 in both the distal and proximal colonic mucosa compared to the control Sprague-Dawley strain. No significant differences in expression were found for TLR2 while as before TLR6 could not be detected in all samples in both strains. Conclusions These data suggest that both early life stress (MS) and a genetic predisposition (WKY) to stress affect the expression of key sentinels of the innate immune system which may have direct relevance for the molecular pathophysiology of IBS.
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Affiliation(s)
- Declan P. McKernan
- Laboratory of Neurogastroenterology, Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
| | - Aoife Nolan
- Laboratory of Neurogastroenterology, Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
| | - Elizabeth K. Brint
- Laboratory of Neurogastroenterology, Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
- Department of Pathology, University College Cork, Cork, Ireland
| | - Siobhain M. O'Mahony
- Laboratory of Neurogastroenterology, Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
- Department of Anatomy, University College Cork, Cork, Ireland
| | - Niall P. Hyland
- Laboratory of Neurogastroenterology, Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
- Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland
| | - John F. Cryan
- Laboratory of Neurogastroenterology, Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
- School of Pharmacy, University College Cork, Cork, Ireland
- Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland
- * E-mail: (JFC); (TGD)
| | - Timothy G. Dinan
- Laboratory of Neurogastroenterology, Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
- Department of Psychiatry, University College Cork, Cork, Ireland
- * E-mail: (JFC); (TGD)
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Irritable bowel syndrome: towards biomarker identification. Trends Mol Med 2009; 15:478-89. [PMID: 19811951 DOI: 10.1016/j.molmed.2009.08.001] [Citation(s) in RCA: 143] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2009] [Revised: 08/02/2009] [Accepted: 08/05/2009] [Indexed: 02/06/2023]
Abstract
Irritable bowel syndrome (IBS), the most common functional gastrointestinal disorder referred to gastroenterologists, affects 7-10% of the general population worldwide. The lack of suitable disease-defining biological markers coupled with a poorly understood underlying pathophysiology complicates patient diagnosis and seriously hampers drug discovery efforts. Over the past few years, a number of potential biomarkers have emerged, and in this review we critically evaluate such candidates. In particular, we highlight the increasing number of studies supporting a low-grade immune activation in IBS and consider how the latest preclinical developments can contribute to the development of more robust and reliable biological markers of this disorder. The successful identification of biomarkers is critical to progressing our understanding of IBS and addressing the unmet therapeutic needs of this debilitating condition.
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