|
1
|
Kilpatrick LA, Church A, Meriwether D, Mahurkar-Joshi S, Li VW, Sohn J, Reist J, Labus JS, Dong T, Jacobs JP, Naliboff BD, Chang L, Mayer EA. Differential brainstem connectivity according to sex and menopausal status in healthy male and female individuals. Biol Sex Differ 2025; 16:25. [PMID: 40251694 PMCID: PMC12007138 DOI: 10.1186/s13293-025-00709-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 04/04/2025] [Indexed: 04/20/2025] Open
Abstract
BACKGROUND Brainstem nuclei play a critical role in both ascending monoaminergic modulation of cortical function and arousal, and in descending bulbospinal pain modulation. Even though sex-related differences in the function of both systems have been reported in animal models, a complete understanding of sex differences, as well as menopausal effects, in brainstem connectivity in humans is lacking. This study evaluated resting-state connectivity of the dorsal raphe nucleus, right and left locus coeruleus complex (LCC), and periaqueductal gray (PAG) according to sex and menopausal status in healthy individuals. In addition, relationships between systemic estrogen levels and brainstem-network connectivity were examined in a subset of participants. METHODS Resting-state fMRI was performed in 47 healthy male (age, 31.2 ± 8.0 years), 53 healthy premenopausal female (age, 24.7 ± 7.3 years; 22 in the follicular phase, 31 in the luteal phase), and 20 postmenopausal female participants (age, 54.6 ± 7.2 years). Permutation Analysis of Linear Models (5000 permutations) was used to evaluate differences in brainstem-network connectivity according to sex and menopausal status, controlling for age. In 10 males and 17 females (9 premenopausal; 8 postmenopausal), estrogen and estrogen metabolite levels in plasma and stool were determined by liquid chromatography-mass spectrometry/mass spectrometry. Relationships between estrogen levels and brainstem-network connectivity were evaluated by partial least squares analysis. RESULTS Left LCC-executive control network connectivity showed an overall sex difference (p = 0.02), with higher connectivity in females than in males; however, this was mainly due to differences between males and premenopausal females (p = 0.008). Additional sex differences were dependent on menopausal status: PAG-default mode network (DMN) connectivity was higher in postmenopausal females than in males (p = 0.04), and PAG-sensorimotor network (SMN) connectivity was higher in premenopausal females than in males (p = 0.03) and postmenopausal females (p = 0.007). Notably, higher free 2-hydroxyestrone levels in stool were reliably associated with higher PAG-SMN and PAG-DMN connectivity in premenopausal females (p < 0.01). CONCLUSIONS Healthy females show higher brainstem-network connectivity involved in cognitive control, sensorimotor function, and self-relevant processes than males, dependent on their menopausal status. Further, 2-hydroxyestrone, implicated in pain, may modulate PAG connectivity in premenopausal females. These findings may relate to differential vulnerabilities to chronic stress-sensitive disorders at different life stages.
Collapse
Affiliation(s)
- Lisa A Kilpatrick
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
- G. Oppenheimer Center for Neurobiology of Stress and Resilience, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
- Goodman-Luskin Microbiome Center, University of California Los Angeles, Los Angeles, CA, USA
| | - Arpana Church
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
- G. Oppenheimer Center for Neurobiology of Stress and Resilience, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
- Goodman-Luskin Microbiome Center, University of California Los Angeles, Los Angeles, CA, USA
| | - David Meriwether
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Swapna Mahurkar-Joshi
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
- G. Oppenheimer Center for Neurobiology of Stress and Resilience, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
- Goodman-Luskin Microbiome Center, University of California Los Angeles, Los Angeles, CA, USA
| | - Vince W Li
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Jessica Sohn
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Juliana Reist
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
- G. Oppenheimer Center for Neurobiology of Stress and Resilience, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Jennifer S Labus
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
- G. Oppenheimer Center for Neurobiology of Stress and Resilience, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
- Goodman-Luskin Microbiome Center, University of California Los Angeles, Los Angeles, CA, USA
- Brain Research Institute, Gonda (Goldschmied) Neuroscience and Genetics Research Center, University of California Los Angeles, Los Angeles, CA, USA
| | - Tien Dong
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
- G. Oppenheimer Center for Neurobiology of Stress and Resilience, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
- Goodman-Luskin Microbiome Center, University of California Los Angeles, Los Angeles, CA, USA
| | - Jonathan P Jacobs
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
- G. Oppenheimer Center for Neurobiology of Stress and Resilience, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
- Goodman-Luskin Microbiome Center, University of California Los Angeles, Los Angeles, CA, USA
- Division of Gastroenterology, Hepatology and Parenteral Nutrition, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA
| | - Bruce D Naliboff
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
- G. Oppenheimer Center for Neurobiology of Stress and Resilience, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
- Goodman-Luskin Microbiome Center, University of California Los Angeles, Los Angeles, CA, USA
| | - Lin Chang
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
- G. Oppenheimer Center for Neurobiology of Stress and Resilience, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
- Goodman-Luskin Microbiome Center, University of California Los Angeles, Los Angeles, CA, USA.
| | - Emeran A Mayer
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
- G. Oppenheimer Center for Neurobiology of Stress and Resilience, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
- Goodman-Luskin Microbiome Center, University of California Los Angeles, Los Angeles, CA, USA.
| |
Collapse
|
|
2
|
Fang Q, Yu L, Tian F, Chen W, Zhai Q, Zhang H. Randomized controlled trials of the effects of capsaicin or menthol on irritable bowel syndrome: a systematic review and meta-analysis. Food Funct 2024; 15:11865-11874. [PMID: 39576289 DOI: 10.1039/d4fo04268a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/10/2024]
Abstract
Irritable bowel syndrome (IBS) is a common intestinal disease characterized by abdominal pain, abdominal distension and irregular defecation frequency, and it has had a high incidence and low cure rate in recent years. Visceral hypersensitivity (VH) is one of the main physiological indicators of IBS, and TRPV1 and TRPM8 (transient receptor potential vanilloid 1 and melastatin 8) play crucial roles in VH and are widely distributed in the intestine, significantly impacting abdominal pain in IBS patients. Under the guidance of PRISMA, four databases were systematically searched at the outset, including PubMed, Web of Science, Embase, and Cochrane Library. Randomized controlled trials (RCTs) reporting specific abdominal pain scores (rather than the incidence rate) in IBS patients receiving capsaicin or menthol (agonist of TRPV1 and TRPM8) interventions were included. A meta-analysis was conducted on the retrieved studies, which consisted of three articles on capsaicin and five articles on menthol, to compare the efficacy of capsaicin and menthol in alleviating abdominal pain in IBS patients under conditions of low heterogeneity. The results demonstrated that menthol had a significant effect in relieving abdominal pain in IBS patients. Conversely, although the effect of capsaicin was not statistically significant, two studies involving long-term capsaicin intervention suggested its potential to reduce VH and subsequently relieve abdominal pain, which may be attributed to the up-regulation of the TRPV1 receptor in the gastrointestinal tract of individuals with IBS.
Collapse
Affiliation(s)
- Qingying Fang
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, Jiangsu, 214122, P. R. China.
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, 214122, P. R. China
| | - Leilei Yu
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, Jiangsu, 214122, P. R. China.
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, 214122, P. R. China
| | - Fengwei Tian
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, Jiangsu, 214122, P. R. China.
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, 214122, P. R. China
| | - Wei Chen
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, Jiangsu, 214122, P. R. China.
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, 214122, P. R. China
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi, Jiangsu 214122, P. R. China
| | - Qixiao Zhai
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, Jiangsu, 214122, P. R. China.
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, 214122, P. R. China
| | - Hao Zhang
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, Jiangsu, 214122, P. R. China.
- School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, 214122, P. R. China
| |
Collapse
|
|
3
|
Zheng HN, Zhi YR, Su YS, Jiang JY, Zhang HZ, Cao F, Wang Y, Chi Y, Zhang Y. Dectin-1 induces TRPV1 sensitization and contributes to visceral hypersensitivity of irritable bowel syndrome in male mice. Eur J Pain 2024; 28:1811-1826. [PMID: 38953581 DOI: 10.1002/ejp.2311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Revised: 06/05/2024] [Accepted: 06/20/2024] [Indexed: 07/04/2024]
Abstract
BACKGROUND Visceral hypersensitivity is considered the core pathophysiological mechanism that causes abdominal pain in patients with irritable bowel syndrome (IBS). Fungal dysbiosis has been proved to contribute to visceral hypersensitivity in IBS patients. However, the underlying mechanisms for Dectin-1, a major fungal recognition receptor, in visceral hypersensitivity are poorly understood. This study aimed to explore the role of Dectin-1 in visceral hypersensitivity and elucidate the impact of Dectin-1 activity on the function of transient receptor potential vanilloid type 1 (TRPV1). METHODS Visceral hypersensitivity model was established by the intracolonic administration of 0.1 mL TNBS (130 μg/mL in 30% ethanol) in the male mice. Fluconazole and nystatin were used as fungicides. Laminarin, a Dectin-1 antagonist and gene knockout (Clec7a-/-) mice were used to interrupt the function of Dectin-1. Colorectal distension-electromyogram recording was performed to assess visceral sensitivity. Immunostaining experiment was performed to determine the localization of Dectin-1 in dorsal root ganglion (DRG) neurons. Calcium imaging study was performed to assay TRPV1-mediated calcium influx in acutely dissociated DRG neurons. RESULTS Pretreatment with fungicides, administration of laminarin or genetic deletion of Clec7a alleviated TNBS-induced visceral hypersensitivity in male mice. The expression of Dectin-1 was upregulated in the DRG and colon of TNBS-treated mice. Colocalization of Dectin-1 and TRPV1 was observed in DRG neurons. Importantly, pretreatment with curdlan, a Dectin-1 agonist, increased TRPV1-mediated calcium influx. CONCLUSIONS Dectin-1 contributes to visceral hypersensitivity in IBS or in inflammatory bowel disease in remission and activation of Dectin-1 induces TRPV1 sensitization. SIGNIFICANCE STATEMENT This work provides direct evidence for the functional regulation of TRPV1 channel by Dectin-1 activity, proposing a new mechanism underlying TRPV1 sensitization. Control of intestinal fungi might be beneficial for the treatment of refractory abdominal pain in patients with IBS or IBD in remission.
Collapse
Affiliation(s)
- Hao-Nan Zheng
- Department of Gastroenterology, Peking University First Hospital, Beijing, China
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China
| | - Yu-Ru Zhi
- Neuroscience Research Institute, Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing, China
- Key Laboratory for Neuroscience, Ministry of Education/National Health Commission of China, Peking University, Beijing, China
| | - Yang-Shuai Su
- Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jin-Yan Jiang
- Neuroscience Research Institute, Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing, China
- Key Laboratory for Neuroscience, Ministry of Education/National Health Commission of China, Peking University, Beijing, China
| | - Hao-Zhou Zhang
- Neuroscience Research Institute, Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing, China
- Key Laboratory for Neuroscience, Ministry of Education/National Health Commission of China, Peking University, Beijing, China
| | - Feng Cao
- Neuroscience Research Institute, Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing, China
- Key Laboratory for Neuroscience, Ministry of Education/National Health Commission of China, Peking University, Beijing, China
| | - Yun Wang
- Neuroscience Research Institute, Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing, China
- Key Laboratory for Neuroscience, Ministry of Education/National Health Commission of China, Peking University, Beijing, China
- PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China
| | - Yan Chi
- Department of Gastroenterology, Peking University First Hospital, Beijing, China
| | - Ying Zhang
- Neuroscience Research Institute, Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing, China
- Key Laboratory for Neuroscience, Ministry of Education/National Health Commission of China, Peking University, Beijing, China
| |
Collapse
|
|
4
|
Van Remoortel S, Hussein H, Boeckxstaens G. Mast cell modulation: A novel therapeutic strategy for abdominal pain in irritable bowel syndrome. Cell Rep Med 2024; 5:101780. [PMID: 39378882 PMCID: PMC11513802 DOI: 10.1016/j.xcrm.2024.101780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 07/10/2024] [Accepted: 09/17/2024] [Indexed: 10/10/2024]
Abstract
Irritable bowel syndrome (IBS) is one of the most prevalent gastrointestinal disorders characterized by recurrent abdominal pain and an altered defecation pattern. Chronic abdominal pain represents the hallmark IBS symptom and is reported to have the most bothersome impact on the patient's quality of life. Unfortunately, effective therapeutic strategies reducing abdominal pain are lacking, mainly attributed to a limited understanding of the contributing mechanisms. In the past few years, exciting new insights have pointed out that altered communication between gut immune cells and pain-sensing nerves acts as a hallmark driver of IBS-related abdominal pain. In this review, we aim to summarize our current knowledge on altered neuro-immune crosstalk as the main driver of altered pain signaling, with a specific focus on altered mast cell functioning herein, and highlight the relevance of targeting mast cell-mediated mechanisms as a novel therapeutic strategy for chronic abdominal pain in IBS patients.
Collapse
Affiliation(s)
- Samuel Van Remoortel
- Translational Research Centre for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium
| | - Hind Hussein
- Translational Research Centre for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium
| | - Guy Boeckxstaens
- Translational Research Centre for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium.
| |
Collapse
|
|
5
|
Chen J, Sun W, Zhu Y, Zhao F, Deng S, Tian M, Wang Y, Gong Y. TRPV1: The key bridge in neuroimmune interactions. JOURNAL OF INTENSIVE MEDICINE 2024; 4:442-452. [PMID: 39310069 PMCID: PMC11411435 DOI: 10.1016/j.jointm.2024.01.008] [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: 10/25/2023] [Revised: 01/07/2024] [Accepted: 01/23/2024] [Indexed: 09/25/2024]
Abstract
The nervous and immune systems are crucial in fighting infections and inflammation and in maintaining immune homeostasis. The immune and nervous systems are independent, yet tightly integrated and coordinated organizations. Numerous molecules and receptors play key roles in enabling communication between the two systems. Transient receptor potential vanilloid subfamily member 1 (TRPV1) is a non-selective cation channel, recently shown to be widely expressed in the neuroimmune axis and implicated in neuropathic pain, autoimmune disorders, and immune cell function. TRPV1 is a key bridge in neuroimmune interactions, allowing for smooth and convenient communication between the two systems. Here, we discuss the coordinated cross-talking between the immune and nervous systems and the functional role and the functioning manner of the TRPV1 involved. We suggest that TRPV1 provides new insights into the collaborative relationship between the nervous and immune systems, highlighting exciting opportunities for advanced therapeutic approaches to treating neurogenic inflammation and immune-mediated diseases.
Collapse
Affiliation(s)
- Jianwei Chen
- Department of Critical Care Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Wenqian Sun
- Department of Critical Care Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Youjia Zhu
- Department of Critical Care Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Feng Zhao
- Department of Critical Care Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Shuixiang Deng
- Department of Critical Care Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Mi Tian
- Department of Critical Care Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Yao Wang
- Department of Critical Care Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Ye Gong
- Department of Critical Care Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
| |
Collapse
|
|
6
|
Thor KB, Marson L, Katofiasc MA, Ricca DJ, Burgard EC. Recent Developments in On-Demand Voiding Therapies. J Pharmacol Exp Ther 2024; 390:302-317. [PMID: 38641354 PMCID: PMC11338280 DOI: 10.1124/jpet.123.002073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 03/28/2024] [Accepted: 03/29/2024] [Indexed: 04/21/2024] Open
Abstract
One cannot survive without regularly urinating and defecating. People with neurologic injury (spinal cord injury, traumatic brain injury, stroke) or disease (multiple sclerosis, Parkinson's disease, spina bifida) and many elderly are unable to voluntarily initiate voiding. The great majority of them require bladder catheters to void urine and "manual bowel programs" with digital rectal stimulation and manual extraction to void stool. Catheter-associated urinary tract infections frequently require hospitalization, whereas manual bowel programs are time consuming (1 to 2 hours) and stigmatizing and cause rectal pain and discomfort. Laxatives and enemas produce defecation, but onset and duration are unpredictable, prolonged, and difficult to control, which can produce involuntary defecation and fecal incontinence. Patients with spinal cord injury (SCI) consider recovery of bladder and bowel function a higher priority than recovery of walking. Bladder and bowel dysfunction are a top reason for institutionalization of elderly. Surveys indicate that convenience, rapid onset and short duration, reliability and predictability, and efficient voiding are priorities of SCI individuals. Despite the severe, unmet medical need, there is no literature regarding on-demand, rapid-onset, short-duration, drug-induced voiding therapies. This article provides in-depth discussion of recent discovery and development of two candidates for on-demand voiding therapies. The first, [Lys3,Gly8,-R-γ-lactam-Leu9]-NKA(3-10) (DTI-117), a neurokinin2 receptor agonist, induces both urination and defecation after systemic administration. The second, capsaicin (DTI-301), is a transient receptor potential cation channel subfamily V member 1 (TRPV1) receptor agonist that induces defecation after intrarectal administration. The review also presents clinical studies of a combination drug therapy administered via iontophoresis and preclinical studies of neuromodulation devices that induce urination and defecation. SIGNIFICANCE STATEMENT: A safe and effective, on-demand, rapid-onset, short-duration, drug-induced, voiding therapy could eliminate or reduce need for bladder catheters, manual bowel programs, and colostomies in patient populations that are unable to voluntarily initiate voiding. People with spinal injury place more importance on restoring bladder and bowel control than restoring their ability to walk. This paradigm-changing therapy would reduce stigmatism and healthcare costs while increasing convenience and quality of life.
Collapse
Affiliation(s)
- Karl B Thor
- Dignify Therapeutics, LLC, Durham, North Carolina
| | | | | | | | | |
Collapse
|
|
7
|
Kilpatrick LA, Gupta A, Meriwether D, Mahurkar-Joshi S, Li VW, Sohn J, Reist J, Labus JS, Dong T, Jacobs JP, Naliboff BD, Chang L, Mayer EA. Differential brainstem connectivity according to sex and menopausal status in healthy men and women. RESEARCH SQUARE 2024:rs.3.rs-4875269. [PMID: 39184081 PMCID: PMC11343298 DOI: 10.21203/rs.3.rs-4875269/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/27/2024]
Abstract
Background Brainstem nuclei play a critical role in both ascending monoaminergic modulation of cortical function and arousal, and in descending bulbospinal pain modulation. Even though sex-related differences in the function of both systems have been reported in animal models, a complete understanding of sex differences, as well as menopausal effects, in brainstem connectivity in humans is lacking. This study evaluated resting-state connectivity of the dorsal raphe nucleus (DRN), right and left locus coeruleus complex (LCC), and periaqueductal gray (PAG) according to sex and menopausal status in healthy individuals. In addition, relationships between systemic estrogen levels and brainstem-network connectivity were examined in a subset of participants. Methods Resting-state fMRI was performed in 50 healthy men (age, 31.2 ± 8.0 years), 53 healthy premenopausal women (age, 24.7 ± 7.3 years; 22 in the follicular phase, 31 in the luteal phase), and 20 postmenopausal women (age, 54.6 ± 7.2 years). Permutation Analysis of Linear Models (5000 permutations) was used to evaluate differences in brainstem-network connectivity according to sex and menopausal status, controlling for age. In 10 men and 17 women (9 premenopausal; 8 postmenopausal), estrogen and estrogen metabolite levels in plasma and stool were determined by liquid chromatography-mass spectrometry/mass spectrometry. Relationships between estrogen levels and brainstem-network connectivity were evaluated by partial least squares analysis. Results Left LCC-executive control network (ECN) connectivity showed an overall sex difference (p = 0.02), with higher connectivity in women than in men; however, this was mainly due to differences between men and pre-menopausal women (p = 0.008). Additional sex differences were dependent on menopausal status: PAG-default mode network (DMN) connectivity was higher in postmenopausal women than in men (p = 0.04), and PAG-sensorimotor network (SMN) connectivity was higher in premenopausal women than in men (p = 0.03) and postmenopausal women (p = 0.007). Notably, higher free 2-hydroxyestrone levels in stool were associated with higher PAG-SMN and PAG-DMN connectivity in premenopausal women (p < 0.01). Conclusions Healthy women show higher brainstem-network connectivity involved in cognitive control, sensorimotor function, and self-relevant processes than men, dependent on their menopausal status. Further, 2-hydroxyestrone, implicated in pain, may modulate PAG connectivity in premenopausal women. These findings may relate to differential vulnerabilities to chronic stress-sensitive disorders at different life stages.
Collapse
|
|
8
|
Ford AC, Vanner S, Kashyap PC, Nasser Y. Chronic Visceral Pain: New Peripheral Mechanistic Insights and Resulting Treatments. Gastroenterology 2024; 166:976-994. [PMID: 38325759 PMCID: PMC11102851 DOI: 10.1053/j.gastro.2024.01.045] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 11/15/2023] [Accepted: 01/05/2024] [Indexed: 02/09/2024]
Abstract
Chronic visceral pain is one of the most common reasons for patients with gastrointestinal disorders, such as inflammatory bowel disease or disorders of brain-gut interaction, to seek medical attention. It represents a substantial burden to patients and is associated with anxiety, depression, reductions in quality of life, and impaired social functioning, as well as increased direct and indirect health care costs to society. Unfortunately, the diagnosis and treatment of chronic visceral pain is difficult, in part because our understanding of the underlying pathophysiologic basis is incomplete. In this review, we highlight recent advances in peripheral pain signaling and specific physiologic and pathophysiologic preclinical mechanisms that result in the sensitization of peripheral pain pathways. We focus on preclinical mechanisms that have been translated into treatment approaches and summarize the current evidence base for directing treatment toward these mechanisms of chronic visceral pain derived from clinical trials. The effective management of chronic visceral pain remains of critical importance for the quality of life of suffers. A deeper understanding of peripheral pain mechanisms is necessary and may provide the basis for novel therapeutic interventions.
Collapse
Affiliation(s)
- Alexander C Ford
- Leeds Institute of Medical Research at St. James's, University of |Leeds, Leeds, United Kingdom; Leeds Gastroenterology Institute, Leeds Teaching Hospitals National Health Service Trust, Leeds, United Kingdom
| | - Stephen Vanner
- Gastrointestinal Diseases Research Unit, Kingston General Hospital, Queen's University, Kingston, Ontario, Canada
| | - Purna C Kashyap
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Yasmin Nasser
- Snyder Institute for Chronic Diseases, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
| |
Collapse
|
|
9
|
Guo X, Lei C, Liang H, An J, Fang Y, Zhang X, Wang Z, Hu C, Jiang X. Chronic Sacral Nerve Stimulation Inhibits Visceral Hypersensitivity in Diarrhea-Predominant Irritable Bowel Syndrome Rats Model. Neuromodulation 2024; 27:295-301. [PMID: 37930296 DOI: 10.1016/j.neurom.2023.08.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 07/08/2023] [Accepted: 08/08/2023] [Indexed: 11/07/2023]
Abstract
OBJECTIVE Sacral nerve stimulation (SNS) is emerging as a novel treatment for irritable bowel syndrome (IBS). However, its effects are limited, and the underlying mechanisms remain largely unknown. MATERIALS AND METHODS In this study, rats were divided into three groups (n = 12 rats per group): 1) the SNS group; 2) the sham SNS group (the sham group for short); and 3) the control group. The SNS and sham groups were exposed to chronic and acute stress to establish an IBS model. Electrode implantation surgery was performed in rats with the IBS model. The SNS group received electrical stimulation for 30 minutes every day for seven days. Abdominal withdrawal reflex (AWR) was used to evaluate the effect of SNS on visceral sensitivity in diarrhea-predominant IBS (IBS-D) rats. The frequency domain of heart rate variability (HRV) was analyzed to assess the effect of SNS on regulating the autonomic function. The expression of transient receptor potential vanilloid 1 (TRPV1) in the colon, spinal cord, and hippocampus was detected by immunohistochemistry to explore the mechanism of SNS in IBS-D rats. RESULTS Compared with the sham group, AWR scores were significantly decreased under different gas volumes of stimulation of 0.4, 0.6, and 0.8 ml for rectal distention in the SNS group (all p < 0.05). However, there was no significant difference <1.0 ml between the two groups (p > 0.05). Compared with the sham group, the frequency domain indexes of HRV were significantly altered. Normalized low-frequency power and low frequency-to-high frequency ratio were significantly decreased, and normalized high-frequency power was significantly increased in the SNS group (all p < 0.05). Moreover, the expression of TRPV1 in the spinal cord and colon in the SNS group was significantly decreased compared with the sham group (both p < 0.05). These results suggested that chronic SNS not only improved the visceral sensitivity and autonomic dysfunction but also decreased the expression of TRPV1 in the spinal cord-gut tissue in IBS-D rats. CONCLUSION Chronic SNS was found to have an inhibitory effect on visceral hypersensitivity in IBS-D rats, providing experimental evidence for its potential clinical application in IBS.
Collapse
Affiliation(s)
- Xiaojuan Guo
- Department of Gastroenterology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Changsheng Lei
- National Engineering Research Center of Neuromodulation, School of Aerospace Engineering, Tsinghua University, Beijing, China
| | - Hanwei Liang
- Department of Gastroenterology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Jiaxu An
- Department of Gastroenterology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Yanbin Fang
- Department of Gastroenterology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Xiaolu Zhang
- Department of Gastroenterology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Zhiyan Wang
- CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China; Department of Psychology, University of Chinese Academy of Science, Beijing, China
| | - Chunhua Hu
- National Engineering Research Center of Neuromodulation, School of Aerospace Engineering, Tsinghua University, Beijing, China
| | - Xuan Jiang
- Department of Gastroenterology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China.
| |
Collapse
|
|
10
|
Wang J, Kumar P, Engelmann C. Comprehensive insights into the multifaceted roles of the transient receptor potential vanilloid 1 channel in the digestive system. Life Sci 2023; 334:122207. [PMID: 37883862 DOI: 10.1016/j.lfs.2023.122207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 10/11/2023] [Accepted: 10/23/2023] [Indexed: 10/28/2023]
Abstract
The transient receptor potential vanilloid (TRPV) channel, a family of calcium transporters comprising six distinct members (TRPV1-6), takes on a paramount role in maintaining intracellular Ca2+ homeostasis in mammalian cells. Notably, TRPV1, among its counterparts, has emerged as the subject of extensive scrutiny, owing to its pervasive presence in diverse cellular, tissue, and organ settings. This ubiquitous distribution underscores its fundamental involvement in the genesis of pain, making it a central focus in pain-related research. However, recent investigations have unveiled that TRPV1's functional significance transcends the realm of pain modulation, extending its influence to encompass a wide spectrum of physiological and pathological processes. The ambit of TRPV1's influence encompasses not only pain responses but also embraces the intricate domains of nervous system disorders, cancer metastasis, as well as afflictions pertaining to the skin and heart. Moreover, compelling evidence now demonstrates that TRPV1 also wields substantial sway in the domain of digestive diseases, further highlighting its versatility and far-reaching impact on human health. Therefore, this comprehensive review endeavors to delve into the multifaceted roles played by TRPV1 in the various organs constituting the digestive system.
Collapse
Affiliation(s)
- Juan Wang
- Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Pavitra Kumar
- Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany.
| | - Cornelius Engelmann
- Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; Berlin Institute of Health (BIH), 10178 Berlin, Germany.
| |
Collapse
|
|
11
|
Sun HZ, Li CY, Shi Y, Li JJ, Wang YY, Han LN, Zhu LJ, Zhang YF. Effect of exogenous hydrogen sulfide in the nucleus tractus solitarius on gastric motility in rats. World J Gastroenterol 2023; 29:4557-4570. [PMID: 37621756 PMCID: PMC10445002 DOI: 10.3748/wjg.v29.i29.4557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 06/29/2023] [Accepted: 07/19/2023] [Indexed: 08/02/2023] Open
Abstract
BACKGROUND Hydrogen sulfide (H2S) is a recently discovered gaseous neurotransmitter in the nervous and gastrointestinal systems. It exerts its effects through multiple signaling pathways, impacting various physiological activities. The nucleus tractus solitarius (NTS), a vital nucleus involved in visceral sensation, was investigated in this study to understand the role of H2S in regulating gastric function in rats. AIM To examine whether H2S affects the nuclear factor kappa-B (NF-κB) and transient receptor potential vanilloid 1 pathways and the neurokinin 1 (NK1) receptor in the NTS. METHODS Immunohistochemical and fluorescent double-labeling techniques were employed to identify cystathionine beta-synthase (CBS) and c-Fos co-expressed positive neurons in the NTS during rat stress. Gastric motility curves were recorded by inserting a pressure-sensing balloon into the pylorus through the stomach fundus. Changes in gastric motility were observed before and after injecting different doses of NaHS (4 nmol and 8 nmol), physiological saline, Capsazepine (4 nmol) + NaHS (4 nmol), pyrrolidine dithiocarbamate (PDTC, 4 nmol) + NaHS (4 nmol), and L703606 (4 nmol) + NaHS (4 nmol). RESULTS We identified a significant increase in the co-expression of c-Fos and CBS positive neurons in the NTS after 1 h and 3 h of restraint water-immersion stress compared to the expressions observed in the control group. Intra-NTS injection of NaHS at different doses significantly inhibited gastric motility in rats (P < 0.01). However, injection of saline, first injection NF-κB inhibitor PDTC or transient receptor potential vanilloid 1 (TRPV1) antagonist Capsazepine or NK1 receptor blockers L703606 and then injection NaHS did not produce significant changes (P > 0.05). CONCLUSION NTS contains neurons co-expressing CBS and c-Fos, and the injection of NaHS into the NTS can suppress gastric motility in rats. This effect may be mediated by activating TRPV1 and NK1 receptors via the NF-κB channel.
Collapse
Affiliation(s)
- Hong-Zhao Sun
- College of Life Science, Qi Lu Normal University, Zhangqiu 250200, Shandong Province, China
| | - Chen-Yu Li
- College of Life Science, Qi Lu Normal University, Zhangqiu 250200, Shandong Province, China
| | - Yuan Shi
- College of Life Science, Qi Lu Normal University, Zhangqiu 250200, Shandong Province, China
| | - Jin-Jin Li
- College of Life Science, Qi Lu Normal University, Zhangqiu 250200, Shandong Province, China
| | - Yi-Ya Wang
- College of Life Science, Qi Lu Normal University, Zhangqiu 250200, Shandong Province, China
| | - Li-Na Han
- College of Life Science, Qi Lu Normal University, Zhangqiu 250200, Shandong Province, China
| | - Lu-Jie Zhu
- College of Life Science, Qi Lu Normal University, Zhangqiu 250200, Shandong Province, China
| | - Ya-Fei Zhang
- College of Life Science, Qi Lu Normal University, Zhangqiu 250200, Shandong Province, China
| |
Collapse
|
|
12
|
Buhner S, Schäuffele S, Giesbertz P, Demir IE, Zeller F, Traidl-Hoffmann C, Schemann M, Gilles S. Allergen-free extracts from birch, ragweed, and hazel pollen activate human and guinea-pig submucous and spinal sensory neurons. Neurogastroenterol Motil 2023:e14559. [PMID: 36989179 DOI: 10.1111/nmo.14559] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 01/16/2023] [Accepted: 02/24/2023] [Indexed: 03/30/2023]
Abstract
BACKGROUND Non-allergenic, low molecular weight components of pollen grains are suspected to trigger changes in gut functions, sometimes leading to inflammatory conditions. Based on extensive neuroimmune communication in the gut wall, we investigated the effects of aqueous pollen extracts (APE) on enteric and spinal sensory neurons. METHODS Using Ca2+ and fast potentiometric imaging, we recorded the responses of guinea-pig and human submucous and guinea-pig dorsal root ganglion (DRG) neurons to microejection of low (<3 kDa) and high (≥3 kDa) molecular weight APEs of birch, ragweed, and hazel. Histamine was determined pharmacologically and by mass spectrometry (LC-MS/MS). KEY RESULTS Birch APE<3kDa evoked strong [Ca+2 ]i signals in the vast majority of guinea-pig DRG neurons, and in guinea-pig and human enteric neurons. The effect of birch APE≥3kDa was much weaker. Fast neuroimaging in human enteric neurons revealed an instantaneous spike discharge after microejection of birch, ragweed, and hazel APE<3kDa [median (interquartile range) at 7.0 Hz (6.2/9.8), 5.7 Hz (4.4/7.1), and 8.4 Hz (4.3/12.5), respectively]. The percentage of responding neurons per ganglion were similar [birch 40.0% (33.3/100.0), ragweed 50.8% (34.4/85.6), and hazel 83.3% (57.1/100.0)]. A mixture of histamine receptor (H1-H3) blockers significantly reduced nerve activation evoked by birch and ragweed APEs<3kDa , but was ineffective on hazel. Histamine concentrations in ragweed, birch and hazel APE's < 3 kDa were 0.764, 0.047, and 0.013 μM, respectively. CONCLUSIONS Allergen-free APEs from birch, ragweed, and hazel evoked strong nerve activation. Altered nerve-immune signaling as a result of severe pollen exposure could be a pathophysiological feature of allergic and non-allergic gut inflammation.
Collapse
Affiliation(s)
- Sabine Buhner
- Chair of Human Biology, Technical University Munich, Freising, Germany
| | | | - Pieter Giesbertz
- Molecular Nutrition Unit, Technical University Munich, Freising, Germany
| | - Ihsan Ekin Demir
- University Hospital Rechts der Isar, Technical University Munich, Munich, Germany
| | - Florian Zeller
- Department of Surgery, Academic Hospital Freising, Freising, Germany
| | - Claudia Traidl-Hoffmann
- Environmental Medicine, Faculty of Medicine, University of Augsburg, Augsburg, Germany
- Institute of Environmental Medicine, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- Christine Kühne Center for Allergy Research and Education (CK-Care), Davos, Switzerland
| | - Michael Schemann
- Chair of Human Biology, Technical University Munich, Freising, Germany
| | - Stefanie Gilles
- Environmental Medicine, Faculty of Medicine, University of Augsburg, Augsburg, Germany
- Institute of Environmental Medicine, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| |
Collapse
|
|
13
|
Sun Y, Liu X, Wang L, Li L, Quan X, Shi H, Wang T, Mei L, Chen Y, Zhang Y, Li J, Meng R, Wang J, Dai F. Losartan attenuates acetic acid enema-induced visceral hypersensitivity by inhibiting the ACE1/Ang II/AT1 receptor axis in enteric glial cells. Eur J Pharmacol 2023; 946:175650. [PMID: 36907262 DOI: 10.1016/j.ejphar.2023.175650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 03/02/2023] [Accepted: 03/07/2023] [Indexed: 03/12/2023]
Abstract
Enteric glial cells (EGCs) play an important role in visceral hypersensitivity associated with irritable bowel syndrome (IBS). Losartan (Los) is known to reduce pain; however, its function in IBS is unclear. The present study aimed to investigate Los's therapeutic effect on visceral hypersensitivity in IBS rats. Thirty rats were randomly divided into control, acetic acid enema (AA), AA + Los low, medium and high dose groups in vivo. EGCs were treated with lipopolysaccharide (LPS) and Los in vitro. The molecular mechanisms were explored by assessing the expression of EGC activation markers, pain mediators, inflammatory factors and angiotensin-converting enzyme 1(ACE1)/angiotensin II (Ang II)/Ang II type 1 (AT1) receptor axis molecules in colon tissue and EGCs. The results showed that the rats in the AA group showed significantly higher visceral hypersensitivity than the control rats, which was alleviated by different doses of Los. The expression of GFAP, S100β, substance P (SP), calcitonin gene-related peptide (CGRP), transient receptor potential vanilloid 1 (TRPV1), tumor necrosis factor (TNF), interleukin-1β (IL-1β) and interleukin-6 (IL-6) was considerably increased in colonic tissues of AA group rats and LPS-treated EGCs compared with control rats and EGCs, and reduced by Los. In addition, Los reversed ACE1/Ang II/AT1 receptor axis upregulation in AA colon tissues and LPS-treated EGCs. These results show that Los inhibits ACE1/Ang II/AT1 receptor axis upregulation by suppressing EGC activation, resulting in reduced expression of pain mediators and inflammatory factors, thereby alleviating visceral hypersensitivity.
Collapse
Affiliation(s)
- Yating Sun
- Department of Gastroenterology, Second Affifiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
| | - Xiaohui Liu
- Department of Bone and Joint Surgery, Second Affifiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
| | - Lianli Wang
- Department of Gastroenterology, Second Affifiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
| | - Laifu Li
- Department of Gastroenterology, Second Affifiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
| | - Xiaojing Quan
- Department of Gastroenterology, Second Affifiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
| | - Haitao Shi
- Department of Gastroenterology, Second Affifiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
| | - Ting Wang
- Department of Gastroenterology, Second Affifiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
| | - Lin Mei
- Department of Gastroenterology, Second Affifiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
| | - Yindi Chen
- Department of Gastroenterology, Xi'an People's Hospital, Xi'an, China.
| | - Yue Zhang
- Department of Gastroenterology, Second Affifiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
| | - Jingyao Li
- Department of Gastroenterology, Second Affifiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
| | - Ruiting Meng
- Department of Gastroenterology, Second Affifiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
| | - Jinhai Wang
- Department of Gastroenterology, Second Affifiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
| | - Fei Dai
- Department of Gastroenterology, Second Affifiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
| |
Collapse
|
|
14
|
Josefsson A, Törnblom H, Simrén M. Type of Rectal Barostat Protocol Affects Classification of Hypersensitivity and Prediction of Symptom Severity in Irritable Bowel Syndrome. J Neurogastroenterol Motil 2022; 28:630-641. [PMID: 36250370 PMCID: PMC9577574 DOI: 10.5056/jnm21214] [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: 10/30/2021] [Revised: 02/15/2022] [Accepted: 03/03/2022] [Indexed: 11/20/2022] Open
Abstract
Background/Aims Visceral hypersensitivity is an important pathophysiologic mechanism in irritable bowel syndrome (IBS). We compared 2 barostat distension protocols and their ability to distinguish between IBS patients and healthy controls, identify subjects with rectal hypersensitivity, and their associations with gastrointestinal symptom severity. Methods We retrospectively reviewed all patients at our unit that had undergone barostat investigations 2002-2014. Protocol 1 (n = 369) used phasic isobaric distensions with stepwise increments in pressure and protocol 2 (n = 153) used pressure controlled ramp inflations. Both protocols terminated when subjects reported pain or maximum pressure was reached. Thresholds for first sensation, urgency, discomfort and pain were established. Age- and gender-matched controls were used for comparison. The gastrointestinal symptom rating scale-IBS, and the hospital anxiety and depression scale were used for symptom reports. Results A significantly higher proportion of patients was classified as having hypersensitivity in protocol 1 vs protocol 2 for all thresholds (P < 0.001). Patients with visceral hypersensitivity, defined based on rectal pain thresholds in protocol 1 had more severe gastrointestinal symptoms overall as well as anxiety, whereas these associations were weaker or in most cases absent when visceral hypersensitivity was defined based on rectal pain thresholds in protocol 2. Conclusion Our study indicates that a rectal barostat protocol using phasic isobaric distensions with stepwise pressure increments is more sensitive in IBS patients with respect to identifying subjects with rectal hypersensitivity and a link with IBS symptoms.
Collapse
Affiliation(s)
- Axel Josefsson
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Hans Törnblom
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Magnus Simrén
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Center for Functional Gastrointestinal and Motility Disorders, University of North Carolina, Chapel Hill, NC, USA
| |
Collapse
|
|
15
|
Hussein H, Boeckxstaens GE. Immune-mediated food reactions in irritable bowel syndrome. Curr Opin Pharmacol 2022; 66:102285. [PMID: 36063569 DOI: 10.1016/j.coph.2022.102285] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 05/23/2022] [Accepted: 08/03/2022] [Indexed: 11/03/2022]
Abstract
Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder characterized by recurrent abdominal pain and an altered defecation pattern. Depending on the criteria used, it affects between 5 and 10% of the general population and has a serious impact on quality of life. Most patients with IBS show an induction or exacerbation of their symptoms, particularly abdominal pain, after eating certain foods. This raises the question of the role played by food in IBS pathophysiology. In this review, we describe the multiple risk factors of IBS, and we give an overview of the role of food as a trigger of IBS, distinguishing between immune and non-immune reactions to food. We finally highlight recent findings identifying an immune-mediated mechanism underlying food-induced abdominal pain in IBS.
Collapse
Affiliation(s)
- Hind Hussein
- KU Leuven Department of Chronic Diseases, Metabolism and Ageing, Leuven, Belgium; Translational Research Centre for Gastrointestinal Disorders, Center for Intestinal Neuroimmune Interaction, Leuven, Belgium
| | - Guy E Boeckxstaens
- KU Leuven Department of Chronic Diseases, Metabolism and Ageing, Leuven, Belgium; Translational Research Centre for Gastrointestinal Disorders, Center for Intestinal Neuroimmune Interaction, Leuven, Belgium.
| |
Collapse
|
|
16
|
Ito K, Kanemitsu Y, Kamiya T, Fukumitsu K, Takeda N, Tajiri T, Kurokawa R, Nishiyama H, Yap J, Fukuda S, Uemura T, Ohkubo H, Maeno K, Ito Y, Oguri T, Takemura M, Niimi A. Functional gastrointestinal disorders are associated with capsaicin cough sensitivity in severe asthma. Allergol Int 2022; 72:271-278. [PMID: 36192325 DOI: 10.1016/j.alit.2022.08.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 08/06/2022] [Accepted: 08/30/2022] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Although sensory nerve dysfunction is related to the pathology of severe uncontrolled asthma and functional gastrointestinal disorders (FGIDs), the impact of comorbid FGIDs on the pathophysiology of severe uncontrolled asthma remains poorly understood. The aim was to clarify the physiological relationships between severe uncontrolled asthma and FGIDs. METHODS Fifty-two patients with severe uncontrolled asthma who visited our hospital between September 2016 and August 2019 were retrospectively analyzed. Clinical characteristics, other comorbidities including gastroesophageal reflux disease (GERD), and biomarkers such as fractional nitric oxide (FeNO) and capsaicin cough sensitivity (C-CS) before the beginning of biologics or bronchial thermoplasty, were compared between patients with and without comorbid FGIDs. C-CS was evaluated by C5 (concentration of inhaled capsaicin that induced five or more coughs), and C5 ≤2.44 μM was defined as heightened C-CS. RESULTS Seventeen patients had comorbid FGIDs. These patients had a lower FeNO level (21.9 ± 1.7 ppb vs. 33.9 ± 2.8 ppb, P = 0.04), a lower C5 threshold (2.24 ± 2.88 μM vs. 8.91 ± 5.5 μM, P < 0.001), a higher prevalence of comorbid GERD (64.7% vs. 31.7%, P = 0.03), and a higher prevalence of heightened C-CS (70.6% vs. 28.6%, P = 0.007) than those without FGIDs. Analysis of covariance showed a significant effect of FGIDs on C-CS in severe uncontrolled asthma without being affected by GERD. CONCLUSIONS Comorbid FGIDs are associated with heightened C-CS in patients with severe uncontrolled asthma, and they may be an important extra-respiratory manifestation of the airway neuronal dysfunction phenotype of severe uncontrolled asthma.
Collapse
Affiliation(s)
- Keima Ito
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Yoshihiro Kanemitsu
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
| | - Takeshi Kamiya
- Department of Medical Innovation, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Kensuke Fukumitsu
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Norihisa Takeda
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Tomoko Tajiri
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Ryota Kurokawa
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Hirono Nishiyama
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Jennifer Yap
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Satoshi Fukuda
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Takehiro Uemura
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Hirotsugu Ohkubo
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Ken Maeno
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Yutaka Ito
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Tetsuya Oguri
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; Department of Education and Research Center for Community Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Masaya Takemura
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; Department of Education and Research Center for Community Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Akio Niimi
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| |
Collapse
|
|
17
|
Camilleri M, Magnus Y, Carlson P, Wang XJ, Chedid V, Maselli D, Taylor A, McKinzie S, Kengunte Nagaraj N, Busciglio I, Nair A. Differential mRNA expression in ileal and colonic biopsies in irritable bowel syndrome with diarrhea or constipation. Am J Physiol Gastrointest Liver Physiol 2022; 323:G88-G101. [PMID: 35502856 PMCID: PMC9291427 DOI: 10.1152/ajpgi.00063.2022] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Altered mucosal functions are documented in jejunal or colorectal mucosa from patients with irritable bowel syndrome (IBS). Our aim was to quantify ileal, ascending, and rectosigmoid colon mucosal expression of genes in IBS-diarrhea (D) and IBS-constipation (C). Forty-four patients with IBS-D, 30 with IBS-C, and 30 healthy volunteers underwent colonoscopic ileal, ascending, and rectosigmoid colon biopsies. Biopsies were stored in RNAlater at -80 °C, purified with on-column DNase, cDNA libraries prepared from 100-200 ng of total RNA, sequenced on Illumina NovaSeq 6000, and analyzed on Illumina's RTA version 3.4.4. Normalized mRNA expression was obtained using MAP-RSeq bioinformatics pipeline. Differential expressions in the groups (Log2-fold change) were measured using the bioinformatics package edgeR 2.6.2, corrected for false discovery rate (PADJ <0.05). There were 30 females with IBS-C and 31 females and 13 males with IBS-D. In IBS-D and IBS-C groups, there were differential expressions of 181 genes in ascending colon and 199 genes in rectosigmoid colon. The majority were gene upregulations in IBS-D with functions reflecting activation of inflammation genes, TRPV1 (visceral hypersensitivity) and neurotransmitters/receptors (specifically purinergic, GABA, and cannabinoid). Although gene differential expressions in the ascending and rectosigmoid colon mucosa of the two groups were different, the diverse upregulated genes involved immune functions, receptors, transmitters, ion channels, and transporters. Conversely, there was reduced expression of PI15 and PI16 genes that inhibit proteases. In patients with IBS-D and IBS-C, differential expressions of genes related to immune, transmitter, nociceptive, protease inhibition, channel, and transporter functions suggest opportunities to reverse the pathobiology and treat patients with IBS.NEW & NOTEWORTHY This study compares gene expression in mucosa of the terminal ileum, right colon, and left colon in patients with diarrhea- or constipation-predominant irritable bowel syndrome (IBS) and contrasts expression between these two disease entities and also between each entity and mucosa from healthy controls. The study shows there is differential expression of genes related to immune, transmitter, nociceptive, ion channel, and transporter functions, as well as reduced serine protease inhibition, in patients with IBS.
Collapse
Affiliation(s)
- Michael Camilleri
- 1Clinical Enteric Neuroscience Translational and Epidemiology Research (C.E.N.T.E.R.), Rochester, Minnesota
| | - Yorick Magnus
- 1Clinical Enteric Neuroscience Translational and Epidemiology Research (C.E.N.T.E.R.), Rochester, Minnesota
| | - Paula Carlson
- 1Clinical Enteric Neuroscience Translational and Epidemiology Research (C.E.N.T.E.R.), Rochester, Minnesota
| | - Xiao Jing Wang
- 1Clinical Enteric Neuroscience Translational and Epidemiology Research (C.E.N.T.E.R.), Rochester, Minnesota
| | - Victor Chedid
- 1Clinical Enteric Neuroscience Translational and Epidemiology Research (C.E.N.T.E.R.), Rochester, Minnesota
| | - Daniel Maselli
- 1Clinical Enteric Neuroscience Translational and Epidemiology Research (C.E.N.T.E.R.), Rochester, Minnesota
| | - Ann Taylor
- 1Clinical Enteric Neuroscience Translational and Epidemiology Research (C.E.N.T.E.R.), Rochester, Minnesota
| | - Sanna McKinzie
- 1Clinical Enteric Neuroscience Translational and Epidemiology Research (C.E.N.T.E.R.), Rochester, Minnesota
| | | | - Irene Busciglio
- 1Clinical Enteric Neuroscience Translational and Epidemiology Research (C.E.N.T.E.R.), Rochester, Minnesota
| | - Asha Nair
- 2Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota
| |
Collapse
|
|
18
|
Barker KH, Higham JP, Pattison LA, Taylor TS, Chessell IP, Welsh F, Smith ESJ, Bulmer DC. Sensitisation of colonic nociceptors by TNFα is dependent on TNFR1 expression and p38 MAPK activity. J Physiol 2022; 600:3819-3836. [PMID: 35775903 PMCID: PMC9543404 DOI: 10.1113/jp283170] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Accepted: 06/28/2022] [Indexed: 11/23/2022] Open
Abstract
Abstract Visceral pain is a leading cause of morbidity in gastrointestinal diseases, which is exacerbated by the gut‐related side‐effects of many analgesics. New treatments are needed and further understanding of the mediators and mechanisms underpinning visceral nociception in disease states is required to facilitate this. The pro‐inflammatory cytokine TNFα is linked to pain in both patients with inflammatory bowel disease and irritable bowel syndrome, and has been shown to sensitize colonic sensory neurons. Somatic, TNFα‐triggered thermal and mechanical hypersensitivity is mediated by TRPV1 signalling and p38 MAPK activity respectively, downstream of TNFR1 receptor activation. We therefore hypothesized that TNFR1‐evoked p38 MAPK activity may also be responsible for TNFα sensitization of colonic afferent responses to the TRPV1 agonist capsaicin, and noxious distension of the bowel. Using Ca2+ imaging of dorsal root ganglion sensory neurons, we observed TNFα‐mediated increases in intracellular [Ca2+] and sensitization of capsaicin responses. The sensitizing effects of TNFα were dependent on TNFR1 expression and attenuated by p38 MAPK inhibition. Consistent with these findings, ex vivo colonic afferent fibre recordings demonstrated an enhanced response to noxious ramp distention of the bowel and bath application of capsaicin following TNFα pre‐treatment. Responses were reversed by p38 MAPK inhibition and absent in tissue from TNFR1 knockout mice. Our findings demonstrate a contribution of TNFR1, p38 MAPK and TRPV1 to TNFα‐induced sensitization of colonic afferents, highlighting the potential utility of these drug targets for the treatment of visceral pain in gastrointestinal disease.
![]() Key points
The pro‐inflammatory cytokine TNFα is elevated in gastrointestinal disease and sensitizes colonic afferents via modulation of TRPA1 and NaV1.8 activity. We further develop this understanding by demonstrating a role for p38 MAPK and TRPV1 in TNFα‐mediated colonic afferent sensitization. Specifically, we show that: TNFα sensitizes sensory neurons and colonic afferents to the TRPV1 agonist capsaicin. TNFα‐mediated sensitization of sensory neurons and colonic nociceptors is dependent on TNFR1 expression. TNFα sensitization of sensory neurons and colonic afferents to capsaicin and noxious ramp distension is abolished by inhibition of p38 MAPK. Collectively these data support the utility of targeting TNFα, TNFR1 and their downstream signalling via p38 MAPK for the treatment of visceral pain in gastrointestinal disease.
Collapse
Affiliation(s)
- Katie H Barker
- Department of Pharmacology, University of Cambridge, Cambridge, CB2 1PD, UK
| | - James P Higham
- Department of Pharmacology, University of Cambridge, Cambridge, CB2 1PD, UK
| | - Luke A Pattison
- Department of Pharmacology, University of Cambridge, Cambridge, CB2 1PD, UK
| | - Toni S Taylor
- Department of Pharmacology, University of Cambridge, Cambridge, CB2 1PD, UK
| | - Iain P Chessell
- Neuroscience, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Fraser Welsh
- Neuroscience, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Ewan St J Smith
- Department of Pharmacology, University of Cambridge, Cambridge, CB2 1PD, UK
| | - David C Bulmer
- Department of Pharmacology, University of Cambridge, Cambridge, CB2 1PD, UK
| |
Collapse
|
|
19
|
Expression of TRP Channels in Colonic Mucosa of IBS-D Patients and Its Correlation with the Severity of the Disease. Gastroenterol Res Pract 2022; 2022:7294775. [PMID: 35677724 PMCID: PMC9168202 DOI: 10.1155/2022/7294775] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Revised: 05/10/2022] [Accepted: 05/17/2022] [Indexed: 11/18/2022] Open
Abstract
Aim Lots of researches have endeavored to elucidate the pathogenetic mechanism of visceral hypersensitivity in order to guide the therapy of diarrhea predominant-irritable bowel syndrome (IBS-D). Transient receptor potential (TRP) channels and their role in visceral nociception have been vastly investigated. We investigated the expression of TRP channels in IBS-D colonic biopsies and its correlation with the severity of the disease. Methods Sigmoid biopsies were obtained from 34 IBS-D patients and 28 healthy controls (HCs). IBS-D was diagnosed according to Rome IV criteria. Their clinical parameters were assessed through questionnaires. Expression of TRPV1, TRPV4, TRPA1, TRPM2, and TRPM8 was evaluated with immunohistology staining. Results Expression levels of TRPV1, TRPV4, and TRPA1 in the colonic mucosa of IBS-D patients were significantly higher than those in HCs (p < 0.05), while there was no obvious difference of TRPM2 and TRPM8 expression between IBS-D patients and HCs. In addition, the expression levels of TRPV1 and TRPA1, but TRPV4, in the colonic mucosa correlated positively with the severity of diseases (r = 0.6303 and 0.4506, respectively, p < 0.05). Conclusions Expression of TRPV1, TRPA1, and TRPV4 in the colonic mucosa was enhanced in IBS-D patients compared with HCs with the former two correlated with the severity of the disease. TRP channels might be promising biomarkers in the diagnosis and estimate of the severity in IBS-D.
Collapse
|
|
20
|
Aguilera-Lizarraga J, Hussein H, Boeckxstaens GE. Immune activation in irritable bowel syndrome: what is the evidence? Nat Rev Immunol 2022; 22:674-686. [PMID: 35296814 DOI: 10.1038/s41577-022-00700-9] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/18/2022] [Indexed: 12/15/2022]
Abstract
Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder that is characterized by abdominal pain and an altered defecation pattern. It affects between 5 and 20% of the general population and can seriously impact quality of life. The pathophysiology of IBS is rather complex and multifactorial including, for example, altered signalling by the gut-brain axis, dysbiosis, abnormal visceral pain signalling and intestinal immune activation. The latter has gained particular interest in recent years, with growing insight into the bidirectional communication between the nervous system and the immune system. In this Review, we detail the current evidence suggesting that immune activation contributes to the pathology seen in patients with IBS and discuss the potential mechanisms involved. Moreover, we describe how immune mediators, particularly those released by mast cells, can directly activate or sensitize pain-transmitting nerves, leading to increased pain signalling and abdominal pain. Finally, we discuss the potential of interventions targeting immune activation as a new therapeutic strategy for patients suffering from IBS.
Collapse
Affiliation(s)
- Javier Aguilera-Lizarraga
- Laboratory for Intestinal Neuroimmune Interactions, Translational Research Centre for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium
| | - Hind Hussein
- Laboratory for Intestinal Neuroimmune Interactions, Translational Research Centre for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium
| | - Guy E Boeckxstaens
- Laboratory for Intestinal Neuroimmune Interactions, Translational Research Centre for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium.
| |
Collapse
|
|
21
|
Xiang Q, Tang X, Cui S, Zhang Q, Liu X, Zhao J, Zhang H, Mao B, Chen W. Capsaicin, the Spicy Ingredient of Chili Peppers: Effects on Gastrointestinal Tract and Composition of Gut Microbiota at Various Dosages. Foods 2022; 11:foods11050686. [PMID: 35267319 PMCID: PMC8909049 DOI: 10.3390/foods11050686] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 02/21/2022] [Accepted: 02/23/2022] [Indexed: 11/16/2022] Open
Abstract
Capsaicin (CAP) is an ingredient of peppers that has biological activities at low doses but causes gastrointestinal (GI) discomfort at high doses. However, the GI effects of high doses of CAP and the evaluation criteria to determine this remain unknown. To elucidate the dose-related effects of CAP on GI health, CAP was administered to mice at 40, 60, and 80 mg/kg doses. The results showed that 40 mg/kg CAP did not negatively affect GI tissues, while 60 and 80 mg/kg CAP damaged GI tissues and caused significant inflammation in the jejunum, ileum, and colon. The levels of serum substance P (SP) and calcitonin gene-related peptide (CGRP) were CAP-dose-dependent, and short-chain fatty acids (SCFAs) content significantly increased in the 80 mg/kg group. Correlation analysis revealed that the underlying mechanisms might be related to the regulation of gut microbiota, especially Bifidobacterium, Lactobacillus, Faecalibacterium, and Butyricimonas. These results suggest that oral administration of 60 and 80 mg/kg CAP in mice causes intestinal inflammation and high levels of serum neuropeptides and cecal SCFAs, which may be related to alterations in gut microbiota.
Collapse
Affiliation(s)
- Qunran Xiang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (Q.X.); (X.T.); (S.C.); (Q.Z.); (X.L.); (J.Z.); (H.Z.); (W.C.)
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
| | - Xin Tang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (Q.X.); (X.T.); (S.C.); (Q.Z.); (X.L.); (J.Z.); (H.Z.); (W.C.)
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
| | - Shumao Cui
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (Q.X.); (X.T.); (S.C.); (Q.Z.); (X.L.); (J.Z.); (H.Z.); (W.C.)
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
| | - Qiuxiang Zhang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (Q.X.); (X.T.); (S.C.); (Q.Z.); (X.L.); (J.Z.); (H.Z.); (W.C.)
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
| | - Xiaoming Liu
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (Q.X.); (X.T.); (S.C.); (Q.Z.); (X.L.); (J.Z.); (H.Z.); (W.C.)
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
| | - Jianxin Zhao
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (Q.X.); (X.T.); (S.C.); (Q.Z.); (X.L.); (J.Z.); (H.Z.); (W.C.)
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
| | - Hao Zhang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (Q.X.); (X.T.); (S.C.); (Q.Z.); (X.L.); (J.Z.); (H.Z.); (W.C.)
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi 214122, China
| | - Bingyong Mao
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (Q.X.); (X.T.); (S.C.); (Q.Z.); (X.L.); (J.Z.); (H.Z.); (W.C.)
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- Correspondence:
| | - Wei Chen
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China; (Q.X.); (X.T.); (S.C.); (Q.Z.); (X.L.); (J.Z.); (H.Z.); (W.C.)
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi 214122, China
| |
Collapse
|
|
22
|
Layer P, Andresen V, Allescher H, Bischoff SC, Claßen M, Elsenbruch S, Freitag M, Frieling T, Gebhard M, Goebel-Stengel M, Häuser W, Holtmann G, Keller J, Kreis ME, Kruis W, Langhorst J, Jansen PL, Madisch A, Mönnikes H, Müller-Lissner S, Niesler B, Pehl C, Pohl D, Raithel M, Röhrig-Herzog G, Schemann M, Schmiedel S, Schwille-Kiuntke J, Storr M, Preiß JC, Andus T, Buderus S, Ehlert U, Engel M, Enninger A, Fischbach W, Gillessen A, Gschossmann J, Gundling F, Haag S, Helwig U, Hollerbach S, Karaus M, Katschinski M, Krammer H, Kuhlbusch-Zicklam R, Matthes H, Menge D, Miehlke S, Posovszky MC, Schaefert R, Schmidt-Choudhury A, Schwandner O, Schweinlin A, Seidl H, Stengel A, Tesarz J, van der Voort I, Voderholzer W, von Boyen G, von Schönfeld J, Wedel T. Update S3-Leitlinie Reizdarmsyndrom: Definition, Pathophysiologie, Diagnostik und Therapie. Gemeinsame Leitlinie der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) und der Deutschen Gesellschaft für Neurogastroenterologie und Motilität (DGNM) – Juni 2021 – AWMF-Registriernummer: 021/016. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2021; 59:1323-1415. [PMID: 34891206 DOI: 10.1055/a-1591-4794] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- P Layer
- Medizinische Klinik, Israelitisches Krankenhaus, Hamburg, Deutschland
| | - V Andresen
- Medizinische Klinik, Israelitisches Krankenhaus, Hamburg, Deutschland
| | - H Allescher
- Zentrum für Innere Medizin, Gastroent., Hepatologie u. Stoffwechsel, Klinikum Garmisch-Partenkirchen, Garmisch-Partenkirchen, Deutschland
| | - S C Bischoff
- Institut für Ernährungsmedizin, Universität Hohenheim, Stuttgart, Deutschland
| | - M Claßen
- Klinik für Kinder- und Jugendmedizin, Klinikum Links der Weser, Bremen, Deutschland
| | - S Elsenbruch
- Klinik für Neurologie, Translational Pain Research Unit, Universitätsklinikum Essen, Essen, Deutschland.,Abteilung für Medizinische Psychologie und Medizinische Soziologie, Ruhr-Universität Bochum, Bochum, Deutschland
| | - M Freitag
- Abteilung Allgemeinmedizin Department für Versorgungsforschung, Universität Oldenburg, Oldenburg, Deutschland
| | - T Frieling
- Medizinische Klinik II, Helios Klinikum Krefeld, Krefeld, Deutschland
| | - M Gebhard
- Gemeinschaftspraxis Pathologie-Hamburg, Hamburg, Deutschland
| | - M Goebel-Stengel
- Innere Medizin II, Helios Klinik Rottweil, Rottweil, und Innere Medizin VI, Psychosomat. Medizin u. Psychotherapie, Universitätsklinikum Tübingen, Tübingen, Deutschland
| | - W Häuser
- Innere Medizin I mit Schwerpunkt Gastroenterologie, Klinikum Saarbrücken, Saarbrücken, Deutschland
| | - G Holtmann
- Faculty of Medicine & Faculty of Health & Behavioural Sciences, Princess Alexandra Hospital, Brisbane, Australien
| | - J Keller
- Medizinische Klinik, Israelitisches Krankenhaus, Hamburg, Deutschland
| | - M E Kreis
- Klinik für Allgemein-, Viszeral- und Gefäßchirurgie, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Deutschland
| | | | - J Langhorst
- Klinik für Integrative Medizin und Naturheilkunde, Sozialstiftung Bamberg, Klinikum am Bruderwald, Bamberg, Deutschland
| | - P Lynen Jansen
- Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten, Berlin, Deutschland
| | - A Madisch
- Klinik für Gastroenterologie, interventionelle Endoskopie und Diabetologie, Klinikum Siloah, Klinikum Region Hannover, Hannover, Deutschland
| | - H Mönnikes
- Klinik für Innere Medizin, Martin-Luther-Krankenhaus, Berlin, Deutschland
| | | | - B Niesler
- Abteilung Molekulare Humangenetik Institut für Humangenetik, Universitätsklinikum Heidelberg, Heidelberg, Deutschland
| | - C Pehl
- Medizinische Klinik, Krankenhaus Vilsbiburg, Vilsbiburg, Deutschland
| | - D Pohl
- Klinik für Gastroenterologie und Hepatologie, Universitätsspital Zürich, Zürich, Schweiz
| | - M Raithel
- Medizinische Klinik II m.S. Gastroenterologie und Onkologie, Waldkrankenhaus St. Marien, Erlangen, Deutschland
| | | | - M Schemann
- Lehrstuhl für Humanbiologie, TU München, Deutschland
| | - S Schmiedel
- I. Medizinische Klinik und Poliklinik Gastroenterologie, Universitätsklinikum Hamburg-Eppendorf, Deutschland
| | - J Schwille-Kiuntke
- Abteilung für Psychosomatische Medizin und Psychotherapie, Medizinische Universitätsklinik Tübingen, Tübingen, Deutschland.,Institut für Arbeitsmedizin, Sozialmedizin und Versorgungsforschung, Universitätsklinikum Tübingen, Tübingen, Deutschland
| | - M Storr
- Zentrum für Endoskopie, Gesundheitszentrum Starnberger See, Starnberg, Deutschland
| | - J C Preiß
- Klinik für Innere Medizin - Gastroenterologie, Diabetologie und Hepatologie, Vivantes Klinikum Neukölln, Berlin, Deutschland
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
23
|
Aguilera-Lizarraga J, Florens M, Hussein H, Boeckxstaens G. Local immune response as novel disease mechanism underlying abdominal pain in patients with irritable bowel syndrome. Acta Clin Belg 2021; 77:889-896. [PMID: 34709996 DOI: 10.1080/17843286.2021.1996069] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
OBJECTIVES Irritable bowel syndrome (IBS) is the most frequently diagnosed functional gastrointestinal disorder, with a prevalence of up to 25% of the global population. IBS patients suffer from abnormal abdominal pain, or visceral hypersensitivity (VHS), associated with altered bowel habits in the absence of an organic detectable cause. The pathophysiology of the disease is incompletely understood, but the dysregulation of the brain-gut axis is well established in IBS. METHODS IBS onset is mainly triggered by infectious gastroenteritis, psychological factors, and dietary factors, but genetic predispositions and intestinal dysbiosis might also play a role. Additionally, immune activation, and particularly chronic mast cell activation, have been shown to underlie the development of abdominal pain in IBS. RESULTS By releasing increased levels of mediators, including histamine, mast cells sensitize enteric nociceptors and lead to VHS development. The mechanisms underlying aberrant mast cell activation in IBS are still under investigation, but we recently showed that a local break in oral tolerance to food antigens led to IgE-mediated mast cell activation and food-induced abdominal pain in preclinical models and in IBS patients. CONCLUSION The concept of food-mediated VHS highlights the potential of therapies targeting upstream mechanisms of mast cell sensitization to treat IBS.
Collapse
Affiliation(s)
- J. Aguilera-Lizarraga
- Center of Intestinal Neuro-immune Interaction, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Belgium
| | - M. Florens
- Center of Intestinal Neuro-immune Interaction, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Belgium
| | - H. Hussein
- Center of Intestinal Neuro-immune Interaction, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Belgium
| | - G. Boeckxstaens
- Center of Intestinal Neuro-immune Interaction, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Belgium
- Department of Gastroenterology & Hepatology, UZ Leuven, Leuven, Belgium
| |
Collapse
|
|
24
|
Burns GL, Hoedt EC, Walker MM, Talley NJ, Keely S. Physiological mechanisms of unexplained (functional) gastrointestinal disorders. J Physiol 2021; 599:5141-5161. [PMID: 34705270 DOI: 10.1113/jp281620] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 09/20/2021] [Indexed: 12/13/2022] Open
Abstract
Functional gastrointestinal disorders (FGIDs) encompass a range of complex conditions with similar clinical characteristics and no overt pathology. Recent recognition of sub-clinical pathologies in FGIDs, in conjunction with physiological and biochemical abnormalities including increased intestinal permeability, microbial profile alterations, differences in metabolites and extra-intestinal manifestations of disease, call into question the designation of these conditions as 'functional'. This is despite significant heterogeneity in both symptom profile and specifics of reported physiological abnormalities hampering efforts to determine defined mechanisms that drive onset and chronicity of symptoms. Instead, the literature demonstrates these conditions are disorders of homeostatic imbalance, with disruptions in both host and microbial function and metabolism. This imbalance is also associated with extraintestinal abnormalities including psychological comorbidities and fatigue that may be a consequence of gastrointestinal disruption. Given the exploitation of such abnormalities will be crucial for improved therapeutic selection, an enhanced understanding of the relationship between alterations in function of the gastrointestinal tract and the response of the immune system is of interest in identifying mechanisms that drive FGID onset and chronicity. Considerations for future research should include the role of sex hormones in regulating physiological functions and treatment responses in patients, as well as the importance of high-level phenotyping of clinical, immune, microbial and physiological parameters in study cohorts. There is opportunity to examine the functional contribution of the microbiota and associated metabolites as a source of mechanistic insight and targets for therapeutic modulation.
Collapse
Affiliation(s)
- Grace L Burns
- School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Newcastle, NSW, Australia.,NHMRC Centre for Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia.,New Lambton Heights, Hunter Medical Research Institute, Newcastle, NSW, Australia
| | - Emily C Hoedt
- NHMRC Centre for Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia.,New Lambton Heights, Hunter Medical Research Institute, Newcastle, NSW, Australia.,School of Medicine and Public Health, College of Health, Medicine and Wellbeing, University of Newcastle, Newcastle, NSW, Australia
| | - Marjorie M Walker
- NHMRC Centre for Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia.,New Lambton Heights, Hunter Medical Research Institute, Newcastle, NSW, Australia.,School of Medicine and Public Health, College of Health, Medicine and Wellbeing, University of Newcastle, Newcastle, NSW, Australia
| | - Nicholas J Talley
- NHMRC Centre for Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia.,New Lambton Heights, Hunter Medical Research Institute, Newcastle, NSW, Australia.,School of Medicine and Public Health, College of Health, Medicine and Wellbeing, University of Newcastle, Newcastle, NSW, Australia
| | - Simon Keely
- School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Newcastle, NSW, Australia.,NHMRC Centre for Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia.,New Lambton Heights, Hunter Medical Research Institute, Newcastle, NSW, Australia
| |
Collapse
|
|
25
|
Xiang Q, Guo W, Tang X, Cui S, Zhang F, Liu X, Zhao J, Zhang H, Mao B, Chen W. Capsaicin—the spicy ingredient of chili peppers: A review of the gastrointestinal effects and mechanisms. Trends Food Sci Technol 2021. [DOI: 10.1016/j.tifs.2021.08.034] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
|
|
26
|
Friesen C, Colombo JM, Deacy A, Schurman JV. An Update on the Assessment and Management of Pediatric Abdominal Pain. PEDIATRIC HEALTH MEDICINE AND THERAPEUTICS 2021; 12:373-393. [PMID: 34393542 PMCID: PMC8354769 DOI: 10.2147/phmt.s287719] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Accepted: 07/15/2021] [Indexed: 12/12/2022]
Abstract
Chronic abdominal pain is very common in children and adolescent and results in high personal and social costs. Most youth with chronic abdominal pain fulfill criteria for a functional abdominal pain disorder (FAPD) as defined by Rome criteria. These are complex conditions with a wide array of biological, psychological, and social factors contributing to the experience of pain. The purpose of the current review is to provide an overview of the pathophysiology of FAPDs and an up-to-date summary of the literature related to FAPDs in children and adolescents, with additional focus on several areas (eg, diet and probiotics) where patients and families frequently have questions or implement self-directed care. We also provide an approach to the assessment and treatment of pediatric FAPDs focusing on the robust literature regarding psychological interventions and much sparser literature regarding medication treatment.
Collapse
Affiliation(s)
- Craig Friesen
- Division of Gastroenterology, Hepatology, and Nutrition; Children's Mercy Kansas City, Kansas City, MO, USA
| | - Jennifer M Colombo
- Division of Gastroenterology, Hepatology, and Nutrition; Children's Mercy Kansas City, Kansas City, MO, USA
| | - Amanda Deacy
- Division of Gastroenterology, Hepatology, and Nutrition; Children's Mercy Kansas City, Kansas City, MO, USA
| | - Jennifer V Schurman
- Division of Gastroenterology, Hepatology, and Nutrition; Children's Mercy Kansas City, Kansas City, MO, USA
| |
Collapse
|
|
27
|
Abstract
The enteric nervous system (ENS) is the largest division of the peripheral nervous system and closely resembles components and functions of the central nervous system. Although the central role of the ENS in congenital enteric neuropathic disorders, including Hirschsprung disease and inflammatory and functional bowel diseases, is well acknowledged, its role in systemic diseases is less understood. Evidence of a disordered ENS has accumulated in neurodegenerative diseases ranging from amyotrophic lateral sclerosis, Alzheimer disease and multiple sclerosis to Parkinson disease as well as neurodevelopmental disorders such as autism. The ENS is a key modulator of gut barrier function and a regulator of enteric homeostasis. A 'leaky gut' represents the gateway for bacterial and toxin translocation that might initiate downstream processes. Data indicate that changes in the gut microbiome acting in concert with the individual genetic background can modify the ENS, central nervous system and the immune system, impair barrier function, and contribute to various disorders such as irritable bowel syndrome, inflammatory bowel disease or neurodegeneration. Here, we summarize the current knowledge on the role of the ENS in gastrointestinal and systemic diseases, highlighting its interaction with various key players involved in shaping the phenotypes. Finally, current flaws and pitfalls related to ENS research in addition to future perspectives are also addressed.
Collapse
|
|
28
|
Holland AM, Bon-Frauches AC, Keszthelyi D, Melotte V, Boesmans W. The enteric nervous system in gastrointestinal disease etiology. Cell Mol Life Sci 2021; 78:4713-4733. [PMID: 33770200 PMCID: PMC8195951 DOI: 10.1007/s00018-021-03812-y] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 02/20/2021] [Accepted: 03/10/2021] [Indexed: 02/06/2023]
Abstract
A highly conserved but convoluted network of neurons and glial cells, the enteric nervous system (ENS), is positioned along the wall of the gut to coordinate digestive processes and gastrointestinal homeostasis. Because ENS components are in charge of the autonomous regulation of gut function, it is inevitable that their dysfunction is central to the pathophysiology and symptom generation of gastrointestinal disease. While for neurodevelopmental disorders such as Hirschsprung, ENS pathogenesis appears to be clear-cut, the role for impaired ENS activity in the etiology of other gastrointestinal disorders is less established and is often deemed secondary to other insults like intestinal inflammation. However, mounting experimental evidence in recent years indicates that gastrointestinal homeostasis hinges on multifaceted connections between the ENS, and other cellular networks such as the intestinal epithelium, the immune system, and the intestinal microbiome. Derangement of these interactions could underlie gastrointestinal disease onset and elicit variable degrees of abnormal gut function, pinpointing, perhaps unexpectedly, the ENS as a diligent participant in idiopathic but also in inflammatory and cancerous diseases of the gut. In this review, we discuss the latest evidence on the role of the ENS in the pathogenesis of enteric neuropathies, disorders of gut-brain interaction, inflammatory bowel diseases, and colorectal cancer.
Collapse
Affiliation(s)
- Amy Marie Holland
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
- Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium
| | - Ana Carina Bon-Frauches
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Daniel Keszthelyi
- Department of Internal Medicine, Division of Gastroenterology-Hepatology, NUTRIM-School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Veerle Melotte
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
- Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Werend Boesmans
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.
- Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium.
| |
Collapse
|
|
29
|
Constante M, De Palma G, Lu J, Jury J, Rondeau L, Caminero A, Collins SM, Verdu EF, Bercik P. Saccharomyces boulardii CNCM I-745 modulates the microbiota-gut-brain axis in a humanized mouse model of Irritable Bowel Syndrome. Neurogastroenterol Motil 2021; 33:e13985. [PMID: 32955166 DOI: 10.1111/nmo.13985] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 08/12/2020] [Accepted: 08/17/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND Gnotobiotic mice colonized with microbiota from patients with irritable bowel syndrome (IBS) and comorbid anxiety (IBS+A) display gut dysfunction and anxiety-like behavior compared to mice colonized with microbiota from healthy volunteers. Using this model, we tested the therapeutic potential of the probiotic yeast Saccharomyces boulardii strain CNCM I-745 (S. bou) and investigated underlying mechanisms. METHODS Germ-free Swiss Webster mice were colonized with fecal microbiota from an IBS+A patient or a healthy control (HC). Three weeks later, mice were gavaged daily with S. boulardii or placebo for two weeks. Anxiety-like behavior (light preference and step-down tests), gastrointestinal transit, and permeability were assessed. After sacrifice, samples were taken for gene expression by NanoString and qRT-PCR, microbiota 16S rRNA profiling, and indole quantification. KEY RESULTS Mice colonized with IBS+A microbiota developed faster gastrointestinal transit and anxiety-like behavior (longer step-down latency) compared to mice with HC microbiota. S. bou administration normalized gastrointestinal transit and anxiety-like behavior in mice with IBS+A microbiota. Step-down latency correlated with colonic Trpv1 expression and was associated with altered microbiota profile and increased Indole-3-acetic acid (IAA) levels. CONCLUSIONS & INFERENCES Treatment with S. bou improves gastrointestinal motility and anxiety-like behavior in mice with IBS+A microbiota. Putative mechanisms include effects on pain pathways, direct modulation of the microbiota, and indole production by commensal bacteria.
Collapse
Affiliation(s)
- Marco Constante
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Giada De Palma
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Jun Lu
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Jennifer Jury
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Liam Rondeau
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Alberto Caminero
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Stephen M Collins
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Elena F Verdu
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Premysl Bercik
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| |
Collapse
|
|
30
|
Szymaszkiewicz A, Włodarczyk J, Wasilewski A, Di Marzo V, Storr M, Fichna J, Zielińska M. Desensitization of transient receptor potential vanilloid type-1 (TRPV1) channel as promising therapy of irritable bowel syndrome: characterization of the action of palvanil in the mouse gastrointestinal tract. Naunyn Schmiedebergs Arch Pharmacol 2020; 393:1357-1364. [PMID: 32002574 PMCID: PMC7351811 DOI: 10.1007/s00210-020-01829-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 01/23/2020] [Indexed: 02/06/2023]
Abstract
TRPV1 are involved in the control of the gastrointestinal (GI) functions and pain sensation. Their activation induces pain but it is followed by desensitization, which in turn causes analgesia. The studies from the last two decades indicate that TRPV1 are involved in visceral hypersensitivity in the GI tract and pathogenesis of irritable bowel syndrome (IBS). Therefore, the aim of this study is to assess the action of fast desensitizing agonist of TRPV1, palvanil (N-palmitoyl-vanillamine), in the murine GI tract and on nociception to evaluate its potential application in the therapy of IBS. The effect of palvanil on smooth muscle contractility was evaluated using organ baths. The impact of palvanil on intestinal secretion was assessed in Ussing chambers. In vivo, the action of palvanil (0.1–1 mg/kg) was assessed in whole GI transit, fecal pellet output, and colonic bead expulsion tests. The antinociceptive potency of palvanil was tested in the mustard oil-induced pain test. Palvanil inhibited colonic contractions (evoked by electrical field stimulation, EFS) and decreased the ion transport in the colon stimulated with forskolin. It did not affect secretion in experiments with veratridine. In vivo, palvanil prolonged whole GI transit at all doses tested. At the lower dose tested, it accelerated colonic motility during first 60 min following injection. By contrast, at the dose of 1 mg/kg, colonic motility was inhibited. Palvanil induced antinociceptive action at all tested doses in mustard oil-induced pain test. TRPV1 fast-desensitizing compounds, i.e., palvanil, may be promising agents in the therapy of IBS since it modulates intestinal motility and reduces visceral pain.
Collapse
Affiliation(s)
- Agata Szymaszkiewicz
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland
| | - Jakub Włodarczyk
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland
| | - Andrzej Wasilewski
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland
| | - Vincenzo Di Marzo
- Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy.,Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health, Université Laval, Quebec City, Canada
| | - Martin Storr
- Walter Brendel Center of Experimental Medicine, Ludwig Maximilians University, Munich, Germany.,Center of Endoscopy, Starnberg, Germany
| | - Jakub Fichna
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland
| | - Marta Zielińska
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland.
| |
Collapse
|
|
31
|
Chey WD, Shah ED, DuPont HL. Mechanism of action and therapeutic benefit of rifaximin in patients with irritable bowel syndrome: a narrative review. Therap Adv Gastroenterol 2020; 13:1756284819897531. [PMID: 32047534 PMCID: PMC6984424 DOI: 10.1177/1756284819897531] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 12/02/2019] [Indexed: 02/04/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder with a multifactorial pathophysiology. The gut microbiota differs between patients with IBS and healthy individuals. After a bout of acute gastroenteritis, postinfection IBS may result in up to approximately 10% of those affected. Small intestinal bacterial overgrowth (SIBO) is more common in patients with IBS than in healthy individuals, and eradication of SIBO with systemic antibiotics has decreased symptoms of IBS in some patients with IBS and SIBO. The nonsystemic (i.e. low oral bioavailability) antibiotic rifaximin is indicated in the United States and Canada for the treatment of adults with IBS with diarrhea (IBS-D). The efficacy and safety of 2-week single and repeat courses of rifaximin have been demonstrated in randomized, placebo-controlled studies of adults with IBS. Rifaximin is widely thought to exert its beneficial clinical effects in IBS-D through manipulation of the gut microbiota. However, current studies indicate that rifaximin induces only modest effects on the gut microbiota of patients with IBS-D, suggesting that the efficacy of rifaximin may involve other mechanisms. Indeed, preclinical data reveal a potential role for rifaximin in the modulation of inflammatory cytokines and intestinal permeability, but these two findings have not yet been examined in the context of clinical studies. The mechanism of action of rifaximin in IBS is likely multifactorial, and further study is needed.
Collapse
Affiliation(s)
- William D. Chey
- Department of Nutrition Sciences, Division of Gastroenterology, Michigan Medicine, 3912 Taubman Center, SPC 5362, Ann Arbor, MI 48109-5362, USA
| | - Eric D. Shah
- Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA
| | - Herbert L. DuPont
- Division of Epidemiology, Human Genetics and Environmental Sciences and Center for Infectious Diseases, University of Texas School of Public Health, Houston, TX, USA
- Mary W. Kelsey Chair in Medical Sciences, Division of Internal Medicine, University of Texas McGovern Medical School Houston, TX, USA
- Kelsey Research Foundation, Houston, TX, USA
| |
Collapse
|
|
32
|
Roman K, Hall C, Schaeffer AJ, Thumbikat P. TRPV1 in experimental autoimmune prostatitis. Prostate 2020; 80:28-37. [PMID: 31573117 PMCID: PMC7313375 DOI: 10.1002/pros.23913] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Accepted: 09/18/2019] [Indexed: 12/27/2022]
Abstract
BACKGROUND Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a disorder that is characterized by persistent pelvic pain in men of any age. Although several studies suggest that the transient receptor potential vanilloid 1 (TRPV1) channel is involved in various pathways of chronic pain, the TRPV1 channel has not been implicated in chronic pelvic pain associated with CP/CPPS. METHODS Male C57BL/6J (B6) and TRPV1 knockout (TRPV1 KO) mice (5-7 weeks old) were used to study the development of pelvic allodynia in a murine model of CP/CPPS called experimental autoimmune prostatitis (EAP). The prostate lobes, dorsal root ganglia (DRG), and spinal cord were excised at day 20. The prostate lobes were assessed for inflammation, TRPV1 expression, and mast cell activity. DRG and spinal cord, between the L6-S4 regions, were analyzed to determine the levels of phosphorylated ERK1/2 (p-ERK 1/2). To examine the therapeutic potential of TRPV1, B6 mice with EAP received intraurethral infusion of a TRPV1 antagonist at day 20 (repeated every 2 days) and pelvic pain was evaluated at days 20, 25, 30, and 35. RESULTS Our data showed that B6 mice with EAP developed pelvic tactile allodynia at days 7, 14, and 20. In contrast, TRPV1 KO mice with EAP do not develop pelvic tactile allodynia at any time point. Although we observed no change in the levels of TRPV1 protein expression in the prostate from B6 mice with EAP, there was evidence of significant inflammation and elevated mast cell activation. Interestingly, the prostate from TRPV1 KO mice with EAP showed a lack of mast cell activation despite evidence of prostate inflammation. Next, we observed a significant increase of p-ERK1/2 in the DRG and spinal cord from B6 mice with EAP; however, p-ERK1/2 expression was unaltered in TRPV1 KO mice with EAP. Finally, we confirmed that intraurethral administration of a TRPV1 antagonist peptide reduced pelvic tactile allodynia in B6 mice with EAP after day 20. CONCLUSIONS We demonstrated that in a murine model of CP/CPPS, the TRPV1 channel is key to persistent pelvic tactile allodynia and blocking TRPV1 in the prostate may be a promising strategy to quell chronic pelvic pain.
Collapse
Affiliation(s)
- Kenny Roman
- Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Christel Hall
- Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Anthony J. Schaeffer
- Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Praveen Thumbikat
- Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| |
Collapse
|
|
33
|
Uno Y. Hypothesis: Mechanism of irritable bowel syndrome in inflammatory bowel disease. Med Hypotheses 2019; 132:109324. [PMID: 31421429 DOI: 10.1016/j.mehy.2019.109324] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2019] [Accepted: 07/23/2019] [Indexed: 02/08/2023]
Abstract
Functional bowel symptoms can be occurred during remission from inflammatory bowel disease. In this case, a low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) diet is effective for the amelioration or prevention of symptoms. However, the reason is not fully explained. This report proposes a hypothesis regarding the entire process in which inflammatory bowel disease with IBS-like symptoms (IBD-IBS) causes symptoms. A detailed process was assumed, starting from high pressure in the lumen and finally to abdominal symptoms. In this process, relationships were linked based on interactions such as ischemia, compliance, pain threshold, visceral hypersensitivity, mast cells, and permeability reported in IBD-IBS. In the process mapping, to understand the relationship between the amount of gas increased by FODMAP and ischemia, the hydrodynamic hypothesis and Ritchie's hypothesis were adapted. Ischemia in dilated intestines due to an increase in gas volume can induce excessive spasms via the mast cells and show the whole process of lowering the pain threshold. From the standpoint of the mechanism of IBD-IBS, the origin trigger may be FODMAP. Therefore, a low-FODMAP diet is recommended to relieve and prevent IBD-IBS symptoms.
Collapse
Affiliation(s)
- Yoshiharu Uno
- Office Uno Column, 419-2, Yota, Onoe-Cho, Kakogawa, Hyogo, Japan.
| |
Collapse
|
|
34
|
Josefsson A, Rosendahl A, Jerlstad P, Näslin G, Törnblom H, Simrén M. Visceral sensitivity remains stable over time in patients with irritable bowel syndrome, but with individual fluctuations. Neurogastroenterol Motil 2019; 31:e13603. [PMID: 31012215 DOI: 10.1111/nmo.13603] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2018] [Revised: 03/26/2019] [Accepted: 04/02/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND Visceral hypersensitivity in irritable bowel syndrome (IBS), measured with rectal balloon distensions, using a barostat, has been suggested to be a phenomenon that is reduced due to habituation at repeated investigations. We investigated the stability of rectal sensitivity in patients with IBS who had undergone a previous rectal barostat study and assessed variations in symptom pattern and severity in relation to rectal sensory function. METHOD Irritable bowel syndrome patients, who had previously been undergone a rectal barostat study, were included. All patients underwent a second study 8-12 years later. Symptoms were characterized by use of questionnaires. KEY RESULTS We included 26 subjects (17 females, median age at the index investigation 44.5 (21-61) years). Pressure and volume sensory thresholds were unchanged at the follow-up compared with the index investigation (P > 0.05 for all). At the index investigation, 8/26 patients had rectal hypersensitivity of which four were reclassified as normosensitive, and sixfrom normo- to hypersensitive, meaning that 10/26 patients were hypersensitive at the follow-up investigation. IBS-QOL had improved significantly in six of nine domains at follow-up (P < 0.05 for all). There were no differences in anxiety, depression, IBS symptom severity, or somatization (P > 0.05) at follow-up. None of these were associated with change in rectal sensitivity at follow-up. CONCLUSIONS AND INFERENCES Rectal hypersensitivity and IBS symptoms remained stable at the group level over 8-12 years in IBS patients, even though individual fluctuations were noted. Our findings contradict previous findings indicating that visceral hypersensitivity is an unstable trait.
Collapse
Affiliation(s)
- Axel Josefsson
- Department of Internal Medicine & Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, Sweden
| | - Amanda Rosendahl
- Department of Internal Medicine & Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, Sweden
| | - Pernilla Jerlstad
- Department of Internal Medicine & Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, Sweden
| | - Gunilla Näslin
- Department of Internal Medicine & Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, Sweden
| | - Hans Törnblom
- Department of Internal Medicine & Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, Sweden
| | - Magnus Simrén
- Department of Internal Medicine & Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, Sweden.,Center for Functional Gastrointestinal and Motility Disorders, University of North Carolina, Chapel Hill, North Carolina
| |
Collapse
|
|
35
|
Multifunctional TRPV1 Ion Channels in Physiology and Pathology with Focus on the Brain, Vasculature, and Some Visceral Systems. BIOMED RESEARCH INTERNATIONAL 2019; 2019:5806321. [PMID: 31263706 PMCID: PMC6556840 DOI: 10.1155/2019/5806321] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Revised: 04/15/2019] [Accepted: 04/28/2019] [Indexed: 02/06/2023]
Abstract
TRPV1 has been originally cloned as the heat and capsaicin receptor implicated in acute pain signalling, while further research has shifted the focus to its importance in chronic pain caused by inflammation and associated with this TRPV1 sensitization. However, accumulating evidence suggests that, apart from pain signalling, TRPV1 subserves many other unrelated to nociception functions in the nervous system. In the brain, TRPV1 can modulate synaptic transmission via both pre- and postsynaptic mechanisms and there is a functional crosstalk between GABA receptors and TRPV1. Other fundamental processes include TRPV1 role in plasticity, microglia-to-neuron communication, and brain development. Moreover, TRPV1 is widely expressed in the peripheral tissues, including the vasculature, gastrointestinal tract, urinary bladder, epithelial cells, and the cells of the immune system. TRPV1 can be activated by a large array of physical (heat, mechanical stimuli) and chemical factors (e.g., protons, capsaicin, resiniferatoxin, and endogenous ligands, such as endovanilloids). This causes two general cell effects, membrane depolarization and calcium influx, thus triggering depending on the cell-type diverse functional responses ranging from neuronal excitation to secretion and smooth muscle contraction. Here, we review recent research on the diverse TRPV1 functions with focus on the brain, vasculature, and some visceral systems as the basis of our better understanding of TRPV1 role in different human disorders.
Collapse
|
|
36
|
Balemans D, Aguilera-Lizarraga J, Florens MV, Jain P, Denadai-Souza A, Viola MF, Alpizar YA, Van Der Merwe S, Vanden Berghe P, Talavera K, Vanner S, Wouters MM, Boeckxstaens GE. Histamine-mediated potentiation of transient receptor potential (TRP) ankyrin 1 and TRP vanilloid 4 signaling in submucosal neurons in patients with irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol 2019; 316:G338-G349. [PMID: 30629470 DOI: 10.1152/ajpgi.00116.2018] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Previously, we showed histamine-mediated sensitization of transient receptor potential (TRP) vanilloid 1 (TRPV1) in patients with irritable bowel syndrome (IBS). Sensitization of TRP ankyrin 1 (TRPA1) and TRP vanilloid 4 (TRPV4) are also involved in aberrant pain perception in preclinical models of somatic pain. Here, we hypothesize that in parallel with TRPV1, histamine sensitizes TRPA1 and TRPV4, contributing to increased visceral pain in patients with IBS. Rectal biopsies were collected from patients with IBS and healthy subjects (HS) to study neuronal sensitivity to TRPA1 and TRPV4 agonists (cinnamaldehyde and GSK1016790A) using intracellular Ca2+ imaging. In addition, the effect of supernatants of rectal biopsies on patients with IBS and HS was assessed on TRPA1 and TRPV4 responses in murine dorsal root ganglion (DRG) sensory neurons. Finally, we evaluated the role of histamine and histamine 1 receptor (H1R) in TRPA1 and TRPV4 sensitization. Application of TRPA1 and TRPV4 agonists evoked significantly higher peak amplitudes and percentage of responding submucosal neurons in biopsies of patients with IBS compared with HS. In HS, pretreatment with histamine significantly increased the Ca2+ responses to cinnamaldehyde and GSK1016790A, an effect prevented by H1R antagonism. IBS supernatants, but not of HS, sensitized TRPA1 and TRPV4 on DRG neurons. This effect was reproduced by histamine and prevented by H1R antagonism. We demonstrate that the mucosal microenvironment in IBS contains mediators, such as histamine, which sensitize TRPV4 and TRPA1 via H1R activation, most likely contributing to increased visceral pain perception in IBS. These data further underscore H1R antagonism as potential treatment for IBS. NEW & NOTEWORTHY We provide evidence for histamine-mediated transient receptor potential (TRP) ankyrin 1 and TRP vanilloid 4 sensitization in irritable bowel syndrome (IBS) via histamine 1 receptor (H1R) activation, most likely contributing to increased visceral pain perception. Our results reveal a general role of sensory TRP channels as histamine effectors in the pathophysiology of IBS and provide novel mechanistic insights into the therapeutic potential of H1R antagonism in IBS.
Collapse
Affiliation(s)
- D Balemans
- Translational Research Center for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven , Leuven , Belgium
| | - J Aguilera-Lizarraga
- Translational Research Center for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven , Leuven , Belgium
| | - M V Florens
- Translational Research Center for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven , Leuven , Belgium
| | - P Jain
- Translational Research Center for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven , Leuven , Belgium
| | - A Denadai-Souza
- Translational Research Center for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven , Leuven , Belgium
| | - M F Viola
- Translational Research Center for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven , Leuven , Belgium
| | - Y A Alpizar
- Laboratory of Ion Channel Research and Transient Receptor Potential Channel Research Platform, Department of Cellular and Molecular Medicine, Katholieke Universiteit Leuven , Leuven , Belgium.,Vlaams Instituut voor Biotechnologie Center for Brain & Disease Research, Katholieke Universiteit Leuven , Belgium
| | - S Van Der Merwe
- Department of Hepatology, University Hospital Leuven, and Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven , Leuven , Belgium
| | - P Vanden Berghe
- Translational Research Center for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven , Leuven , Belgium
| | - K Talavera
- Laboratory of Ion Channel Research and Transient Receptor Potential Channel Research Platform, Department of Cellular and Molecular Medicine, Katholieke Universiteit Leuven , Leuven , Belgium.,Vlaams Instituut voor Biotechnologie Center for Brain & Disease Research, Katholieke Universiteit Leuven , Belgium
| | - S Vanner
- Gastrointestinal Diseases Research Unit, Kingston General Hospital, Queen's University , Kingston , Canada
| | - M M Wouters
- Translational Research Center for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven , Leuven , Belgium
| | - G E Boeckxstaens
- Translational Research Center for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven , Leuven , Belgium
| |
Collapse
|
|
37
|
Misery L, Duboc H, Coffin B, Brenaut E, Huet F, Taieb C. Association between two painful and poorly understood conditions: Irritable bowel and sensitive skin syndromes. Eur J Pain 2019; 23:160-166. [DOI: 10.1002/ejp.1296] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Affiliation(s)
- Laurent Misery
- Laboratory of Neurosciences University of Western Brittany Brest France
- Department of Dermatology University Hospital of Brest Brest France
| | - Henri Duboc
- Department of Gastroenterology AP‐HP Hospital Louis Mourier Colombes France
- Faculty of Medicine Denis Diderot University Paris 7 Paris France
| | - Benoit Coffin
- Department of Gastroenterology AP‐HP Hospital Louis Mourier Colombes France
- Faculty of Medicine Denis Diderot University Paris 7 Paris France
| | - Emilie Brenaut
- Laboratory of Neurosciences University of Western Brittany Brest France
- Department of Dermatology University Hospital of Brest Brest France
| | - Flavien Huet
- Laboratory of Neurosciences University of Western Brittany Brest France
- Department of Dermatology University Hospital of Brest Brest France
| | - Charles Taieb
- EMMA Fontenay‐sous‐Bois France
- Necker Enfants Malades Hospital Paris France
| |
Collapse
|
|
38
|
Van Gerven L, Steelant B, Hellings PW. Nasal hyperreactivity in rhinitis: A diagnostic and therapeutic challenge. Allergy 2018; 73:1784-1791. [PMID: 29624710 DOI: 10.1111/all.13453] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/26/2018] [Indexed: 12/14/2022]
Abstract
Although nasal hyperreactivity (NHR) is a common feature in patients suffering from allergic and nonallergic rhinitis, it is widely neglected during history taking, underdiagnosed in the majority of patients with rhinitis and rhinosinusitis, not considered as an outcome parameter in clinical trials on novel treatments for rhinitis and rhinosinusitis, and no target for routine treatment. In contrast to the simple nature of diagnosing NHR by a history of nasal symptoms induced by nonspecific exogenous and/or endogenous triggers, quantification is hardly performed in routine clinic given the lack of a simple tool for its diagnosis. So far, limited efforts have been invested into gaining better insight in the underlying pathophysiology of NHR, helping us to explain why some patients with inflammation develop NHR and others not. Of note, environmental and microbial factors have been reported to influence NHR, contributing to the complex nature of understanding the development of NHR. As a consequence of the neglect of NHR as a key clinical feature of rhinitis and chronic rhinosinusitis (CRS), patients with NHR might be suboptimally controlled and/or dissatisfied with current treatment. We here aim to provide a comprehensive overview of current knowledge on the pathophysiology, and the available tools to diagnose and treat NHR.
Collapse
Affiliation(s)
- L. Van Gerven
- Clinical Division of Otorhinolaryngology; Head & Neck Surgery; University Hospitals Leuven; Leuven Belgium
- Laboratory of Clinical Immunology; Department of Microbiology and Immunology; KU Leuven; Leuven Belgium
| | - B. Steelant
- Laboratory of Clinical Immunology; Department of Microbiology and Immunology; KU Leuven; Leuven Belgium
| | - P. W. Hellings
- Clinical Division of Otorhinolaryngology; Head & Neck Surgery; University Hospitals Leuven; Leuven Belgium
- Laboratory of Clinical Immunology; Department of Microbiology and Immunology; KU Leuven; Leuven Belgium
- Department of Otorhinolaryngology; Academic Medical Center; Amsterdam The Netherlands
| |
Collapse
|
|
39
|
The Transient Receptor Potential Vanilloid 1 Is Associated with Active Inflammation in Ulcerative Colitis. Mediators Inflamm 2018; 2018:6570371. [PMID: 30150894 PMCID: PMC6087567 DOI: 10.1155/2018/6570371] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Revised: 05/10/2018] [Accepted: 05/29/2018] [Indexed: 12/19/2022] Open
Abstract
The transient receptor potential vanilloid 1 (TRPV1) may play a role in the pathogenesis of ulcerative colitis (UC). The aim of the study was to determine the gene and protein expression of TRPV1 in UC patients and noninflamed controls. Gene expression was performed by RT-PCR, and protein expression was performed by immunohistochemistry. The gene expression of TRPV1 was significantly increased in the remission UC group compared to active UC patients (P = 0.002), and an upregulation of the TRPV1 gene was associated with clinical outcomes such as age at diagnosis (<40 years) (P = 0.02) and clinical disease course characterized by relapsing and continuous activity (P = 0.07). TRPV1 immunoreactive cells were conspicuously higher in all intestinal layers from active UC patients compared with noninflamed control tissue. These findings suggest that TRPV1 might be involved in UC pathogenesis.
Collapse
|
|
40
|
Rizopoulos T, Papadaki-Petrou H, Assimakopoulou M. Expression Profiling of the Transient Receptor Potential Vanilloid (TRPV) Channels 1, 2, 3 and 4 in Mucosal Epithelium of Human Ulcerative Colitis. Cells 2018; 7:E61. [PMID: 29914124 PMCID: PMC6025154 DOI: 10.3390/cells7060061] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Revised: 06/11/2018] [Accepted: 06/14/2018] [Indexed: 12/13/2022] Open
Abstract
The Transient Receptor Potential (TRP) family of selective and non-selective ion channels is well represented throughout the mammalian gastrointestinal track. Several members of the Transient Receptor Potential Vanilloid (TRPV) subfamily have been identified in contributing to modulation of mobility, secretion and sensitivity of the human intestine. Previous studies have focused on the detection of TRPV mRNA levels in colon tissue of patients with inflammatory bowel disease (IBD) whereas little information exists regarding TRPV channel expression in the colonic epithelium. The aim of this study was to evaluate the expression levels of TRPV1, TRPV2, TRPV3 and TRPV4 in mucosa epithelial cells of colonic biopsies from patients with ulcerative colitis (UC) in comparison to colonic resections from non-IBD patients (control group). Immunohistochemistry, using specific antibodies and quantitative analyses of TRPV-immunostained epithelial cells, was performed in semi-serial sections of the samples. TRPV1 expression was significantly decreased whereas TRPV4 expression was significantly increased in the colonic epithelium of UC patients compared to patients in the control group (p < 0.05). No significant difference for TRPV2 and TRPV3 expression levels between UC and control specimens was detected (p > 0.05). There was no correlation between TRPV channel expression and the clinical features of the disease (p > 0.05). Further investigation is needed to clarify the role of TRPV channels in human bowel inflammatory response.
Collapse
Affiliation(s)
- Theodoros Rizopoulos
- Department of Anatomy, Histology and Embryology, School of Medicine, University of Patras, Rion 26504, Greece.
| | - Helen Papadaki-Petrou
- Department of Anatomy, Histology and Embryology, School of Medicine, University of Patras, Rion 26504, Greece.
| | - Martha Assimakopoulou
- Department of Anatomy, Histology and Embryology, School of Medicine, University of Patras, Rion 26504, Greece.
| |
Collapse
|
|
41
|
Camilleri M. Toward an effective peripheral visceral analgesic: responding to the national opioid crisis. Am J Physiol Gastrointest Liver Physiol 2018; 314:G637-G646. [PMID: 29470146 PMCID: PMC6032061 DOI: 10.1152/ajpgi.00013.2018] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
This minireiew summarizes recent new developments in visceral analgesics. This promising field is important, as a new approach to address abdominal pain with peripheral visceral analgesics is considered a key approach to addressing the current opioid crisis. Some of the novel compounds address peripheral pain mechanisms through modulation of opioid receptors via biased ligands, nociceptin/orphanin FQ opioid peptide (NOP) receptor, or dual action on NOP and μ-opioid receptor, buprenorphine and morphiceptin analogs. Other compounds target nonopioid mechanisms, including cannabinoid (CB2), N-methyl-d-aspartate, calcitonin gene-related peptide, estrogen, and adenosine A2B receptors and transient receptor potential (TRP) channels (TRPV1, TRPV4, and TRPM8). Although current evidence is based predominantly on animal models of visceral pain, early human studies also support the evidence from the basic and animal research. This augurs well for the development of nonaddictive, visceral analgesics for treatment of chronic abdominal pain, an unmet clinical need.
Collapse
Affiliation(s)
- Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research Center, Mayo Clinic, Rochester, Minnesota
| |
Collapse
|
|
42
|
Hammer J. Identification of Individuals with Functional Dyspepsia With a Simple, Minimally Invasive Test: A Single Center Cohort Study of the Oral Capsaicin Test. Am J Gastroenterol 2018. [PMID: 29533398 DOI: 10.1038/ajg.2018.16] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES The diagnosis of functional dyspepsia (FD) is challenging due to the lack of reliable biological markers to support the diagnosis. We assessed the relevance of a previously validated simple test for chemical hypersensitivity in the setting of a gastrointestinal outpatient department. METHODS A total of 224 outpatients who were referred for evaluation of gastrointestinal symptoms in the absence of alarm symptoms swallowed a capsule containing 0.75 mg capsaicin. Severity of symptoms before and after capsule ingestion was assessed by a graded questionnaire and the difference in aggregate symptom scores (delta) was calculated. RESULTS Sensitivity of the test was between 0.51-0.59, specificity was 0.84-0.89 and positive predictive value for the diagnosis of FD 70-71%. FD patients had significantly higher median delta symptom scores (10.0; 25% quartile: 3.0; 75% quartile: 16.0) as compared to inflammatory bowel disease (2.5; 1.0/8.5)(P=0.003), peptic ulcer disease (0.0; -1.5/4.5) (P<0.001), irritable bowel syndrome (3.0;0.5/8.5)(P=0.001), and patients classified with "other disease" (2.5;0.0/5.0)(P<0.001). Patients with gastroesophageal reflux disease had significantly lower symptom scores if FD was not concomitantly diagnosed (2.0; 0.0/6.0) than if FD was present (10.0; 4.0/15.0). CONCLUSIONS Hypersensitivity for capsaicin discriminates functional dyspepsia from patients with other GI disorders. The capsaicin test is a simple and non invasive method to detect a large subgroup of functional dyspepsia with chemical hypersensitivity. These findings might open new diagnostic options in functional dyspepsia and possibly new therapeutic options by targeting the specific capsaicin receptor TRPV1.
Collapse
Affiliation(s)
- Johann Hammer
- Abteilung fìr Gastroenterologie und Hepatologie, Universitätsklinik fìr Innere Medizin 3, Vienna, Austria
| |
Collapse
|
|
43
|
Beckers AB, Weerts ZZRM, Masclee AAM, Keszthelyi D. Letter: the neglected analgesic properties of red pepper in the clinical management of the irritable bowel syndrome pain-Authors' reply. Aliment Pharmacol Ther 2018; 47:154-155. [PMID: 29226395 DOI: 10.1111/apt.14442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/08/2022]
Affiliation(s)
- A B Beckers
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Z Z R M Weerts
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, The Netherlands
| | - A A M Masclee
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, The Netherlands
| | - D Keszthelyi
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, The Netherlands
| |
Collapse
|
|
44
|
Tuck CJ, Vanner SJ. Dietary therapies for functional bowel symptoms: Recent advances, challenges, and future directions. Neurogastroenterol Motil 2018; 30. [PMID: 29094792 DOI: 10.1111/nmo.13238] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Accepted: 09/27/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND Functional gastrointestinal symptoms in irritable bowel syndrome (IBS) and quiescent inflammatory bowel disease (IBD) cause significant morbidity and a reduction in quality of life. Multiple dietary therapies are now available to treat these symptoms, but supporting evidence for many is limited. In addition to a further need for studies demonstrating efficacy and mechanism of action of dietary therapies, the risk of nutritional inadequacy, alterations to the microbiome and changes in quality of life are key concerns requiring elucidation. Identifying predictors of response to dietary therapy is an important goal as management could be tailored to the individual to target specific dietary components, and thereby reduce the level of dietary restriction necessary. PURPOSE This review discusses the available dietary therapies to treat symptoms in patients with IBS and patients with quiescent IBD suffering from IBS symptoms, with the aim to understand where current dietary evidence lies and how to move forward in dietary research in this field.
Collapse
Affiliation(s)
- C J Tuck
- Gastrointestinal Diseases Research Unit, Kingston General Hospital, Queen's University, Kingston, ON, Canada
| | - S J Vanner
- Gastrointestinal Diseases Research Unit, Kingston General Hospital, Queen's University, Kingston, ON, Canada
| |
Collapse
|
|
45
|
Beckers AB, Weerts ZZRM, Helyes Z, Masclee AAM, Keszthelyi D. Review article: transient receptor potential channels as possible therapeutic targets in irritable bowel syndrome. Aliment Pharmacol Ther 2017; 46:938-952. [PMID: 28884838 DOI: 10.1111/apt.14294] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Revised: 06/06/2017] [Accepted: 08/17/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND Abdominal pain in irritable bowel syndrome (IBS) remains challenging to treat effectively. Researchers have attempted to elucidate visceral nociceptive processes in order to guide treatment development. Transient receptor potential (TRP) channels have been implied in the generation (TRPV1, TRPV4, TRPA1) and inhibition (TRPM8) of visceral pain signals. Pathological changes in their functioning have been demonstrated in inflammatory conditions, and appear to be present in IBS as well. AIM To provide a comprehensive review of the current literature on TRP channels involved in visceral nociception. In particular, we emphasise the clinical implications of these nociceptors in the treatment of IBS. METHODS Evidence to support this review was obtained from an electronic database search via PubMed using the search terms "visceral nociception," "visceral hypersensitivity," "irritable bowel syndrome" and "transient receptor potential channels." After screening the abstracts the articles deemed relevant were cross-referenced for additional manuscripts. RESULTS Recent studies have resulted in significant advances in our understanding of TRP channel mediated visceral nociception. The diversity of TRP channel sensitization pathways is increasingly recognised. Endogenous TRP agonists, including poly-unsaturated fatty acid metabolites and hydrogen sulphide, have been implied in augmented visceral pain generation in IBS. New potential targets for treatment development have been identified (TRPA1 and TRPV4,) and alternative means of affecting TRP channel signalling (partial antagonists, downstream targeting and RNA-based therapy) are currently being explored. CONCLUSIONS The improved understanding of mechanisms involved in visceral nociception provides a solid basis for the development of new treatment strategies for abdominal pain in IBS.
Collapse
Affiliation(s)
- A B Beckers
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, Limburg, The Netherlands
| | - Z Z R M Weerts
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, Limburg, The Netherlands
| | - Z Helyes
- Department of Pharmacology and Pharmacotherapy, Molecular Pharmacology Research Team, University of Pécs Medical School, János Szentágothai Research Centre, University of Pécs, Pécs, Baranya, Hungary
| | - A A M Masclee
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, Limburg, The Netherlands
| | - D Keszthelyi
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, Limburg, The Netherlands
| |
Collapse
|
|
46
|
Fabisiak A, Włodarczyk J, Fabisiak N, Storr M, Fichna J. Targeting Histamine Receptors in Irritable Bowel Syndrome: A Critical Appraisal. J Neurogastroenterol Motil 2017; 23:341-348. [PMID: 28551943 PMCID: PMC5503283 DOI: 10.5056/jnm16203] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Revised: 03/10/2017] [Accepted: 04/07/2017] [Indexed: 12/19/2022] Open
Abstract
Irritable bowel syndrome is a group of functional gastrointestinal disorders with not yet fully clarified etiology. Recent evidence suggesting that mast cells may play a central role in the pathogenesis of irritable bowel syndrome paves the way for agents targeting histamine receptors as a potential therapeutic option in clinical treatment. In this review, the role of histamine and histamine receptors is debated. Moreover, the clinical evidence of anti-histamine therapeutics in irritable bowel syndrome is discussed.
Collapse
Affiliation(s)
- Adam Fabisiak
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz,
Poland
| | - Jakub Włodarczyk
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz,
Poland
| | - Natalia Fabisiak
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz,
Poland
| | - Martin Storr
- Center of Endoscopy, Starnberg,
Germany
- Walter Brendel Center of Experimental Medicine, Ludwig Maximilians University of Munich, Munich,
Germany
| | - Jakub Fichna
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz,
Poland
- Correspondence: Jakub Fichna, PhD, DSc, Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland, Tel: +48-42-272-5707, Fax: +48-42-272-5694, E-mail:
| |
Collapse
|
|
47
|
Smith SM, Dworkin RH, Turk DC, Baron R, Polydefkis M, Tracey I, Borsook D, Edwards RR, Harris RE, Wager TD, Arendt-Nielsen L, Burke LB, Carr DB, Chappell A, Farrar JT, Freeman R, Gilron I, Goli V, Haeussler J, Jensen T, Katz NP, Kent J, Kopecky EA, Lee DA, Maixner W, Markman JD, McArthur JC, McDermott MP, Parvathenani L, Raja SN, Rappaport BA, Rice ASC, Rowbotham MC, Tobias JK, Wasan AD, Witter J. The Potential Role of Sensory Testing, Skin Biopsy, and Functional Brain Imaging as Biomarkers in Chronic Pain Clinical Trials: IMMPACT Considerations. THE JOURNAL OF PAIN 2017; 18:757-777. [PMID: 28254585 PMCID: PMC5484729 DOI: 10.1016/j.jpain.2017.02.429] [Citation(s) in RCA: 97] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Revised: 01/19/2017] [Accepted: 02/16/2017] [Indexed: 02/08/2023]
Abstract
Valid and reliable biomarkers can play an important role in clinical trials as indicators of biological or pathogenic processes or as a signal of treatment response. Currently, there are no biomarkers for pain qualified by the U.S. Food and Drug Administration or the European Medicines Agency for use in clinical trials. This article summarizes an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials meeting in which 3 potential biomarkers were discussed for use in the development of analgesic treatments: 1) sensory testing, 2) skin punch biopsy, and 3) brain imaging. The empirical evidence supporting the use of these tests is described within the context of the 4 categories of biomarkers: 1) diagnostic, 2) prognostic, 3) predictive, and 4) pharmacodynamic. Although sensory testing, skin punch biopsy, and brain imaging are promising tools for pain in clinical trials, additional evidence is needed to further support and standardize these tests for use as biomarkers in pain clinical trials. PERSPECTIVE The applicability of sensory testing, skin biopsy, and brain imaging as diagnostic, prognostic, predictive, and pharmacodynamic biomarkers for use in analgesic treatment trials is considered. Evidence in support of their use and outlining problems is presented, as well as a call for further standardization and demonstrations of validity and reliability.
Collapse
|
|
48
|
Pace MC, Passavanti MB, De Nardis L, Bosco F, Sansone P, Pota V, Barbarisi M, Palagiano A, Iannotti FA, Panza E, Aurilio C. Nociceptor plasticity: A closer look. J Cell Physiol 2017; 233:2824-2838. [PMID: 28488779 DOI: 10.1002/jcp.25993] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2016] [Revised: 04/20/2017] [Accepted: 05/09/2017] [Indexed: 12/17/2022]
Abstract
Nociceptors are receptors specifically involved in detecting a tissue damage and transducing it in an electrical signal. Nociceptor activation provoked by any kind of acute lesion is related to the release of several mediators of inflammation, within the framework of a process defined as "peripheral sensitization." This results in an exaggerated response to the painful stimulus, clinically defined as "primary hyperalgesia." The concept of "neuroplasticity" may explain the adaptive mechanisms carried out by the Nervous System in relation to a "harmful" damage; also, neuroplasticity mechanisms are also fundamental for rehabilitative intervention protocols. Here we review several studies that addressed the role of different receptors and ionic channels discovered on nociceptor surface and their role in pain perception. The changes in expression, distribution, and functioning of receptors and ionic channels are thought to be a part of the neuroplasticity property, through which the Nervous System constantly adapts to external stimuli. Moreover, some of the reviewed mediators are also been associated to "central sensitization," a process that results in pain chronicization when the painful stimulation is particularly prolonged or intense, and lastly leads to the memorization of the uncomfortable painful perception.
Collapse
Affiliation(s)
- Maria Caterina Pace
- Department of Anaesthesiological, Surgical and Emergency Sciences, Second University of Naples, Naples, Italy
| | - Maria Beatrice Passavanti
- Department of Anaesthesiological, Surgical and Emergency Sciences, Second University of Naples, Naples, Italy
| | - Lorenzo De Nardis
- Department of Anaesthesiological, Surgical and Emergency Sciences, Second University of Naples, Naples, Italy
| | - Fabio Bosco
- Department of Anaesthesiological, Surgical and Emergency Sciences, Second University of Naples, Naples, Italy
| | - Pasquale Sansone
- Department of Anaesthesiological, Surgical and Emergency Sciences, Second University of Naples, Naples, Italy
| | - Vincenzo Pota
- Department of Anaesthesiological, Surgical and Emergency Sciences, Second University of Naples, Naples, Italy
| | - Manlio Barbarisi
- Laboratory of Applied Biotechnology, Department of Anaesthesiological, Surgical and Emergency Sciences, Second University of Naples, Naples, Italy
| | - Antonio Palagiano
- Department of Women, Child and General and Specialized Surgery, Second University of Naples, Naples, Italy
| | - Fabio Arturo Iannotti
- Institute of Biomolecular Chemistry (ICB) Research National Council (CNR), Pozzuoli, Italy
| | - Elisabetta Panza
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Caterina Aurilio
- Department of Anaesthesiological, Surgical and Emergency Sciences, Second University of Naples, Naples, Italy
| |
Collapse
|
|
49
|
Balemans D, Boeckxstaens GE, Talavera K, Wouters MM. Transient receptor potential ion channel function in sensory transduction and cellular signaling cascades underlying visceral hypersensitivity. Am J Physiol Gastrointest Liver Physiol 2017; 312:G635-G648. [PMID: 28385695 DOI: 10.1152/ajpgi.00401.2016] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Revised: 03/21/2017] [Accepted: 04/01/2017] [Indexed: 01/31/2023]
Abstract
Visceral hypersensitivity is an important mechanism underlying increased abdominal pain perception in functional gastrointestinal disorders including functional dyspepsia, irritable bowel syndrome, and inflammatory bowel disease in remission. Although the exact pathophysiological mechanisms are poorly understood, recent studies described upregulation and altered functions of nociceptors and their signaling pathways in aberrant visceral nociception, in particular the transient receptor potential (TRP) channel family. A variety of TRP channels are present in the gastrointestinal tract (TRPV1, TRPV3, TRPV4, TRPA1, TRPM2, TRPM5, and TRPM8), and modulation of their function by increased activation or sensitization (decreased activation threshold) or altered expression in visceral afferents have been reported in visceral hypersensitivity. TRP channels directly detect or transduce osmotic, mechanical, thermal, and chemosensory stimuli. In addition, pro-inflammatory mediators released in tissue damage or inflammation can activate receptors of the G protein-coupled receptor superfamily leading to TRP channel sensitization and activation, which amplify pain and neurogenic inflammation. In this review, we highlight the present knowledge on the functional roles of neuronal TRP channels in visceral hypersensitivity and discuss the signaling pathways that underlie TRP channel modulation. We propose that a better understanding of TRP channels and their modulators may facilitate the development of more selective and effective therapies to treat visceral hypersensitivity.
Collapse
Affiliation(s)
- Dafne Balemans
- Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium; and
| | - Guy E Boeckxstaens
- Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium; and
| | - Karel Talavera
- Laboratory of Ion Channel Research and TRP Research Platform Leuven, Department of Cellular and Molecular Medicine, University of Leuven, Leuven Belgium
| | - Mira M Wouters
- Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium; and
| |
Collapse
|
|
50
|
Boeckxstaens GE, Wouters MM. Neuroimmune factors in functional gastrointestinal disorders: A focus on irritable bowel syndrome. Neurogastroenterol Motil 2017; 29. [PMID: 28027594 DOI: 10.1111/nmo.13007] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Accepted: 11/11/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND Abnormal abdominal pain perception is the most bothersome and difficult to treat symptom of functional gastrointestinal disorders (FGIDs). Visceral pain stimuli are perceived and transmitted by afferent neurons residing in the dorsal root ganglia that have sensory nerve endings in the gut wall and mesentery. Accumulating evidence indicates that peripheral activation and sensitization of these sensory nerve endings by bioactive mediators released by activated immune cells, in particular mast cells, can lead to aberrant neuroimmune interactions and the development and maintenance of visceral hypersensitivity. Besides direct neuronal activation, low concentrations of proteases, histamine, and serotonin can chronically sensitize nociceptors, such as TRP channels, leading to persistent aberrant pain perception. PURPOSE This review discusses the potential mechanisms underlying aberrant neuroimmune interactions in peripheral sensitization of sensory nerves. A better understanding of the cells, mediators, and molecular mechanisms triggering persistent aberrant neuroimmune interactions brings new insights into their contribution to the physiology and pathophysiology of visceral pain perception and provides novel opportunities for more efficient therapeutic treatments for these disorders.
Collapse
Affiliation(s)
- G E Boeckxstaens
- Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven University, Leuven, Belgium
| | - M M Wouters
- Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven University, Leuven, Belgium
| |
Collapse
|