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Onisor D, Avram C, Ruta F, Brusnic O, Boeriu A, Stoian M, Boicean A, Sasaran M. Burden of Common Mental Disorders in Ulcerative Colitis and Irritable Bowel Syndrome Patients: An Analysis of Risk Factors. J Clin Med 2025; 14:499. [PMID: 39860505 PMCID: PMC11766210 DOI: 10.3390/jcm14020499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Revised: 12/31/2024] [Accepted: 01/10/2025] [Indexed: 01/27/2025] Open
Abstract
Background: Common mental disorders are an underdiagnosed comorbidity, which can significantly worsen the prognosis of the main disease and decrease the quality of life. We aimed to investigate the prevalence of depression and anxiety in a cohort of irritable bowel syndrome with diarrhea (IBS-D) and ulcerative colitis (UC) patients and to evaluate the risk factors for their occurrence. Materials and Methods: A total of 112 patients were evaluated. Multivariable analysis was used to determine associations between patient factors and common mental disorders, evaluated with PHQ-9 and GAD-7 questionnaires. Results: We found a significantly higher prevalence of moderate and severe anxiety among patients with IBS-D, when compared with the UC group (p < 0.01). Linear regression analysis revealed an inverse association between anti-TNF-alpha monoclonal antibodies treatment and a higher PHQ-9 score (p = 0.02). Multivariate analysis revealed that, in patients with UC, the presence of children has been associated with a higher GAD-7 score (p = 0.01), both individually and in combination with a higher duration of the disease. (p < 0.01). For IBS-D, a combination of active employment status and religious belief, active employment status and higher educational level, as well as religious belief and the presence of children correlated with higher GAD-7 scores (p = 0.03, p = 0.03 and p = 0.02, respectively). Conclusions: Infliximab used in the treatment for UC improved the parameters of depression. Patients with UC who have university education and a longer duration of the disease are at increased risk of developing depression and anxiety, especially if they have children in care. Regarding IBS-D patients who have an active work status, religious beliefs and caregivers are at increased risk of developing anxiety.
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Affiliation(s)
- Danusia Onisor
- Department of Internal Medicine VII, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, Gheorghe Marinescu Street No. 38, 540136 Targu Mures, Romania; (D.O.); (O.B.); (A.B.)
| | - Calin Avram
- Department of Medical Informatics and Biostatistics, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, Gheorghe Marinescu Street No. 38, 540136 Targu Mures, Romania
| | - Florina Ruta
- Department Community Nutrition and Food Safety, Faculty of General Medicine, “George Emil Palade” University of Medicine, Pharmacy, Science, and Technology of Targu Mures, 540142 Targu Mures, Romania
| | - Olga Brusnic
- Department of Internal Medicine VII, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, Gheorghe Marinescu Street No. 38, 540136 Targu Mures, Romania; (D.O.); (O.B.); (A.B.)
| | - Alina Boeriu
- Department of Internal Medicine VII, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, Gheorghe Marinescu Street No. 38, 540136 Targu Mures, Romania; (D.O.); (O.B.); (A.B.)
| | - Mircea Stoian
- Department of Anesthesiology and Intensive Care, George Emil Palade University of Medicine, Pharmacy, Sciences and Technology of Targu Mures, 540139 Targu Mures, Romania;
| | - Adrian Boicean
- Faculty of Medicine, Lucian Blaga University of Sibiu, 550169 Sibiu, Romania;
| | - Maria Sasaran
- Department of Pediatrics III, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, Gheorghe Marinescu Street No. 38, 540136 Targu Mures, Romania;
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Brooks SG, Lopez LM, Mashoudy KD, Yosipovitch G, Czarnowicki T. Addressing Unmet Needs in Atopic Dermatitis: Evaluating Disease-Modifying Capabilities of Current and Emerging Therapies. Dermatitis 2024. [PMID: 39465269 DOI: 10.1089/derm.2024.0261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/29/2024]
Abstract
Atopic dermatitis (AD) is a highly burdensome inflammatory skin condition affecting nearly one-quarter of the pediatric population and often continuing into adulthood. Despite recent advancements in systemic therapies providing temporary symptom relief over the past decade, AD frequently remains difficult to control, necessitating increased dosages or alternative treatments due to recurrent disease. This review synthesizes current literature to identify unmet needs of treating AD beyond medication-related limitations and evaluates existing therapies for their efficacy in modifying underlying disease mechanisms. Key findings include variability in AD pathophysiology and phenotypes across different age groups and ethnicities, indicating a need for research into endotype-specific treatments. The literature also comprises evidence suggesting that select current drugs, such as targeted biologics and Janus Kinase (JAK) inhibitors, may offer long-term disease-modifying benefits. Future management strategies should explore novel approaches, including manipulation of the microbiome, immune response, and neural function, as these may lead to additional improvements in AD treatment and long-term symptom relief.
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Affiliation(s)
- Sarah G Brooks
- From the Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Coral Gables, Florida, USA
| | - Lourdes M Lopez
- From the Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Coral Gables, Florida, USA
| | - Kayla D Mashoudy
- From the Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Coral Gables, Florida, USA
| | - Gil Yosipovitch
- From the Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Coral Gables, Florida, USA
| | - Tali Czarnowicki
- From the Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Coral Gables, Florida, USA
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Brenner DM, Ladewski AM, Kinsinger SW. Development and Current State of Digital Therapeutics for Irritable Bowel Syndrome. Clin Gastroenterol Hepatol 2024; 22:222-234. [PMID: 37743035 DOI: 10.1016/j.cgh.2023.09.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 09/07/2023] [Accepted: 09/11/2023] [Indexed: 09/26/2023]
Abstract
BACKGROUND & AIMS Irritable bowel syndrome (IBS) is a common, debilitating disorder characterized by abdominal pain and disordered bowel habits. Current pharmacologic treatments often provide incomplete symptom relief and may be poorly tolerated. Furthermore, alleviation of gastrointestinal symptoms does not always translate into improved quality of life for IBS patients. Current treatment guidelines recommend brain-gut behavior therapy (BGBT) in conjunction with other IBS therapies, and, in randomized controlled trials, BGBT has been shown to improve symptoms, patient satisfaction, functioning, and quality of life. Access to BGBT is limited by lack of adequately trained gastrointestinal psychologists, patient time constraints, and cost. Furthermore, clinician knowledge that BGBT is specific, and different from psychotherapy approaches for common mental health disorders, may limit referrals even where available. This review provides an overview of the pathophysiology of IBS, disease burden, unmet therapeutic needs, evidence base of novel digital therapeutics for IBS, and guidance on the introduction and appropriateness of these interventions for patients. METHODS We searched the literature for available published data relating to the use of novel digital therapeutics to provide cognitive behavioral therapy and gut-directed hypnotherapy in the treatment of irritable bowel syndrome. RESULTS Clinical trial data support the development and utility of digital therapeutics designed to deliver self-guided cognitive behavioral therapy and hypnotherapy for the treatment of IBS. CONCLUSIONS BGBTs are effective, guideline-recommended treatments for IBS. Digital therapeutic devices offer accessible, cost-effective treatment options for delivery of adjunctive BGBT for the treatment of IBS. The decision to recommend digital BGBTs should be guided by careful patient assessment that includes mental health screening and risk assessment.
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Affiliation(s)
- Darren M Brenner
- Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
| | - Amy M Ladewski
- Department of Digestive Health, Digestive Health Center, Northwestern Memorial Hospital, Chicago, Illinois
| | - Sarah Wimberly Kinsinger
- Division of Gastroenterology and Nutrition, Department of Medicine, Loyola University Medical Center, Maywood, Illinois
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Yang L, He P, Zhang L, Li K. Altered resting-state brain functional activities and networks in Crohn's disease: a systematic review. Front Neurosci 2024; 18:1319359. [PMID: 38332859 PMCID: PMC10851432 DOI: 10.3389/fnins.2024.1319359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Accepted: 01/10/2024] [Indexed: 02/10/2024] Open
Abstract
Background Crohn's disease (CD) is a non-specific chronic inflammatory disease of the gastrointestinal tract and is a phenotype of inflammatory bowel disease (IBD). The current study sought to compile the resting-state functional differences in the brain between CD patients and healthy controls. Methods The online databases PubMed, Web of Science Core, and EMBASE were used to find the published neuroimage studies. The search period was from the beginning through December 15, 2023. The predetermined inclusion and exclusion criteria allowed for the identification of the studies. The studies were assembled by two impartial reviewers, who also assessed their quality and bias. Results This review comprised 16 resting-state fMRI studies in total. The included studies generally had modest levels of bias. According to the research, emotional processing and pain processing were largely linked to increased or decreased brain activity in patients with CD. The DMN, CEN, and limbic systems may have abnormalities in patients with CD, according to research on brain networks. Several brain regions showed functional changes in the active CD group compared to the inactive CD group and the healthy control group, respectively. The abnormalities in brain areas were linked to changes in mood fluctuations (anxiety, melancholy) in patients with CD. Conclusion Functional neuroimaging helps provide a better understanding of the underlying neuropathological processes in patients with CD. In this review, we summarize as follows: First, these findings indicate alterations in brain function in patients with CD, specifically affecting brain regions associated with pain, emotion, cognition, and visceral sensation; second, disease activity may have an impact on brain functions in patients with CD; and third, psychological factors may be associated with altered brain functions in patients with CD.
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Affiliation(s)
- Ling Yang
- Radiology Department, Chongqing General Hospital, Chongqing, China
- Department of Radiology Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China
| | - Peipei He
- Radiology Department, Chongqing General Hospital, Chongqing, China
| | - Lingqin Zhang
- Radiology Department, Chongqing General Hospital, Chongqing, China
| | - Kang Li
- Radiology Department, Chongqing General Hospital, Chongqing, China
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5
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Singh A. Brain-derived neurotrophic factor - a key player in the gastrointestinal system. PRZEGLAD GASTROENTEROLOGICZNY 2023; 18:380-392. [PMID: 38572454 PMCID: PMC10985741 DOI: 10.5114/pg.2023.132957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 08/24/2023] [Indexed: 04/05/2024]
Abstract
Brain-derived neurotrophic factor (BDNF) is highly expressed throughout the gastrointestinal (GI) tract and plays a critical role in the regulation of intestinal motility, secretion, sensation, immunity, and mucosal integrity. Dysregulation of BDNF signalling has been implicated in the pathophysiology of various GI disorders including inflammatory bowel disease, irritable bowel syndrome, functional dyspepsia, and diabetic gastroenteropathy. This review provides a comprehensive overview of BDNF localization, synthesis, receptors, and signalling mechanisms in the gut. In addition, current evidence on the diverse physiologic and pathophysiologic roles of BDNF in the control of intestinal peristalsis, mucosal transport processes, visceral sensation, neuroimmune interactions, gastrointestinal mucosal healing, and enteric nervous system homeostasis are discussed. Finally, the therapeutic potential of targeting BDNF for the treatment of functional GI diseases is explored. Advancing knowledge of BDNF biology and mechanisms of action may lead to new therapies based on harnessing the gut trophic effects of this neurotrophin.
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Affiliation(s)
- Arjun Singh
- Department of Medicine, Division of Gastroenterology and Hepatology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, United States
- Molecular Pharmacology Program and Chemistry, Memorial Sloan Kettering Cancer Center, New York, United States
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Nakagawa Y, Yamada S. Alterations in Brain Neural Network and Stress System in Atopic Dermatitis: Novel Therapeutic Interventions. J Pharmacol Exp Ther 2023; 385:78-87. [PMID: 36828629 DOI: 10.1124/jpet.122.001482] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 01/02/2023] [Accepted: 02/03/2023] [Indexed: 02/26/2023] Open
Abstract
Atopic dermatitis is a common chronic inflammatory skin disease, with most cases experiencing skin barrier dysfunction and enhanced allergen entry, accompanied by cytokine production which evokes predominantly type-2-skewed immune responses, itch, and scratching behavior. Although intense itch and excessive scratching behavior affect progression of skin lesions, it is unclear what causes them. Data suggest that scratching behavior stimulates brain dopaminergic reward and habit learning systems, strengthening habitual scratching behavior, while nocturnal scratching behavior presumably increases locus coeruleus-noradrenergic system activity, prompting sleep disturbances. At the early stage of atopic dermatitis, increased cortisol levels, due to hypothalamic-pituitary-adrenal axis overactivation caused by such system stimulation, can induce dorsolateral prefrontal cortex disturbance with reinforcement of habitual scratching behavior and may aggravate type-2-skewed immune responses in the skin. During the later phases, whereas blunted hypothalamic-pituitary-adrenal axis function and the shift of type-2-dominated to type-1-co-dominated inflammation are induced, noradrenergic system overactivation-associated dorsolateral prefrontal cortex disruption is ongoing and responsible for itch cognitive distortion to catastrophize about itch, which leads to a vicious spiral along with habitual scratching behavior and skin lesions. Data are presented in this review indicating that while skin immune system dysfunction initiates pathologic changes in atopic dermatitis, brain neural network and stress system alterations can promote the progression of this condition. It is also suggested that cognitive distortion contributes to pathology in atopic dermatitis as with some psychiatric disorders and chronic pain. The proposed mechanistic model could lead to development of novel medications for slowing or terminating the relentless progression of this disorder. SIGNIFICANCE STATEMENT: Although conventional pharmacological interventions focusing on skin homeostasis and itch occurrence significantly attenuate clinical signs in atopic dermatitis patients, achievement of 100% improvement is less than 40% in several double-blind, randomized, placebo-controlled trials. Our model predicts that itch cognitive distortion, due to dorsolateral prefrontal cortex disturbance, can significantly contribute to the progression of atopic dermatitis and that agents capable of improving brain neural network, stress system, and skin homeostasis may be effective as interventions in the treatment of this condition.
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Affiliation(s)
- Yutaka Nakagawa
- Center for Pharma-Food Research (CPFR), Division of Pharmaceutical Sciences, Graduate School of Integrative Pharmaceutical and Nutritional Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, Japan
| | - Shizuo Yamada
- Center for Pharma-Food Research (CPFR), Division of Pharmaceutical Sciences, Graduate School of Integrative Pharmaceutical and Nutritional Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, Japan
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7
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Alam MJ, Chen JDZ. Electrophysiology as a Tool to Decipher the Network Mechanism of Visceral Pain in Functional Gastrointestinal Disorders. Diagnostics (Basel) 2023; 13:627. [PMID: 36832115 PMCID: PMC9955347 DOI: 10.3390/diagnostics13040627] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 01/27/2023] [Accepted: 02/07/2023] [Indexed: 02/11/2023] Open
Abstract
Abdominal pain, including visceral pain, is prevalent in functional gastrointestinal (GI) disorders (FGIDs), affecting the overall quality of a patient's life. Neural circuits in the brain encode, store, and transfer pain information across brain regions. Ascending pain signals actively shape brain dynamics; in turn, the descending system responds to the pain through neuronal inhibition. Pain processing mechanisms in patients are currently mainly studied with neuroimaging techniques; however, these techniques have a relatively poor temporal resolution. A high temporal resolution method is warranted to decode the dynamics of the pain processing mechanisms. Here, we reviewed crucial brain regions that exhibited pain-modulatory effects in an ascending and descending manner. Moreover, we discussed a uniquely well-suited method, namely extracellular electrophysiology, that captures natural language from the brain with high spatiotemporal resolution. This approach allows parallel recording of large populations of neurons in interconnected brain areas and permits the monitoring of neuronal firing patterns and comparative characterization of the brain oscillations. In addition, we discussed the contribution of these oscillations to pain states. In summary, using innovative, state-of-the-art methods, the large-scale recordings of multiple neurons will guide us to better understanding of pain mechanisms in FGIDs.
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Affiliation(s)
- Md Jahangir Alam
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
| | - Jiande D. Z. Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
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Nisticò V, Rossi RE, D'Arrigo AM, Priori A, Gambini O, Demartini B. Functional neuroimaging in Irritable Bowel Syndrome: a systematic review highlights common brain alterations with Functional Movement Disorders. J Neurogastroenterol Motil 2022; 28:185-203. [PMID: 35189600 PMCID: PMC8978134 DOI: 10.5056/jnm21079] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 09/03/2021] [Accepted: 11/24/2021] [Indexed: 12/02/2022] Open
Abstract
Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder characterized by recurring abdominal pain and altered bowel habits without detectable organic causes. This study aims to provide a comprehensive overview of the literature on functional neuroimaging in IBS and to highlight brain alterations similarities with other functional disorders - functional movement disorders in particular. We conducted the bibliographic search via PubMed in August 2020 and included 50 studies following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines for systematic reviews. Overall, our findings showed an aberrant activation and functional connectivity of the insular, cingulate, sensorimotor and frontal cortices, the amygdala and the hippocampus, suggesting an altered activity of the homeostatic and salience network and of the autonomous nervous system. Moreover, glutamatergic dysfunction in the anterior insula and hypothalamic pituitary axis dysregulation were often reported. These alterations seem to be very similar to those observed in patients with functional movement disorders. Hence, we speculate that different functional disturbances might share a common pathophysiology and we discussed our findings in the light of a Bayesian model framework.
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Affiliation(s)
- Veronica Nisticò
- Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milan, Italy.,"Aldo Ravelli" Research Center for Neurotechnology and Experimental Brain Therapeutics, Università degli Studi di Milano, Milan, Italy.,Department of Psychology, University of Milan-Bicocca, Milan, Italy
| | - Roberta E Rossi
- Gastro-intestinal Surgery and Liver Transplantation Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.,Department of Pathophysiology and Organ Transplant, Università degli Studi di Milano, Milan, Italy
| | - Andrea M D'Arrigo
- Department of Neurology, ASST Fatebenefratelli Sacco, Ospedale Fatebenefratelli, Milan, Italy
| | - Alberto Priori
- Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milan, Italy.,"Aldo Ravelli" Research Center for Neurotechnology and Experimental Brain Therapeutics, Università degli Studi di Milano, Milan, Italy.,III Clinica Neurologica, ASST Santi Paolo e Carlo, Presidio San Paolo, Milan, Italy
| | - Orsola Gambini
- Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milan, Italy.,"Aldo Ravelli" Research Center for Neurotechnology and Experimental Brain Therapeutics, Università degli Studi di Milano, Milan, Italy.,Unità di Psichiatria 52, ASST Santi Paolo e Carlo, Presidio San Paolo, Milan, Italy
| | - Benedetta Demartini
- Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milan, Italy.,"Aldo Ravelli" Research Center for Neurotechnology and Experimental Brain Therapeutics, Università degli Studi di Milano, Milan, Italy.,Unità di Psichiatria 52, ASST Santi Paolo e Carlo, Presidio San Paolo, Milan, Italy
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Chen M, Ruan G, Chen L, Ying S, Li G, Xu F, Xiao Z, Tian Y, Lv L, Ping Y, Cheng Y, Wei Y. Neurotransmitter and Intestinal Interactions: Focus on the Microbiota-Gut-Brain Axis in Irritable Bowel Syndrome. Front Endocrinol (Lausanne) 2022; 13:817100. [PMID: 35250873 PMCID: PMC8888441 DOI: 10.3389/fendo.2022.817100] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 01/05/2022] [Indexed: 12/12/2022] Open
Abstract
Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder of unknown etiology. IBS is caused by a disruption in the gut-brain axis. Given the importance of the gut microbiota in maintaining local and systemic homeostasis of immunity, endocrine, and other physiological processes, the microbiota-gut-brain axis has been proposed as a key regulator in IBS. Neurotransmitters have been shown to affect blood flow regulation, intestinal motility, nutrient absorption, the gastrointestinal immune system, and the microbiota in recent studies. It has the potential role to play a function in the pathophysiology of the gastrointestinal and neurological systems. Transmitters and their receptors, including 5-hydroxytryptamine, dopamine, γ-aminobutyric acid, and histamine, play an important role in IBS, especially in visceral sensitivity and gastrointestinal motility. Studies in this field have shed light on revealing the mechanism by which neurotransmitters act in the pathogenesis of IBS and discovering new therapeutic strategies based on traditional pharmacological approaches that target the nervous system or novel therapies that target the microbiota.
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Affiliation(s)
- Minjia Chen
- Department of Gastroenterology, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
- Department of Pathogenic Biology and Immunology, School of Basic Medicine, Ningxia Medical University, Yinchuan, China
| | - Guangcong Ruan
- Department of Gastroenterology, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Lu Chen
- Department of Gastroenterology, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Senhong Ying
- Department of Gastroenterology, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Guanhu Li
- Department of Gastroenterology, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Fenghua Xu
- Department of Gastroenterology, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Zhifeng Xiao
- Department of Gastroenterology, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Yuting Tian
- Department of Gastroenterology, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Linling Lv
- Department of Gastroenterology, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Yi Ping
- Department of Gastroenterology, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Yi Cheng
- Department of Gastroenterology, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
- *Correspondence: Yanling Wei, ; Yi Cheng,
| | - Yanling Wei
- Department of Gastroenterology, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
- *Correspondence: Yanling Wei, ; Yi Cheng,
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Bülbül M, Sinen O. Centrally Administered Neuropeptide-S Alleviates Gastrointestinal Dysmotility Induced by Neonatal Maternal Separation. Neurogastroenterol Motil 2022; 34:e14269. [PMID: 34561917 DOI: 10.1111/nmo.14269] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 07/18/2021] [Accepted: 08/31/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND Neuropeptide-S (NPS) regulates autonomic outflow, stress response, and gastrointestinal (GI) motor functions. This study aimed to investigate the effects of NPS on GI dysmotility induced by neonatal maternal separation (MS). METHODS MS was conducted by isolating newborn pups from dams from postnatal day 1 to day 14. In adulthood, rats were also exposed to chronic homotypic stress (CHS). Visceral sensitivity was assessed by colorectal distension-induced abdominal contractions. Gastric emptying (GE) was measured following CHS, whereas fecal output was monitored daily. NPS or NPS receptor (NPSR) antagonist was centrally applied simultaneously with electrocardiography and gastric motility recording. Immunoreactivities for NPS, NPSR, corticotropin-releasing factor (CRF), choline acetyltransferase (ChAT), tyrosine hydroxylase (TH), and c-Fos were assessed by immunohistochemistry. KEY RESULTS NPS alleviated the MS-induced visceral hypersensitivity. Under basal conditions, central exogenous or endogenous NPS had no effect on GE and gastric motility. NPS restored CHS-induced gastric and colonic dysmotility in MS rats while increasing sympatho-vagal balance without affecting vagal outflow. NPSR expression was detected in CRF-producing cells of hypothalamic paraventricular nucleus, and central amygdala, but not in Barrington's nucleus. Moreover, NPSR was present in ChAT-expressing neurons in dorsal motor nucleus of the vagus (DMV), and nucleus ambiguus (NAmb) in addition to the TH-positive neurons in C1/A1, and locus coeruleus (LC). Neurons adjacent to the adrenergic cells in LC were found to produce NPS. NPS administration caused c-Fos expression in C1/A1 cells, while no immunoreactivity was detected in DMV or NAmb. CONCLUSIONS NPS/NPSR system might be a novel target for the treatment of stress-related GI dysmotility.
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Affiliation(s)
- Mehmet Bülbül
- Department of Physiology, Faculty of Medicine, Akdeniz University, Antalya, Turkey
| | - Osman Sinen
- Department of Physiology, Faculty of Medicine, Akdeniz University, Antalya, Turkey
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11
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Jacobs JP, Gupta A, Bhatt RR, Brawer J, Gao K, Tillisch K, Lagishetty V, Firth R, Gudleski GD, Ellingson BM, Labus JS, Naliboff BD, Lackner JM, Mayer EA. Cognitive behavioral therapy for irritable bowel syndrome induces bidirectional alterations in the brain-gut-microbiome axis associated with gastrointestinal symptom improvement. MICROBIOME 2021; 9:236. [PMID: 34847963 PMCID: PMC8630837 DOI: 10.1186/s40168-021-01188-6] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 11/04/2021] [Indexed: 05/07/2023]
Abstract
BACKGROUND There is growing recognition that bidirectional signaling between the digestive tract and the brain contributes to irritable bowel syndrome (IBS). We recently showed in a large randomized controlled trial that cognitive behavioral therapy (CBT) reduces IBS symptom severity. This study investigated whether baseline brain and gut microbiome parameters predict CBT response and whether response is associated with changes in the brain-gut-microbiome (BGM) axis. METHODS Eighty-four Rome III-diagnosed IBS patients receiving CBT were drawn from the Irritable Bowel Syndrome Outcome Study (IBSOS; ClinicalTrials.gov NCT00738920) for multimodal brain imaging and psychological assessments at baseline and after study completion. Fecal samples were collected at baseline and post-treatment from 34 CBT recipients for 16S rRNA gene sequencing, untargeted metabolomics, and measurement of short-chain fatty acids. Clinical measures, brain functional connectivity and microstructure, and microbiome features associated with CBT response were identified by multivariate linear and negative binomial models. RESULTS At baseline, CBT responders had increased fecal serotonin levels, and increased Clostridiales and decreased Bacteroides compared to non-responders. A random forests classifier containing 11 microbial genera predicted CBT response with high accuracy (AUROC 0.96). Following treatment, CBT responders demonstrated reduced functional connectivity in regions of the sensorimotor, brainstem, salience, and default mode networks and changes in white matter in the basal ganglia and other structures. Brain changes correlated with microbiome shifts including Bacteroides expansion in responders. CONCLUSIONS Pre-treatment intestinal microbiota and serotonin levels were associated with CBT response, suggesting that peripheral signals from the microbiota can modulate central processes affected by CBT that generate abdominal symptoms in IBS. CBT response is characterized by co-correlated shifts in brain networks and gut microbiome that may reflect top-down effects of the brain on the microbiome during CBT. Video abstract.
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Affiliation(s)
- Jonathan P Jacobs
- G. Oppenheimer Center for Neurobiology of Stress and Resilience, UCLA, Los Angeles, CA, USA
- David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
- Vatche and Tamar Manoukian Division of Digestive Diseases, UCLA, Los Angeles, CA, USA
- Division of Gastroenterology, Hepatology and Parenteral Nutrition, Veterans Administration Greater Los Angeles Healthcare System, Los Angeles, CA, USA
| | - Arpana Gupta
- G. Oppenheimer Center for Neurobiology of Stress and Resilience, UCLA, Los Angeles, CA, USA
- David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
- Vatche and Tamar Manoukian Division of Digestive Diseases, UCLA, Los Angeles, CA, USA
| | - Ravi R Bhatt
- Imaging Genetics Center, Mark and Mary Stevens Institute for Neuroimaging and Informatics, Keck School of Medicine at USC, University of Southern California, Los Angeles, USA
| | - Jacob Brawer
- G. Oppenheimer Center for Neurobiology of Stress and Resilience, UCLA, Los Angeles, CA, USA
- David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
- Vatche and Tamar Manoukian Division of Digestive Diseases, UCLA, Los Angeles, CA, USA
| | - Kan Gao
- G. Oppenheimer Center for Neurobiology of Stress and Resilience, UCLA, Los Angeles, CA, USA
- David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
- Vatche and Tamar Manoukian Division of Digestive Diseases, UCLA, Los Angeles, CA, USA
| | - Kirsten Tillisch
- G. Oppenheimer Center for Neurobiology of Stress and Resilience, UCLA, Los Angeles, CA, USA
- David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
- Vatche and Tamar Manoukian Division of Digestive Diseases, UCLA, Los Angeles, CA, USA
| | - Venu Lagishetty
- David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
- Vatche and Tamar Manoukian Division of Digestive Diseases, UCLA, Los Angeles, CA, USA
- Division of Gastroenterology, Hepatology and Parenteral Nutrition, Veterans Administration Greater Los Angeles Healthcare System, Los Angeles, CA, USA
| | - Rebecca Firth
- Division of Behavioral Medicine, Jacobs School of Medicine, University at Buffalo, SUNY, Buffalo, NY, USA
| | - Gregory D Gudleski
- Division of Behavioral Medicine, Jacobs School of Medicine, University at Buffalo, SUNY, Buffalo, NY, USA
| | - Benjamin M Ellingson
- David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
- Department of Radiological Sciences, UCLA, Los Angeles, CA, USA
- Department of Psychiatry and Biobehavioral Sciences, UCLA, Los Angeles, CA, USA
| | - Jennifer S Labus
- G. Oppenheimer Center for Neurobiology of Stress and Resilience, UCLA, Los Angeles, CA, USA
- David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
- Vatche and Tamar Manoukian Division of Digestive Diseases, UCLA, Los Angeles, CA, USA
| | - Bruce D Naliboff
- G. Oppenheimer Center for Neurobiology of Stress and Resilience, UCLA, Los Angeles, CA, USA
- David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
- Vatche and Tamar Manoukian Division of Digestive Diseases, UCLA, Los Angeles, CA, USA
| | - Jeffrey M Lackner
- Division of Behavioral Medicine, Jacobs School of Medicine, University at Buffalo, SUNY, Buffalo, NY, USA
| | - Emeran A Mayer
- G. Oppenheimer Center for Neurobiology of Stress and Resilience, UCLA, Los Angeles, CA, USA.
- David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
- Vatche and Tamar Manoukian Division of Digestive Diseases, UCLA, Los Angeles, CA, USA.
- G. Oppenheimer Center for Neurobiology of Stress and Resilience, Vatche and Tamar Manoukian Division of Digestive Diseases, David School of Medicine at UCLA, CHS 42-210 MC737818, 10833 Le Conte Avenue, Los Angeles, USA.
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12
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Role of serum amitriptyline concentration and CYP2C19 polymorphism in predicting the response to low-dose amitriptyline in irritable bowel syndrome. Dig Liver Dis 2021; 53:1422-1427. [PMID: 33753003 DOI: 10.1016/j.dld.2021.02.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 02/07/2021] [Accepted: 02/19/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Low-dose amitriptyline (AMT) is an effective treatment for diarrhea-dominant irritable bowel syndrome (IBS-D). Its efficacy depends upon its serum concentration and the patient's CYP2C19 genotype. AIMS To identify the association between serum AMT and nortriptyline (NT) concentration and CYP2C19 polymorphism and the clinical response in IBS-D patients. METHODS Ninety IBS-D patients were treated of AMT for 6 weeks. Efficacy was evaluated by the results of the Adequate Relief question each week and an IBS severity scoring system (IBS-SSS) at 0, 3, and 6 weeks. CYP2C19 genotyping was performed by direct sequencing. AMT and NT steady-state serum concentrations were detected by high-performance liquid chromatography. RESULTS The CYP2C19 polymorphism exhibited a significant influence on the NT serum concentration but did not predict the clinical efficacy of AMT for treating IBS-D. The NT steady-state and dose-corrected serum concentrations were significantly correlated with an improvement in the IBS-SSS score after 6 weeks, whereas the AMT serum concentration was not correlated with clinical improvement. The cut-off NT steady-state serum concentration of 2.91 ng/ml may help distinguish responders from non-responders. CONCLUSIONS NT serum concentration but not CYP2C19 polymorphism may be correlated with the clinical efficacy of AMT for treating IBS-D, and such a response may occur at the upper NT threshold of 2.91 ng/ml.
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13
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Gros M, Gros B, Mesonero JE, Latorre E. Neurotransmitter Dysfunction in Irritable Bowel Syndrome: Emerging Approaches for Management. J Clin Med 2021; 10:jcm10153429. [PMID: 34362210 PMCID: PMC8347293 DOI: 10.3390/jcm10153429] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/13/2021] [Accepted: 07/28/2021] [Indexed: 02/06/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder whose aetiology is still unknown. Most hypotheses point out the gut-brain axis as a key factor for IBS. The axis is composed of different anatomic and functional structures intercommunicated through neurotransmitters. However, the implications of key neurotransmitters such as norepinephrine, serotonin, glutamate, GABA or acetylcholine in IBS are poorly studied. The aim of this review is to evaluate the current evidence about neurotransmitter dysfunction in IBS and explore the potential therapeutic approaches. IBS patients with altered colorectal motility show augmented norepinephrine and acetylcholine levels in plasma and an increased sensitivity of central serotonin receptors. A decrease of colonic mucosal serotonin transporter and a downregulation of α2 adrenoceptors are also correlated with visceral hypersensitivity and an increase of 5-hydroxyindole acetic acid levels, enhanced expression of high affinity choline transporter and lower levels of GABA. Given these neurotransmitter dysfunctions, novel pharmacological approaches such as 5-HT3 receptor antagonists and 5-HT4 receptor agonists are being explored for IBS management, for their antiemetic and prokinetic effects. GABA-analogous medications are being considered to reduce visceral pain. Moreover, agonists and antagonists of muscarinic receptors are under clinical trials. Targeting neurotransmitter dysfunction could provide promising new approaches for IBS management.
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Affiliation(s)
- Mónica Gros
- Centro de Salud Univérsitas, Hospital Clínico Universitario Lozano Blesa, 50009 Zaragoza, Spain;
- Instituto de Investigación Sanitaria de Aragón (IIS Aragón), 50009 Zaragoza, Spain; (B.G.); (J.E.M.)
| | - Belén Gros
- Instituto de Investigación Sanitaria de Aragón (IIS Aragón), 50009 Zaragoza, Spain; (B.G.); (J.E.M.)
- Servicio de Urgencias, Hospital Universitario Miguel Servet, 50009 Zaragoza, Spain
| | - José Emilio Mesonero
- Instituto de Investigación Sanitaria de Aragón (IIS Aragón), 50009 Zaragoza, Spain; (B.G.); (J.E.M.)
- Departamento de Farmacología, Fisiología y Medicina Legal y Forense, Facultad de Veterinaria, Universidad de Zaragoza, 50009 Zaragoza, Spain
- Instituto Agroalimentario de Aragón—IA2—(Universidad de Zaragoza—CITA), 50013 Zaragoza, Spain
| | - Eva Latorre
- Instituto de Investigación Sanitaria de Aragón (IIS Aragón), 50009 Zaragoza, Spain; (B.G.); (J.E.M.)
- Instituto Agroalimentario de Aragón—IA2—(Universidad de Zaragoza—CITA), 50013 Zaragoza, Spain
- Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, 50009 Zaragoza, Spain
- Correspondence:
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14
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Umrani S, Jamshed W, Rizwan A. Association Between Psychological Disorders and Irritable Bowel Syndrome. Cureus 2021; 13:e14513. [PMID: 34007764 PMCID: PMC8121199 DOI: 10.7759/cureus.14513] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Introduction Irritable bowel syndrome (IBS) is an idiopathic, functional and chronic relapsing disorder. Physiological and psychological variables have been linked with etiology of IBS. In this study, we will determine the prevalence of IBS in local setting and its association with anxiety and depression. Materials and methods This cross-section study was conducted in multiple cities of Pakistan. One thousand and seven hundred and sixty (1,760) participants from general population between the age group 18 to 50 were enrolled in the study after informed consent. Diagnosis of IBS was made by assessing participants via ROME III criteria. Hospital anxiety and depression scale (HADS) was used to determine if the participants had anxiety and depression. Results IBS was present in 456 (25.9%) participants. IBS was significantly more prevalent in females compared to males. Anxiety was significantly more common in participants with IBS compared to participants without IBS (53.0% vs. 23.0%; p-value < 0.00001). Similarly, depression was significantly more common in participants with IBS (50.6% vs. 21.5%; p-value < 0.00001). Conclusion IBS is very common in Pakistan, but rarely diagnosed. It is important anyone, particularly at young age, presenting with diarrhea or constipation should be evaluated for IBS. Simultaneously, patients diagnosed with IBS should be screened for anxiety and depression, and managed accordingly.
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Affiliation(s)
- Salman Umrani
- Internal Medicine, University Hospital of North Tees, Stockton-on-Tees, GBR
| | - Waleed Jamshed
- Internal Medicine, Central Park Medical College, Lahore, PAK
| | - Amber Rizwan
- Family Medicine, Jinnah Post Graduate Medical Center, Karachi, PAK
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15
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Fan Y, Bao C, Wei Y, Wu J, Zhao Y, Zeng X, Qin W, Wu H, Liu P. Altered functional connectivity of the amygdala in Crohn's disease. Brain Imaging Behav 2021; 14:2097-2106. [PMID: 31628591 DOI: 10.1007/s11682-019-00159-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Crohn's disease (CD), a chronic inflammatory bowel disease, involved in brain structural and functional changes, including the amygdala. Amygdala is a key structure in the limbic system and its related circuits are implicated in processing of emotion, pain and sensory. However, limited study of the amygdala is elucidated in CD. This study mainly investigated altered functional connectivity (FC) of the amygdala in CD patients during resting-state. Magnetic resonance imaging scans were acquired from 42 CD patients and 35 healthy controls (HCs). Whole amygdala bilaterally were selected as regions of interest (ROIs). Voxel-based morphometry and FC methods were applied to investigate the differences of structure or intrinsic connectivity of the amygdala between the two groups, separately. Pearson correlations were performed to explore relationships between the clinical characteristics and neuroimaging findings in CD patients. Based on the whole amygdala bilaterally as ROIs, compared with HCs, CD patients showed no statistical differences of grey matter destiny but exhibited decreased FC between the amygdala and insula, parahippocampus, as well as anterior middle cingulate cortex/dorsal anterior cingulate cortex. CD patients had negative correlation between the disease duration and amygdala-insula connectivity. In the patient group, patients with higher anxiety or depression scores revealed increased FC of the amygdala with thalamus and orbitofrontal cortex. Our results reveal that aberrant FC of the amygdala may be involved in processing of visceral pain and sensation, and emotion in CD. These findings may further enhance the understanding of neural mechanisms of CD.
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Affiliation(s)
- Yingying Fan
- Life Science Research Center, School of Life Science and Technology, Xidian University, Xi'an, 710071, China
- Engineering Research Center of Molecular and Neuro Imaging Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an, 710071, China
| | - Chunhui Bao
- Key Laboratory of Acupuncture and Immunological Effects, Shanghai University of Traditional Chinese Medicine, Shanghai, 200030, China
| | - Ying Wei
- Life Science Research Center, School of Life Science and Technology, Xidian University, Xi'an, 710071, China
- Engineering Research Center of Molecular and Neuro Imaging Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an, 710071, China
| | - Jiayu Wu
- Life Science Research Center, School of Life Science and Technology, Xidian University, Xi'an, 710071, China
- Engineering Research Center of Molecular and Neuro Imaging Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an, 710071, China
| | - Yingsong Zhao
- Life Science Research Center, School of Life Science and Technology, Xidian University, Xi'an, 710071, China
- Engineering Research Center of Molecular and Neuro Imaging Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an, 710071, China
| | - Xiao Zeng
- Life Science Research Center, School of Life Science and Technology, Xidian University, Xi'an, 710071, China
- Engineering Research Center of Molecular and Neuro Imaging Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an, 710071, China
| | - Wei Qin
- Life Science Research Center, School of Life Science and Technology, Xidian University, Xi'an, 710071, China
- Engineering Research Center of Molecular and Neuro Imaging Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an, 710071, China
| | - Huangan Wu
- Key Laboratory of Acupuncture and Immunological Effects, Shanghai University of Traditional Chinese Medicine, Shanghai, 200030, China.
| | - Peng Liu
- Life Science Research Center, School of Life Science and Technology, Xidian University, Xi'an, 710071, China.
- Engineering Research Center of Molecular and Neuro Imaging Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an, 710071, China.
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16
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Pharmacology of Herbal Sexual Enhancers: A Review of Psychiatric and Neurological Adverse Effects. Pharmaceuticals (Basel) 2020; 13:ph13100309. [PMID: 33066617 PMCID: PMC7602496 DOI: 10.3390/ph13100309] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 10/09/2020] [Accepted: 10/12/2020] [Indexed: 12/13/2022] Open
Abstract
Sexual enhancers increase sexual potency, sexual pleasure, or libido. Substances increasing libido alter the concentrations of specific neurotransmitters or sex hormones in the central nervous system. Interestingly, the same pathways are involved in the mechanisms underlying many psychiatric and neurological disorders, and adverse reactions associated with the use of aphrodisiacs are strongly expected. However, sexual enhancers of plant origin have gained popularity over recent years, as natural substances are often regarded as a safer alternative to modern medications and are easily acquired without prescription. We reviewed the psychiatric and neurological adverse effects associated with the consumption of herbal aphrodisiacs Areca catechu L., Argemone Mexicana L., Citrus aurantium L., Eurycoma longifolia Jack., Lepidium meyenii Walp., Mitragyna speciosa Korth., Panax ginseng C. A. Mey, Panax quinquefolius L., Pausinystalia johimbe (K. Schum.) Pierre ex Beille, Piper methysticum G. Forst., Ptychopetalum olacoides Benth., Sceletium tortuosum (L.) N. E. Brown, Turnera diffusa Willd. ex. Schult., Voacanga africana Stapf ex Scott-Elliot, and Withania somnifera (L.) Dunal. A literature search was conducted on the PubMed, Scopus, and Web of Science databases with the aim of identifying all the relevant articles published on the issue up to June 2020. Most of the selected sexual enhancers appeared to be safe at therapeutic doses, although mild to severe adverse effects may occur in cases of overdosing or self-medication with unstandardized products. Drug interactions are more concerning, considering that herbal aphrodisiacs are likely used together with other plant extracts and/or pharmaceuticals. However, few data are available on the side effects of several plants included in this review, and more clinical studies with controlled administrations should be conducted to address this issue.
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Rahal H, Videlock EJ, Icenhour A, Shih W, Naliboff B, Gupta A, Mayer EA, Chang L. Importance of trauma-related fear in patients with irritable bowel syndrome and early adverse life events. Neurogastroenterol Motil 2020; 32:e13896. [PMID: 32558017 PMCID: PMC7483907 DOI: 10.1111/nmo.13896] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 02/25/2020] [Accepted: 05/05/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND Although early adverse life events (EALs) are prevalent among patients with irritable bowel syndrome (IBS), the impact of fear or dissociation experienced during the trauma has not been evaluated. We investigated the prevalence of fear at the time of trauma and its association with IBS status among individuals with early-life trauma before the age of 18. METHODS Among participants with ≥1 EAL, association of fear and dissociation with IBS status was determined with logistic regression, and improvement in prediction of IBS over ETI score alone was determined with the likelihood ratio test. Controlling for age, sex, and IBS status, we then examined the association of each EAL with reported fear. KEY RESULTS Compared to healthy controls (HCs), IBS subjects reported a higher prevalence of fear (60.4% vs 36.2%, P < .0005) and dissociation (23.5% vs 13.0%, P < .0005) at the time of EAL. Fear, but not dissociation, improved prediction of IBS over the total number of EALs (odds ratio = 2.00, P < .0001). CONCLUSIONS AND INFERENCES This study highlights the importance of EAL-related factors such as fear in addition to the presence or absence of EALs in IBS pathophysiology.
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Affiliation(s)
- Harman Rahal
- G Oppenheimer Center for Neurobiology of Stress and Resilience, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, 10833 Le Conte Avenue, CHS 42-210, Los Angeles, California 90095-7378, United States
| | - Elizabeth J. Videlock
- G Oppenheimer Center for Neurobiology of Stress and Resilience, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, 10833 Le Conte Avenue, CHS 42-210, Los Angeles, California 90095-7378, United States
| | - Adriane Icenhour
- Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45147 Essen, Germany
| | - Wendy Shih
- G Oppenheimer Center for Neurobiology of Stress and Resilience, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, 10833 Le Conte Avenue, CHS 42-210, Los Angeles, California 90095-7378, United States,Center of Health Research, School of Public Health, Loma Linda University, Loma Linda, California
| | - Bruce Naliboff
- G Oppenheimer Center for Neurobiology of Stress and Resilience, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, 10833 Le Conte Avenue, CHS 42-210, Los Angeles, California 90095-7378, United States
| | - Arpana Gupta
- G Oppenheimer Center for Neurobiology of Stress and Resilience, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, 10833 Le Conte Avenue, CHS 42-210, Los Angeles, California 90095-7378, United States
| | - Emeran A. Mayer
- G Oppenheimer Center for Neurobiology of Stress and Resilience, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, 10833 Le Conte Avenue, CHS 42-210, Los Angeles, California 90095-7378, United States
| | - Lin Chang
- G Oppenheimer Center for Neurobiology of Stress and Resilience, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, 10833 Le Conte Avenue, CHS 42-210, Los Angeles, California 90095-7378, United States
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18
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Kurahashi M, Kito Y, Hara M, Takeyama H, Sanders KM, Hashitani H. Norepinephrine Has Dual Effects on Human Colonic Contractions Through Distinct Subtypes of Alpha 1 Adrenoceptors. Cell Mol Gastroenterol Hepatol 2020; 10:658-671.e1. [PMID: 32376421 PMCID: PMC7474159 DOI: 10.1016/j.jcmgh.2020.04.015] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 04/24/2020] [Accepted: 04/27/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Colonic musculature contain smooth muscle cells (SMC), interstitial cells of Cajal (ICC), and platelet-derived growth factor receptor α+ cells (PDGFRα+ cells), which are electrically coupled and operate together as the SIP syncytium. PDGFRα+ cells have enriched expression of small conductance Ca2+-activated K+ (SK) channels. Purinergic enteric neural input activates SK channels in PDGFRα+ cells, hyperpolarizes SMC, and inhibits colonic contractions. Recently we discovered that PDGFRα+ cells in mouse colon have enriched expression of α1A adrenoceptors (ARs), which coupled to activation of SK channels and inhibited colonic motility, and α1A ARs were principal targets for sympathetic regulation of colonic motility. Here we investigated whether PDGFRα+ cells in human colon express α1A ARs and share the roles as targets for sympathetic regulation of colonic motility. METHODS Isometric tension recording, intracellular recording, and Ca2+ imaging were performed on muscles of the human colon. Responses to α1 ARs agonists or electric field stimulation with AR antagonists and neuroleptic reagents were studied. RESULTS Exogenous or endogenous norepinephrine released from nerve fibers inhibited colonic contractions through binding to α1A ARs or enhanced colonic contractions by acting on α1D ARs. Inhibitory responses were blocked by apamin, an antagonist of SK channels. Phenylephrine, α1 AR agonists, or norepinephrine increased intracellular [Ca2+] in PDGFRα+ cells, but not in ICC, and hyperpolarized SMCs by binding to α1 ARs expressed by PDGFRα+ cells. CONCLUSIONS Human colonic contractions are inhibited by α1A ARs expressed in PDGFRα+ cells and activated by α1D ARs expressed in SMC.
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Affiliation(s)
- Masaaki Kurahashi
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada.
| | - Yoshihiko Kito
- Department of Pharmacology, Saga University, Saga, Japan
| | - Masayasu Hara
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Hiromitsu Takeyama
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Kenton M Sanders
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada
| | - Hikaru Hashitani
- Department of Cell Physiology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
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19
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Kurahashi M, Kito Y, Baker SA, Jennings LK, Dowers JGR, Koh SD, Sanders KM. A novel postsynaptic signal pathway of sympathetic neural regulation of murine colonic motility. FASEB J 2020; 34:5563-5577. [PMID: 32086857 DOI: 10.1096/fj.201903134r] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 02/04/2020] [Accepted: 02/13/2020] [Indexed: 01/14/2023]
Abstract
Transcriptome data revealed α1 adrenoceptors (ARs) expression in platelet-derived growth factor receptor α+ cells (PDGFRα+ cells) in murine colonic musculature. The role of PDGFRα+ cells in sympathetic neural regulation of murine colonic motility was investigated. Norepinephrine (NE), via α1A ARs, activated a small conductance Ca2+ -activated K+ (SK) conductance, evoked outward currents and hyperpolarized PDGFRα+ cells (the α1A AR-SK channel signal pathway). α1 AR agonists increased intracellular Ca2+ transients in PDGFRα+ cells and inhibited spontaneous phasic contractions (SPCs) of colonic muscle through activation of a SK conductance. Sympathetic nerve stimulation inhibited both contractions of distal colon and propulsive contractions represented by the colonic migrating motor complexes (CMMCs) via the α1A AR-SK channel signal pathway. Postsynaptic signaling through α1A ARs in PDGFRα+ cells is a novel mechanism that conveys part of stress responses in the colon. PDGFRα+ cells appear to be a primary effector of sympathetic neural regulation of murine colonic motility.
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Affiliation(s)
- Masaaki Kurahashi
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV, USA
| | - Yoshihiko Kito
- Department of Pharmacology, Saga University, Saga, Japan
| | - Salah A Baker
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV, USA
| | - Libby K Jennings
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV, USA
| | - James G R Dowers
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV, USA
| | - Sang Don Koh
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV, USA
| | - Kenton M Sanders
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV, USA
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20
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Mayer EA, Labus J, Aziz Q, Tracey I, Kilpatrick L, Elsenbruch S, Schweinhardt P, Van Oudenhove L, Borsook D. Role of brain imaging in disorders of brain-gut interaction: a Rome Working Team Report. Gut 2019; 68:1701-1715. [PMID: 31175206 PMCID: PMC6999847 DOI: 10.1136/gutjnl-2019-318308] [Citation(s) in RCA: 89] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 03/18/2019] [Accepted: 03/24/2019] [Indexed: 12/12/2022]
Abstract
Imaging of the living human brain is a powerful tool to probe the interactions between brain, gut and microbiome in health and in disorders of brain-gut interactions, in particular IBS. While altered signals from the viscera contribute to clinical symptoms, the brain integrates these interoceptive signals with emotional, cognitive and memory related inputs in a non-linear fashion to produce symptoms. Tremendous progress has occurred in the development of new imaging techniques that look at structural, functional and metabolic properties of brain regions and networks. Standardisation in image acquisition and advances in computational approaches has made it possible to study large data sets of imaging studies, identify network properties and integrate them with non-imaging data. These approaches are beginning to generate brain signatures in IBS that share some features with those obtained in other often overlapping chronic pain disorders such as urological pelvic pain syndromes and vulvodynia, suggesting shared mechanisms. Despite this progress, the identification of preclinical vulnerability factors and outcome predictors has been slow. To overcome current obstacles, the creation of consortia and the generation of standardised multisite repositories for brain imaging and metadata from multisite studies are required.
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Affiliation(s)
- Emeran A Mayer
- G. Oppenheimer Center for Neurobiology of Stress and Resilience, Vatche and Tamar Manoukian Division of Digestive Diseases David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Jennifer Labus
- G. Oppenheimer Center for Neurobiology of Stress and Resilience, Vatche and Tamar Manoukian Division of Digestive Diseases David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Qasim Aziz
- Neurogastroenterology Group, Queen Mary University of London, London, UK
| | - Irene Tracey
- Departments of Anaesthetics and Clinical Neurology, Pembroke College, Oxford, UK
| | - Lisa Kilpatrick
- G. Oppenheimer Center for Neurobiology of Stress and Resilience, Vatche and Tamar Manoukian Division of Digestive Diseases David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Sigrid Elsenbruch
- Institute of Medical Psychology & Behavioral Immunobiology, University Hospital Essen, University of Duisburg, Duisburg, Germany
| | | | - Lukas Van Oudenhove
- Translational Research in GastroIntestinal Disorders, KU Leuven Department of Clinical and Experimental Medicine, University of Leuven, Leuven, Belgium
| | - David Borsook
- Center for Pain and the Brain, Boston Children's, Massachusetts General and McLean Hospitals, Harvard Medical School, Boston, Massachusetts, USA
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Jin Q, Duan S, Li G, Sun L, Hu Y, Hu C, Zhao J, von Deneen KM, Qian L, Wang H, Ji G, Wu K, Fan D, Cui G, Nie Y, Zhang Y. Sex-related differences in resting-state brain activity and connectivity in the orbital frontal cortex and insula in patients with functional constipation. Neurogastroenterol Motil 2019; 31:e13566. [PMID: 30729624 DOI: 10.1111/nmo.13566] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Revised: 11/28/2018] [Accepted: 01/13/2019] [Indexed: 02/06/2023]
Abstract
Functional magnetic resonance imaging (fMRI) has been used to investigate sex-related differences in brain abnormalities in patients with irritable bowel syndrome (IBS). Like IBS, women with functional constipation (FC) are 2.1 times as many as men. No study has been performed yet to examine sex-related differences in brain activity and connectivity in patients with FC. Here, we employed resting-state fMRI with amplitude of low-frequency fluctuation (ALFF) to investigate brain functional differences in 51 patients with FC (34 females) and 52 healthy controls (34 females). Results showed abdominal pain and abdominal distension correlated with trait (TAI) and state (SAI) anxiety ratings in the female FC group, and abdominal distension correlated with sensation of incomplete evacuation in the male FC group. Two-way ANOVA revealed sex effects on ALFF in precentral gyrus, thalamus, insula (INS), and orbital frontal cortex (OFC, PFWE < 0.05). Post hoc test showed that the female FC group had lower ALFF than males in these brain regions (P < 0.01), and ALFF in INS and OFC was correlated with abdominal pain and difficulty of defecation, respectively. Seed voxel correlation analysis showed that the female FC group had weaker connectivity than males between INS and lateral OFC (lOFC). INS-lOFC connectivity was negatively correlated with the anxiety score in the female FC group and was negatively correlated with abdominal distension in the male FC group. These findings provide the first insight into sex-related differences in patients with FC and highlight that INS and OFC play an important role in modulating the intrinsic functional connectivity of the resting brain network showing that this role is influenced by sex.
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Affiliation(s)
- Qingchao Jin
- Center for Brain Imaging, School of Life Science and Technology, Xidian University, Xi'an, China
| | - Shijun Duan
- Department of Radiology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China
| | - Guanya Li
- Center for Brain Imaging, School of Life Science and Technology, Xidian University, Xi'an, China
| | - Lijuan Sun
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Yang Hu
- Center for Brain Imaging, School of Life Science and Technology, Xidian University, Xi'an, China
| | - Chunxin Hu
- Center for Brain Imaging, School of Life Science and Technology, Xidian University, Xi'an, China
| | - Jizheng Zhao
- Center for Brain Imaging, School of Life Science and Technology, Xidian University, Xi'an, China.,College of Mechanical and Electronic Engineering, Northwest A&F University, Yangling, China
| | - Karen M von Deneen
- Center for Brain Imaging, School of Life Science and Technology, Xidian University, Xi'an, China
| | - Long Qian
- Center for MRI Research, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Huaning Wang
- Department of Psychiatry, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Gang Ji
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Kaichun Wu
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Daiming Fan
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Guangbin Cui
- Department of Radiology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China
| | - Yongzhan Nie
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Yi Zhang
- Center for Brain Imaging, School of Life Science and Technology, Xidian University, Xi'an, China
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22
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Zhang QE, Wang F, Qin G, Zheng W, Ng CH, Ungvari GS, Yuan Z, Mei S, Wang G, Xiang YT. Depressive symptoms in patients with irritable bowel syndrome: a meta-analysis of comparative studies. Int J Biol Sci 2018; 14:1504-1512. [PMID: 30263003 PMCID: PMC6158731 DOI: 10.7150/ijbs.25001] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Accepted: 05/13/2018] [Indexed: 12/15/2022] Open
Abstract
Depression is common in patients with irritable bowel syndrome (IBS), but the reported prevalence across different studies is inconsistent. This meta-analysis systematically examined the presence and severity of depressive symptoms in patients with IBS. Two investigators independently performed a literature search. The pooled depressive symptom severity was calculated using a random effects model. Subgroup, sensitivity and meta-regression analyses were conducted to examine the moderating factors of the development of depressive symptoms. Twenty four studies (n=2,837) comparing depressive symptoms between IBS patients (n=1,775) and healthy controls (n=1,062) were identified; 14 (58.3%) studies were rated as high quality. Compared to healthy controls, IBS patients had more frequent (OR=9.21, 95%CI: 4.56-18.57, P<0.001; I2=76%) and more severe depressive symptoms (n=1,480, SMD=2.02, 95%CI: 1.56-2.48, P<0.001; I2=94%). Subgroup analyses revealed that patients with all IBS subtypes had more severe depressive symptoms than controls. In addition, versions of the Hamilton Depression Rating Scale (HAM-D) and IBS diagnostic criteria were significantly associated with depressive symptom severity. Meta-regression analyses revealed that female gender, younger age and small sample size were significantly associated with more severe depressive symptoms. In conclusion, meta-analytic data showed that IBS patients had more frequent and severe depressive symptoms than healthy controls. Adequate screening and treatment for depression should be developed and implemented in this patient population.
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Affiliation(s)
- Qing-E Zhang
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China
| | - Fei Wang
- Guangdong Mental Health Center, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangdong Province, China
- Unit of Psychiatry, Faculty of Health Sciences, University of Macau, Macao SAR, China
| | - Geng Qin
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing, China
| | - Wei Zheng
- The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, China
| | - Chee H. Ng
- Department of Psychiatry, University of Melbourne, Melbourne, Victoria, Australia
| | - Gabor S. Ungvari
- University of Notre Dame Australia, Perth, Australia
- Division of Psychiatry, University of Western Australia Medical School, Perth, Australia
| | - Zhen Yuan
- Unit of Psychiatry, Faculty of Health Sciences, University of Macau, Macao SAR, China
| | - Songli Mei
- School of Public Health, Jilin University, Jilin province, China
| | - Gang Wang
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China
| | - Yu-Tao Xiang
- Unit of Psychiatry, Faculty of Health Sciences, University of Macau, Macao SAR, China
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23
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Yaoita F, Muto M, Murakami H, Endo S, Kozawa M, Tsuchiya M, Tadano T, Tan-No K. Involvement of peripheral alpha2A adrenoceptor in the acceleration of gastrointestinal transit and abdominal visceral pain induced by intermittent deprivation of REM sleep. Physiol Behav 2018; 186:52-61. [DOI: 10.1016/j.physbeh.2018.01.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Revised: 01/11/2018] [Accepted: 01/11/2018] [Indexed: 02/06/2023]
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24
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Nan J, Zhang L, Chen Q, Zong N, Zhang P, Ji X, Ma S, Zhang Y, Huang W, Du Z, Xia Y, Zhang M. White Matter Microstructural Similarity and Diversity of Functional Constipation and Constipation-predominant Irritable Bowel Syndrome. J Neurogastroenterol Motil 2018; 24:107-118. [PMID: 29291612 PMCID: PMC5753909 DOI: 10.5056/jnm17038] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Revised: 05/24/2017] [Accepted: 08/16/2017] [Indexed: 12/21/2022] Open
Abstract
Background/Aims The Rome III criteria separated chronic constipation into functional constipation (FC) and constipation-predominant irritable bowel syndrome (IBS-C), but some researchers questioned the partitioning and treated both as distinct parts of a continuum. The study aims to explore the similarity and diversity of brain white matter between FC and IBS-C. Methods The voxel-wise analysis of the diffusion parameters was used to quantify the white matter changes of female brains in 18 FC patients and 20 IBS-C patients compared with a comparison group with 19 healthy controls by tract-based spatial statistics. The correlations between diffusive parameters and clinical symptoms were evaluated using a Pearson's correlation. Results In comparison to healthy controls, FC patients showed a decrease of fractional anisotropy (FA) and an increase of radial diffusivity (RD) in multiple major fibers encompassing the corpus callosum (CC, P = 0.001 at peak), external capsule (P = 0.002 at peak), corona radiata (CR, P = 0.001 at peak), and superior longitudinal fasciculus (SLF, P = 0.002 at peak). In contrast, IBS-C patients showed FA and RD aberrations in the CC (P = 0.048 at peak). Moreover, the direct comparison between FC and IBS-C showed only RD differences in the CR and SLF. In addition, FA and RD in the CC were significantly associated with abdominal pain for all patients, whereas FA in CR (P = 0.016) and SLF (P = 0.040) were significantly associated with the length of time per attempt and incomplete evacuation separately for FC patients. Conclusion These results may improve our understanding of the pathophysiological mechanisms underlying different types of constipation.
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Affiliation(s)
- Jiaofen Nan
- School of Computer and Communication Engineering, Zhengzhou University of Light Industry, Zhengzhou, China
| | - Liangliang Zhang
- School of Computer and Communication Engineering, Zhengzhou University of Light Industry, Zhengzhou, China
| | - Qiqiang Chen
- School of Computer and Communication Engineering, Zhengzhou University of Light Industry, Zhengzhou, China
| | - Nannan Zong
- School of Computer and Communication Engineering, Zhengzhou University of Light Industry, Zhengzhou, China
| | - Peiyong Zhang
- First Affiliated Hospital of Xinxiang Medical University, Weihui, China
| | - Xing Ji
- First Affiliated Hospital of Yan'an University, Yan'an, China
| | - Shaohui Ma
- Department of Medical Imaging, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yuchen Zhang
- Department of Medical Imaging, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Wei Huang
- School of Computer and Communication Engineering, Zhengzhou University of Light Industry, Zhengzhou, China
| | - Zhongzhou Du
- School of Computer and Communication Engineering, Zhengzhou University of Light Industry, Zhengzhou, China
| | - Yongquan Xia
- School of Computer and Communication Engineering, Zhengzhou University of Light Industry, Zhengzhou, China
| | - Ming Zhang
- Department of Medical Imaging, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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25
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Abstract
BACKGROUND Psychological factors have been prominently implicated in the causation as well as maintenance of irritable bowel syndrome (IBS). Studies comparing psychiatric morbidity in IBS with healthy controls have reported contrasting findings. The current study was undertaken to assess the prevalence of anxiety and depression in patients with IBS in comparison to healthy controls and to explore the relationship, if any, of anxiety and depression with various subtypes of IBS. MATERIALS AND METHODS Fifty consecutive patients of IBS (diagnosed as per Rome III criteria) between 18 and 65 years of age and fifty age- and sex-matched healthy controls were assessed for the presence of anxiety and depression using Hamilton Rating Scale for Anxiety (HAMA) and Hamilton Rating Scale for Depression (HAMD), respectively. RESULTS The patient group scored higher than controls (P < 0.001) in both HAMA and HAMD scores. The HAMA scores were significantly higher (P < 0.001) in the severe IBS group compared to those with moderate IBS. HAMA scores predicted 25.6% (R2 = 0.256) of variance in IBS severity scores. However, there was no significant difference between the two groups in terms of HAMD scores. CONCLUSION The high prevalence of psychiatric comorbidities such as anxiety and depression in IBS samples in our study provides evidence in favor of proper screening for these disorders in gastrointestinal clinics. Recognition and treatment for these comorbidities can improve the quality of life as well as overall outcomes.
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Affiliation(s)
- Arko Banerjee
- Department of Gastroenterology, School of Digestive and Liver Diseases, IPGMER and SSKM Hospital, Kolkata, West Bengal, India
| | - Sujit Sarkhel
- Department of Psychiatry, Institute of Psychiatry, IPGMER and SSKM Hospital, Kolkata, West Bengal, India
| | - Rajib Sarkar
- Department of Gastroenterology, School of Digestive and Liver Diseases, IPGMER and SSKM Hospital, Kolkata, West Bengal, India
| | - Gopal Krishna Dhali
- Department of Gastroenterology, School of Digestive and Liver Diseases, IPGMER and SSKM Hospital, Kolkata, West Bengal, India
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26
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Lee C, Doo E, Choi JM, Jang SH, Ryu HS, Lee JY, Oh JH, Park JH, Kim YS. The Increased Level of Depression and Anxiety in Irritable Bowel Syndrome Patients Compared with Healthy Controls: Systematic Review and Meta-analysis. J Neurogastroenterol Motil 2017; 23:349-362. [PMID: 28672433 PMCID: PMC5503284 DOI: 10.5056/jnm16220] [Citation(s) in RCA: 140] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2016] [Revised: 06/08/2017] [Accepted: 06/10/2017] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND/AIMS Irritable bowel syndrome (IBS) patients commonly experience psychiatric disorders, such as depression and anxiety. This meta-analysis sought to compare depression and anxiety levels between IBS patients and healthy controls. METHODS We searched major electronic databases (PubMed, EMBASE, MEDLINE, and Cochrane library) to find comparative studies on IBS patients and healthy controls. The primary outcome was a standardized mean difference (SMD) of anxiety and depression levels; sub-group analyses were conducted according to IBS-subtypes. RESULTS In total, 2293 IBS patients and 4951 healthy controls from 27 studies were included. In random effect analysis, depression and anxiety levels were significantly higher in IBS patients (pooled SMD = 0.76; 95% CI, 0.62-0.90; P < 0.001; I2 = 77.2% and pooled SMD = 0.84; 95% CI, 0.67-1.01; P < 0.001; I2 = 85.6%, respectively). Both analyses' funnel plots showed symmetry. In meta-regression analysis, heterogeneity was due to the studied region and questionnaire type for both depression and anxiety. In sub-group analyses of IBS-subtype, the pooled SMDs of depression and anxiety levels (IBS with predominant constipation: 0.83 and 0.81, IBS with predominant diarrhea: 0.73 and 0.65, and IBS with mixed bowel habits: 0.62 and 0.75; P < 0.001, respectively) were significantly higher in all IBS-subtypes. CONCLUSIONS The present meta-analysis showed depression and anxiety levels to be higher in IBS patients than in healthy controls, regardless of IBS-subtype. However, the gender effect on psychological factors among IBS patients could not be determined and should be evaluated in prospective studies.
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Affiliation(s)
- Changhyun Lee
- Department of Internal Medicine and Healthcare Research Institute, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul,
Korea
| | - Eunyoung Doo
- Department of Internal Medicine and Healthcare Research Institute, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul,
Korea
| | - Ji Min Choi
- Department of Internal Medicine and Healthcare Research Institute, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul,
Korea
| | - Seung-ho Jang
- Department of Psychiatry, School of Medicine, Wonkwang University, Iksan, Jeollabuk-do,
Korea
| | - Han-Seung Ryu
- Department of Gastroenterology and Digestive Disease Research Institute, Wonkwang University School of Medicine, Iksan, Jeollabuk-do,
Korea
| | - Ju Yup Lee
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu,
Korea
| | - Jung Hwan Oh
- Division of Gastroenterology, Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul,
Korea
| | - Jung Ho Park
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul,
Korea
| | - Yong Sung Kim
- Division of Gastroenterology, Department of Internal Medicine, Wonkwang University Sanbon Hospital, Gunpo, Gyeonggi-do,
Korea
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27
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Gupta A, Cole S, Labus JS, Joshi S, Nguyen TJ, Kilpatrick LA, Tillisch K, Naliboff BD, Chang L, Mayer EA. Gene expression profiles in peripheral blood mononuclear cells correlate with salience network activity in chronic visceral pain: A pilot study. Neurogastroenterol Motil 2017; 29:10.1111/nmo.13027. [PMID: 28191693 PMCID: PMC5503466 DOI: 10.1111/nmo.13027] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Accepted: 12/12/2016] [Indexed: 12/17/2022]
Abstract
BACKGROUND Distinct gene expression profiles in peripheral blood mononuclear cells (PBMCs) consistent with increased sympathetic nervous system activity have been described in different populations under chronic stress. Neuroinflammatory brain changes, possibly related to the migration of primed monocytes to the brain, have been implicated in the pathophysiology of chronic pain. Irritable bowel syndrome (IBS) is a stress-sensitive gastrointestinal disorder associated with altered brain-gut interactions and increased sympathetic/vagal tone and anxiety. Reports about immune alterations in IBS are conflicting. This pilot study aimed to test how PBMC gene expression inflammatory profiles are correlated with altered brain signatures in the salience system. METHODS Sixteen IBS and 16 healthy controls (HCs) completed resting state MRI scans. Gene expression profiles in PBMCs were assessed using human transcriptome array-2. Bioinformatic analyses determined differential expression of PBMCs between IBS and HCs. Partial least squares, a multivariate analysis technique, was used to identify disease correlations between PBMC gene expression profiles and functional activity in the brain's salience network. KEY RESULTS Regions of the salience network, including the mid cingulate cortex, and mid and superior temporal gyrus were positively correlated with several pro-inflammatory genes (interleukin 6, APOL2) in IBS, but negatively correlated with several anti-inflammatory genes (KRT8, APOA4) in HCs. CONCLUSIONS & INFERENCES Based on rodent studies, one may speculate that chronically activated stress signaling pathways in IBS maintain a pro-inflammatory state in the periphery. Alternatively, primed monocytes may migrate to the brain during stress, inducing regional neuroinflammatory changes in salience regions involved in the modulation of visceral sensitivity.
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Affiliation(s)
- Arpana Gupta
- Oppenheimer Center for Neurobiology of Stress and Resilience, UCLA,David Geffen School of Medicine, UCLA,Division of Digestive Diseases, UCLA
| | - Steve Cole
- David Geffen School of Medicine, UCLA,Department of Hematology-Oncology, UCLA
| | - Jennifer S. Labus
- Oppenheimer Center for Neurobiology of Stress and Resilience, UCLA,David Geffen School of Medicine, UCLA,Division of Digestive Diseases, UCLA
| | - Swapna Joshi
- Oppenheimer Center for Neurobiology of Stress and Resilience, UCLA,David Geffen School of Medicine, UCLA,Division of Digestive Diseases, UCLA,Center for Systems Biomedicine, UCLA
| | - Trang J. Nguyen
- Oppenheimer Center for Neurobiology of Stress and Resilience, UCLA
| | - Lisa A. Kilpatrick
- Oppenheimer Center for Neurobiology of Stress and Resilience, UCLA,David Geffen School of Medicine, UCLA,Division of Digestive Diseases, UCLA
| | - Kirsten Tillisch
- Oppenheimer Center for Neurobiology of Stress and Resilience, UCLA,David Geffen School of Medicine, UCLA,Division of Digestive Diseases, UCLA,Integrative Medicine, GLA, VHA
| | - Bruce D. Naliboff
- Oppenheimer Center for Neurobiology of Stress and Resilience, UCLA,David Geffen School of Medicine, UCLA,Division of Digestive Diseases, UCLA
| | - Lin Chang
- Oppenheimer Center for Neurobiology of Stress and Resilience, UCLA,David Geffen School of Medicine, UCLA,Division of Digestive Diseases, UCLA
| | - Emeran A. Mayer
- Oppenheimer Center for Neurobiology of Stress and Resilience, UCLA,David Geffen School of Medicine, UCLA,Division of Digestive Diseases, UCLA,Ahmanson-Lovelace Brain Mapping Center, UCLA
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28
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Mittal R, Debs LH, Patel AP, Nguyen D, Patel K, O'Connor G, Grati M, Mittal J, Yan D, Eshraghi AA, Deo SK, Daunert S, Liu XZ. Neurotransmitters: The Critical Modulators Regulating Gut-Brain Axis. J Cell Physiol 2017; 232:2359-2372. [PMID: 27512962 DOI: 10.1002/jcp.25518] [Citation(s) in RCA: 376] [Impact Index Per Article: 47.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Accepted: 08/10/2016] [Indexed: 12/17/2022]
Abstract
Neurotransmitters, including catecholamines and serotonin, play a crucial role in maintaining homeostasis in the human body. Studies on these neurotransmitters mainly revolved around their role in the "fight or flight" response, transmitting signals across a chemical synapse and modulating blood flow throughout the body. However, recent research has demonstrated that neurotransmitters can play a significant role in the gastrointestinal (GI) physiology. Norepinephrine (NE), epinephrine (E), dopamine (DA), and serotonin have recently been a topic of interest because of their roles in the gut physiology and their potential roles in GI and central nervous system pathophysiology. These neurotransmitters are able to regulate and control not only blood flow, but also affect gut motility, nutrient absorption, GI innate immune system, and the microbiome. Furthermore, in pathological states, such as inflammatory bowel disease (IBD) and Parkinson's disease, the levels of these neurotransmitters are dysregulated, therefore causing a variety of GI symptoms. Research in this field has shown that exogenous manipulation of catecholamine serum concentrations can help in decreasing symptomology and/or disease progression. In this review article, we discuss the current state-of-the-art research and literature regarding the role of neurotransmitters in regulation of normal GI physiology, their impact on several disease processes, and novel work focused on the use of exogenous hormones and/or psychotropic medications to improve disease symptomology. J. Cell. Physiol. 232: 2359-2372, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Rahul Mittal
- Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, Florida
| | - Luca H Debs
- Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, Florida
| | - Amit P Patel
- Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, Florida
| | - Desiree Nguyen
- Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, Florida
| | - Kunal Patel
- Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, Florida
| | - Gregory O'Connor
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida
| | - M'hamed Grati
- Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, Florida
| | - Jeenu Mittal
- Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, Florida
| | - Denise Yan
- Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, Florida
| | - Adrien A Eshraghi
- Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, Florida
| | - Sapna K Deo
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida
| | - Sylvia Daunert
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida
| | - Xue Zhong Liu
- Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, Florida
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29
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Duboc H, Dior M, Coffin B. Le syndrome de l’intestin irritable : nouvelles pistes physiopathologiques et conséquences pratiques. Rev Med Interne 2016; 37:536-43. [DOI: 10.1016/j.revmed.2015.12.030] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Accepted: 12/30/2015] [Indexed: 02/06/2023]
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30
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Muscatello MRA, Bruno A, Mento C, Pandolfo G, Zoccali RA. Personality traits and emotional patterns in irritable bowel syndrome. World J Gastroenterol 2016; 22:6402-15. [PMID: 27605876 PMCID: PMC4968122 DOI: 10.3748/wjg.v22.i28.6402] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2016] [Revised: 05/26/2016] [Accepted: 06/15/2016] [Indexed: 02/06/2023] Open
Abstract
The review focuses on those personality traits (neuroticism, extraversion, openness to experience, agreeableness, and conscientiousness), constructs (alexithymia and distressed - Type D personality) and emotional patterns (negative and positive) that are of particular concern in health psychology, with the aim to highlight their potential role on the pathogenesis, onset, symptom clusters, clinical course, and outcome of irritable bowel syndrome (IBS). Personality traits and emotional patterns play key roles in affecting autonomic, immune, inflammatory, and endocrine functions, thus contributing not only to IBS clinical expression and symptomatic burden, but also to disease physiopathology. In this sense, psychological treatments should address those personality traits and emotional features that are constitutive of, and integral to IBS. The biopsychosocial model of illness applied to IBS acknowledges the interaction between biological, psychological, environmental, and social factors in relation to pain and functional disability. A holistic approach to IBS should take into account the heterogeneous nature of the disorder, and differentiate treatments for different types of IBS, also considering the marked individual differences in prevalent personality traits and emotional patterns. Beyond medications, and lifestyle/dietary interventions, psychological and educational treatments may provide the optimal chance of addressing clinical symptoms, comorbid conditions, and quality of life in IBS patients.
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31
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Weaver KR, Sherwin LB, Walitt B, Melkus GD, Henderson WA. Neuroimaging the brain-gut axis in patients with irritable bowel syndrome. World J Gastrointest Pharmacol Ther 2016; 7:320-333. [PMID: 27158548 PMCID: PMC4848255 DOI: 10.4292/wjgpt.v7.i2.320] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2015] [Revised: 10/06/2015] [Accepted: 02/24/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To summarize and synthesize current literature on neuroimaging the brain-gut axis in patients with irritable bowel syndrome (IBS).
METHODS: A database search for relevant literature was conducted using PubMed, Scopus and Embase in February 2015. Date filters were applied from the year 2009 and onward, and studies were limited to those written in the English language and those performed upon human subjects. The initial search yielded 797 articles, out of which 38 were pulled for full text review and 27 were included for study analysis. Investigations were reviewed to determine study design, methodology and results, and data points were placed in tabular format to facilitate analysis of study findings across disparate investigations.
RESULTS: Analysis of study data resulted in the abstraction of four key themes: Neurohormonal differences, anatomic measurements of brain structure and connectivity, differences in functional responsiveness of the brain during rectal distention, and confounding/correlating patient factors. Studies in this review noted alterations of glutamate in the left hippocampus (HIPP), commonalities across IBS subjects in terms of brain oscillation patterns, cortical thickness/gray matter volume differences, and neuroanatomical regions with increased activation in patients with IBS: Anterior cingulate cortex, mid cingulate cortex, amygdala, anterior insula, posterior insula and prefrontal cortex. A striking finding among interventions was the substantial influence that patient variables (e.g., sex, psychological and disease related factors) had upon the identification of neuroanatomical differences in structure and connectivity.
CONCLUSION: The field of neuroimaging can provide insight into underlying physiological differences that distinguish patients with IBS from a healthy population.
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Abstract
Chronic visceral pain syndromes are important clinical problems with largely unmet medical needs. Based on the common overlap with other chronic disorders of visceral or somatic pain, mood and affect, and their responsiveness to centrally targeted treatments, an important role of central nervous system in their pathophysiology is likely. A growing number of brain imaging studies in irritable bowel syndrome, functional dyspepsia, and bladder pain syndrome/interstitial cystitis has identified abnormalities in evoked brain responses, resting state activity, and connectivity, as well as in gray and white matter properties. Structural and functional alterations in brain regions of the salience, emotional arousal, and sensorimotor networks, as well as in prefrontal regions, are the most consistently reported findings. Some of these changes show moderate correlations with behavioral and clinical measures. Most recently, data-driven machine-learning approaches to larger data sets have been able to classify visceral pain syndromes from healthy control subjects. Future studies need to identify the mechanisms underlying the altered brain signatures of chronic visceral pain and identify targets for therapeutic interventions.
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Zhu L, Zhao L, Qu R, Zhu HY, Wang Y, Jiang X, Xu GY. Adrenergic stimulation sensitizes TRPV1 through upregulation of cystathionine β-synthetase in a rat model of visceral hypersensitivity. Sci Rep 2015; 5:16109. [PMID: 26527188 PMCID: PMC4630780 DOI: 10.1038/srep16109] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2015] [Accepted: 10/05/2015] [Indexed: 02/08/2023] Open
Abstract
The pathogenesis of pain in irritable bowel syndrome (IBS) is poorly understood and treatment remains difficult. The present study was designed to investigate roles of adrenergic signaling and the endogenous hydrogen sulfide producing enzyme cystathionine β-synthetase (CBS) in a previously validated rat model of IBS induced by neonatal colonic inflammation (NCI). Here we showed that NCI-induced visceral hypersensitivity (VH) was significantly attenuated by β2 subunit inhibitor but not by β1 or β3 or α subunit inhibitor. NCI markedly elevated plasma norepinephrine (NE) concentration without alteration in expression of β2 subunit receptors in dorsal root ganglion (DRGs) innervating the colon. In addition, NCI markedly enhanced TRPV1 and CBS expression in the colon DRGs. CBS inhibitor AOAA reversed the upregulation of TRPV1 in NCI rats. In vitro experiments showed that incubation of DRG cells with NE markedly enhanced expression of TRPV1, which was reversed by application of AOAA. Incubation of DRG cells with the H2S donor NaHS greatly enhanced TRPV1 expression. Collectively, these data suggest that activation of adrenergic signaling by NCI sensitizes TRPV1 channel activity, which is likely mediated by upregulation of CBS expression in peripheral sensory neurons, thus contributing to chronic visceral hypersensitivity.
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Affiliation(s)
- Liyan Zhu
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Department of Neurobiology and Physiology, Institute of Neuroscience, Soochow University, Suzhou 215123, P.R. China
| | - Liting Zhao
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Department of Neurobiology and Physiology, Institute of Neuroscience, Soochow University, Suzhou 215123, P.R. China
| | - Ruobing Qu
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Department of Neurobiology and Physiology, Institute of Neuroscience, Soochow University, Suzhou 215123, P.R. China
| | - Hong-Yan Zhu
- Center for Translational Medicine, the Affiliated Zhangjiagang Hospital of Soochow University, Zhangjiagang, 215600, P.R. China
| | - Yongmeng Wang
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Department of Neurobiology and Physiology, Institute of Neuroscience, Soochow University, Suzhou 215123, P.R. China
| | - Xinghong Jiang
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Department of Neurobiology and Physiology, Institute of Neuroscience, Soochow University, Suzhou 215123, P.R. China
| | - Guang-Yin Xu
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Department of Neurobiology and Physiology, Institute of Neuroscience, Soochow University, Suzhou 215123, P.R. China.,Center for Translational Medicine, the Affiliated Zhangjiagang Hospital of Soochow University, Zhangjiagang, 215600, P.R. China
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Abstract
Despite an extensive body of reported information about peripheral and central mechanisms involved in the pathophysiology of IBS symptoms, no comprehensive disease model has emerged that would guide the development of novel, effective therapies. In this Review, we will first describe novel insights into some key components of brain-gut interactions, starting with the emerging findings of distinct functional and structural brain signatures of IBS. We will then point out emerging correlations between these brain networks and genomic, gastrointestinal, immune and gut-microbiome-related parameters. We will incorporate this new information, as well as the reported extensive literature on various peripheral mechanisms, into a systems-based disease model of IBS, and discuss the implications of such a model for improved understanding of the disorder, and for the development of more-effective treatment approaches in the future.
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Affiliation(s)
- Emeran A Mayer
- Department of Medicine, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095-7378, USA
| | - Jennifer S Labus
- Department of Medicine, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095-7378, USA
| | - Kirsten Tillisch
- Department of Medicine, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095-7378, USA and West Los Angeles VA Medical Center, 11301 Wilshire Boulevard, Los Angeles, CA 90073, USA
| | - Steven W Cole
- Department of Medicine, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095-7378, USA
| | - Pierre Baldi
- Institute for Genomics and Bioinformatics, University of California at Irvine, 4038 Bren Hall, Irvine, CA 92697-3435, USA
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Orand A, Gupta A, Shih W, Presson AP, Hammer C, Niesler B, Heendeniya N, Mayer EA, Chang L. Catecholaminergic Gene Polymorphisms Are Associated with GI Symptoms and Morphological Brain Changes in Irritable Bowel Syndrome. PLoS One 2015; 10:e0135910. [PMID: 26288143 PMCID: PMC4546052 DOI: 10.1371/journal.pone.0135910] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2014] [Accepted: 07/28/2015] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND Genetic and environmental factors contribute to the pathophysiology of irritable bowel syndrome (IBS). In particular, early adverse life events (EALs) and the catecholaminergic system have been implicated. AIMS To investigate whether catecholaminergic SNPs with or without interacting with EALs are associated with: 1) a diagnosis of IBS, 2) IBS symptoms and 3) morphological alterations in brain regions associated with somatosensory, viscerosensory, and interoceptive processes. METHODS In 277 IBS and 382 healthy control subjects (HCs), 11 SNPs in genes of the catecholaminergic signaling pathway were genotyped. A subset (121 IBS, 209 HCs) underwent structural brain imaging (magnetic resonance imaging [MRI]). Logistic and linear regressions evaluated each SNP separately and their interactions with EALs in predicting IBS and GI symptom severity, respectively. General linear models determined grey matter (GM) alterations from the SNPs and EALs that were predictive of IBS. RESULTS 1) DIAGNOSIS: There were no statistically significant associations between the SNPs and IBS status with or without the interaction with EAL after adjusting for multiple comparisons. 2) SYMPTOMS: GI symptom severity was associated with ADRA1D rs1556832 (P = 0.010). 3) Brain morphometry: In IBS, the homozygous genotype of the major ADRA1D allele was associated with GM increases in somatosensory regions (FDR q = 0.022), left precentral gyrus (q = 0.045), and right hippocampus (q = 0.009). In individuals with increasing sexual abuse scores, the ADRAβ2 SNP was associated with GM changes in the left posterior insula (q = 0.004) and left putamen volume (q = 0.029). CONCLUSION In IBS, catecholaminergic SNPs are associated with symptom severity and morphological changes in brain regions concerned with sensory processing and modulation and affect regulation. Thus, certain adrenergic receptor genes may facilitate or worsen IBS symptoms.
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Affiliation(s)
- Alexa Orand
- Oppenheimer Center for the Neurobiology of Stress, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America
| | - Arpana Gupta
- Oppenheimer Center for the Neurobiology of Stress, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America
| | - Wendy Shih
- Department of Biostatistics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America
| | - Angela P. Presson
- Department of Biostatistics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America
- Division of Epidemiology, Department of Internal Medicine, University of Utah, Salt Lake City, Utah, United States of America
| | - Christian Hammer
- Institute of Human Genetics, Department of Human Molecular Genetics, University of Heidelberg, Heidelberg, Germany
| | - Beate Niesler
- Institute of Human Genetics, Department of Human Molecular Genetics, University of Heidelberg, Heidelberg, Germany
| | - Nuwanthi Heendeniya
- Oppenheimer Center for the Neurobiology of Stress, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America
| | - Emeran A. Mayer
- Oppenheimer Center for the Neurobiology of Stress, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America
| | - Lin Chang
- Oppenheimer Center for the Neurobiology of Stress, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America
- * E-mail:
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Lee YT, Hu LY, Shen CC, Huang MW, Tsai SJ, Yang AC, Hu CK, Perng CL, Huang YS, Hung JH. Risk of Psychiatric Disorders following Irritable Bowel Syndrome: A Nationwide Population-Based Cohort Study. PLoS One 2015. [PMID: 26222511 PMCID: PMC4519183 DOI: 10.1371/journal.pone.0133283] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Background Irritable bowel syndrome (IBS) is the most common functional gastrointestinal (GI) disorder observed in patients who visit general practitioners for GI-related complaints. A high prevalence of psychiatric comorbidities, particularly anxiety and depressive disorders, has been reported in patients with IBS. However, a clear temporal relationship between IBS and psychiatric disorders has not been well established. Objective We explored the relationship between IBS and the subsequent development of psychiatric disorders including schizophrenia, bipolar disorder, depressive disorder, anxiety disorder, and sleep disorder. Methods We selected patients who were diagnosed with IBS caused by gastroenteritis, according to the data in the Taiwan National Health Insurance Research Database. A comparison cohort was formed of patients without IBS who were matched according to age and sex. The incidence rate and the hazard ratios (HRs) of subsequent new-onset psychiatric disorders were calculated for both cohorts, based on psychiatrist diagnoses. Results The IBS cohort consisted of 4689 patients, and the comparison cohort comprised 18756 matched control patients without IBS. The risks of depressive disorder (HR = 2.71, 95% confidence interval [CI] = 2.30–3.19), anxiety disorder (HR = 2.89, 95% CI = 2.42–3.46), sleep disorder (HR = 2.47, 95% CI = 2.02–3.02), and bipolar disorder (HR = 2.44, 95% CI = 1.34–4.46) were higher in the IBS cohort than in the comparison cohort. In addition, the incidence of newly diagnosed depressive disorder, anxiety disorder, and sleep disorder remained significantly increased in all of the stratified follow-up durations (0–1, 1–5, ≥5 y). Conclusions IBS may increase the risk of subsequent depressive disorder, anxiety disorder, sleep disorder, and bipolar disorder. The risk ratios are highest for these disorders within 1 year of IBS diagnosis, but the risk remains statistically significant for more than 5 years. Clinicians should pay particular attention to psychiatric comorbidities in IBS patients.
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Affiliation(s)
- Yao-Tung Lee
- Department of Psychiatry, Taipei Medical University, Shuang-Ho Hospital, New Taipei City, Taiwan
| | - Li-Yu Hu
- Department of Psychiatry, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Cheng-Che Shen
- Department of Psychiatry, Chiayi Branch, Taichung Veterans General Hospital, Chiayi, Taiwan
- Department of information magagement, National Chung-Cheng University, Chiayi, Taiwan
- School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Min-Wei Huang
- Bali Psychiatric Center, Ministry of Health and Welfare, New Taipei, Taiwan
| | - Shih-Jen Tsai
- School of Medicine, National Yang-Ming University, Taipei, Taiwan
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Albert C. Yang
- School of Medicine, National Yang-Ming University, Taipei, Taiwan
- Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chang-Kuo Hu
- Division of Neurosurgery, Department of surgery, Chiayi Branch, Taichung Veterans General Hospital, Chiayi, Taiwan
| | - Chin-Lin Perng
- School of Medicine, National Yang-Ming University, Taipei, Taiwan
- Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yi-Shin Huang
- School of Medicine, National Yang-Ming University, Taipei, Taiwan
- Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Jeng-Hsiu Hung
- Department of Obstetrics and Gynecology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taipei, Taiwan
- School of Medicine, Tzu Chi University, Hualien, Taiwan
- * E-mail:
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Kennedy PJ, Allen AP, O'Neill A, Quigley EMM, Cryan JF, Dinan TG, Clarke G. Acute tryptophan depletion reduces kynurenine levels: implications for treatment of impaired visuospatial memory performance in irritable bowel syndrome. Psychopharmacology (Berl) 2015; 232:1357-71. [PMID: 25338777 DOI: 10.1007/s00213-014-3767-z] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2014] [Accepted: 10/06/2014] [Indexed: 12/18/2022]
Abstract
RATIONALE A visuospatial episodic memory impairment has recently been identified in irritable bowel syndrome. Increased tryptophan metabolism along the kynurenine pathway has also been reported in irritable bowel syndrome, which may play a role in altered cognitive performance as peripheral kynurenine can cross the blood brain barrier and lead to the production of neuroactive metabolites, which modulate glutamatergic and cholinergic signalling, key neurotransmitter systems involved in cognitive function. OBJECTIVES Utilising the acute tryptophan depletion (ATD) protocol, the aim of this study was to examine if manipulating peripheral levels of tryptophan regulates cognitive performance in irritable bowel syndrome and also to determine for the first time if the ATD protocol alters kynurenine supply to the central nervous system. METHODS In this double-blind, placebo-controlled, crossover design study, nine female patients with irritable bowel syndrome and 14 matched female healthy controls participant completed a range of tests from the CANTAB(®) following ATD and placebo. Plasma tryptophan and kynurenine, self-report measures of gastrointestinal symptoms, mood and arousal were determined pre- and post-treatment on each study day. RESULTS Following placebo (p = 0.016) but not ATD (p > 0.05), patients with irritable bowel syndrome exhibited impaired visuospatial memory performance (Paired Associates Learning (PAL) test). In addition, ATD significantly decreased (p < 0.001) and placebo significantly increased (p < 0.001) plasma kynurenine levels in both groups. CONCLUSIONS Manipulating peripheral tryptophan and kynurenine levels using ATD modulates hippocampal-mediated cognitive performance in irritable bowel syndrome but not healthy controls. These data may have important implications for reducing cognitive impairment in irritable bowel syndrome.
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Affiliation(s)
- Paul J Kennedy
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
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Hashimoto T, Kitajo K, Kajihara T, Ueno K, Suzuki C, Asamizuya T, Iriki A. Neural correlates of electrointestinography: Insular activity modulated by signals recorded from the abdominal surface. Neuroscience 2015; 289:1-8. [DOI: 10.1016/j.neuroscience.2014.12.057] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2014] [Revised: 11/07/2014] [Accepted: 12/27/2014] [Indexed: 01/08/2023]
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Interactions of early adversity with stress-related gene polymorphisms impact regional brain structure in females. Brain Struct Funct 2015; 221:1667-79. [PMID: 25630611 DOI: 10.1007/s00429-015-0996-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2014] [Accepted: 01/21/2015] [Indexed: 12/17/2022]
Abstract
Early adverse life events (EALs) have been associated with regional thinning of the subgenual cingulate cortex (sgACC), a brain region implicated in the development of disorders of mood and affect, and often comorbid functional pain disorders, such as irritable bowel syndrome (IBS). Regional neuroinflammation related to chronic stress system activation has been suggested as a possible mechanism underlying these neuroplastic changes. However, the interaction of genetic and environmental factors in these changes is poorly understood. The current study aimed to evaluate the interactions of EALs and candidate gene polymorphisms in influencing thickness of the sgACC. 210 female subjects (137 healthy controls; 73 IBS) were genotyped for stress and inflammation-related gene polymorphisms. Genetic variation with EALs, and diagnosis on sgACC thickness was examined, while controlling for race, age, and total brain volume. Compared to HCs, IBS had significantly reduced sgACC thickness (p = 0.03). Regardless of disease group (IBS vs. HC), thinning of the left sgACC was associated with a significant gene-gene environment interaction between the IL-1β genotype, the NR3C1 haplotype, and a history of EALs (p = 0.05). Reduced sgACC thickness in women with the minor IL-1β allele, was associated with EAL total scores regardless of NR3C1 haplotype status (p = 0.02). In subjects homozygous for the major IL-1β allele, reduced sgACC with increasing levels of EALs was seen only with the less common NR3C1 haplotype (p = 0.02). These findings support an interaction between polymorphisms related to stress and inflammation and early adverse life events in modulating a key region of the emotion arousal circuit.
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Anxiety and depression comorbidities in irritable bowel syndrome (IBS): a systematic review and meta-analysis. Eur Arch Psychiatry Clin Neurosci 2014; 264:651-60. [PMID: 24705634 DOI: 10.1007/s00406-014-0502-z] [Citation(s) in RCA: 390] [Impact Index Per Article: 35.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Accepted: 03/26/2014] [Indexed: 12/17/2022]
Abstract
Irritable bowel syndrome (IBS) has been associated with high prevalence of psychological disorders. However, it remains unclear whether IBS and each of its subtypes (predominant diarrhea IBS-D, constipation IBS-C, mixed IBS-M) are associated with higher anxiety and depressive symptoms levels. This study aimed to determine the associations of IBS and each of its subtypes with anxiety and/or depression. We conducted a systematic review and meta-analysis using five electronic databases (PubMed, PsychINFO, BIOSIS, Science Direct, and Cochrane CENTRAL). We selected case-control studies comparing anxiety and depression levels of patients with IBS to healthy controls, using standardized rating scales. Outcomes were measured as random pooled standardized mean differences (SMD). Ten studies were included in our analysis (885 patients and 1,384 healthy controls). Patients with IBS had significant higher anxiety and depression levels than controls (respectively, SMD = 0.76, 95 % CI 0.47; 0.69, p < 0.01, I2 = 81.7 % and SMD = 0.80, 95 % CI 0.42; 1.19, p < 0.01, I2 = 90.7 %). This significant difference was confirmed for patients with IBS-C and -D subtypes for anxiety, and only in IBS-D patients for depression. However, other IBS subtypes had a statistical trend to be associated with both anxiety and depressive symptomatology, which suggests a lack of power due to the small number of studies included. Patients with IBS had significantly higher levels of anxiety and depression than healthy controls. Anxiety and depression symptomatology should be systematically checked and treated in IBS patients, as psychological factors are important moderators of symptom severity, symptom persistence, decisions to seek treatment, and response to treatment.
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Abstract
The gastrointestinal tract is innervated by several distinct populations of neurons, whose cell bodies either reside within (intrinsic) or outside (extrinsic) the gastrointestinal wall. Normally, most individuals are unaware of the continuous, complicated functions of these neurons. However, for patients with gastrointestinal disorders, such as IBD and IBS, altered gastrointestinal motility, discomfort and pain are common, debilitating symptoms. Although bouts of intestinal inflammation underlie the symptoms associated with IBD, increasing preclinical and clinical evidence indicates that infection and inflammation are also key risk factors for the development of other gastrointestinal disorders. Notably, a strong correlation exists between prior exposure to gut infection and symptom occurrence in IBS. This Review discusses the evidence for neuroplasticity (structural, synaptic or intrinsic changes that alter neuronal function) affecting gastrointestinal function. Such changes are evident during inflammation and, in many cases, long after healing of the damaged tissues, when the nervous system fails to reset back to normal. Neuroplasticity within distinct populations of neurons has a fundamental role in the aberrant motility, secretion and sensation associated with common clinical gastrointestinal disorders. To find appropriate therapeutic treatments for these disorders, the extent and time course of neuroplasticity must be fully appreciated.
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Abstract
The past decade has witnessed an explosion of knowledge regarding the vast microbial community that resides within our intestine-the gut microbiota. The topic has generated great expectations in terms of gaining a better understanding of disorders ranging from IBD to metabolic disorders and obesity. IBS is a condition for which investigators have long been in search of plausible underlying pathogeneses and it is inevitable that altered composition or function of the gut microbiota will be considered as a potential aetiological factor in at least a subset of patients with IBS. This Review describes the evidence implicating the gut microbiota in not only the expression of the intestinal manifestations of IBS, but also the psychiatric morbidity that coexists in up to 80% of patients with IBS. The evidence described herein ranges from proof-of-concept studies in animals to observational studies and clinical trials in humans. The gut microbiota is subject to influences from a diverse range of factors including diet, antibiotic usage, infection and stress. These factors have previously been implicated in the pathophysiology of IBS and further prompt consideration of a role for the gut microbiota in IBS.
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Muscatello MRA, Bruno A, Scimeca G, Pandolfo G, Zoccali RA. Role of negative affects in pathophysiology and clinical expression of irritable bowel syndrome. World J Gastroenterol 2014; 20:7570-7586. [PMID: 24976697 PMCID: PMC4069288 DOI: 10.3748/wjg.v20.i24.7570] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2013] [Revised: 01/18/2014] [Accepted: 04/03/2014] [Indexed: 02/06/2023] Open
Abstract
Irritable bowel syndrome (IBS) is regarded as a multifactorial disease in which alterations in the brain-gut axis signaling play a major role. The biopsychosocial model applied to the understanding of IBS pathophysiology assumes that psychosocial factors, interacting with peripheral/central neuroendocrine and immune changes, may induce symptoms of IBS, modulate symptom severity, influence illness experience and quality of life, and affect outcome. The present review focuses on the role of negative affects, including depression, anxiety, and anger, on pathogenesis and clinical expression of IBS. The potential role of the autonomic nervous system, stress-hormone system, and immune system in the pathophysiology of both negative affects and IBS are taken into account. Psychiatric comorbidity and subclinical variations in levels of depression, anxiety, and anger are further discussed in relation to the main pathophysiological and symptomatic correlates of IBS, such as sensorimotor functions, gut microbiota, inflammation/immunity, and symptom reporting.
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Adult cyclical vomiting syndrome: a disorder of allostatic regulation? Exp Brain Res 2014; 232:2541-7. [DOI: 10.1007/s00221-014-3939-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2014] [Accepted: 03/25/2014] [Indexed: 10/25/2022]
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Zhang C, Rui YY, Zhou YY, Ju Z, Zhang HH, Hu CY, Xiao Y, Xu GY. Adrenergic β2-receptors mediates visceral hypersensitivity induced by heterotypic intermittent stress in rats. PLoS One 2014; 9:e94726. [PMID: 24733123 PMCID: PMC3986230 DOI: 10.1371/journal.pone.0094726] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2014] [Accepted: 03/18/2014] [Indexed: 12/12/2022] Open
Abstract
Chronic visceral pain in patients with irritable bowel syndrome (IBS) has been difficult to treat effectively partially because its pathophysiology is not fully understood. Recent studies show that norepinephrine (NE) plays an important role in the development of visceral hypersensitivity. In this study, we designed to investigate the role of adrenergic signaling in visceral hypersensitivity induced by heterotypical intermittent stress (HIS). Abdominal withdrawal reflex scores (AWRs) used as visceral sensitivity were determined by measuring the visceromoter responses to colorectal distension. Colon-specific dorsal root ganglia neurons (DRGs) were labeled by injection of DiI into the colon wall and were acutely dissociated for whole-cell patch-clamp recordings. Blood plasma level of NE was measured using radioimmunoassay kits. The expression of β2-adrenoceptors was measured by western blotting. We showed that HIS-induced visceral hypersensitivity was attenuated by systemic administration of a β-adrenoceptor antagonist propranolol, in a dose-dependent manner, but not by a α-adrenoceptor antagonist phentolamine. Using specific β-adrenoceptor antagonists, HIS-induced visceral hypersensitivity was alleviated by β2 adrenoceptor antagonist but not by β1- or β3-adrenoceptor antagonist. Administration of a selective β2-adrenoceptor antagonist also normalized hyperexcitability of colon-innervating DRG neurons of HIS rats. Furthermore, administration of β-adrenoceptor antagonist suppressed sustained potassium current density (IK) without any alteration of fast-inactivating potassium current density (IA). Conversely, administration of NE enhanced the neuronal excitability and produced visceral hypersensitivity in healthy control rats, and blocked by β2-adrenoceptor antagonists. In addition, HIS significantly enhanced the NE concentration in the blood plasma but did not change the expression of β2-adrenoceptor in DRGs and the muscularis externa of the colon. The present study might provide a potential molecular target for therapy of visceral hypersensitivity in patents with IBS.
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Affiliation(s)
- Chunhua Zhang
- Department of Gastroenterology, the Second Affiliated Hospital, Soochow University, Suzhou, P. R. China
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Department of Neurobiology, Soochow University, Suzhou, P. R. China
| | - Yun-Yun Rui
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Department of Neurobiology, Soochow University, Suzhou, P. R. China
| | - Yuan-Yuan Zhou
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Department of Neurobiology, Soochow University, Suzhou, P. R. China
| | - Zhong Ju
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Department of Neurobiology, Soochow University, Suzhou, P. R. China
| | - Hong-Hong Zhang
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Department of Neurobiology, Soochow University, Suzhou, P. R. China
| | - Chuang-Ying Hu
- Department of Gastroenterology, the Second Affiliated Hospital, Soochow University, Suzhou, P. R. China
| | - Ying Xiao
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Department of Neurobiology, Soochow University, Suzhou, P. R. China
| | - Guang-Yin Xu
- Department of Gastroenterology, the Second Affiliated Hospital, Soochow University, Suzhou, P. R. China
- Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Department of Neurobiology, Soochow University, Suzhou, P. R. China
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Early adverse life events and resting state neural networks in patients with chronic abdominal pain: evidence for sex differences. Psychosom Med 2014; 76:404-12. [PMID: 25003944 PMCID: PMC4113723 DOI: 10.1097/psy.0000000000000089] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Early adverse life events (EALs) and sex have been identified as vulnerability factors for the development of several stress-sensitive disorders, including irritable bowel syndrome (IBS). We aimed to identify disease and sex-based differences in resting state (RS) connectivity associated with EALs in individuals with IBS. METHOD A history of EALs before age 18 years was assessed using the early trauma inventory. RS functional magnetic resonance imaging was used to identify patterns of intrinsic brain oscillations in the form of RS networks in 168 people (58 people with IBS, 28 were female; 110 healthy controls, 72 were female). Partial least squares, a multivariate analysis technique, was used to identify disease and sex differences and possible correlations between EALs and functional connectivity in six identified RS networks. RESULTS Associations between EALs and RS networks were observed. Although a history of EALs was associated with altered connectivity in the salience/executive control network to a similar extent in male and female patients with IBS (bootstrap ratio = 3.28-5.61; p = .046), male patients with IBS demonstrated additional EAL-related alterations in the cerebellar network (bootstrap ratio = 3.92-6.79; p = .022). CONCLUSIONS This cross sectional study identified correlations between RS networks and EALs in individuals with IBS. These results suggest that exposure to EALs before age 18 years can shape adult RS in both male and female patients in the salience/executive control network, a brain network that has been implicated in the pathophysiology of central pain amplification.
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Charrua A, Pinto R, Taylor A, Canelas A, Ribeiro-da-Silva A, Cruz CD, Birder LA, Cruz F. Can the adrenergic system be implicated in the pathophysiology of bladder pain syndrome/interstitial cystitis? A clinical and experimental study. Neurourol Urodyn 2013; 34:489-96. [PMID: 24375689 DOI: 10.1002/nau.22542] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2013] [Accepted: 11/29/2013] [Indexed: 12/20/2022]
Abstract
AIMS To evaluate sympathetic system activity in bladder pain syndrome/interstitial cystitis (BPS/IC) patients and to investigate if chronic adrenergic stimulation in intact rats induces BPS/IC-like bladder modifications. METHODS Clinical study--In BPS/IC patients and aged and body mass index matched volunteers TILT test was undertaken and catecholamines were measured in plasma and 24 hr urine samples. Experimental study--Phenylephrine was injected subcutaneously (14 days) to female Wistar rats. Pain behavior, spinal Fos expression, urinary spotting, number of fecal pellets expelled, frequency of reflex bladder contractions, and urothelial height were analyzed. Urothelium permeability was investigated by trypan blue staining. Immunoreactivity against caspase 3 and bax were studied in the urothelium and against alpha-1-adrenoreceptor and TRPV1 in suburothelial nerves. Mast cell number was determined in the sub-urothelium. In rats with lipopolysaccharide-induced cystitis, urinary catecholamines, and Vesicular Monoamine Transporter 2 (VMAT2) expression in bladder nerves were analyzed. RESULTS The TILT test showed an increase of sympathetic activity. Noradrenaline levels in blood at resting conditions and in 24-hr urine samples were higher in BPS/IC patients. Phenylephrine administration increased visceral pain, spinal Fos expression, bladder reflex activity, urinary spotting and the number of expelled fecal pellets. The mucosa showed urothelial thinning and increased immunoreactivity for caspase 3 and bax. Trypan blue staining was only observed in phenylephrine treated animals. Suburothelial nerves co-expressed alpha1 and TRPV1. Mastocytosis was present in the suburothelium. Cystitis increased sympathetic nerve density and urinary noradrenaline levels. CONCLUSIONS Excessive adrenergic stimulation of the bladder may contribute to the pathophysiological mechanisms of BPS/IC.
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Affiliation(s)
- Ana Charrua
- Department of Experimental Biology, Faculty of Medicine, University of Porto, Porto, Portugal.,IBMC - Instituto de Biologia Molecular e Celular, University of Porto, Porto, Portugal.,Department of Renal, Urologic and Infectious Disease, Faculty of Medicine, University of Porto, Porto, Portugal.,Department of Urology, S. João Hospital, Porto, Portugal
| | - Rui Pinto
- IBMC - Instituto de Biologia Molecular e Celular, University of Porto, Porto, Portugal.,Department of Renal, Urologic and Infectious Disease, Faculty of Medicine, University of Porto, Porto, Portugal.,Department of Urology, S. João Hospital, Porto, Portugal
| | - Anna Taylor
- Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
| | - André Canelas
- Department of Experimental Biology, Faculty of Medicine, University of Porto, Porto, Portugal
| | | | - Célia D Cruz
- Department of Experimental Biology, Faculty of Medicine, University of Porto, Porto, Portugal.,IBMC - Instituto de Biologia Molecular e Celular, University of Porto, Porto, Portugal
| | - Lori Ann Birder
- Departments of Medicine and Pharmacology-Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Francisco Cruz
- IBMC - Instituto de Biologia Molecular e Celular, University of Porto, Porto, Portugal.,Department of Renal, Urologic and Infectious Disease, Faculty of Medicine, University of Porto, Porto, Portugal.,Department of Urology, S. João Hospital, Porto, Portugal
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