|
1
|
Zhu Y, Gong S, Li S, Li Y, Wang Y, Wu G, Chen JDZ. Small Intestinal Slow Wave Dysrhythmia and Blunted Postprandial Responses in Diabetic Rats. Neurogastroenterol Motil 2025; 37:e14993. [PMID: 39763295 PMCID: PMC11996008 DOI: 10.1111/nmo.14993] [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: 12/12/2023] [Revised: 12/03/2024] [Accepted: 12/17/2024] [Indexed: 04/15/2025]
Abstract
BACKGROUND Gastric dysmotility and gastric slow wave dysrhythmias have been well documented in patients with diabetes. However, little is known on the effect of hyperglycemia on small intestine motility, such as intestinal slow waves, due to limited options in measuring its activity. Moreover, food intake and digestion process have been reported to alter the small intestine motility in normal rats, but their roles in that of diabetic rats remains unknown. This study aimed to explore the effect of hyperglycemia on small intestinal myoelectrical activity (IMA) and responses to various meals in diabetic and normal rats. METHODS IMA was recorded via chronically implanted serosal electrodes in the proximal small intestine in rats with type 2 diabetes induced by high-fat diet feeding followed by a low dose of streptozotocin (30 mg/kg) and normal rats. The percentage of normal slow wave (%NSW), dominant power, and dominant frequency (DF) were assessed from the IMA under various conditions. Oral glucose tolerance test was performed, and blood was collected via the tail vein at baseline and 15, 30, 60, 90, 120, and 180 min after glucose administration for the measurement of blood glucose. Regular laboratory chow, high-fat diet, and small or large nutrient liquid meal were used to explore IMA responses to different meals in diabetic and normal rats. RESULTS (1) Compared with a postprandial increase in DF in normal rats (p = 0.007), diabetic rats showed a blunted postprandial response in DF (p = 0.145) after a regular chow. However, no difference was found in %NSW between diabetic and normal rats in both fasting and fed states; (2) In the fasting state, %NSW was correlated with the blood glucose level in diabetic rats (r = -0.817, p = 0.004, N = 8) as well as HbA1C (r = -0.871, p = 0.005, N = 8). After glucose administration, the increase in blood glucose was correlated with a decrease in %NSW (r = -0.655, p < 0.001, N = 8). (3) %NSW in diabetic rats during the 30-min postprandial state was not altered after a meal, either liquid or solid, regular or high-fat diet, small or large meal, suggesting an absence of gastric-small intestinal reflex. CONCLUSIONS In type 2 diabetic rats, the regularity of intestinal slow waves is negatively correlated with the blood glucose level in both fasting and fed states. Diabetic rats exhibit a blunted postprandial response in intestinal slow waves compared with normal rats. There seems to be a lack of gastric-small intestinal reflex upon food ingestion in diabetic rats.
Collapse
Affiliation(s)
- Ying Zhu
- Division of Gastroenterology, School of MedicineUniversity of MichiganAnn ArborMichiganUSA
- Division of GastroenterologyNorthern Jiangsu People's Hospital Affiliated to Yangzhou UniversityYangzhou, JiangsuChina
| | - Shiyuan Gong
- Division of Gastroenterology, School of MedicineUniversity of MichiganAnn ArborMichiganUSA
- Department of Biomedical Engineering, School of EngineeringUniversity of MichiganAnn ArborMichiganUSA
| | - Shiying Li
- Division of Gastroenterology, School of MedicineUniversity of MichiganAnn ArborMichiganUSA
| | - Yan Li
- Division of Gastroenterology, School of MedicineUniversity of MichiganAnn ArborMichiganUSA
| | - Yan Wang
- Division of Gastroenterology, School of MedicineUniversity of MichiganAnn ArborMichiganUSA
| | - Gaojue Wu
- Division of Gastroenterology, School of MedicineUniversity of MichiganAnn ArborMichiganUSA
| | - Jiande D. Z. Chen
- Division of Gastroenterology, School of MedicineUniversity of MichiganAnn ArborMichiganUSA
| |
Collapse
|
|
2
|
Wu G, Li F, Li Y, Li S, Alam MJ, Chen JDZ. Progressive impairment in gastric and duodenal slow waves and autonomic function during progression of type 2 diabetes in rats. Am J Physiol Gastrointest Liver Physiol 2025; 328:G386-G398. [PMID: 39993032 DOI: 10.1152/ajpgi.00278.2024] [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: 09/03/2024] [Revised: 10/06/2024] [Accepted: 02/11/2025] [Indexed: 02/26/2025]
Abstract
The abnormalities of gastrointestinal (GI) slow waves play key roles in the pathophysiology of diabetic gastroparesis, which is highly prevalent in type 2 diabetes (T2D). Although relatively well-investigated in diabetic enteric neuropathy, abnormalities and progressive impairments of gastric slow waves (GSWs) and duodenal slow waves (DSWs) are underinvestigated during the progression of T2D. The aim of this study was to explore alterations in GSW and DSW during the development of diabetes induced by high-fat diet (HFD) followed by a low dose of streptozotocin (STZ). Weekly recordings of slow waves from healthy, prediabetic to diabetes stages exhibited a progressively decreased percentage of normal slow waves (%NSW) starting after HFD feeding (prediabetic stage) in the fasting state and starting after STZ injection (diabetic stage) in the postprandial state. The postprandial increase in the power of slow waves observed in normal control rats was absent starting from 2 wk after HFD and persisted after STZ. The mechanism might be attributed to both progressively increased blood glucose (BG) and impaired autonomic function in view of the following results: 1) the %NSW was negatively correlated with the fasting BG; 2) during the oral glucose tolerance test, %NSW of DSW and BG exhibited a positive correlation in rats with hemoglobin A1C (HbA1C) < 5.0%, but a negative correlation in rats with HbA1C ≥ 5.0%; and 3) in comparison with baseline (healthy stage) of the same cohort, plasma pancreatic polypeptide (reflecting vagal activity) was progressively decreased, whereas plasma norepinephrine (reflecting sympathetic activity) was progressively increased.NEW & NOTEWORTHY This study recorded the progressive impairment in the regularity of gastric and duodenal slow waves in a rat model mimicking the progression to type 2 diabetes including the stage of health, prediabetic stage, and diabetes. The progressive impairment in gastric/duodenal slow waves might be attributed to the progressive increase in blood glucose and impairment in autonomic function.
Collapse
Affiliation(s)
- Gaojue Wu
- Division of Gastroenterology and Hepatology, School of Medicine, University of Michigan, Ann Arbor, Michigan, United States
| | - Fei Li
- Division of Gastroenterology and Hepatology, School of Medicine, University of Michigan, Ann Arbor, Michigan, United States
| | - Yan Li
- Division of Gastroenterology and Hepatology, School of Medicine, University of Michigan, Ann Arbor, Michigan, United States
| | - Shiying Li
- Division of Gastroenterology and Hepatology, School of Medicine, University of Michigan, Ann Arbor, Michigan, United States
| | - Md Jahangir Alam
- Division of Gastroenterology and Hepatology, School of Medicine, University of Michigan, Ann Arbor, Michigan, United States
| | - Jiande D Z Chen
- Division of Gastroenterology and Hepatology, School of Medicine, University of Michigan, Ann Arbor, Michigan, United States
| |
Collapse
|
|
3
|
O'Riordan KJ, Moloney GM, Keane L, Clarke G, Cryan JF. The gut microbiota-immune-brain axis: Therapeutic implications. Cell Rep Med 2025; 6:101982. [PMID: 40054458 PMCID: PMC11970326 DOI: 10.1016/j.xcrm.2025.101982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 10/15/2024] [Accepted: 01/29/2025] [Indexed: 03/21/2025]
Abstract
The microbiota-gut-brain axis has major implications for human health including gastrointestinal physiology, brain function, and behavior. The immune system represents a key pathway of communication along this axis with the microbiome implicated in neuroinflammation in health and disease. In this review, we discuss the mechanisms as to how the gut microbiota interacts with the brain, focusing on innate and adaptive immunity that are often disrupted in gut-brain axis disorders. We also consider the implications of these observations and how they can be advanced by interdisciplinary research. Leveraging an increased understanding of how these interactions regulate immunity has the potential to usher in a new era of precision neuropsychiatric clinical interventions for psychiatric, neurodevelopmental, and neurological disorders.
Collapse
Affiliation(s)
| | - Gerard M Moloney
- APC Microbiome Ireland, University College Cork, T12 YT20 Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
| | - Lily Keane
- APC Microbiome Ireland, University College Cork, T12 YT20 Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
| | - Gerard Clarke
- APC Microbiome Ireland, University College Cork, T12 YT20 Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland
| | - John F Cryan
- APC Microbiome Ireland, University College Cork, T12 YT20 Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.
| |
Collapse
|
|
4
|
Zhang P, Zhang C, Zheng B, Liu Y, Zhang D, Xiao H. The "brain-gut" mechanism of postherpetic neuralgia: a mini-review. Front Neurol 2025; 16:1535136. [PMID: 40129863 PMCID: PMC11932021 DOI: 10.3389/fneur.2025.1535136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Accepted: 02/17/2025] [Indexed: 03/26/2025] Open
Abstract
Postherpetic neuralgia (PHN), a representative type of neuropathic pain, has attracted much research on its diagnosis and therapy at the molecular level. Interestingly, this study based on the brain-gut axis provided a novel point of view to interpret the mechanism of PHN. Past neuroanatomical and neuroimaging studies of pain suggest that the prefrontal cortex, anterior cingulate cortex, amygdala, and other regions of the brain may play crucial roles in the descending inhibition of PHN. Dominant bacterial species in patients with PHN, such as Lactobacillus, generate short-chain fatty acids, including butyrate. Evidence indicates that disturbance of some metabolites (such as butyrate) is closely related to the development of hyperalgesia. In addition, tryptophan and 5-HT in the intestinal tract act as neurotransmitters that regulate the descending transmission of neuropathic pain signals. Concurrently, the enteric nervous system establishes close connections with the central nervous system through the vagus nerve and other pathways. This review aims to investigate and elucidate the molecular mechanisms associated with PHN, focusing on the interplay among PHN, the gut microbiota, and relevant metabolites while scrutinizing its pathogenesis.
Collapse
Affiliation(s)
- Peijun Zhang
- Department of Pain Management, West China Hospital, Sichuan University, Chengdu, China
| | - Cuomaoji Zhang
- Department of Anesthesiology, Affiliated Sport Hospital of Chengdu Sport University, Chengdu Sport University, Chengdu, Sichuan, China
| | - Bixin Zheng
- Department of Pain Management, West China Hospital, Sichuan University, Chengdu, China
| | - Yuntao Liu
- Department of Pain Management, West China Hospital, Sichuan University, Chengdu, China
| | - Dingkun Zhang
- Laboratory of Clinical Proteomics and Metabolomics, Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Hong Xiao
- Department of Pain Management, West China Hospital, Sichuan University, Chengdu, China
| |
Collapse
|
|
5
|
Quigley EMM, Noble O, Ansari U. The Suggested Relationships Between Common GI Symptoms and Joint Hypermobility, POTS, and MCAS. Gastroenterol Hepatol (N Y) 2024; 20:479-489. [PMID: 39205953 PMCID: PMC11348541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
An increasing number of reports suggest an association between a newly recognized disease cluster and significant and often disabling gastrointestinal (GI) symptoms. This cluster is composed of diagnoses of hypermobility spectrum disorders (HSDs) such as joint hypermobility and hypermobile variant Ehlers-Danlos syndrome (hEDS), postural orthostatic tachycardia syndrome (POTS), and mast cell activation syndrome (MCAS). The diagnosis of these entities remains a challenge, as the pathophysiology of each has not been completely elucidated and the diagnostic criteria continue to evolve. This article describes a cohort of young adult females who shared similar GI symptoms, with intractable nausea and vomiting being most prominent and gastroesophageal reflux disease and constipation also occurring. Most strikingly, these females also exhibited or reported a history of HSD, hEDS, POTS, and/or MCAS. The clinical course of their GI symptoms was remarkable for considerable challenges in management, and artificial nutritional support proved necessary for some. This article describes the clinical features and outcomes of their GI manifestations, examines how these manifestations might be linked to their systemic syndromes, and discusses whether a shared pathophysiology exists. Pending the definition of a common thread between these conditions, this article seeks to raise awareness of their clinical definitions and foster research that will hopefully improve outcomes for these patients.
Collapse
Affiliation(s)
- Eamonn M. M. Quigley
- Division of Gastroenterology and Hepatology, Lynda K. and David M. Under wood Center for Digestive Disorders, Houston Methodist Hospital and Weill Cornell Medical College, Houston, Texas
| | - Oscar Noble
- Division of Gastroenterology and Hepatology, Lynda K. and David M. Under wood Center for Digestive Disorders, Houston Methodist Hospital and Weill Cornell Medical College, Houston, Texas
| | - Usman Ansari
- Division of Gastroenterology and Hepatology, Lynda K. and David M. Under wood Center for Digestive Disorders, Houston Methodist Hospital and Weill Cornell Medical College, Houston, Texas
| |
Collapse
|
|
6
|
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
|
|
7
|
de Mora F, Messlinger K. Is calcitonin gene-related peptide (CGRP) the missing link in food histamine-induced migraine? A review of functional gut-to-trigeminovascular system connections. Drug Discov Today 2024; 29:103941. [PMID: 38447930 DOI: 10.1016/j.drudis.2024.103941] [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: 09/27/2023] [Revised: 02/21/2024] [Accepted: 02/29/2024] [Indexed: 03/08/2024]
Abstract
Calcitonin gene-related peptide (CGRP) and histamine plasma concentrations increase during migraine attacks. Both mediators are potent vasodilators, and they have been shown to reciprocally contribute to the release of each other in the trigeminovascular system, possibly driving migraine development. A high-histamine-content diet triggers migraine in patients who have histamine degradation deficiency owing to diaminooxidase (DAO) gene mutations. Therefore, studying functional links between exogenous histamine and CGRP seems promising for the understanding of diet-induced migraine generation. Notably, there is a lack of knowledge about the interplay of the enteric nervous system and the spinal/trigeminal somatosensory system with regard to CGRP and histamine. Based on background evidence, we propose that a functional interconnection between exogenous histamine and CGRP contributes to migraine development.
Collapse
Affiliation(s)
- Fernando de Mora
- Department of Pharmacology, Therapeutics and Toxicology, Edificio V, Universidad Autónoma de Barcelona, Campus UAB - 08193 Bellaterra, Barcelona, Spain
| | - Karl Messlinger
- Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsstr. 17, D-91054 Erlangen, Germany.
| |
Collapse
|
|
8
|
Dudzińska E, Grabrucker AM, Kwiatkowski P, Sitarz R, Sienkiewicz M. The Importance of Visceral Hypersensitivity in Irritable Bowel Syndrome-Plant Metabolites in IBS Treatment. Pharmaceuticals (Basel) 2023; 16:1405. [PMID: 37895876 PMCID: PMC10609912 DOI: 10.3390/ph16101405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 09/28/2023] [Accepted: 10/02/2023] [Indexed: 10/29/2023] Open
Abstract
The visceral stimuli from the digestive tract are transmitted via afferent nerves through the spinal cord to the brain, where they are felt as pain. The overreaction observed in the brain of irritable bowel syndrome (IBS) patients may be due to increased peripheral sensitivity to stimuli from the gastrointestinal tract. Although the exact pathway is uncertain, attenuation of visceral hypersensitivity is still of interest in treating IBS. It has been shown that stress stimulates the sympathetic nervous system while inhibiting the vagus nerve (VN). In addition, stress factors lead to dysbiosis and chronic low-grade inflammation of the intestinal mucosa, which can lead to lower gastrointestinal visceral hypersensitivity. Therefore, an important goal in the treatment of IBS is the normalization of the intestinal microflora. An interesting option seems to be nutraceuticals, including Terminalia chebula, which has antibacterial and antimicrobial activity against various pathogenic Gram-positive and Gram-negative bacteria. Additionally, short-term transcutaneous vagus nerve stimulation can reduce the stress-induced increase in intestinal permeability, thereby reducing inflammation. The conducted studies also indicate a relationship between the stimulation of the vagus nerve (VN) and the activation of neuromodulatory networks in the central nervous system. Therefore, it seems reasonable to conclude that a two-way action through stimulating the VN and using nutraceuticals may become an effective therapy in treating IBS.
Collapse
Affiliation(s)
- Ewa Dudzińska
- Department of Dietetics and Nutrition Education, Medical University of Lublin, 20-093 Lublin, Poland
| | - Andreas M. Grabrucker
- Department of Biological Sciences, University of Limerick, V94 PH61 Limerick, Ireland;
- Bernal Institute, University of Limerick, V94 PH61 Limerick, Ireland
- Health Research Institute (HRI), University of Limerick, V94 PH61 Limerick, Ireland
| | - Paweł Kwiatkowski
- Department of Diagnostic Immunology, Pomeranian Medical University in Szczecin, Al. Powstancow Wlkp. 72, 70-111 Szczecin, Poland;
| | - Robert Sitarz
- Department of Human Anatomy, Medical University of Lublin, 20-090 Lublin, Poland;
- First Department of Surgical Oncology, St. John’s Cancer Center, 20-090 Lublin, Poland
| | - Monika Sienkiewicz
- Department of Pharmaceutical Microbiology and Microbiological Diagnostic, Medical University of Lodz, Muszynskiego 1, 90-151 Lodz, Poland;
| |
Collapse
|
|
9
|
Peng S, Xia Y, Wang Y, Yu X, Wu Z, Zhang L, Xu K, Shen L, Luo H. Research hotspots and trend analysis of abdominal pain in inflammatory bowel disease: a bibliometric and visualized analysis. Front Pharmacol 2023; 14:1220418. [PMID: 37808188 PMCID: PMC10552780 DOI: 10.3389/fphar.2023.1220418] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Accepted: 09/11/2023] [Indexed: 10/10/2023] Open
Abstract
Aims: The study aimed to provide a bibliometric and visual analysis of research on abdominal pain in inflammatory bowel disease and discuss the current status, research hotspots, and future developments. Methods: We used the Web of Science Core Collection to comprehensively search the literature on abdominal pain-related research in IBD published between 2003 and 2022. The bibliometric and visual analysis was performed through CiteSpace, VOSviewer software, R language, and the bibliometric online analysis platform, including authors, institutions, countries, journals, references, and keywords in the literature. Results: A total of 3,503 relevant articles are included, indicating that the number of articles in this field has increased in recent years. The United States leads the way with a dominant position in terms of article output, followed by China and JAPAN. United States (967 articles), University of Calgary (98 articles), and World Journal of Gastroenterology (127 articles) are the top publishing countries, institutions, and journals, respectively; keyword analysis shows that gut microbiota, depression, stress, visceral hypersensitivity, and multidisciplinary approach are the hot spots and trends in this research area. Conclusion: Abdominal pain-related studies in IBD have received increasing attention in the past two decades. This study provides the first bibliometric analysis of papers in this research area using visualization software and data information mining. It provides insights into this field's current status, hot spots, and trends. However, many outstanding issues in this research area still need further exploration to provide a theoretical basis for its clinical application.
Collapse
Affiliation(s)
- Shuai Peng
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Digestive Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yuan Xia
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Digestive Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Ying Wang
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Digestive Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xiaoyun Yu
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zunan Wu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Digestive Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Li Zhang
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Ke Xu
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Lei Shen
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Digestive Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Hesheng Luo
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Digestive Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| |
Collapse
|
|
10
|
Mousavi T, Sharifnia M, Nikfar S, Abdollahi M. Pharmacotherapy for gastric and intestinal cramping pain: current and emerging therapies. Expert Opin Pharmacother 2023; 24:2021-2033. [PMID: 37788098 DOI: 10.1080/14656566.2023.2265830] [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: 05/04/2023] [Accepted: 09/28/2023] [Indexed: 10/05/2023]
Abstract
INTRODUCTION Acute gastrointestinal cramping pain (GICP) is a debilitating condition that affects many people worldwide, significantly reducing their quality of life. As such, prompt treatment is crucial. AREAS COVERED This article will explore relevant literature from databases such as PubMed, Scopus, Google Scholar, Cochrane Library, and Web of Science. Additionally, we searched ClinicalTrials.gov and the WHO ICTRP database for the latest clinical trials. EXPERT OPINION Consensus dictates that antispasmodics such as hyoscine-N-butyl bromide and mebeverine should be the primary treatment for GICP. If these prove ineffective, patients can switch to an antispasmodic with a different mode of action or add acetaminophen/NSAIDs for more severe cases. Currently, several antispasmodics are undergoing clinical trials, including drotaverine, alverine, pinaverium, otilonium bromide, fenoverine, tiropramide, otilonium bromide, trimebutine, and peppermint oil. Well-designed head-to-head studies are necessary to evaluate current antispasmodics' safety, efficacy, pharmacokinetic, and pharmacoeconomics profiles. Recent studies have shown that fixed-dose combinations of antispasmodics + NSAIDs or two different antispasmodics can improve patient compliance and synergistically reduce GICP. Therefore, it is recommended that the global availability and accessibility of these products be enhanced.
Collapse
Affiliation(s)
- Taraneh Mousavi
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), Tehran University of Medical Sciences, Tehran, Iran
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammadhossein Sharifnia
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), Tehran University of Medical Sciences, Tehran, Iran
| | - Shekoufeh Nikfar
- Department of Pharmacoeconomics and Pharmaceutical Administration, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Personalized Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Abdollahi
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), Tehran University of Medical Sciences, Tehran, Iran
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Personalized Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
11
|
Elbeltagi R, Al-Beltagi M, Saeed NK, Bediwy AS. COVID-19-induced gastrointestinal autonomic dysfunction: A systematic review. World J Clin Cases 2023; 11:5246-5266. [DOI: 10.12998/wjcc.v11.i22.5246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 06/10/2023] [Accepted: 07/03/2023] [Indexed: 08/03/2023] Open
Abstract
In recent years, because of the growing desire to improve the noninvasiveness and safety of tumor treatments, sonodynamic therapy has gradually become a popular research topic. However, due to the complexity of the therapeutic process, the relevant mechanisms have not yet been fully elucidated. One of the widely accepted possibilities involves the effect of reactive oxygen species. In this review, the mechanism of reactive oxygen species production by sonodynamic therapy (SDT) and ways to enhance the sonodynamic production of reactive oxygen species are reviewed. Then, the clinical application and limitations of SDT are discussed. In conclusion, current research on sonodynamic therapy should focus on the development of sonosensitizers that efficiently produce active oxygen, exhibit biological safety, and promote the clinical transformation of sonodynamic therapy.
Collapse
Affiliation(s)
- Reem Elbeltagi
- Department of Medicine, The Royal College of Surgeons in Ireland-Medical University of Bahrain, Busiateen 15503, Muharraq, Bahrain
| | - Mohammed Al-Beltagi
- Department of Paediatrics, Faculty of Medicine, Tanta University, Tanta 31511, Algharbia, Egypt
- Department of Paediatrics, University Medical Center, Arabian Gulf University, Manama 26671, Manama, Bahrain
- Department of Paediatrics, University Medical Center, King Abdulla Medical City, Arabian Gulf University, Dr Sulaiman Al Habib Medical Group, Manama 26671, Manama, Bahrain
| | - Nermin Kamal Saeed
- Medical Microbiology Section, Pathology Department, Salmaniya Medical Complex, Ministry of Health, Kingdom of Bahrain, Manama 12, Manama, Bahrain
- Microbiology Section, Pathology Department, The Royal College of Surgeons in Ireland-Medical University of Bahrain, Busaiteen 15503, Muharraq, Bahrain
| | - Adel Salah Bediwy
- Department of Chest Disease, Faculty of Medicine, Tanta University, Tanta 31527, Algharbia, Egypt
- Department of Pulmonology, University Medical Center, King Abdulla Medical City, Arabian Gulf University, Dr Sulaiman Al Habib Medical Group, Manama 26671, Manama, Bahrain
| |
Collapse
|
|
12
|
Elbeltagi R, Al-Beltagi M, Saeed NK, Bediwy AS. COVID-19-induced gastrointestinal autonomic dysfunction: A systematic review. World J Clin Cases 2023; 11:5252-5272. [PMID: 37621592 PMCID: PMC10445067 DOI: 10.12998/wjcc.v11.i22.5252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 06/10/2023] [Accepted: 07/03/2023] [Indexed: 08/04/2023] Open
Abstract
BACKGROUND It is common for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection to occur in the gastrointestinal tract, which can present itself as an initial symptom. The severity of coronavirus disease 2019 (COVID-19) is often reflected in the prevalence of gastrointestinal symptoms. COVID-19 can damage the nerve supply to the digestive system, leading to gastrointestinal autonomic dysfunction. There is still much to learn about how COVID-19 affects the autonomic nervous system and the gastrointestinal tract. AIM To thoroughly explore the epidemiology and clinical aspects of COVID-19-induced gastrointestinal autonomic dysfunction, including its manifestations, potential mechanisms, diagnosis, differential diagnosis, impact on quality of life, prognosis, and management and prevention strategies. METHODS We conducted a thorough systematic search across various databases and performed an extensive literature review. Our review encompassed 113 studies published in English from January 2000 to April 18, 2023. RESULTS According to most of the literature, gastrointestinal autonomic dysfunction can seriously affect a patient's quality of life and ultimate prognosis. Numerous factors can influence gastrointestinal autonomic nervous functions. Studies have shown that SARS-CoV-2 has a well-documented affinity for both neural and gastrointestinal tissues, and the virus can produce various gastrointestinal symptoms by reaching neural tissues through different pathways. These symptoms include anorexia, dysgeusia, heartburn, belching, chest pain, regurgitation, vomiting, epigastric burn, diarrhea, abdominal pain, bloating, irregular bowel movements, and constipation. Diarrhea is the most prevalent symptom, followed by anorexia, nausea, vomiting, and abdominal pain. Although COVID-19 vaccination may rarely induce autonomic dysfunction and gastrointestinal symptoms, COVID-19-induced autonomic effects significantly impact the patient's condition, general health, prognosis, and quality of life. Early diagnosis and proper recognition are crucial for improving outcomes. It is important to consider the differential diagnosis, as these symptoms may be induced by diseases other than COVID-19-induced autonomic dysfunction. Treating this dysfunction can be a challenging task. CONCLUSION To ensure the best possible outcomes for COVID-19 patients, it is essential to take a multidisciplinary approach involving providing supportive care, treating the underlying infection, managing dysfunction, monitoring for complications, and offering nutritional support. Close monitoring of the patient's condition is crucial, and prompt intervention should be taken if necessary. Furthermore, conducting thorough research on the gastrointestinal autonomic dysfunction caused by COVID-19 is vital to manage it effectively.
Collapse
Affiliation(s)
- Reem Elbeltagi
- Department of Medicine, The Royal College of Surgeons in Ireland-Medical University of Bahrain, Busiateen 15503, Muharraq, Bahrain
| | - Mohammed Al-Beltagi
- Department of Paediatrics, Faculty of Medicine, Tanta University, Tanta 31511, Algharbia, Egypt
- Department of Paediatrics, University Medical Center, Arabian Gulf University, Manama 26671, Manama, Bahrain
- Department of Paediatrics, University Medical Center, King Abdulla Medical City, Arabian Gulf University, Dr Sulaiman Al Habib Medical Group, Manama 26671, Manama, Bahrain
| | - Nermin Kamal Saeed
- Medical Microbiology Section, Pathology Department, Salmaniya Medical Complex, Ministry of Health, Kingdom of Bahrain, Manama 12, Manama, Bahrain
- Microbiology Section, Pathology Department, The Royal College of Surgeons in Ireland-Medical University of Bahrain, Busaiteen 15503, Muharraq, Bahrain
| | - Adel Salah Bediwy
- Department of Chest Disease, Faculty of Medicine, Tanta University, Tanta 31527, Algharbia, Egypt
- Department of Pulmonology, University Medical Center, King Abdulla Medical City, Arabian Gulf University, Dr Sulaiman Al Habib Medical Group, Manama 26671, Manama, Bahrain
| |
Collapse
|
|
13
|
Osman U, Latha Kumar A, Sadagopan A, Mahmoud A, Begg M, Tarhuni M, N Fotso M, Gonzalez NA, Sanivarapu RR. The Effects of Serotonin Receptor Type 7 Modulation on Bowel Sensitivity and Smooth Muscle Tone in Patients With Irritable Bowel Syndrome. Cureus 2023; 15:e42532. [PMID: 37637561 PMCID: PMC10460130 DOI: 10.7759/cureus.42532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Accepted: 07/26/2023] [Indexed: 08/29/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a gut-brain disorder involving alterations in intestinal sensitivity and motility. Currently, IBS has no cure, and treatment focuses on the management of symptoms. The diverse, and sometimes contradictory, collections of symptoms reported across the different subtypes of IBS make treatment, as well as diagnosis, difficult for physicians. All subtypes of IBS have one symptom in common: abdominal pain caused by differences in the level of visceral sensitivity. Though current research on this topic is in its infancy, some researchers have proven, through experimental studies, that 5-hydroxytryptamine (serotonin) receptor type 7 (5-HT7) affects both visceral sensitivity and smooth muscle tone in the bowel. Therefore, this review will be discussing the future possibility of alleviating abdominal pain in patients with IBS and related disorders by modulating the 5-HT7 receptor.
Collapse
Affiliation(s)
- Usama Osman
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Abishek Latha Kumar
- Internal Medicine, Pediatrics, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Aishwarya Sadagopan
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Anas Mahmoud
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Maha Begg
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Mawada Tarhuni
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Monique N Fotso
- Obstetrics and Gynecology, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Natalie A Gonzalez
- Pediatrics, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Raghavendra R Sanivarapu
- Pulmonary and Critical Care Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| |
Collapse
|
|
14
|
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
|
|
15
|
Spinal cord astrocyte P2X7Rs mediate the inhibitory effect of electroacupuncture on visceral hypersensitivity of rat with irritable bowel syndrome. Purinergic Signal 2023; 19:43-53. [PMID: 35389158 PMCID: PMC9984627 DOI: 10.1007/s11302-021-09830-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 11/17/2021] [Indexed: 10/18/2022] Open
Abstract
This study explored the role of P2X7 receptors in spinal cord astrocytes in the electroacupuncture-induced inhibition of visceral hypersensitivity (VH) in rats with irritable bowel syndrome (IBS). Visceral hypersensitivity of IBS was intracolonically induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS). Visceromotor responses to colorectal distension (CRD-20,40,60,80 mmHg) and abdominal withdrawal reflex scoring (AWRs) were recorded after electroacupuncture at bilateral Zusanli (ST36) and Sanyinjiao (SP6) acupoints to evaluate the analgesic effect of electroacupuncture on visceral pain in rats with IBS. Fluorocitric acid (FCA), an astrocyte activity inhibitor, was injected intrathecally before electroacupuncture intervention and AWRs were recorded. Western blot and real-time qPCR were used to detect the expression of NMDA and P2X7 receptor to observe the regulation effect of electroacupuncture on NMDA receptor in the spinal cord of rats with visceral hypersensitivity. Intrathecal injection of P2X7 agonist or antagonist was administered before electroacupuncture treatment. To observe the effect of P2X7 receptor in spinal astrocytes on the inhibition of visceral hyperalgesia by electroacupuncture, the changes of AWR score, NMDA receptor in the spinal cord, and GFAP expression in astrocytes were detected. Inflammation of the colon had basically subsided at day 21 post-TNBS; persistent visceral hypersensitivity could be suppressed by electroacupuncture. This analgesic effect could be inhibited by FCA. The analgesic effect, downregulation of NMDA receptor NR1 subunit, and P2X7 protein of electroacupuncture were all reversed by FCA. P2X7 receptor antagonist A740003 can cooperate with EA to carry out analgesic effect in rats with visceral pain and downregulate the expression of NR1, NR2B, and GFAP in spinal dorsal horn. However, the P2X7 receptor agonist BzATP could partially reverse the analgesic effect of EA, inhibiting the downregulatory effect of EA on the expression of NR1, NR2B, and GFAP. These results indicate that EA may downregulate the expression of the NMDA receptor by inhibiting the P2X7 receptor in the spinal cord, thereby inhibiting spinal cord sensitization in IBS rats with visceral pain, in which astrocytes are an important medium.
Collapse
|
|
16
|
Outcome predictors and clinical presentation of syringomyelia. Asian J Surg 2023; 46:705-711. [PMID: 35868963 DOI: 10.1016/j.asjsur.2022.06.150] [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: 11/29/2021] [Accepted: 06/30/2022] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND The prognosis of syringomyelia is not yet established. Syringomyelia derived from different etiologies contributes to similar symptoms. OBJECTIVE Assess the syringomyelia in our medical institutes and describe the etiologies and clinical appearance of the disorder. And identify the predictors of a good outcome and to find the most suitable timing of surgical intervention according to our results. METHODS This retrospective cohort study used databases in our hospitals to analyze 70 cases of syringomyelia between 1997 and 2014. All available information was obtained from medical records and radiological reports. We used American Spinal Injuries Association disability scores (ASIA scores), the modified Nurick classification system, and recorded the number of days the patient was hospitalized, for neurological and functional assessment. Univariate and multivariate analyses were used to evaluate the relationship between clinical factors and outcomes. RESULTS Non-communicating syringomyelia was the most common type of syringomyelia. In univariate analysis, autonomic dysfunction and motor impairment were strong predictors of poor neurological and functional outcomes. In addition to the above factors, syrinxes at the cervical level predicted better functional outcomes than at any spinal level in multivariate analysis. CONCLUSIONS Motor impairment, which is commonly seen in patients with syringomyelia in Taiwan, is a strong predictor to poor neurological and functional outcomes. Our study indicates that patients without autonomic dysfunction or motor impairment should receive timely surgical intervention to prevent symptomatic deterioration. We also found that cervical syringomyelia in particular has the potential for good functional recovery after adequate intervention.
Collapse
|
|
17
|
Luz-Veiga M, Azevedo-Silva J, Fernandes JC. Beyond Pain Relief: A Review on Cannabidiol Potential in Medical Therapies. Pharmaceuticals (Basel) 2023; 16:155. [PMID: 37259306 PMCID: PMC9958812 DOI: 10.3390/ph16020155] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/11/2023] [Accepted: 01/17/2023] [Indexed: 07/30/2023] Open
Abstract
The phytocannabinoid cannabidiol (CBD) is receiving increasing attention due to its pharmacological properties. Although CBD is extracted from Cannabis sativa, it lacks the psychoactive effects of Δ9-tetrahydrocannabinol (THC) and has become an attractive compound for pharmacological uses due to its anti-inflammatory, antioxidant, anticonvulsant, and anxiolytic potential. The molecular mechanisms involved in CBD's biological effects are not limited to its interaction with classical cannabinoid receptors, exerting anti-inflammatory or pain-relief effects. Several pieces of evidence demonstrate that CBD interacts with other receptors and cellular signaling cascades, which further support CBD's therapeutic potential beyond pain management. In this review, we take a closer look at the molecular mechanisms of CBD and its potential therapeutic application in the context of cancer, neurodegeneration, and autoimmune diseases.
Collapse
Affiliation(s)
- Mariana Luz-Veiga
- CBQF—Centro de Biotecnologia e Química Fina—Laboratório Associado, Escola Superior de Biotecnologia, Universidade Católica Portuguesa, 4169-005 Porto, Portugal
| | - João Azevedo-Silva
- CBQF—Centro de Biotecnologia e Química Fina—Laboratório Associado, Escola Superior de Biotecnologia, Universidade Católica Portuguesa, 4169-005 Porto, Portugal
| | - João C. Fernandes
- CBQF—Centro de Biotecnologia e Química Fina—Laboratório Associado, Escola Superior de Biotecnologia, Universidade Católica Portuguesa, 4169-005 Porto, Portugal
- Amyris Bio Products Portugal, Unipessoal Lda, 4169-005 Porto, Portugal
| |
Collapse
|
|
18
|
Management of Pelvic Pain in Patients with Crohn's Disease-Current Overview. J Clin Med 2023; 12:jcm12020526. [PMID: 36675454 PMCID: PMC9862261 DOI: 10.3390/jcm12020526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 12/29/2022] [Accepted: 01/04/2023] [Indexed: 01/11/2023] Open
Abstract
Crohn's disease (CD) is a subtype of chronic inflammatory bowel diseases (IBD) with characteristic skip lesions and transmural inflammation that may affect the entire gastrointestinal tract from the mouth to the anus. Persistent pain is one of the main symptoms of CD. This pain has multifactorial pathogenesis, but most often arises from intestinal inflammation itself, as well as from gut distention or partial intestinal obstruction. Some current evidence also suggests sensitization of sensory pathways, as well as modulation of those signals by the central nervous system, which highlights the impact of biopsychosocial factors. To date, most studies have focused only on the pain located in the abdomen, while pelvic pain has rarely been explored, despite it being a common symptom. The aim of this study is to provide an abbreviated summary of the current state of knowledge on the origins and treatment of pelvic pain in CD.
Collapse
|
|
19
|
Ceuleers H, Hanning N, De bruyn M, De Man JG, De Schepper HU, Li Q, Liu L, Abrams S, Smet A, Joossens J, Augustyns K, De Meester I, Pasricha PJ, De Winter BY. The Effect of Serine Protease Inhibitors on Visceral Pain in Different Rodent Models With an Intestinal Insult. Front Pharmacol 2022; 13:765744. [PMID: 35721192 PMCID: PMC9201642 DOI: 10.3389/fphar.2022.765744] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 05/02/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Serine proteases are believed to play a key role in the origin of abdominal pain in IBD and IBS. We previously demonstrated a reduction of visceral pain in a post-inflammatory IBS rat model after a single intraperitoneal or intracolonic administration of a serine protease inhibitor. The aim of this study was to investigate the efficacy of serine protease inhibition on visceral pain in two different animal models involving a colonic insult based either on acute inflammation or on neonatal irritation. Moreover, protease profiling was explored in the acute colitis model. Methods: An acute 2,4,6-trinitrobenzenesulphonic acid (TNBS) colitis rat model and a chronic neonatal acetic acid mouse model were used in this study. Visceral sensitivity was quantified by visceromotor responses (VMRs) to colorectal distension, 30 min after intraperitoneal administration of the serine protease inhibitors nafamostat, UAMC-00050 or their vehicles. Colonic samples from acute colitis rats were used to quantify the mRNA expression of a panel of serine proteases and mast cell tryptase by immunohistochemistry. Finally, proteolytic activities in colonic and fecal samples were characterized using fluorogenic substrates. Key Results: We showed a significant and pressure-dependent increase in visceral hypersensitivity in acute colitis and neonatal acetic acid models. UAMC-00050 and nafamostat significantly reduced VMRs in both animal models. In acute colitis rats, the administration of a serine protease inhibitor did not affect the inflammatory parameters. Protease profiling of these acute colitis animals revealed an increased tryptase immunoreactivity and a downregulation of matriptase at the mRNA level after inflammation. The administration of UAMC-00050 resulted in a decreased elastase-like activity in the colon associated with a significantly increased elastase-like activity in fecal samples of acute colitis animals. Conclusion: In conclusion, our results suggest that serine proteases play an important role in visceral hypersensitivity in an acute TNBS colitis model in rats and a neonatal acetic acid model in mice. Moreover, we hypothesize a potential mechanism of action of UAMC-00050 via the alteration of elastase-like proteolytic activity in acute inflammation. Taken together, we provided fundamental evidence for serine protease inhibitors as a promising new therapeutic strategy for abdominal pain in gastrointestinal diseases.
Collapse
Affiliation(s)
- Hannah Ceuleers
- Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerp, Belgium
- Center for Neurogastroenterology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- Infla-Med, Centre of Excellence, University of Antwerp, Antwerp, Belgium
| | - Nikita Hanning
- Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerp, Belgium
- Infla-Med, Centre of Excellence, University of Antwerp, Antwerp, Belgium
| | - Michelle De bruyn
- Infla-Med, Centre of Excellence, University of Antwerp, Antwerp, Belgium
- Laboratory of Medical Biochemistry, University of Antwerp, Antwerp, Belgium
| | - Joris G De Man
- Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerp, Belgium
- Infla-Med, Centre of Excellence, University of Antwerp, Antwerp, Belgium
| | - Heiko U De Schepper
- Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerp, Belgium
- Infla-Med, Centre of Excellence, University of Antwerp, Antwerp, Belgium
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
| | - Qian Li
- Center for Neurogastroenterology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Liansheng Liu
- Center for Neurogastroenterology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Steven Abrams
- Global Health Institute, University of Antwerp, Antwerp, Belgium
- Data Science Institute, UHasselt, Hasselt, Belgium
| | - Annemieke Smet
- Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerp, Belgium
- Infla-Med, Centre of Excellence, University of Antwerp, Antwerp, Belgium
| | - Jurgen Joossens
- Laboratory of Medicinal Chemistry, University of Antwerp, Antwerp, Belgium
| | - Koen Augustyns
- Infla-Med, Centre of Excellence, University of Antwerp, Antwerp, Belgium
- Laboratory of Medicinal Chemistry, University of Antwerp, Antwerp, Belgium
| | - Ingrid De Meester
- Infla-Med, Centre of Excellence, University of Antwerp, Antwerp, Belgium
- Laboratory of Medical Biochemistry, University of Antwerp, Antwerp, Belgium
| | - Pankaj J Pasricha
- Center for Neurogastroenterology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Benedicte Y De Winter
- Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerp, Belgium
- Infla-Med, Centre of Excellence, University of Antwerp, Antwerp, Belgium
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium
| |
Collapse
|
|
20
|
Wen L, Tang L, Zhang M, Wang C, Li S, Wen Y, Tu H, Tian H, Wei J, Liang P, Yang C, Li G, Gao Y. Gallic Acid Alleviates Visceral Pain and Depression via Inhibition of P2X7 Receptor. Int J Mol Sci 2022; 23:ijms23116159. [PMID: 35682841 PMCID: PMC9181225 DOI: 10.3390/ijms23116159] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 05/30/2022] [Accepted: 05/30/2022] [Indexed: 12/12/2022] Open
Abstract
Chronic visceral pain can occur in many disorders, the most common of which is irritable bowel syndrome (IBS). Moreover, depression is a frequent comorbidity of chronic visceral pain. The P2X7 receptor is crucial in inflammatory processes and is closely connected to developing pain and depression. Gallic acid, a phenolic acid that can be extracted from traditional Chinese medicine, has been demonstrated to be anti-inflammatory and anti-depressive. In this study, we investigated whether gallic acid could alleviate comorbid visceral pain and depression by reducing the expression of the P2X7 receptor. To this end, the pain thresholds of rats with comorbid visceral pain and depression were gauged using the abdominal withdraw reflex score, whereas the depression level of each rat was quantified using the sucrose preference test, the forced swimming test, and the open field test. The expressions of the P2X7 receptor in the hippocampus, spinal cord, and dorsal root ganglion (DRG) were assessed by Western blotting and quantitative real-time PCR. Furthermore, the distributions of the P2X7 receptor and glial fibrillary acidic protein (GFAP) in the hippocampus and DRG were investigated in immunofluorescent experiments. The expressions of p-ERK1/2 and ERK1/2 were determined using Western blotting. The enzyme-linked immunosorbent assay was utilized to measure the concentrations of IL-1β, TNF-α, and IL-10 in the serum. Our results demonstrate that gallic acid was able to alleviate both pain and depression in the rats under study. Gallic acid also reduced the expressions of the P2X7 receptor and p-ERK1/2 in the hippocampi, spinal cords, and DRGs of these rats. Moreover, gallic acid treatment decreased the serum concentrations of IL-1β and TNF-α, while raising IL-10 levels in these rats. Thus, gallic acid may be an effective novel candidate for the treatment of comorbid visceral pain and depression by inhibiting the expressions of the P2X7 receptor in the hippocampus, spinal cord, and DRG.
Collapse
Affiliation(s)
- Lequan Wen
- Joint Program of Nanchang University and Queen Mary University of London, Nanchang University, 461 Bayi Avenue, Nanchang 330006, China; (L.W.); (L.T.); (H.T.); (C.Y.)
| | - Lirui Tang
- Joint Program of Nanchang University and Queen Mary University of London, Nanchang University, 461 Bayi Avenue, Nanchang 330006, China; (L.W.); (L.T.); (H.T.); (C.Y.)
| | - Mingming Zhang
- Department of Physiology, Basic Medical College, Nanchang University, 461 Bayi Avenue, Nanchang 330006, China; (M.Z.); (Y.W.); (G.L.)
| | - Congrui Wang
- Second Clinic Medical College, Nanchang University, 461 Bayi Avenue, Nanchang 330006, China; (C.W.); (S.L.); (P.L.)
| | - Shujuan Li
- Second Clinic Medical College, Nanchang University, 461 Bayi Avenue, Nanchang 330006, China; (C.W.); (S.L.); (P.L.)
| | - Yuqing Wen
- Department of Physiology, Basic Medical College, Nanchang University, 461 Bayi Avenue, Nanchang 330006, China; (M.Z.); (Y.W.); (G.L.)
| | - Hongcheng Tu
- Basic Medical College, Nanchang University, 461 Bayi Avenue, Nanchang 330006, China; (H.T.); (J.W.)
| | - Haokun Tian
- Joint Program of Nanchang University and Queen Mary University of London, Nanchang University, 461 Bayi Avenue, Nanchang 330006, China; (L.W.); (L.T.); (H.T.); (C.Y.)
| | - Jingyi Wei
- Basic Medical College, Nanchang University, 461 Bayi Avenue, Nanchang 330006, China; (H.T.); (J.W.)
| | - Peiwen Liang
- Second Clinic Medical College, Nanchang University, 461 Bayi Avenue, Nanchang 330006, China; (C.W.); (S.L.); (P.L.)
| | - Changsen Yang
- Joint Program of Nanchang University and Queen Mary University of London, Nanchang University, 461 Bayi Avenue, Nanchang 330006, China; (L.W.); (L.T.); (H.T.); (C.Y.)
| | - Guodong Li
- Department of Physiology, Basic Medical College, Nanchang University, 461 Bayi Avenue, Nanchang 330006, China; (M.Z.); (Y.W.); (G.L.)
| | - Yun Gao
- Department of Physiology, Basic Medical College, Nanchang University, 461 Bayi Avenue, Nanchang 330006, China; (M.Z.); (Y.W.); (G.L.)
- Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, 461 Bayi Avenue, Nanchang 330006, China
- Correspondence: ; Tel.: +86-791-86360586
| |
Collapse
|
|
21
|
Decraecker L, Boeckxstaens G, Denadai-Souza A. Inhibition of Serine Proteases as a Novel Therapeutic Strategy for Abdominal Pain in IBS. Front Physiol 2022; 13:880422. [PMID: 35665224 PMCID: PMC9161638 DOI: 10.3389/fphys.2022.880422] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 04/26/2022] [Indexed: 02/06/2023] Open
Abstract
Serine proteases are heavily present in the gastrointestinal tract where they are essential in numerous physiological processes. An imbalance in the proteolytic activity is a central mechanism underlying abdominal pain in irritable bowel syndrome (IBS). Therefore, protease inhibitors are emerging as a promising therapeutic tool to manage abdominal pain in this functional gastrointestinal disorder. With this review, we provide an up-to-date overview of the implications of serine proteases in the development of abdominal pain in IBS, along with a critical assessment of the current developments and prospects of protease inhibitors as a therapeutic tool. In particular, we highlight the current knowledge gap concerning the identity of dysregulated serine proteases that are released by the rectal mucosa of IBS patients. Finally, we suggest a workflow with state-of-the-art techniques that will help address the knowledge gap, guiding future research towards the development of more effective and selective protease inhibitors to manage abdominal pain in IBS.
Collapse
|
|
22
|
Lin CH, Lin HY, Ho EP, Ke YC, Cheng MF, Shiue CY, Wu CH, Liao PH, Hsu AYH, Chu LA, Liu YD, Lin YH, Tai YC, Shun CT, Chiu HM, Wu MS. Reply to: "Letter to the Editor by Derkinderen and Colleagues". Mov Disord 2022; 37:665-666. [PMID: 35092086 PMCID: PMC9306538 DOI: 10.1002/mds.28947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 01/16/2022] [Indexed: 11/28/2022] Open
Affiliation(s)
- Chin-Hsien Lin
- Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Han-Yi Lin
- Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - En-Pong Ho
- Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yi-Ci Ke
- Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Mei-Fang Cheng
- Department of Nuclear Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chyng-Yann Shiue
- Department of Nuclear Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chi-Han Wu
- Department of Nuclear Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
| | | | | | - Li-An Chu
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan.,Brain Research Center, National Tsing Hua University, Hsinchu, Taiwan
| | - Ya-Ding Liu
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan.,Brain Research Center, National Tsing Hua University, Hsinchu, Taiwan
| | - Ya-Hui Lin
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan.,Brain Research Center, National Tsing Hua University, Hsinchu, Taiwan
| | - Yi-Cheng Tai
- Department of Neurology, E-Da Hospital, Kaohsiung, Taiwan
| | - Chia-Tung Shun
- Department of Pathology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Han-Mo Chiu
- Department of Integrated Diagnostics & Therapeutics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Ming-Shiang Wu
- Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
| |
Collapse
|
|
23
|
Paine P. Review article: current and future treatment approaches for pain in IBS. Aliment Pharmacol Ther 2021; 54 Suppl 1:S75-S88. [PMID: 34927753 DOI: 10.1111/apt.16550] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 07/15/2021] [Accepted: 07/15/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Abdominal pain is a core symptom of IBS and a primary driver of care seeking. Visceral hypersensitivity is a key pathophysiological mechanism and therapeutic target for pain in IBS, with components of peripheral and central sensitisation and psychological factors. AIM To review current and future treatment approaches specifically for the pain component of IBS. METHODS Pubmed search terms included combinations of irritable bowel, pain, visceral hypersensitivity, novel, new, emerging, future and advances. RESULTS Established non-pharmacological treatments for IBS pain include the low FODMAP diet, probiotics and psychological interventions, especially hypnotherapy. Tricyclics remain the best evidenced pharmacological approach with GCC agonists, tenapanor, lubiprostone, eluxadoline and 5HT3 antagonists second line according to patient characteristics and availability. Less well-evidenced current options include anti-spasmodics, peppermint oil, SSRIs, SNRIs, alpha 2 delta ligands, melatonin and histamine antagonists. Patients are vulnerable to iatrogenesis and harmful approaches to be avoided include opioids and unwarranted surgical interventions. For severe pain, the concept of augmentation with combined gut-brain neuromodulators and psychotherapy in a multi-disciplinary setting is considered. A plethora of molecular targets and ligands are emerging from pre-clinical studies, together with early clinical evidence for a range of pharmacological, dietary, neurostimulation and novel psychological treatment delivery methods which are reviewed. The history of such emerging approaches, however, merits both caution and optimism in equal measure. CONCLUSIONS Despite good in-roads and emerging options, the management of abdominal pain remains one of the biggest challenges and research priorities for patients with IBS.
Collapse
Affiliation(s)
- Peter Paine
- Department of Gastroenterology, University of Manchester, Salford Royal Foundation Trust, Salford, UK
| |
Collapse
|
|
24
|
Takahashi K, Khwaja IG, Schreyer JR, Bulmer D, Peiris M, Terai S, Aziz Q. Post-inflammatory Abdominal Pain in Patients with Inflammatory Bowel Disease During Remission: A Comprehensive Review. CROHN'S & COLITIS 360 2021; 3:otab073. [PMID: 36777266 PMCID: PMC9802269 DOI: 10.1093/crocol/otab073] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Indexed: 11/13/2022] Open
Abstract
Patients with inflammatory bowel disease often experience ongoing pain even after achieving mucosal healing (i.e., post-inflammatory pain). Factors related to the brain-gut axis, such as peripheral and central sensitization, altered sympatho-vagal balance, hypothalamic-pituitary-adrenal axis activation, and psychosocial factors, play a significant role in the development of post-inflammatory pain. A comprehensive study investigating the interaction between multiple predisposing factors, including clinical psycho-physiological phenotypes, molecular mechanisms, and multi-omics data, is still needed to fully understand the complex mechanism of post-inflammatory pain. Furthermore, current treatment options are limited and new treatments consistent with the underlying pathophysiology are needed to improve clinical outcomes.
Collapse
Affiliation(s)
- Kazuya Takahashi
- Centre for Neuroscience, Surgery and Trauma, Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Iman Geelani Khwaja
- Centre for Neuroscience, Surgery and Trauma, Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Jocelyn Rachel Schreyer
- Centre for Neuroscience, Surgery and Trauma, Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - David Bulmer
- Department of Pharmacology, University of Cambridge, Cambridge, UK
| | - Madusha Peiris
- Centre for Neuroscience, Surgery and Trauma, Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Qasim Aziz
- Centre for Neuroscience, Surgery and Trauma, Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| |
Collapse
|
|
25
|
Helwig U, Koch AK, Reichel C, Jessen P, Büning J, Schreiber S, Langhorst J. A Prospective Multicenter Study on the Prevalence of Fructose Malabsorption in Patients with Chronic Inflammatory Bowel Disease. Digestion 2021; 102:397-403. [PMID: 32516791 DOI: 10.1159/000507851] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 04/12/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Patients with chronic inflammatory bowel disease (IBD) might have a higher prevalence of fructose malabsorption than healthy controls. This study's aim was to determine the prevalence and symptom severity of fructose malabsorption in patients with active and inactive IBD. METHODS The present study was a multicenter noninterventional diagnostic pilot trial. Two hundred fifty-one participants were recruited from 12 outpatient clinics for internal medicine across Germany and from the University of Kiel. Fructose malabsorption was diagnosed by hydrogen breath testing. Patients diagnosed with bacterial overgrowth, non-H2 producers, and patients who were tested positive for lactose malabsorption were excluded. Gastrointestinal symptoms during breath testing were evaluated using four-point subjective items to determine severity of bloating, abdominal pain, and diarrhea. RESULTS Two hundred five patients (45 with active IBD, 80 with IBD in remission, and 81 healthy controls) were analyzed. The number of patients diagnosed with fructose malabsorption - 35/44 (79.6%) in patients with active IBD, 59/80 (73.8%) inactive IBD, and 66/81 (81.5%) in healthy controls - did not differ between the groups (χ2 [2, N = 205] = 1.48, p = 0.48). However, abdominal pain was more frequent in patients with active IBD than patients with IBD in remission (z = -2.936, p = 0.010), and diarrhea was more frequent in patients with active IBD than in healthy controls (z = 2.489, p = 0.038). CONCLUSIONS Fructose malabsorption is not more common among patients with IBD than healthy subjects. However, the greater prevalence of patient-reported symptoms among patients with IBD may be of pathological and therapeutic relevance.
Collapse
Affiliation(s)
- Ulf Helwig
- Medical Practice for Internal Medicine Oldenburg, Oldenburg, Germany, .,Department of Internal Medicine, Christian-Albrechts University of Kiel, Kiel, Germany,
| | - Anna K Koch
- Department of Internal and Integrative Medicine, Kliniken Essen-Mitte, Faculty of Medicine Essen, University of Duisburg-Essen, Essen, Germany
| | - Christoph Reichel
- Rehabilitation Center Bad Brückenau, Clinic Hartwald, Bad Brückenau, Germany.,Institute of Hygiene and Public Health, Bad Brückenau, Germany
| | - Petra Jessen
- Medical Practice for Internal Medicine, Kiel, Germany
| | - Jürgen Büning
- Medical Practice for Gastroenterology Lübeck, Lübeck, Germany
| | - Stefan Schreiber
- Department of Internal Medicine, Christian-Albrechts University of Kiel, Kiel, Germany
| | - Jost Langhorst
- Department of Internal and Integrative Medicine, Klinikum Bamberg, Bamberg, Germany.,Chair for Integrative Medicine, Faculty of Medicine, University of Duisburg-Essen, Essen, Germany
| | | |
Collapse
|
|
26
|
Kuwahara A, Matsuda K, Kuwahara Y, Asano S, Inui T, Marunaka Y. Microbiota-gut-brain axis: enteroendocrine cells and the enteric nervous system form an interface between the microbiota and the central nervous system. Biomed Res 2021; 41:199-216. [PMID: 33071256 DOI: 10.2220/biomedres.41.199] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The microbiota-gut-brain axis transmits bidirectional communication between the gut and the central nervous system and links the emotional and cognitive centers of the brain with peripheral gut functions. This communication occurs along the axis via local, paracrine, and endocrine mechanisms involving a variety of gut-derived peptide/amine produced by enteroendocrine cells. Neural networks, such as the enteric nervous system, and the central nervous system, including the autonomic nervous system, also transmit information through the microbiota-gut-brain axis. Recent advances in research have described the importance of the gut microbiota in influencing normal physiology and contributing to disease. We are only beginning to understand this bidirectional communication system. In this review, we summarize the available data supporting the existence of these interactions, highlighting data related to the contribution of enteroendocrine cells and the enteric nervous system as an interface between the gut microbiota and brain.
Collapse
Affiliation(s)
- Atsukazu Kuwahara
- Research Unit for Epithelial Physiology and Research Center for Drug Discovery and Pharmaceutical Development Science, Research Organization of Science and Technology, Ritsumeikan University
| | - Kyoko Matsuda
- Department of Molecular Physiology, College of Pharmaceutical Sciences, Ritsumeikan University
| | - Yuko Kuwahara
- Research Unit for Epithelial Physiology and Research Center for Drug Discovery and Pharmaceutical Development Science, Research Organization of Science and Technology, Ritsumeikan University
| | - Shinji Asano
- Department of Molecular Physiology, College of Pharmaceutical Sciences, Ritsumeikan University
| | | | - Yoshinori Marunaka
- Research Unit for Epithelial Physiology and Research Center for Drug Discovery and Pharmaceutical Development Science, Research Organization of Science and Technology, Ritsumeikan University.,Department of Molecular Cell Physiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine.,Research Institute for Clinical Physiology, Kyoto Industrial Health Association
| |
Collapse
|
|
27
|
McGing JJ, Radford SJ, Francis ST, Serres S, Greenhaff PL, Moran GW. Review article: The aetiology of fatigue in inflammatory bowel disease and potential therapeutic management strategies. Aliment Pharmacol Ther 2021; 54:368-387. [PMID: 34228817 DOI: 10.1111/apt.16465] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 09/30/2020] [Accepted: 05/20/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Fatigue is the inability to achieve or maintain an expected work output resulting from central or peripheral mechanisms. The prevalence of inflammatory bowel disease (IBD) fatigue can reach 86% in active disease, persisting in 50%-52% of patients with mild to inactive disease. Fatigue is the commonest reason for work absence in IBD, and patients often report fatigue burden to be greater than that of primary disease symptoms. Relatively few evidence-based treatment options exist, and the aetiology is poorly understood. AIM To review the available data and suggest a possible aetiology of IBD fatigue and to consider the efficacy of existing management strategies and highlight potential future interventions. METHODS We reviewed fatigue-related literature in IBD using PubMed database. RESULTS Disease related factors such as inflammation and pharmacological treatments negatively impact skeletal muscle and brain physiology, likely contributing to fatigue symptoms. Secondary factors such as malnutrition, anaemia, sleep disturbance and psychological comorbidity are potential determinants. Immune profile, faecal microbiota composition and physical fitness differ significantly between fatigued and non-fatigued patients, suggesting these may be aetiological factors. Solution-focused therapy, high-dosage thiamine supplementation and biological therapy may reduce fatigue perception in IBD. The effect of physical activity interventions is inconclusive. CONCLUSIONS A multimodal approach is likely required to treat IBD fatigue. Established reversible factors like anaemia, micronutrient deficiencies and active disease should initially be resolved. Psychosocial intervention shows potential efficacy in reducing fatigue perception in quiescent disease. Restoring physical deconditioning by exercise training intervention may further improve fatigue burden.
Collapse
Affiliation(s)
- Jordan J McGing
- School of Medicine, University of Nottingham, Nottingham, UK.,Sir Peter Mansfield Imaging Centre, University of Nottingham, Nottingham, UK
| | - Shellie Jean Radford
- School of Medicine, University of Nottingham, Nottingham, UK.,National Institute of Health Research Nottingham Biomedical Research Centre (NIHR), Nottingham University Hospitals and University of Nottingham, Nottingham, UK
| | - Susan T Francis
- Sir Peter Mansfield Imaging Centre, University of Nottingham, Nottingham, UK.,National Institute of Health Research Nottingham Biomedical Research Centre (NIHR), Nottingham University Hospitals and University of Nottingham, Nottingham, UK
| | - Sébastien Serres
- School of Life Sciences, University of Nottingham, Nottingham, UK
| | - Paul L Greenhaff
- National Institute of Health Research Nottingham Biomedical Research Centre (NIHR), Nottingham University Hospitals and University of Nottingham, Nottingham, UK.,MRC Versus Arthritis Centre for Musculoskeletal Ageing Research, National Institute for Health Research (NIHR), Nottingham Biomedical Research Centre, School of Life Sciences, University of Nottingham, Nottingham, UK
| | - Gordon W Moran
- School of Medicine, University of Nottingham, Nottingham, UK.,National Institute of Health Research Nottingham Biomedical Research Centre (NIHR), Nottingham University Hospitals and University of Nottingham, Nottingham, UK
| |
Collapse
|
|
28
|
Garrett A, Rakhilin N, Wang N, McKey J, Cofer G, Anderson RB, Capel B, Johnson GA, Shen X. Mapping the peripheral nervous system in the whole mouse via compressed sensing tractography. J Neural Eng 2021; 18. [PMID: 33979784 DOI: 10.1088/1741-2552/ac0089] [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: 12/03/2020] [Accepted: 05/12/2021] [Indexed: 11/12/2022]
Abstract
Objective.The peripheral nervous system (PNS) connects the central nervous system with the rest of the body to regulate many physiological functions and is therapeutically targeted to treat diseases such as epilepsy, depression, intestinal dysmotility, chronic pain, and more. However, we still lack understanding of PNS innervation in most organs because the large span, diffuse nature, and small terminal nerve bundle fibers have precluded whole-organism, high resolution mapping of the PNS. We sought to produce a comprehensive peripheral nerve atlas for use in future interrogation of neural circuitry and selection of targets for neuromodulation.Approach.We used diffusion tensor magnetic resonance imaging (DT-MRI) with high-speed compressed sensing to generate a tractogram of the whole mouse PNS. The tractography generated from the DT-MRI data is validated using lightsheet microscopy on optically cleared, antibody stained tissue.Main results.Herein we demonstrate the first comprehensive PNS tractography in a whole mouse. Using this technique, we scanned the whole mouse in 28 h and mapped PNS innervation and fiber network in multiple organs including heart, lung, liver, kidneys, stomach, intestines, and bladder at 70µm resolution. This whole-body PNS tractography map has provided unparalleled information; for example, it delineates the innervation along the gastrointestinal tract by multiple sacral levels and by the vagal nerves. The map enabled a quantitative tractogram that revealed relative innervation of the major organs by each vertebral foramen as well as the vagus nerve.Significance.This novel high-resolution nerve atlas provides a potential roadmap for future neuromodulation therapies and other investigations into the neural circuits which drive homeostasis and disease throughout the body.
Collapse
Affiliation(s)
- Aliesha Garrett
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, United States of America
| | - Nikolai Rakhilin
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, United States of America
| | - Nian Wang
- Duke Center for In Vivo Microscopy, Duke University Medical Center, Durham, NC, United States of America
| | - Jennifer McKey
- Department of Cell Biology, School of Medicine, Duke University, Durham, NC, United States of America
| | - Gary Cofer
- Duke Center for In Vivo Microscopy, Duke University Medical Center, Durham, NC, United States of America
| | - Robert Bj Anderson
- Duke Center for In Vivo Microscopy, Duke University Medical Center, Durham, NC, United States of America
| | - Blanche Capel
- Department of Cell Biology, School of Medicine, Duke University, Durham, NC, United States of America
| | - G Allan Johnson
- Duke Center for In Vivo Microscopy, Duke University Medical Center, Durham, NC, United States of America
| | - Xiling Shen
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, United States of America
| |
Collapse
|
|
29
|
The Role of Epigenomic Regulatory Pathways in the Gut-Brain Axis and Visceral Hyperalgesia. Cell Mol Neurobiol 2021; 42:361-376. [PMID: 34057682 DOI: 10.1007/s10571-021-01108-0] [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] [Received: 01/06/2021] [Accepted: 05/24/2021] [Indexed: 01/07/2023]
Abstract
The gut-brain axis (GBA) is broadly accepted to describe the bidirectional circuit that links the gastrointestinal tract with the central nervous system (CNS). Interest in the GBA has grown dramatically over past two decades along with advances in our understanding of the importance of the axis in the pathophysiology of numerous common clinical disorders including mood disorders, neurodegenerative disease, diabetes mellitus, non-alcohol fatty liver disease (NAFLD) and enhanced abdominal pain (visceral hyperalgesia). Paralleling the growing interest in the GBA, there have been seminal developments in our understanding of how environmental factors such as psychological stress and other extrinsic factors alter gene expression, primarily via epigenomic regulatory mechanisms. This process has been driven by advances in next-generation multi-omics methods and bioinformatics. Recent reviews address various components of GBA, but the role of epigenomic regulatory pathways in chronic stress-associated visceral hyperalgesia in relevant regions of the GBA including the amygdala, spinal cord, primary afferent (nociceptive) neurons, and the intestinal barrier has not been addressed. Rapidly developing evidence suggests that intestinal epithelial barrier dysfunction and microbial dysbiosis play a potentially significant role in chronic stress-associated visceral hyperalgesia in nociceptive neurons innervating the lower intestine via downregulation in intestinal epithelial cell tight junction protein expression and increase in paracellular permeability. These observations support an important role for the regulatory epigenome in the development of future diagnostics and therapeutic interventions in clinical disorders affecting the GBA.
Collapse
|
|
30
|
Mavroudis G, Strid H, Jonefjäll B, Simrén M. Visceral hypersensitivity is together with psychological distress and female gender associated with severity of IBS-like symptoms in quiescent ulcerative colitis. Neurogastroenterol Motil 2021; 33:e13998. [PMID: 33034406 DOI: 10.1111/nmo.13998] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 09/01/2020] [Accepted: 09/07/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND A subset of ulcerative colitis (UC) patients in remission demonstrate IBS-like symptoms. Visceral hypersensitivity is a key pathophysiological mechanism in IBS, but its relevance to IBS-like symptoms in inactive UC remains unclear. METHODS UC patients in remission (UCR) were screened for IBS-like symptoms. Rectal sensitivity was assessed with rectal balloon distensions, with determination of sensory thresholds and unpleasantness/pain intensity ratings. Patients completed questionnaires evaluating gastrointestinal (GI) and psychological symptoms. Age- and gender-matched IBS subjects and healthy controls (HC) also underwent a rectal sensitivity test. KEY RESULTS We included 36 UCR patients (18 with IBS-like symptoms (UCR + IBS) and 18 without (UCR - IBS)), 36 IBS subjects, and 14 HC. UCR and IBS patients were more sensitive to rectal balloon distensions than HC, but no differences between UCR and IBS patients were observed. UCR + IBS patients had lower sensory thresholds and higher unpleasantness ratings than UCR - IBS. In UCR patients, the overall GI symptom severity, pain, and bloating, but not diarrhea, constipation or satiety, were associated with rectal sensitivity. In multivariate analyses, rectal sensitivity, psychological distress, and female gender were identified as factors independently associated with GI symptom severity. 61% of UCR patients demonstrated rectal hypersensitivity, and these patients more commonly reported at least mild bloating and pain, and overall GI symptoms, compared to those with normal rectal sensitivity. CONCLUSION & INFERENCES Visceral hypersensitivity was associated with IBS-like symptoms, in particular pain and bloating, in inactive UC. Together with psychological factors and female gender, visceral hypersensitivity seems to be involved in GI symptom generation in quiescent UC.
Collapse
Affiliation(s)
- Georgios Mavroudis
- Department of Internal Medicine, Kungälv Hospital, Kungälv, Sweden.,Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Hans Strid
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Internal Medicine, Södra Älvsborg Hospital, Borås, Sweden
| | - Börje Jonefjäll
- Department of Internal Medicine, Kungälv Hospital, Kungälv, Sweden.,Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Magnus Simrén
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Internal Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden
| |
Collapse
|
|
31
|
Huang Y, Wang C, Tian X, Mao Y, Hou B, Sun Y, Gu X, Ma Z. Pioglitazone Attenuates Experimental Colitis-Associated Hyperalgesia through Improving the Intestinal Barrier Dysfunction. Inflammation 2021; 43:568-578. [PMID: 31989391 PMCID: PMC7170986 DOI: 10.1007/s10753-019-01138-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Impaired intestinal mucosal integrity during colitis involves the peroxisome proliferator-activated receptor-γ (PPARγ), an important anti-inflammatory factor in intestinal mucosa homoeostasis, which is a potential target in colitis. Recurrent chronic pain is a vital pathogenetic feature of colitis. Nevertheless, potential functions of PPARγ in the colitis-associated hyperalgesia remain unclear. This study aimed to investigate biological roles of pioglitazone in relieving colitis-associated pain hypersensitivity by a PPARγ tight junction protein-dependent mechanism during the course of dextran sodium sulfate (DSS)-induced intestinal inflammation. The DSS-induced colitis model was generated in C57BL/6 mice. Changes in colitis induced the injury of intestinal mucosal barrier and hyperalgesia after a 6-day treatment of pioglitazone (25 mg/kg, IP injection) were assessed through immunofluorescent, hematoxylin and eosin (H&E) staining, western blot analysis, and determination of paw withdrawal mechanical threshold. A significant reduction of paw withdrawal mechanical threshold occurred after DSS treatment. Follow-up data showed that systematic administration of PPARγ agonist pioglitazone ameliorated the DSS-induced colitis and the development of colitis-associated hyperalgesia by repairing the intestinal mucosal barrier. The tight junction proteins ZO-1 and Claudin-5 were upregulated by PPARγ signaling, which in turn promoted the improvement of intestinal barrier function. Moreover, pioglitazone inhibited phosphorylation of ERK and NF-κB in the colon and decreased the levels of inflammatory cytokines in both colon spine tissues. Furthermore, systemically pioglitazone treatment inhibited the activation of microglia and astrocytes, as well as DSS-induced phosphorylation of NR2B subunit in spinal cord, which was correspondingly consistent with the pain behavior. Pioglitazone ameliorates DSS-induced colitis and attenuates colitis-associated mechanical hyperalgesia, with improving integrity of the intestinal mucosal barrier by directly upregulating tight junction proteins. The PPARγ-tight junction protein signaling might be a potential therapeutic target for the treatment of colitis-associated chronic pain.
Collapse
Affiliation(s)
- Yulin Huang
- Department of Anaesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, 210008, Jiangsu province, China
| | - Chenchen Wang
- Department of Anaesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, 210008, Jiangsu province, China
| | - Xinyu Tian
- Department of Anaesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, 210008, Jiangsu province, China
| | - Yanting Mao
- Department of Anaesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, 210008, Jiangsu province, China
| | - Bailin Hou
- Department of Anaesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, 210008, Jiangsu province, China
| | - Yu'e Sun
- Department of Anaesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, 210008, Jiangsu province, China
| | - Xiaoping Gu
- Department of Anaesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, 210008, Jiangsu province, China.
| | - Zhengliang Ma
- Department of Anaesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, 210008, Jiangsu province, China.
| |
Collapse
|
|
32
|
Banfi D, Moro E, Bosi A, Bistoletti M, Cerantola S, Crema F, Maggi F, Giron MC, Giaroni C, Baj A. Impact of Microbial Metabolites on Microbiota-Gut-Brain Axis in Inflammatory Bowel Disease. Int J Mol Sci 2021; 22:1623. [PMID: 33562721 PMCID: PMC7915037 DOI: 10.3390/ijms22041623] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 01/29/2021] [Accepted: 02/02/2021] [Indexed: 02/07/2023] Open
Abstract
The complex bidirectional communication system existing between the gastrointestinal tract and the brain initially termed the "gut-brain axis" and renamed the "microbiota-gut-brain axis", considering the pivotal role of gut microbiota in sustaining local and systemic homeostasis, has a fundamental role in the pathogenesis of Inflammatory Bowel Disease (IBD). The integration of signals deriving from the host neuronal, immune, and endocrine systems with signals deriving from the microbiota may influence the development of the local inflammatory injury and impacts also more distal brain regions, underlying the psychophysiological vulnerability of IBD patients. Mood disorders and increased response to stress are frequently associated with IBD and may affect the disease recurrence and severity, thus requiring an appropriate therapeutic approach in addition to conventional anti-inflammatory treatments. This review highlights the more recent evidence suggesting that alterations of the microbiota-gut-brain bidirectional communication axis may concur to IBD pathogenesis and sustain the development of both local and CNS symptoms. The participation of the main microbial-derived metabolites, also defined as "postbiotics", such as bile acids, short-chain fatty acids, and tryptophan metabolites in the development of IBD-associated gut and brain dysfunction will be discussed. The last section covers a critical evaluation of the main clinical evidence pointing to the microbiome-based therapeutic approaches for the treatment of IBD-related gastrointestinal and neuropsychiatric symptoms.
Collapse
Affiliation(s)
- Davide Banfi
- Department of Medicine and Surgery, University of Insubria, via H Dunant 5, 21100 Varese, Italy; (D.B.); (A.B.); (M.B.); (F.M.); (A.B.)
| | - Elisabetta Moro
- Department of Internal Medicine and Therapeutics, Section of Pharmacology, University of Pavia, via Ferrata 9, 27100 Pavia, Italy; (E.M.); (F.C.)
| | - Annalisa Bosi
- Department of Medicine and Surgery, University of Insubria, via H Dunant 5, 21100 Varese, Italy; (D.B.); (A.B.); (M.B.); (F.M.); (A.B.)
| | - Michela Bistoletti
- Department of Medicine and Surgery, University of Insubria, via H Dunant 5, 21100 Varese, Italy; (D.B.); (A.B.); (M.B.); (F.M.); (A.B.)
| | - Silvia Cerantola
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Largo Meneghetti 2, 35131 Padova, Italy; (S.C.); (M.C.G.)
| | - Francesca Crema
- Department of Internal Medicine and Therapeutics, Section of Pharmacology, University of Pavia, via Ferrata 9, 27100 Pavia, Italy; (E.M.); (F.C.)
| | - Fabrizio Maggi
- Department of Medicine and Surgery, University of Insubria, via H Dunant 5, 21100 Varese, Italy; (D.B.); (A.B.); (M.B.); (F.M.); (A.B.)
| | - Maria Cecilia Giron
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Largo Meneghetti 2, 35131 Padova, Italy; (S.C.); (M.C.G.)
| | - Cristina Giaroni
- Department of Medicine and Surgery, University of Insubria, via H Dunant 5, 21100 Varese, Italy; (D.B.); (A.B.); (M.B.); (F.M.); (A.B.)
- Centre of Neuroscience, University of Insubria, 21100 Varese, Italy
| | - Andreina Baj
- Department of Medicine and Surgery, University of Insubria, via H Dunant 5, 21100 Varese, Italy; (D.B.); (A.B.); (M.B.); (F.M.); (A.B.)
| |
Collapse
|
|
33
|
Marathe CS, Jones KL, Wu T, Rayner CK, Horowitz M. Gastrointestinal autonomic neuropathy in diabetes. Auton Neurosci 2020; 229:102718. [PMID: 32916479 DOI: 10.1016/j.autneu.2020.102718] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 04/22/2020] [Accepted: 07/22/2020] [Indexed: 02/07/2023]
Abstract
Gastrointestinal autonomic neuropathy represents an important and diverse, but poorly appreciated, manifestation of diabetic autonomic neuropathy that impacts negatively on quality of life. There is no test to assess gastrointestinal autonomic nerve damage directly in humans; cardiovascular autonomic reflex tests are often used as a surrogate, but are suboptimal. Gastrointestinal symptoms are common in diabetes, but usually correlate only weakly with disordered motility. Diabetic gastroparesis, or abnormally delayed gastric emptying, occurs frequently and is the best characterized manifestation of gastrointestinal autonomic neuropathy. There is a bi-directional relationship between postprandial glycaemia and the rate of gastric emptying. However, autonomic neuropathy can affect the function of any gut segment from the esophagus to the anus. Current management options for gastrointestinal autonomic neuropathy are, for the main part, empirical and sub-optimal.
Collapse
Affiliation(s)
- Chinmay S Marathe
- Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Australia; Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, Australia; Endocrine and Metabolic Unit, Royal Adelaide Hospital, Australia.
| | - Karen L Jones
- Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Australia; Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, Australia; Endocrine and Metabolic Unit, Royal Adelaide Hospital, Australia.
| | - Tongzhi Wu
- Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Australia; Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, Australia.
| | - Christopher K Rayner
- Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Australia; Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, Australia; Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Australia.
| | - Michael Horowitz
- Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Australia; Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, Australia; Endocrine and Metabolic Unit, Royal Adelaide Hospital, Australia.
| |
Collapse
|
|
34
|
Rea K, Dinan TG, Cryan JF. Gut Microbiota: A Perspective for Psychiatrists. Neuropsychobiology 2020; 79:50-62. [PMID: 31726457 DOI: 10.1159/000504495] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Accepted: 10/31/2019] [Indexed: 11/19/2022]
Abstract
There is mounting evidence that the trillions of microbes that inhabit our gut are a substantial contributing factor to mental health and, equally, to the progression of neuropsychiatric disorders. The extraordinary complexity of the gut ecosystem, and how it interacts with the intestinal epithelium to manifest physiological changes in the brain to influence mood and behaviour, has been the subject of intense scientific scrutiny over the last 2 decades. To further complicate matters, we each harbour a unique microbiota community that is subject to change by a number of factors including diet, exercise, stress, health status, genetics, medication, and age, amongst others. The microbiota-gut-brain axis is a dynamic matrix of tissues and organs including the gastrointestinal (GI) microbiota, immune cells, gut tissue, glands, the autonomic nervous system (ANS), and the brain that communicate in a complex multidirectional manner through a number of anatomically and physiologically distinct systems. Long-term perturbations to this homeostatic environment may contribute to the progression of a number of disorders by altering physiological processes including hypothalamic-pituitary-adrenal axis activation, neurotransmitter systems, immune function, and the inflammatory response. While an appropriate, co-ordinated physiological response, such as an immune or stress response, is necessary for survival, a dysfunctional response can be detrimental to the host, contributing to the development of a number of central nervous system disorders.
Collapse
Affiliation(s)
- Kieran Rea
- APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Timothy G Dinan
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland
| | - John F Cryan
- APC Microbiome Ireland, University College Cork, Cork, Ireland, .,Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland,
| |
Collapse
|
|
35
|
Bistoletti M, Bosi A, Banfi D, Giaroni C, Baj A. The microbiota-gut-brain axis: Focus on the fundamental communication pathways. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2020; 176:43-110. [PMID: 33814115 DOI: 10.1016/bs.pmbts.2020.08.012] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Michela Bistoletti
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Annalisa Bosi
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Davide Banfi
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Cristina Giaroni
- Department of Medicine and Surgery, University of Insubria, Varese, Italy.
| | - Andreina Baj
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| |
Collapse
|
|
36
|
Bosi A, Banfi D, Bistoletti M, Giaroni C, Baj A. Tryptophan Metabolites Along the Microbiota-Gut-Brain Axis: An Interkingdom Communication System Influencing the Gut in Health and Disease. Int J Tryptophan Res 2020; 13:1178646920928984. [PMID: 32577079 PMCID: PMC7290275 DOI: 10.1177/1178646920928984] [Citation(s) in RCA: 119] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Accepted: 05/02/2020] [Indexed: 12/12/2022] Open
Abstract
The ‘microbiota-gut-brain axis’ plays a fundamental role in maintaining host homeostasis, and different immune, hormonal, and neuronal signals participate to this interkingdom communication system between eukaryota and prokaryota. The essential aminoacid tryptophan, as a precursor of several molecules acting at the interface between the host and the microbiota, is fundamental in the modulation of this bidirectional communication axis. In the gut, tryptophan undergoes 3 major metabolic pathways, the 5-HT, kynurenine, and AhR ligand pathways, which may be directly or indirectly controlled by the saprophytic flora. The importance of tryptophan metabolites in the modulation of the gastrointestinal tract is suggested by several preclinical and clinical studies; however, a thorough revision of the available literature has not been accomplished yet. Thus, this review attempts to cover the major aspects on the role of tryptophan metabolites in host-microbiota cross-talk underlaying regulation of gut functions in health conditions and during disease states, with particular attention to 2 major gastrointestinal diseases, such as irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), both characterized by psychiatric disorders. Research in this area opens the possibility to target tryptophan metabolism to ameliorate the knowledge on the pathogenesis of both diseases, as well as to discover new therapeutic strategies based either on conventional pharmacological approaches or on the use of pre- and probiotics to manipulate the microbial flora.
Collapse
Affiliation(s)
- Annalisa Bosi
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Davide Banfi
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Michela Bistoletti
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Cristina Giaroni
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Andreina Baj
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| |
Collapse
|
|
37
|
Theofanous SA, Florens MV, Appeltans I, Denadai Souza A, Wood JN, Wouters MM, Boeckxstaens GE. Ephrin-B2 signaling in the spinal cord as a player in post-inflammatory and stress-induced visceral hypersensitivity. Neurogastroenterol Motil 2020; 32:e13782. [PMID: 32004400 DOI: 10.1111/nmo.13782] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2019] [Revised: 11/07/2019] [Accepted: 11/27/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND Ephrin-B2/EphB receptor signaling contributes to persistent pain states such as postinflammatory and neuropathic pain. Visceral hypersensitivity (VHS) is a major mechanism underlying abdominal pain in patients with irritable bowel syndrome (IBS) and inflammatory bowel diseases (IBD) in remission, but the underlying pathophysiology remains unclear. Here, we evaluated the spinal ephrin-B2/EphB pathway in VHS in 2 murine models of VHS, that is, postinflammatory TNBS colitis and maternal separation (MS). METHODS Wild-type (WT) mice and mice lacking ephrin-B2 in Nav 1.8 nociceptive neurons (cKO) were studied. VHS was induced by: 1. intracolonic instillation of TNBS or 2. water avoidance stress (WAS) in mice that underwent maternal separation (MS). VHS was assessed by quantifying the visceromotor response (VMRs) during colorectal distention. Colonic tissue and spinal cord were collected for histology, gene, and protein expression evaluation. KEY RESULTS In WT mice, but not cKO mice, TNBS induced VHS at day 14 after instillation, which returned to baseline perception from day 28 onwards. In MS WT mice, WAS induced VHS for up to 4 weeks. In cKO however, visceral pain perception returned to basal level by week 4. The development of VHS in WT mice was associated with significant upregulation of spinal ephrin-B2 and EphB1 mRNA expression or protein levels in the TNBS model and upregulation of spinal ephrin-B2 protein in the MS model. No changes were observed in cKO mice. VHS was not associated with persistent intestinal inflammation. CONCLUSIONS AND INFERENCES Overall, our data indicate that the ephrin-B2/EphB1 spinal signaling pathway is involved in VHS and may represent a novel therapeutic target.
Collapse
Affiliation(s)
| | - Morgane V Florens
- Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium
| | - Iris Appeltans
- Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium
| | | | - John N Wood
- Molecular Nociception Group, Wolfson Institute for Biomedical Research (WIBR), University College London (UCL), London, UK
| | - Mira M Wouters
- Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium
| | - Guy E Boeckxstaens
- Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium
| |
Collapse
|
|
38
|
Zhu S, He M, Liu Z, Qin Z, Wang Z, Duan L. Shared genetic susceptibilities for irritable bowel syndrome and depressive disorder in Chinese patients uncovered by pooled whole-exome sequencing. J Adv Res 2020; 23:113-121. [PMID: 32099673 PMCID: PMC7029050 DOI: 10.1016/j.jare.2020.01.016] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 12/25/2019] [Accepted: 01/28/2020] [Indexed: 02/07/2023] Open
Abstract
Irritable bowel syndrome (IBS) is the most prevalent functional gastrointestinal disorder presenting a high comorbidity with depressive disorder (DD). Many studies have confirmed that these two disease share the similar pathophysiological process, but evidence of the genetic risks is limited. This study aimed to analyze the genetic susceptibilities for IBS and DD in Chinese patients. Pooled whole-exome sequencing (pooled-WES) was performed to identify the candidate variants in the group of diarrhea predominant IBS (IBS-D) patients, DD patients, and healthy controls (HC). Then, targeted sequencing was used to validate the candidate variants in three additional cohorts of IBS-D, DD, and HC. Four variants associated with both IBS-D and DD were identified through pooled-WES, and three of them were validated in targeted sequencing. SYT8 rs3741231 G allele and SSPO rs12536873 TT genotype were associated with both IBS-D and DD. The genes of these variants are important in neurogenesis and neurotransmission. In addition, we found COL6A1 rs13051496, a unique risk variation for IBS-D. It increased the IBS-D risk and had a positive correlation with the scores of abdominal bloating and dissatisfaction of bowel habits. Through the results of this study, it provides a genetic basis for the high comorbidity of IBS-D and DD.
Collapse
Affiliation(s)
- Shiwei Zhu
- Department of Gastroenterology, Peking University Third Hospital, No. 49 North Garden Rd., Haidian District, Beijing 100191, China
| | - Meibo He
- Department of Gastroenterology, Peking University Third Hospital, No. 49 North Garden Rd., Haidian District, Beijing 100191, China
| | - Zuojing Liu
- Department of Gastroenterology, Peking University Third Hospital, No. 49 North Garden Rd., Haidian District, Beijing 100191, China
| | - Zelian Qin
- Department of Plastic Surgery, Peking University Third Hospital, No.49 North Garden Rd., Haidian District, Beijing 100191, China
| | - Zhiren Wang
- Department of Science & Technology, Peking University HuiLongGuan Clinical Medical School, Beijing HuiLongGuan Hospital, Huilongguan Town, Changping District, Beijing 100096, China
| | - Liping Duan
- Department of Gastroenterology, Peking University Third Hospital, No. 49 North Garden Rd., Haidian District, Beijing 100191, China
| |
Collapse
|
|
39
|
Abstract
Intravital microscopy is a powerful technique to observe dynamic processes with single-cell resolution in live animals. No intravital window has been developed for imaging the colon due to its anatomic location and motility, although the colon is a key organ where the majority of microbiota reside and common diseases such as inflammatory bowel disease, functional gastrointestinal disorders, and colon cancer occur. Here we describe an intravital murine colonic window with a stabilizing ferromagnetic scaffold for chronic imaging, minimizing motion artifacts while maximizing long-term survival by preventing colonic obstruction. Using this setup, we image fluorescently-labeled stem cells, bacteria, and immune cells in live animal colons. Furthermore, we image nerve activity via calcium imaging in real time to demonstrate that electrical sacral nerve stimulation can activate colonic enteric neurons. The simple implantable apparatus enables visualization of live processes in the colon, which will open the window to a broad range of studies. Performing intravital imaging of the colon in mouse models is challenging due to the colon’s anatomic location and motility. Here, the authors develop a murine colonic window for intravital chronic imaging that maximises long-term animal survival and minimises motion artefacts.
Collapse
|
|
40
|
Qin HY, Xavier Wong HL, Zang KH, Li X, Bian ZX. Enterochromaffin cell hyperplasia in the gut: Factors, mechanism and therapeutic clues. Life Sci 2019; 239:116886. [PMID: 31678286 DOI: 10.1016/j.lfs.2019.116886] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Accepted: 09/16/2019] [Indexed: 02/08/2023]
Abstract
Enterochromaffin (EC) cell is the main cell type that responsible for 5-hydroxytryptamine (5-HT) synthesis, storage and release of the gut. Intestinal 5-HT play a key role in visceral sensation, intestinal motility and permeability, EC cell hyperplasia and increased 5-HT bioavailability in the gut have been found to be involved in the symptoms generation of irritable bowel syndrome and inflammatory bowel disease. EC cells originate from intestinal stem cells, the interaction between proliferation and differentiation signals on intestinal stem cells enable EC cell number to be regulated in a normal level. This review focuses on the impact factors, pathogenesis mechanisms, and therapeutic clues for intestinal EC cells hyperplasia, and showed that EC cell hyperplasia was observed under the condition of physiological stress, intestinal infection or intestinal inflammation, the disordered proliferation and/or differentiation of intestinal stem cells as well as their progenitor cells all contribute to the pathogenesis of intestinal EC cell hyperplasia. The altered intestinal niche, i.e. increased corticotrophin releasing factor (CRF) signal, elevated nerve growth factor (NGF) signal, and Th2-dominant cytokines production, has been found to have close correlation with intestinal EC cell hyperplasia. Currently, CRF receptor antagonist, nuclear factor-κB inhibitor, and NGF receptor neutralizing antibody have been proved useful to attenuate intestinal EC cell hyperplasia, which may provide a promising clue for the therapeutic strategy in EC cell hyperplasia related diseases.
Collapse
Affiliation(s)
- Hong-Yan Qin
- Department of Pharmacy, First Hospital of Lanzhou University, Lanzhou, China
| | - Hoi Leong Xavier Wong
- Institute of Brain and Gut Axis (IBAG), Centre of Clinical Research for Chinese Medicine, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Kai-Hong Zang
- College of Pharmacy, Gansu University of Traditional Chinese Medicine, Lanzhou, China
| | - Xun Li
- Fifth Department of General Surgery, First Hospital of Lanzhou University, Lanzhou, China; Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, China.
| | - Zhao-Xiang Bian
- Institute of Brain and Gut Axis (IBAG), Centre of Clinical Research for Chinese Medicine, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China.
| |
Collapse
|
|
41
|
Talavera K, Startek JB, Alvarez-Collazo J, Boonen B, Alpizar YA, Sanchez A, Naert R, Nilius B. Mammalian Transient Receptor Potential TRPA1 Channels: From Structure to Disease. Physiol Rev 2019; 100:725-803. [PMID: 31670612 DOI: 10.1152/physrev.00005.2019] [Citation(s) in RCA: 253] [Impact Index Per Article: 42.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The transient receptor potential ankyrin (TRPA) channels are Ca2+-permeable nonselective cation channels remarkably conserved through the animal kingdom. Mammals have only one member, TRPA1, which is widely expressed in sensory neurons and in non-neuronal cells (such as epithelial cells and hair cells). TRPA1 owes its name to the presence of 14 ankyrin repeats located in the NH2 terminus of the channel, an unusual structural feature that may be relevant to its interactions with intracellular components. TRPA1 is primarily involved in the detection of an extremely wide variety of exogenous stimuli that may produce cellular damage. This includes a plethora of electrophilic compounds that interact with nucleophilic amino acid residues in the channel and many other chemically unrelated compounds whose only common feature seems to be their ability to partition in the plasma membrane. TRPA1 has been reported to be activated by cold, heat, and mechanical stimuli, and its function is modulated by multiple factors, including Ca2+, trace metals, pH, and reactive oxygen, nitrogen, and carbonyl species. TRPA1 is involved in acute and chronic pain as well as inflammation, plays key roles in the pathophysiology of nearly all organ systems, and is an attractive target for the treatment of related diseases. Here we review the current knowledge about the mammalian TRPA1 channel, linking its unique structure, widely tuned sensory properties, and complex regulation to its roles in multiple pathophysiological conditions.
Collapse
Affiliation(s)
- Karel Talavera
- Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven; VIB Center for Brain and Disease Research, Leuven, Belgium
| | - Justyna B Startek
- Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven; VIB Center for Brain and Disease Research, Leuven, Belgium
| | - Julio Alvarez-Collazo
- Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven; VIB Center for Brain and Disease Research, Leuven, Belgium
| | - Brett Boonen
- Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven; VIB Center for Brain and Disease Research, Leuven, Belgium
| | - Yeranddy A Alpizar
- Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven; VIB Center for Brain and Disease Research, Leuven, Belgium
| | - Alicia Sanchez
- Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven; VIB Center for Brain and Disease Research, Leuven, Belgium
| | - Robbe Naert
- Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven; VIB Center for Brain and Disease Research, Leuven, Belgium
| | - Bernd Nilius
- Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven; VIB Center for Brain and Disease Research, Leuven, Belgium
| |
Collapse
|
|
42
|
Clinical Study of Thirteen Patients with Spinal Cord Infarction. J Stroke Cerebrovasc Dis 2019; 28:104418. [PMID: 31585772 DOI: 10.1016/j.jstrokecerebrovasdis.2019.104418] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 08/27/2019] [Accepted: 09/12/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND A concept of sensory tracts in the spinal cord has been established in relation to a dorsolateral pathway which is located in the posterior part of the lateral column and conveys the deep sense. METHODS The clinical status at onset, neurological symptoms, and magnetic resonance imaging (MRI) findings in 13 patients of spinal cord infarction were studied. RESULTS The clinical status was acute in 11 patients and subacute in 2 patients. Palsy of the extremities was noted in 11 patients. Segmental sensory disturbance was shown in all patients. One patient showed disturbance of all senses and paraplegia, which indicated transverse myelopathy. In the other 12 patients, 11 patients showed impairment of pain sense although joint position sense was preserved, excluding 1 patient whose sensory disturbance showed dysesthesia alone. In these 11 patients, soft touch and vibration senses were impaired in 7 patients. Abnormality of spinal cord MRI was detected 7 patients. The lesions were located in the cervical cord in 3 patients, cervical to thoracic cord in 1 patient, and thoracic cord in 3 patients. CONCLUSIONS In the 11 patients in whom pain sense was impaired and joint position sense was preserved, involvement of the anterior spinal cord artery (ASCA) was the mainstay. Impairment of vibration sense was accompanied in 7 patients in patients of ASCA infarction. It was speculated that impairment of vibration sense can occur in patients with ASCA infarction whose ischemia spread to the dorsolateral pathway in the posterior part of the lateral column.
Collapse
|
|
43
|
Cryan JF, O'Riordan KJ, Cowan CSM, Sandhu KV, Bastiaanssen TFS, Boehme M, Codagnone MG, Cussotto S, Fulling C, Golubeva AV, Guzzetta KE, Jaggar M, Long-Smith CM, Lyte JM, Martin JA, Molinero-Perez A, Moloney G, Morelli E, Morillas E, O'Connor R, Cruz-Pereira JS, Peterson VL, Rea K, Ritz NL, Sherwin E, Spichak S, Teichman EM, van de Wouw M, Ventura-Silva AP, Wallace-Fitzsimons SE, Hyland N, Clarke G, Dinan TG. The Microbiota-Gut-Brain Axis. Physiol Rev 2019; 99:1877-2013. [PMID: 31460832 DOI: 10.1152/physrev.00018.2018] [Citation(s) in RCA: 2690] [Impact Index Per Article: 448.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota (the trillions of microorganisms within and on our bodies) as one of the key regulators of gut-brain function and has led to the appreciation of the importance of a distinct microbiota-gut-brain axis. This axis is gaining ever more traction in fields investigating the biological and physiological basis of psychiatric, neurodevelopmental, age-related, and neurodegenerative disorders. The microbiota and the brain communicate with each other via various routes including the immune system, tryptophan metabolism, the vagus nerve and the enteric nervous system, involving microbial metabolites such as short-chain fatty acids, branched chain amino acids, and peptidoglycans. Many factors can influence microbiota composition in early life, including infection, mode of birth delivery, use of antibiotic medications, the nature of nutritional provision, environmental stressors, and host genetics. At the other extreme of life, microbial diversity diminishes with aging. Stress, in particular, can significantly impact the microbiota-gut-brain axis at all stages of life. Much recent work has implicated the gut microbiota in many conditions including autism, anxiety, obesity, schizophrenia, Parkinson’s disease, and Alzheimer’s disease. Animal models have been paramount in linking the regulation of fundamental neural processes, such as neurogenesis and myelination, to microbiome activation of microglia. Moreover, translational human studies are ongoing and will greatly enhance the field. Future studies will focus on understanding the mechanisms underlying the microbiota-gut-brain axis and attempt to elucidate microbial-based intervention and therapeutic strategies for neuropsychiatric disorders.
Collapse
Affiliation(s)
- John F. Cryan
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Kenneth J. O'Riordan
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Caitlin S. M. Cowan
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Kiran V. Sandhu
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Thomaz F. S. Bastiaanssen
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Marcus Boehme
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Martin G. Codagnone
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Sofia Cussotto
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Christine Fulling
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Anna V. Golubeva
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Katherine E. Guzzetta
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Minal Jaggar
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Caitriona M. Long-Smith
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Joshua M. Lyte
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Jason A. Martin
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Alicia Molinero-Perez
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Gerard Moloney
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Emanuela Morelli
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Enrique Morillas
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Rory O'Connor
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Joana S. Cruz-Pereira
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Veronica L. Peterson
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Kieran Rea
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Nathaniel L. Ritz
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Eoin Sherwin
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Simon Spichak
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Emily M. Teichman
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Marcel van de Wouw
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Ana Paula Ventura-Silva
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Shauna E. Wallace-Fitzsimons
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Niall Hyland
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Gerard Clarke
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| | - Timothy G. Dinan
- APC Microbiome Ireland, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland; and Department of Physiology, University College Cork, Cork, Ireland
| |
Collapse
|
|
44
|
Van Remoortel S, Ceuleers H, Arora R, Van Nassauw L, De Man JG, Buckinx R, De Winter BY, Timmermans JP. Mas-related G protein-coupled receptor C11 (Mrgprc11) induces visceral hypersensitivity in the mouse colon: A novel target in gut nociception? Neurogastroenterol Motil 2019; 31:e13623. [PMID: 31119828 DOI: 10.1111/nmo.13623] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 04/24/2019] [Accepted: 04/26/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND Visceral hypersensitivity, an important cause of abdominal pain in disorders such as IBD and IBS, presents with a poorly understood pathophysiology and limited treatment options. Several members of the Mas-related G protein-coupled receptor family (Mrgprs) have become promising targets in pain research. The potential link between the murine Mrgpr C11 (Mrgprc11) and gut nociception is currently uninvestigated. Therefore, we explored the expression and functional role of Mrgprc11 in the gut nociceptive innervation. METHODS Mrgprc11 expression was evaluated in DRG neurons innervating the mouse colon using in situ hybridization and immunohistochemistry. Visceromotor responses to colorectal distension (CRD) assessed the effect of the Mrgprc11 agonist, BAM(8-22), on colonic pain sensitivity in healthy mice. Moreover, we determined pERK1/2-immunoreactivity in the thoracolumbar spinal cord after noxious CRD. Finally, from a translational point of view, we looked for expression of the human counterpart of Mrgprc11, MRGPRX1, in human thoracolumbar DRGs. KEY RESULTS In situ hybridization and immunohistochemistry revealed Mrgprc11 expression in colonic DRG neurons. Intracolonic administration of BAM(8-22) significantly increased colonic pain sensitivity in an Mrgprc11-dependent manner, and led to a significantly increased degree of neuronal activation in the splanchnic spinal cord upon noxious stimulation. Furthermore, MRGPRX1 expression was also detected in human thoracolumbar DRG neurons. CONCLUSIONS & INFERENCES: Our findings established a novel function for Mrgprc11 in the gut nociceptive innervation and propose the receptor as a new player in visceral hypersensitivity. Given the presence of MRGPRX1 in human DRG neurons, our study warrants future research on its therapeutic potential in abdominal pain disorders.
Collapse
Affiliation(s)
- Samuel Van Remoortel
- Laboratory of Cell Biology and Histology, University of Antwerp, Antwerp, Belgium
| | - Hannah Ceuleers
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, Antwerp, Belgium
| | - Rohit Arora
- Laboratory of Cell Biology and Histology, University of Antwerp, Antwerp, Belgium
| | - Luc Van Nassauw
- Laboratory of Human Anatomy and Embryology, Division ASTARC, University of Antwerp, Antwerp, Belgium
| | - Joris G De Man
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, Antwerp, Belgium
| | - Roeland Buckinx
- Laboratory of Cell Biology and Histology, University of Antwerp, Antwerp, Belgium
| | - Benedicte Y De Winter
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, Antwerp, Belgium
| | | |
Collapse
|
|
45
|
Marine Toxins and Nociception: Potential Therapeutic Use in the Treatment of Visceral Pain Associated with Gastrointestinal Disorders. Toxins (Basel) 2019; 11:toxins11080449. [PMID: 31370176 PMCID: PMC6723473 DOI: 10.3390/toxins11080449] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 07/24/2019] [Accepted: 07/26/2019] [Indexed: 12/12/2022] Open
Abstract
Visceral pain, of which the pathogenic basis is currently largely unknown, is a hallmark symptom of both functional disorders, such as irritable bowel syndrome, and inflammatory bowel disease. Intrinsic sensory neurons in the enteric nervous system and afferent sensory neurons of the dorsal root ganglia, connecting with the central nervous system, represent the primary neuronal pathways transducing gut visceral pain. Current pharmacological therapies have several limitations, owing to their partial efficacy and the generation of severe adverse effects. Numerous cellular targets of visceral nociception have been recognized, including, among others, channels (i.e., voltage-gated sodium channels, VGSCs, voltage-gated calcium channels, VGCCs, Transient Receptor Potential, TRP, and Acid-sensing ion channels, ASICs) and neurotransmitter pathways (i.e., GABAergic pathways), which represent attractive targets for the discovery of novel drugs. Natural biologically active compounds, such as marine toxins, able to bind with high affinity and selectivity to different visceral pain molecular mediators, may represent a useful tool (1) to improve our knowledge of the physiological and pathological relevance of each nociceptive target, and (2) to discover therapeutically valuable molecules. In this review we report the most recent literature describing the effects of marine toxin on gastrointestinal visceral pain pathways and the possible clinical implications in the treatment of chronic pain associated with gut diseases.
Collapse
|
|
46
|
Abstract
Beyond their well-known role in embryonic development of the central and peripheral nervous system, neurotrophins, particularly nerve growth factor and brain-derived neurotrophic factor, exert an essential role in pain production and sensitization. This has mainly been studied within the framework of somatic pain, and even antibodies (tanezumab and fasinumab) have recently been developed for their use in chronic somatic painful conditions, such as osteoarthritis or low back pain. However, data suggest that neurotrophins also exert an important role in the occurrence of visceral pain and visceral sensitization. Visceral pain is a distressing symptom that prompts many consultations and is typically encountered in both 'organic' (generally inflammatory) and 'functional' (displaying no obvious structural changes in routine clinical evaluations) disorders of the gut, such as inflammatory bowel disease and irritable bowel syndrome, respectively. The present review provides a summary of neurotrophins as a molecular family and their role in pain in general and addresses recent investigations of the involvement of nerve growth factor and brain-derived neurotrophic factor in visceral pain, particularly that associated with inflammatory bowel disease and irritable bowel syndrome.
Collapse
|
|
47
|
Glutamatergic Signaling Along The Microbiota-Gut-Brain Axis. Int J Mol Sci 2019; 20:ijms20061482. [PMID: 30934533 PMCID: PMC6471396 DOI: 10.3390/ijms20061482] [Citation(s) in RCA: 211] [Impact Index Per Article: 35.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 03/04/2019] [Accepted: 03/21/2019] [Indexed: 12/21/2022] Open
Abstract
A complex bidirectional communication system exists between the gastrointestinal tract and the brain. Initially termed the “gut-brain axis” it is now renamed the “microbiota-gut-brain axis” considering the pivotal role of gut microbiota in maintaining local and systemic homeostasis. Different cellular and molecular pathways act along this axis and strong attention is paid to neuroactive molecules (neurotransmitters, i.e., noradrenaline, dopamine, serotonin, gamma aminobutyric acid and glutamate and metabolites, i.e., tryptophan metabolites), sustaining a possible interkingdom communication system between eukaryota and prokaryota. This review provides a description of the most up-to-date evidence on glutamate as a neurotransmitter/neuromodulator in this bidirectional communication axis. Modulation of glutamatergic receptor activity along the microbiota-gut-brain axis may influence gut (i.e., taste, visceral sensitivity and motility) and brain functions (stress response, mood and behavior) and alterations of glutamatergic transmission may participate to the pathogenesis of local and brain disorders. In this latter context, we will focus on two major gut disorders, such as irritable bowel syndrome and inflammatory bowel disease, both characterized by psychiatric co-morbidity. Research in this area opens the possibility to target glutamatergic neurotransmission, either pharmacologically or by the use of probiotics producing neuroactive molecules, as a therapeutic approach for the treatment of gastrointestinal and related psychiatric disorders.
Collapse
|
|
48
|
Shin KM, Ko IG, Kim SE, Jin JJ, Hwang L, Kim SH, Seo JH, Kim BK, Na YG. Low-frequency electroacupncture improves locomotor function after sciatic crushed nerve injury in rats. J Exerc Rehabil 2019; 14:927-933. [PMID: 30656150 PMCID: PMC6323326 DOI: 10.12965/jer.1836594.297] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 11/26/2018] [Indexed: 11/22/2022] Open
Abstract
Sciatic crushed nerve injury (SCI) causes pain-related gait and swelling in the affected limb. Electroacupuncture (EA) is a modified acupuncture technique, and analgesic effect of EA on different types of pain has been documented. Scientific functional index (SFI) is a mathematical formula to represent parameters of normal and experimental footprints. We investigated the effect of low-frequency EA on functional recovery following SCI in rats. For this study, immunohistochemistry for c-Fos in the ventral lateral periaqueductal gray (vlPAG) and paraventricular nucleus (PVN) and western blot for neurofilament (NF) and brain-derived neurotrophic factor (BDNF) in the sciatic nerve were conducted. To induce crush injury on the sciatic nerve, sciatic nerve was crushed for 30 sec using a surgical clip. The rats in the acupuncture groups received acupuncture bilaterally at respective site, once a day for 14 days. The rats in the EA group received 100-Hz electrical stimulation for 10 min once a day during 14 days. SCI decreased SFI value, in contrast, EA increased SFI value. c-Fos expression in the vlPAG and PVN was increased following SCI, in contrast, EA suppressed c-Fos expression. NF expression in the sciatic nerve was decreased by SCI, in contrast, EA increased NF expression. BDNF expression in the sciatic nerve was increased by SCI, in contrast, EA suppressed BDNF expression. In the present study, EA showed effectiveness on functional recovery from SCI.
Collapse
Affiliation(s)
- Key-Moon Shin
- Department of Physiology, College of Medicine, Kyung Hee University, Seoul, Korea
| | - Il-Gyu Ko
- Department of Physiology, College of Medicine, Kyung Hee University, Seoul, Korea
| | - Sung-Eun Kim
- Department of Physiology, College of Medicine, Kyung Hee University, Seoul, Korea
| | - Jun-Jang Jin
- Department of Physiology, College of Medicine, Kyung Hee University, Seoul, Korea
| | - Lakkyong Hwang
- Department of Physiology, College of Medicine, Kyung Hee University, Seoul, Korea
| | - Sang-Hoon Kim
- Department of Physiology, College of Medicine, Kyung Hee University, Seoul, Korea.,Department of Sport & Health Science, College of Natural Science, Sangmyung University, Seoul, Korea
| | - Jin-Hee Seo
- Department of Adaptive Physical Education, Baekseok University, Cheonan, Korea
| | - Bo-Kyun Kim
- Department of Emergency Technology, College of Health Science, Gachon University, Incheon, Korea
| | - Yong Gil Na
- Department of Urology, Chungnam National University Hospital, Chungnam National University College of Medicine, Daejeon, Korea
| |
Collapse
|
|
49
|
Bao C, Liu P, Liu H, Jin X, Shi Y, Wu L, Zeng X, Zhang J, Wang D, Calhoun VD, Tian J, Wu H. Difference in regional neural fluctuations and functional connectivity in Crohn's disease: a resting-state functional MRI study. Brain Imaging Behav 2018; 12:1795-1803. [PMID: 29464530 PMCID: PMC6218319 DOI: 10.1007/s11682-018-9850-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Patients with Crohn's disease (CD) are shown to have abnormal changes in brain structures. This study aimed to further investigate whether these patients have abnormal brain activities and network connectivity. Sixty patients with CD and 40 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging (fMRI) scans. Amplitude of low-frequency fluctuation (ALFF) and seed-based functional connectivity (FC) were used to assess differences in spontaneous regional brain activity and functional connectivity. Compared to the HCs, patients with CD showed significantly higher ALFF values in hippocampus and parahippocampus (HIPP/paraHIPP), anterior cingulate cortex, insula, superior frontal cortex and precuneus. The ALFF values were significantly lower in secondary somatosensory cortex (S2), precentral gyrus, and medial prefrontal cortex. Functional connectivities between left HIPP and left inferior temporal cortex, and right middle cingulate cortex, HIPP, and fusiform area were significantly lower. The functional connectivities between right HIPP and right inferior orbitofrontal cortex and left HIPP were also significantly lower. Patients with CD showed higher or lower spontaneous activity in multiple brain regions. Altered activities in these brain regions may collectively reflect abnormal function and regulation of visceral pain and sensation, external environmental monitoring, and cognitive processing in these patients. Lower functional connectivity of the hippocampus-limbic system was observed in these patients. These findings may provide more information to elucidate the neurobiological mechanisms of the disease.
Collapse
Affiliation(s)
- Chunhui Bao
- Key Laboratory of Acupuncture and Immunological Effects, Shanghai University of Traditional Chinese Medicine, Shanghai, 200030, China
| | - Peng Liu
- Life Sciences Research Center, School of Life Sciences and Technology, Xidian University, Xi'an, Shaanxi, 710071, China
| | - Huirong Liu
- Outpatient Department, Shanghai Research Institute of Acupuncture and Meridian, Shanghai University of Traditional Chinese Medicine, Shanghai, 200030, China.
| | - Xiaoming Jin
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Yin Shi
- Outpatient Department, Shanghai Research Institute of Acupuncture and Meridian, Shanghai University of Traditional Chinese Medicine, Shanghai, 200030, China
| | - Luyi Wu
- Key Laboratory of Acupuncture and Immunological Effects, Shanghai University of Traditional Chinese Medicine, Shanghai, 200030, China
| | - Xiaoqing Zeng
- Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Jianye Zhang
- Department of Radiology, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai, 200030, China
| | - Di Wang
- Key Laboratory of Acupuncture and Immunological Effects, Shanghai University of Traditional Chinese Medicine, Shanghai, 200030, China
| | - Vince D Calhoun
- The Mind Research Network, Albuquerque, NM, 87131, USA
- Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque, NM, 87131, USA
| | - Jie Tian
- Life Sciences Research Center, School of Life Sciences and Technology, Xidian University, Xi'an, Shaanxi, 710071, China
| | - Huangan Wu
- Key Laboratory of Acupuncture and Immunological Effects, Shanghai University of Traditional Chinese Medicine, Shanghai, 200030, China.
| |
Collapse
|
|
50
|
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
|