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Wang Y, Duan C, Du X, Zhu Y, Wang L, Hu J, Sun Y. Vagus Nerve and Gut-Brain Communication. Neuroscientist 2025; 31:262-278. [PMID: 39041416 DOI: 10.1177/10738584241259702] [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] [Indexed: 07/24/2024]
Abstract
The vagus nerve, as an important component of the gut-brain axis, plays a crucial role in the communication between the gut and brain. It influences food intake, fat metabolism, and emotion by regulating the gut-brain axis, which is closely associated with the development of gastrointestinal, psychiatric, and metabolism-related disorders. In recent years, significant progress has been made in understanding the vagus-mediated regulatory pathway, highlighting its profound implications in the development of many diseases. Here, we summarize the latest advancements in vagus-mediated gut-brain pathways and the novel interventions targeting the vagus nerve. This will provide valuable insights for future research on treatment of obesity and gastrointestinal and depressive disorders based on vagus nerve stimulation.
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Affiliation(s)
- Yiyang Wang
- Division of Physical Biology, CAS Key Laboratory of Interfacial Physics Technology, Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Chenxi Duan
- Division of Physical Biology, CAS Key Laboratory of Interfacial Physics Technology, Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Xinyi Du
- Institute of Materiobiology, College of Sciences, Shanghai University, Shanghai, China
| | - Ying Zhu
- Division of Physical Biology, CAS Key Laboratory of Interfacial Physics Technology, Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai, China
- Institute of Materiobiology, College of Sciences, Shanghai University, Shanghai, China
| | - Lihua Wang
- Division of Physical Biology, CAS Key Laboratory of Interfacial Physics Technology, Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai, China
- Institute of Materiobiology, College of Sciences, Shanghai University, Shanghai, China
| | - Jun Hu
- Institute of Materiobiology, College of Sciences, Shanghai University, Shanghai, China
- The Interdisciplinary Research Center, Shanghai Synchrotron Radiation Facility, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, China
| | - Yanhong Sun
- Institute of Materiobiology, College of Sciences, Shanghai University, Shanghai, China
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Atalar K, Alim E, Yigman Z, Belen HB, Erten F, Sahin K, Soylu A, Dizakar SOA, Bahcelioglu M. Transauricular vagal nerve stimulation suppresses inflammatory responses in the gut and brain in an inflammatory bowel disease model. J Anat 2025; 246:602-615. [PMID: 39707162 PMCID: PMC11911132 DOI: 10.1111/joa.14178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 10/30/2024] [Accepted: 10/30/2024] [Indexed: 12/23/2024] Open
Abstract
Inflammatory bowel disease (IBD) encompasses Crohn's disease (CD) and ulcerative colitis (UC), is a major health problem on a global scale and its treatment is unsatisfactory. We aimed to investigate the effects of transauricular vagal nerve stimulation (tVNS) on inflammation in rats with IBD induced by trinitrobenzene sulfonic acid (TNBS). A total of 36 adult female Sprague-Dawley rats were given TNBS, or vehicle, and tVNS, or sham, every other day for 30 min for 10 days. Postmortem macroscopic and microscopic colon morphology were evaluated by histological staining. Additionally, IL-1β, IL-6, IL-10, and TNF-α cytokine levels in the colon and the brain were evaluated by immunohistochemistry and western blotting analysis. TNBS induced epithelial damage, inflammation, ulceration, and thickened mucosal layer in the colonic tissues. Administration of tVNS significantly ameliorated the severity of TNBS-induced tissue damage and inflammatory response. TNBS also alters pro-inflammatory and anti-inflammatory balance in the brain tissue. TVNS application significantly suppressed the protein levels of pro-inflammatory cytokines, namely IL-1β, IL-6, and TNF- α while augmenting the level of anti-inflammatory cytokine IL-10 in the colonic and the brain tissue. We have shown that TNBS-mediated colonic inflammation and tissue damage are associated with neuroinflammatory responses in the brain tissue. Also demonstrated for the first time that neuroinflammatory response in the gut-brain axis is suppressed by tVNS in the IBD model. Non-invasive tVNS stands out as a new potential treatment option for types of IBD.
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Affiliation(s)
- Kerem Atalar
- Department of Anatomy, Faculty of Medicine, Neuroscience and Neurotechnology Center of Excellence (NÖROM) and Neuropsychiatry Center, Gazi University, Ankara, Türkiye
| | - Ece Alim
- Department of Anatomy, Faculty of Medicine, Neuroscience and Neurotechnology Center of Excellence (NÖROM), Gazi University, Ankara, Türkiye
| | - Zeynep Yigman
- Department of Histology and Embryology, Faculty of Medicine, Neuroscience and Neurotechnology Center of Excellence (NÖROM), Gazi University, Türkiye
| | - Hayrunnisa Bolay Belen
- Department of Neurology and Algology, Faculty of Medicine, Neuroscience and Neurotechnology Center of Excellence (NÖROM), Neuropsychiatry Center, Gazi University, Ankara, Türkiye
| | - Fusun Erten
- Department of Veterinary Medicine, Pertek Sakine Genc Vocational School, Munzur University, Tunceli, Türkiye
| | - Kazım Sahin
- Department of Animal Nutrition and Nutritional Diseases, Faculty of Veterinary Medicine, Fırat University, Elazığ, Türkiye
| | - Ayse Soylu
- Department of Anatomy Faculty of Medicine, Gazi University, Ankara, Türkiye
| | | | - Meltem Bahcelioglu
- Department of Anatomy, Faculty of Medicine, Neuroscience and Neurotechnology Center of Excellence (NÖROM) and Neuropsychiatry Center, Gazi University, Ankara, Türkiye
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Stebbing MJ, Shafton AD, Davey CE, Di Natale MR, Furness JB, McAllen RM. A ganglionic intestinointestinal reflex activated by acute noxious challenge. Am J Physiol Gastrointest Liver Physiol 2024; 326:G360-G373. [PMID: 38226653 DOI: 10.1152/ajpgi.00145.2023] [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: 07/11/2023] [Revised: 12/13/2023] [Accepted: 01/07/2024] [Indexed: 01/17/2024]
Abstract
To investigate noxious stimulation-responsive neural circuits that could influence the gut, we recorded from intestinally directed (efferent) nerve filaments dissected from mesenteric nerves close to the small intestine in anesthetized rats. These exhibited baseline multiunit activity that was almost unaffected by vagotomy (VagX) and reduced only slightly by cutting the splanchnic nerves. The activity was halved by hexamethonium (Hex) treatment. When an adjacent gut segment received an intraluminal stimulus 2,4,6-trinitrobenzenesulfonate (TNBS) in 30% ethanol, mesenteric efferent nerve activity increased for more than 1 h. The increased activity was almost unaffected by bilateral vagotomy or splanchnic nerve section, indicating a lack of central nervous involvement, but it was 60% reduced by hexamethonium. Spike sorting discriminated efferent single and predominantly single-unit spike trains that responded to TNBS, were unaffected by splachnectomy but were silenced by hexamethonium. After noxious stimulation of one segment, the adjacent segment showed no evidence of suppression of gut motility or vasoconstriction. We conclude that luminal application of a noxious stimulus to the small intestine activates an entirely peripheral, intestinointestinal reflex pathway. This pathway involves enteric intestinofugal neurons that excite postganglionic sympathetic neurons via a nicotinic synapse. We suggest that the final sympathetic efferent neurons that respond to a tissue damaging stimulus are distinct from vasoconstrictor, secretomotor, and motility inhibiting neurons.NEW & NOTEWORTHY An intraluminal noxious chemical stimulus applied to one segment of small intestine increased mesenteric efferent nerve activity to an adjacent segment. This was identified as a peripheral ganglionic reflex that did not require vagal or spinal connections. Hexamethonium blocked most, but not all, ongoing and reflex mesenteric efferent activity. The prevertebral sympathetic efferent neurons that are activated likely affect inflammatory and immune functions of other gut segments.
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Affiliation(s)
- Martin J Stebbing
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
- Department of Anatomy and Physiology, University of Melbourne, Parkville, Victoria, Australia
| | - Anthony D Shafton
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
| | - Catherine E Davey
- Department of Biomedical Engineering, University of Melbourne, Parkville, Victoria, Australia
| | | | - John B Furness
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
- Department of Anatomy and Physiology, University of Melbourne, Parkville, Victoria, Australia
| | - Robin M McAllen
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
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Zhang S, Liu Y, Li S, Ye F, Yin J. Autonomic and cytokine mechanisms of acute electroacupuncture in a rodent model of functional dyspepsia. Neurogastroenterol Motil 2024; 36:e14702. [PMID: 37983919 DOI: 10.1111/nmo.14702] [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: 04/08/2023] [Revised: 10/11/2023] [Accepted: 10/17/2023] [Indexed: 11/22/2023]
Abstract
BACKGROUND Cytokines have been presumed to play an important role in the pathophysiology of functional dyspepsia (FD). Electroacupuncture (EA) has been used for FD treatment; however, its mechanisms remain largely unknown. This study aimed to (1) compare the plasma levels of cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-10, in "FD" rats with normal control rats; (2) investigate whether EA, using chronically implanted electrodes, could inhibit the release of these cytokines; and (3) explore the correlation of cytokine levels with plasma norepinephrine (NE) levels and gastric emptying (GE). METHODS A rodent model of FD was established via neonatal treatment with intragastric iodoacetamide. After 8 weeks, the rats were implanted with electrodes at acupoint ST36 for EA. The plasma levels of cytokines and NE were measured using enzyme-linked immunosorbent assay. We explored the correlations of cytokine levels with NE levels and GE. KEY RESULTS (i) "FD" rats demonstrated increased levels of TNF-α, IL-1β, and IL-6 (p < 0.05 each) compared with the control rats. (ii) EA significantly decreased the plasma levels of TNF-α, IL-1β, and IL-6 in "FD" rats (p < 0.05 each) compared with sham EA. (iii) The plasma levels of NE were positively correlated with those of IL-6 (r = 0.86, p < 0.05) and IL-1β (r = 0.81, p < 0.05), whereas NE levels and GE were negatively correlated with IL-10 levels (r = -0.870, p < 0.05 and r = -0.791, p < 0.05, respectively). CONCLUSIONS EA inhibits the release of proinflammatory cytokines probably via the suppression of sympathetic activity in "FD" rats.
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Affiliation(s)
- Sujuan Zhang
- Department of Gastroenterology, No. 983 Hospital of Chinese People's Liberation Army, Tianjin, China
| | - Yi Liu
- Department of Traditional Chinese Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Shiying Li
- Division of Gastroenterology and Hepatology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA
| | - Feng Ye
- Department of Hepatology, First Affiliated Hospital of Xi'an Jiao tong University, Xi'an, China
| | - Jieyun Yin
- Transtimulation Research Inc., Houston, Texas, USA
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van Baarle L, Stakenborg M, Matteoli G. Enteric neuro-immune interactions in intestinal health and disease. Semin Immunol 2023; 70:101819. [PMID: 37632991 DOI: 10.1016/j.smim.2023.101819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 07/19/2023] [Accepted: 08/11/2023] [Indexed: 08/28/2023]
Abstract
The enteric nervous system is an autonomous neuronal circuit that regulates many processes far beyond the peristalsis in the gastro-intestinal tract. This circuit, consisting of enteric neurons and enteric glial cells, can engage in many intercellular interactions shaping the homeostatic microenvironment in the gut. Perhaps the most well documented interactions taking place, are the intestinal neuro-immune interactions which are essential for the fine-tuning of oral tolerance. In the context of intestinal disease, compelling evidence demonstrates both protective and detrimental roles for this bidirectional neuro-immune signaling. This review discusses the different immune cell types that are recognized to engage in neuronal crosstalk during intestinal health and disease. Highlighting the molecular pathways involved in the neuro-immune interactions might inspire novel strategies to target intestinal disease.
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Affiliation(s)
- Lies van Baarle
- Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Herestraat 49, O&N1 box 701, 3000 Leuven, Belgium
| | - Michelle Stakenborg
- Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Herestraat 49, O&N1 box 701, 3000 Leuven, Belgium
| | - Gianluca Matteoli
- Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Herestraat 49, O&N1 box 701, 3000 Leuven, Belgium.
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Sahn B, Pascuma K, Kohn N, Tracey KJ, Markowitz JF. Transcutaneous auricular vagus nerve stimulation attenuates inflammatory bowel disease in children: a proof-of-concept clinical trial. Bioelectron Med 2023; 9:23. [PMID: 37849000 PMCID: PMC10583463 DOI: 10.1186/s42234-023-00124-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Accepted: 09/11/2023] [Indexed: 10/19/2023] Open
Abstract
BACKGROUND Vagus nerve stimulation is an investigational anti-inflammatory therapy targeting the nervous system to modulate immune activity. This study evaluated the efficacy and safety of transcutaneous auricular VNS (ta-VNS) in patients with pediatric-onset Crohn's disease (CD) or ulcerative colitis (UC). METHODS Participants were 10-21 years of age with mild/moderate CD or UC and fecal calprotectin (FC) > 200 ug/g within 4 weeks of study entry. Subjects were randomized to receive either ta-VNS targeting the cymba conchae of the external left ear, or sham stimulation, of 5 min duration once daily for a 2-week period, followed by a cross over to the alternative stimulation for an additional 2 weeks. At week 4, all subjects received ta-VNS of 5 min duration twice daily until week 16. Primary study endpoints were clinical remission, and a ≥ 50% reduction in FC level from baseline to week 16. Heart rate variability measurements and patient-reported outcome questionnaires were completed during interval and week 16 assessments. RESULTS Twenty-two subjects were enrolled and analyzed (10 CD, 12 UC). Six of 10 with CD had a wPCDAI > 12.5 and 6/12 with UC had a PUCAI > 10 at baseline, correlating to mild to moderate symptom activity. Among the 12 subjects with active symptomatic disease indices at baseline, clinical remission was achieved in 3/6 (50%) with CD and 2/6 (33%) with UC at week 16. Despite all subjects having FC levels ≥ 200 within 4 weeks of enrollment, five subjects (4 UC, 1 CD) had FC levels < 200 at the baseline visit and were excluded from the FC analysis. Of the remaining 17, median baseline FC was 907 µg/g (IQR 411-2,120). At week 16, 11/17 (64.7%) of those with baseline FC ≥ 200 had a ≥ 50% reduction in FC (95% CI 38.3-85.8). In the UC subjects, there was an 81% median reduction in FC vs baseline (833 µg/g; p = 0.03) while in the CD subjects, median reduction in FC at 16 weeks was 51% (357 µg/g; p = 0.09). There were no safety concerns. CONCLUSION Noninvasive ta-VNS attenuated signs and symptoms in a pediatric cohort with mild to moderate inflammatory bowel disease. TRIAL REGISTRATION NCT03863704-Date of registration 3/4/2019.
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Affiliation(s)
- Benjamin Sahn
- Division of Pediatric Gastroenterology, Liver Diseases, & Nutrition, Steven & Alexandra Cohen Children's Medical Center, Northwell Health, 1991 Marcus Ave, Suite M100, New Hyde Park, NY, 11042, USA.
- Feinstein Institutes for Medical Research, Manhasset, NY, USA.
| | - Kristine Pascuma
- Division of Pediatric Gastroenterology, Liver Diseases, & Nutrition, Steven & Alexandra Cohen Children's Medical Center, Northwell Health, 1991 Marcus Ave, Suite M100, New Hyde Park, NY, 11042, USA
| | - Nina Kohn
- Feinstein Institutes for Medical Research, Manhasset, NY, USA
- Biostatistics Unit, Office of Academic Affairs, New Hyde Park, NY, USA
| | - Kevin J Tracey
- Feinstein Institutes for Medical Research, Manhasset, NY, USA
| | - James F Markowitz
- Division of Pediatric Gastroenterology, Liver Diseases, & Nutrition, Steven & Alexandra Cohen Children's Medical Center, Northwell Health, 1991 Marcus Ave, Suite M100, New Hyde Park, NY, 11042, USA
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7
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Osman S, Tashtush A, Reed DE, Lomax AE. Analysis of the spinal and vagal afferent innervation of the mouse colon using neuronal retrograde tracers. Cell Tissue Res 2023:10.1007/s00441-023-03769-3. [PMID: 37004577 DOI: 10.1007/s00441-023-03769-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 03/24/2023] [Indexed: 04/04/2023]
Abstract
The gut-brain axis has received increasing attention recently due to evidence that colonic microbes can affect brain function and behavior. However, little is known about the innervation of the colon by a major component of the gut-brain axis, vagal afferent neurons. Furthermore, it is currently unknown whether individual NG neurons or DRG neurons innervate both the proximal and distal colon. We aimed to quantify the number of vagal and spinal afferent neurons that innervate the colon; and determine whether these individual neurons simultaneously innervate the mouse proximal and distal colon. C57Bl/6 mice received injections of a combination of retrograde tracers that were either injected into the muscularis externa of the proximal or the distal colon: fast blue, DiI and DiO. Five to seven percent of lumbosacral and thoracolumbar spinal afferent neurons, and 25% of vagal afferent neurons were labelled by injections of DiI and DiO into the colon. We also found that approximately 8% of NG neurons innervate the distal colon. Ten percent of labeled thoracolumbar and 15% of labeled lumbosacral DRG neurons innervate both the distal and proximal colon. Eighteen percent of labeled NG neurons innervated both the distal and proximal colon. In conclusion, vagal afferent innervation of the distal colon is less extensive than the proximal colon, whereas a similar gradient was not observed for the spinal afferent innervation. Furthermore, overlap appears to exist between the receptive fields of vagal and spinal afferent neurons that innervate the proximal and distal colon.
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Affiliation(s)
- Samira Osman
- Gastrointestinal Diseases Research Unit, Queen's University, 76 Stuart Street, Kingston, ON, K7L 2V7, Canada
| | - Ayssar Tashtush
- Gastrointestinal Diseases Research Unit, Queen's University, 76 Stuart Street, Kingston, ON, K7L 2V7, Canada
- Department of Physiology, Jordan University of Science and Technology, Irbid, Jordan
| | - David E Reed
- Gastrointestinal Diseases Research Unit, Queen's University, 76 Stuart Street, Kingston, ON, K7L 2V7, Canada
- Department of Medicine, Queen's University, ON, Kingston, Canada
| | - Alan E Lomax
- Gastrointestinal Diseases Research Unit, Queen's University, 76 Stuart Street, Kingston, ON, K7L 2V7, Canada.
- Department of Medicine, Queen's University, ON, Kingston, Canada.
- Department of Biomedical and Molecular Sciences, Queen's University, ON, Kingston, Canada.
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Yasmin F, Sahito AM, Mir SL, Khatri G, Shaikh S, Gul A, Hassan SA, Koritala T, Surani S. Electrical neuromodulation therapy for inflammatory bowel disease. World J Gastrointest Pathophysiol 2022; 13:128-142. [PMID: 36187600 PMCID: PMC9516456 DOI: 10.4291/wjgp.v13.i5.128] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 02/19/2022] [Accepted: 07/18/2022] [Indexed: 02/08/2023] Open
Abstract
Inflammatory bowel disease (IBD) is an inflammatory disease of the gastrointestinal (GI) tract. It has financial and quality of life impact on patients. Although there has been a significant advancement in treatments, a considerable number of patients do not respond to it or have severe side effects. Therapeutic approaches such as electrical neuromodulation are being investigated to provide alternate options. Although bioelectric neuromodulation technology has evolved significantly in the last decade, sacral nerve stimulation (SNS) for fecal incontinence remains the only neuromodulation protocol commonly utilized use for GI disease. For IBD treatment, several electrical neuromodulation techniques have been studied, such as vagus NS, SNS, and tibial NS. Several animal and clinical experiments were conducted to study the effectiveness, with encouraging results. The precise underlying mechanisms of action for electrical neuromodulation are unclear, but this modality appears to be promising. Randomized control trials are required to investigate the efficacy of intrinsic processes. In this review, we will discuss the electrical modulation therapy for the IBD and the data pertaining to it.
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Affiliation(s)
- Farah Yasmin
- Department of Medicine, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Abdul Moiz Sahito
- Department of Medicine, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Syeda Lamiya Mir
- Department of Medicine, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Govinda Khatri
- Department of Medicine, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Somina Shaikh
- Department of Medicine, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Ambresha Gul
- Department of Medicine, People’s University of Medical and Health Sciences, Nawabshah 67480, Pakistan
| | - Syed Adeel Hassan
- Department of Medicine, University of Louisville, Louiseville, KY 40292, United States
| | - Thoyaja Koritala
- Department of Medicine, Mayo Clinic, Rochester, NY 55902, United States
| | - Salim Surani
- Department of Medicine, Texas A&M University, College Station, TX 77843, United States
- Department of Anesthesiology, Mayo Clinic, Rochester, MN 55902, United States
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9
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Stavely R, Rahman AA, Sahakian L, Prakash MD, Robinson AM, Hassanzadeganroudsari M, Filippone RT, Fraser S, Eri R, Bornstein JC, Apostolopoulos V, Nurgali K. Divergent Adaptations in Autonomic Nerve Activity and Neuroimmune Signaling Associated With the Severity of Inflammation in Chronic Colitis. Inflamm Bowel Dis 2022; 28:1229-1243. [PMID: 35380670 DOI: 10.1093/ibd/izac060] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND The autonomic nervous system (ANS) is thought to play a critical role in the anti-inflammatory reflex pathway in acute colitis via its interaction with the spleen and colon. Inflammation in the intestine is associated with a blunting of vagal signaling and increased sympathetic activity. As a corollary, methods to restore sympatho-vagal balance are being investigated as therapeutic strategies for the treatment of intestinal inflammation. Nevertheless, it is indefinite whether these autonomic signaling adaptations in colitis are detrimental or beneficial to controlling intestinal inflammation. In this study, models of moderate and severe chronic colitis are utilized to resolve the correlations between sympatho-vagal signaling and the severity of intestinal inflammation. METHODS Spleens and colons were collected from Winnie (moderate colitis), Winnie-Prolapse (severe colitis), and control C57BL/6 mice. Changes to the size and histomorphology of spleens were evaluated. Flow cytometry was used to determine the expression of adrenergic and cholinergic signaling proteins in splenic B and T lymphocytes. The inflammatory profile of the spleen and colon was determined using a RT-PCR gene array. Blood pressure, heart rate, splanchnic sympathetic nerve and vagus nerve activity were recorded. RESULTS Spleens and colons from Winnie and Winnie-Prolapse mice exhibited gross abnormalities by histopathology. Genes associated with a pro-inflammatory response were upregulated in the colons from Winnie and further augmented in colons from Winnie-Prolapse mice. Conversely, many pro-inflammatory markers were downregulated in the spleens from Winnie-Prolapse mice. Heightened activity of the splanchnic nerve was observed in Winnie but not Winnie-Prolapse mice. Conversely, vagal nerve activity was greater in Winnie-Prolapse mice compared with Winnie mice. Splenic lymphocytes expressing α1 and β2 adrenoreceptors were reduced, but those expressing α7 nAChR and producing acetylcholine were increased in Winnie and Winnie-Prolapse mice. CONCLUSIONS Sympathetic activity may correlate with an adaptive mechanism to reduce the severity of chronic colitis. The Winnie and Winnie-Prolapse mouse models of moderate and severe chronic colitis are well suited to examine the pathophysiology of progressive chronic intestinal inflammation.
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Affiliation(s)
- Rhian Stavely
- Institute for Health and Sport, Victoria University, Western Centre for Health Research and Education, Sunshine Hospital, Melbourne, Victoria, Australia.,Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Ahmed A Rahman
- Institute for Health and Sport, Victoria University, Western Centre for Health Research and Education, Sunshine Hospital, Melbourne, Victoria, Australia.,Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Lauren Sahakian
- Institute for Health and Sport, Victoria University, Western Centre for Health Research and Education, Sunshine Hospital, Melbourne, Victoria, Australia
| | - Monica D Prakash
- Institute for Health and Sport, Victoria University, Western Centre for Health Research and Education, Sunshine Hospital, Melbourne, Victoria, Australia.,School of Health and Biomedical Sciences, RMIT University, Melbourne, Victoria, Australia
| | - Ainsley M Robinson
- Institute for Health and Sport, Victoria University, Western Centre for Health Research and Education, Sunshine Hospital, Melbourne, Victoria, Australia
| | - Majid Hassanzadeganroudsari
- Institute for Health and Sport, Victoria University, Western Centre for Health Research and Education, Sunshine Hospital, Melbourne, Victoria, Australia
| | - Rhiannon T Filippone
- Institute for Health and Sport, Victoria University, Western Centre for Health Research and Education, Sunshine Hospital, Melbourne, Victoria, Australia
| | - Sarah Fraser
- Institute for Health and Sport, Victoria University, Western Centre for Health Research and Education, Sunshine Hospital, Melbourne, Victoria, Australia
| | - Rajaraman Eri
- School of Health Sciences, The University of Tasmania, Launceston, Tasmania, Australia
| | - Joel C Bornstein
- Department of Physiology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Vasso Apostolopoulos
- Institute for Health and Sport, Victoria University, Western Centre for Health Research and Education, Sunshine Hospital, Melbourne, Victoria, Australia
| | - Kulmira Nurgali
- Institute for Health and Sport, Victoria University, Western Centre for Health Research and Education, Sunshine Hospital, Melbourne, Victoria, Australia.,Department of Medicine Western Health, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Victoria, Australia.,Regenerative Medicine and Stem Cells Program, Australian Institute of Musculoskeletal Science (AIMSS), Melbourne, Victoria, Australia
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10
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Cao Q, Mertens RT, Sivanathan KN, Cai X, Xiao P. Macrophage orchestration of epithelial and stromal cell homeostasis in the intestine. J Leukoc Biol 2022; 112:313-331. [PMID: 35593111 PMCID: PMC9543232 DOI: 10.1002/jlb.3ru0322-176r] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 04/29/2022] [Accepted: 05/02/2022] [Indexed: 11/06/2022] Open
Abstract
The intestinal tract is a complex ecosystem where numerous cell types of epithelial, immune, neuronal, and endothelial origin coexist in an intertwined, highly organized manner. The functional equilibrium of the intestine relies heavily on the proper crosstalk and cooperation among each cell population. Furthermore, macrophages are versatile, innate immune cells that participate widely in the modulation of inflammation and tissue remodeling. Emerging evidence suggest that macrophages are central in orchestrating tissue homeostasis. Herein, we describe how macrophages interact with epithelial cells, neurons, and other types of mesenchymal cells under the context of intestinal inflammation, followed by the therapeutic implications of cellular crosstalk pertaining to the treatment of inflammatory bowel disease.
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Affiliation(s)
- Qian Cao
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Randall Tyler Mertens
- Department of Immunology, Harvard Medical School, Boston, Massachusetts, USA.,Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Kisha Nandini Sivanathan
- Department of Immunology, Harvard Medical School, Boston, Massachusetts, USA.,Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Xuechun Cai
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Peng Xiao
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Department of Immunology, Harvard Medical School, Boston, Massachusetts, USA.,Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA.,The Key Laboratory for Immunity and Inflammatory Diseases of Zhejiang Province, Hangzhou, China.,Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China
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11
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Goggins E, Mitani S, Tanaka S. Clinical perspectives on vagus nerve stimulation: present and future. Clin Sci (Lond) 2022; 136:695-709. [PMID: 35536161 PMCID: PMC9093220 DOI: 10.1042/cs20210507] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 04/15/2022] [Accepted: 04/22/2022] [Indexed: 12/30/2022]
Abstract
The vagus nerve, the great wanderer, is involved in numerous processes throughout the body and vagus nerve stimulation (VNS) has the potential to modulate many of these functions. This wide-reaching capability has generated much interest across a range of disciplines resulting in several clinical trials and studies into the mechanistic basis of VNS. This review discusses current preclinical and clinical evidence supporting the efficacy of VNS in different diseases and highlights recent advancements. Studies that provide insights into the mechanism of VNS are considered.
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Affiliation(s)
- Eibhlin Goggins
- Division of Nephrology and Center for Immunity, Inflammation, and Regenerative Medicine, University of Virginia, Charlottesville, VA, U.S.A
| | - Shuhei Mitani
- Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Shinji Tanaka
- Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
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12
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Zhu Y, Duan S, Wang M, Deng Z, Li J. Neuroimmune Interaction: A Widespread Mutual Regulation and the Weapons for Barrier Organs. Front Cell Dev Biol 2022; 10:906755. [PMID: 35646918 PMCID: PMC9130600 DOI: 10.3389/fcell.2022.906755] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 04/26/2022] [Indexed: 12/12/2022] Open
Abstract
Since the embryo, the nervous system and immune system have been interacting to regulate each other’s development and working together to resist harmful stimuli. However, oversensitive neural response and uncontrolled immune attack are major causes of various diseases, especially in barrier organs, while neural-immune interaction makes it worse. As the first defense line, the barrier organs give a guarantee to maintain homeostasis in external environment. And the dense nerve innervation and abundant immune cell population in barrier organs facilitate the neuroimmune interaction, which is the physiological basis of multiple neuroimmune-related diseases. Neuroimmune-related diseases often have complex mechanisms and require a combination of drugs, posing challenges in finding etiology and treatment. Therefore, it is of great significance to illustrate the specific mechanism and exact way of neuro-immune interaction. In this review, we first described the mutual regulation of the two principal systems and then focused on neuro-immune interaction in the barrier organs, including intestinal tract, lungs and skin, to clarify the mechanisms and provide ideas for clinical etiology exploration and treatment.
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Affiliation(s)
- Yan Zhu
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, China
| | - Shixin Duan
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, China
| | - Mei Wang
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, China
| | - Zhili Deng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Zhili Deng, ; Ji Li,
| | - Ji Li
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Zhili Deng, ; Ji Li,
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13
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Erin N, Shurin GV, Baraldi JH, Shurin MR. Regulation of Carcinogenesis by Sensory Neurons and Neuromediators. Cancers (Basel) 2022; 14:2333. [PMID: 35565462 PMCID: PMC9102554 DOI: 10.3390/cancers14092333] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 04/26/2022] [Accepted: 05/05/2022] [Indexed: 12/12/2022] Open
Abstract
Interactions between the immune system and the nervous system are crucial in maintaining homeostasis, and disturbances of these neuro-immune interactions may participate in carcinogenesis and metastasis. Nerve endings have been identified within solid tumors in humans and experimental animals. Although the involvement of the efferent sympathetic and parasympathetic innervation in carcinogenesis has been extensively investigated, the role of the afferent sensory neurons and the neuropeptides in tumor development, growth, and progression is recently appreciated. Similarly, current findings point to the significant role of Schwann cells as part of neuro-immune interactions. Hence, in this review, we mainly focus on local and systemic effects of sensory nerve activity as well as Schwann cells in carcinogenesis and metastasis. Specific denervation of vagal sensory nerve fibers, or vagotomy, in animal models, has been reported to markedly increase lung metastases of breast carcinoma as well as pancreatic and gastric tumor growth, with the formation of liver metastases demonstrating the protective role of vagal sensory fibers against cancer. Clinical studies have revealed that patients with gastric ulcers who have undergone a vagotomy have a greater risk of stomach, colorectal, biliary tract, and lung cancers. Protective effects of vagal activity have also been documented by epidemiological studies demonstrating that high vagal activity predicts longer survival rates in patients with colon, non-small cell lung, prostate, and breast cancers. However, several studies have reported that inhibition of sensory neuronal activity reduces the development of solid tumors, including prostate, gastric, pancreatic, head and neck, cervical, ovarian, and skin cancers. These contradictory findings are likely to be due to the post-nerve injury-induced activation of systemic sensory fibers, the level of aggressiveness of the tumor model used, and the local heterogeneity of sensory fibers. As the aggressiveness of the tumor model and the level of the inflammatory response increase, the protective role of sensory nerve fibers is apparent and might be mostly due to systemic alterations in the neuro-immune response. Hence, more insights into inductive and permissive mechanisms, such as systemic, cellular neuro-immunological mechanisms of carcinogenesis and metastasis formation, are needed to understand the role of sensory neurons in tumor growth and spread.
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Affiliation(s)
- Nuray Erin
- Department of Medical Pharmacology, Immunopharmacology, and Immuno-Oncology Unit, School of Medicine, Akdeniz University, 07070 Antalya, Turkey
| | - Galina V. Shurin
- Department of Pathology, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, 15213 PA, USA; (G.V.S.); (M.R.S.)
| | - James H. Baraldi
- Department of Neuroscience, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, 15213 PA, USA;
| | - Michael R. Shurin
- Department of Pathology, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, 15213 PA, USA; (G.V.S.); (M.R.S.)
- Department of Immunology, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, 15213 PA, USA
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14
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Populin L, Stebbing MJ, Furness JB. Neuronal regulation of the gut immune system and neuromodulation for treating inflammatory bowel disease. FASEB Bioadv 2021; 3:953-966. [PMID: 34761177 PMCID: PMC8565205 DOI: 10.1096/fba.2021-00070] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 08/04/2021] [Accepted: 08/10/2021] [Indexed: 02/06/2023] Open
Abstract
The gut immune system in the healthy intestine is anti-inflammatory, but can move to a pro-inflammatory state when the gut is challenged by pathogens or in disease. The nervous system influences the level of inflammation through enteric neurons and extrinsic neural connections, particularly vagal and sympathetic innervation of the gastrointestinal tract, each of which exerts anti-inflammatory effects. Within the enteric nervous system (ENS), three neuron types that influence gut immune cells have been identified, intrinsic primary afferent neurons (IPANs), vasoactive intestinal peptide (VIP) neurons that project to the mucosa, and cholinergic neurons that influence macrophages in the external muscle layers. The enteric neuropeptides, calcitonin gene-related peptide (CGRP), tachykinins, and neuromedin U (NMU), which are contained in IPANs, and VIP produced by the mucosa innervating neurons, all influence immune cells, notably innate lymphoid cells (ILCs). ILC2 are stimulated by VIP to release IL-22, which promotes microbial defense and tissue repair. Enteric neurons are innervated by the vagus, and, in the large intestine, by the pelvic nerves. Vagal nerve stimulation reduces gut inflammation, which may be both by stimulation of efferent (motor) pathways to the ENS, and stimulation of afferent pathways that connect to integrating centers in the CNS. Efferent pathways from the CNS have their anti-inflammatory effects through either or both vagal efferent neurons and sympathetic pathways. The final neurons in sympathetic pathways reduce gut inflammation by the action of noradrenaline on β2 adrenergic receptors expressed by immune cells. Activation of neural anti-inflammatory pathways is an attractive option to treat inflammatory bowel disease that is refractory to other treatments. Further investigation of the ways in which enteric reflexes, vagal pathways and sympathetic pathways integrate their effects to modulate the gut immune system and gut inflammation is needed to optimize neuromodulation therapy.
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Affiliation(s)
- Luis Populin
- Department of NeuroscienceSchool of Medicine and Public HealthUniversity of Wisconsin‐MadisonMadisonWisconsinUSA
| | - Martin J. Stebbing
- Florey Institute of Neuroscience and Mental HealthParkvilleVICAustralia
- Department of Anatomy & PhysiologyUniversity of MelbourneParkvilleVICAustralia
| | - John B. Furness
- Florey Institute of Neuroscience and Mental HealthParkvilleVICAustralia
- Department of Anatomy & PhysiologyUniversity of MelbourneParkvilleVICAustralia
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15
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Yang RX, Song WJ, Wu ZQ, Goyal H, Xu HG. Association of Serum Neuron-Specific Enolase and C-Reactive Protein With Disease Location and Endoscopic Inflammation Degree in Patients With Crohn's Disease. Front Med (Lausanne) 2021; 8:663920. [PMID: 34513858 PMCID: PMC8427157 DOI: 10.3389/fmed.2021.663920] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 07/26/2021] [Indexed: 12/22/2022] Open
Abstract
Objective: The objective of this study was to explore the association between serum markers neuron-specific enolase (NSE) and C-reactive protein (CRP) with intestinal lesion location and degree of inflammation in patients with Crohn's disease (CD). Design: The levels of serum NSE, CRP, and fecal calprotectin (FC) in patients with CD were analyzed retrospectively. The severity of inflammatory lesions in the intestinal wall was accessed using the Simple Endoscopic Score for Crohn's disease (SES-CD). Results: The levels of NSE in patients with CD were higher than those of healthy individuals (14.87 vs. 12.68 ng/ml, P < 0.001). The levels of CRP in patients with CD were higher than those of healthy individuals (12.30 vs. 3.40 mg/l, P < 0.001). The FC levels in patients with CD were higher than those of patients with non-inflammatory bowel disease (1,143.90 vs. 114.21 μg/g, P < 0.05). The levels of NSE in CD with ileal lesions and simultaneous ileal and colon lesions were significantly higher than those in patients with CD with colonic lesions. However, the CRP was higher in patients with colonic lesions than those with ileal lesions. The levels of NSE in patients with severe inflammation were higher than those in patients with moderate inflammation (15.95 vs. 13.89 ng/ml, P < 0.05). Similarly, the NSE levels in patients with CD with severe inflammation were higher than those in patients with CD with mild inflammation (15.95 vs. 13.53 ng/mL, P < 0.05). The levels of CRP in severe inflammation were higher than those in moderate inflammation (29.80 vs. 19.60 mg/l, P < 0.05). In addition, the CRP levels in severe inflammation were higher than those in mild inflammation (29.80 vs. 5.86 mg/l, P < 0.05). ROC curve analysis showed that when NSE was combined with CRP for distinguishing between patients with CD and those without CD, sensitivity increased to 80.41%, specificity increased to 74.66%, and a highest AUC was equal to 0.843. Conclusion: Our study shows that serum NSE and CRP can be used to assess the severity of CD as well as the location of intestinal involvement. Therefore, NSE and CRP could be used as the non-invasive tests in detecting the location and severity of disease in patients with CD in daily routine practice.
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Affiliation(s)
- Rui-Xia Yang
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Wei-Juan Song
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zhi-Qi Wu
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Hemant Goyal
- Department of Internal Medicine, Wright Center for Graduate Medical Education, Scranton, PA, United States
| | - Hua-Guo Xu
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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16
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Duan H, Cai X, Luan Y, Yang S, Yang J, Dong H, Zeng H, Shao L. Regulation of the Autonomic Nervous System on Intestine. Front Physiol 2021; 12:700129. [PMID: 34335306 PMCID: PMC8317205 DOI: 10.3389/fphys.2021.700129] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Accepted: 06/22/2021] [Indexed: 12/12/2022] Open
Abstract
Intestine is composed of various types of cells including absorptive epithelial cells, goblet cells, endocrine cells, Paneth cells, immunological cells, and so on, which play digestion, absorption, neuroendocrine, immunological function. Intestine is innervated with extrinsic autonomic nerves and intrinsic enteric nerves. The neurotransmitters and counterpart receptors are widely distributed in the different intestinal cells. Intestinal autonomic nerve system includes sympathetic and parasympathetic nervous systems, which regulate cellular proliferation and function in intestine under physiological and pathophysiological conditions. Presently, distribution and functional characteristics of autonomic nervous system in intestine were reviewed. How autonomic nervous system regulates intestinal cell proliferation was discussed. Function of autonomic nervous system on intestinal diseases was extensively reviewed. It might be helpful to properly manipulate autonomic nervous system during treating different intestinal diseases.
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Affiliation(s)
- Hongyi Duan
- Medical College of Nanchang University, Nanchang, China
| | - Xueqin Cai
- Medical College of Nanchang University, Nanchang, China
| | - Yingying Luan
- Medical College of Nanchang University, Nanchang, China
| | - Shuo Yang
- Medical College of Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang University, Nanchang, China
| | - Juan Yang
- Medical College of Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang University, Nanchang, China
| | - Hui Dong
- Medical College of Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Interdisciplinary Science, Nanchang University, Nanchang, China
| | - Huihong Zeng
- Medical College of Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Interdisciplinary Science, Nanchang University, Nanchang, China
| | - Lijian Shao
- Medical College of Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Interdisciplinary Science, Nanchang University, Nanchang, China
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17
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Mikami Y, Tsunoda J, Kiyohara H, Taniki N, Teratani T, Kanai T. Vagus nerve-mediated intestinal immune regulation: therapeutic implications for inflammatory bowel diseases. Int Immunol 2021; 34:97-106. [PMID: 34240133 DOI: 10.1093/intimm/dxab039] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 07/07/2021] [Indexed: 12/13/2022] Open
Abstract
The pathophysiology of inflammatory bowel disease (IBD) involves immunological, genetic and environmental factors. Through its ability to sense environmental stimuli, the autonomic nervous system plays a key role in the development and persistence of IBD. The vagus nerve (VN), which contains sensory and motor neurons, travels throughout the body to innervate the gut and other visceral organs in the thoracic and abdominopelvic cavities. Recent studies show that the VN has anti-inflammatory effects via the release of acetylcholine, in what is known as the cholinergic anti-inflammatory pathway (CAIP). In the gut immune system, the CAIP is proposed to be activated directly by signals from the gut and indirectly by signals from the liver, which receives gut-derived bioactive substances via the portal vein and senses the status of the gut. The gut-brain axis and liver-brain-gut reflex arc regulate a wide variety of peripheral immune cells to maintain homeostasis in the gut. Therefore, targeting the neural reflex by methods such as VN stimulation is now under investigation for suppressing intestinal inflammation associated with IBD. In this review, we describe the role of the VN in the regulation of intestinal immunity, and we discuss novel therapeutic approaches for IBD that target neuroimmune interactions.
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Affiliation(s)
- Yohei Mikami
- Division of Gastroenterology and Hepatology, Department of Internal Medicine
| | - Junya Tsunoda
- Department of Surgery, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, Japan
| | - Hiroki Kiyohara
- Division of Gastroenterology and Hepatology, Department of Internal Medicine
| | - Nobuhito Taniki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine
| | - Toshiaki Teratani
- Division of Gastroenterology and Hepatology, Department of Internal Medicine
| | - Takanori Kanai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine.,AMED-CREST, Japan Agency for Medical Research and Development, Tokyo, Japan
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18
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Meroni E, Stakenborg N, Gomez-Pinilla PJ, Stakenborg M, Aguilera-Lizarraga J, Florens M, Delfini M, de Simone V, De Hertogh G, Goverse G, Matteoli G, Boeckxstaens GE. Vagus Nerve Stimulation Promotes Epithelial Proliferation and Controls Colon Monocyte Infiltration During DSS-Induced Colitis. Front Med (Lausanne) 2021; 8:694268. [PMID: 34307422 PMCID: PMC8292675 DOI: 10.3389/fmed.2021.694268] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 06/07/2021] [Indexed: 12/12/2022] Open
Abstract
Background: We previously showed increased susceptibility to dextran sulfate sodium (DSS)-induced colitis in vagotomized mice. Here, we evaluated whether vagus nerve stimulation (VNS) is able to reduce the severity of DSS colitis and aimed to unravel the mechanism involved. Methods: Colitis was induced in wild type mice by 2.5% DSS administration in drinking water for 5 days. VNS (5 Hz, 1 ms, 1 mA) was applied 1 day prior to and after 4 days of DSS administration to evaluate changes in epithelial integrity and inflammatory response, respectively. Epithelial integrity was assessed using TUNEL and Ki67 staining. Monocytes, immature and mature macrophages were sorted from colonic samples and gene expression levels of pro-inflammatory cytokines were studied. Results: VNS applied prior to DSS administration (i.e., prophylactic VNS) reduced disease activity index (VNS 0.8 ± 0.6 vs. sham 2.8 ± 0.7, p < 0.001, n = 5) and tended to improve histology score. Prophylactic VNS significantly increased epithelial cell proliferation and diminished apoptosis compared to sham stimulation. VNS applied at day 4 during DSS administration (i.e., therapeutic VNS) decreased the influx of monocytes, monocyte-derived macrophages and neutrophils, and significantly reduced pro-inflammatory cytokine expression (i.e., Tnfα and Cxcl1) in immature macrophages compared to sham stimulation. Conclusions: A single period of VNS applied prior to DSS exposure reduced DSS-induced colitis by an improvement in epithelial integrity. On the other hand, VNS applied during the inflammatory phase of DSS colitis reduced cytokine expression in immature macrophages. Our data further underscores the potential of VNS as novel therapeutic approach for inflammatory bowel diseases.
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Affiliation(s)
- Elisa Meroni
- Translational Research Center for Gastrointestinal Disorders (TARGID), Lab for Intestinal Neuro-Immune Interaction, Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven - University of Leuven, Leuven, Belgium
| | - Nathalie Stakenborg
- Translational Research Center for Gastrointestinal Disorders (TARGID), Lab for Intestinal Neuro-Immune Interaction, Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven - University of Leuven, Leuven, Belgium
| | - Pedro J Gomez-Pinilla
- Translational Research Center for Gastrointestinal Disorders (TARGID), Lab for Intestinal Neuro-Immune Interaction, Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven - University of Leuven, Leuven, Belgium
| | - Michelle Stakenborg
- Translational Research Center for Gastrointestinal Disorders (TARGID), Lab for Mucosal Immunology, Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven - University of Leuven, Leuven, Belgium
| | - Javier Aguilera-Lizarraga
- Translational Research Center for Gastrointestinal Disorders (TARGID), Lab for Intestinal Neuro-Immune Interaction, Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven - University of Leuven, Leuven, Belgium
| | - Morgane Florens
- Translational Research Center for Gastrointestinal Disorders (TARGID), Lab for Intestinal Neuro-Immune Interaction, Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven - University of Leuven, Leuven, Belgium
| | - Marcello Delfini
- Translational Research Center for Gastrointestinal Disorders (TARGID), Lab for Intestinal Neuro-Immune Interaction, Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven - University of Leuven, Leuven, Belgium
| | - Veronica de Simone
- Translational Research Center for Gastrointestinal Disorders (TARGID), Lab for Mucosal Immunology, Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven - University of Leuven, Leuven, Belgium
| | - Gert De Hertogh
- Department of Pathology, Universitair Ziekenhuis Leuven, Leuven, Belgium
| | - Gera Goverse
- Translational Research Center for Gastrointestinal Disorders (TARGID), Lab for Mucosal Immunology, Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven - University of Leuven, Leuven, Belgium
| | - Gianluca Matteoli
- Translational Research Center for Gastrointestinal Disorders (TARGID), Lab for Mucosal Immunology, Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven - University of Leuven, Leuven, Belgium
| | - Guy E Boeckxstaens
- Translational Research Center for Gastrointestinal Disorders (TARGID), Lab for Intestinal Neuro-Immune Interaction, Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven - University of Leuven, Leuven, Belgium
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19
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Liu Y, Forsythe P. Vagotomy and insights into the microbiota-gut-brain axis. Neurosci Res 2021; 168:20-27. [DOI: 10.1016/j.neures.2021.04.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 04/01/2021] [Accepted: 04/01/2021] [Indexed: 12/12/2022]
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20
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Sympathetic Denervation Alters the Inflammatory Response of Resident Muscularis Macrophages upon Surgical Trauma and Ameliorates Postoperative Ileus in Mice. Int J Mol Sci 2021; 22:ijms22136872. [PMID: 34206766 PMCID: PMC8268963 DOI: 10.3390/ijms22136872] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 06/20/2021] [Accepted: 06/22/2021] [Indexed: 01/22/2023] Open
Abstract
Interactions between the peripheral nervous system and resident macrophages (MMs) modulate intestinal homeostatic functions. Activation of β2-adrenergic receptors on MMs has been shown to reduce bacterial challenges. These MMs are also crucial for the development of bowel inflammation in postoperative ileus (POI), an iatrogenic, noninfectious inflammation-based motility disorder. However, the role of the sympathetic nervous system (SNS) in the immune modulation of these MMs during POI or other noninfectious diseases is largely unknown. By employing 6-OHDA-induced denervation, we investigated the changes in the muscularis externa by RNA-seq, quantitative PCR, and flow cytometry. Further, we performed transcriptional phenotyping of sorted CX3CR1+ MMs and ex vivo LPS/M-CSF stimulation on these MMs. By combining denervation with a mouse POI model, we explored distinct changes on CX3CR1+ MMs as well as in the muscularis externa and their functional outcome during POI. Our results identify SNS as an important mediator in noninfectious postoperative inflammation. Upon denervation, MMs anti-inflammatory genes were reduced, and the muscularis externa profile is shaped toward a proinflammatory status. Further, denervation reduced MMs anti-inflammatory genes also in the early phase of POI. Finally, reduced leukocyte infiltration into the muscularis led to a quicker recovery of bowel motility in the late phase of POI.
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21
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Stakenborg N, Boeckxstaens GE. Bioelectronics in the brain-gut axis: focus on inflammatory bowel disease (IBD). Int Immunol 2021; 33:337-348. [PMID: 33788920 PMCID: PMC8183669 DOI: 10.1093/intimm/dxab014] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 03/30/2021] [Indexed: 12/17/2022] Open
Abstract
Accumulating evidence shows that intestinal homeostasis is mediated by cross-talk between the nervous system, enteric neurons and immune cells, together forming specialized neuroimmune units at distinct anatomical locations within the gut. In this review, we will particularly discuss how the intrinsic and extrinsic neuronal circuitry regulates macrophage function and phenotype in the gut during homeostasis and aberrant inflammation, such as observed in inflammatory bowel disease (IBD). Furthermore, we will provide an overview of basic and translational IBD research using these neuronal circuits as a novel therapeutic tool. Finally, we will highlight the different challenges ahead to make bioelectronic neuromodulation a standard treatment for intestinal immune-mediated diseases.
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Affiliation(s)
- Nathalie Stakenborg
- Center of Intestinal Neuro-immune Interaction, Translational Research Center for GI Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing, University of Leuven, Herestraat 49, O&N1 bus 701, Leuven 3000, Belgium
| | - Guy E Boeckxstaens
- Center of Intestinal Neuro-immune Interaction, Translational Research Center for GI Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing, University of Leuven, Herestraat 49, O&N1 bus 701, Leuven 3000, Belgium
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22
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Bonaz B, Sinniger V, Pellissier S. Therapeutic Potential of Vagus Nerve Stimulation for Inflammatory Bowel Diseases. Front Neurosci 2021; 15:650971. [PMID: 33828455 PMCID: PMC8019822 DOI: 10.3389/fnins.2021.650971] [Citation(s) in RCA: 88] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 03/01/2021] [Indexed: 12/12/2022] Open
Abstract
The vagus nerve is a mixed nerve, comprising 80% afferent fibers and 20% efferent fibers. It allows a bidirectional communication between the central nervous system and the digestive tract. It has a dual anti-inflammatory properties via activation of the hypothalamic pituitary adrenal axis, by its afferents, but also through a vago-vagal inflammatory reflex involving an afferent (vagal) and an efferent (vagal) arm, called the cholinergic anti-inflammatory pathway. Indeed, the release of acetylcholine at the end of its efferent fibers is able to inhibit the release of tumor necrosis factor (TNF) alpha by macrophages via an interneuron of the enteric nervous system synapsing between the efferent vagal endings and the macrophages and releasing acetylcholine. The vagus nerve also synapses with the splenic sympathetic nerve to inhibit the release of TNF-alpha by splenic macrophages. It can also activate the spinal sympathetic system after central integration of its afferents. This anti-TNF-alpha effect of the vagus nerve can be used in the treatment of chronic inflammatory bowel diseases, represented by Crohn’s disease and ulcerative colitis where this cytokine plays a key role. Bioelectronic medicine, via vagus nerve stimulation, may have an interest in this non-drug therapeutic approach as an alternative to conventional anti-TNF-alpha drugs, which are not devoid of side effects feared by patients.
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Affiliation(s)
- Bruno Bonaz
- Division of Hepato-Gastroenterology, Centre Hospitalier Universitaire Grenoble Alpes, Grenoble, France.,Grenoble Institute of Neurosciences, Inserm U1216, University Grenoble Alpes, Grenoble, France
| | - Valérie Sinniger
- Division of Hepato-Gastroenterology, Centre Hospitalier Universitaire Grenoble Alpes, Grenoble, France.,Grenoble Institute of Neurosciences, Inserm U1216, University Grenoble Alpes, Grenoble, France
| | - Sonia Pellissier
- Laboratoire Inter-Universitaire de Psychologie Personnalité, Cognition, Changement Social, University Grenoble Alpes, University Savoie Mont Blanc, Grenoble, France
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23
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Kulkarni S, Kurapati S, Bogunovic M. Neuro-innate immune interactions in gut mucosal immunity. Curr Opin Immunol 2021; 68:64-71. [PMID: 33130386 PMCID: PMC11095515 DOI: 10.1016/j.coi.2020.09.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 09/13/2020] [Accepted: 09/17/2020] [Indexed: 12/14/2022]
Abstract
The gastrointestinal (GI) tract performs a set of vital physiological functions related to food and water consumption. To help regulate these complex physiological processes, the GI tract is innervated by extensive neural networks. The GI tract also serves as the largest immune organ aimed to protect hosts from harmful microbes and toxins ingested with food. It emerges that the enteric nervous and immune systems are highly integrated to optimize digestion while reinforcing immune protection. In this review, we will discuss key cellular players involved in the neuro-immune interactions within the GI mucosa with the focus on the recently uncovered neural pathways that regulate mucosal immunity in a context relevant to GI health and disease.
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Affiliation(s)
- Subhash Kulkarni
- Department of Medicine, Center for Neurogastroenterology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
| | - Sravya Kurapati
- Department of Pathology, University of Massachusetts Medical School, Worcester, MA, United States; Penn State Biomedical Sciences Ph.D. Program, Penn State University College of Medicine, Hershey, PA, United States
| | - Milena Bogunovic
- Department of Pathology, University of Massachusetts Medical School, Worcester, MA, United States.
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24
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Conde SV, Sacramento JF, Martins FO. Immunity and the carotid body: implications for metabolic diseases. Bioelectron Med 2020; 6:24. [PMID: 33353562 PMCID: PMC7756955 DOI: 10.1186/s42234-020-00061-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 11/24/2020] [Indexed: 12/14/2022] Open
Abstract
Neuro-immune communication has gained enormous interest in recent years due to increasing knowledge of the way in which the brain coordinates functional alterations in inflammatory and autoimmune responses, and the mechanisms of neuron-immune cell interactions in the context of metabolic diseases such as obesity and type 2 diabetes. In this review, we will explain how this relationship between the nervous and immune system impacts the pro- and anti-inflammatory pathways with specific reference to the hypothalamus-pituitary-adrenal gland axis and the vagal reflex and will explore the possible involvement of the carotid body (CB) in the neural control of inflammation. We will also highlight the mechanisms of vagal anti-inflammatory reflex control of immunity and metabolism, and the consequences of functional disarrangement of this reflex in settlement and development of metabolic diseases, with special attention to obesity and type 2 diabetes. Additionally, the role of CB in the interplay between metabolism and immune responses will be discussed, with specific reference to the different stimuli that promote CB activation and the balance between sympathetic and parasympathetic in this context. In doing so, we clarify the multivarious neuronal reflexes that coordinate tissue-specific responses (gut, pancreas, adipose tissue and liver) critical to metabolic control, and metabolic disease settlement and development. In the final section, we will summarize how electrical modulation of the carotid sinus nerve may be utilized to adjust these reflex responses and thus control inflammation and metabolic diseases, envisioning new therapeutics horizons.
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Affiliation(s)
- Silvia V Conde
- iNOVA4Health, CEDOC, NOVA Medical School, NMS, Universidade Nova de Lisboa, Rua Câmara Pestana, n°6, Edifício 2, piso 3, 1150-274, Lisbon, Portugal.
| | - Joana F Sacramento
- iNOVA4Health, CEDOC, NOVA Medical School, NMS, Universidade Nova de Lisboa, Rua Câmara Pestana, n°6, Edifício 2, piso 3, 1150-274, Lisbon, Portugal
| | - Fatima O Martins
- iNOVA4Health, CEDOC, NOVA Medical School, NMS, Universidade Nova de Lisboa, Rua Câmara Pestana, n°6, Edifício 2, piso 3, 1150-274, Lisbon, Portugal
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25
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Inducing a stressed phenotype in healthy recipient mice by adoptively transferring CD4 + lymphocytes from mice undergoing chronic psychosocial stress. Psychoneuroendocrinology 2020; 122:104898. [PMID: 33126029 DOI: 10.1016/j.psyneuen.2020.104898] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 09/01/2020] [Accepted: 10/02/2020] [Indexed: 11/22/2022]
Abstract
Although chronic stress is an acknowledged risk factor for the development of somatic and affective disorders, the cellular and molecular mechanisms underlying stress-induced pathologies are not fully understood. Interestingly, rodent studies involving immune cell transfer suggest that CD4+ T cells might be at least in part involved in reactivation of a chemically-induced colitis by stress. However, until now evidence is lacking that these immune cell types are indeed involved in the development of a "stressed phenotype". The aim of the present study was, therefore, to assess the effects of adoptively transferring total mesenteric lymph node cells (mesLNCs) and CD4+ mesLNCs isolated from chronically-stressed mice into healthy recipient mice on various physiological, immunological and behavioral parameters. To induce chronic psychosocial stress in donor mice we employed the chronic subordinate colony housing (CSC) paradigm. Our data indicate that transfer of total or CD4+ mesLNCs from CSC mice, compared with respective cells from single-housed control (SHC) mice, promoted splenomegaly and interferon (IFN)-γ secretion from in vitro anti-CD3-stimulated mesLNCs in naïve recipient mice. This effect was independent of recipient mice additionally being administered with dextran sulfate sodium (DSS) or not. Transfer of CD4+ mesLNCs additionally increased adrenal weight and secretion of IL-6 from in vitro anti-CD3 stimulated mesLNCs in recipients administered with DSS. Importantly, transfer of neither cell type from CSC vs. SHC donor mice affected anxiety-related behavior of recipient mice in the light-dark box. Taken together, our data demonstrate that typical physiological and immunological, but not behavioral, effects of chronic stress can be induced in naïve recipient mice by adoptively transferring mesLNCs, in particular CD4+ mesLNCs, from chronically stressed donor mice.
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26
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Cheng J, Shen H, Chowdhury R, Abdi T, Selaru F, Chen JDZ. Potential of Electrical Neuromodulation for Inflammatory Bowel Disease. Inflamm Bowel Dis 2020; 26:1119-1130. [PMID: 31782957 DOI: 10.1093/ibd/izz289] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Indexed: 12/12/2022]
Abstract
Inflammatory bowel disease (IBD) is a common chronic inflammatory disease of the digestive tract that is often debilitating. It affects patients' quality of life and imposes a financial burden. Despite advances in treatment with medications such as biologics, a large proportion of patients do not respond to medical therapy or develop adverse events. Therefore, alternative treatment options such as electrical neuromodulation are currently being investigated. Electrical neuromodulation, also called bioelectronic medicine, is emerging as a potential new treatment for IBD. Over the past decade, advancements have been made in electrical neuromodulation. A number of electrical neuromodulation methods, such as vagus nerve stimulation, sacral nerve stimulation, and tibial nerve stimulation, have been tested to treat IBD. A series of animal and clinical trials have been performed to evaluate efficacy with promising results. Although the exact underlying mechanisms of action for electrical neuromodulation remain to be explored, this modality is promising. Further randomized controlled trials and basic experiments are needed to investigate efficacy and clarify intrinsic mechanisms.
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Affiliation(s)
- Jiafei Cheng
- Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Division of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Hong Shen
- Division of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Reezwana Chowdhury
- Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Tsion Abdi
- Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Florin Selaru
- Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jiande D Z Chen
- Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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27
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Abdo SA, Wadie W, Abdelsalam RM, Khattab MM. Potential Anti-Inflammatory Effect of Escitalopram in Iodoacetamide-Induced Colitis in Depressed Ovariectomized Rats: Role of α7-nAChR. Inflammation 2020; 42:2056-2064. [PMID: 31429015 DOI: 10.1007/s10753-019-01068-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Escitalopram, a drug of choice in the treatment of depression, was recently shown to possess an anti-inflammatory activity. The aim of the present study was to elucidate the effect of escitalopram on peripheral inflammatory cascades in iodoacetamide-induced colitis associated with depressive behavior in ovariectomized rats. Moreover, the role of α-7 nicotinic acetylcholine receptor in mediating the anti-colitic effect of escitalopram was examined using a nicotinic receptor antagonist methyllycaconitine citrate. Colitis was induced by intracolonic injection of 4% iodoacetamide in ovariectomized rats. Escitalopram (10 mg/kg/day, i.p.) was then injected for 1 week and several parameters including macroscopic (colon mass index and ulcerative area), microscopic (histopathology and scoring), and biochemical (myeloperoxidase and tumor necrosis factor-α) were determined. Colitis induction in ovariectomized rats resulted in a marked increase in colon mass index, ulcerative area, histopathological scoring, myeloperoxidase activity and tumor necrosis factor-α levels. These effects were ameliorated by escitalopram, even in the presence of methyllycaconitine indicating that α-7 nicotinic acetylcholine receptor does not mediate the anti-inflammatory effect of escitalopram. The present study revealed the beneficial effect of escitalopram in iodoacetamide induced colitis in ovariectomized rats and suggests that it may represent a new therapeutic agent for the treatment of inflammatory bowel disease, especially in patients with or at high risk of depressive behavior.
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Affiliation(s)
- Salah A Abdo
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
| | - Walaa Wadie
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Rania M Abdelsalam
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Mahmoud M Khattab
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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Jarczyk J, Yard BA, Hoeger S. The Cholinergic Anti-Inflammatory Pathway as a Conceptual Framework to Treat Inflammation-Mediated Renal Injury. Kidney Blood Press Res 2020; 44:435-448. [PMID: 31307039 DOI: 10.1159/000500920] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Accepted: 05/12/2019] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND The cholinergic anti-inflammatory pathway, positioned at the interface of the nervous and immune systems, is the efferent limb of the "inflammatory reflex" which mainly signals through the vagus nerve. As such, the brain can modulate peripheral inflammatory responses by the activation of vagal efferent fibers. Importantly, immune cells in the spleen express most cholinergic system components such as acetylcholine (ACh), choline acetyltransferase, acetylcholinesterase, and both muscarinic and nicotinic ACh receptors, making communication between both systems possible. In general, this communication down-regulates the inflammation, achieved through different mechanisms and depending on the cells involved. SUMMARY With the awareness that the cholinergic anti-inflammatory pathway serves to prevent or limit inflammation in peripheral organs, vagus nerve stimulation has become a promising strategy in the treatment of several inflammatory conditions. Both pharmacological and non-pharmacological methods have been used in many studies to limit organ injury as a consequence of inflammation. Key Messages: In this review, we will highlight our current knowledge of the cholinergic anti-inflammatory pathway, with emphasis on its potential clinical use in the treatment of inflammation-triggered kidney injury.
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Affiliation(s)
- Jonas Jarczyk
- Department of Urology, University Medical Center Mannheim, Medical Faculty Mannheim, Ruprecht-Karls-University Heidelberg, Mannheim, Germany
| | - Benito A Yard
- Vth Medical Department, University Medical Center Mannheim, Medical Faculty Mannheim, Ruprecht-Karls-University Heidelberg, Mannheim, Germany
| | - Simone Hoeger
- Vth Medical Department, University Medical Center Mannheim, Medical Faculty Mannheim, Ruprecht-Karls-University Heidelberg, Mannheim, Germany, .,Bioassay GmbH, Heidelberg, Germany,
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29
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Xue R, Wan Y, Sun X, Zhang X, Gao W, Wu W. Nicotinic Mitigation of Neuroinflammation and Oxidative Stress After Chronic Sleep Deprivation. Front Immunol 2019; 10:2546. [PMID: 31736967 PMCID: PMC6828928 DOI: 10.3389/fimmu.2019.02546] [Citation(s) in RCA: 98] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Accepted: 10/14/2019] [Indexed: 12/12/2022] Open
Abstract
Sleep deprivation negatively influences all aspects of health. Oxidative stress and inflammatory responses induced by sleep deprivation participate in its adverse effects but the regulatory mechanisms to counteract them remain poorly understood. In mice subjected to sleep deprivation for 7 days, we found activation of microglia and astrocyte accompanied by down-regulation of α7 nicotinic acetylcholine receptor (α7-nAChR) and reduced activation of downstream PI3K/AKT/GSK-3β. These changes occurred with an increase of pro-inflammatory factors, together with reduced levels of anti-inflammatory factors, transcriptor Nrf-2, and anti-oxidant enzyme HO-1. Administration of an α7-nAChR agonist PHA-543613 induced activation of PI3K/AKT/GSK-3β, and reversed changes in pro-inflammatory and anti-inflammatory factors, Nrf-2 and HO-1. These results suggest that stimulation of α7-nAChR reduce neuroinflammation and oxidative stress after chronic sleep deprivation.
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Affiliation(s)
- Rong Xue
- Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China
| | - Yahui Wan
- Department of Neurology, Tianjin Medical University General Hospital Airport Hospital, Tianjin, China
| | - Xiaoqian Sun
- Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China
| | - Xuan Zhang
- Department of Neurology, Tianjin Medical University General Hospital Airport Hospital, Tianjin, China
| | - Wei Gao
- Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China
| | - Wei Wu
- Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China
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30
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Stofkova A, Murakami M. Neural activity regulates autoimmune diseases through the gateway reflex. Bioelectron Med 2019; 5:14. [PMID: 32232103 PMCID: PMC7098223 DOI: 10.1186/s42234-019-0030-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Accepted: 07/18/2019] [Indexed: 12/15/2022] Open
Abstract
The brain, spinal cord and retina are protected from blood-borne compounds by the blood-brain barrier (BBB), blood-spinal cord barrier (BSCB) and blood-retina barrier (BRB) respectively, which create a physical interface that tightly controls molecular and cellular transport. The mechanical and functional integrity of these unique structures between blood vessels and nervous tissues is critical for maintaining organ homeostasis. To preserve the stability of these barriers, interplay between constituent barrier cells, such as vascular endothelial cells, pericytes, glial cells and neurons, is required. When any of these cells are defective, the barrier can fail, allowing blood-borne compounds to encroach neural tissues and cause neuropathologies. Autoimmune diseases of the central nervous system (CNS) and retina are characterized by barrier disruption and the infiltration of activated immune cells. Here we review our recent findings on the role of neural activity in the regulation of these barriers at the vascular endothelial cell level in the promotion of or protection against the development of autoimmune diseases. We suggest nervous system reflexes, which we named gateway reflexes, are fundamentally involved in these diseases. Although their reflex arcs are not completely understood, we identified the activation of specific sensory neurons or receptor cells to which barrier endothelial cells respond as effectors that regulate gateways for immune cells to enter the nervous tissue. We explain this novel mechanism and describe its role in neuroinflammatory conditions, including models of multiple sclerosis and posterior autoimmune uveitis.
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Affiliation(s)
- Andrea Stofkova
- 1Department of Physiology, Third Faculty of Medicine, Charles University, Prague, Czech Republic
- 2Division of Molecular Psychoimmunology, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-0815 Japan
| | - Masaaki Murakami
- 2Division of Molecular Psychoimmunology, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-0815 Japan
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31
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Basso L, Serhan N, Tauber M, Gaudenzio N. Peripheral neurons: Master regulators of skin and mucosal immune response. Eur J Immunol 2019; 49:1984-1997. [DOI: 10.1002/eji.201848027] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 06/06/2019] [Accepted: 07/17/2019] [Indexed: 12/27/2022]
Affiliation(s)
- Lilian Basso
- Unité de Différenciation Epithéliale et Autoimmunité Rhumatoïde (UDEAR), UMR 1056, INSERM Université de Toulouse Toulouse France
| | - Nadine Serhan
- Unité de Différenciation Epithéliale et Autoimmunité Rhumatoïde (UDEAR), UMR 1056, INSERM Université de Toulouse Toulouse France
| | - Marie Tauber
- Unité de Différenciation Epithéliale et Autoimmunité Rhumatoïde (UDEAR), UMR 1056, INSERM Université de Toulouse Toulouse France
| | - Nicolas Gaudenzio
- Unité de Différenciation Epithéliale et Autoimmunité Rhumatoïde (UDEAR), UMR 1056, INSERM Université de Toulouse Toulouse France
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32
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Antunes GL, Silveira JS, Kaiber DB, Luft C, da Costa MS, Marques EP, Ferreira FS, Breda RV, Wyse ATS, Stein RT, Pitrez PM, da Cunha AA. Cholinergic anti-inflammatory pathway confers airway protection against oxidative damage and attenuates inflammation in an allergic asthma model. J Cell Physiol 2019; 235:1838-1849. [PMID: 31332773 DOI: 10.1002/jcp.29101] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Accepted: 06/27/2019] [Indexed: 12/20/2022]
Abstract
Asthma is characterized by the influx of inflammatory cells, especially of eosinophils as well as reactive oxygen species (ROS) production, driven by the release of the T helper 2 (Th2)-cell-associated cytokines. The cholinergic anti-inflammatory pathway (CAP) inhibit cytokines production and controls inflammation. Thus, we investigated the effects of pharmacological activation of CAP by neostigmine on oxidative stress and airway inflammation in an allergic asthma model. After the OVA challenge, mice were treated with neostigmine. We showed that CAP activation by neostigmine reduced the levels of pro-inflammatory cytokines (IL-4, IL-5, IL-13, IL-1β, and TNF-α), which resulted in a decrease of eosinophils influx. Furthermore, neostigmine also conferred airway protection against oxidative stress, attenuating ROS production through the increase of antioxidant defense, evidenced by the catalase (CAT) activity. We propose, for the first time, that pharmacological activation of the CAP can lead to new possibilities in the therapeutic management of allergic asthma.
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Affiliation(s)
- Géssica Luana Antunes
- Laboratory of Pediatric Respirology, Infant Center, School of Medical, Pontifícia Universidade Católica do Rio Grande do Sul, PUCRS, Porto Alegre, Brazil
| | - Josiane Silva Silveira
- Laboratory of Pediatric Respirology, Infant Center, School of Medical, Pontifícia Universidade Católica do Rio Grande do Sul, PUCRS, Porto Alegre, Brazil
| | - Daniela Benvenutti Kaiber
- Laboratory of Pediatric Respirology, Infant Center, School of Medical, Pontifícia Universidade Católica do Rio Grande do Sul, PUCRS, Porto Alegre, Brazil
| | - Carolina Luft
- Laboratory of Pediatric Respirology, Infant Center, School of Medical, Pontifícia Universidade Católica do Rio Grande do Sul, PUCRS, Porto Alegre, Brazil
| | - Mariana Severo da Costa
- Laboratory of Pediatric Respirology, Infant Center, School of Medical, Pontifícia Universidade Católica do Rio Grande do Sul, PUCRS, Porto Alegre, Brazil
| | - Eduardo Peil Marques
- Laboratory of Neuroprotection and Metabolic Disease, Department of Biochemistry, Universidade Federal do Rio Grande do Sul, UFRGS, Porto Alegre, Brazil
| | - Fernanda Silva Ferreira
- Laboratory of Neuroprotection and Metabolic Disease, Department of Biochemistry, Universidade Federal do Rio Grande do Sul, UFRGS, Porto Alegre, Brazil
| | - Ricardo Vaz Breda
- Laboratory of Neurosciences, Brain Institute - BraIns, Pontifícia Universidade Católica do Rio Grande do Sul, PUCRS, Porto Alegre, Brazil
| | - Angela T S Wyse
- Laboratory of Neuroprotection and Metabolic Disease, Department of Biochemistry, Universidade Federal do Rio Grande do Sul, UFRGS, Porto Alegre, Brazil
| | - Renato Tetelbom Stein
- Laboratory of Pediatric Respirology, Infant Center, School of Medical, Pontifícia Universidade Católica do Rio Grande do Sul, PUCRS, Porto Alegre, Brazil
| | - Paulo Márcio Pitrez
- Laboratory of Pediatric Respirology, Infant Center, Pontifícia Universidade Católica do Rio Grande do Sul, PUCRS, Hospital Moinhos de Vento, HMV, Porto Alegre, Brazil
| | - Aline Andrea da Cunha
- Laboratory of Pediatric Respirology, Infant Center, Pontifícia Universidade Católica do Rio Grande do Sul, PUCRS, Hospital Moinhos de Vento, HMV, Porto Alegre, Brazil
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33
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Brinkman DJ, Ten Hove AS, Vervoordeldonk MJ, Luyer MD, de Jonge WJ. Neuroimmune Interactions in the Gut and Their Significance for Intestinal Immunity. Cells 2019; 8:670. [PMID: 31269754 PMCID: PMC6679154 DOI: 10.3390/cells8070670] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Revised: 06/24/2019] [Accepted: 06/28/2019] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel diseases (IBD) have a complex, multifactorial pathophysiology with an unmet need for effective treatment. This calls for novel strategies to improve disease outcome and quality of life for patients. Increasing evidence suggests that autonomic nerves and neurotransmitters, as well as neuropeptides, modulate the intestinal immune system, and thereby regulate the intestinal inflammatory processes. Although the autonomic nervous system is classically divided in a sympathetic and parasympathetic branch, both play a pivotal role in the crosstalk with the immune system, with the enteric nervous system acting as a potential interface. Pilot clinical trials that employ vagus nerve stimulation to reduce inflammation are met with promising results. In this paper, we review current knowledge on the innervation of the gut, the potential of cholinergic and adrenergic systems to modulate intestinal immunity, and comment on ongoing developments in clinical trials.
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Affiliation(s)
- David J Brinkman
- Tytgat Institute for Intestinal and Liver Research, Amsterdam UMC, University of Amsterdam, Amsterdam 1105 BK, The Netherlands
- Department of Surgery, Catharina Hospital, 5623 EJ Eindhoven, The Netherlands
| | - Anne S Ten Hove
- Tytgat Institute for Intestinal and Liver Research, Amsterdam UMC, University of Amsterdam, Amsterdam 1105 BK, The Netherlands
| | - Margriet J Vervoordeldonk
- Tytgat Institute for Intestinal and Liver Research, Amsterdam UMC, University of Amsterdam, Amsterdam 1105 BK, The Netherlands
- Galvani Bioelectronics, Stevenage SG1 2NY, UK
| | - Misha D Luyer
- Department of Surgery, Catharina Hospital, 5623 EJ Eindhoven, The Netherlands
| | - Wouter J de Jonge
- Tytgat Institute for Intestinal and Liver Research, Amsterdam UMC, University of Amsterdam, Amsterdam 1105 BK, The Netherlands.
- Department of General, Visceral-, Thoracic and Vascular Surgery, University Hospital Bonn, 53127 Bonn, Germany.
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34
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Hong GS, Zillekens A, Schneiker B, Pantelis D, de Jonge WJ, Schaefer N, Kalff JC, Wehner S. Non-invasive transcutaneous auricular vagus nerve stimulation prevents postoperative ileus and endotoxemia in mice. Neurogastroenterol Motil 2019; 31:e13501. [PMID: 30406957 DOI: 10.1111/nmo.13501] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 09/26/2018] [Accepted: 10/02/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND The cholinergic anti-inflammatory pathway comprises the perception of peripheral inflammation by afferent sensory neurons and reflex activation of efferent vagus nerve activity to regulate inflammation. Activation of this pathway was shown to reduce the inflammatory response and improve outcome of postoperative ileus (POI) and sepsis in rodents. Herein, we tested if a non-invasive auricular electrical transcutaneous vagus nerve stimulation (tVNS) affects inflammation in models of POI or endotoxemia. METHODS Mice underwent tVNS or sham stimulation before and after induction of either POI by intestinal manipulation (IM) or endotoxemia by lipopolysaccharide administration. Some animals underwent a preoperative right cervical vagotomy. Neuronal activation of the solitary tract nucleus (NTS) and the dorsal motor nucleus of the vagus nerve (DMV) were analyzed by immunohistological detection of c-fos+ cells. Gene and protein expression of IL-6, MCP-1, IL-1β as well as leukocyte infiltration and gastrointestinal transit were analyzed at different time points after IM. IL-6, TNFα, and IL-1β serum levels were analyzed 3 hours after lipopolysaccharide administration. RESULTS tVNS activated the NTS and DMV and reduced intestinal cytokine expression, reduced leukocyte recruitment to the manipulated intestine segment, and improved gastrointestinal transit after IM. Endotoxemia-induced IL-6 and TNF-α release was also reduced by tVNS. The protective effects of tVNS on POI and endotoxemia were abrogated by vagotomy. CONCLUSION tVNS prevents intestinal and systemic inflammation. Activation of the DMV indicates an afferent to efferent central circuitry of the tVNS stimulation and the beneficial effects of tVNS depend on an intact vagus nerve. tVNS may become a non-invasive approach for treatment of POI.
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Affiliation(s)
- Gun-Soo Hong
- Department of Surgery, University of Bonn, Bonn, Germany
| | - Anne Zillekens
- Department of Surgery, University of Bonn, Bonn, Germany
| | | | | | - Wouter J de Jonge
- Tytgat Institute of Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands
| | - Nico Schaefer
- Department of Surgery, University of Bonn, Bonn, Germany
| | - Joerg C Kalff
- Department of Surgery, University of Bonn, Bonn, Germany
| | - Sven Wehner
- Department of Surgery, University of Bonn, Bonn, Germany
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Pérez-López JA, Rojas-Hernández S, Campos-Rodríguez R, Arciniega-Martínez IM, Cruz-Hernández TR, Reséndiz-Albor AA, Drago-Serrano ME. Posterior Subdiaphragmatic Vagotomy Downmodulates the IgA Levels in the Small Intestine of BALB/c Mice. Neuroimmunomodulation 2019; 26:292-300. [PMID: 31918430 DOI: 10.1159/000505097] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Accepted: 11/28/2019] [Indexed: 11/19/2022] Open
Abstract
OBJECTIVE The posterior vagus nerve trunk innervates the entire small intestine, and elucidating its modulatory role in the IgA response was the aim of this study. METHODS Two groups of six male BALB/c mice underwent sham or posterior subdiaphragmatic vagotomy and were euthanized on the 14th postoperative day; then, the small intestines were dissected. The intestinal fluid was harvested for antibody analysis by ELISA, and cell suspensions from Peyer's patches and lamina propria were prepared for cytofluorometric analysis of plasma cells and T lymphocytes. The CD4+ T cells were labeled for the intracellular IgA-producing interleukins (ILs)-4, -5, -6, and -10; transforming growth factor (TGF)-β; and the inflammatory cytokines tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and IL-12. In the intestinal tissue samples, myeloperoxidase (MPO) visualization and the enzymatic activity were assessed by immunohistochemistry and ELISA, respectively. The data were analyzed by Student's t test, and the differences were considered significant at p < 0.05. RESULTS In the vagotomy group, the IgA levels and the CD4+ T cells labeled with mediators that promote IgA secretion, including IL-4 (only at lamina propria), TNF-α, and IFN-γ, were decreased, whereas the lamina propria IgA+ plasma cells and MPO presence/activity were increased; changes in the IgM levels, IgM+ plasma cells, and CD4+ T cells labeled with TGF-β, which have a role in class switch recombination, were not observed. CONCLUSION The downmodulating impact of vagotomy on IgA levels may result from defective IgA secretion without affecting class switch recombination, whereas vagotomy evoked a proinflammatory response regarding MPO. These findings may reflect the role of the vagus nerve on the control of the IgA response in the small intestine.
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Affiliation(s)
- José Alfredo Pérez-López
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City, Mexico
| | - Saúl Rojas-Hernández
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City, Mexico
| | - Rafael Campos-Rodríguez
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City, Mexico
| | - Ivonne Maciel Arciniega-Martínez
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City, Mexico
| | - Teresita Rocío Cruz-Hernández
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City, Mexico
| | - Aldo Arturo Reséndiz-Albor
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City, Mexico
| | - Maria Elisa Drago-Serrano
- Departamento de Sistemas Biológicos, Universidad Autónoma Metropolitana, Unidad Xochimilco, Mexico City, Mexico,
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Fornai M, van den Wijngaard RM, Antonioli L, Pellegrini C, Blandizzi C, de Jonge WJ. Neuronal regulation of intestinal immune functions in health and disease. Neurogastroenterol Motil 2018; 30:e13406. [PMID: 30058092 DOI: 10.1111/nmo.13406] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Accepted: 06/11/2018] [Indexed: 12/26/2022]
Abstract
BACKGROUND Nerve-mucosa interactions control various elements of gastrointestinal functions, including mucosal host defense, gut barrier function, and epithelial cell growth and differentiation. In both intestinal and extra-intestinal diseases, alterations of autonomic nerve activity have been observed to be concurrent with the disease course, such as in inflammatory and functional bowel diseases, and neurodegenerative diseases. This is relevant as the extrinsic autonomic nervous system is increasingly recognized to modulate gut inflammatory responses. The molecular and cellular mechanisms through which the extrinsic and intrinsic nerve pathways may regulate digestive mucosal functions have been investigated in several pre-clinical and clinical studies. PURPOSE The present review focuses on the involvement of neural pathways in gastrointestinal disease, and addresses the current strategies to intervene with neuronal pathway as a means of treatment.
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Affiliation(s)
- M Fornai
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.,Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands
| | - R M van den Wijngaard
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands
| | - L Antonioli
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - C Pellegrini
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - C Blandizzi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - W J de Jonge
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands
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Reardon C, Murray K, Lomax AE. Neuroimmune Communication in Health and Disease. Physiol Rev 2018; 98:2287-2316. [PMID: 30109819 PMCID: PMC6170975 DOI: 10.1152/physrev.00035.2017] [Citation(s) in RCA: 78] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Revised: 04/09/2018] [Accepted: 04/09/2018] [Indexed: 12/14/2022] Open
Abstract
The immune and nervous systems are tightly integrated, with each system capable of influencing the other to respond to infectious or inflammatory perturbations of homeostasis. Recent studies demonstrating the ability of neural stimulation to significantly reduce the severity of immunopathology and consequently reduce mortality have led to a resurgence in the field of neuroimmunology. Highlighting the tight integration of the nervous and immune systems, afferent neurons can be activated by a diverse range of substances from bacterial-derived products to cytokines released by host cells. While activation of vagal afferents by these substances dominates the literature, additional sensory neurons are responsive as well. It is becoming increasingly clear that although the cholinergic anti-inflammatory pathway has become the predominant model, a multitude of functional circuits exist through which neuronal messengers can influence immunological outcomes. These include pathways whereby efferent signaling occurs independent of the vagus nerve through sympathetic neurons. To receive input from the nervous system, immune cells including B and T cells, macrophages, and professional antigen presenting cells express specific neurotransmitter receptors that affect immune cell function. Specialized immune cell populations not only express neurotransmitter receptors, but express the enzymatic machinery required to produce neurotransmitters, such as acetylcholine, allowing them to act as signaling intermediaries. Although elegant experiments have begun to decipher some of these interactions, integration of these molecules, cells, and anatomy into defined neuroimmune circuits in health and disease is in its infancy. This review describes these circuits and highlights continued challenges and opportunities for the field.
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Affiliation(s)
- Colin Reardon
- Department of Anatomy, Physiology, and Cell Biology, UC Davis School of Veterinary Medicine, UC Davis, Davis, California ; and Department of Biomedical and Molecular Sciences and Department of Medicine, Queen's University , Kingston, Ontario , Canada
| | - Kaitlin Murray
- Department of Anatomy, Physiology, and Cell Biology, UC Davis School of Veterinary Medicine, UC Davis, Davis, California ; and Department of Biomedical and Molecular Sciences and Department of Medicine, Queen's University , Kingston, Ontario , Canada
| | - Alan E Lomax
- Department of Anatomy, Physiology, and Cell Biology, UC Davis School of Veterinary Medicine, UC Davis, Davis, California ; and Department of Biomedical and Molecular Sciences and Department of Medicine, Queen's University , Kingston, Ontario , Canada
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Meroni E, Stakenborg N, Gomez-Pinilla PJ, De Hertogh G, Goverse G, Matteoli G, Verheijden S, Boeckxstaens GE. Functional characterization of oxazolone-induced colitis and survival improvement by vagus nerve stimulation. PLoS One 2018; 13:e0197487. [PMID: 29791477 PMCID: PMC5965883 DOI: 10.1371/journal.pone.0197487] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Accepted: 05/03/2018] [Indexed: 12/26/2022] Open
Abstract
Background Oxazolone-induced colitis has been frequently used in literature as a model of IBD, but insights into the underlying immune response and pathological features are surprisingly still very limited. Vagus nerve stimulation (VNS) has proven to be effective in innate and Th1/Th17 predominant inflammatory models, including pre-clinical models of colitis, however to what extent VNS is also effective in ameliorating Th2-driven colitis remains to be studied. In the present study, we therefore further characterized the immune response in oxazolone-induced colitis and investigated the potential therapeutic effect of VNS. Methods Colitis was induced in Balb/c mice by cutaneous sensitization with 3% oxazolone followed by intracolonic administration of 1% oxazolone 7 days later. To evaluate the effect of VNS on the development of Th2-driven colitis, VNS and sham-treated mice were challenged with 1% oxazolone. Results Intracolonic oxazolone administration resulted in a severe destruction of the colonic mucosa and a rapid drop in body temperature leading to a 65% mortality rate at day 5. Severe infiltration of neutrophils and monocytes was detected 6h after oxazolone administration which was associated with a Th2-type inflammatory response. VNS significantly improved survival rate which correlated with decreased levels of HMGB1 and reduced colonic (il6 and cxcl1 mRNA) and serum cytokine levels (IL-6, TNFα and CXCL1) compared to sham treated mice. Conclusions Oxazolone-induced colitis rather represents a model of sepsis and, at best, may resemble a severe type of ulcerative colitis, associated with early and severe mucosal damage and a high mortality rate. VNS reduces colonic inflammation and improves survival in this model, supporting the anti-inflammatory properties of VNS, even in an aggressive model as oxazolone-induced colitis.
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Affiliation(s)
- Elisa Meroni
- KU Leuven, Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium
| | - Nathalie Stakenborg
- KU Leuven, Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium
| | - Pedro J. Gomez-Pinilla
- KU Leuven, Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium
| | - Gert De Hertogh
- KU Leuven, Department of Imaging and Pathology, Translational Cell and Tissue Research, Leuven, Belgium
| | - Gera Goverse
- KU Leuven, Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium
| | - Gianluca Matteoli
- KU Leuven, Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium
| | - Simon Verheijden
- KU Leuven, Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium
| | - Guy E. Boeckxstaens
- KU Leuven, Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium
- * E-mail:
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Abstract
The nervous system regulates immunity and inflammation. The molecular detection of pathogen fragments, cytokines, and other immune molecules by sensory neurons generates immunoregulatory responses through efferent autonomic neuron signaling. The functional organization of this neural control is based on principles of reflex regulation. Reflexes involving the vagus nerve and other nerves have been therapeutically explored in models of inflammatory and autoimmune conditions, and recently in clinical settings. The brain integrates neuro-immune communication, and brain function is altered in diseases characterized by peripheral immune dysregulation and inflammation. Here we review the anatomical and molecular basis of the neural interface with immunity, focusing on peripheral neural control of immune functions and the role of the brain in the model of the immunological homunculus. Clinical advances stemming from this knowledge within the framework of bioelectronic medicine are also briefly outlined.
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Affiliation(s)
- Valentin A Pavlov
- Center for Biomedical Science and Center for Bioelectronic Medicine, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York 11030, USA; , ,
| | - Sangeeta S Chavan
- Center for Biomedical Science and Center for Bioelectronic Medicine, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York 11030, USA; , ,
| | - Kevin J Tracey
- Center for Biomedical Science and Center for Bioelectronic Medicine, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York 11030, USA; , ,
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40
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Willemze RA, Welting O, van Hamersveld HP, Meijer SL, Folgering JHA, Darwinkel H, Witherington J, Sridhar A, Vervoordeldonk MJ, Seppen J, de Jonge WJ. Neuronal control of experimental colitis occurs via sympathetic intestinal innervation. Neurogastroenterol Motil 2018; 30. [PMID: 28745812 DOI: 10.1111/nmo.13163] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Accepted: 06/20/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND Vagus nerve stimulation is currently clinically evaluated as a treatment for inflammatory bowel disease. However, the mechanism by which this therapeutic intervention can have an immune-regulatory effect in colitis remains unclear. We determined the effect of intestine-specific vagotomy or intestine-specific sympathectomy of the superior mesenteric nerve (SMN) on dextran sodium sulfate (DSS)-induced colitis in mice. Furthermore, we tested the efficacy of therapeutic SMN stimulation to treat DSS-induced colitis in rats. METHODS Vagal and SMN fibers were surgically dissected to achieve intestine-specific vagotomy and sympathectomy. Chronic SMN stimulation was achieved by implantation of a cuff electrode. Stimulation was done twice daily for 5 minutes using a biphasic pulse (10 Hz, 200 μA, 2 ms). Disease activity index (DAI) was used as a clinical parameter for colitis severity. Colonic cytokine expression was measured by quantitative PCR and ELISA. KEY RESULTS Intestine-specific vagotomy had no effect on DSS-induced colitis in mice. However, SMN sympathectomy caused a significantly higher DAI compared to sham-operated mice. Conversely, SMN stimulation led to a significantly improved DAI compared to sham stimulation, although no other parameters of colitis were affected significantly. CONCLUSIONS & INFERENCES Our results indicate that sympathetic innervation regulates the intestinal immune system as SMN denervation augments, and SMN stimulation ameliorates DSS-induced colitis. Surprisingly, intestine-specific vagal nerve denervation had no effect in DSS-induced colitis.
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Affiliation(s)
- R A Willemze
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands
| | - O Welting
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands
| | - H P van Hamersveld
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands
| | - S L Meijer
- Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands
| | | | - H Darwinkel
- Brains On-Line B.V., Groningen, The Netherlands
| | | | - A Sridhar
- Galvani Bioelectronics, Stevenage, UK
| | | | - J Seppen
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands
| | - W J de Jonge
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands
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41
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Murray K, Reardon C. The cholinergic anti-inflammatory pathway revisited. Neurogastroenterol Motil 2018; 30:10.1111/nmo.13288. [PMID: 29468816 PMCID: PMC5826620 DOI: 10.1111/nmo.13288] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Accepted: 12/13/2017] [Indexed: 12/12/2022]
Abstract
Inflammatory bowel disease negatively affects the quality of life of millions of patients around the world. Although the precise etiology of the disease remains elusive, aberrant immune system activation is an underlying cause. As such, therapies that selectively inhibit immune cell activation without broad immunosuppression are desired. Inhibition of immune cell activation preventing pro-inflammatory cytokine production through neural stimulation has emerged as one such treatment. These therapeutics are based on the discovery of the cholinergic anti-inflammatory pathway, a reflex arc that induces efferent vagal nerve signaling to reduce immune cell activation and consequently mortality during septic shock. Despite the success of preclinical and clinical trials, the neural circuitry and mechanisms of action of these immune-regulatory circuits are controversial. At the heart of this controversy is the protective effect of vagal nerve stimulation despite an apparent lack of neuroanatomical connections between the vagus and target organs. Additional studies have further emphasized the importance of sympathetic innervation of these organs, and that alternative neural circuits could be involved in neural regulation of the immune system. Such controversies also extend to the regulation of intestinal inflammation, with the importance of efferent vagus nerve signals in question. Experiments that better characterize these pathways have now been performed by Willemze et al. in this issue of Neurogastroenterology & Motility. These continued efforts will be critical to the development of better neurostimulator based therapeutics for inflammatory bowel disease.
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Affiliation(s)
- Kaitlin Murray
- Department. of Anatomy, Physiology, and Cell Biology, UC Davis School of Veterinary Medicine, UC Davis, Davis, California, United States of America
| | - Colin Reardon
- Department. of Anatomy, Physiology, and Cell Biology, UC Davis School of Veterinary Medicine, UC Davis, Davis, California, United States of America,Corresponding author: Colin Reardon PhD, Assistant Professor, University of California, Davis, VM: Anatomy, Physiology, & Cell Biology, 1089 Veterinary Medicine Drive, VM3B, Room 2007, Davis, CA 95616, Ph: 530-752-7496,
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Seyedabadi M, Rahimian R, Ghia JE. The role of alpha7 nicotinic acetylcholine receptors in inflammatory bowel disease: involvement of different cellular pathways. Expert Opin Ther Targets 2018; 22:161-176. [PMID: 29298542 DOI: 10.1080/14728222.2018.1420166] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Autonomic imbalance plays a pivotal role in the pathophysiology of inflammatory bowel diseases (IBD). The central nervous system (CNS) cooperates dynamically with the immune system to regulate inflammation through humoral and neural pathways. In particular, acetylcholine (Ach), the main neurotransmitter in the vagus nerve, decreases the production of pro-inflammatory cytokines through a mechanism dependent on the α7 nicotinic Ach receptors (α7nAChRs). Areas covered: Here, we review the evidence for involvement of the cholinergic anti-inflammatory pathway (CAP) in IBD. We also elaborate the role of α7nAChRs and subsequent cellular pathways in CAP. Finally, we review potential therapeutic implications of modulators of these receptors. Expert opinion: Alpha7nAChR modulators possess both cognitive improving and anti-inflammatory properties. Although, these agents demonstrated therapeutic benefits in experimental models, their efficacy has not always been translated in clinical trials. Thus, development of more specific α7nAChR ligands as well as more experimental studies and better controlled trials, especially in the field of IBD, are encouraged for a progress in this field.
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Affiliation(s)
- Mohammad Seyedabadi
- a Department of Pharmacology, School of Medicine , Bushehr University of Medical Sciences , Bushehr , Iran.,b The Persian Gulf Biomedical Sciences Research Institute , Bushehr University of Medical Sciences , Bushehr , Iran.,c Education Development Center , Bushehr University of Medical Sciences , Bushehr , Iran
| | - Reza Rahimian
- d Department of Psychiatry and Neuroscience, Faculty of Medicine , CERVO Brain Research Center, Laval University , Quebec , Quebec , Canada
| | - Jean-Eric Ghia
- e Department of Immunology , University of Manitoba , Winnipeg , Manitoba , Canada.,f Department of Internal Medicine Section of Gastroenterology, and Inflammatory Bowel Disease Clinical & Research Center , University of Manitoba , Winnipeg , Manitoba , Canada
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Safavynia SA, Goldstein PA. The Role of Neuroinflammation in Postoperative Cognitive Dysfunction: Moving From Hypothesis to Treatment. Front Psychiatry 2018; 9:752. [PMID: 30705643 PMCID: PMC6345198 DOI: 10.3389/fpsyt.2018.00752] [Citation(s) in RCA: 190] [Impact Index Per Article: 27.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Accepted: 12/19/2018] [Indexed: 12/13/2022] Open
Abstract
Postoperative cognitive dysfunction (POCD) is a common complication of the surgical experience and is common in the elderly and patients with preexisting neurocognitive disorders. Animal and human studies suggest that neuroinflammation from either surgery or anesthesia is a major contributor to the development of POCD. Moreover, a large and growing body of literature has focused on identifying potential risk factors for the development of POCD, as well as identifying candidate treatments based on the neuroinflammatory hypothesis. However, variability in animal models and clinical cohorts makes it difficult to interpret the results of such studies, and represents a barrier for the development of treatment options for POCD. Here, we present a broad topical review of the literature supporting the role of neuroinflammation in POCD. We provide an overview of the cellular and molecular mechanisms underlying the pathogenesis of POCD from pre-clinical and human studies. We offer a brief discussion of the ongoing debate on the root cause of POCD. We conclude with a list of current and hypothesized treatments for POCD, with a focus on recent and current human randomized clinical trials.
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Affiliation(s)
- Seyed A Safavynia
- Department of Anesthesiology, Weill Cornell Medical College, New York, NY, United States
| | - Peter A Goldstein
- Department of Anesthesiology, Weill Cornell Medical College, New York, NY, United States.,Department of Medicine, Weill Cornell Medical College, New York, NY, United States.,Neuroscience Graduate Program, Weill Cornell Medical College, New York, NY, United States
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Verheijden S, Boeckxstaens GE. Neuroimmune interaction and the regulation of intestinal immune homeostasis. Am J Physiol Gastrointest Liver Physiol 2018; 314:G75-G80. [PMID: 28912251 DOI: 10.1152/ajpgi.00425.2016] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Many essential gastrointestinal functions, including motility, secretion, and blood flow, are regulated by the autonomic nervous system (ANS), both through intrinsic enteric neurons and extrinsic (sympathetic and parasympathetic) innervation. Recently identified neuroimmune mechanisms, in particular the interplay between enteric neurons and muscularis macrophages, are now considered to be essential for fine-tuning peristalsis. These findings shed new light on how intestinal immune cells can support enteric nervous function. In addition, both intrinsic and extrinsic neural mechanisms control intestinal immune homeostasis in different layers of the intestine, mainly by affecting macrophage activation through neurotransmitter release. In this mini-review, we discuss recent insights on immunomodulation by intrinsic enteric neurons and extrinsic innervation, with a particular focus on intestinal macrophages. In addition, we discuss the relevance of these novel mechanisms for intestinal immune homeostasis in physiological and pathological conditions, mainly focusing on motility disorders (gastroparesis and postoperative ileus) and inflammatory disorders (colitis).
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Affiliation(s)
- Simon Verheijden
- Translational Research Center of Gastrointestinal Disorders, KU Leuven, Leuven , Belgium
| | - Guy E Boeckxstaens
- Translational Research Center of Gastrointestinal Disorders, KU Leuven, Leuven , Belgium.,Division of Gastroenterology and Hepatology, University Hospital Leuven , Leuven, Belgium
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Bonaz B, Sinniger V, Pellissier S. The Vagus Nerve in the Neuro-Immune Axis: Implications in the Pathology of the Gastrointestinal Tract. Front Immunol 2017; 8:1452. [PMID: 29163522 PMCID: PMC5673632 DOI: 10.3389/fimmu.2017.01452] [Citation(s) in RCA: 237] [Impact Index Per Article: 29.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2017] [Accepted: 10/17/2017] [Indexed: 12/12/2022] Open
Abstract
The vagus nerve (VN) is the longest nerve of the organism and a major component of the parasympathetic nervous system which constitutes the autonomic nervous system (ANS), with the sympathetic nervous system. There is classically an equilibrium between the sympathetic and parasympathetic nervous systems which is responsible for the maintenance of homeostasis. An imbalance of the ANS is observed in various pathologic conditions. The VN, a mixed nerve with 4/5 afferent and 1/5 efferent fibers, is a key component of the neuro-immune and brain-gut axes through a bidirectional communication between the brain and the gastrointestinal (GI) tract. A dual anti-inflammatory role of the VN is observed using either vagal afferents, targeting the hypothalamic–pituitary–adrenal axis, or vagal efferents, targeting the cholinergic anti-inflammatory pathway. The sympathetic nervous system and the VN act in synergy, through the splenic nerve, to inhibit the release of tumor necrosis factor-alpha (TNFα) by macrophages of the peripheral tissues and the spleen. Because of its anti-inflammatory effect, the VN is a therapeutic target in the treatment of chronic inflammatory disorders where TNFα is a key component. In this review, we will focus on the anti-inflammatory role of the VN in inflammatory bowel diseases (IBD). The anti-inflammatory properties of the VN could be targeted pharmacologically, with enteral nutrition, by VN stimulation (VNS), with complementary medicines or by physical exercise. VNS is one of the alternative treatments for drug resistant epilepsy and depression and one might think that VNS could be used as a non-drug therapy to treat inflammatory disorders of the GI tract, such as IBD, irritable bowel syndrome, and postoperative ileus, which are all characterized by a blunted autonomic balance with a decreased vagal tone.
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Affiliation(s)
- Bruno Bonaz
- Division of Hepato-Gastroenterology, Grenoble University Hospital, Grenoble, Alpes, France.,U1216, INSERM, GIN, Grenoble Institute of Neurosciences, University Grenoble Alpes, Grenoble, France
| | - Valérie Sinniger
- Division of Hepato-Gastroenterology, Grenoble University Hospital, Grenoble, Alpes, France.,U1216, INSERM, GIN, Grenoble Institute of Neurosciences, University Grenoble Alpes, Grenoble, France
| | - Sonia Pellissier
- Laboratoire Inter-Universitaire de Psychologie, Personnalité, Cognition et Changement Social LIP/PC2S-EA4145, University Savoie Mont Blanc, Chambéry, France
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AlSharari SD, Bagdas D, Akbarali HI, Lichtman PA, Raborn ES, Cabral GA, Carroll FI, McGee EA, Damaj MI. Sex Differences and Drug Dose Influence the Role of the α7 Nicotinic Acetylcholine Receptor in the Mouse Dextran Sodium Sulfate-Induced Colitis Model. Nicotine Tob Res 2017; 19:460-468. [PMID: 27639096 DOI: 10.1093/ntr/ntw245] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Accepted: 09/16/2016] [Indexed: 02/06/2023]
Abstract
Introduction α7 nicotinic acetylcholine receptors (nAChRs) play an important role in vagus nerve-based cholinergic anti-inflammatory effects. This study was designed to assess the role of α7 nAChRs in dextran sodium sulfate (DSS)-induced colitis in male and female mouse. We first compared disease activity and pathogenesis of colitis in α7 knockout and wild-type mice. We then evaluated the effect of several α7 direct and indirect agonists on the severity of disease in the DSS-induced colitis. Methods Male and female adult mice were administered 2.5% DSS solution freely in the drinking water for 7 consecutive days and the colitis severity (disease activity index) was evaluated as well as colon length, colon histology, and levels of tumor necrosis factor-alpha colonic levels. Results Male, but not female, α7 knockout mice displayed a significantly increased colitis severity and higher tumor necrosis factor-alpha levels as compared with their littermate wild-type mice. Moreover, pretreatment with selective α7 ligands PHA-543613, choline, and PNU-120596 decreased colitis severity in male but not female mice. The anti-colitis effects of these α7 compounds dissipated when administered at higher doses. Conclusions Our results suggest the presence of a α7-dependent anti-colitis endogenous tone in male mice. Finally, our results show for the first time that female mice are less sensitive to the anti-colitis activity of α7 agonists. Ovarian hormones may play a key role in the sex difference effect of α7 nAChRs modulation of colitis in the mouse. Implications Our collective results suggest that targeting α7 nAChRs could represent a viable therapeutic approach for intestinal inflammation diseases such as ulcerative colitis with the consideration of sex differences.
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Affiliation(s)
- Shakir D AlSharari
- Department of Pharmacology and Toxicology, King Saud University, Riyadh, Saudi Arabia.,Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA
| | - Deniz Bagdas
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA.,Experimental Animals Breeding and Research Center, Faculty of Medicine, Uludag University, Bursa, Turkey
| | - Hamid I Akbarali
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA
| | - Patraic A Lichtman
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA
| | - Erinn S Raborn
- Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA
| | - Guy A Cabral
- Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA
| | - F Ivy Carroll
- Center for Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, NC
| | - Elizabeth A McGee
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Vermont, Burlington, VT
| | - M Imad Damaj
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA
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Lai NY, Mills K, Chiu IM. Sensory neuron regulation of gastrointestinal inflammation and bacterial host defence. J Intern Med 2017; 282:5-23. [PMID: 28155242 PMCID: PMC5474171 DOI: 10.1111/joim.12591] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Sensory neurons in the gastrointestinal tract have multifaceted roles in maintaining homeostasis, detecting danger and initiating protective responses. The gastrointestinal tract is innervated by three types of sensory neurons: dorsal root ganglia, nodose/jugular ganglia and intrinsic primary afferent neurons. Here, we examine how these distinct sensory neurons and their signal transducers participate in regulating gastrointestinal inflammation and host defence. Sensory neurons are equipped with molecular sensors that enable neuronal detection of diverse environmental signals including thermal and mechanical stimuli, inflammatory mediators and tissue damage. Emerging evidence shows that sensory neurons participate in host-microbe interactions. Sensory neurons are able to detect pathogenic and commensal bacteria through specific metabolites, cell-wall components, and toxins. Here, we review recent work on the mechanisms of bacterial detection by distinct subtypes of gut-innervating sensory neurons. Upon activation, sensory neurons communicate to the immune system to modulate tissue inflammation through antidromic signalling and efferent neural circuits. We discuss how this neuro-immune regulation is orchestrated through transient receptor potential ion channels and sensory neuropeptides including substance P, calcitonin gene-related peptide, vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide. Recent studies also highlight a role for sensory neurons in regulating host defence against enteric bacterial pathogens including Salmonella typhimurium, Citrobacter rodentium and enterotoxigenic Escherichia coli. Understanding how sensory neurons respond to gastrointestinal flora and communicate with immune cells to regulate host defence enhances our knowledge of host physiology and may form the basis for new approaches to treat gastrointestinal diseases.
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Affiliation(s)
- N Y Lai
- Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA
| | - K Mills
- Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA
| | - I M Chiu
- Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA
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Zhao HM, Han F, Xu R, Huang XY, Cheng SM, Huang MF, Yue HY, Wang X, Zou Y, Xu HL, Liu DY. Therapeutic effect of curcumin on experimental colitis mediated by inhibiting CD8 +CD11c + cells. World J Gastroenterol 2017; 23:1804-1815. [PMID: 28348486 PMCID: PMC5352921 DOI: 10.3748/wjg.v23.i10.1804] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2016] [Revised: 12/25/2016] [Accepted: 01/17/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To verify whether curcumin (Cur) can treat inflammatory bowel disease by regulating CD8+CD11c+ cells.
METHODS We evaluated the suppressive effect of Cur on CD8+CD11c+ cells in spleen and Peyer’s patches (PPs) in colitis induced by trinitrobenzene sulfonic acid. Mice with colitis were treated by 200 mg/kg Cur for 7 d. On day 8, the therapeutic effect of Cur was evaluated by visual assessment and histological examination, while co-stimulatory molecules of CD8+CD11c+ cells in the spleen and PPs were measured by flow cytometry. The levels of interleukin (IL)-10, interferon (IFN)-γ and transforming growth factor (TGF)-β1 in spleen and colonic mucosa were determined by ELISA.
RESULTS The disease activity index, colon weight, weight index of colon and histological score of experimental colitis were obviously decreased after Cur treatment, while the body weight and colon length recovered. After treatment with Cur, CD8+CD11c+ cells were decreased in the spleen and PPs, and the expression of major histocompatibility complex II, CD205, CD40, CD40L and intercellular adhesion molecule-1 was inhibited. IL-10, IFN-γ and TGF-β1 levels were increased compared with those in mice with untreated colitis.
CONCLUSION Cur can effectively treat experimental colitis, which is realized by inhibiting CD8+CD11c+ cells.
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Carmona-Rivera C, Purmalek MM, Moore E, Waldman M, Walter PJ, Garraffo HM, Phillips KA, Preston KL, Graf J, Kaplan MJ, Grayson PC. A role for muscarinic receptors in neutrophil extracellular trap formation and levamisole-induced autoimmunity. JCI Insight 2017; 2:e89780. [PMID: 28194438 DOI: 10.1172/jci.insight.89780] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Levamisole, an anthelmintic drug with cholinergic properties, has been implicated in cases of drug-induced vasculitis when added to cocaine for profit purposes. Neutrophil extracellular trap (NET) formation is a cell death mechanism characterized by extrusion of chromatin decorated with granule proteins. Aberrant NET formation and degradation have been implicated in idiopathic autoimmune diseases that share features with levamisole-induced autoimmunity as well as in drug-induced autoimmunity. This study's objective was to determine how levamisole modulates neutrophil biology and its putative effects on the vasculature. Murine and human neutrophils exposed to levamisole demonstrated enhanced NET formation through engagement of muscarinic subtype 3 receptor. Levamisole-induced NETosis required activation of Akt and the RAF/MEK/ERK pathway, ROS induction through the nicotinamide adenine dinucleotide phosphate oxidase, and peptidylarginine deiminase activation. Sera from two cohorts of patients actively using levamisole-adulterated cocaine displayed autoantibodies against NET components. Cutaneous biopsy material obtained from individuals exposed to levamisole suggests that neutrophils produce NETs in areas of vasculitic inflammation and thrombosis. NETs generated by levamisole were toxic to endothelial cells and impaired endothelium-dependent vasorelaxation. Stimulation of muscarinic receptors on neutrophils by cholinergic agonists may contribute to the pathophysiology observed in drug-induced autoimmunity through the induction of inflammatory responses and neutrophil-induced vascular damage.
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Affiliation(s)
- Carmelo Carmona-Rivera
- Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), and
| | - Monica M Purmalek
- Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), and
| | - Erica Moore
- Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), and
| | - Meryl Waldman
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Peter J Walter
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - H Martin Garraffo
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Karran A Phillips
- National Institute on Drug Abuse (NIDA), National Institutes of Health, Baltimore, Maryland, USA
| | - Kenzie L Preston
- National Institute on Drug Abuse (NIDA), National Institutes of Health, Baltimore, Maryland, USA
| | - Jonathan Graf
- Division of Rheumatology, UCSF, San Francisco, California, USA
| | - Mariana J Kaplan
- Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), and
| | - Peter C Grayson
- Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), and
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Liu GX, Gan HT. Effect of enteric nervous system on intestinal epithelial barrier in inflammatory bowel disease. Shijie Huaren Xiaohua Zazhi 2017; 25:107-113. [DOI: 10.11569/wcjd.v25.i2.107] [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] [Indexed: 02/06/2023] Open
Abstract
Both enteric nervous system and intestinal epithelial barrier are vital components to ensure gut homeostasis. Recent studies have shown the implications of their close relationship for gut health and disease. By secreting neurotransmitters, the enteric nervous system plays an important role in regulating the epithelial barrier function. Meanwhile, communicating largely through the vagal nerve, the central nervous system could also interact with the intestinal epithelium through the enteric nervous system. Although the etiology and pathogenesis of inflammatory bowel disease remain elusive, increasing evidence has shown that the dysregulation of enteric nervous system affects both epithelial integrity and barrier function, which contributes to the occurrence and development of inflammatory bowel disease. This review will summarize the current knowledge regarding the effect of enteric nervous system on intestinal epithelial barrier and its implication in the development of inflammatory bowel disease.
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