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Stakenborg N, Viola MF, Boeckxstaens G. Intestinal neuron-associated macrophages in health and disease. Nat Immunol 2025:10.1038/s41590-025-02150-6. [PMID: 40399608 DOI: 10.1038/s41590-025-02150-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Accepted: 02/14/2025] [Indexed: 05/23/2025]
Abstract
Neuron-macrophage cross-talk in the intestine plays a crucial role in the maintenance of tissue homeostasis and the modulation of immune responses throughout life. Here, we describe how gut neuron-macrophage interactions shift macrophage phenotype and function from early development to adulthood and how this cross-talk modulates the macrophage function in response to infection and inflammation. We highlight how a neural microenvironment instructs a neuron-associated macrophage phenotype in the gut and show that their phenotype may resemble nerve-associated macrophages in other organs. Finally, we note that the loss of neuron-associated macrophages or a shift in their phenotype can contribute to enteric neurodegeneration in the gastrointestinal tract, causing gut motility disorders.
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Affiliation(s)
- Nathalie Stakenborg
- Center of Intestinal Neuro-Immune Interactions, Translational Research Center for GI Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing, KU Leuven-University of Leuven, Leuven, Belgium
| | - Maria Francesca Viola
- Developmental Biology of the Immune System, Life & Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany
| | - Guy Boeckxstaens
- Center of Intestinal Neuro-Immune Interactions, Translational Research Center for GI Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing, KU Leuven-University of Leuven, Leuven, Belgium.
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2
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Lambert GW, Patel M, Lambert EA. The Influence of the Sympathetic Nervous System on Cardiometabolic Health in Response to Weight Gain or Weight Loss. Metabolites 2025; 15:286. [PMID: 40422864 DOI: 10.3390/metabo15050286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2025] [Revised: 04/17/2025] [Accepted: 04/22/2025] [Indexed: 05/28/2025] Open
Abstract
Alterations in sympathetic nervous activity are evident in response to changes in body weight. Sympathetic nervous activity and sympathetic responses to weight change are regionalized, with alterations in end organ function dependent on the changes occurring in the brain regulatory pathways invoked and in the effector organs engaged. The obesity-induced activation of the sympathetic nervous system likely contributes to the initiation and worsening of cardiometabolic risk factors, including elevated blood pressure, cardiac dysfunction, dyslipidaemia, increased fasting blood glucose, insulin resistance, and non-alcoholic steatohepatitis. Unintended weight loss, as occurs in cachexia, is driven, at least in part, by the activation of sympathetic nervous-stimulated thermogenesis. The complexity of sympathetic nervous regulation renders the use of global measures of sympathetic activity problematic and the development of targeted therapies difficult, but these are not without promise or precedent. Knowledge of the central and peripheral pathways involved in sympathetic nervous regulation has opened up opportunities for pharmacological, surgical, and device-based approaches to mitigating the burden of disease development and progression. In this narrative review, we elaborate on sympathetic activity in response to changes in body weight, the brain pathways involved, and the cardiovascular and metabolic risks associated with perturbations in regional sympathetic activity.
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Affiliation(s)
- Gavin W Lambert
- School of Health Sciences and Iverson Health Innovation Research Institute, Swinburne University of Technology, Hawthorn, VIC 3122, Australia
| | - Mariya Patel
- School of Health Sciences and Iverson Health Innovation Research Institute, Swinburne University of Technology, Hawthorn, VIC 3122, Australia
| | - Elisabeth A Lambert
- School of Health Sciences and Iverson Health Innovation Research Institute, Swinburne University of Technology, Hawthorn, VIC 3122, Australia
- Medical Technology Victoria (MedTechVic) Research Hub, Hawthorn, VIC 3122, Australia
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3
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Dalrymple AN, Jones ST, Fallon JB, Shepherd RK, Weber DJ. Overcoming failure: improving acceptance and success of implanted neural interfaces. Bioelectron Med 2025; 11:6. [PMID: 40083033 PMCID: PMC11907899 DOI: 10.1186/s42234-025-00168-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Accepted: 02/06/2025] [Indexed: 03/16/2025] Open
Abstract
Implanted neural interfaces are electronic devices that stimulate or record from neurons with the purpose of improving the quality of life of people who suffer from neural injury or disease. Devices have been designed to interact with neurons throughout the body to treat a growing variety of conditions. The development and use of implanted neural interfaces is increasing steadily and has shown great success, with implants lasting for years to decades and improving the health and quality of life of many patient populations. Despite these successes, implanted neural interfaces face a multitude of challenges to remain effective for the lifetime of their users. The devices are comprised of several electronic and mechanical components that each may be susceptible to failure. Furthermore, implanted neural interfaces, like any foreign body, will evoke an immune response. The immune response will differ for implants in the central nervous system and peripheral nervous system, as well as over time, ultimately resulting in encapsulation of the device. This review describes the challenges faced by developers of neural interface systems, particularly devices already in use in humans. The mechanical and technological failure modes of each component of an implant system is described. The acute and chronic reactions to devices in the peripheral and central nervous system and how they affect system performance are depicted. Further, physical challenges such as micro and macro movements are reviewed. The clinical implications of device failures are summarized and a guide for determining the severity of complication was developed and provided. Common methods to diagnose and examine mechanical, technological, and biological failure modes at various stages of development and testing are outlined, with an emphasis on chronic in vivo characterization of implant systems. Finally, this review concludes with an overview of some of the innovative solutions developed to reduce or resolve the challenges faced by implanted neural interface systems.
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Affiliation(s)
- Ashley N Dalrymple
- Department of Biomedical Engineering, University of Utah, Salt Lake City, UT, USA.
- Department of Physical Medicine and Rehabilitation, University of Utah, Salt Lake City, UT, USA.
- NERVES Lab, University of Utah, Salt Lake City, UT, USA.
- Department of Mechanical Engineering, Carnegie Mellon University, Pittsburgh, PA, USA.
- NeuroMechatronics Lab, Carnegie Mellon University, Pittsburgh, PA, USA.
| | - Sonny T Jones
- Department of Biomedical Engineering, University of Utah, Salt Lake City, UT, USA
- NERVES Lab, University of Utah, Salt Lake City, UT, USA
| | - James B Fallon
- Bionics Institute, St. Vincent's Hospital, Melbourne, VIC, Australia
- Medical Bionics Department, University of Melbourne, Melbourne, VIC, Australia
| | - Robert K Shepherd
- Bionics Institute, St. Vincent's Hospital, Melbourne, VIC, Australia
| | - Douglas J Weber
- Department of Mechanical Engineering, Carnegie Mellon University, Pittsburgh, PA, USA
- NeuroMechatronics Lab, Carnegie Mellon University, Pittsburgh, PA, USA
- Neuroscience Institute, Carnegie Mellon University, Pittsburgh, PA, USA
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Junyi L, Yueyang W, Bin L, Xiaohong D, Wenhui C, Ning Z, Hong Z. Gut Microbiota Mediates Neuroinflammation in Alzheimer's Disease: Unraveling Key Factors and Mechanistic Insights. Mol Neurobiol 2025; 62:3746-3763. [PMID: 39317889 DOI: 10.1007/s12035-024-04513-w] [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: 03/24/2024] [Accepted: 09/18/2024] [Indexed: 09/26/2024]
Abstract
The gut microbiota, the complex community of microorganisms that inhabit the gastrointestinal tract, has emerged as a key player in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease (AD). AD is characterized by progressive cognitive decline and neuronal loss, associated with the accumulation of amyloid-β plaques, neurofibrillary tangles, and neuroinflammation in the brain. Increasing evidence suggests that alterations in the composition and function of the gut microbiota, known as dysbiosis, may contribute to the development and progression of AD by modulating neuroinflammation, a chronic and maladaptive immune response in the central nervous system. This review aims to comprehensively analyze the current role of the gut microbiota in regulating neuroinflammation and glial cell function in AD. Its objective is to deepen our understanding of the pathogenesis of AD and to discuss the potential advantages and challenges of using gut microbiota modulation as a novel approach for the diagnosis, treatment, and prevention of AD.
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Affiliation(s)
- Liang Junyi
- Heilongjiang University of Traditional Chinese Medicine, Harbin, 150040, Heilongjiang Province, China
| | - Wang Yueyang
- Heilongjiang University of Traditional Chinese Medicine, Harbin, 150040, Heilongjiang Province, China
| | - Liu Bin
- Heilongjiang University of Traditional Chinese Medicine, Harbin, 150040, Heilongjiang Province, China.
| | - Dong Xiaohong
- Jiamusi College, Heilongjiang University of Traditional Chinese Medicine, Jiamusi, Heilongjiang Province, China
| | - Cai Wenhui
- Heilongjiang University of Traditional Chinese Medicine, Harbin, 150040, Heilongjiang Province, China
| | - Zhang Ning
- Heilongjiang University of Traditional Chinese Medicine, Harbin, 150040, Heilongjiang Province, China
| | - Zhang Hong
- Heilongjiang Jiamusi Central Hospital, Jiamusi, Heilongjiang Province, China
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5
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Soreq H, Bar A, Paldor I. The cholinergic synapses. HANDBOOK OF CLINICAL NEUROLOGY 2025; 211:23-35. [PMID: 40340063 DOI: 10.1016/b978-0-443-19088-9.00003-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/10/2025]
Abstract
Acetylcholine (ACh) is a leading regulatory neurotransmitter in the nervous system, which functions both directly and as modulator of other neurotransmitters. It is found in the central and peripheral nervous system, as well as in the autonomic system-both sympathetic and parasympathetic. In the central nervous system (CNS), ACh functions not only as a neurotransmitter, but also as a modulator of cognitive functions, including long-term and short-term memory, limbic activation, and alertness. No process in the mammalian body can commence without its participation.
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Affiliation(s)
- Hermona Soreq
- Edmond and Lily Safra Center for Brain Sciences, Hebrew University of Jerusalem, Jerusalem, Israel; Department of Biological Chemistry, Alexander Silberman Institute of Life Sciences, Faculty of Mathematics and Science, Hebrew University of Jerusalem, Jerusalem, Israel.
| | - Adi Bar
- Department of Biological Chemistry, Alexander Silberman Institute of Life Sciences, Faculty of Mathematics and Science, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Iddo Paldor
- Department of Biological Chemistry, Alexander Silberman Institute of Life Sciences, Faculty of Mathematics and Science, Hebrew University of Jerusalem, Jerusalem, Israel; Neurosurgery Department, Shaare Zedek Medical Center, Jerusalem, Israel
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6
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Matarazzo JV, Williams-Wynn DT, Fallon JB, Payne SC. Magnetically Coupled Percutaneous Connector for Chronic Electrical Peripheral Nerve Stimulation and Recording in Awake Rats. IEEE Trans Biomed Eng 2025; 72:35-42. [PMID: 39093683 DOI: 10.1109/tbme.2024.3436649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/04/2024]
Abstract
A fast-growing field of neuroscience and medicine is the treatment of disease via electrical stimulation of the peripheral nervous system. Peripheral nerve stimulation delivers stimulation to nerves of the periphery where the target nerve can and is often located deep within the abdomen. Long-term preclinical animal models that demonstrate the safety and/or efficacy of electrical stimulation have predominantly used a skull mount to connect to neural interfaces. When targeting nerves of the extremities and abdomen, this mount location is less favourable due to its distance to the implant causing complications in surgery and to the longevity of the device in vivo. OBJECTIVE Here we aimed to develop and validate a chronic magnetic percutaneous connector designed for placement on the dorsal-lumbar aspect of the spine of awake, freely moving rats. METHODS A pedestal and external connector was developed, bench tested to assess for continuity, durability and disconnection forces, and validated in awake rats chronically implanted with an abdominal vagus nerve electrode array. The implanted pedestal and external connector were designed with custom PCBs, spring-loaded pins, magnets and biocompatible 3D printed housing. RESULTS The magnetic coupling mechanism allowed disconnection with minimal force, was highly reliable in maintaining electrical connection in awake rats and allowed recording of electrically evoked compound action potentials after chronic implantation. CONCLUSION In conclusion, this percutaneous connector is a useful research tool for peripheral nerve stimulation studies. SIGNIFICANCE The connector described will allow investigation into the safety and efficacy of emerging neuromodulation therapies for the treatment of disease.
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de Melo PS, Gianlorenco AC, Marduy A, Kim CK, Choi H, Song JJ, Fregni F. A Mechanistic Analysis of the Neural Modulation of the Inflammatory System Through Vagus Nerve Stimulation: A Systematic Review and Meta-analysis. Neuromodulation 2025; 28:43-53. [PMID: 38795094 DOI: 10.1016/j.neurom.2024.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Revised: 03/03/2024] [Accepted: 03/04/2024] [Indexed: 05/27/2024]
Abstract
OBJECTIVE We aimed to conduct a systematic review and meta-analysis assessing the antiinflammatory effects of various VNS methods while exploring multiple antiinflammatory pathways. MATERIALS AND METHODS We included clinical trials that used electrical stimulation of the vagus nerve and assessed inflammatory markers up to October 2022. We excluded studies lacking control groups, those with combined interventions, or abstracts without full text. We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and the Cochrane Handbook for Systematic Reviews. For each inflammatory marker, a random-effects meta-analysis using the inverse variance method was performed. Methods used include transcutaneous auricular VNS (taVNS), transcutaneous cervical VNS (tcVNS), invasive cervical VNS (iVNS), and electroacupuncture VNS (eaVNS). Main reported outcomes included tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1ß, C-reactive protein (CRP), and IL-10. Risk of bias was evaluated using the Cochrane Collaboration Tool (RoB 2.0). RESULTS This review included 15 studies, involving 597 patients. No statistically significant general VNS effect was observed on TNF-α, IL-6, and IL-1ß. However, CRP, IL-10, and interferon (IFN)-γ were significantly modulated by VNS across all methods. Subgroup analysis revealed specific stimulation techniques producing significant results, such as taVNS effects in IL-1ß and IL-10, and iVNS in IL-6, whereas tcVNS and eaVNS did not convey significant pooled results individually. Cumulative exposure to VNS, higher risk of bias, study design, and pulse width were identified as effect size predictors in our meta-regression models. CONCLUSIONS Pooling all VNS techniques indicated the ability of VNS to modulate inflammatory markers such as CRP, IL-10, and IFN-γ. Individually, methods such as taVNS were effective in modulating IL-1ß and IL-10, whereas iVNS modulated IL-6. However, different VNS techniques should be separately analyzed in larger, homogeneous, and powerful studies to achieve a clearer and more consistent understanding of the effect of each VNS method on the inflammatory system.
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Affiliation(s)
- Paulo S de Melo
- Medicine, Escola Bahiana de Medicina e Saúde Pública, Salvador, Bahia, Brazil; Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Anna C Gianlorenco
- Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Physical Therapy, Federal University of São Carlos, Brazil
| | - Anna Marduy
- Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Medicine, União Metropolitana de Ensino e Cultura (UNIME), Salvador, Bahia, Brazil
| | - Chi K Kim
- Department of Neurology, Korea University Guro Hospital, Seoul, South Korea
| | - Hyuk Choi
- Department of Medical Sciences, Graduate School of Medicine, Korea University, Seoul, South Korea; Neurive Co, Ltd, Gimhae, South Korea
| | - Jae-Jun Song
- Department of Otorhinolaryngology-Head and Neck Surgery, Korea University Medical Center, Seoul, South Korea; Neurive Co, Ltd, Gimhae, South Korea
| | - Felipe Fregni
- Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
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Hesampour F, Tshikudi DM, Bernstein CN, Ghia JE. Exploring the efficacy of Transcutaneous Auricular Vagus nerve stimulation (taVNS) in modulating local and systemic inflammation in experimental models of colitis. Bioelectron Med 2024; 10:29. [PMID: 39648211 PMCID: PMC11626753 DOI: 10.1186/s42234-024-00162-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Accepted: 11/11/2024] [Indexed: 12/10/2024] Open
Abstract
BACKGROUND Current inflammatory bowel disease (IBD) treatments often fail to achieve lasting remission and have adverse effects. Vagus nerve stimulation (VNS) offers a promising therapy due to its anti-inflammatory effects. Its invasive nature, however, has led to the development of non-invasive methods like transcutaneous auricular VNS (taVNS). This study assesses taVNS's impact on acute colitis progression, inflammatory, anti-inflammatory, and apoptosis-related markers. METHODS Male C57BL/6 mice (11-12 weeks) were used for dextran sulfate sodium (DSS)- and dinitrobenzene sulfonic acid (DNBS)-induced colitis studies. The administration of taVNS or no stimulation (anesthesia without stimulation) for 10 min per mouse began one day before colitis induction and continued daily until sacrifice. Ulcerative colitis (UC)-like colitis was induced by administering 5% DSS in drinking water for 5 days, after which the mice were sacrificed. Crohn's disease (CD)-like colitis was induced through a single intrarectal injection of DNBS/ethanol, with the mice sacrificed after 3 days. Disease activity index (DAI), macroscopic evaluations, and histological damage were assessed. Colon, spleen, and blood samples were analyzed via qRT-PCR and ELISA. One-way or two-way ANOVA with Bonferroni and Šídák tests were applied. RESULTS taVNS improved DAI, macroscopic, and histological scores in DSS colitis mice, but only partially mitigated weight loss and DAI in DNBS colitis mice. In DSS colitis, taVNS locally decreased colonic inflammation by downregulating pro-inflammatory markers (IL-1β, TNF-α, Mip1β, MMP 9, MMP 2, and Nos2) at the mRNA level and upregulating anti-inflammatory TGF-β in non-colitic conditions at both mRNA and protein levels and IL-10 mRNA levels in both non-colitic and colitic conditions. Systemically, taVNS decreased splenic TNF-α in non-colitic mice and increased serum levels of TGF-β in colitic mice and splenic levels in non-colitic and colitic mice. Effects were absent in DNBS-induced colitis. Additionally, taVNS decreased pro-apoptotic markers (Bax, Bak1, and caspase 8) in non-colitic and colitic conditions and increased the pro-survival molecule Bad in non-colitic mice. CONCLUSIONS This study demonstrates that taVNS has model-dependent local and systemic effects, reducing inflammation and apoptosis in UC-like colitis while offering protective benefits in non-colitic conditions. These findings encourage further research into underlying mechanisms and developing adjunct therapies for UC.
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Affiliation(s)
- Fatemeh Hesampour
- Immunology, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Canada
| | - Diane M Tshikudi
- Immunology, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Canada
| | - Charles N Bernstein
- Internal Medicine Section of Gastroenterology, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Canada
- Inflammatory Bowel Disease Clinical & Research Centre, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Canada
| | - Jean-Eric Ghia
- Immunology, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Canada.
- Internal Medicine Section of Gastroenterology, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Canada.
- Inflammatory Bowel Disease Clinical & Research Centre, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Canada.
- Children's Hospital Research Institute of Manitoba, Winnipeg, Canada.
- Department of Immunology, Internal Medicine Section of Gastroenterology, Apotex Centre 431, 750 McDermot Avenue, Winnipeg, MB, R3E 0T5, Canada.
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Liu FJ, Wu J, Gong LJ, Yang HS, Chen H. Non-invasive vagus nerve stimulation in anti-inflammatory therapy: mechanistic insights and future perspectives. Front Neurosci 2024; 18:1490300. [PMID: 39605787 PMCID: PMC11599236 DOI: 10.3389/fnins.2024.1490300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Accepted: 10/24/2024] [Indexed: 11/29/2024] Open
Abstract
Non-invasive vagus nerve stimulation (VNS) represents a transformative approach for managing a broad spectrum of inflammatory and autoimmune conditions, including rheumatoid arthritis and inflammatory bowel disease. This comprehensive review delineates the mechanisms underlying VNS, emphasizing the cholinergic anti-inflammatory pathway, and explores interactions within the neuro-immune and vagus-gut axes based on both clinical outcomes and pre-clinical models. Clinical applications have confirmed the efficacy of VNS in managing specific autoimmune diseases, such as rheumatoid arthritis, and chronic inflammatory conditions like inflammatory bowel disease, showcasing the variability in stimulation parameters and patient responses. Concurrently, pre-clinical studies have provided insights into the potential of VNS in modulating cardiovascular and broader inflammatory responses, paving the way for its translational application in clinical settings. Innovations in non-invasive VNS technology and precision neuromodulation are enhancing its therapeutic potential, making it a viable option for patients who are unresponsive to conventional treatments. Nonetheless, the widespread adoption of this promising therapy is impeded by regulatory challenges, patient compliance issues, and the need for extensive studies on long-term efficacy and safety. Future research directions will focus on refining VNS technology, optimizing treatment parameters, and exploring synergistic effects with other therapeutic modalities, which could revolutionize the management of chronic inflammatory and autoimmune disorders.
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Affiliation(s)
- Fu-Jun Liu
- Neurology Medical Center II, Foresea Life Insurance Guangzhou General Hospital, Guangzhou, China
| | - Jing Wu
- Department of Medical Imaging, Foresea Life Insurance Guangzhou General Hospital, Guangzhou, China
| | - Li-Jun Gong
- Center of Surgical Anesthesia, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Hong-Shuai Yang
- Central Operating Room, Foresea Life Insurance Guangzhou General Hospital, Guangzhou, China
| | - Huan Chen
- Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
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Yang J, Liang J, Hu N, He N, Liu B, Liu G, Qin Y. The Gut Microbiota Modulates Neuroinflammation in Alzheimer's Disease: Elucidating Crucial Factors and Mechanistic Underpinnings. CNS Neurosci Ther 2024; 30:e70091. [PMID: 39460538 PMCID: PMC11512114 DOI: 10.1111/cns.70091] [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: 08/07/2024] [Revised: 09/18/2024] [Accepted: 10/08/2024] [Indexed: 10/28/2024] Open
Abstract
BACKGROUND AND PURPOSE Alzheimer's disease (AD) is characterized by progressive cognitive decline and neuronal loss, commonly linked to amyloid-β plaques, neurofibrillary tangles, and neuroinflammation. Recent research highlights the gut microbiota as a key player in modulating neuroinflammation, a critical pathological feature of AD. Understanding the role of the gut microbiota in this process is essential for uncovering new therapeutic avenues and gaining deeper insights into AD pathogenesis. METHODS This review provides a comprehensive analysis of how gut microbiota influences neuroinflammation and glial cell function in AD. A systematic literature search was conducted, covering studies from 2014 to 2024, including reviews, clinical trials, and animal studies. Keywords such as "gut microbiota," "Alzheimer's disease," "neuroinflammation," and "blood-brain barrier" were used. RESULTS Dysbiosis, or the imbalance in gut microbiota composition, has been implicated in the modulation of key AD-related mechanisms, including neuroinflammation, blood-brain barrier integrity, and neurotransmitter regulation. These disruptions may accelerate the onset and progression of AD. Additionally, therapeutic strategies targeting gut microbiota, such as probiotics, prebiotics, and fecal microbiota transplantation, show promise in modulating AD pathology. CONCLUSIONS The gut microbiota is a pivotal factor in AD pathogenesis, influencing neuroinflammation and disease progression. Understanding the role of gut microbiota in AD opens avenues for innovative diagnostic, preventive, and therapeutic strategies.
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Affiliation(s)
- Jianshe Yang
- Harbin Institute of Physical EducationHarbinHeilongjiang ProvinceChina
| | - Junyi Liang
- Heilongjiang University of Traditional Chinese MedicineHarbinHeilongjiang ProvinceChina
| | - Niyuan Hu
- Harbin Institute of Physical EducationHarbinHeilongjiang ProvinceChina
| | - Ningjuan He
- Harbin Institute of Physical EducationHarbinHeilongjiang ProvinceChina
| | - Bin Liu
- Heilongjiang University of Traditional Chinese MedicineHarbinHeilongjiang ProvinceChina
| | - Guoliang Liu
- Harbin Institute of Physical EducationHarbinHeilongjiang ProvinceChina
| | - Ying Qin
- Harbin Institute of Physical EducationHarbinHeilongjiang ProvinceChina
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11
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Populin LC, Rajala AZ, Matkowskyj KA, Saha S, Zeng W, Christian B, McVea A, Tay EX, Mueller EM, Malone ME, Brust-Mascher I, McMillan AB, Ludwig KA, Suminski AJ, Reardon C, Furness JB. Characterization of idiopathic chronic diarrhea and associated intestinal inflammation and preliminary observations of effects of vagal nerve stimulation in a non-human primate. Neurogastroenterol Motil 2024; 36:e14876. [PMID: 39072841 PMCID: PMC11321913 DOI: 10.1111/nmo.14876] [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: 03/20/2024] [Revised: 05/26/2024] [Accepted: 07/11/2024] [Indexed: 07/30/2024]
Abstract
BACKGROUND Diarrhea is commonly associated with irritable bowel syndrome, inflammatory bowel disease, microscopic colitis, and other gastrointestinal dysfunctions. Spontaneously occurring idiopathic chronic diarrhea is frequent in rhesus macaques, but has not been used as a model for the investigation of diarrhea or its treatment. We characterized this condition and present preliminary data demonstrating that left vagal nerve stimulation provides relief. METHODS Stool consistency scores were followed for up to 12 years. Inflammation was assessed by plasma C-reactive protein, [18F]fluorodeoxyglucose (FDG) uptake, measured by positron emission tomography (PET), multiplex T cell localization, endoscopy and histology. The vagus was stimulated for 9 weeks in conscious macaques, using fully implanted electrodes, under wireless control. KEY RESULTS Macaques exhibited recurrent periods of diarrhea for up to 12 years, and signs of inflammation: elevated plasma C-reactive protein, increased bowel FDG uptake and increased mucosal T helper1 T-cells. The colon and distal ileum were endoscopically normal, and histology revealed mild colonic inflammation. Application of vagal nerve stimulation to conscious macaques (10 Hz, 30 s every 3 h; 24 h a day for 9 weeks) significantly reduced severity of diarrhea and also reduced inflammation, as measured by FDG uptake and C-reactive protein. CONCLUSIONS AND INFERENCES These macaques exhibit spontaneously occurring diarrhea with intestinal inflammation that can be reduced by VNS. The data demonstrate the utility of this naturally occurring primate model to study the physiology and treatments for chronic diarrhea and the neural control circuits influencing diarrhea and inflammation that are not accessible in human subjects.
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Affiliation(s)
- Luis C Populin
- Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI
| | - Abigail Z Rajala
- Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI
| | - Kristina A Matkowskyj
- Department of Pathology & Laboratory Medicine, University of Wisconsin-Madison, Madison, WI
| | - Sumona Saha
- Division of Gastroenterology and Hepatology, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Weifeng Zeng
- Department of Surgery, Dental and Plastic Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI
| | - Bradley Christian
- Department of Medical Physics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI
| | - Andrew McVea
- Department of Medical Physics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI
| | - Emmy Xue Tay
- Department of Anatomy, Physiology and Cell Biology, UC Davis
| | - Ellie M Mueller
- Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI
| | - Margaret E Malone
- Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI
| | | | - Alan B McMillan
- Department of Medical Physics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI
- Department of Radiology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI
| | - Kip A Ludwig
- Department of Neurological Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI
| | - Aaron J Suminski
- Department of Neurological Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI
| | - Colin Reardon
- Department of Anatomy, Physiology and Cell Biology, UC Davis
| | - John B Furness
- Department of Anatomy & Physiology, University of Melbourne, Parkville, VIC 3010, Australia
- Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3010, Australia
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12
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Huang Y, Yao K, Zhang Q, Huang X, Chen Z, Zhou Y, Yu X. Bioelectronics for electrical stimulation: materials, devices and biomedical applications. Chem Soc Rev 2024; 53:8632-8712. [PMID: 39132912 DOI: 10.1039/d4cs00413b] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/13/2024]
Abstract
Bioelectronics is a hot research topic, yet an important tool, as it facilitates the creation of advanced medical devices that interact with biological systems to effectively diagnose, monitor and treat a broad spectrum of health conditions. Electrical stimulation (ES) is a pivotal technique in bioelectronics, offering a precise, non-pharmacological means to modulate and control biological processes across molecular, cellular, tissue, and organ levels. This method holds the potential to restore or enhance physiological functions compromised by diseases or injuries by integrating sophisticated electrical signals, device interfaces, and designs tailored to specific biological mechanisms. This review explains the mechanisms by which ES influences cellular behaviors, introduces the essential stimulation principles, discusses the performance requirements for optimal ES systems, and highlights the representative applications. From this review, we can realize the potential of ES based bioelectronics in therapy, regenerative medicine and rehabilitation engineering technologies, ranging from tissue engineering to neurological technologies, and the modulation of cardiovascular and cognitive functions. This review underscores the versatility of ES in various biomedical contexts and emphasizes the need to adapt to complex biological and clinical landscapes it addresses.
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Affiliation(s)
- Ya Huang
- Department of Biomedical Engineering, City University of Hong Kong, Hong Kong, China
| | - Kuanming Yao
- Department of Biomedical Engineering, City University of Hong Kong, Hong Kong, China
| | - Qiang Zhang
- Department of Biomedical Engineering, City University of Hong Kong, Hong Kong, China
| | - Xingcan Huang
- Department of Biomedical Engineering, City University of Hong Kong, Hong Kong, China
| | - Zhenlin Chen
- Department of Biomedical Engineering, City University of Hong Kong, Hong Kong, China
| | - Yu Zhou
- Department of Electronic and Computer Engineering, The Hong Kong University of Science and Technology, Hong Kong, China.
| | - Xinge Yu
- Department of Biomedical Engineering, City University of Hong Kong, Hong Kong, China
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13
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Truyens M, Lernout H, De Vos M, Laukens D, Lobaton T. Unraveling the fatigue puzzle: insights into the pathogenesis and management of IBD-related fatigue including the role of the gut-brain axis. Front Med (Lausanne) 2024; 11:1424926. [PMID: 39021817 PMCID: PMC11252009 DOI: 10.3389/fmed.2024.1424926] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Accepted: 06/17/2024] [Indexed: 07/20/2024] Open
Abstract
A significant percentage of patients with an inflammatory bowel disease (IBD) encounter fatigue which can profoundly diminish patients' quality of life, particularly during periods of disease remission when gastrointestinal symptoms have receded. Various contributing risk factors have been identified including active inflammation, anemia, psychological, lifestyle and drug-related factors. While addressing these risk factors has been suggested as the initial approach to managing fatigue, a considerable number of patients still experience persisting symptoms, the primary causes of which remain incompletely understood. Recent insights suggest that dysfunction of the gut-brain axis may play a pathogenic role. This review provides an overview of established risk factors for fatigue, alongside emerging perspectives on the role of the gut-brain axis, and potential treatment strategies.
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Affiliation(s)
- Marie Truyens
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
- Department of Gastroenterology, University Hospital Ghent, Ghent, Belgium
| | - Hannah Lernout
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
- VIB Center for Inflammation Research (IRC), Ghent University, Ghent, Belgium
| | - Martine De Vos
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
| | - Debby Laukens
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
- VIB Center for Inflammation Research (IRC), Ghent University, Ghent, Belgium
- Ghent Gut Inflammation Group (GGIG), Ghent University, Ghent, Belgium
| | - Triana Lobaton
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
- Department of Gastroenterology, University Hospital Ghent, Ghent, Belgium
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14
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Moura MM, Monteiro A, Salgado AJ, Silva NA, Monteiro S. Disrupted autonomic pathways in spinal cord injury: Implications for the immune regulation. Neurobiol Dis 2024; 195:106500. [PMID: 38614275 DOI: 10.1016/j.nbd.2024.106500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 03/25/2024] [Accepted: 04/04/2024] [Indexed: 04/15/2024] Open
Abstract
Spinal Cord Injury (SCI) disrupts critical autonomic pathways responsible for the regulation of the immune function. Consequently, individuals with SCI often exhibit a spectrum of immune dysfunctions ranging from the development of damaging pro-inflammatory responses to severe immunosuppression. Thus, it is imperative to gain a more comprehensive understanding of the extent and mechanisms through which SCI-induced autonomic dysfunction influences the immune response. In this review, we provide an overview of the anatomical organization and physiology of the autonomic nervous system (ANS), elucidating how SCI impacts its function, with a particular focus on lymphoid organs and immune activity. We highlight recent advances in understanding how intraspinal plasticity that follows SCI may contribute to aberrant autonomic activity in lymphoid organs. Additionally, we discuss how sympathetic mediators released by these neuron terminals affect immune cell function. Finally, we discuss emerging innovative technologies and potential clinical interventions targeting the ANS as a strategy to restore the normal regulation of the immune response in individuals with SCI.
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Affiliation(s)
- Maria M Moura
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal; ICVS/3B's Associate Lab, PT Government Associated Lab, 4710-057 Braga, Guimarães, Portugal
| | - Andreia Monteiro
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal; ICVS/3B's Associate Lab, PT Government Associated Lab, 4710-057 Braga, Guimarães, Portugal
| | - António J Salgado
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal; ICVS/3B's Associate Lab, PT Government Associated Lab, 4710-057 Braga, Guimarães, Portugal
| | - Nuno A Silva
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal; ICVS/3B's Associate Lab, PT Government Associated Lab, 4710-057 Braga, Guimarães, Portugal
| | - Susana Monteiro
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal; ICVS/3B's Associate Lab, PT Government Associated Lab, 4710-057 Braga, Guimarães, Portugal.
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15
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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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16
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Budhiraja A, Mehta A, Alhamo MA, Swedarsky R, Dahle S, Isseroff RR. Vagus nerve stimulation: Potential for treating chronic wounds. Wound Repair Regen 2024; 32:108-117. [PMID: 38235529 DOI: 10.1111/wrr.13151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Revised: 11/16/2023] [Accepted: 12/10/2023] [Indexed: 01/19/2024]
Abstract
Vagus nerve stimulation (VNS) has been approved as a treatment for various conditions, including drug-resistant epilepsy, migraines, chronic cluster headaches and treatment-resistant depression. It is known to have anti-inflammatory, anti-nociceptive and anti-adrenergic effects, and its therapeutic potential for diverse pathologies is being investigated. VNS can be achieved through invasive (iVNS) or non-invasive (niVNS) means, targeting different branches of the vagus nerve. iVNS devices require surgical implantation and have associated risks, while niVNS devices are generally better tolerated and have a better safety profile. Studies have shown that both iVNS and niVNS can reduce inflammation and pain perception in patients with acute and chronic conditions. VNS devices, such as the VNS Therapy System and MicroTransponder Vivistim, have received Food and Drug Administration approval for specific indications. Other niVNS devices, like NEMOS and gammaCore, have shown effectiveness in managing epilepsy, pain and migraines. VNS has also demonstrated potential in autoimmune disorders, such as rheumatoid arthritis and Crohn's disease, as well as neurological disorders like epilepsy and migraines. In addition, VNS has been explored in cardiovascular disorders, including post-operative atrial fibrillation and myocardial ischemia-reperfusion injury, and has shown positive outcomes. The mechanisms behind VNS's effects include the cholinergic anti-inflammatory pathway, modulation of cytokines and activation of specialised pro-resolving mediators. The modulation of inflammation by VNS presents a promising avenue for investigating its potential to improve the healing of chronic wounds. However, more research is needed to understand the specific mechanisms and optimise the use of VNS in wound healing. Ongoing clinical trials may support the use of this modality as an adjunct to improve healing.
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Affiliation(s)
- Anuj Budhiraja
- California Northstate University College of Medicine, Elk Grove, California, USA
| | - Alisha Mehta
- California Northstate University College of Medicine, Elk Grove, California, USA
| | - Moyasar A Alhamo
- Department of Dermatology, University of California, Davis, California, USA
| | | | - Sara Dahle
- Department of Dermatology, University of California, Davis, California, USA
- Podiatry Section, VA Northern California Health Care System, California, USA
| | - R Rivkah Isseroff
- Department of Dermatology, University of California, Davis, California, USA
- Dermatology Section, VA Northern California Health Care System, California, USA
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17
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Jelinek M, Lipkova J, Duris K. Vagus nerve stimulation as immunomodulatory therapy for stroke: A comprehensive review. Exp Neurol 2024; 372:114628. [PMID: 38042360 DOI: 10.1016/j.expneurol.2023.114628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 10/20/2023] [Accepted: 11/27/2023] [Indexed: 12/04/2023]
Abstract
Stroke is a devastating cerebrovascular pathology with high morbidity and mortality. Inflammation plays a central role in the pathophysiology of stroke. Vagus nerve stimulation (VNS) is a promising immunomodulatory method that has shown positive effects in stroke treatment, including neuroprotection, anti-apoptosis, anti-inflammation, antioxidation, reduced infarct volume, improved neurological scores, and promotion of M2 microglial polarization. In this review, we summarize the current knowledge about the vagus nerve's immunomodulatory effects through the cholinergic anti-inflammatory pathway (CAP) and provide a comprehensive assessment of the available experimental literature focusing on the use of VNS in stroke treatment.
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Affiliation(s)
- Matyas Jelinek
- Department of Pathophysiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic; Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Jolana Lipkova
- Department of Pathophysiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Kamil Duris
- Department of Pathophysiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic; Department of Neurosurgery, The University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
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18
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Payne SC, Osborne PB, Thompson A, Eiber CD, Keast JR, Fallon JB. Selective recording of physiologically evoked neural activity in a mixed autonomic nerve using a minimally invasive array. APL Bioeng 2023; 7:046110. [PMID: 37928642 PMCID: PMC10625482 DOI: 10.1063/5.0164951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Accepted: 10/16/2023] [Indexed: 11/07/2023] Open
Abstract
Real-time closed-loop control of neuromodulation devices requires long-term monitoring of neural activity in the peripheral nervous system. Although many signal extraction methods exist, few are both clinically viable and designed for extracting small signals from fragile peripheral visceral nerves. Here, we report that our minimally invasive recording and analysis technology extracts low to negative signal to noise ratio (SNR) neural activity from a visceral nerve with a high degree of specificity for fiber type and class. Complex activity was recorded from the rat pelvic nerve that was physiologically evoked during controlled bladder filling and voiding, in an extensively characterized in vivo model that provided an excellent test bed to validate our technology. Urethane-anesthetized male rats (n = 12) were implanted with a four-electrode planar array and the bladder instrumented for continuous-flow cystometry, which measures urodynamic function by recording bladder pressure changes during constant infusion of saline. We demonstrated that differential bipolar recordings and cross-correlation analyses extracts afferent and efferent activity, and discriminated between subpopulations of fibers based on conduction velocity. Integrated Aδ afferent fiber activity correlated with bladder pressure during voiding (r2: 0.66 ± 0.06) and was not affected by activating nociceptive afferents with intravesical capsaicin (r2: 0.59 ± 0.14, P = 0.54, and n = 3). Collectively, these results demonstrate our minimally invasive recording and analysis technology is selective in extracting mixed neural activity with low/negative SNR. Furthermore, integrated afferent activity reliably correlates with bladder pressure and is a promising first step in developing closed-loop technology for bladder control.
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Affiliation(s)
| | - Peregrine B. Osborne
- Department of Anatomy and Physiology, University of Melbourne, Victoria 3010, Australia
| | | | - Calvin D. Eiber
- Department of Anatomy and Physiology, University of Melbourne, Victoria 3010, Australia
| | - Janet R. Keast
- Department of Anatomy and Physiology, University of Melbourne, Victoria 3010, Australia
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19
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Nair V, Dalrymple AN, Yu Z, Balakrishnan G, Bettinger CJ, Weber DJ, Yang K, Robinson JT. Miniature battery-free bioelectronics. Science 2023; 382:eabn4732. [PMID: 37943926 DOI: 10.1126/science.abn4732] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 09/28/2023] [Indexed: 11/12/2023]
Abstract
Miniature wireless bioelectronic implants that can operate for extended periods of time can transform how we treat disorders by acting rapidly on precise nerves and organs in a way that drugs cannot. To reach this goal, materials and methods are needed to wirelessly transfer energy through the body or harvest energy from the body itself. We review some of the capabilities of emerging energy transfer methods to identify the performance envelope for existing technology and discover where opportunities lie to improve how much-and how efficiently-we can deliver energy to the tiny bioelectronic implants that can support emerging medical technologies.
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Affiliation(s)
- Vishnu Nair
- Rice Neuroengineering Initiative, Rice University, Houston, TX, USA
| | - Ashley N Dalrymple
- Department of Mechanical Engineering, Carnegie Mellon University, Pittsburgh, PA, USA
- Department of Biomedical Engineering, University of Utah, Salt Lake City, UT, USA
- Department of Physical Medicine and Rehabilitation, University of Utah, Salt Lake City, UT, USA
| | - Zhanghao Yu
- Department of Electrical and Computer Engineering, Rice University, Houston, TX, USA
| | - Gaurav Balakrishnan
- Department of Materials Science & Engineering, Carnegie Mellon University, Pittsburgh, PA, USA
| | - Christopher J Bettinger
- Department of Materials Science & Engineering, Carnegie Mellon University, Pittsburgh, PA, USA
| | - Douglas J Weber
- Department of Mechanical Engineering, Carnegie Mellon University, Pittsburgh, PA, USA
- Neuroscience Institute, Carnegie Mellon University, Pittsburgh, PA, USA
- Center for Neural Basis of Cognition, Pittsburgh, PA, USA
| | - Kaiyuan Yang
- Department of Electrical and Computer Engineering, Rice University, Houston, TX, USA
| | - Jacob T Robinson
- Rice Neuroengineering Initiative, Rice University, Houston, TX, USA
- Department of Electrical and Computer Engineering, Rice University, Houston, TX, USA
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20
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Trevizan-Bau P, Mazzone SB. Neuroimmune pathways regulating airway inflammation. Ann Allergy Asthma Immunol 2023; 131:550-560. [PMID: 37517657 DOI: 10.1016/j.anai.2023.07.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 05/24/2023] [Accepted: 07/20/2023] [Indexed: 08/01/2023]
Abstract
Airways diseases are typically accompanied by inflammation, which has long been known to contribute to obstruction, mucus hypersecretion, dyspnea, cough, and other characteristic symptoms displayed in patients. Clinical interventions, therefore, often target inflammation to reverse lung pathology and reduce morbidity. The airways and lungs are densely innervated by subsets of nerve fibers, which are not only impacted by pulmonary inflammation but, in addition, likely serve as important regulators of immune cell function. This bidirectional neuroimmune crosstalk is supported by close spatial relationships between immune cells and airway nerve fibers, complementary neural and immune signaling pathways, local specialized airway chemosensory cells, and dedicated reflex circuits. In this article, we review the recent literature on this topic and present state-of-the-art evidence supporting the role of neuroimmune interactions in airway inflammation. In addition, we extend this evidence to synthesize considerations for the clinical translation of these discoveries to improve the management of patients with airway disease.
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Affiliation(s)
- Pedro Trevizan-Bau
- Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria, Australia; Department of Microbiology and Immunology, University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Stuart B Mazzone
- Department of Anatomy and Physiology, University of Melbourne, Melbourne, Victoria, Australia.
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21
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Ten Hove AS, Mallesh S, Zafeiropoulou K, de Kleer JWM, van Hamersveld PHP, Welting O, Hakvoort TBM, Wehner S, Seppen J, de Jonge WJ. Sympathetic activity regulates epithelial proliferation and wound healing via adrenergic receptor α 2A. Sci Rep 2023; 13:17990. [PMID: 37863979 PMCID: PMC10589335 DOI: 10.1038/s41598-023-45160-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 10/17/2023] [Indexed: 10/22/2023] Open
Abstract
Innervation of the intestinal mucosa by the sympathetic nervous system is well described but the effects of adrenergic receptor stimulation on the intestinal epithelium remain equivocal. We therefore investigated the effect of sympathetic neuronal activation on intestinal cells in mouse models and organoid cultures, to identify the molecular routes involved. Using publicly available single-cell RNA sequencing datasets we show that the α2A isoform is the most abundant adrenergic receptor in small intestinal epithelial cells. Stimulation of this receptor with norepinephrine or a synthetic specific α2A receptor agonist promotes epithelial proliferation and stem cell function, while reducing differentiation in vivo and in intestinal organoids. In an anastomotic healing mouse model, adrenergic receptor α2A stimulation resulted in improved anastomotic healing, while surgical sympathectomy augmented anastomotic leak. Furthermore, stimulation of this receptor led to profound changes in the microbial composition, likely because of altered epithelial antimicrobial peptide secretion. Thus, we established that adrenergic receptor α2A is the molecular delegate of intestinal epithelial sympathetic activity controlling epithelial proliferation, differentiation, and host defense. Therefore, this receptor could serve as a newly identified molecular target to improve mucosal healing in intestinal inflammation and wounding.
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Affiliation(s)
- Anne S Ten Hove
- Tytgat Institute for Liver and Intestinal Research, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 69-71, 1105 BK, Amsterdam, The Netherlands.
| | - Shilpashree Mallesh
- Department of General, Visceral-, Thoracic and Vascular Surgery, University Hospital Bonn, Bonn, Germany
| | - Konstantina Zafeiropoulou
- Tytgat Institute for Liver and Intestinal Research, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 69-71, 1105 BK, Amsterdam, The Netherlands
| | - Janna W M de Kleer
- Tytgat Institute for Liver and Intestinal Research, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 69-71, 1105 BK, Amsterdam, The Netherlands
| | - Patricia H P van Hamersveld
- Tytgat Institute for Liver and Intestinal Research, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 69-71, 1105 BK, Amsterdam, The Netherlands
| | - Olaf Welting
- Tytgat Institute for Liver and Intestinal Research, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 69-71, 1105 BK, Amsterdam, The Netherlands
| | - Theodorus B M Hakvoort
- Tytgat Institute for Liver and Intestinal Research, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 69-71, 1105 BK, Amsterdam, The Netherlands
| | - Sven Wehner
- Department of General, Visceral-, Thoracic and Vascular Surgery, University Hospital Bonn, Bonn, Germany
| | - Jurgen Seppen
- Tytgat Institute for Liver and Intestinal Research, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 69-71, 1105 BK, Amsterdam, The Netherlands
| | - Wouter J de Jonge
- Tytgat Institute for Liver and Intestinal Research, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 69-71, 1105 BK, Amsterdam, The Netherlands.
- Department of General, Visceral-, Thoracic and Vascular Surgery, University Hospital Bonn, Bonn, Germany.
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22
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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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Petsakou A, Liu Y, Liu Y, Comjean A, Hu Y, Perrimon N. Epithelial Ca 2+ waves triggered by enteric neurons heal the gut. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.14.553227. [PMID: 37645990 PMCID: PMC10461974 DOI: 10.1101/2023.08.14.553227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/01/2023]
Abstract
A fundamental and unresolved question in regenerative biology is how tissues return to homeostasis after injury. Answering this question is essential for understanding the etiology of chronic disorders such as inflammatory bowel diseases and cancer. We used the Drosophila midgut to investigate this question and discovered that during regeneration a subpopulation of cholinergic enteric neurons triggers Ca2+ currents among enterocytes to promote return of the epithelium to homeostasis. Specifically, we found that down-regulation of the cholinergic enzyme Acetylcholinesterase in the epithelium enables acetylcholine from defined enteric neurons, referred as ARCENs, to activate nicotinic receptors in enterocytes found near ARCEN-innervations. This activation triggers high Ca2+ influx that spreads in the epithelium through Inx2/Inx7 gap junctions promoting enterocyte maturation followed by reduction of proliferation and inflammation. Disrupting this process causes chronic injury consisting of ion imbalance, Yki activation and increase of inflammatory cytokines together with hyperplasia, reminiscent of inflammatory bowel diseases. Altogether, we found that during gut regeneration the conserved cholinergic pathway facilitates epithelial Ca2+ waves that heal the intestinal epithelium. Our findings demonstrate nerve- and bioelectric-dependent intestinal regeneration which advance the current understanding of how a tissue returns to its homeostatic state after injury and could ultimately help existing therapeutics.
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Affiliation(s)
| | - Yifang Liu
- Department of Genetics, Harvard Medical School, Boston, USA
| | - Ying Liu
- Department of Genetics, Harvard Medical School, Boston, USA
| | - Aram Comjean
- Department of Genetics, Harvard Medical School, Boston, USA
| | - Yanhui Hu
- Department of Genetics, Harvard Medical School, Boston, USA
| | - Norbert Perrimon
- Department of Genetics, Harvard Medical School, Boston, USA
- Howard Hughes Medical Institute, Boston, USA
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Post Z, Manfready RA, Keshavarzian A. Overview of the Gut-Brain Axis: From Gut to Brain and Back Again. Semin Neurol 2023; 43:506-517. [PMID: 37562457 DOI: 10.1055/s-0043-1771464] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/12/2023]
Abstract
The gut-brain axis refers to a bidirectional communication pathway linking the gastrointestinal system to the central nervous system. The hardware of this multifaceted pathway takes many forms, at once structural (neurons, microglia, intestinal epithelial cell barrier), chemical (neurotransmitters, enteroendocrine hormones, bacterial metabolites), and cellular (immune signaling, inflammatory pathways). The gut-brain axis is exquisitely influenced by our environment, diet, and behaviors. Here, we will describe recent progress in understanding the gut-brain axis in neurological disease, using Parkinson's disease as a guide. We will see that each component of the gut-brain axis is heavily mediated by intestinal microbiota and learn how gut-brain communication can go awry in microbial dysbiosis.
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Affiliation(s)
- Zoë Post
- Division of Digestive Diseases and Nutrition, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois
| | - Richard A Manfready
- Division of Digestive Diseases and Nutrition, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, Illinois
- Departments of Physiology and Anatomy & Cell Biology, Rush University Medical Center, Chicago, Illinois
| | - Ali Keshavarzian
- Division of Digestive Diseases and Nutrition, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois
- Rush Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, Illinois
- Departments of Physiology and Anatomy & Cell Biology, Rush University Medical Center, Chicago, Illinois
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Villalobos J, Payne SC, Ward GM, Andrikopoulos S, Hyakumura T, MacIsaac RJ, Fallon JB. Stimulation parameters for directional vagus nerve stimulation. Bioelectron Med 2023; 9:16. [PMID: 37464423 DOI: 10.1186/s42234-023-00117-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 06/09/2023] [Indexed: 07/20/2023] Open
Abstract
BACKGROUND Autonomic nerve stimulation is used as a treatment for a growing number of diseases. We have previously demonstrated that application of efferent vagus nerve stimulation (eVNS) has promising glucose lowering effects in a rat model of type 2 diabetes. This paradigm combines high frequency pulsatile stimulation to block nerve activation in the afferent direction with low frequency stimulation to activate the efferent nerve section. In this study we explored the effects of the parameters for nerve blocking on the ability to inhibit nerve activation in the afferent direction. The overarching aim is to establish a blocking stimulation strategy that could be applied using commercially available implantable pulse generators used in the clinic. METHODS Male rats (n = 20) had the anterior abdominal vagus nerve implanted with a multi-electrode cuff. Evoked compound action potentials (ECAP) were recorded at the proximal end of the electrode cuff. The efficacy of high frequency stimulation to block the afferent ECAP was assessed by changes in the threshold and saturation level of the response. Blocking frequency and duty cycle of the blocking pulses were varied while maintaining a constant 4 mA current amplitude. RESULTS During application of blocking at lower frequencies (≤ 4 kHz), the ECAP threshold increased (ANOVA, p < 0.001) and saturation level decreased (p < 0.001). Application of higher duty cycles (> 70%) led to an increase in evoked neural response threshold (p < 0.001) and a decrease in saturation level (p < 0.001). During the application of a constant pulse width and frequency (1 or 1.6 kHz, > 70% duty cycle), the charge delivered per pulse had a significant influence on the magnitude of the block (ANOVA, p = 0.003), and was focal (< 2 mm range). CONCLUSIONS This study has determined the range of frequencies, duty cycles and currents of high frequency stimulation that generate an efficacious, focal axonal block of a predominantly C-fiber tract. These findings could have potential application for the treatment of type 2 diabetes.
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Affiliation(s)
- Joel Villalobos
- Bionics Institute, East Melbourne, Vic, Australia
- Department of Medical Bionics, University of Melbourne, Parkville, Vic, Australia
| | - Sophie C Payne
- Bionics Institute, East Melbourne, Vic, Australia
- Department of Medical Bionics, University of Melbourne, Parkville, Vic, Australia
| | - Glenn M Ward
- Bionics Institute, East Melbourne, Vic, Australia
- Department of Endocrinology and Diabetes, St Vincent's Hospital Melbourne, Fitzroy, Vic, Australia
- Department of Medicine, St Vincent's Hospital Melbourne, University of Melbourne, Fitzroy, Vic, Australia
| | - Sofianos Andrikopoulos
- Australian Centre for Accelerating Diabetes Innovations, University of Melbourne, Parkville, Australia
- Department of Medicine (Austin Health), University of Melbourne, Heidelberg, Vic, Australia
| | - Tomoko Hyakumura
- Bionics Institute, East Melbourne, Vic, Australia
- Department of Medical Bionics, University of Melbourne, Parkville, Vic, Australia
| | - Richard J MacIsaac
- Bionics Institute, East Melbourne, Vic, Australia
- Department of Endocrinology and Diabetes, St Vincent's Hospital Melbourne, Fitzroy, Vic, Australia
- Department of Medicine, St Vincent's Hospital Melbourne, University of Melbourne, Fitzroy, Vic, Australia
- Australian Centre for Accelerating Diabetes Innovations, University of Melbourne, Parkville, Australia
| | - James B Fallon
- Bionics Institute, East Melbourne, Vic, Australia.
- Department of Medical Bionics, University of Melbourne, Parkville, Vic, Australia.
- Australian Diabetes Society, Sydney, NSW, Australia.
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Nakamura Y, Matsumoto H, Wu CH, Fukaya D, Uni R, Hirakawa Y, Katagiri M, Yamada S, Ko T, Nomura S, Wada Y, Komuro I, Nangaku M, Inagi R, Inoue T. Alpha 7 nicotinic acetylcholine receptors signaling boosts cell-cell interactions in macrophages effecting anti-inflammatory and organ protection. Commun Biol 2023; 6:666. [PMID: 37353597 PMCID: PMC10290099 DOI: 10.1038/s42003-023-05051-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 06/16/2023] [Indexed: 06/25/2023] Open
Abstract
Activation of the cholinergic anti-inflammatory pathway (CAP) via vagus nerve stimulation has been shown to improve acute kidney injury in rodent models. While alpha 7 nicotinic acetylcholine receptor (α7nAChR) positive macrophages are thought to play a crucial role in this pathway, their in vivo significance has not been fully understood. In this study, we used macrophage-specific α7nAChR-deficient mice to confirm the direct activation of α7nAChRs in macrophages. Our findings indicate that the administration of GTS-21, an α7nAChR-specific agonist, protects injured kidneys in wild-type mice but not in macrophage-specific α7nAChR-deficient mice. To investigate the signal changes or cell reconstructions induced by α7nAChR activation in splenocytes, we conducted single-cell RNA-sequencing of the spleen. Ligand-receptor analysis revealed an increase in macrophage-macrophage interactions. Using macrophage-derived cell lines, we demonstrated that GTS-21 increases cell contact, and that the contact between macrophages receiving α7nAChR signals leads to a reduction in TNF-α. Our results suggest that α7nAChR signaling increases macrophage-macrophage interactions in the spleen and has a protective effect on the kidneys.
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Affiliation(s)
- Yasuna Nakamura
- Department of Physiology of Visceral Function and Body Fluid, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Hirotaka Matsumoto
- School of Information and Data Sciences, Nagasaki University, Nagasaki, Japan
| | - Chia-Hsien Wu
- Department of Physiology of Visceral Function and Body Fluid, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Daichi Fukaya
- Department of Nephrology, Saitama Medical University, Saitama, Japan
| | - Rie Uni
- Division of CKD pathophysiology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Yosuke Hirakawa
- Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Mikako Katagiri
- Department of Cardiovascular Medicine, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
| | - Shintaro Yamada
- Department of Cardiovascular Medicine, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Toshiyuki Ko
- Department of Cardiovascular Medicine, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Seitaro Nomura
- Department of Cardiovascular Medicine, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Youichiro Wada
- Isotope Science Center, The University of Tokyo, Tokyo, Japan
| | - Issei Komuro
- Department of Cardiovascular Medicine the University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Masaomi Nangaku
- Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Reiko Inagi
- Division of CKD pathophysiology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Tsuyoshi Inoue
- Department of Physiology of Visceral Function and Body Fluid, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
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27
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Matarazzo JV, Ajay EA, Payne SC, Trang EP, Thompson AC, Marroquin JB, Wise AK, Fallon JB, Richardson RT. Combined optogenetic and electrical stimulation of the sciatic nerve for selective control of sensory fibers. Front Neurosci 2023; 17:1190662. [PMID: 37360169 PMCID: PMC10285517 DOI: 10.3389/fnins.2023.1190662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 05/22/2023] [Indexed: 06/28/2023] Open
Abstract
Introduction Electrical stimulation offers a drug-free alternative for the treatment of many neurological conditions, such as chronic pain. However, it is not easy to selectively activate afferent or efferent fibers of mixed nerves, nor their functional subtypes. Optogenetics overcomes these issues by controlling activity selectively in genetically modified fibers, however the reliability of responses to light are poor compared to electrical stimulation and the high intensities of light required present considerable translational challenges. In this study we employed a combined protocol of optical and electrical stimulation to the sciatic nerve in an optogenetic mouse model to allow for better selectivity, efficiency, and safety to overcome fundamental limitations of electrical-only and optical-only stimulation. Methods The sciatic nerve was surgically exposed in anesthetized mice (n = 12) expressing the ChR2-H134R opsin via the parvalbumin promoter. A custom-made peripheral nerve cuff electrode and a 452 nm laser-coupled optical fiber were used to elicit neural activity utilizing optical-only, electrical-only, or combined stimulation. Activation thresholds for the individual and combined responses were measured. Results Optically evoked responses had a conduction velocity of 34.3 m/s, consistent with ChR2-H134R expression in proprioceptive and low-threshold mechanoreceptor (Aα/Aβ) fibers which was also confirmed via immunohistochemical methods. Combined stimulation, utilizing a 1 ms near-threshold light pulse followed by an electrical pulse 0.5 ms later, approximately halved the electrical threshold for activation (p = 0.006, n = 5) and resulted in a 5.5 dB increase in the Aα/Aβ hybrid response amplitude compared to the electrical-only response at equivalent electrical levels (p = 0.003, n = 6). As a result, there was a 3.25 dB increase in the therapeutic stimulation window between the Aα/Aβ fiber and myogenic thresholds (p = 0.008, n = 4). Discussion The results demonstrate that light can be used to prime the optogenetically modified neural population to reside near threshold, thereby selectively reducing the electrical threshold for neural activation in these fibers. This reduces the amount of light needed for activation for increased safety and reduces potential off-target effects by only stimulating the fibers of interest. Since Aα/Aβ fibers are potential targets for neuromodulation in chronic pain conditions, these findings could be used to develop effective strategies to selectively manipulate pain transmission pathways in the periphery.
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Affiliation(s)
| | - Elise A. Ajay
- Bionics Institute, East Melbourne, VIC, Australia
- Department of Engineering, University of Melbourne, Parkville, VIC, Australia
| | - Sophie C. Payne
- Bionics Institute, East Melbourne, VIC, Australia
- Medical Bionics Department, University of Melbourne, Fitzroy, VIC, Australia
| | - Ella P. Trang
- Bionics Institute, East Melbourne, VIC, Australia
- Medical Bionics Department, University of Melbourne, Fitzroy, VIC, Australia
| | - Alex C. Thompson
- Bionics Institute, East Melbourne, VIC, Australia
- Medical Bionics Department, University of Melbourne, Fitzroy, VIC, Australia
| | | | - Andrew K. Wise
- Bionics Institute, East Melbourne, VIC, Australia
- Medical Bionics Department, University of Melbourne, Fitzroy, VIC, Australia
- Department of Surgery, University of Melbourne, Fitzroy, VIC, Australia
| | - James B. Fallon
- Bionics Institute, East Melbourne, VIC, Australia
- Medical Bionics Department, University of Melbourne, Fitzroy, VIC, Australia
- Department of Surgery, University of Melbourne, Fitzroy, VIC, Australia
| | - Rachael T. Richardson
- Bionics Institute, East Melbourne, VIC, Australia
- Medical Bionics Department, University of Melbourne, Fitzroy, VIC, Australia
- Department of Surgery, University of Melbourne, Fitzroy, VIC, Australia
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28
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Steins H, Mierzejewski M, Brauns L, Stumpf A, Kohler A, Heusel G, Corna A, Herrmann T, Jones PD, Zeck G, von Metzen R, Stieglitz T. A flexible protruding microelectrode array for neural interfacing in bioelectronic medicine. MICROSYSTEMS & NANOENGINEERING 2022; 8:131. [PMID: 36568135 PMCID: PMC9772315 DOI: 10.1038/s41378-022-00466-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 06/23/2022] [Accepted: 07/07/2022] [Indexed: 05/31/2023]
Abstract
Recording neural signals from delicate autonomic nerves is a challenging task that requires the development of a low-invasive neural interface with highly selective, micrometer-sized electrodes. This paper reports on the development of a three-dimensional (3D) protruding thin-film microelectrode array (MEA), which is intended to be used for recording low-amplitude neural signals from pelvic nervous structures by penetrating the nerves transversely to reduce the distance to the axons. Cylindrical gold pillars (Ø 20 or 50 µm, ~60 µm height) were fabricated on a micromachined polyimide substrate in an electroplating process. Their sidewalls were insulated with parylene C, and their tips were optionally modified by wet etching and/or the application of a titanium nitride (TiN) coating. The microelectrodes modified by these combined techniques exhibited low impedances (~7 kΩ at 1 kHz for Ø 50 µm microelectrode with the exposed surface area of ~5000 µm²) and low intrinsic noise levels. Their functionalities were evaluated in an ex vivo pilot study with mouse retinae, in which spontaneous neuronal spikes were recorded with amplitudes of up to 66 µV. This novel process strategy for fabricating flexible, 3D neural interfaces with low-impedance microelectrodes has the potential to selectively record neural signals from not only delicate structures such as retinal cells but also autonomic nerves with improved signal quality to study neural circuits and develop stimulation strategies in bioelectronic medicine, e.g., for the control of vital digestive functions.
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Affiliation(s)
- Helen Steins
- NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany
- Laboratory for Biomedical Microtechnology, Department of Microsystems Engineering, University of Freiburg, Freiburg, Germany
| | - Michael Mierzejewski
- NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany
| | - Lisa Brauns
- NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany
| | - Angelika Stumpf
- NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany
| | - Alina Kohler
- NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany
| | - Gerhard Heusel
- NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany
| | - Andrea Corna
- NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany
- Institute of Biomedical Electronics, TU Wien, Vienna, Austria
| | - Thoralf Herrmann
- NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany
| | - Peter D. Jones
- NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany
| | - Günther Zeck
- NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany
- Institute of Biomedical Electronics, TU Wien, Vienna, Austria
| | - Rene von Metzen
- NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany
| | - Thomas Stieglitz
- Laboratory for Biomedical Microtechnology, Department of Microsystems Engineering, University of Freiburg, Freiburg, Germany
- Bernstein Center Freiburg, University of Freiburg, Freiburg, Germany
- BrainLinks-BrainTools, University of Freiburg, Freiburg, Germany
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Noninvasive Vagus Nerve Stimulation in the Treatment of Methamphetamine Use Disorder: A Review Article. IRANIAN JOURNAL OF PSYCHIATRY AND BEHAVIORAL SCIENCES 2022. [DOI: 10.5812/ijpbs-123423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
: Methamphetamine (MA) use and the mortality it causes are increasing worldwide. The neurobiological mechanisms underlying the destructive effects of MA use are complex; however, there is much evidence that MA induces the dysfunction of monoaminergic transmission and causes oxidative stress, neuroinflammation, gliosis, and apoptosis. These toxic effects are associated with cardiotoxicity and neurotoxicity and with an imbalance in the autonomic nervous system, which altogether manifest themselves in clinical symptoms, such as neuropsychiatric disorders and cardiovascular diseases. There is no approved treatment for methamphetamine use disorder (MUD) despite all efforts made to date. The behavioral and pharmacological approaches currently used for the treatment of MUD are not completely effective. In this study, it is hypothesized that the stimulation of the vagus nerve and biological pathways underlying the processes of this stimulation might be effective as adjunctive therapy. Despite the potential effects of vagus nerve stimulation (VNS) to improve MUD, no study has yet examined the clinical potential effects of VNS in patients with the disorder. Therefore, further studies, including experimental and clinical trials, are needed to examine the effects of VNS on MUD.
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Payne SC, Romas E, Hyakumura T, Muntz F, Fallon JB. Abdominal vagus nerve stimulation alleviates collagen-induced arthritis in rats. Front Neurosci 2022; 16:1012133. [PMID: 36478876 PMCID: PMC9721112 DOI: 10.3389/fnins.2022.1012133] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 10/31/2022] [Indexed: 09/10/2024] Open
Abstract
Rheumatoid arthritis (RA) is a chronic, autoimmune inflammatory disease. Despite therapeutic advances, a significant proportion of RA patients are resistant to pharmacological treatment. Stimulation of the cervical vagus nerve is a promising alternative bioelectric neuromodulation therapeutic approach. However, recent clinical trials show cervical vagus nerve stimulation (VNS) was not effective in a significant proportion of drug resistant RA patients. Here we aim to assess if abdominal vagus nerve stimulation reduces disease severity in a collagen-induced arthritis (CIA) rat model. The abdominal vagus nerve of female Dark Agouti rats was implanted and CIA induced using collagen type II injection. VNS (1.6 mA, 200 μs pulse width, 50 μs interphase gap, 27 Hz frequency) was applied to awake freely moving rats for 3 h/day (days 11-17). At 17 days following the collagen injection, unstimulated CIA rats (n = 8) had significantly worse disease activity index, tumor necrosis factor-alpha (TNF-α) and receptor activator of NFκB ligand (RANKL) levels, synovitis and cartilage damage than normal rats (n = 8, Kruskal-Wallis: P < 0.05). However, stimulated CIA rats (n = 5-6) had significantly decreased inflammatory scores and ankle swelling (Kruskal-Wallis: P < 0.05) compared to unstimulated CIA rats (n = 8). Levels of tumor necrosis factor-alpha (TNF-α) remained at undetectable levels in stimulated CIA rats while levels of receptor activator of NFκB ligand (RANKL) were significantly less in stimulated CIA rats compared to unstimulated CIA rats (P < 0.05). Histopathological score of inflammation and cartilage loss in stimulated CIA rats were no different from that of normal (P > 0.05). In conclusion, abdominal VNS alleviates CIA and could be a promising therapy for patients with RA.
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Affiliation(s)
- Sophie C. Payne
- Bionics Institute, East Melbourne, VIC, Australia
- Medical Bionics Department, University of Melbourne, Parkville, VIC, Australia
| | - Evange Romas
- Bionics Institute, East Melbourne, VIC, Australia
- Department of Rheumatology, St. Vincent’s Hospital Melbourne, Fitzroy, VIC, Australia
| | - Tomoko Hyakumura
- Bionics Institute, East Melbourne, VIC, Australia
- Medical Bionics Department, University of Melbourne, Parkville, VIC, Australia
| | - Fenella Muntz
- Experimental Sciences Medical Unit, St. Vincent’s Hospital Melbourne, Fitzroy, VIC, Australia
| | - James B. Fallon
- Bionics Institute, East Melbourne, VIC, Australia
- Medical Bionics Department, University of Melbourne, Parkville, VIC, Australia
- Department of Otolaryngology, University of Melbourne, Parkville, VIC, Australia
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31
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Moesch M, Usemann J, Bruder E, Romero P, Schwab C, Niesler B, Tapia-Laliena MA, Khasanov R, Nisar T, Holland-Cunz S, Keck S. Associations of Mucosal Nerve Fiber Innervation Density with Hirschsprung-Associated Enterocolitis: A Retrospective Three-Center Cohort Study. Eur J Pediatr Surg 2022. [PMID: 35777734 DOI: 10.1055/a-1889-6355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
OBJECTIVE Hirschsprung's disease (HSCR) is a congenital intestinal neurodevelopmental disorder characterized by the absence of enteric ganglion cells in the distal colon. Although Hirschsprung-associated enterocolitis (HAEC) is the most frequent life-threatening complication in HSCR, to date reliable biomarkers predicting the likelihood of HAEC are yet to be established. We established a three-center retrospective study including 104 HSCR patients surgically treated between 1998 and 2019. MATERIALS AND METHODS Patient-derived cryopreserved or paraffin-preserved colonic tissue at surgery was analyzed via βIII-tubulin immunohistochemistry. We subsequently determined extrinsic mucosal nerve fiber density in resected rectosigmoid specimens and classified HSCR patients accordingly into nerve fiber-high or fiber-low groups. We compared the distribution of clinical parameters obtained from medical records between the fiber-high (n = 36) and fiber-low (n = 68) patient groups. We assessed the association between fiber phenotype and enterocolitis using univariate and multivariate logistic regression adjusted for age at operation. RESULTS Enterocolitis was more prevalent in patients with sparse mucosal nerve fiber innervation (fiber-low phenotype, 87%) compared with the fiber-high phenotype (13%; p = 0.002). In addition, patients developing enterocolitis had a younger age at surgery (3 vs. 7 months; p = 0.016). In the univariate analysis, the odds for enterocolitis development in the fiber-low phenotype was 5.26 (95% confidence interval [CI], 1.67-16.59; p = 0.005) and 4.01 (95% CI, 1.22-13.17; p = 0.022) when adjusted for age. CONCLUSION Here, we showed that HSCR patients with a low mucosal nerve fiber innervation grade in the distal aganglionic colon have a higher risk of developing HAEC. Consequently, histopathologic analysis of the nerve fiber innervation grade could serve as a novel sensitive prognostic marker associated with the development of enterocolitis in HSCR patients.
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Affiliation(s)
- Michèle Moesch
- Department of Pediatric Surgery, University Children's Hospital Basel, Basel, BS, Switzerland
| | - Jakob Usemann
- Department of Pediatric Pulmonology, UKBB Ringgold Standard Institution, Basel, BS, Switzerland
| | - Elisabeth Bruder
- Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
| | - Philipp Romero
- Division of Pediatric Surgery, University of Heidelberg, Heidelberg, Baden-Württemberg, Germany
| | - Constantin Schwab
- Institute of Pathology, University Hospital Heidelberg Institute of Pathology Ringgold Standard Institution, Heidelberg, Baden-Württemberg, Germany
| | - Beate Niesler
- Department of Human Molecular Genetics, University Hospital Heidelberg Institute of Human Genetics Ringgold Standard Institution, Heidelberg, Baden-Württemberg, Germany
| | | | - Rasul Khasanov
- Department of Pediatric Surgery, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Tauseef Nisar
- Department of Pediatric Surgery, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | | | - Stefan Holland-Cunz
- Department of Pediatric Surgery, University Children's Hospital Basel, Basel, BS, Switzerland
| | - Simone Keck
- Department of Pediatric Surgery, University Children's Hospital Basel, Basel, BS, Switzerland
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Ge L, Liu S, Li S, Yang J, Hu G, Xu C, Song W. Psychological stress in inflammatory bowel disease: Psychoneuroimmunological insights into bidirectional gut–brain communications. Front Immunol 2022; 13:1016578. [PMID: 36275694 PMCID: PMC9583867 DOI: 10.3389/fimmu.2022.1016578] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 09/20/2022] [Indexed: 11/13/2022] Open
Abstract
Inflammatory bowel disease (IBD), mainly including ulcerative colitis (UC) and Crohn’s disease (CD), is an autoimmune gastrointestinal disease characterized by chronic inflammation and frequent recurrence. Accumulating evidence has confirmed that chronic psychological stress is considered to trigger IBD deterioration and relapse. Moreover, studies have demonstrated that patients with IBD have a higher risk of developing symptoms of anxiety and depression than healthy individuals. However, the underlying mechanism of the link between psychological stress and IBD remains poorly understood. This review used a psychoneuroimmunology perspective to assess possible neuro-visceral integration, immune modulation, and crucial intestinal microbiome changes in IBD. Furthermore, the bidirectionality of the brain–gut axis was emphasized in the context, indicating that IBD pathophysiology increases the inflammatory response in the central nervous system and further contributes to anxiety- and depression-like behavioral comorbidities. This information will help accurately characterize the link between psychological stress and IBD disease activity. Additionally, the clinical application of functional brain imaging, microbiota-targeted treatment, psychotherapy and antidepressants should be considered during the treatment and diagnosis of IBD with behavioral comorbidities. This review elucidates the significance of more high-quality research combined with large clinical sample sizes and multiple diagnostic methods and psychotherapy, which may help to achieve personalized therapeutic strategies for IBD patients based on stress relief.
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Affiliation(s)
- Li Ge
- Shandong Provincial Key Laboratory for Rheumatic Disease and Translational Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
- School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Shuman Liu
- School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Sha Li
- School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Jing Yang
- Department of Gastroenterology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Guangran Hu
- School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Changqing Xu
- Department of Gastroenterology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Wengang Song
- Shandong Provincial Key Laboratory for Rheumatic Disease and Translational Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
- School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
- *Correspondence: Wengang Song,
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Fornaro R, Actis GC, Caviglia GP, Pitoni D, Ribaldone DG. Inflammatory Bowel Disease: Role of Vagus Nerve Stimulation. J Clin Med 2022; 11:5690. [PMID: 36233558 PMCID: PMC9572047 DOI: 10.3390/jcm11195690] [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: 08/16/2022] [Revised: 09/19/2022] [Accepted: 09/24/2022] [Indexed: 11/19/2022] Open
Abstract
Vagus nerve stimulation (VNS) is an accepted therapy for the treatment of refractory forms of epilepsy and depression. The brain-gut axis is increasingly being studied as a possible etiological factor of chronic inflammatory diseases, including inflammatory bowel diseases (IBD). A significant percentage of IBD patients lose response to treatments or experience side effects. In this perspective, VNS has shown the first efficacy data. The aim of this narrative review is to underline the biological plausibility of the use of VNS in patients affected by IBD, collect all clinical data in the literature, and hypothesize a target IBD population on which to focus the next clinical study.
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Affiliation(s)
- Riccardo Fornaro
- Department of Neurosurgery, University Hospital “Maggiore Della Carità”, 28100 Novara, Italy
| | | | - Gian Paolo Caviglia
- Department of Medical Sciences, Division of Gastroenterology, University of Torino, 10126 Torino, Italy
| | - Demis Pitoni
- Department of Medical Sciences, Division of Gastroenterology, University of Torino, 10126 Torino, Italy
| | - Davide Giuseppe Ribaldone
- Department of Medical Sciences, Division of Gastroenterology, University of Torino, 10126 Torino, Italy
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34
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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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35
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Brinkman DJ, Simon T, Ten Hove AS, Zafeiropoulou K, Welting O, van Hamersveld PHP, Willemze RA, Yim AYFL, Verseijden C, Hakvoort TBM, Luyer MD, Vervoordeldonk MJ, Blancou P, de Jonge WJ. Electrical stimulation of the splenic nerve bundle ameliorates dextran sulfate sodium-induced colitis in mice. J Neuroinflammation 2022; 19:155. [PMID: 35715845 PMCID: PMC9204975 DOI: 10.1186/s12974-022-02504-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 06/01/2022] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND Vagus nerve stimulation has been suggested to affect immune responses, partly through a neuronal circuit requiring sympathetic innervation of the splenic nerve bundle and norepinephrine (NE) release. Molecular and cellular mechanisms of action remain elusive. Here, we investigated the therapeutic value of this neuromodulation in inflammatory bowel disease (IBD) by applying electrical splenic nerve bundle stimulation (SpNS) in mice with dextran sulfate sodium (DSS)-induced colitis. METHODS Cuff electrodes were implanted around the splenic nerve bundle in mice, whereupon mice received SpNS or sham stimulation. Stimulation was applied 6 times daily for 12 days during DSS-induced colitis. Colonic and splenic tissues were collected for transcriptional analyses by qPCR and RNA-sequencing (RNA-seq). In addition, murine and human splenocytes were stimulated with lipopolysaccharide (LPS) in the absence or presence of NE. Single-cell RNA-seq data from publicly available data sets were analyzed for expression of β-adrenergic receptors (β-ARs). RESULTS Colitic mice undergoing SpNS displayed reduced colon weight/length ratios and showed improved Disease Activity Index scores with reduced Tumor Necrosis Factor α mRNA expression in the colon compared with sham stimulated mice. Analyses of splenocytes from SpNS mice using RNA-seq demonstrated specific immune metabolism transcriptome profile changes in myeloid cells. Splenocytes showed expression of β-ARs in myeloid and T cells. Cytokine production was reduced by NE in mouse and human LPS-stimulated splenocytes. CONCLUSIONS Together, our results demonstrate that SpNS reduces clinical features of colonic inflammation in mice with DSS-induced colitis possibly by inhibiting splenic myeloid cell activation. Our data further support exploration of the clinical use of SpNS for patients with IBD.
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Affiliation(s)
- David J Brinkman
- Tytgat Institute for Liver and Intestinal Research, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Room S2-162, Meibergdreef 69, 1105 BK, Amsterdam, The Netherlands.
- Department of Surgery, Catharina Hospital, Eindhoven, The Netherlands.
| | - Thomas Simon
- Institut de Pharmacologie Moléculaire et Cellulaire, Université Côte d'Azur, CNRS, Nice, France
| | - Anne S Ten Hove
- Tytgat Institute for Liver and Intestinal Research, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Room S2-162, Meibergdreef 69, 1105 BK, Amsterdam, The Netherlands
| | - Konstantina Zafeiropoulou
- Tytgat Institute for Liver and Intestinal Research, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Room S2-162, Meibergdreef 69, 1105 BK, Amsterdam, The Netherlands
- Department of Pediatric Surgery, Emma Children's Hospital, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
| | - Olaf Welting
- Tytgat Institute for Liver and Intestinal Research, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Room S2-162, Meibergdreef 69, 1105 BK, Amsterdam, The Netherlands
| | - Patricia H P van Hamersveld
- Tytgat Institute for Liver and Intestinal Research, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Room S2-162, Meibergdreef 69, 1105 BK, Amsterdam, The Netherlands
| | - Rose A Willemze
- Tytgat Institute for Liver and Intestinal Research, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Room S2-162, Meibergdreef 69, 1105 BK, Amsterdam, The Netherlands
| | - Andrew Y F Li Yim
- Tytgat Institute for Liver and Intestinal Research, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Room S2-162, Meibergdreef 69, 1105 BK, Amsterdam, The Netherlands
- Department of Clinical Genetics, Genome Diagnostics Laboratory, Amsterdam Reproduction and Development, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Caroline Verseijden
- Tytgat Institute for Liver and Intestinal Research, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Room S2-162, Meibergdreef 69, 1105 BK, Amsterdam, The Netherlands
| | - Theodorus B M Hakvoort
- Tytgat Institute for Liver and Intestinal Research, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Room S2-162, Meibergdreef 69, 1105 BK, Amsterdam, The Netherlands
| | - Misha D Luyer
- Department of Surgery, Catharina Hospital, Eindhoven, The Netherlands
| | - Margriet J Vervoordeldonk
- Tytgat Institute for Liver and Intestinal Research, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Room S2-162, Meibergdreef 69, 1105 BK, Amsterdam, The Netherlands
- Galvani Bioelectronics, Stevenage, UK
| | - Philippe Blancou
- Institut de Pharmacologie Moléculaire et Cellulaire, Université Côte d'Azur, CNRS, Nice, France
| | - Wouter J de Jonge
- Tytgat Institute for Liver and Intestinal Research, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Room S2-162, Meibergdreef 69, 1105 BK, Amsterdam, The Netherlands
- Department of Surgery, University of Bonn, Bonn, Germany
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36
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Abstract
Complementary and alternative medicine (CAM) is a growing entity within inflammatory bowel disease (IBD). CAM includes mind-based therapies, body-based therapies, supplements, vitamins, and probiotics. Limitations currently exist for health care providers as it pertains to IBD and CAM that stem from knowledge gaps, conflicting reports, limited oversight, and a lack of well-organized clinical data. Even without well-described data, patients are turning to these forms of therapy at increasing rates. It is imperative that the ongoing review of CAM therapies is performed, and future trials are performed to better understand efficacy as well as adverse effects related to these therapies.
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37
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Ahmed U, Chang YC, Zafeiropoulos S, Nassrallah Z, Miller L, Zanos S. Strategies for precision vagus neuromodulation. Bioelectron Med 2022; 8:9. [PMID: 35637543 PMCID: PMC9150383 DOI: 10.1186/s42234-022-00091-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 05/05/2022] [Indexed: 12/21/2022] Open
Abstract
The vagus nerve is involved in the autonomic regulation of physiological homeostasis, through vast innervation of cervical, thoracic and abdominal visceral organs. Stimulation of the vagus with bioelectronic devices represents a therapeutic opportunity for several disorders implicating the autonomic nervous system and affecting different organs. During clinical translation, vagus stimulation therapies may benefit from a precision medicine approach, in which stimulation accommodates individual variability due to nerve anatomy, nerve-electrode interface or disease state and aims at eliciting therapeutic effects in targeted organs, while minimally affecting non-targeted organs. In this review, we discuss the anatomical and physiological basis for precision neuromodulation of the vagus at the level of nerve fibers, fascicles, branches and innervated organs. We then discuss different strategies for precision vagus neuromodulation, including fascicle- or fiber-selective cervical vagus nerve stimulation, stimulation of vagal branches near the end-organs, and ultrasound stimulation of vagus terminals at the end-organs themselves. Finally, we summarize targets for vagus neuromodulation in neurological, cardiovascular and gastrointestinal disorders and suggest potential precision neuromodulation strategies that could form the basis for effective and safe therapies.
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Affiliation(s)
- Umair Ahmed
- Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, New York, USA
| | - Yao-Chuan Chang
- Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, New York, USA
| | - Stefanos Zafeiropoulos
- Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, New York, USA
| | - Zeinab Nassrallah
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, USA
| | - Larry Miller
- Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, New York, USA
| | - Stavros Zanos
- Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, New York, USA.
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, USA.
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38
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Payne SC, Ward G, Fallon JB, Hyakumura T, Prins JB, Andrikopoulos S, MacIsaac RJ, Villalobos J. Blood glucose modulation and safety of efferent vagus nerve stimulation in a type 2 diabetic rat model. Physiol Rep 2022; 10:e15257. [PMID: 35439355 PMCID: PMC9017977 DOI: 10.14814/phy2.15257] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 03/16/2022] [Accepted: 03/17/2022] [Indexed: 12/21/2022] Open
Abstract
Vagus nerve stimulation is emerging as a promising treatment for type 2 diabetes. Here, we evaluated the ability of stimulation of the vagus nerve to reduce glycemia in awake, freely moving metabolically compromised rats. A model of type 2 diabetes (n = 10) was induced using a high‐fat diet and low doses of streptozotocin. Stimulation of the abdominal vagus nerve was achieved by pairing 15 Hz pulses on a distal pair of electrodes with high‐frequency blocking stimulation (26 kHz, 4 mA) on a proximal pair of electrodes to preferentially produce efferent conducting activity (eVNS). Stimulation was well tolerated in awake, freely moving rats. During 1 h of eVNS, glycemia decreased in 90% of subjects (−1.25 ± 1.25 mM h, p = 0.017), and 2 dB above neural threshold was established as the most effective “dose” of eVNS (p = 0.009). Following 5 weeks of implantation, eVNS was still effective, resulting in significantly decreased glycemia (−1.7 ± 0.6 mM h, p = 0.003) during 1 h of eVNS. There were no overt changes in fascicle area or signs of histopathological damage observed in implanted vagal nerve tissue following chronic implantation and stimulation. Demonstration of the biocompatibility and safety of eVNS in awake, metabolically compromised animals is a critical first step to establishing this therapy for clinical use. With further development, eVNS could be a promising novel therapy for treating type 2 diabetes.
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Affiliation(s)
- Sophie C Payne
- Bionics Institute, East Melbourne, Victoria, Australia.,Department of Medical Bionics, University of Melbourne, Parkville, Victoria, Australia
| | - Glenn Ward
- Bionics Institute, East Melbourne, Victoria, Australia.,Department of Endocrinology and Diabetes, St Vincent's Hospital Melbourne, Fitzroy, Victoria, Australia.,Melbourne Medical School, University of Melbourne, Parkville, Victoria, Australia
| | - James B Fallon
- Bionics Institute, East Melbourne, Victoria, Australia.,Department of Medical Bionics, University of Melbourne, Parkville, Victoria, Australia
| | - Tomoko Hyakumura
- Bionics Institute, East Melbourne, Victoria, Australia.,Department of Medical Bionics, University of Melbourne, Parkville, Victoria, Australia
| | - Johannes B Prins
- Melbourne Medical School, University of Melbourne, Parkville, Victoria, Australia.,Department of Endocrinology, Royal Melbourne Hospital, Parkville, Victoria, Australia.,Australian Centre for Accelerating Diabetes Innovations, University of Melbourne, Melbourne, Australia
| | - Sofianos Andrikopoulos
- Australian Centre for Accelerating Diabetes Innovations, University of Melbourne, Melbourne, Australia.,Department of Medicine (Austin Health), University of Melbourne, Heidelberg, Victoria, Australia
| | - Richard J MacIsaac
- Bionics Institute, East Melbourne, Victoria, Australia.,Department of Endocrinology and Diabetes, St Vincent's Hospital Melbourne, Fitzroy, Victoria, Australia.,Melbourne Medical School, University of Melbourne, Parkville, Victoria, Australia.,Australian Centre for Accelerating Diabetes Innovations, University of Melbourne, Melbourne, Australia
| | - Joel Villalobos
- Bionics Institute, East Melbourne, Victoria, Australia.,Department of Medical Bionics, University of Melbourne, Parkville, Victoria, Australia
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Khodadadi F, Ketabchi F, Khodabandeh Z, Tavassoli A, Lewis GF, Bahaoddini A. The effect of subdiaphragmatic vagotomy on heart rate variability and lung inflammation in rats with severe hemorrhagic shock. BMC Cardiovasc Disord 2022; 22:181. [PMID: 35439928 PMCID: PMC9020113 DOI: 10.1186/s12872-022-02594-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 03/28/2022] [Indexed: 11/10/2022] Open
Abstract
Background The influence of cutting the sub-diaphragmatic branch of the vagus nerve on heart rate variability (HRV) and inflammatory reaction to severe hemorrhagic shock has not been determined prior to this study. Methods Male Sprague–Dawley rats were divided into four groups of Sham, sub-diaphragmatic vagotomized (Vag), subacute (135 ± 2 min) hemorrhagic shock (SHS), and sub-diaphragmatic vagotomized with SHS (Vag + SHS). Hemodynamic parameters were recorded and HRV calculated during multiple phases in a conscious model of hemorrhagic shock. The expressions of TNF-α and iNOS were measured in the spleen and lung tissues at the conclusion of the protocol. Results Decreases in blood pressure during blood withdrawal were identical in the SHS and Vag + SHS groups. However, heart rate only decreased in the Nadir-1 phase of the SHS group. HRV indicated increased power in the very-low, low, and high (VLF, LF, and HF) frequency bands during the Nadir-1 phase of the SHS and Vag + SHS groups, albeit the values were higher in the SHS group. In the recovery phase, the HF bands were only lower in the SHS group. After hemorrhagic shock followed by resuscitation, the expression of TNF-α and iNOS increased in the spleen and lung of the SHS group, and the expression of these genes was significantly lower in the Vag + SHS group than in the SHS group. Conclusion Parasympathetic activity increases during the hypotensive phase of hemorrhagic shock, whereas the cardiac vagal tone decreases in the recovery phase. Sub-diapragmatic vagotomy blunts the cardiac vagal tone during hemorrhagic shock, but its effect is reversed in the recovery phase. The vagus nerve plays a role in proinflammatory responses in the lungs and spleen in subacute hemorrhagic shock followed by resuscitation.
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Affiliation(s)
- Fateme Khodadadi
- Department of Biology, College of Sciences, Shiraz University, Shiraz, Iran
| | - Farzaneh Ketabchi
- Department of Physiology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Khodabandeh
- Stem Cell Technology Research Center, Shiraz University of Medical Science, Shiraz, Iran
| | - Alireza Tavassoli
- Department of Pathology, Fasa University of Medical Sciences, Fasa, Iran
| | - Gregory F Lewis
- Intelligent Systems Engineering, Indiana University, Bloomington, IN, USA.,The Traumatic Stress Research Consortium at the Kinsey Institute, Indiana University, Bloomington, IN, USA
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40
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Müller I, Kym U, Galati V, Tharakan S, Subotic U, Krebs T, Stathopoulos E, Schmittenbecher P, Cholewa D, Romero P, Reingruber B, Holland-Cunz S, Keck S. Cholinergic Signaling Attenuates Pro-Inflammatory Interleukin-8 Response in Colonic Epithelial Cells. Front Immunol 2022; 12:781147. [PMID: 35069554 PMCID: PMC8770536 DOI: 10.3389/fimmu.2021.781147] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 12/14/2021] [Indexed: 12/20/2022] Open
Abstract
Infants affected by Hirschsprung disease (HSCR), a neurodevelopmental congenital disorder, lack ganglia of the intrinsic enteric nervous system (aganglionosis) in a variable length of the colon, and are prone to developing severe Hirschsprung-associated enterocolitis (HAEC). HSCR patients typically show abnormal dense innervation of extrinsic cholinergic nerve fibers throughout the aganglionic rectosigmoid. Cholinergic signaling has been reported to reduce inflammatory response. Consequently, a sparse extrinsic cholinergic innervation in the mucosa of the rectosigmoid correlates with increased inflammatory immune cell frequencies and higher incidence of HAEC in HSCR patients. However, whether cholinergic signals influence the pro-inflammatory immune response of intestinal epithelial cells (IEC) is unknown. Here, we analyzed colonic IEC isolated from 43 HSCR patients with either a low or high mucosal cholinergic innervation density (fiber-low versus fiber-high) as well as from control tissue. Compared to fiber-high samples, IEC purified from fiber-low rectosigmoid expressed significantly higher levels of IL-8 but not TNF-α, IL-10, TGF-β1, Muc-2 or tight junction proteins. IEC from fiber-low rectosigmoid showed higher IL-8 protein concentrations in cell lysates as well as prominent IL-8 immunoreactivity compared to IEC from fiber-high tissue. Using the human colonic IEC cell line SW480 we demonstrated that cholinergic signals suppress lipopolysaccharide-induced IL-8 secretion via the alpha 7 nicotinic acetylcholine receptor (a7nAChR). In conclusion, we showed for the first time that the presence of a dense mucosal cholinergic innervation is associated with decreased secretion of IEC-derived pro-inflammatory IL-8 in the rectosigmoid of HSCR patients likely dependent on a7nAChR activation. Owing to the association between IL-8 and enterocolitis-prone, fiber-low HSCR patients, targeted therapies against IL-8 might be a promising immunotherapy candidate for HAEC treatment.
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Affiliation(s)
- Isabelle Müller
- Department of Pediatric Surgery, University Children's Hospital Basel (UKBB) and University of Basel, Basel, Switzerland
| | - Urs Kym
- Department of Pediatric Surgery, University Children's Hospital Basel (UKBB) and University of Basel, Basel, Switzerland
| | - Virginie Galati
- Department of Pediatric Surgery, University Children's Hospital Basel (UKBB) and University of Basel, Basel, Switzerland
| | - Sasha Tharakan
- Department of Pediatric Surgery, University Children's Hospital Zürich, Zürich, Switzerland
| | - Ulrike Subotic
- Department of Pediatric Surgery, University Children's Hospital Basel (UKBB) and University of Basel, Basel, Switzerland.,Department of Pediatric Surgery, University Children's Hospital Zürich, Zürich, Switzerland
| | - Thomas Krebs
- Department of Pediatric Surgery, Children's Hospital of Eastern Switzerland, St. Gallen, Switzerland
| | - Eleuthere Stathopoulos
- Department of Pediatric Surgery, University Hospital of Lausanne (CHUV), Lausanne, Switzerland
| | | | - Dietmar Cholewa
- Department of Pediatric Surgery, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Philipp Romero
- Department of Pediatric Surgery, University Hospital of Heidelberg, Heidelberg, Germany
| | - Bertram Reingruber
- Department of Pediatric Surgery, Florence Nightingale Hospital, Düsseldorf, Germany
| | | | - Stefan Holland-Cunz
- Department of Pediatric Surgery, University Children's Hospital Basel (UKBB) and University of Basel, Basel, Switzerland
| | - Simone Keck
- Department of Pediatric Surgery, University Children's Hospital Basel (UKBB) and University of Basel, Basel, Switzerland
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41
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Matisz C, Gruber A. Neuroinflammatory remodeling of the anterior cingulate cortex as a key driver of mood disorders in gastrointestinal disease and disorders. Neurosci Biobehav Rev 2022; 133:104497. [DOI: 10.1016/j.neubiorev.2021.12.020] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 11/10/2021] [Accepted: 12/09/2021] [Indexed: 02/08/2023]
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Falvey A, Metz CN, Tracey KJ, Pavlov VA. Peripheral nerve stimulation and immunity: the expanding opportunities for providing mechanistic insight and therapeutic intervention. Int Immunol 2022; 34:107-118. [PMID: 34498051 PMCID: PMC8783605 DOI: 10.1093/intimm/dxab068] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Accepted: 09/07/2021] [Indexed: 12/29/2022] Open
Abstract
Pre-clinical research advances our understanding of the vagus nerve-mediated regulation of immunity and clinical trials successfully utilize electrical vagus nerve stimulation in the treatment of patients with inflammatory disorders. This symbiotic relationship between pre-clinical and clinical research exploring the vagus nerve-based 'inflammatory reflex' has substantially contributed to establishing the field of bioelectronic medicine. Recent studies identify a crosstalk between the vagus nerve and other neural circuitries in controlling inflammation and delineate new neural immunoregulatory pathways. Here we outline current mechanistic insights into the role of vagal and non-vagal neural pathways in neuro-immune communication and inflammatory regulation. We also provide a timely overview of expanding opportunities for bioelectronic neuromodulation in the treatment of various inflammatory disorders.
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Affiliation(s)
- Aidan Falvey
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA
| | - Christine N Metz
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA
| | - Kevin J Tracey
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA
| | - Valentin A Pavlov
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA
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43
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Tynan A, Brines M, Chavan SS. Control of inflammation using non-invasive neuromodulation: past, present and promise. Int Immunol 2022; 34:119-128. [PMID: 34558623 PMCID: PMC8783606 DOI: 10.1093/intimm/dxab073] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 09/20/2021] [Indexed: 12/14/2022] Open
Abstract
The nervous system has been increasingly recognized as a novel and accessible target in the regulation of inflammation. The use of implantable and invasive devices targeting neural circuits has yielded successful results in clinical settings but does have some risk or adverse effects. Recent advances in technology and understanding of mechanistic pathways have opened new avenues of non-invasive neuromodulation. Through this review we discuss the novel research and outcomes of major modalities of non-invasive neuromodulation in the context of inflammation including transcutaneous electrical, magnetic and ultrasound neuromodulation. In addition to highlighting the scientific observations and breakthroughs, we discuss the underlying mechanisms and pathways for neural regulation of inflammation.
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Affiliation(s)
- Aisling Tynan
- Laboratory of Biomedical Science, Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell Health, 350 Community Drive, Manhasset, NY, USA
| | - Michael Brines
- Laboratory of Biomedical Science, Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell Health, 350 Community Drive, Manhasset, NY, USA
| | - Sangeeta S Chavan
- Laboratory of Biomedical Science, Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell Health, 350 Community Drive, Manhasset, NY, USA
- Elmezzi Graduate School of Molecular Medicine, 350 Community Drive, Manhasset, NY, USA
- Donald and Barbara Zucker School of Medicine at Hofstra University, Hempstead, NY, USA
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44
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Abstract
The brain and gastrointestinal tract are critical sensory organs responsible for detecting, relaying, integrating, and responding to signals derived from the internal and external environment. At the interface of this sensory function, immune cells in the intestines and brain consistently survey environmental factors, eliciting responses that inform on the physiological state of the body. Recent research reveals that cross-talk along the gut-brain axis regulates inflammatory nociception, inflammatory responses, and immune homeostasis. Here, we discuss molecular and cellular mechanisms involved in the signaling of inflammation across the gut-brain axis. We further highlight interactions between the gut and the brain in inflammation-associated diseases.
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Affiliation(s)
- Gulistan Agirman
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Kristie B Yu
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Elaine Y Hsiao
- Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
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45
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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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46
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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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47
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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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48
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Moraes RN, Laske TG, Leimgruber P, Stabach JA, Marinari PE, Horning MM, Laske NR, Rodriguez JV, Eye GN, Kordell JE, Gonzalez M, Eyring T, Lemons C, Helmick KE, Delaski KM, Ware LH, Jones JC, Songsasen N. Inside out: heart rate monitoring to advance the welfare and conservation of maned wolves ( Chrysocyon brachyurus). CONSERVATION PHYSIOLOGY 2021; 9:coab044. [PMID: 34188936 PMCID: PMC8224209 DOI: 10.1093/conphys/coab044] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 02/12/2021] [Accepted: 05/18/2021] [Indexed: 06/13/2023]
Abstract
Anthropogenic change is a major threat to individual species and biodiversity. Yet the behavioral and physiological responses of animals to these changes remain understudied. This is due to the technological challenges in assessing these effects in situ. Using captive maned wolves (Chrysocyon brachyurus, n = 6) as a model, we deployed implantable biologgers and collected physiological data on heart rate (HR) and heart rate variability (HRV) over a 1-year period. To test for links between HR and changes in the environment we analysed HR daily rhythms and responses to potential stressors (e.g. physical restraint, change in housing conditions, short-distance transportation and unfamiliar human presence). The 2-min HR averages ranged from 33 to 250 bpm, with an overall rest average of 73 bpm and a maximum of 296 bpm. On average, HRV was higher in females (227 ± 51 ms) than in males (151 ± 51 ms). As expected, HR increased at dusk and night when animals were more active and in response to stressors. Sudden decreases in HR were observed during transportation in three wolves, suggestive of fear bradycardia. We provide the first non-anesthetic HR values for the species and confirm that behaviour does not always reflect the shifts in autonomic tone in response to perceived threats. Because strong HR responses often were not revealed by observable changes in behaviour, our findings suggest that the number and variety of stressors in ex situ or in situ environments for maned wolves and most wildlife species may be underestimated. Our study also shows that integrating biologging with behavioral observations can provide vital information to guide captive management. Similar technology can be used to advance in situ research for developing more effective welfare, management and conservation plans for the species.
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Affiliation(s)
- Rosana N Moraes
- Center for Species Survival, Smithsonian Conservation Biology Institute, Front Royal, VA, 22630, USA
- Department of Physiology, Federal University of Parana, Curitiba, PR, 81530-900, Brazil
| | - Timothy G Laske
- Department of Surgery, University of Minnesota, Minneapolis, MN, 55455, USA
- AF Solutions, Medtronic Inc., Mounds View, MN, 55112, USA
| | - Peter Leimgruber
- Conservation Ecology Center, Smithsonian Conservation Biology Institute, Front Royal, VA, 22630, USA
| | - Jared A Stabach
- Conservation Ecology Center, Smithsonian Conservation Biology Institute, Front Royal, VA, 22630, USA
| | - Paul E Marinari
- Center for Species Survival, Smithsonian Conservation Biology Institute, Front Royal, VA, 22630, USA
| | - Megan M Horning
- Center for Species Survival, Smithsonian Conservation Biology Institute, Front Royal, VA, 22630, USA
- Conservation Ecology Center, Smithsonian Conservation Biology Institute, Front Royal, VA, 22630, USA
| | - Noelle R Laske
- Center for Species Survival, Smithsonian Conservation Biology Institute, Front Royal, VA, 22630, USA
| | - Juan V Rodriguez
- Center for Species Survival, Smithsonian Conservation Biology Institute, Front Royal, VA, 22630, USA
- Department of Parks and Recreation, Maryland-National Capital Park and Planning commission, Clinton, MD, 20735, USA
| | - Ginger N Eye
- Center for Species Survival, Smithsonian Conservation Biology Institute, Front Royal, VA, 22630, USA
| | - Jessica E Kordell
- Center for Species Survival, Smithsonian Conservation Biology Institute, Front Royal, VA, 22630, USA
| | - Marissa Gonzalez
- Center for Species Survival, Smithsonian Conservation Biology Institute, Front Royal, VA, 22630, USA
| | - Tom Eyring
- Center for Species Survival, Smithsonian Conservation Biology Institute, Front Royal, VA, 22630, USA
| | - Christopher Lemons
- Center for Species Survival, Smithsonian Conservation Biology Institute, Front Royal, VA, 22630, USA
| | - Kelly E Helmick
- Department of Conservation Medicine, Smithsonian Conservation Biology Institute, Front Royal, VA, 22630, USA
| | - Kristina M Delaski
- Department of Conservation Medicine, Smithsonian Conservation Biology Institute, Front Royal, VA, 22630, USA
| | - Lisa H Ware
- Department of Conservation Medicine, Smithsonian Conservation Biology Institute, Front Royal, VA, 22630, USA
| | - Julia C Jones
- Department of Conservation Medicine, Smithsonian Conservation Biology Institute, Front Royal, VA, 22630, USA
| | - Nucharin Songsasen
- Center for Species Survival, Smithsonian Conservation Biology Institute, Front Royal, VA, 22630, USA
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49
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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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50
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Sokal DM, McSloy A, Donegà M, Kirk J, Colas RA, Dolezalova N, Gomez EA, Gupta I, Fjordbakk CT, Ouchouche S, Matteucci PB, Schlegel K, Bashirullah R, Werling D, Harman K, Rowles A, Yazicioglu RF, Dalli J, Chew DJ, Perkins JD. Splenic Nerve Neuromodulation Reduces Inflammation and Promotes Resolution in Chronically Implanted Pigs. Front Immunol 2021; 12:649786. [PMID: 33859641 PMCID: PMC8043071 DOI: 10.3389/fimmu.2021.649786] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 03/11/2021] [Indexed: 11/28/2022] Open
Abstract
Neuromodulation of the immune system has been proposed as a novel therapeutic strategy for the treatment of inflammatory conditions. We recently demonstrated that stimulation of near-organ autonomic nerves to the spleen can be harnessed to modulate the inflammatory response in an anesthetized pig model. The development of neuromodulation therapy for the clinic requires chronic efficacy and safety testing in a large animal model. This manuscript describes the effects of longitudinal conscious splenic nerve neuromodulation in chronically-implanted pigs. Firstly, clinically-relevant stimulation parameters were refined to efficiently activate the splenic nerve while reducing changes in cardiovascular parameters. Subsequently, pigs were implanted with a circumferential cuff electrode around the splenic neurovascular bundle connected to an implantable pulse generator, using a minimally-invasive laparoscopic procedure. Tolerability of stimulation was demonstrated in freely-behaving pigs using the refined stimulation parameters. Longitudinal stimulation significantly reduced circulating tumor necrosis factor alpha levels induced by systemic endotoxemia. This effect was accompanied by reduced peripheral monocytopenia as well as a lower systemic accumulation of CD16+CD14high pro-inflammatory monocytes. Further, lipid mediator profiling analysis demonstrated an increased concentration of specialized pro-resolving mediators in peripheral plasma of stimulated animals, with a concomitant reduction of pro-inflammatory eicosanoids including prostaglandins. Terminal electrophysiological and physiological measurements and histopathological assessment demonstrated integrity of the splenic nerves up to 70 days post implantation. These chronic translational experiments demonstrate that daily splenic nerve neuromodulation, via implanted electronics and clinically-relevant stimulation parameters, is well tolerated and is able to prime the immune system toward a less inflammatory, pro-resolving phenotype.
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Affiliation(s)
- David M. Sokal
- Translation and Engineering, Galvani Bioelectronics, Stevenage, United Kingdom
| | - Alex McSloy
- Clinical Science & Services, The Royal Veterinary College, Hatfield, United Kingdom
| | - Matteo Donegà
- Translation and Engineering, Galvani Bioelectronics, Stevenage, United Kingdom
| | - Joseph Kirk
- Clinical Science & Services, The Royal Veterinary College, Hatfield, United Kingdom
| | - Romain A. Colas
- Centre for Inflammation and Therapeutic Innovation, Queen Mary University of London, London, United Kingdom
| | - Nikola Dolezalova
- Department of Surgery, University of Cambridge, Cambridge, United Kingdom
| | - Esteban A. Gomez
- Centre for Inflammation and Therapeutic Innovation, Queen Mary University of London, London, United Kingdom
| | - Isha Gupta
- Translation and Engineering, Galvani Bioelectronics, Stevenage, United Kingdom
| | | | - Sebastien Ouchouche
- Translation and Engineering, Galvani Bioelectronics, Stevenage, United Kingdom
| | - Paul B. Matteucci
- Translation and Engineering, Galvani Bioelectronics, Stevenage, United Kingdom
| | - Kristina Schlegel
- Translation and Engineering, Galvani Bioelectronics, Stevenage, United Kingdom
| | - Rizwan Bashirullah
- Translation and Engineering, Galvani Bioelectronics, Stevenage, United Kingdom
| | - Dirk Werling
- Department of Pathobiology and Population Sciences, Royal Veterinary College, Hatfield, United Kingdom
| | - Kim Harman
- Clinical Science & Services, The Royal Veterinary College, Hatfield, United Kingdom
| | - Alison Rowles
- Non-Clinical Safety, GlaxoSmithKline, Ware, United Kingdom
| | | | - Jesmond Dalli
- Centre for Inflammation and Therapeutic Innovation, Queen Mary University of London, London, United Kingdom
| | - Daniel J. Chew
- Translation and Engineering, Galvani Bioelectronics, Stevenage, United Kingdom
| | - Justin D. Perkins
- Clinical Science & Services, The Royal Veterinary College, Hatfield, United Kingdom
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