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Dai S, Mo Y, Wang Y, Xiang B, Liao Q, Zhou M, Li X, Li Y, Xiong W, Li G, Guo C, Zeng Z. Chronic Stress Promotes Cancer Development. Front Oncol 2020; 10:1492. [PMID: 32974180 PMCID: PMC7466429 DOI: 10.3389/fonc.2020.01492] [Citation(s) in RCA: 190] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 07/13/2020] [Indexed: 11/24/2022] Open
Abstract
Stress is an inevitable part of life. Chronic stress on account of reasons like adversity, depression, anxiety, or loneliness/social isolation can endanger human health. Recent studies have shown that chronic stress can induce tumorigenesis and promote cancer development. This review describes the latest progress of research on the molecular mechanisms by which chronic stress promotes cancer development. Primarily, chronic stress activates the classic neuroendocrine system [the hypothalamic-pituitary-adrenal (HPA) axis] and the sympathetic nervous system (SNS) and leads to a decline and dysfunction of the prefrontal cortex and the hippocampus under stress. Stress hormones produced during the activation of both the HPA axis and the SNS can promote tumorigenesis and cancer development through a variety of mechanisms. Chronic stress can also cause corresponding changes in the body's immune function and inflammatory response, which is significant because a long-term inflammatory response and the decline of the body's immune surveillance capabilities are implicated in tumorigenesis. Stress management is essential for both healthy people and cancer patients. Whether drugs that limit the signaling pathways downstream of the HPA axis or the SNS can suppress chronic stress-induced cancers or prolong patient survival deserves further study.
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Affiliation(s)
- Shirui Dai
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Yongzhen Mo
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China
| | - Yumin Wang
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China
| | - Bo Xiang
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Qianjin Liao
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China
| | - Ming Zhou
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Xiaoling Li
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Yong Li
- Department of Medicine, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, United States
| | - Wei Xiong
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Guiyuan Li
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Can Guo
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Zhaoyang Zeng
- NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, China
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van Thiel IAM, de Jonge WJ, Chiu IM, van den Wijngaard RM. Microbiota-neuroimmune cross talk in stress-induced visceral hypersensitivity of the bowel. Am J Physiol Gastrointest Liver Physiol 2020; 318:G1034-G1041. [PMID: 32308040 PMCID: PMC7642838 DOI: 10.1152/ajpgi.00196.2019] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Visceral hypersensitivity of the lower gastrointestinal tract, defined as an increased response to colorectal distension, frequently prompts episodes of debilitating abdominal pain in irritable bowel syndrome (IBS). Although the pathophysiology of IBS is not yet fully elucidated, it is well known that stress is a major risk factor for development and acts as a trigger of pain sensation. Stress modulates both immune responses as well as the gut microbiota and vice versa. Additionally, either microbes themselves or through involvement of the immune system, activate or sensitize afferent nociceptors. In this paper, we review current knowledge on the influence of stress along the gut-brain-microbiota axis and exemplify relevant neuroimmune cross talk mechanisms in visceral hypersensitivity, working toward understanding how gut microbiota-neuroimmune cross talk contributes to visceral pain sensation in IBS patients.
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Affiliation(s)
- Isabelle A. M. van Thiel
- 1Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centers, Amsterdam, The Netherlands,2Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
| | - Wouter J. de Jonge
- 1Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centers, Amsterdam, The Netherlands,2Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands,3Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, Amsterdam, The Netherlands,4Department of General, Visceral, Thoracic, and Vascular Surgery, University Hospital Bonn, Bonn, Germany
| | - Isaac M. Chiu
- 5Department of Immunology, Harvard Medical School. Boston, Massachusetts
| | - Rene M. van den Wijngaard
- 1Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centers, Amsterdam, The Netherlands,2Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands,3Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, Amsterdam, The Netherlands
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3
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Costa J, Ahluwalia A. Advances and Current Challenges in Intestinal in vitro Model Engineering: A Digest. Front Bioeng Biotechnol 2019; 7:144. [PMID: 31275931 PMCID: PMC6591368 DOI: 10.3389/fbioe.2019.00144] [Citation(s) in RCA: 131] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Accepted: 05/28/2019] [Indexed: 12/30/2022] Open
Abstract
The physiological environment of the intestine is characterized by its variegated composition, numerous functions and unique dynamic conditions, making it challenging to recreate the organ in vitro. This review outlines the requirements for engineering physiologically relevant intestinal in vitro models, mainly focusing on the importance of the mechano-structural cues that are often neglected in classic cell culture systems. More precisely: the topography, motility and flow present in the intestinal epithelium. After defining quantitative descriptors for these features, we describe the current state of the art, citing relevant approaches used to address one (or more) of the elements in question, pursuing a progressive conceptual construction of an "ideal" biomimetic intestinal model. The review concludes with a critical assessment of the currently available methods to summarize the important features of the intestinal tissue in the light of their different applications.
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Affiliation(s)
| | - Arti Ahluwalia
- Research Center “E. Piaggio” and Department of Information Engineering, University of Pisa, Pisa, Italy
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4
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Muthusamy N, Sommerville LJ, Moeser AJ, Stumpo DJ, Sannes P, Adler K, Blackshear PJ, Weimer JM, Ghashghaei HT. MARCKS-dependent mucin clearance and lipid metabolism in ependymal cells are required for maintenance of forebrain homeostasis during aging. Aging Cell 2015; 14:764-73. [PMID: 26010231 PMCID: PMC4568964 DOI: 10.1111/acel.12354] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/12/2015] [Indexed: 12/28/2022] Open
Abstract
Ependymal cells (ECs) form a barrier responsible for selective movement of fluids and molecules between the cerebrospinal fluid and the central nervous system. Here, we demonstrate that metabolic and barrier functions in ECs decline significantly during aging in mice. The longevity of these functions in part requires the expression of the myristoylated alanine-rich protein kinase C substrate (MARCKS). Both the expression levels and subcellular localization of MARCKS in ECs are markedly transformed during aging. Conditional deletion of MARCKS in ECs induces intracellular accumulation of mucins, elevated oxidative stress, and lipid droplet buildup. These alterations are concomitant with precocious disruption of ependymal barrier function, which results in the elevation of reactive astrocytes, microglia, and macrophages in the interstitial brain tissue of young mutant mice. Interestingly, similar alterations are observed during normal aging in ECs and the forebrain interstitium. Our findings constitute a conceptually new paradigm in the potential role of ECs in the initiation of various conditions and diseases in the aging brain.
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Affiliation(s)
- Nagendran Muthusamy
- Department of Molecular Biomedical Sciences College of Veterinary Medicine North Carolina State University Raleigh NC 27607 USA
| | - Laura J. Sommerville
- Department of Molecular Biomedical Sciences College of Veterinary Medicine North Carolina State University Raleigh NC 27607 USA
| | - Adam J. Moeser
- Department of Population Health and Pathobiology College of Veterinary Medicine North Carolina State University Raleigh NC 27607 USA
- Center for Comparative Medicine and Translational Research College of Veterinary Medicine North Carolina State University Raleigh NC 27607 USA
| | - Deborah J. Stumpo
- Laboratory of Signal Transduction National Institute of Environmental Health Sciences Durham NC 27709 USA
| | - Philip Sannes
- Department of Molecular Biomedical Sciences College of Veterinary Medicine North Carolina State University Raleigh NC 27607 USA
- Center for Comparative Medicine and Translational Research College of Veterinary Medicine North Carolina State University Raleigh NC 27607 USA
| | - Kenneth Adler
- Department of Molecular Biomedical Sciences College of Veterinary Medicine North Carolina State University Raleigh NC 27607 USA
| | - Perry J. Blackshear
- Laboratory of Signal Transduction National Institute of Environmental Health Sciences Durham NC 27709 USA
| | - Jill M. Weimer
- Sanford Research Children's Health Research and Department of Pediatric University of South Dakota Sanford School of Medicine Sioux Falls SD 57104 USA
| | - H. Troy Ghashghaei
- Department of Molecular Biomedical Sciences College of Veterinary Medicine North Carolina State University Raleigh NC 27607 USA
- Center for Comparative Medicine and Translational Research College of Veterinary Medicine North Carolina State University Raleigh NC 27607 USA
- Program in Genetics North Carolina State University Raleigh NC 27607 USA
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5
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Rodiño-Janeiro BK, Alonso-Cotoner C, Pigrau M, Lobo B, Vicario M, Santos J. Role of Corticotropin-releasing Factor in Gastrointestinal Permeability. J Neurogastroenterol Motil 2015; 21:33-50. [PMID: 25537677 PMCID: PMC4288093 DOI: 10.5056/jnm14084] [Citation(s) in RCA: 83] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Revised: 10/06/2014] [Accepted: 10/07/2014] [Indexed: 12/11/2022] Open
Abstract
The interface between the intestinal lumen and the mucosa is the location where the majority of ingested immunogenic particles face the scrutiny of the vast gastrointestinal immune system. Upon regular physiological conditions, the intestinal micro-flora and the epithelial barrier are well prepared to process daily a huge amount of food-derived antigens and non-immunogenic particles. Similarly, they are ready to prevent environmental toxins and microbial antigens to penetrate further and interact with the mucosal-associated immune system. These functions promote the development of proper immune responses and oral tolerance and prevent disease and inflammation. Brain-gut axis structures participate in the processing and execution of response signals to external and internal stimuli. The brain-gut axis integrates local and distant regulatory networks and super-systems that serve key housekeeping physiological functions including the balanced functioning of the intestinal barrier. Disturbance of the brain-gut axis may induce intestinal barrier dysfunction, increasing the risk of uncontrolled immunological reactions, which may indeed trigger transient mucosal inflammation and gut disease. There is a large body of evidence indicating that stress, through the brain-gut axis, may cause intestinal barrier dysfunction, mainly via the systemic and peripheral release of corticotropin-releasing factor. In this review, we describe the role of stress and corticotropin-releasing factor in the regulation of gastrointestinal permeability, and discuss the link to both health and pathological conditions.
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Affiliation(s)
- Bruno K Rodiño-Janeiro
- Neuro-Immuno-Gastroenterology Group, Digestive Diseases Research Unit, Gastroenterology Department, Hospital Universitari Vall d'Hebron, Vall d' Hebron Research Institute; and Department of Medicine, Universitat Autònoma de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Barcelona, Spain
| | - Carmen Alonso-Cotoner
- Neuro-Immuno-Gastroenterology Group, Digestive Diseases Research Unit, Gastroenterology Department, Hospital Universitari Vall d'Hebron, Vall d' Hebron Research Institute; and Department of Medicine, Universitat Autònoma de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Barcelona, Spain
| | - Marc Pigrau
- Neuro-Immuno-Gastroenterology Group, Digestive Diseases Research Unit, Gastroenterology Department, Hospital Universitari Vall d'Hebron, Vall d' Hebron Research Institute; and Department of Medicine, Universitat Autònoma de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Barcelona, Spain
| | - Beatriz Lobo
- Neuro-Immuno-Gastroenterology Group, Digestive Diseases Research Unit, Gastroenterology Department, Hospital Universitari Vall d'Hebron, Vall d' Hebron Research Institute; and Department of Medicine, Universitat Autònoma de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Barcelona, Spain
| | - María Vicario
- Neuro-Immuno-Gastroenterology Group, Digestive Diseases Research Unit, Gastroenterology Department, Hospital Universitari Vall d'Hebron, Vall d' Hebron Research Institute; and Department of Medicine, Universitat Autònoma de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Barcelona, Spain
| | - Javier Santos
- Neuro-Immuno-Gastroenterology Group, Digestive Diseases Research Unit, Gastroenterology Department, Hospital Universitari Vall d'Hebron, Vall d' Hebron Research Institute; and Department of Medicine, Universitat Autònoma de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Barcelona, Spain
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6
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Selenium-enriched Agaricus bisporus mushroom protects against increase in gut permeability ex vivo and up-regulates glutathione peroxidase 1 and 2 in hyperthermally-induced oxidative stress in rats. Nutrients 2014; 6:2478-92. [PMID: 24962481 PMCID: PMC4073163 DOI: 10.3390/nu6062478] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Revised: 05/28/2014] [Accepted: 06/18/2014] [Indexed: 11/17/2022] Open
Abstract
Dietary effects of organic Se supplementation in the form of Se-enriched Agaricus bisporus mushroom on ileal mucosal permeability and antioxidant selenoenzymes status in heat induced oxidative stress in rats were evaluated. Acute heat stress (40 °C, 21% relative humidity, 90 min exposure) increased ileum baseline short circuit current (Isc; 2.40-fold) and epithelial conductance (Ge; 2.74-fold). Dietary supplementation with Se-enriched A. bisporus (1 µg Se/g feed) reduced (p < 0.05) ileum Isc and Ge during heat stress to 1.74 and 1.91 fold, respectively, indicating protection from heat stress-induced mucosal permeability increase. The expression of ileum glutathione peroxidase (GPx-) 1 and 2 mRNAs were up-regulated (p < 0.05) by 1.90 and 1.87-fold, respectively, for non-heat stress rats on the Se-enriched diet relative to the control. The interplay between heat stress and dietary Se is complex. For rats on the control diet, heat stress alone increased ileum expression of GPx-1 (2.33-fold) and GPx-2 (2.23-fold) relative to thermoneutral conditions. For rats on the Se-enriched diet, heat stress increased (p < 0.05) GPx-1 expression only. Rats on Se-enriched + α-tocopherol diet exhibited increased expression of both genes (p < 0.05). Thus, dietary Se-enriched A. bisporus protected against increase in ileum permeability and up-regulated GPx-1 and GPx-2 expression, selenoenzymes relevant to mitigating oxidative stress.
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7
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Meleine M, Matricon J. Gender-related differences in irritable bowel syndrome: Potential mechanisms of sex hormones. World J Gastroenterol 2014; 20:6725-6743. [PMID: 24944465 PMCID: PMC4051914 DOI: 10.3748/wjg.v20.i22.6725] [Citation(s) in RCA: 148] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2013] [Revised: 02/08/2014] [Accepted: 03/19/2014] [Indexed: 02/06/2023] Open
Abstract
According to epidemiological studies, twice as many women as men are affected by irritable bowel syndrome (IBS) in western countries, suggesting a role for sex hormones in IBS pathophysiology. Despite growing evidence about the implications of sex hormones in IBS symptom modulation, data on mechanisms by which they influence disease development are sparse. This review aims to determine the state of knowledge about the role of sex hormones in sensorimotor dysfunctions and to address the possible interplay of sex hormones with common risk factors associated with IBS. The scientific bibliography was searched using the following keywords: irritable bowel syndrome, sex, gender, ovarian hormone, estradiol, progesterone, testosterone, symptoms, pain, sensitivity, motility, permeability, stress, immune system, brain activity, spinal, supraspinal, imaging. Ovarian hormones variations along the menstrual cycle affect sensorimotor gastrointestinal function in both healthy and IBS populations. They can modulate pain processing by interacting with neuromodulator systems and the emotional system responsible for visceral pain perception. These hormones can also modulate the susceptibility to stress, which is a pivotal factor in IBS occurrence and symptom severity. For instance, estrogen-dependent hyper-responsiveness to stress can promote immune activation or impairments of gut barrier function. In conclusion, whereas it is important to keep in mind that ovarian hormones cannot be considered as a causal factor of IBS, they arguably modulate IBS onset and symptomatology. However, our understanding of the underlying mechanisms remains limited and studies assessing the link between IBS symptoms and ovarian hormone levels are needed to improve our knowledge of the disease evolution with regard to gender. Further studies assessing the role of male hormones are also needed to understand fully the role of sex hormones in IBS. Finally, investigation of brain-gut interactions is critical to decipher how stress, ovarian hormones, and female brain processing of pain can translate into gut dysfunctions.
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Rezzi S, Martin FP, Alonso C, Guilarte M, Vicario M, Ramos L, Martínez C, Lobo B, Saperas E, Malagelada JR, Santos J, Kochhar S. Metabotyping of Biofluids Reveals Stress-Based Differences in Gut Permeability in Healthy Individuals. J Proteome Res 2009; 8:4799-809. [DOI: 10.1021/pr900525w] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Serge Rezzi
- Bioanalytical Science Department, Metabonomics & Biomarkers Group, Nestlé Research Center, Lausanne, Switzerland, and Digestive Diseases Research Unit, Institut de Recerca, Department of Gastroenterology; Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Department of Medicine, Barcelona, Spain
| | - François-Pierre Martin
- Bioanalytical Science Department, Metabonomics & Biomarkers Group, Nestlé Research Center, Lausanne, Switzerland, and Digestive Diseases Research Unit, Institut de Recerca, Department of Gastroenterology; Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Department of Medicine, Barcelona, Spain
| | - Carmen Alonso
- Bioanalytical Science Department, Metabonomics & Biomarkers Group, Nestlé Research Center, Lausanne, Switzerland, and Digestive Diseases Research Unit, Institut de Recerca, Department of Gastroenterology; Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Department of Medicine, Barcelona, Spain
| | - Mar Guilarte
- Bioanalytical Science Department, Metabonomics & Biomarkers Group, Nestlé Research Center, Lausanne, Switzerland, and Digestive Diseases Research Unit, Institut de Recerca, Department of Gastroenterology; Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Department of Medicine, Barcelona, Spain
| | - María Vicario
- Bioanalytical Science Department, Metabonomics & Biomarkers Group, Nestlé Research Center, Lausanne, Switzerland, and Digestive Diseases Research Unit, Institut de Recerca, Department of Gastroenterology; Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Department of Medicine, Barcelona, Spain
| | - Laura Ramos
- Bioanalytical Science Department, Metabonomics & Biomarkers Group, Nestlé Research Center, Lausanne, Switzerland, and Digestive Diseases Research Unit, Institut de Recerca, Department of Gastroenterology; Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Department of Medicine, Barcelona, Spain
| | - Cristina Martínez
- Bioanalytical Science Department, Metabonomics & Biomarkers Group, Nestlé Research Center, Lausanne, Switzerland, and Digestive Diseases Research Unit, Institut de Recerca, Department of Gastroenterology; Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Department of Medicine, Barcelona, Spain
| | - Beatriz Lobo
- Bioanalytical Science Department, Metabonomics & Biomarkers Group, Nestlé Research Center, Lausanne, Switzerland, and Digestive Diseases Research Unit, Institut de Recerca, Department of Gastroenterology; Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Department of Medicine, Barcelona, Spain
| | - Esteban Saperas
- Bioanalytical Science Department, Metabonomics & Biomarkers Group, Nestlé Research Center, Lausanne, Switzerland, and Digestive Diseases Research Unit, Institut de Recerca, Department of Gastroenterology; Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Department of Medicine, Barcelona, Spain
| | - Juan Ramón Malagelada
- Bioanalytical Science Department, Metabonomics & Biomarkers Group, Nestlé Research Center, Lausanne, Switzerland, and Digestive Diseases Research Unit, Institut de Recerca, Department of Gastroenterology; Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Department of Medicine, Barcelona, Spain
| | - Javier Santos
- Bioanalytical Science Department, Metabonomics & Biomarkers Group, Nestlé Research Center, Lausanne, Switzerland, and Digestive Diseases Research Unit, Institut de Recerca, Department of Gastroenterology; Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Department of Medicine, Barcelona, Spain
| | - Sunil Kochhar
- Bioanalytical Science Department, Metabonomics & Biomarkers Group, Nestlé Research Center, Lausanne, Switzerland, and Digestive Diseases Research Unit, Institut de Recerca, Department of Gastroenterology; Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Department of Medicine, Barcelona, Spain
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9
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Silva MA. Intestinal dendritic cells and epithelial barrier dysfunction in Crohn's disease. Inflamm Bowel Dis 2009; 15:436-53. [PMID: 18821596 DOI: 10.1002/ibd.20660] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Crohn's disease (CD) is a chronic gastrointestinal inflammatory disorder considered to be the result of an inappropriate and exaggerated mucosal immune reaction to yet undefined triggers from the gut flora in genetically predisposed individuals. This inflammatory phenomenon has been characterized by an adaptive T-cell response in addition to an abnormal function of the innate immune system. Dendritic cells (DCs) are constituents of this innate system, inducing T-cell activation via antigen presentation. In the gut, mucosal DCs are separated from the luminal milieu by a monolayer of cylindrical epithelial cells that forms an anatomical and physiological barrier that controls the normal traffic of antigens between both compartments. An imbalance of colonic and ileal DC distribution in tissues from CD patients as well as functional differences between DCs isolated from normal and diseased intestinal samples have been demonstrated. Moreover, a gut barrier defect in the para- and transepithelial routes in addition to a significant reduction in the intestinal secretion of epithelial products involved in barrier function has been well documented in CD. Therefore, this may expose the diseased mucosa to overwhelming amounts of antigens, resulting in abnormal DC activation and a subsequent imbalance in their distribution. In conclusion, this review provides a summary of relevant progress in CD, intestinal epithelial permeability, and DCs highlighting a potential relationship between increased epithelial permeability and abnormal DC distribution during the pathogenesis of intestinal inflammation.
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Affiliation(s)
- Manuel A Silva
- Department of Pathology and Molecular Medicine, Intestinal Disease Research Programme, McMaster University, Hamilton, Ontario, Canada.
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10
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Alonso C, Guilarte M, Vicario M, Ramos L, Ramadan Z, Antolín M, Martínez C, Rezzi S, Saperas E, Kochhar S, Santos J, Malagelada JR. Maladaptive intestinal epithelial responses to life stress may predispose healthy women to gut mucosal inflammation. Gastroenterology 2008; 135:163-172.e1. [PMID: 18455999 DOI: 10.1053/j.gastro.2008.03.036] [Citation(s) in RCA: 89] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2007] [Revised: 02/24/2008] [Accepted: 03/13/2008] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS Irritable bowel syndrome (IBS), a highly prevalent disorder among women, has been associated with life stress, but the peripheral mechanisms involved remain largely unexplored. METHODS A 20-cm jejunal segment perfusion was performed in 2 groups of young healthy women, equilibrated by menstrual phase, experiencing either low (LS; n = 13) or moderate background stress (MS; n = 11). Intestinal effluents were collected every 15 minutes, for 30 minutes under basal conditions, and for 1 hour after cold pain stress. Cardiovascular and psychological response, changes in circulating stress and gonadal hormones, and epithelial function (net water flux, albumin output and luminal release of tryptase and alpha-defensins) to cold stress were determined. RESULTS Cold pain induced a psychological response stronger in the MS than in the LS group, but similar increases in heart rate, blood pressure, adrenocorticotrophic hormone, and cortisol, whereas estradiol and progesterone remained unaltered. Notably, the jejunal epithelium of MS females showed a chloride-related decrease in peak secretory response (Delta[15-0 minutes]: LS, 97.5 [68.4-135.0]; MS, 48.8 [36.6-65.0] microL/min/cm; P < .001) combined with a marked enhancement of albumin permeability (LS(AUC), 6.35 [0.9-9.6]; MS(AUC), 13.97 [8.3-23.1] mg/60 min; P = .008) after cold stress. Epithelial response in both groups was associated with similar increases in luminal tryptase and alpha-defensins release. CONCLUSIONS Increased exposure to life events determines a defective jejunal epithelial response to incoming stimuli. This abnormal response may represent an initial step in the development of prolonged mucosal dysfunction, a finding that could be linked to enhanced susceptibility for IBS.
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Affiliation(s)
- Carmen Alonso
- Digestive Diseases Research Unit, Institut de Reçerca, Department of Gastroenterology, Barcelona, Spain
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11
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Moeser AJ, Klok CV, Ryan KA, Wooten JG, Little D, Cook VL, Blikslager AT. Stress signaling pathways activated by weaning mediate intestinal dysfunction in the pig. Am J Physiol Gastrointest Liver Physiol 2007; 292:G173-81. [PMID: 16901995 DOI: 10.1152/ajpgi.00197.2006] [Citation(s) in RCA: 212] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Weaning in the piglet is a stressful event associated with gastrointestinal disorders and increased disease susceptibility. Although stress is thought to play a role in postweaning intestinal disease, the mechanisms by which stress influences intestinal pathophysiology in the weaned pig are not understood. The objectives of these experiments were to investigate the impact of weaning on gastrointestinal health in the pig and to assess the role of stress signaling pathways in this response. Nineteen-day-old pigs were weaned, and mucosal barrier function and ion transport were assessed in jejunal and colonic tissues mounted on Ussing chambers. Weaning caused marked disturbances in intestinal barrier function, as demonstrated by significant (P < 0.01) reductions in transepithelial electrical resistance and increases in intestinal permeability to [3H]mannitol in both the jejunum and colon compared with intestinal tissues from age-matched, unweaned control pigs. Weaned intestinal tissues exhibited increased intestinal secretory activity, as demonstrated by elevated short-circuit current that was sensitive to treatment with tetrodotoxin and indomethacin, suggesting activation of enteric neural and prostaglandin synthesis pathways in weaned intestinal tissues. Western blot analyses of mucosal homogenates showed increased expression of corticotrophin-releasing factor (CRF) receptor 1 in the jejunum and colon of weaned intestinal tissues. Pretreatment of pigs with the CRF receptor antagonist alpha-helical CRF(9-41), which was injected intraperitoneally 30 min prior to weaning, abolished the stress-induced mucosal changes. Our results indicate that weaning stress induces mucosal dysfunction mediated by intestinal CRF receptors and activated by enteric nerves and prostanoid pathways.
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Affiliation(s)
- Adam J Moeser
- Center for Comparative Translational and Molecular Research, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606, USA
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12
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Schroeder B, Duncker S, Barth S, Bauerfeind R, Gruber AD, Deppenmeier S, Breves G. Preventive effects of the probiotic Escherichia coli strain Nissle 1917 on acute secretory diarrhea in a pig model of intestinal infection. Dig Dis Sci 2006; 51:724-31. [PMID: 16614995 DOI: 10.1007/s10620-006-3198-8] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2005] [Accepted: 06/13/2005] [Indexed: 02/07/2023]
Abstract
Pretreatment with the probiotic Escherichia colistrain Nissle 1917 (EcN) was assessed in a pig model of intestinal infection to prevent acute secretory diarrhea. In the model 10(10) colony forming units of the porcine enterotoxigenic Escherichia coli Abbotstown (EcA) was given via orogastric tube to weaned piglets at day 21 postpartum (-EcN/+EcA group, n = 7). Forty-eight hours after challenge electrophysiological parameters of isolated intact jejunal epithelia were characterized in Ussing chambers. In agreement with clinical signs of diarrhea, tissues of challenged animals showed an overshoot of secretory response after stimulation of the cAMP-mediated second messenger pathway by forskolin, indicating higher excitability of chloride secretory systems under infected conditions. The data were compared with respective measurements from animals that got a daily dose of 10(10) cfu of the probiotic EcN over 10 days before EcA challenge (+EcN/+EcA group; n = 4), from a group that received only EcN (+EcN/-EcA; n = 4), or from a group that remained totally untreated (-EcN/-EcA; n = 6). EcN pretreatment completely abolished clinical signs of secretory diarrhea in +EcN/+EcA animals. Furthermore, jejunum epithelia of these animals did not exhibit an overshoot of secretory response upon stimulation with forskolin. Our studies demonstrate for the first time the efficacy of prophylactic EcN in pig small intestine for preventing an effect of toxigenic EcA. This infection model with freshly weaned piglets may be predestinated to further characterize EcN effects on the cellular level, i.e., involved second messenger pathways, or it may also be useful to examine the efficacy of other substrates or microbe strains against secretory stimuli.
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Affiliation(s)
- B Schroeder
- Department of Physiology, School of Veterinary Medicine Hannover, Germany.
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13
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Koutsos E, Arias V. Intestinal Ecology: Interactions Among the Gastrointestinal Tract, Nutrition, and the Microflora. J APPL POULTRY RES 2006. [DOI: 10.1093/japr/15.1.161] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
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14
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Ait-Belgnaoui A, Bradesi S, Fioramonti J, Theodorou V, Bueno L. Acute stress-induced hypersensitivity to colonic distension depends upon increase in paracellular permeability: role of myosin light chain kinase. Pain 2005; 113:141-7. [PMID: 15621374 DOI: 10.1016/j.pain.2004.10.002] [Citation(s) in RCA: 122] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2004] [Revised: 09/24/2004] [Accepted: 09/30/2004] [Indexed: 12/15/2022]
Abstract
Hypersensitivity to rectal or colonic distension characterizes most patients with IBS and increased gut permeability has been described in post-dysenteric IBS patients. However, no link has been established between these two events. The aim of this study was to determine (i) whether chemical blockade of stress-induced increase of colonic paracellular permeability by 2,4,6 triaminopyrimidine (TAP) affects the concomitant hypersensitivity to colonic distension, (ii) the role of epithelial cell contraction in the stress-induced increased permeability and hyperalgesia, using a myosin light chain kinase inhibitor (ML-7). The effect of acute partial restraint stress (PRS) on visceral sensitivity to colorectal distension (RD) was assessed by abdominal muscle electromyography. Colonic paracellular permeability was determined by measuring percentage of urinary 51Cr-EDTA recovery after intracolonic infusion. The effect of stress on both parameters was evaluated after TAP, ML-7 or vehicle pretreated animals. PRS significantly increased colonic paracellular permeability and the number of spike bursts for all volumes of RD applied compared to sham. TAP suppressed the stress-induced increase of colonic paracellular permeability and sensitivity to colonic distension. Similarly, ML-7 blocked the stress-induced increase of colonic paracellular permeability and sensitivity. Neither ML-7 nor TAP had any effect on both permeability and sensitivity in absence of stress. The increase of colonic permeability induced by PRS results from epithelial cell cytoskeleton contraction through myosin light chain kinase activation and this increase is responsible for stress-induced rectal hypersensitivity.
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Affiliation(s)
- Afifa Ait-Belgnaoui
- Neuro-Gastroenterology and Nutrition Unit, INRA, 180, chemin de Tournefeuille BP 03, 31931 Toulouse cedex 9, France
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15
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Velin AK, Ericson AC, Braaf Y, Wallon C, Söderholm JD. Increased antigen and bacterial uptake in follicle associated epithelium induced by chronic psychological stress in rats. Gut 2004; 53:494-500. [PMID: 15016742 PMCID: PMC1774000 DOI: 10.1136/gut.2003.028506] [Citation(s) in RCA: 93] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND Chronic stress affects the course of inflammatory bowel disease and experimental colitis, and may also initiate intestinal inflammation in rats. AIM To investigate the effects of stress on the M cell containing follicle associated epithelium, specialised in antigen uptake. SUBJECTS AND METHODS Wistar rats were submitted to acute water avoidance stress for one hour or chronic water avoidance stress for 1 hour/day for 10 consecutive days. Permeability to (51)Cr-EDTA, horseradish peroxidase, and chemically killed Escherichia coli K-12 was studied in both villus and follicle associated epithelium in Ussing chambers. Segments were further examined by light, electron, and confocal microscopy. RESULTS Acute stress increased horseradish peroxidase flux in villus as well as in follicle associated epithelium. Chronic stress further increased permeability to horseradish peroxidase in villus and follicle associated epithelium, in the latter by almost fourfold. Moreover, chronic stress induced over 30 times increased E coli passage in follicle associated epithelium whereas there was no significant increase in villus epithelium. Bacterial uptake was confirmed by confocal microscopy showing fluorescent bacteria penetrating and passing through the epithelial surface. CONCLUSIONS These results show that the barrier function of follicle associated epithelium can be modulated, and that chronic stress enhances the uptake of luminal antigens and bacteria via the follicle associated epithelium. This can increase antigen exposure in Peyer's patches thereby having implications in the initiation of proinflammatory immune responses within the intestinal mucosa.
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Affiliation(s)
- A K Velin
- Department of Biomedicine and Surgery, Division of Surgery, Clinical Research Centre, Faculty of Health Sciences, University Hospital, Linköping, Sweden.
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Ataka K, Kuge T, Venkova K, Greenwood-Van Meerveld B. Seirogan (wood creosote) inhibits stress-induced ion secretion in rat intestinal epithelium. Dig Dis Sci 2003; 48:1303-9. [PMID: 12870787 DOI: 10.1023/a:1024155125366] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
Acute stress in often associated with abnormalities in gastrointestinal function, including enhanced secretion of water and electrolytes that leads to diarrhea. The goal of our study was to investigate whether Seirogan inhibits stress-induced intestinal secretion in Wistar-Kyoto rats. Electrogenic ion secretion was measured in modified Ussing chambers as an increase in basal short-circuit current (Isc) across isolated rat jejunal or colonic mucosal sheets. Mucosal preparations from rats exposed to cold restraint stress showed a significant increase in basal Isc compared to controls. The cumulative addition of Seirogan to the Ussing chamber caused a concentration-dependent reduction of the stress-induced increase of basal Isc to levels resembling nonstressed controls. In a separate experiment, Seirogan (15 mg/kg) administered by oral gavage inhibited stress-induced secretion and normalized basal Isc in the jejunum and colon. The results suggest that Seirogan may be an effective therapy for patients with stress-associated diarrhea.
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Affiliation(s)
- Koji Ataka
- Oklahoma Foundation for Digestive Research Basic Science Labs, VA Medical Center, 921 NE 13th St., Oklahoma City, Oklahoma 73104, USA
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Nemeth L, Rolle U, Reen DJ, Puri P. Nitrergic hyperinnervation in appendicitis and in appendices histologically classified as normal. Arch Pathol Lab Med 2003; 127:573-578. [PMID: 12708900 DOI: 10.5858/2003-127-0573-nhiaai] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT The pathogenesis of appendicitis remains poorly understood. Despite new diagnostic techniques, appendices removed from patients with suspected appendicitis often appear histologically normal on conventional examination. There is increasing evidence of involvement of the enteric nervous system in immune regulation and in inflammatory responses in the gastrointestinal system. OBJECTIVE To investigate the nitrergic innervation of (a) acutely inflamed appendices, (b) appendices classified as histologically normal from patients with a clinical diagnosis of appendicitis, and (c) normal control appendix specimens, using the whole-mount preparation technique. PATIENTS AND DESIGN Full-thickness specimens were collected from 28 acutely inflamed appendices (age range, 3.2-13.4 years), 31 histologically normal appendices removed from patients (age range, 5.7-13.6 years) with suspected appendicitis, and 23 histologically normal appendices from patients (age range, newborn to 12.1 years) undergoing elective abdominal surgery (controls). Whole-mount preparation using nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase histochemistry and neuronal nitric oxide synthase immunohistochemistry were performed. The density of myenteric plexus was measured with a computerized analysis system. RESULTS The density of myenteric plexus in normal appendix specimens was similar to that of large bowel from the newborn period up to 3 years of age; this density decreased significantly thereafter. The myenteric plexus of normal appendix specimens from patients older than 4 years demonstrated smaller ganglia connected by thin nerve bundles, compared to larger ganglia and nerve bundles in large bowel. Significant neuronal hypertrophy was found in 55% of acutely inflamed and 41% of histologically classified normal appendix specimens. The myenteric plexus of these appendix specimens had even thicker nerve bundles connecting an increased number of ganglion cells. CONCLUSIONS Differences in the architecture of the myenteric plexus in patients older than 3 years suggest an altered function and motility of appendix in the early years of life. The significant increase in neuronal components of the myenteric plexus in a high proportion of acutely inflamed and histologically normal appendix specimens is unlikely to have developed during a single acute inflammatory episode. This suggests an underlying chronic abnormality as a secondary response to chronic luminal obstruction or repeated inflammatory episodes in the histologically normal appendix.
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Affiliation(s)
- Laszlo Nemeth
- Children's Research Centre, Our Lady's Hospital for Sick Children, University College, Dublin, Ireland
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