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Eslami M, Raji-Amirhasani A, Khaksari M, Keshavarzi Z, Rostamzadeh F, Sabet N, Jafari E, Soltani Z, Karamouzian S. The changes of digestive system inflammatory, oxidative stress, and histopathology factors following oral mesenchymal stem cells administration in rats with traumatic brain injury. BMC Neurosci 2025; 26:20. [PMID: 40050727 PMCID: PMC11884162 DOI: 10.1186/s12868-025-00936-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Accepted: 02/10/2025] [Indexed: 03/10/2025] Open
Abstract
BACKGROUND AND AIMS Mucous mesenchymal stem cells can migrate to damaged areas, and their use is proposed as a new approach to treating diseases. The present study aimed to investigate the effect of oral mesenchymal stem cells (OMSCs) on inflammatory, oxidative stress, and histopathological indices in the tissues of the stomach, intestine, and colon after traumatic brain injury (TBI). METHODS AND MATERIALS Adult male rats were randomly divided into four groups: Sham, TBI, Vehicle (Veh), and Stem cell (SC). Intravenous injection of OMSCs was performed at 1 and 24 h after injury. The inflammatory, oxidative stress, and histopathological indices of the tissues of the stomach, small intestine, and colon were evaluated 48 h after injury. RESULTS After TBI, IL-1β and IL-6 levels increased and IL-10 levels decreased in the tissues of the stomach, small intestine, and colon, but the administration of OMSCS prevented these changes to a large extent. Oxidative stress indices (MDA, PC, TAC, SOD, and CAT) showed an increase in oxidative stress after TBI, but oxidative stress was less severe in the OMSC group. The administration of OMSCs after TBI improved the histopathological outcome in the tissues of the stomach, small intestine, and colon. CONCLUSION Administration of OMSCs in rats suffering from TBI can improve inflammatory, oxidative stress, and histopathological indices in the tissues of the stomach, small intestine, and colon, which shows the beneficial effect of using OMSCs in TBI.
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Affiliation(s)
- Masoud Eslami
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Alireza Raji-Amirhasani
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Mohammad Khaksari
- Endocrinology and Metabolism Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Zakieh Keshavarzi
- Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Farzaneh Rostamzadeh
- Cardiovascular Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Nazanin Sabet
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Elham Jafari
- Pathology and Stem Cells Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Zahra Soltani
- Endocrinology and Metabolism Research Center, Kerman University of Medical Sciences, Kerman, Iran.
| | - Saeed Karamouzian
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.
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Zamudio-Flores J, Cerqueda D, Phillips-Farfán B, Guerrero-Flores S, Salinas-García AF, Meléndez-Herrera E, Sélem-Mojica N, Kline AE, Lajud N. Environmental enrichment-induced cognitive recovery after a moderate pediatric traumatic brain injury is associated with the gut microbiota and neuroinflammation. Exp Neurol 2025; 385:115109. [PMID: 39662794 DOI: 10.1016/j.expneurol.2024.115109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 11/11/2024] [Accepted: 12/04/2024] [Indexed: 12/13/2024]
Abstract
Pediatric traumatic brain injury (TBI) is a significant health concern, yet access to rehabilitation therapies for children remains limited. Environmental enrichment (EE) is a preclinical model of neurorehabilitation that promotes behavioral recovery and reduces neuroinflammation after TBI. While the gut microbiota has recently emerged as a potential therapeutic target for treating TBI sequelae in adults, its role in recovery after pediatric TBI remains unclear. Therefore, our aim was to assess the effect of EE on gut microbiota and its correlation with cognition as well as microglial morphology in a preclinical model of pediatric TBI. Male rats underwent a controlled cortical impact of moderate severity or sham injury at postnatal day 21 and were then randomly assigned to either EE or standard (STD) housing. Cognition was evaluated using the Morris water maze (MWM) on post-injury days 14-19. Microglial morphology and caecum microbiota was characterized on post-injury day 21. Cognitive deficits and increased microglial activation in the ipsilateral cortex were observed in the STD-housed TBI rats but not those in EE. TBI decreased microbiota α-diversity, while PERMANOVA analysis showed that both TBI and EE modified microbiota β-diversity. Furthermore, regression models indicated that microglial morphology in the ipsilateral cortex and Lactobacillus reuteri predicted behavioral outcomes, while Prevotellaceae NK3B31 was associated with microglial morphology. The data suggest that EE mitigates TBI-induced alterations in gut microbiota and that there is a complex interplay between EE, microbiota and microglial morphology that predicts behavioral recovery in pediatric rats.
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Affiliation(s)
- Jonathan Zamudio-Flores
- División de Neurociencias, Centro de Investigación Biomédica de Michoacán - Instituto Mexicano del Seguro Social, Morelia, Michoacán, Mexico; Instituto de Investigaciones sobre los Recursos Naturales - Universidad Michoacana de San Nicolás de Hidalgo, Morelia, Michoacán, Mexico
| | - Daniel Cerqueda
- Red de Manejo Biorracional de Plagas y Vectores, Instituto de Ecología, A. C., Xalapa, Mexico
| | | | | | - Ana Fernanda Salinas-García
- División de Neurociencias, Centro de Investigación Biomédica de Michoacán - Instituto Mexicano del Seguro Social, Morelia, Michoacán, Mexico; Instituto de Investigaciones sobre los Recursos Naturales - Universidad Michoacana de San Nicolás de Hidalgo, Morelia, Michoacán, Mexico
| | - Esperanza Meléndez-Herrera
- Instituto de Investigaciones sobre los Recursos Naturales - Universidad Michoacana de San Nicolás de Hidalgo, Morelia, Michoacán, Mexico
| | - Nelly Sélem-Mojica
- Centro de Ciencias Matemáticas, Universidad Nacional Autónoma de, Mexico
| | - Anthony E Kline
- Physical Medicine & Rehabilitation, University of Pittsburgh, Pittsburgh, PA, United States of America; Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, United States of America; Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, United States of America; Center for the Neural Basis of Cognition, University of Pittsburgh, Pittsburgh, PA, United States of America; Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, United States of America; Psychology, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Naima Lajud
- División de Neurociencias, Centro de Investigación Biomédica de Michoacán - Instituto Mexicano del Seguro Social, Morelia, Michoacán, Mexico.
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Evanson NK, Veldhi P, Scherpenberg C, Riccobono JM, Eid H, McGuire JL. Extracranial Effects of Traumatic Brain Injury: A Narrative Review. Clin Pract 2025; 15:47. [PMID: 40136583 PMCID: PMC11941004 DOI: 10.3390/clinpract15030047] [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: 01/31/2025] [Revised: 02/21/2025] [Accepted: 02/23/2025] [Indexed: 03/27/2025] Open
Abstract
BACKGROUND Traumatic brain injury (TBI) is often associated with other injuries and comorbidities. However, even isolated TBI directly leads to dysfunction in multiple body systems outside the central nervous system. These extracranial effects of TBI target systems including the autonomic nervous, cardiovascular, renal, pulmonary, immune, gastrointestinal, and hemostasis systems, as well as causing significant alteration to systemic metabolism. AIM This review is intended to outline the effects of TBI on other body systems, and place these in context with treatment considerations for these patients. SIGNIFICANCE Systemic effects of TBI have implications for acute and critical care management of patients with TBI, including pharmacologic treatment. They also affect treatment decisions in chronic TBI care, as well as TBI-unrelated routine medical care for patients with chronic TBI. In addition, extracranial effects of TBI should be considered in research settings. CONCLUSIONS It is important for clinicians and researchers to be aware of these extracranial effects, and consider their effects on pathology, treatment decisions, and interpretation of research findings.
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Affiliation(s)
- Nathan K. Evanson
- Division of Pediatric Rehabilitation Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
- Department of Pediatrics, University of Cincinnati, Cincinnati, OH 45267, USA
- Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Pratyusha Veldhi
- Kentucky College of Osteopathic Medicine, University of Pikeville, Pikeville, KY 41501, USA
| | - Caitlyn Scherpenberg
- Division of Pediatric Rehabilitation Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
| | - John M. Riccobono
- Division of Pediatric Rehabilitation Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Haitham Eid
- Medical Sciences Program, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Jennifer L. McGuire
- Department of Neurosurgery, University of Cincinnati, Cincinnati, OH 45267, USA
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Dixon CT, Yang P, McCall K. Traumatic injury leads to ovarian cell death and reproductive disturbances in Drosophila melanogaster. Biol Open 2025; 14:BIO061825. [PMID: 39957518 PMCID: PMC11892359 DOI: 10.1242/bio.061825] [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: 11/15/2024] [Accepted: 01/29/2025] [Indexed: 02/18/2025] Open
Abstract
Traumatic injury (TI), or global blunt force trauma, can arise from many sources such as car crashes, sports and intimate partner violence. Effects from these injuries impact the whole organism and can lead to many different pathologies, such as inflammation, neurodegeneration, gut dysbiosis, and female reproductive detriments. Drosophila melanogaster has recently emerged as a powerful model to study traumatic injuries due to their high conservation of physiological effects post-trauma and the genetic toolset that they leverage. Previously, we reported female-specific reproductive deficits post mild TI in Drosophila. Here we investigate the effects of more severe trauma on females and found an increased retention of mature eggs and decrease in egg laying. Additionally, severe trauma led to an increase of midstage egg chamber death and formation of melanization, a known marker of immune activation. These studies provide a valuable invertebrate model to understand disturbances to female reproduction post-trauma.
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Affiliation(s)
- Cameron T. Dixon
- Department of Biology,Boston University, Boston, MA 02215, USA
- Molecular Biology, Cell Biology and Biochemistry Program, Boston University, Boston, MA 02215, USA
| | - Pamela Yang
- Department of Biology,Boston University, Boston, MA 02215, USA
| | - Kimberly McCall
- Department of Biology,Boston University, Boston, MA 02215, USA
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5
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Mao Y, Li F, Shen L, Huang C. Construction and validation of a prediction nomogram model for acute gastrointestinal failure in patients with severe traumatic brain injury. Medicine (Baltimore) 2025; 104:e41423. [PMID: 39928796 PMCID: PMC11812995 DOI: 10.1097/md.0000000000041423] [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: 03/22/2024] [Revised: 01/11/2025] [Accepted: 01/15/2025] [Indexed: 02/12/2025] Open
Abstract
This study aims to establish and validate the prediction model of acute gastrointestinal failure (AGF) in patients with severe traumatic brain injury. A total of 665 inpatients from Shaoxing People's Hospital from January 2018 to January 2024 were admitted and randomly divided into training group (466 cases) and validation group (199 cases). Data were collected by general situation questionnaire and AGF assessment tool. According to the results of multivariate logistic regression analysis, the prediction nomogram model was established with R software. Bootstrap method was used for internal verification of the model, and verification group was used for external verification. The area under receiver operating characteristic (ROC) curve, Hosmer-Lemeshow test and calibration curves were used to evaluate the differentiation and calibration degree of the model. Multivariate Logistic regression analysis showed that pulmonary infection, hypoxemia, glasgow coma scale (GCS) score ≤ 8 on admission, hyponatremia and metabolic acidosis were independent risk factors for AGF in patients with severe traumatic brain injury (P < .05). On this basis, a new prediction model was constructed, as follows: logit P = -4.998 + 0.858 × pulmonary infection + 0.923 × hypoxemia + 1.488 × GCS score ≤ 8 + 1.274 × hyponatremia + 1.020 × metabolic acidosis. The area under ROC of the new model was 0.787 (95% CI: 0.831-0.909), and the cutoff point was 0.4589. The sensitivity and specificity of the model were 69.74% and 76.15%, respectively. Hosmer-Lemeshow goodness of fit test showed that the prediction model had a good fitting effect (χ2 = 4.828, P = .681). External verification showed that the Hosmer-Lemeshow goodness of fit test showed that the prediction model had a good fitting effect (χ2 = 12.712, P = .122). Calibration curves showed the nomogram established fits well with the real data. The prediction model constructed in this study has good differentiation and calibration degree, which can intuitively and easily select high-risk patients, and provide reference for early screening and gastrointestinal nursing intervention.
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Affiliation(s)
- Yadi Mao
- Department of Neurosurgery, Shaoxing People’s Hospital, Zhongxinbei Road 568th, Yuecheng District, Shaoxing, Zhejiang, China
| | - Fei Li
- Department of Neurosurgery, Shaoxing People’s Hospital, Zhongxinbei Road 568th, Yuecheng District, Shaoxing, Zhejiang, China
| | - Lidi Shen
- Department of Neurosurgery, Shaoxing People’s Hospital, Zhongxinbei Road 568th, Yuecheng District, Shaoxing, Zhejiang, China
| | - Chunmin Huang
- Department of Neurosurgery, Shaoxing People’s Hospital, Zhongxinbei Road 568th, Yuecheng District, Shaoxing, Zhejiang, China
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Chen Y, Sun W, Mei H, Zhu S. Partially hydrolyzed guar gum alleviates neurological deficits and gastrointestinal dysfunction in mice with traumatic brain injury. Neurosurg Rev 2025; 48:103. [PMID: 39883194 DOI: 10.1007/s10143-024-03161-x] [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: 10/31/2024] [Revised: 12/06/2024] [Accepted: 12/23/2024] [Indexed: 01/31/2025]
Abstract
Traumatic brain injury (TBI)-associated neuroinflammation and neurotoxicity can induce gastrointestinal dysfunction through the brain-gut axis. Partially hydrolyzed guar gum (PHGG) was demonstrated to exert beneficial health effects by altering gut microbiota and short-chain fatty acids (SCFAs) production. Our study aimed to explore the effects of PHGG on gastrointestinal dysfunction in TBI mouse models. Controlled cortical impact (CCI)-induced TBI mouse models were administrated with PHGG (600 mg/kg/d) for 21 consecutive days. Behavioral tests (modified neurological severity score and beam walk test) and Y‑maze assay were performed to evaluate neurological functions and cognitive impairment. Enzyme-linked immunosorbent assay, reverse transcription-quantitative polymerase chain reaction, and western blotting examined the levels of inflammatory cytokines, intestinal mucosal damage markers, intestinal tight junction proteins, and NLRP3 inflammasome-related molecules in the serum, cerebral cortex, and colon tissues. The histological changes in the cerebral cortex and colon tissues were observed through hematoxylin and eosin and Nissl staining. Liquid chromatography/mass spectrometry analyzed SCFA amounts in the cecum contents and bile acid levels in the serum. PHGG administration alleviated neurological deficits and cognitive perturbations, reduced neuroinflammation, and attenuated cortical tissue damage and neuron loss in TBI mice. PHGG ameliorated intestinal barrier impairment, upregulated intestinal production of SCFAs, and elevated serum bile acid levels in TBI mice. Besides, PHGG treatment repressed NLRP3 inflammasome activation in TBI mice. Overexpressing NLRP3 reversed the beneficial effects of PHGG against TBI in mice. PHGG ameliorates neuroinflammation and gastrointestinal dysfunction in TBI murine models by inhibiting NLRP3 inflammasome activation.
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Affiliation(s)
- Yao Chen
- Department of Infection Control, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou, Jiangsu Province, 225300, China
| | - Wenbin Sun
- Department of Critical Care Medicine, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Zhou shan hui shui Community,199 Hailing South Road, Taizhou, Jiangsu Province, 225300, China
| | - Haifeng Mei
- Department of Critical Care Medicine, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Zhou shan hui shui Community,199 Hailing South Road, Taizhou, Jiangsu Province, 225300, China
| | - Shang Zhu
- Department of Critical Care Medicine, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Zhou shan hui shui Community,199 Hailing South Road, Taizhou, Jiangsu Province, 225300, China.
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7
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Wongsripuemtet P, Ohnuma T, Minic Z, Vavilala MS, Miller JB, Laskowitz DT, Meurer WJ, Hu X, Korley FK, Sheng H, Krishnamoorthy V. Early Autonomic Dysfunction in Traumatic Brain Injury: An Article Review on the Impact on Multiple Organ Dysfunction. J Clin Med 2025; 14:557. [PMID: 39860563 PMCID: PMC11765831 DOI: 10.3390/jcm14020557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Revised: 01/09/2025] [Accepted: 01/14/2025] [Indexed: 01/27/2025] Open
Abstract
Background/Objectives: Traumatic brain injury (TBI) is a complex condition and a leading cause of injury-related disability and death, with significant impacts on patient outcomes. Extracranial organ involvement plays a critical role in the outcome of patients following TBI. Method: This review aims to provide a comprehensive overview of the pathophysiology, clinical presentation, and challenges in diagnosing patients with autonomic dysfunction after TBI. The databases used in this review include PubMed/MEDLINE, Cochrane Central Register, and Scopus. Results: Of 172 articles identified for screening, 98 were ultimately included in the review. Conclusion: This review summarized the current evidence on the pathophysiology, clinical presentation, and diagnosis of early autonomic dysfunction. It also emphasizes the effects of autonomic dysfunction on end-organ damage. These insights aim to guide clinicians and researchers toward improving the care for and understanding of autonomic dysfunction in TBI patients, while underscoring the need for further research in this area.
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Affiliation(s)
- Pattrapun Wongsripuemtet
- Critical Care and Perioperative Population Health Research (CAPER) Program, Department of Anesthesiology, Duke University, Durham, NC 27708, USA; (T.O.); (V.K.)
- Department of Anesthesiology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Tetsu Ohnuma
- Critical Care and Perioperative Population Health Research (CAPER) Program, Department of Anesthesiology, Duke University, Durham, NC 27708, USA; (T.O.); (V.K.)
- Departments of Anesthesiology, Duke University, Durham, NC 27708, USA;
| | - Zeljka Minic
- Department of Emergency Medicine, Wayne State University School of Medicine, Detroit, MI 48202, USA;
- Faculty of Biotechnology and Drug Development, University of Rijeka, 51000 Rijeka, Croatia
| | - Monica S. Vavilala
- Departments of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA 98109, USA;
| | - Joseph B. Miller
- Department of Emergency Medicine, Henry Ford Health System, Detroit, MI 48202, USA
| | | | - William J. Meurer
- Department of Emergency Medicine, University of Michigan, Ann Arbor, MI 48109, USA; (W.J.M.); (F.K.K.)
- Department of Emergency Neurology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Xiao Hu
- School of Nursing, Emory University, Atlanta, GA 30322, USA;
| | - Frederick K. Korley
- Department of Emergency Medicine, University of Michigan, Ann Arbor, MI 48109, USA; (W.J.M.); (F.K.K.)
- The Max Harry Weil Institute for Critical Care Research and Innovation, Ann Arbor, MI 48109, USA
| | - Huaxin Sheng
- Departments of Anesthesiology, Duke University, Durham, NC 27708, USA;
| | - Vijay Krishnamoorthy
- Critical Care and Perioperative Population Health Research (CAPER) Program, Department of Anesthesiology, Duke University, Durham, NC 27708, USA; (T.O.); (V.K.)
- Departments of Anesthesiology, Duke University, Durham, NC 27708, USA;
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8
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Mazarati A. Gut-microbiota-brain Axis and post-traumatic epilepsy. Epilepsia Open 2024. [PMID: 39688879 DOI: 10.1002/epi4.13113] [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: 10/04/2024] [Revised: 11/22/2024] [Accepted: 11/27/2024] [Indexed: 12/18/2024] Open
Abstract
There has been growing evidence that perturbations in gut-microbiota-brain axis (GMBA) are involved in mechanisms of chronic sequelae of traumatic brain injury (TBI). This review discusses the connection between GMBA and post-traumatic epilepsy (PTE), the latter being a common outcome of TBI. The focus is on two aspects of post-TBI GMBA dysfunction that are relevant to epilepsy. First are impairments in intestinal permeability with subsequent translocation of gut bacteria into the bloodstream. Specifically, endotoxemia following TBI may have a serendipitous protective effect against PTE through lipopolysaccharide conditioning, which may be leveraged for the development of therapeutic interventions. Second are changes in microbial composition (i.e., dysbiosis). Here, the GMBA-PTE connection is explored from predictive biomarker perspective, whereby the risk of PTE can be stratified based on specific microbial profiles. Finally, microbiota transplantation is discussed both as a tool to examine the role of gut microbiota in PTE and as a prelude to novel approaches for PTE therapy and prevention.
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Affiliation(s)
- Andrey Mazarati
- Department of Pediatrics and Children's Discovery and Innovation Institute, David Geffen School of Medicine at the University of California, Los Angeles, California, USA
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9
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Wu J, Ren R, Chen T, Su LD, Tang T. Neuroimmune and neuroinflammation response for traumatic brain injury. Brain Res Bull 2024; 217:111066. [PMID: 39241894 DOI: 10.1016/j.brainresbull.2024.111066] [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: 06/15/2024] [Revised: 08/18/2024] [Accepted: 09/02/2024] [Indexed: 09/09/2024]
Abstract
Traumatic brain injury (TBI) is one of the major diseases leading to mortality and disability, causing a serious disease burden on individuals' ordinary lives as well as socioeconomics. In primary injury, neuroimmune and neuroinflammation are both responsible for the TBI. Besides, extensive and sustained injury induced by neuroimmune and neuroinflammation also prolongs the course and worsens prognosis of TBI. Therefore, this review aims to explore the role of neuroimmune, neuroinflammation and factors associated them in TBI as well as the therapies for TBI. Thus, we conducted by searching PubMed, Scopus, and Web of Science databases for articles published between 2010 and 2023. Keywords included "traumatic brain injury," "neuroimmune response," "neuroinflammation," "astrocytes," "microglia," and "NLRP3." Articles were selected based on relevance and quality of evidence. On this basis, we provide the cellular and molecular mechanisms of TBI-induced both neuroimmune and neuroinflammation response, as well as the different factors affecting them, are introduced based on physiology of TBI, which supply a clear overview in TBI-induced chain-reacting, for a better understanding of TBI and to offer more thoughts on the future therapies for TBI.
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Affiliation(s)
- Junyun Wu
- Neuroscience Care Unit, Second Affiliated Hospital of Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, Zhejiang 310009, China
| | - Reng Ren
- Neuroscience Care Unit, Second Affiliated Hospital of Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, Zhejiang 310009, China
| | - Tao Chen
- Neuroscience Care Unit, Second Affiliated Hospital of Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, Zhejiang 310009, China
| | - Li-Da Su
- Neuroscience Care Unit, Second Affiliated Hospital of Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, Zhejiang 310009, China.
| | - Tianchi Tang
- Department of Neurosurgery, Second Affiliated Hospital of Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, Zhejiang 310009, China.
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10
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Pagkou D, Kogias E, Foroglou N, Kotzampassi K. Probiotics in Traumatic Brain Injury: New Insights into Mechanisms and Future Perspectives. J Clin Med 2024; 13:4546. [PMID: 39124812 PMCID: PMC11313054 DOI: 10.3390/jcm13154546] [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: 06/12/2024] [Revised: 07/19/2024] [Accepted: 07/30/2024] [Indexed: 08/12/2024] Open
Abstract
Traumatic brain injury (TBI) is a serious global public health issue, recognized as a chronic and progressive disease that can affect multiple organs, including the gastrointestinal (GI) tract. Research shows that there is a specific link between the GI tract and the central nervous system, termed the gut-brain axis, which consists of bidirectional exchange between these two. Several preclinical and clinical studies have demonstrated intestinal barrier dysfunction, intestinal inflammation and gut dysbiosis in patients with TBI. It is proven that probiotics can modulate the inflammatory process and modify gut microbiota. Numerous animal studies and human clinical trials have proven the effectiveness of selected bacterial strains as an adjuvant treatment in reducing inflammation, infection rates and time spent in intensive care of hospitalized patients suffering from brain injury. Thus, this review summarizes the current evidence regarding the beneficial effects of probiotic administration in patients suffering from TBI-related complications. This review will help identify novel therapeutic strategies in the future as probiotics have an extensive history of apparently safe use.
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Affiliation(s)
- Diamantoula Pagkou
- Department of Neurosurgery, AHEPA University Hospital, Aristotle University of Thessaloniki, Kiriakidi 1, 54636 Thessaloniki, Greece; (E.K.); (N.F.)
| | - Evangelos Kogias
- Department of Neurosurgery, AHEPA University Hospital, Aristotle University of Thessaloniki, Kiriakidi 1, 54636 Thessaloniki, Greece; (E.K.); (N.F.)
| | - Nikolaos Foroglou
- Department of Neurosurgery, AHEPA University Hospital, Aristotle University of Thessaloniki, Kiriakidi 1, 54636 Thessaloniki, Greece; (E.K.); (N.F.)
| | - Katerina Kotzampassi
- Department of Surgery, Aristotle University of Thessaloniki, Kiriakidi 1, 54636 Thessaloniki, Greece;
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11
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Guangliang H, Tao W, Danxin W, Lei L, Ye M. Critical Knowledge Gaps and Future Priorities Regarding the Intestinal Barrier Damage After Traumatic Brain Injury. World Neurosurg 2024; 188:136-149. [PMID: 38789030 DOI: 10.1016/j.wneu.2024.05.105] [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: 03/01/2024] [Revised: 05/16/2024] [Accepted: 05/17/2024] [Indexed: 05/26/2024]
Abstract
The analysis aims to provide a comprehensive understanding of the current landscape of research on the Intestinal barrier damage after traumatic brain injury (TBI), elucidate specific mechanisms, and address knowledge gaps to help guide the development of targeted therapeutic interventions and improve outcomes for individuals with TBI. A total of 2756 relevant publications by 13,778 authors affiliated within 3198 institutions in 79 countries were retrieved from the Web of Science. These publications have been indexed by 1139 journals and cited 158, 525 references. The most productive author in this field was Sikiric P, and the University of Pittsburgh was identified as the most influential institution. The United States was found to be the leading country in terms of article output and held a dominant position in this field. The International Journal of Molecular Sciences was identified as a major source of publications in this area. In terms of collaboration, the cooperation between the United States and China was found to be the most extensive among countries, institutions, and authors, indicating a high level of influence in this field. Keyword co-occurrence network analysis revealed several hotspots in this field, including the microbiome-gut-brain axis, endoplasmic reticulum stress, cellular autophagy, ischemia-reperfusion, tight junctions, and intestinal permeability. The analysis of keyword citation bursts suggested that ecological imbalance and gut microbiota may be the forefront of future research. The findings of this study can serve as a reference and guiding perspective for future research in this field.
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Affiliation(s)
- He Guangliang
- Hainan Vocational of Science and Technology, International School of Nursing, Haikou, China; HeJiang Affiliated Hospital of Southwest Medical University, Department of Respiratory and Critical Care Medicine, Luzhou, China
| | - Wang Tao
- Hainan Medical University, International School of Nursing, Haikou, China; Foshan University, Medical College, Guangdong, China
| | - Wang Danxin
- The First Affiliated Hospital of Hainan Medical University, Nursing Department, Haikou, China
| | - Liu Lei
- The First Affiliated Hospital of Hainan Medical University, Respiratory Medicine Department, Haikou, China
| | - Min Ye
- Hainan Vocational of Science and Technology, International School of Nursing, Haikou, China; Hainan Medical University, International School of Nursing, Haikou, China.
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12
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Rahman Z, Pasam T, Rishab, Dandekar MP. Binary classification model of machine learning detected altered gut integrity in controlled-cortical impact model of traumatic brain injury. Int J Neurosci 2024; 134:163-174. [PMID: 35758006 DOI: 10.1080/00207454.2022.2095271] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 06/23/2022] [Indexed: 10/17/2022]
Abstract
Aim of the study: To examine the effect of controlled-cortical impact (CCI), a preclinical model of traumatic brain injury (TBI), on intestinal integrity using a binary classification model of machine learning (ML).Materials and methods: Adult, male C57BL/6 mice were subjected to CCI surgery using a stereotaxic impactor (Impact One™). The rotarod and hot-plate tests were performed to assess the neurological deficits.Results: Mice underwent CCI displayed a remarkable neurological deficit as noticed by decreased latency to fall and lesser paw withdrawal latency in rotarod and hot plate test, respectively. Animals were sacrificed 3 days post-injury (dpi). The colon sections were stained with hematoxylin and eosin (H&E) to integrate with machinery tool-based algorithms. Several stained colon images were captured to build a dataset for ML model to predict the impact of CCI vs sham procedure. The best results were obtained with VGG16 features with SVM RBF kernel and VGG16 features with stacked fully connected layers on top. We achieved a test accuracy of 84% and predicted the disrupted gut permeability and epithelium wall of colon in CCI group as compared to sham-operated mice.Conclusion: We suggest that ML may become an important tool in the development of preclinical TBI model and discovery of newer therapeutics.
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Affiliation(s)
- Zara Rahman
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, India
| | - Tulasi Pasam
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, India
| | - Rishab
- Department of Computer Science and Engineering, International Institute of Information Technology (IIIT), Hyderabad, India
| | - Manoj P Dandekar
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, India
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13
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Smith AM, Challagundla L, McGee IG, Warfield ZJ, Santos CDSE, Garrett MR, Grayson BE. Temporal shifts to the gut microbiome associated with cognitive dysfunction following high-fat diet consumption in a juvenile model of traumatic brain injury. Physiol Genomics 2024; 56:301-316. [PMID: 38145288 PMCID: PMC11283908 DOI: 10.1152/physiolgenomics.00113.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 12/04/2023] [Accepted: 12/22/2023] [Indexed: 12/26/2023] Open
Abstract
The gut-brain axis interconnects the central nervous system (CNS) and the commensal bacteria of the gastrointestinal tract. The composition of the diet consumed by the host influences the richness of the microbial populations. Traumatic brain injury (TBI) produces profound neurocognitive damage, but it is unknown how diet influences the microbiome following TBI. The present work investigates the impact of a chow diet versus a 60% fat diet (HFD) on fecal microbiome populations in juvenile rats following TBI. Twenty-day-old male rats were placed on one of two diets for 9 days before sustaining either a Sham or TBI via the Closed Head Injury Model of Engineered Rotational Acceleration (CHIMERA). Fecal samples were collected at both 1- and 9-days postinjury. Animals were cognitively assessed in the novel object recognition tests at 8 days postinjury. Fecal microbiota DNA was isolated and sequenced. Twenty days of HFD feeding did not alter body weight, but fat mass was elevated in HFD compared with Chow rats. TBI animals had a greater percentage of entries to the novel object quadrant than Sham counterparts, P < 0.05. The Firmicutes/Bacteroidetes ratio was significantly higher in TBI than in the Sham, P < 0.05. Microbiota of the Firmicutes lineage exhibited perturbations by both injury and diet that were sustained at both time points. Linear regression analyses were performed to associate bacteria with metabolic and neurocognitive endpoints. For example, counts of Lachnospiraceae were negatively associated with percent entries into the novel object quadrant. Taken together, these data suggest that both diet and injury produce robust shifts in microbiota, which may have long-term implications for chronic health.NEW & NOTEWORTHY Traumatic brain injury (TBI) produces memory and learning difficulties. Diet profoundly influences the populations of gut microbiota. Following traumatic brain injury in a pediatric model consuming either a healthy or high-fat diet (HFD), significant shifts in bacterial populations occur, of which, some are associated with diet, whereas others are associated with neurocognitive performance. More work is needed to determine whether these microbes can therapeutically improve learning following trauma to the brain.
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Affiliation(s)
- Allie M Smith
- Department of Neurology, University of Mississippi Medical Center, Jackson, Mississippi, United States
| | - Lavanya Challagundla
- Department of Cell and Molecular Biology, University of Mississippi Medical Center, Jackson, Mississippi, United States
| | - Ian G McGee
- Department of Neurology, University of Mississippi Medical Center, Jackson, Mississippi, United States
| | - Zyra J Warfield
- Department of Neurology, University of Mississippi Medical Center, Jackson, Mississippi, United States
| | | | - Michael R Garrett
- Department of Cell and Molecular Biology, University of Mississippi Medical Center, Jackson, Mississippi, United States
| | - Bernadette E Grayson
- Department of Neurology, University of Mississippi Medical Center, Jackson, Mississippi, United States
- Department of Anesthesiology, University of Mississippi Medical Center, Jackson, Mississippi, United States
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14
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Yu J, Chen Y, Wang J, Wu H. Research progress on the relationship between traumatic brain injury and brain-gut-microbial axis. IBRAIN 2024; 10:477-487. [PMID: 39691426 PMCID: PMC11649388 DOI: 10.1002/ibra.12153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 03/12/2024] [Accepted: 03/14/2024] [Indexed: 12/19/2024]
Abstract
Traumatic brain injury (TBI) is a common disease with a high rate of death and disability, which poses a serious threat to human health; thus, the effective treatment of TBI has been a high priority. The brain-gut-microbial (BGM) axis, as a bidirectional communication network for information exchange between the brain and gut, plays a crucial role in neurological diseases. This article comprehensively explores the interrelationship between the BGM axis and TBI, including its physiological effects, basic pathophysiology, and potential therapeutic strategies. It highlights how the bidirectional regulatory pathways of the BGM axis could provide new insights into clinical TBI treatment and underscores the necessity for advanced research and development of innovative clinical treatments for TBI.
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Affiliation(s)
- Jie Yu
- Department of NeurosurgeryAffiliated Hospital of Zunyi Medical UniversityZunyiGuizhouChina
| | - Yun‐Xin Chen
- Department of NeurosurgeryAffiliated Hospital of Zunyi Medical UniversityZunyiGuizhouChina
| | - Jin‐Wei Wang
- Department of NeurosurgeryAffiliated Hospital of Zunyi Medical UniversityZunyiGuizhouChina
| | - Hai‐Tao Wu
- Department of NeurosurgeryAffiliated Hospital of Zunyi Medical UniversityZunyiGuizhouChina
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15
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Kakinuma Y. Non-neuronal cholinergic system in the heart influences its homeostasis and an extra-cardiac site, the blood-brain barrier. Front Cardiovasc Med 2024; 11:1384637. [PMID: 38601043 PMCID: PMC11004362 DOI: 10.3389/fcvm.2024.1384637] [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: 02/10/2024] [Accepted: 03/18/2024] [Indexed: 04/12/2024] Open
Abstract
The non-neuronal cholinergic system of the cardiovascular system has recently gained attention because of its origin. The final product of this system is acetylcholine (ACh) not derived from the parasympathetic nervous system but from cardiomyocytes, endothelial cells, and immune cells. Accordingly, it is defined as an ACh synthesis system by non-neuronal cells. This system plays a dispensable role in the heart and cardiomyocytes, which is confirmed by pharmacological and genetic studies using murine models, such as models with the deletion of vesicular ACh transporter gene and modulation of the choline acetyltransferase (ChAT) gene. In these models, this system sustained the physiological function of the heart, prevented the development of cardiac hypertrophy, and negatively regulated the cardiac metabolism and reactive oxygen species production, resulting in sustained cardiac homeostasis. Further, it regulated extra-cardiac organs, as revealed by heart-specific ChAT transgenic (hChAT tg) mice. They showed enhanced functions of the blood-brain barrier (BBB), indicating that the augmented system influences the BBB through the vagus nerve. Therefore, the non-neuronal cardiac cholinergic system indirectly influences brain function. This mini-review summarizes the critical cardiac phenotypes of hChAT tg mice and focuses on the effect of the system on BBB functions. We discuss the possibility that a cholinergic signal or vagus nerve influences the expression of BBB component proteins to consolidate the barrier, leading to the downregulation of inflammatory responses in the brain, and the modulation of cardiac dysfunction-related effects on the brain. This also discusses the possible interventions using the non-neuronal cardiac cholinergic system.
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Affiliation(s)
- Yoshihiko Kakinuma
- Department of Bioregulatory Science, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
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16
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Ziaka M, Exadaktylos A. Pathophysiology of acute lung injury in patients with acute brain injury: the triple-hit hypothesis. Crit Care 2024; 28:71. [PMID: 38454447 PMCID: PMC10918982 DOI: 10.1186/s13054-024-04855-w] [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: 02/24/2024] [Accepted: 03/01/2024] [Indexed: 03/09/2024] Open
Abstract
It has been convincingly demonstrated in recent years that isolated acute brain injury (ABI) may cause severe dysfunction of peripheral extracranial organs and systems. Of all potential target organs and systems, the lung appears to be the most vulnerable to damage after ABI. The pathophysiology of the bidirectional brain-lung interactions is multifactorial and involves inflammatory cascades, immune suppression, and dysfunction of the autonomic system. Indeed, the systemic effects of inflammatory mediators in patients with ABI create a systemic inflammatory environment ("first hit") that makes extracranial organs vulnerable to secondary procedures that enhance inflammation, such as mechanical ventilation (MV), surgery, and infections ("second hit"). Moreover, accumulating evidence supports the knowledge that gut microbiota constitutes a critical superorganism and an organ on its own, potentially modifying various physiological functions of the host. Furthermore, experimental and clinical data suggest the existence of a communication network among the brain, gastrointestinal tract, and its microbiome, which appears to regulate immune responses, gastrointestinal function, brain function, behavior, and stress responses, also named the "gut-microbiome-brain axis." Additionally, recent research evidence has highlighted a crucial interplay between the intestinal microbiota and the lungs, referred to as the "gut-lung axis," in which alterations during critical illness could result in bacterial translocation, sustained inflammation, lung injury, and pulmonary fibrosis. In the present work, we aimed to further elucidate the pathophysiology of acute lung injury (ALI) in patients with ABI by attempting to develop the "double-hit" theory, proposing the "triple-hit" hypothesis, focused on the influence of the gut-lung axis on the lung. Particularly, we propose, in addition to sympathetic hyperactivity, blast theory, and double-hit theory, that dysbiosis and intestinal dysfunction in the context of ABI alter the gut-lung axis, resulting in the development or further aggravation of existing ALI, which constitutes the "third hit."
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Affiliation(s)
- Mairi Ziaka
- Clinic for Geriatric Medicine, Center for Geriatric Medicine and Rehabilitation, Kantonsspital Baselland, Bruderholz, Switzerland.
- Department of Emergency Medicine, Inselspital, University Hospital, University of Bern, Bern, Switzerland.
| | - Aristomenis Exadaktylos
- Department of Emergency Medicine, Inselspital, University Hospital, University of Bern, Bern, Switzerland
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17
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DeSana AJ, Estus S, Barrett TA, Saatman KE. Acute gastrointestinal permeability after traumatic brain injury in mice precedes a bloom in Akkermansia muciniphila supported by intestinal hypoxia. Sci Rep 2024; 14:2990. [PMID: 38316862 PMCID: PMC10844296 DOI: 10.1038/s41598-024-53430-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 01/31/2024] [Indexed: 02/07/2024] Open
Abstract
Traumatic brain injury (TBI) increases gastrointestinal morbidity and associated mortality. Clinical and preclinical studies implicate gut dysbiosis as a consequence of TBI and an amplifier of brain damage. However, little is known about the association of gut dysbiosis with structural and functional changes of the gastrointestinal tract after an isolated TBI. To assess gastrointestinal dysfunction, mice received a controlled cortical impact or sham brain injury and intestinal permeability was assessed at 4 h, 8 h, 1 d, and 3 d after injury by oral administration of 4 kDa FITC Dextran prior to euthanasia. Quantification of serum fluorescence revealed an acute, short-lived increase in permeability 4 h after TBI. Despite transient intestinal dysfunction, no overt morphological changes were evident in the ileum or colon across timepoints from 4 h to 4 wks post-injury. To elucidate the timeline of microbiome changes after TBI, 16 s gene sequencing was performed on DNA extracted from fecal samples collected prior to and over the first month after TBI. Differential abundance analysis revealed that the phylum Verrucomicrobiota was increased at 1, 2, and 3 d after TBI. The Verrucomicrobiota species was identified by qPCR as Akkermansia muciniphila, an obligate anaerobe that resides in the intestinal mucus bilayer and produces short chain fatty acids (e.g. butyrate) utilized by intestinal epithelial cells. We postulated that TBI promotes intestinal changes favorable for the bloom of A. muciniphila. Consistent with this premise, the relative area of mucus-producing goblet cells in the medial colon was significantly increased at 1 d after injury, while colon hypoxia was significantly increased at 3 d. Our findings reveal acute gastrointestinal functional changes coupled with an increase of beneficial bacteria suggesting a potential compensatory response to systemic stress after TBI.
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Affiliation(s)
- Anthony J DeSana
- Department of Physiology, University of Kentucky, Biomedical and Biological Sciences Research Building (BBSRB), B473, 741 South Limestone St., Lexington, KY, 40536, USA
- Spinal Cord and Brain Injury Research Center, University of Kentucky, Biomedical and Biological Sciences Research Building (BBSRB), B473, 741 South Limestone St., Lexington, KY, 40536, USA
| | - Steven Estus
- Department of Physiology, University of Kentucky, Biomedical and Biological Sciences Research Building (BBSRB), B473, 741 South Limestone St., Lexington, KY, 40536, USA
- Sanders Brown Center on Aging, University of Kentucky, Lee T. Todd, Jr. Building, Rm: 537, 789 South Limestone St., Lexington, KY, 40536, USA
| | - Terrence A Barrett
- Division of Digestive Diseases and Nutrition, Department of Internal Medicine - Digestive Health, University of Kentucky, Lexington, KY, 40536, USA
- Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Medical Science Building, MN649, 780 Rose St., Lexington, KY, 40536, USA
| | - Kathryn E Saatman
- Department of Physiology, University of Kentucky, Biomedical and Biological Sciences Research Building (BBSRB), B473, 741 South Limestone St., Lexington, KY, 40536, USA.
- Spinal Cord and Brain Injury Research Center, University of Kentucky, Biomedical and Biological Sciences Research Building (BBSRB), B473, 741 South Limestone St., Lexington, KY, 40536, USA.
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18
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Guha L, Agnihotri TG, Jain A, Kumar H. Gut microbiota and traumatic central nervous system injuries: Insights into pathophysiology and therapeutic approaches. Life Sci 2023; 334:122193. [PMID: 37865177 DOI: 10.1016/j.lfs.2023.122193] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 10/12/2023] [Accepted: 10/18/2023] [Indexed: 10/23/2023]
Abstract
Traumatic brain injury and spinal cord injury are two distinct but fundamentally similar types of acute insults to the central nervous system (CNS) that often culminate in death or cognitive and motor impairment. Over the past decade, researchers have tapped into research to discover the potential role being played by gut bacteria in CNS. After an acute CNS injury, the altered composition of the gut microbiota disturbs the balance of the bidirectional gut-brain axis, aggravating secondary CNS injury, motor dysfunctions, and cognitive deficits, which worsens the patient's prognosis. Some of the well-known therapeutic interventions which can also be used as adjuvant therapy for alleviating CNS injuries include, the use of pro and prebiotics, fecal microbiota transplantation, and microbial engineering. In this review, we aim to discuss the importance of gut microbes in our nervous system, anatomy, and signaling pathways involved in regulating the gut-brain axis, the alteration of the gut microbiome in CNS injuries, and the therapeutic strategies to target gut microbiomes in traumatic CNS injuries.
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Affiliation(s)
- Lahanya Guha
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat 382355, India
| | - Tejas Girish Agnihotri
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat 382355, India
| | - Aakanchha Jain
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat 382355, India
| | - Hemant Kumar
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat 382355, India.
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19
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Sgro M, Ray J, Foster E, Mychasiuk R. Making migraine easier to stomach: the role of the gut-brain-immune axis in headache disorders. Eur J Neurol 2023; 30:3605-3621. [PMID: 37329292 DOI: 10.1111/ene.15934] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 05/30/2023] [Accepted: 06/12/2023] [Indexed: 06/19/2023]
Abstract
BACKGROUND AND PURPOSE Headache disorders place a significant burden on the healthcare system, being the leading cause of disability in those under 50 years. Novel studies have interrogated the relationship between headache disorders and gastrointestinal dysfunction, suggesting a link between the gut-brain-immune (GBI) axis and headache pathogenesis. Although the exact mechanisms driving the complex relationship between the GBI axis and headache disorders remain unclear, there is a growing appreciation that a healthy and diverse microbiome is necessary for optimal brain health. METHODS A literature search was performed through multiple reputable databases in search of Q1 journals within the field of headache disorders and gut microbiome research and were critically and appropriately evaluated to investigate and explore the following; the role of the GBI axis in dietary triggers of headache disorders and the evidence indicating that diet can be used to alleviate headache severity and frequency. The relationship between the GBI axis and post-traumatic headache is then synthesized. Finally, the scarcity of literature regarding paediatric headache disorders and the role that the GBI axis plays in mediating the relationship between sex hormones and headache disorders are highlighted. CONCLUSIONS There is potential for novel therapeutic targets for headache disorders if understanding of the GBI axis in their aetiology, pathogenesis and recovery is increased.
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Affiliation(s)
- Marissa Sgro
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Jason Ray
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia
- Department of Neurology, Alfred Health, Melbourne, Victoria, Australia
- Department of Neurology, Austin Health, Melbourne, Victoria, Australia
| | - Emma Foster
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia
- Department of Neurology, Alfred Health, Melbourne, Victoria, Australia
- Department of Neurology, Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Richelle Mychasiuk
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia
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20
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Dixon C, McCall K. Characterization of female reproductive disturbances post-traumatic injury in Drosophila melanogaster. MICROPUBLICATION BIOLOGY 2023; 2023:10.17912/micropub.biology.000883. [PMID: 37799197 PMCID: PMC10550377 DOI: 10.17912/micropub.biology.000883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Figures] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 09/01/2023] [Accepted: 09/19/2023] [Indexed: 10/07/2023]
Abstract
Traumatic injuries (TIs) from intimate partner violence, vehicular collisions, high-impact sports, and even mundane activities can be fatal. However, survivors of TIs can have pathophysiological disturbances post-injury, including neurodegenerative diseases, mental illness, and metabolic disorders.Reproductive issues are a known consequence of TI especially in women, however this has remained poorly understood. Drosophila melanogaster has recently emerged as a stellar model of TI, however reproductive consequences have not been reported. Using the Drosophila model, we find reproductive consequences in the form of decreased egg laying and the retention of mature egg chambers mimicking issues in ovulation. These findings indicate that reproductive consequences of TI are conserved between Drosophila and humans.
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Affiliation(s)
- Cameron Dixon
- Molecular Biology, Cell Biology, and Biochemistry Graduate Program, Boston University, Boston, Massachusetts, United States
| | - Kimberly McCall
- Department of Biology, Boston University, Boston, Massachusetts, United States
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21
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Estuani J, Godinho J, Borges SC, Neves CQ, Milani H, Buttow NC. Global cerebral ischemia followed by long-term reperfusion promotes neurodegeneration, oxidative stress, and inflammation in the small intestine in Wistar rats. Tissue Cell 2023; 81:102033. [PMID: 36764059 DOI: 10.1016/j.tice.2023.102033] [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: 06/30/2022] [Revised: 10/10/2022] [Accepted: 01/20/2023] [Indexed: 01/23/2023]
Abstract
AIMS Brain ischemia and reperfusion may occur in several clinical conditions that have high rates of mortality and disability, compromising an individual's quality of life. Brain injury can affect organs beyond the brain, such as the gastrointestinal tract. The present study investigated the effects of cerebral ischemia on the ileum and jejunum during a chronic reperfusion period by examining oxidative stress, inflammatory parameters, and the myenteric plexus in Wistar rats. MAIN METHODS Ischemia was induced by the four-vessel occlusion model for 15 min with 52 days of reperfusion. Oxidative stress and inflammatory markers were evaluated using biochemical techniques. Gastrointestinal transit time was evaluated, and immunofluorescence techniques were used to examine morpho-quantitative aspects of myenteric neurons. KEY FINDINGS Brain ischemia and reperfusion promoted inflammation, characterized by increases in myeloperoxidase and N-acetylglycosaminidase activity, oxidative stress, and lipid hydroperoxides, decreases in superoxide dismutase and catalase activity, a decrease in levels of reduced glutathione, neurodegeneration in the gut, and slow gastrointestinal transit. SIGNIFICANCE Chronic ischemia and reperfusion promoted a slow gastrointestinal transit time, oxidative stress, and inflammation and neurodegeneration in the small intestine in rats. These findings indicate that the use of antioxidant and antiinflammatory molecules even after a long period of reperfusion may be useful to alleviate the consequences of this pathology.
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Affiliation(s)
- Julia Estuani
- Biosciences and Pathophysiology Program, State University of Maringá, Maringá, PR, Brazil
| | - Jacqueline Godinho
- Pharmaceutical Sciences Program, State University of Maringá, Maringá, PR, Brazil
| | | | - Camila Quaglio Neves
- Program in Biological Sciences, State University of Maringá, Maringá, PR, Brazil
| | - Humberto Milani
- Department of Pharmacology and Therapeutics, State University of Maringá, Maringá, PR, Brazil
| | - Nilza Cristina Buttow
- Department of Morphological Sciences, State University of Maringá, Av. Colombo 5790, block H79 room 105 A, CEP: 87020-900 Maringá, PR, Brazil.
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22
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Characteristics of Gut Microbiome After Traumatic Brain Injury. J Neurosurg Anesthesiol 2023; 35:86-90. [PMID: 34238913 DOI: 10.1097/ana.0000000000000789] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 05/24/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Preclinical studies have reported significant changes in the gut microbiome after traumatic brain injury (TBI). We hypothesized that TBI induces the growth of Proteobacteria in the human gut. Our primary outcome was to study the profile of the human fecal microbiome after TBI and the secondary outcome was to identify colonization with colistin-resistant and multidrug-resistant pathogens. METHODS Consecutive patients with moderate-severe TBI admitted to the neurotrauma-intensive care unit within 48 hours of injury were enrolled into this observational study. Samples from rectal swabs obtained on days 0, 3, and 7 after admission were assessed for microbial growth and antibiotic resistance. Demographic data and variables such as hypotension, blood transfusion, surgery, start of nasogastric feeding, use of antibiotics, length of hospital stay and mortality were noted. RESULTS One hundred one patients were enrolled into this study; 57 (56.4%) underwent surgery, 80 (79.2%) required blood transfusion, 15 (14.9%) had an episode of hypotension, 37 (36.6%) received enteral feed within the first 3 days, and 79 (78.2%) received antibiotics. Rectal microbiological samples were collected from 101, 95, and 85 patients on days 0, 3, and 7, respectively. All organisms isolated at the 3 time-points belonged to the Proteobacteria phylum, with Enterobacteriaceae forming the largest group. Colistin-resistant organisms were found in 17 (16.8%) of 101 patients and multidrug-resistant organisms in 25 (64.1%) of the 39 patients in whom isolates were tested against the entire panel of antimicrobials. CONCLUSION TBI is associated with widespread colonization with Proteobacteria as early as 48 hours after injury. Colonization with colistin and multidrug-resistant organisms highlights the importance of the judicious use of antibiotics.
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23
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Involvement of Microbiome Gut–Brain Axis in Neuroprotective Effect of Quercetin in Mouse Model of Repeated Mild Traumatic Brain Injury. Neuromolecular Med 2022:10.1007/s12017-022-08732-z. [DOI: 10.1007/s12017-022-08732-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 11/24/2022] [Indexed: 12/14/2022]
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24
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Sgro M, Iacono G, Yamakawa GR, Kodila ZN, Marsland BJ, Mychasiuk R. Age matters: Microbiome depletion prior to repeat mild traumatic brain injury differentially alters microbial composition and function in adolescent and adult rats. PLoS One 2022; 17:e0278259. [PMID: 36449469 PMCID: PMC9710846 DOI: 10.1371/journal.pone.0278259] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 11/13/2022] [Indexed: 12/02/2022] Open
Abstract
Dysregulation of the gut microbiome has been shown to perpetuate neuroinflammation, alter intestinal permeability, and modify repetitive mild traumatic brain injury (RmTBI)-induced deficits. However, there have been no investigations regarding the comparative effects that the microbiome may have on RmTBI in adolescents and adults. Therefore, we examined the influence of microbiome depletion prior to RmTBI on microbial composition and metabolome, in adolescent and adult Sprague Dawley rats. Rats were randomly assigned to standard or antibiotic drinking water for 14 days, and to subsequent sham or RmTBIs. The gut microbiome composition and metabolome were analysed at baseline, 1 day after the first mTBI, and at euthanasia (11 days following the third mTBI). At euthanasia, intestinal samples were also collected to quantify tight junction protein (TJP1 and occludin) expression. Adolescents were significantly more susceptible to microbiome depletion via antibiotic administration which increased pro-inflammatory composition and metabolites. Furthermore, RmTBI induced a transient increase in 'beneficial bacteria' (Lachnospiraceae and Faecalibaculum) in only adolescents that may indicate compensatory action in response to the injury. Finally, microbiome depletion prior to RmTBI generated a microbiome composition and metabolome that exemplified a potentially chronic pathogenic and inflammatory state as demonstrated by increased Clostridium innocuum and Erysipelatoclostridium and reductions in Bacteroides and Clostridium Sensu Stricto. Results highlight that adolescents are more vulnerable to RmTBI compared to adults and dysbiosis prior to injury may exacerbate secondary inflammatory cascades.
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Affiliation(s)
- Marissa Sgro
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Giulia Iacono
- Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Glenn R. Yamakawa
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Zoe N. Kodila
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Benjamin J. Marsland
- Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Richelle Mychasiuk
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia
- * E-mail:
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Li Z, He H, Ni M, Wang Z, Guo C, Niu Y, Xing S, Song M, Wang Y, Jiang Y, Yu L, Li M, Xu H. Microbiome-Metabolome Analysis of the Immune Microenvironment of the Cecal Contents, Soft Feces, and Hard Feces of Hyplus Rabbits. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:5725442. [PMID: 36466090 PMCID: PMC9713467 DOI: 10.1155/2022/5725442] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 08/16/2022] [Indexed: 01/14/2024]
Abstract
The intestinal microbiota and its metabolites play vital roles in host growth, development, and immune regulation. This study analyzed the microbial community distribution and the cytokine and short-chain fatty acid (SCFA) content of cecal contents (Con group), soft feces (SF group), and hard feces (HF group) of 60-day-old Hyplus rabbits and verified the effect of soft feces on the cecal immune microenvironment by coprophagy prevention (CP). The results showed that there were significant differences in the levels of phylum and genus composition, cytokines, and SCFAs among the Con group, SF group, and HF group. The correlation analysis of cytokines and SCFAs with differential microbial communities showed that Muribaculaceae, Ruminococcaceae_UCG-014, Ruminococcaceae_NK4A214_group, and Christensenellaceae_R-7_Group are closely related to cytokines and SCFAs. After CP treatment, the contents of propionic acid, butyric acid, IL-4, and IL-10 in cecum decreased significantly, whereas TNF-α and IL-1β increased significantly. Moreover, the inhibition of coprophagy led to the downregulation of the expression levels of tight junction proteins (Claudin-1, Occludin, and ZO-1) related to intestinal inflammation and intestinal barrier function, and the ring-like structure of ZO-1 was disrupted. In conclusion, coprophagy can not only help rabbits obtain more probiotics and SCFAs but also play an essential role in improving the immune microenvironment of cecum.
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Affiliation(s)
- Zhichao Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China
| | - Hui He
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China
| | - Mengke Ni
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China
| | - Zhouyan Wang
- Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Chaohui Guo
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China
| | - Yufang Niu
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China
| | - Shanshan Xing
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China
| | - Mingkun Song
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China
| | - Yaling Wang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China
| | - Yixuan Jiang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China
| | - Lei Yu
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China
| | - Ming Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China
| | - Huifen Xu
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China
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The Potential Role of m6A in the Regulation of TBI-Induced BGA Dysfunction. Antioxidants (Basel) 2022; 11:antiox11081521. [PMID: 36009239 PMCID: PMC9405408 DOI: 10.3390/antiox11081521] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 07/31/2022] [Accepted: 08/02/2022] [Indexed: 02/01/2023] Open
Abstract
The brain–gut axis (BGA) is an important bidirectional communication pathway for the development, progress and interaction of many diseases between the brain and gut, but the mechanisms remain unclear, especially the post-transcriptional regulation of BGA after traumatic brain injury (TBI). RNA methylation is one of the most important modifications in post-transcriptional regulation. N6-methyladenosine (m6A), as the most abundant post-transcriptional modification of mRNA in eukaryotes, has recently been identified and characterized in both the brain and gut. The purpose of this review is to describe the pathophysiological changes in BGA after TBI, and then investigate the post-transcriptional bidirectional regulation mechanisms of TBI-induced BGA dysfunction. Here, we mainly focus on the characteristics of m6A RNA methylation in the post-TBI BGA, highlight the possible regulatory mechanisms of m6A modification in TBI-induced BGA dysfunction, and finally discuss the outcome of considering m6A as a therapeutic target to improve the recovery of the brain and gut dysfunction caused by TBI.
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27
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Grotemeyer A, McFleder RL, Wu J, Wischhusen J, Ip CW. Neuroinflammation in Parkinson's Disease - Putative Pathomechanisms and Targets for Disease-Modification. Front Immunol 2022; 13:878771. [PMID: 35663989 PMCID: PMC9158130 DOI: 10.3389/fimmu.2022.878771] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 04/20/2022] [Indexed: 12/15/2022] Open
Abstract
Parkinson’s disease (PD) is a progressive and debilitating chronic disease that affects more than six million people worldwide, with rising prevalence. The hallmarks of PD are motor deficits, the spreading of pathological α-synuclein clusters in the central nervous system, and neuroinflammatory processes. PD is treated symptomatically, as no causally-acting drug or procedure has been successfully established for clinical use. Various pathways contributing to dopaminergic neuron loss in PD have been investigated and described to interact with the innate and adaptive immune system. We discuss the possible contribution of interconnected pathways related to the immune response, focusing on the pathophysiology and neurodegeneration of PD. In addition, we provide an overview of clinical trials targeting neuroinflammation in PD.
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Affiliation(s)
| | | | - Jingjing Wu
- Department of Neurology, University Hospital Würzburg, Würzburg, Germany
| | - Jörg Wischhusen
- Section for Experimental Tumor Immunology, Department of Obstetrics and Gynecology, University Hospital of Würzburg, Würzburg, Germany
| | - Chi Wang Ip
- Department of Neurology, University Hospital Würzburg, Würzburg, Germany
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28
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Nwafor DC, Brichacek AL, Foster CH, Lucke-Wold BP, Ali A, Colantonio MA, Brown CM, Qaiser R. Pediatric Traumatic Brain Injury: An Update on Preclinical Models, Clinical Biomarkers, and the Implications of Cerebrovascular Dysfunction. J Cent Nerv Syst Dis 2022; 14:11795735221098125. [PMID: 35620529 PMCID: PMC9127876 DOI: 10.1177/11795735221098125] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 04/14/2022] [Indexed: 11/15/2022] Open
Abstract
Traumatic brain injury (TBI) is a leading cause of pediatric morbidity and mortality. Recent studies suggest that children and adolescents have worse post-TBI outcomes and take longer to recover than adults. However, the pathophysiology and progression of TBI in the pediatric population are studied to a far lesser extent compared to the adult population. Common causes of TBI in children are falls, sports/recreation-related injuries, non-accidental trauma, and motor vehicle-related injuries. A fundamental understanding of TBI pathophysiology is crucial in preventing long-term brain injury sequelae. Animal models of TBI have played an essential role in addressing the knowledge gaps relating to pTBI pathophysiology. Moreover, a better understanding of clinical biomarkers is crucial to diagnose pTBI and accurately predict long-term outcomes. This review examines the current preclinical models of pTBI, the implications of pTBI on the brain’s vasculature, and clinical pTBI biomarkers. Finally, we conclude the review by speculating on the emerging role of the gut-brain axis in pTBI pathophysiology.
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Affiliation(s)
- Divine C. Nwafor
- Department of Neuroscience, West Virginia University School of Medicine, Morgantown, WV, USA
- West Virginia University School of Medicine, Morgantown, WV, USA
- Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV, USA
| | - Allison L. Brichacek
- Department of Microbiology, Immunology, and Cell Biology, West Virginia University School of Medicine, Morgantown, WV, USA
| | - Chase H. Foster
- Department of Neurosurgery, George Washington University Hospital, Washington D.C., USA
| | | | - Ahsan Ali
- Department of Neuroscience, West Virginia University School of Medicine, Morgantown, WV, USA
| | | | - Candice M. Brown
- Department of Neuroscience, West Virginia University School of Medicine, Morgantown, WV, USA
- Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV, USA
- Department of Microbiology, Immunology, and Cell Biology, West Virginia University School of Medicine, Morgantown, WV, USA
| | - Rabia Qaiser
- Department of Neurosurgery, Baylor Scott and White, Temple, TX, USA
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29
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Aghakhani N. Relationship between mild traumatic brain injury and the gut microbiome: A scoping review. J Neurosci Res 2022; 100:827-834. [PMID: 34964504 DOI: 10.1002/jnr.25004] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 10/07/2021] [Accepted: 12/10/2021] [Indexed: 12/14/2022]
Abstract
There is increasing evidence for the important role of gut microbiota (GMB) in the development and progression of neurologic pathologies. Some studies have shown that modifying the microbiome profile can confer benefits to patients. Mild traumatic brain injury (mTBI) is a common occurrence in the general population. Although most patients recover, in a minority, disabling symptoms can persist for several months. We carried out a review of the literature to assess the effect of mTBI on GMB and to determine whether alleviating dysbiosis can improve clinical outcomes in mTBI patients. We performed searches in Medline/PubMed and Embase using the keywords "MTBI" AND "microbiome" OR "microbiota". Additional articles were identified by manual searches and using the Google search engine. In animal models, a clear perturbation of GMB was reported following TBI and probiotic supplementation (Lactobacillus acidophilus or Clostridium butyricum) improved neurologic function. There were no studies on changes in GMB after mTBI in humans; however, pre- or probiotic supplementation reduced the infection rate in patients with severe TBI and shortened the time spent in the intensive care unit without conferring any neurologic benefits. Thus, although the findings from animal models are promising, clinical studies are needed to determine whether therapeutic strategies that restore gut microbiome profile can improve long-term outcomes of patients with mTBI.
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Affiliation(s)
- Nozar Aghakhani
- Department of Neurosurgery, Center for Evaluation and Multidisciplinary Care of the Mild Traumatic Brain Injury, Bicêtre University Hospital, Le Kremlin-Bicêtre, France
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30
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Rao RK, McConnell DD, Litofsky NS. The impact of cigarette smoking and nicotine on traumatic brain injury: a review. Brain Inj 2022; 36:1-20. [PMID: 35138210 DOI: 10.1080/02699052.2022.2034186] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 10/28/2021] [Indexed: 11/02/2022]
Abstract
INTRODUCTION Traumatic Brain Injury (TBI) and tobacco smoking are both serious public health problems. Many people with TBI also smoke. Nicotine, a component of tobacco smoke, has been identified as a premorbid neuroprotectant in other neurological disorders. This study aims to provide better understanding of relationships between tobacco smoking and nicotine use and effect on outcome/recovery from TBI. METHODS PubMed database, SCOPUS, and PTSDpub were searched for relevant English-language papers. RESULTS Twenty-nine human clinical studies and nine animal studies were included. No nicotine-replacement product use in human TBI clinical studies were identified. While smoking tobacco prior to injury can be harmful primarily due to systemic effects that can compromise brain function, animal studies suggest that nicotine as a pharmacological agent may augment recovery of cognitive deficits caused by TBI. CONCLUSIONS While tobacco smoking before or after TBI has been associated with potential harms, many clinical studies downplay correlations for most expected domains. On the other hand, nicotine could provide potential treatment for cognitive deficits following TBI by reversing impaired signaling pathways in the brain including those involving nAChRs, TH, and dopamine. Future studies regarding the impact of cigarette smoking and vaping on patients with TBI are needed .
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Affiliation(s)
- Rohan K Rao
- Division of Neurological Surgery, University of Missouri School of Medicine, Columbia, Missouri, USA
| | - Diane D McConnell
- Division of Neurological Surgery, University of Missouri School of Medicine, Columbia, Missouri, USA
| | - N Scott Litofsky
- Division of Neurological Surgery, University of Missouri School of Medicine, Columbia, Missouri, USA
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31
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You W, Zhu Y, Wei A, Du J, Wang Y, Zheng P, Tu M, Wang H, Wen L, Yang X. Traumatic Brain Injury Induces Gastrointestinal Dysfunction and Dysbiosis of Gut Microbiota Accompanied by Alterations of Bile Acid Profile. J Neurotrauma 2022; 39:227-237. [PMID: 33677989 DOI: 10.1089/neu.2020.7526] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Gastrointestinal dysfunction is a common peripheral organ complication after traumatic brain injury (TBI), yet the underlying mechanism remains unknown. TBI has been demonstrated to cause gut microbiota dysbiosis in animal models, although the impacts of gut microbiota dysbiosis on gastrointestinal dysfunction were not examined. Bile acids are key metabolites between gut microbiota and host interactions. Therefore, the aim of this study was to investigate the mechanistic links between them by detecting the alterations of gut microbiota and bile acid profile after TBI. For that, we established TBI in mice using a lateral fluid percussion injury model. Gut microbiota was examined by 16S rRNA sequencing, and bile acids were profiled by ultra-performance liquid chromatography-tandem mass spectrometry. Our results showed that TBI caused intestinal inflammation and gut barrier impairment. Alterations of gut microbiota and bile acid profile were observed. The diversity of gut microbiota experienced a time dependent change from 1 h to 7 days post-injury. Levels of bile acids in feces and plasma were decreased after TBI, and the decrease was more significant in secondary bile acids, which may contribute to intestinal inflammation. Specific bacterial taxa such as Staphylococcus and Lachnospiraceae that may contribute to the bile acid metabolic changes were identifed. In conclusion, our study suggested that TBI-induced gut microbiota dysbiosis may contribute to gastrointestinal dysfunction via altering bile acid profile. Gut microbiota may be a potential treatment target for TBI-induced gastrointestinal dysfunction.
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Affiliation(s)
- Wendong You
- Emergency and Trauma Center and The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Yuanrun Zhu
- Emergency and Trauma Center and The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Anqi Wei
- Emergency and Trauma Center and The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Juan Du
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Yadong Wang
- Emergency and Trauma Center and The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Peidong Zheng
- Emergency and Trauma Center and The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Mengdi Tu
- Emergency and Trauma Center and The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Hao Wang
- Emergency and Trauma Center and The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Department of Neurosurgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Liang Wen
- Emergency and Trauma Center and The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
- Department of Neurosurgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Xiaofeng Yang
- Emergency and Trauma Center and The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
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SCFA Treatment Alleviates Pathological Signs of Migraine and Related Intestinal Alterations in a Mouse Model of NTG-Induced Migraine. Cells 2021; 10:cells10102756. [PMID: 34685736 PMCID: PMC8535085 DOI: 10.3390/cells10102756] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/04/2021] [Accepted: 10/06/2021] [Indexed: 12/13/2022] Open
Abstract
Background: There is a growing realization that the gut–brain axis signaling is critical for maintaining the health and homeostasis of the Central Nervous System (CNS) and the intestinal environment. The role of Short-Chain Fatty Acids (SCFAs), such as Sodium Propionate (SP) and Sodium Butyrate (SB), has been reported to counteract inflammation activation in the central and Enteric Nervous System (ENS). Methods: In this study, we evaluated the role of the SCFAs in regulating the pathophysiology of migraine and correlated dysregulations in the gut environment in a mouse model of Nitroglycerine (NTG)-induced migraine. Results: We showed that, following behavioral tests evaluating pain and photophobia, the SP and SB treatments attenuated pain attacks provoked by NTG. Moreover, treatments with both SCFAs reduced histological damage in the trigeminal nerve nucleus and decreased the expression of proinflammatory mediators. Ileum evaluation following NTG injection reported that SCFA treatments importantly restored intestinal mucosa alterations, as well as the release of neurotransmitters in the ENS. Conclusions: Taken together, these results provide evidence that SCFAs exert powerful effects, preventing inflammation through the gut–brain axis, suggesting a new insight into the potential application of SCFAs as novel supportive therapies for migraine and correlated intestinal alterations.
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33
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Kim TJ, Torres L, Paz A, Lee JS, Park SH, Choi HA, Ko SB. Neostigmine for Treating Acute Colonic Pseudo-Obstruction in Neurocritically Ill Patients. J Clin Neurol 2021; 17:563-569. [PMID: 34595865 PMCID: PMC8490912 DOI: 10.3988/jcn.2021.17.4.563] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 05/11/2021] [Accepted: 05/11/2021] [Indexed: 12/26/2022] Open
Abstract
Background and Purpose Acute colonic pseudo-obstruction (ACPO) is a common but understudied complication in neurocritically ill patients. The acetylcholinesterase inhibitor neostigmine can be used to treat ACPO in patients who do not respond to conventional treatment. This study investigated the effectiveness and adverse events when using neostigmine to manage ACPO in neurocritically ill patients. Methods This retrospective study investigated patients with ACPO who were treated using neostigmine in the neurological intensive-care units at two centers between March 2017 and August 2020. Neostigmine was administered intravenously or subcutaneously (at doses ranging from 0.25 mg to 2 mg) according to the protocols at the two centers. The outcomes were bowel movements and the changes in colon diameters on abdominal radiographs. Safety events such as bradycardia, vomiting, salivation, and sweating were evaluated. Results This study included 31 subjects with a mean age of 46.8 years (65.4% males). All patients had a bowel movement at a median of 120 minutes after administering neostigmine. The colon diameter decreased by a median of 17.5 mm (paired t-test: p<0.001) regardless of the dose and treatment protocols. Multilevel analysis confirmed that the mean colon diameter decreased from 66 mm pretreatment to 47.5 mm posttreatment (p<0.001), with an intraclass correlation coefficient of 13%. Three patients (9.7%) exhibited hypersalivation, sweating, bradycardia, and vomiting. Bradycardia (heart rate, 42 beats/minute) occurred in one patient (3.2%), and was successfully managed by injecting atropine. Conclusions Neostigmine injection is a safe and effective treatment option for ACPO in neurocritically ill patients who fail to respond to conservative management.
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Affiliation(s)
- Tae Jung Kim
- Department of Neurology, Seoul National University Hospital, Seoul, Korea.,Department of Critical Care Medicine, Seoul National University Hospital, Seoul, Korea
| | - Luis Torres
- Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Atzhiry Paz
- Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Ji Sung Lee
- Department of Clinical Epidemiology and Biostatistics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Soo Hyun Park
- Department of Neurology, Inha University Hospital, Incheon, Korea
| | - Huimahn Alex Choi
- Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
| | - Sang Bae Ko
- Department of Neurology, Seoul National University Hospital, Seoul, Korea.,Department of Critical Care Medicine, Seoul National University Hospital, Seoul, Korea.
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34
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Scharenbrock AR, Katzenberger RJ, Fischer MC, Ganetzky B, Wassarman DA. Beta-blockers reduce intestinal permeability and early mortality following traumatic brain injury in Drosophila. MICROPUBLICATION BIOLOGY 2021; 2021:10.17912/micropub.biology.000461. [PMID: 34723144 PMCID: PMC8553408 DOI: 10.17912/micropub.biology.000461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 09/20/2021] [Accepted: 09/20/2021] [Indexed: 11/17/2022]
Abstract
Traumatic brain injury (TBI) frequently leads to non-neurological consequences such as intestinal permeability. The beta-blocker drug labetalol, which inhibits binding of catecholamine neurotransmitters to adrenergic receptors, reduces intestinal permeability in a rat TBI model. Using a Drosophila melanogaster TBI model, we previously found a strong positive correlation between intestinal permeability and mortality within 24 hours of TBI in a standard laboratory line (w1118 ) and across genetically diverse inbred lines from the Drosophila Genetic Reference Panel (DGRP). Here, we report that feeding injured w1118 flies the beta-blockers labetalol and metoprolol reduced intestinal permeability and mortality. Additionally, metoprolol reduced intestinal permeability when 18 DGRP fly lines were analyzed in aggregate, but neither beta-blocker affected mortality. These data indicate that the mechanism underlying disruption of the intestinal barrier by adrenergic signaling following TBI is conserved between humans and flies and that mortality following TBI in flies is not strictly dependent on disruption of the intestinal barrier. Thus, the fly TBI model is useful for shedding light on the mechanism and consequences of adrenergic signaling between the brain and intestine following TBI in humans.
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Affiliation(s)
- Amanda R Scharenbrock
- Department of Medical Genetics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706
| | - Rebeccah J Katzenberger
- Department of Medical Genetics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706
| | - Megan C Fischer
- Department of Medical Genetics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706
| | - Barry Ganetzky
- Department of Genetics, College of Agricultural and Life Sciences, University of Wisconsin-Madison, Madison, WI 53706
| | - David A Wassarman
- Department of Medical Genetics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706,
Correspondence to: David A Wassarman ()
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35
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McDonald SD, Walker WC, Cusack SE, Yoash-Gantz RE, Pickett TC, Cifu DX, Mid-Atlantic Mirecc Workgroup V, Tupler LA. Health symptoms after war zone deployment-related mild traumatic brain injury: contributions of mental disorders and lifetime brain injuries. Brain Inj 2021; 35:1338-1348. [PMID: 34543115 DOI: 10.1080/02699052.2021.1959058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
PRIMARY OBJECTIVE To gain a better understanding of the complex relationship between combat deployment-related mild traumatic brain injury (mTBI) and persistent post-concussive symptoms (PPCSs), taking into consideration a wide range of potentially mediating and confounding factors. RESEARCH DESIGN Cross-sectional. METHODS AND PROCEDURES Subjects were 613 U. S. military Veterans and Service Members who served during operations Enduring Freedom, Iraqi Freedom, or New Dawn (OEF/OIF/OND) and completed a structured interview of mental disorders and a battery of questionnaires. Hierarchical binary logistic regression analyses were used to test the hypotheses. MAIN OUTCOMES AND RESULTS After accounting for mental disorders, lifetime mTBIs outside of OEF/OIF/OND deployment, medical conditions, and injury/demographic characteristics, deployment-related mTBI continued to be associated with several PPCSs (headaches, sleep disturbance, and difficulty making decisions). Deployment-related mTBI was also associated with two symptoms not normally associated with mTBI (nausea/upset stomach and numbness/tingling). CONCLUSIONS After adjusting for a wide range of factors, OEF/OIF/OND deployment-related mTBI was still associated with PPCSs on average 10 years after the injury. These findings suggest that mTBI sustained during OEF/OIF/OND deployment may have enduring negative health effects. More studies are needed that prospectively and longitudinally track health and mental health outcomes after TBI.
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Affiliation(s)
- Scott D McDonald
- Mental Health Service, Hunter Holmes McGuire Va Medical Center, Richmond, VA, USA.,Department Of Psychology, Virginia Commonwealth University, Richmond, VA, USA.,Department Of Physical Medicine And Rehabilitation, School Of Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - William C Walker
- Mental Health Service, Hunter Holmes McGuire Va Medical Center, Richmond, VA, USA.,Department Of Physical Medicine And Rehabilitation, School Of Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Shannon E Cusack
- Department Of Psychology, Virginia Commonwealth University, Richmond, VA, USA.,Virginia Institute for Psychiatric and Behavioral Genetics (Vipbg), School of Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Ruth E Yoash-Gantz
- Va Mid-Atlantic Mental Illness, Research, And Clinical Center, Durham, NC, USA
| | | | - David X Cifu
- Mental Health Service, Hunter Holmes McGuire Va Medical Center, Richmond, VA, USA.,Department Of Physical Medicine And Rehabilitation, School Of Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | | | - Larry A Tupler
- Va Mid-Atlantic Mental Illness, Research, And Clinical Center, Durham, NC, USA.,Durham VA Medical Center, Durham, NC, USA.,Duke University Medical Center, Durham, NC, USA
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36
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Zhu Y, Chen Z, You W, Wang Y, Tu M, Zheng P, Wen L, Yang X. A Retrospective Clinical Analysis of the Serum Bile Acid Alteration Caused by Traumatic Brain Injury. Front Neurol 2021; 12:624378. [PMID: 34512494 PMCID: PMC8424180 DOI: 10.3389/fneur.2021.624378] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 07/09/2021] [Indexed: 12/23/2022] Open
Abstract
Traumatic brain injury (TBI) can cause damage to peripheral organ systems, such as digestive organ system, and alterations of gut microbiota in addition to brain injury. Our previous study found that TBI induced gastrointestinal dysfunction accompanied by alterations of bile acid metabolism. Bile acid and its receptors have been reported to play important roles in various neurological diseases. To further examine the changes of bile acid metabolism in TBI patients, we performed a retrospective clinical analysis. In this study, 177 patients were included, and the results showed that TBI patients had more frequent antibiotic use compared with a control group. Regression analysis identified TBI as an independent factor for reduction of serum bile acid level (B = -1.762, p = 0.006), even with antibiotic use taken into a regression model. Sub-group regression analysis of TBI patients showed that antibiotic use was negatively associated with bile acid level, while creatinine and triglyceride were positively associated with bile acid level. In conclusion, these data indicated that TBI could greatly reduce serum bile acid. This study provided preliminary but novel clinical evidence of TBI interfering with bile acid metabolism, and further studies with large sample sizes are needed to validate these findings in the future.
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Affiliation(s)
- Yuanrun Zhu
- The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Zijian Chen
- Zhejiang University School of Medicine, Hangzhou, China.,Shaoxing Hospital of Traditional Chinese Medicine, Zhejiang Chinese Medical University, Shaoxing, China
| | - Wendong You
- The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yadong Wang
- The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Mengdi Tu
- Zhejiang University School of Medicine, Hangzhou, China
| | - Peidong Zheng
- Zhejiang University School of Medicine, Hangzhou, China
| | - Liang Wen
- The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaofeng Yang
- The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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McDonald SJ, Sharkey JM, Sun M, Kaukas LM, Shultz SR, Turner RJ, Leonard AV, Brady RD, Corrigan F. Beyond the Brain: Peripheral Interactions after Traumatic Brain Injury. J Neurotrauma 2021; 37:770-781. [PMID: 32041478 DOI: 10.1089/neu.2019.6885] [Citation(s) in RCA: 87] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Traumatic brain injury (TBI) is a leading cause of death and disability, and there are currently no pharmacological treatments known to improve patient outcomes. Unquestionably, contributing toward a lack of effective treatments is the highly complex and heterogenous nature of TBI. In this review, we highlight the recent surge of research that has demonstrated various central interactions with the periphery as a potential major contributor toward this heterogeneity and, in particular, the breadth of research from Australia. We describe the growing evidence of how extracranial factors, such as polytrauma and infection, can significantly alter TBI neuropathology. In addition, we highlight how dysregulation of the autonomic nervous system and the systemic inflammatory response induced by TBI can have profound pathophysiological effects on peripheral organs, such as the heart, lung, gastrointestinal tract, liver, kidney, spleen, and bone. Collectively, this review firmly establishes TBI as a systemic condition. Further, the central and peripheral interactions that can occur after TBI must be further explored and accounted for in the ongoing search for effective treatments.
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Affiliation(s)
- Stuart J McDonald
- Department Neuroscience, Monash University, Melbourne, Victoria, Australia.,Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, Victoria, Australia
| | - Jessica M Sharkey
- Discipline of Anatomy and Pathology, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, South Australia, Australia
| | - Mujun Sun
- Department Neuroscience, Monash University, Melbourne, Victoria, Australia
| | - Lola M Kaukas
- School of Health Sciences, University of South Australia, Adelaide, South Australia, Australia
| | - Sandy R Shultz
- Department Neuroscience, Monash University, Melbourne, Victoria, Australia.,Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia
| | - Renee J Turner
- Discipline of Anatomy and Pathology, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, South Australia, Australia
| | - Anna V Leonard
- Discipline of Anatomy and Pathology, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, South Australia, Australia
| | - Rhys D Brady
- Department Neuroscience, Monash University, Melbourne, Victoria, Australia
| | - Frances Corrigan
- School of Health Sciences, University of South Australia, Adelaide, South Australia, Australia
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Buchmann Godinho D, da Silva Fiorin F, Schneider Oliveira M, Furian AF, Rechia Fighera M, Freire Royes LF. The immunological influence of physical exercise on TBI-induced pathophysiology: Crosstalk between the spleen, gut, and brain. Neurosci Biobehav Rev 2021; 130:15-30. [PMID: 34400178 DOI: 10.1016/j.neubiorev.2021.08.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 08/04/2021] [Accepted: 08/08/2021] [Indexed: 12/16/2022]
Abstract
Traumatic brain injury (TBI) is a non-degenerative and non-congenital insult to the brain and is recognized as a global public health problem, with a high incidence of neurological disorders. Despite the causal relationship not being entirely known, it has been suggested that multiorgan inflammatory response involving the autonomic nervous system and the spleen-gut brain axis dysfunction exacerbate the TBI pathogenesis in the brain. Thus, applying new therapeutic tools, such as physical exercise, have been described in the literature to act on the immune modulation induced by brain injuries. However, there are caveats to consider when interpreting the effects of physical exercise on this neurological injury. Given the above, this review will highlight the main findings of the literature involving peripheral immune responses in TBI-induced neurological damage and how changes in the cellular metabolism of the spleen-gut brain axis elicited by different protocols of physical exercise alter the pathophysiology induced by this neurological injury.
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Affiliation(s)
- Douglas Buchmann Godinho
- Laboratório de Bioquímica do Exercício, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil; Programa de Pós-Graduação em Bioquímica Toxicológica, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil
| | - Fernando da Silva Fiorin
- Programa de Pós-Graduação em Neuroengenharia, Instituto Internacional de Neurociências Edmond e Lily Safra, Instituto Santos Dumont, Macaíba, RN, Brazil
| | - Mauro Schneider Oliveira
- Centro de Ciências da Saúde, Programa de Pós-Graduação em Farmacologia, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil
| | - Ana Flavia Furian
- Centro de Ciências da Saúde, Programa de Pós-Graduação em Farmacologia, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil
| | - Michele Rechia Fighera
- Laboratório de Bioquímica do Exercício, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil; Centro de Ciências da Saúde, Departamento de Clínica Médica e Pediatria, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil
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39
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Sabet N, Soltani Z, Khaksari M. Multipotential and systemic effects of traumatic brain injury. J Neuroimmunol 2021; 357:577619. [PMID: 34058510 DOI: 10.1016/j.jneuroim.2021.577619] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 05/07/2021] [Accepted: 05/24/2021] [Indexed: 02/06/2023]
Abstract
Traumatic brain injury (TBI) is one of the leading causes of disability and mortality of people at all ages. Biochemical, cellular and physiological events that occur during primary injury lead to a delayed and long-term secondary damage that can last from hours to years. Secondary brain injury causes tissue damage in the central nervous system and a subsequent strong and rapid inflammatory response that may lead to persistent inflammation. However, this inflammatory response is not limited to the brain. Inflammatory mediators are transferred from damaged brain tissue to the bloodstream and produce a systemic inflammatory response in peripheral organs, including the cardiovascular, pulmonary, gastrointestinal, renal and endocrine systems. Complications of TBI are associated with its multiple and systemic effects that should be considered in the treatment of TBI patients. Therefore, in this review, an attempt was made to examine the systemic effects of TBI in detail. It is hoped that this review will identify the mechanisms of injury and complications of TBI, and open a window for promising treatment in TBI complications.
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Affiliation(s)
- Nazanin Sabet
- Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Sciences, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran; Department of Physiology and Pharmacology, Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Zahra Soltani
- Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Sciences, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran; Department of Physiology and Pharmacology, Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran.
| | - Mohammad Khaksari
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
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40
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Mazarati A, Medel-Matus JS, Shin D, Jacobs JP, Sankar R. Disruption of intestinal barrier and endotoxemia after traumatic brain injury: Implications for post-traumatic epilepsy. Epilepsia 2021; 62:1472-1481. [PMID: 33893636 DOI: 10.1111/epi.16909] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 04/01/2021] [Accepted: 04/05/2021] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Traumatic brain injury (TBI) may lead to the disruption of the intestinal barrier (IB), and to the escape of products of commensal gut bacteria, including lipopolysaccharide (LPS), into the bloodstream. We examined whether lateral fluid percussion injury (LFPI) and post-traumatic epilepsy (PTE) are associated with the increased intestinal permeability and endotoxemia, and whether these events in turn are associated with PTE. METHODS LFPI was delivered to adult male Sprague-Dawley rats. Before, 1 week, and 7 months after LFPI, the IB permeability was examined by measuring plasma concentration of fluorescein isothiocyanate-labeled dextran (FD4) upon its enteral administration. Plasma LPS concentration was measured in the same animals, using enzyme-linked immunosorbent assay. PTE was examined 7 months after LFPI, with use of video-EEG (electroencephalography) monitoring. RESULTS One week after LFPI, the IB disruption was detected in 14 of 17 and endotoxemia - in 10 of 17 rats, with a strong positive correlation between FD4 and LPS levels, and between plasma levels of each of the analytes and the severity of neuromotor deficit. Seven months after LFPI, IB disruption was detected in 13 of 15 and endotoxemia in 8 of 15 rats, with a strong positive correlation between plasma levels of the two analytes. Five of 15 LFPI rats developed PTE. Plasma levels of both FD4 and LPS were significantly higher in animals with PTE than among the animals without PTE. The analysis of seven rats, which were examined repeatedly at 1 week and at 7 months, confirmed that late IB disruption and endotoxemia were not due to lingering of impairments occurring shortly after LFPI. SIGNIFICANCE LFPI leads to early and remote disruption of IB and a secondary endotoxemia. Early and late perturbations may occur in different subjects. Early changes reflect the severity of acute post-traumatic motor dysfunction, whereas late changes are associated with PTE.
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Affiliation(s)
- Andrey Mazarati
- Department of Pediatrics, David Geffen School of Medicine at the University of California, Los Angeles (UCLA), Los Angeles, CA, USA.,UCLA Children's Discovery and Innovation Institute, Los Angeles, California, USA.,UCLA Microbiome Center, Los Angeles, CA, USA
| | - Jesus-Servando Medel-Matus
- Department of Pediatrics, David Geffen School of Medicine at the University of California, Los Angeles (UCLA), Los Angeles, CA, USA
| | - Don Shin
- Department of Pediatrics, David Geffen School of Medicine at the University of California, Los Angeles (UCLA), Los Angeles, CA, USA
| | - Jonathan P Jacobs
- UCLA Microbiome Center, Los Angeles, CA, USA.,Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles (UCLA), Los Angeles, CA, USA.,Division of Gastroenterology, Hepatology and Parenteral Nutrition, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA
| | - Raman Sankar
- Department of Pediatrics, David Geffen School of Medicine at the University of California, Los Angeles (UCLA), Los Angeles, CA, USA.,UCLA Children's Discovery and Innovation Institute, Los Angeles, California, USA.,Department of Neurology, David Geffen School of Medicine at the University of California, Los Angeles (UCLA), Los Angeles, CA, USA
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41
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George AK, Behera J, Homme RP, Tyagi N, Tyagi SC, Singh M. Rebuilding Microbiome for Mitigating Traumatic Brain Injury: Importance of Restructuring the Gut-Microbiome-Brain Axis. Mol Neurobiol 2021; 58:3614-3627. [PMID: 33774742 PMCID: PMC8003896 DOI: 10.1007/s12035-021-02357-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 03/10/2021] [Indexed: 12/20/2022]
Abstract
Traumatic brain injury (TBI) is a damage to the brain from an external force that results in temporary or permanent impairment in brain functions. Unfortunately, not many treatment options are available to TBI patients. Therefore, knowledge of the complex interplay between gut microbiome (GM) and brain health may shed novel insights as it is a rapidly expanding field of research around the world. Recent studies show that GM plays important roles in shaping neurogenerative processes such as blood-brain-barrier (BBB), myelination, neurogenesis, and microglial maturation. In addition, GM is also known to modulate many aspects of neurological behavior and cognition; however, not much is known about the role of GM in brain injuries. Since GM has been shown to improve cellular and molecular functions via mitigating TBI-induced pathologies such as BBB permeability, neuroinflammation, astroglia activation, and mitochondrial dysfunction, herein we discuss how a dysbiotic gut environment, which in fact, contributes to central nervous system (CNS) disorders during brain injury and how to potentially ward off these harmful effects. We further opine that a better understanding of GM-brain (GMB) axis could help assist in designing better treatment and management strategies in future for the patients who are faced with limited options.
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Affiliation(s)
- Akash K George
- Eye and Vision Science Laboratory, Department of Physiology, University of Louisville School of Medicine, Louisville, Kentucky, 40202, USA.,Department of Physiology, University of Louisville School of Medicine, Louisville, Kentucky, 40202, USA
| | - Jyotirmaya Behera
- Bone Biology Laboratory, Department of Physiology, University of Louisville School of Medicine, Louisville, Kentucky, 40202, USA
| | - Rubens P Homme
- Eye and Vision Science Laboratory, Department of Physiology, University of Louisville School of Medicine, Louisville, Kentucky, 40202, USA.,Department of Physiology, University of Louisville School of Medicine, Louisville, Kentucky, 40202, USA
| | - Neetu Tyagi
- Bone Biology Laboratory, Department of Physiology, University of Louisville School of Medicine, Louisville, Kentucky, 40202, USA
| | - Suresh C Tyagi
- Department of Physiology, University of Louisville School of Medicine, Louisville, Kentucky, 40202, USA
| | - Mahavir Singh
- Eye and Vision Science Laboratory, Department of Physiology, University of Louisville School of Medicine, Louisville, Kentucky, 40202, USA. .,Department of Physiology, University of Louisville School of Medicine, Louisville, Kentucky, 40202, USA.
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The association of traumatic brain injury, gut microbiota and the corresponding metabolites in mice. Brain Res 2021; 1762:147450. [PMID: 33773978 DOI: 10.1016/j.brainres.2021.147450] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 02/22/2021] [Accepted: 03/21/2021] [Indexed: 01/05/2023]
Abstract
BACKGROUND Traumatic Brain Injury (TBI) present a significant burden to global health. Close association and mutual regulation exist between the brain and gut microbiota. In addition, metabolites may play an important role as intermediary mediators of the brain and gut microbiota. Consequently, the study sought to investigate the alterations in gut microbiota and metabolites after TBI and conducted a comprehensive analysis of the correlation between gut microbiota and metabolites after TBI in mice. METHODS Changes in intestinal microbiota and metabolites in mice after moderate or severe traumatic brain injury were detected through 16S rDNA sequencing and the non-target LC-MS technology. Additionally, Pearson correlation analysis was used to explore the association between the microbiota and metabolites. RESULTS TBI was able to change the composition of intestinal microbiota, resulting to a decrease in microbial diversity in the intestinal tract (sham vs sTBI: 8.35 ± 0.12 vs 7.71 ± 0.5, p < 0.01; sTBI vs mTBI: 7.71 ± 0.5 vs 8.25 ± 0.34, p < 0.05). The results also showed that TBI could change the types and abundance of metabolites (723 in mTBI and sham groups; 1221 in sTBI and sham groups; 324 in mTBI and sTBI groups). Moreover, some of the altered gut metabolites were significantly correlated with part of the altered gut microbes after TBI. CONCLUSIONS TBI significantly changed intestinal microbiota as well as metabolites. Some of the altered microbiota and metabolites had a significant association. The results from this study provide information that paves way for future studies utilizing the brain gut axis theory in the diagnosis and treatment of TBI.
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Appiah SA, Foxx CL, Langgartner D, Palmer A, Zambrano CA, Braumüller S, Schaefer EJ, Wachter U, Elam BL, Radermacher P, Stamper CE, Heinze JD, Salazar SN, Luthens AK, Arnold AL, Reber SO, Huber-Lang M, Lowry CA, Halbgebauer R. Evaluation of the gut microbiome in association with biological signatures of inflammation in murine polytrauma and shock. Sci Rep 2021; 11:6665. [PMID: 33758228 PMCID: PMC7988149 DOI: 10.1038/s41598-021-85897-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 03/05/2021] [Indexed: 12/03/2022] Open
Abstract
Severe injuries are frequently accompanied by hemorrhagic shock and harbor an increased risk for complications. Local or systemic inflammation after trauma/hemorrhage may lead to a leaky intestinal epithelial barrier and subsequent translocation of gut microbiota, potentially worsening outcomes. To evaluate the extent with which trauma affects the gut microbiota composition, we performed a post hoc analysis of a murine model of polytrauma and hemorrhage. Four hours after injury, organs and plasma samples were collected, and the diversity and composition of the cecal microbiome were evaluated using 16S rRNA gene sequencing. Although cecal microbial alpha diversity and microbial community composition were not found to be different between experimental groups, norepinephrine support in shock animals resulted in increased alpha diversity, as indicated by higher numbers of distinct microbial features. We observed that the concentrations of proinflammatory mediators in plasma and intestinal tissue were associated with measures of microbial alpha and beta diversity and the presence of specific microbial drivers of inflammation, suggesting that the composition of the gut microbiome at the time of trauma, or shortly after trauma exposure, may play an important role in determining physiological outcomes. In conclusion, we found associations between measures of gut microbial alpha and beta diversity and the severity of systemic and local gut inflammation. Furthermore, our data suggest that four hours following injury is too early for development of global changes in the alpha diversity or community composition of the intestinal microbiome. Future investigations with increased temporal-spatial resolution are needed in order to fully elucidate the effects of trauma and shock on the gut microbiome, biological signatures of inflammation, and proximal and distal outcomes.
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Affiliation(s)
- Sandra A Appiah
- Department of Integrative Physiology and Center for Microbial Exploration, University of Colorado Boulder, Boulder, CO, 80309, USA
| | - Christine L Foxx
- Department of Integrative Physiology and Center for Microbial Exploration, University of Colorado Boulder, Boulder, CO, 80309, USA
| | - Dominik Langgartner
- Laboratory for Molecular Psychosomatics, Department of Psychosomatic Medicine and Psychotherapy, University Ulm, 89081, Ulm, Germany
| | - Annette Palmer
- Institute of Clinical and Experimental Trauma Immunology, Centre for Biomedical Research, University Hospital Ulm, University Ulm, Helmholtzstr. 8/1, 89081, Ulm, Germany
| | - Cristian A Zambrano
- Department of Integrative Physiology and Center for Microbial Exploration, University of Colorado Boulder, Boulder, CO, 80309, USA
- Center for Neuroscience, University of Colorado Boulder, Boulder, CO, 80309, USA
| | - Sonja Braumüller
- Institute of Clinical and Experimental Trauma Immunology, Centre for Biomedical Research, University Hospital Ulm, University Ulm, Helmholtzstr. 8/1, 89081, Ulm, Germany
| | - Evan J Schaefer
- Department of Integrative Physiology and Center for Microbial Exploration, University of Colorado Boulder, Boulder, CO, 80309, USA
| | - Ulrich Wachter
- Institute for Anaesthesiological Pathophysiology and Process Development, University of Ulm, Ulm, Germany
| | - Brooke L Elam
- Department of Integrative Physiology and Center for Microbial Exploration, University of Colorado Boulder, Boulder, CO, 80309, USA
| | - Peter Radermacher
- Institute for Anaesthesiological Pathophysiology and Process Development, University of Ulm, Ulm, Germany
| | - Christopher E Stamper
- Department of Integrative Physiology and Center for Microbial Exploration, University of Colorado Boulder, Boulder, CO, 80309, USA
| | - Jared D Heinze
- Department of Integrative Physiology and Center for Microbial Exploration, University of Colorado Boulder, Boulder, CO, 80309, USA
| | - Stephanie N Salazar
- Department of Integrative Physiology and Center for Microbial Exploration, University of Colorado Boulder, Boulder, CO, 80309, USA
| | - Amalia K Luthens
- Department of Integrative Physiology and Center for Microbial Exploration, University of Colorado Boulder, Boulder, CO, 80309, USA
| | - Andrea L Arnold
- Department of Integrative Physiology and Center for Microbial Exploration, University of Colorado Boulder, Boulder, CO, 80309, USA
| | - Stefan O Reber
- Laboratory for Molecular Psychosomatics, Department of Psychosomatic Medicine and Psychotherapy, University Ulm, 89081, Ulm, Germany
| | - Markus Huber-Lang
- Institute of Clinical and Experimental Trauma Immunology, Centre for Biomedical Research, University Hospital Ulm, University Ulm, Helmholtzstr. 8/1, 89081, Ulm, Germany.
| | - Christopher A Lowry
- Department of Integrative Physiology and Center for Microbial Exploration, University of Colorado Boulder, Boulder, CO, 80309, USA
- Center for Neuroscience, University of Colorado Boulder, Boulder, CO, 80309, USA
- Department of Physical Medicine and Rehabilitation and Center for Neuroscience, University of Colorado Anschutz, Medical Campus, Aurora, CO, 80045, USA
- Rocky Mountain Mental Illness Research Education and Clinical Center (MIRECC), Rocky Mountain Regional Veterans Affairs Medical Center (RMRVAMC), Aurora, CO, 80045, USA
- Military and Veteran Microbiome Consortium for Research and Education (MVM-CoRE), Aurora, CO, 80045, USA
| | - Rebecca Halbgebauer
- Institute of Clinical and Experimental Trauma Immunology, Centre for Biomedical Research, University Hospital Ulm, University Ulm, Helmholtzstr. 8/1, 89081, Ulm, Germany
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Walrand S, Gaulmin R, Aubin R, Sapin V, Coste A, Abbot M. Nutritional factors in sport-related concussion. Neurochirurgie 2021; 67:255-258. [PMID: 33582206 DOI: 10.1016/j.neuchi.2021.02.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 02/06/2021] [Indexed: 11/28/2022]
Abstract
BACKGROUND Sports concussion is a major problem that affects thousands of people every year. Concussion-related neurometabolic changes are thought to underlie neurophysiological alterations and post-concussion symptoms, such as headaches and sensitivity to light and noise, disabilities of concentration and tiredness. The injury triggers a complex neurometabolic cascade involving multiple mechanisms. There are pharmaceutical treatments that target one mechanism, but specific nutrients have been found to impact several pathways, thus offering a broader approach. This has prompted intensive research into the use of nutrient supplements as a concussion prevention and treatment strategy. METHOD We realised a bibliographic state of art providing a contemporary clinical and preclinical studies dealing with nutritional factors in sport-related concussion. RESULTS Numerous supplements, including n-3 polyunsaturated fatty acids, sulfur amino acids, antioxidants and minerals, have shown promising results as aids to concussion recovery or prevention in animal studies, most of which use a fluid percussion technique to cause brain injury, and in a few human studies of severe or moderate traumatic brain injury. Current ongoing human trials can hopefully provide us with more information, in particular, on new options, i.e. probiotics, lactate or amino acids, for the use of nutritional supplements for concussed athletes. CONCLUSION Nutritional supplementation has emerged as a potential strategy to prevent and/or reduce the deleterious effects of sports-related concussion and subconcussive impacts.
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Affiliation(s)
- S Walrand
- Service de Nutrition Clinique, CHU Clermont-Ferrand, Université Clermont-Auvergne, 63000 Clermont-Ferrand, France.
| | - R Gaulmin
- Service médical, ASM Clermont-Auvergne Rugby, 63028 Clermont-Ferrand cedex 2, France
| | - R Aubin
- Service médical, ASM Clermont-Auvergne Rugby, 63028 Clermont-Ferrand cedex 2, France
| | - V Sapin
- Service de Biochimie & Génétique Moléculaire, CHU Clermont-Ferrand, Université Clermont Auvergne, 63000 Clermont-Ferrand, France
| | - A Coste
- Service de Neurochirurgie, CHU Clermont-Ferrand, 63000 Clermont-Ferrand, France
| | - M Abbot
- Service médical, ASM Clermont-Auvergne Rugby, 63028 Clermont-Ferrand cedex 2, France; Service de Médecine du Sport, CHU Clermont-Ferrand, 63000 Clermont-Ferrand, France
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45
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Mikaelyan KA, Krylov KY, Petrova MV, Shestopalov AE. [Intestine morphology and microbiocenosis changes in critically ill patients in neurosurgery]. ZHURNAL VOPROSY NEĬROKHIRURGII IMENI N. N. BURDENKO 2021; 85:104-110. [PMID: 33560626 DOI: 10.17116/neiro202185011104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
In recent years, the effect of critical conditions on intestine and the role of such changes in maintenance and progression of systemic disorders are of particular attention. This issue is relevant in critically ill neurosurgical patients too. Intestine morphology and microbiome changes in these patients represent a wide field for researches in intensive care and prevention of secondary damage to other organs and systems. This review ensures a current approach to the problem of intestine morphology and microbiome changes in critically ill neurosurgical patients. We reviewed the data from clinical studies and experiments reproducing a critical condition in animals. Most publications are indexed in the PubMed, e-library, Google Scholar databases. We also analyzed the data from NEJM, JAMA, Lancet, Critical Care and other issues. The manuscript contains an overview of 44 foreign and 13 domestic references; over 50% of researches were published within the past 5 years. Searching depth was over 50 years.
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Affiliation(s)
- K A Mikaelyan
- Russian Peoples' Friendship University, Moscow, Russia
| | - K Yu Krylov
- Pirogov Russian National Research Medical University, Moscow, Russia
| | - M V Petrova
- Russian Peoples' Friendship University, Moscow, Russia
| | - A E Shestopalov
- Federal Research Clinical Center of Intensive Care and Rehabilitation, Lytkino, Russia
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Faden AI, Barrett JP, Stoica BA, Henry RJ. Bidirectional Brain-Systemic Interactions and Outcomes After TBI. Trends Neurosci 2021; 44:406-418. [PMID: 33495023 DOI: 10.1016/j.tins.2020.12.004] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 12/23/2020] [Accepted: 12/31/2020] [Indexed: 12/16/2022]
Abstract
Traumatic brain injury (TBI) is a debilitating disorder associated with chronic progressive neurodegeneration and long-term neurological decline. Importantly, there is now substantial and increasing evidence that TBI can negatively impact systemic organs, including the pulmonary, gastrointestinal (GI), cardiovascular, renal, and immune system. Less well appreciated, until recently, is that such functional changes can affect both the response to subsequent insults or diseases, as well as contribute to chronic neurodegenerative processes and long-term neurological outcomes. In this review, we summarize evidence showing bidirectional interactions between the brain and systemic organs following TBI and critically assess potential underlying mechanisms.
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Affiliation(s)
- Alan I Faden
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD, USA.
| | - James P Barrett
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Bogdan A Stoica
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Rebecca J Henry
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD, USA
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Hanscom M, Loane DJ, Aubretch T, Leser J, Molesworth K, Hedgekar N, Ritzel RM, Abulwerdi G, Shea-Donohue T, Faden AI. Acute colitis during chronic experimental traumatic brain injury in mice induces dysautonomia and persistent extraintestinal, systemic, and CNS inflammation with exacerbated neurological deficits. J Neuroinflammation 2021; 18:24. [PMID: 33461596 PMCID: PMC7814749 DOI: 10.1186/s12974-020-02067-x] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 12/21/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Disruptions of brain-gut axis have been implicated in the progression of a variety of gastrointestinal (GI) disorders and central nervous system (CNS) diseases and injuries, including traumatic brain injury (TBI). TBI is a chronic disease process characterized by persistent secondary injury processes which can be exacerbated by subsequent challenges. Enteric pathogen infection during chronic TBI worsened cortical lesion volume; however, the pathophysiological mechanisms underlying the damaging effects of enteric challenge during chronic TBI remain unknown. This preclinical study examined the effect of intestinal inflammation during chronic TBI on associated neurobehavioral and neuropathological outcomes, systemic inflammation, and dysautonomia. METHODS Dextran sodium sulfate (DSS) was administered to adult male C57BL/6NCrl mice 28 days following craniotomy (Sham) or TBI for 7 days to induce intestinal inflammation, followed by a return to normal drinking water for an additional 7 to 28 days for recovery; uninjured animals (Naïve) served as an additional control group. Behavioral testing was carried out prior to, during, and following DSS administration to assess changes in motor and cognitive function, social behavior, and mood. Electrocardiography was performed to examine autonomic balance. Brains were collected for histological and molecular analyses of injury lesion, neurodegeneration, and neuroinflammation. Blood, colons, spleens, mesenteric lymph nodes (mLNs), and thymus were collected for morphometric analyses and/or immune characterization by flow cytometry. RESULTS Intestinal inflammation 28 days after craniotomy or TBI persistently induced, or exacerbated, respectively, deficits in fine motor coordination, cognition, social behavior, and anxiety-like behavior. Behavioral changes were associated with an induction, or exacerbation, of hippocampal neuronal cell loss and microglial activation in Sham and TBI mice administered DSS, respectively. Acute DSS administration resulted in a sustained systemic immune response with increases in myeloid cells in blood and spleen, as well as myeloid cells and lymphocytes in mesenteric lymph nodes. Dysautonomia was also induced in Sham and TBI mice administered DSS, with increased sympathetic tone beginning during DSS administration and persisting through the first recovery week. CONCLUSION Intestinal inflammation during chronic experimental TBI causes a sustained systemic immune response and altered autonomic balance that are associated with microglial activation, increased neurodegeneration, and persistent neurological deficits.
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Affiliation(s)
- Marie Hanscom
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF #6-016, Baltimore, MD, 21201, USA.
| | - David J Loane
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF #6-016, Baltimore, MD, 21201, USA
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, Dublin, Ireland
| | - Taryn Aubretch
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF #6-016, Baltimore, MD, 21201, USA
| | - Jenna Leser
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF #6-016, Baltimore, MD, 21201, USA
| | - Kara Molesworth
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF #6-016, Baltimore, MD, 21201, USA
| | - Nivedita Hedgekar
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF #6-016, Baltimore, MD, 21201, USA
| | - Rodney M Ritzel
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF #6-016, Baltimore, MD, 21201, USA
| | - Gelareh Abulwerdi
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF #6-016, Baltimore, MD, 21201, USA
| | - Terez Shea-Donohue
- Division of Translational Radiation Sciences (DTRS), Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Alan I Faden
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF #6-016, Baltimore, MD, 21201, USA
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48
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Chao CM, Hsu CC, Huang CC, Wang CH, Lin MT, Chang CP, Lin HJ, Chio CC. Selective brain cooling achieves peripheral organs protection in hemorrhagic shock resuscitation via preserving the integrity of the brain-gut axis. Int J Med Sci 2021; 18:2920-2929. [PMID: 34220319 PMCID: PMC8241763 DOI: 10.7150/ijms.61191] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Accepted: 05/23/2021] [Indexed: 01/08/2023] Open
Abstract
Background: Although whole-body cooling has been reported to improve the ischemic/reperfusion injury in hemorrhagic shock (HS) resuscitation, it is limited by its adverse reactions following therapeutic hypothermia. HS affects the experimental and clinical bowel disorders via activation of the brain-gut axis. It is unknown whether selective brain cooling achieves beneficial effects in HS resuscitation via preserving the integrity of the brain-gut axis. Methods: Male Sprague-Dawley rats were bled to hypovolemic HS and resuscitated with blood transfusion followed by retrograde jugular vein flush (RJVF) with 4 °C or 36 °C normal saline. The mean arterial blood pressure, cerebral blood flow, and brain and core temperature were measured. The integrity of intestinal tight junction proteins and permeability, blood pro-inflammatory cytokines, and multiple organs damage score were determined. Results: Following blood transfusion resuscitation, HS rats displayed gut barrier disruption, increased blood levels of pro-inflammatory cytokines, and peripheral vital organ injuries. Intrajugular-based infusion cooled the brain robustly with a minimal effect on body temperature. This brain cooling significantly reduced the HS resuscitation-induced gut disruption, systemic inflammation, and peripheral vital organ injuries in rats. Conclusion: Resuscitation with selective brain cooling achieves peripheral vital organs protection in hemorrhagic shock resuscitation via preserving the integrity of the brain-gut axis.
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Affiliation(s)
- Chien-Ming Chao
- Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, Tainan, Taiwan.,Department of Nursing, Min-Hwei College of Health Care Management, Tainan, Taiwan
| | - Chien-Chin Hsu
- Department of Emergency Medicine, Chi Mei Medical Center, Tainan, Taiwan
| | - Chien-Cheng Huang
- Department of Emergency Medicine, Chi Mei Medical Center, Tainan, Taiwan.,Department of Senior Services, Southern Taiwan University of Science and Technology, Tainan, Taiwan.,Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chung-Han Wang
- Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan
| | - Mao-Tsun Lin
- Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan
| | - Ching-Ping Chang
- Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan
| | - Hung-Jung Lin
- Department of Emergency Medicine, Chi Mei Medical Center, Tainan, Taiwan.,Department of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chung-Ching Chio
- Division of Neurosurgery, Department of Surgery, Chi Mei Medical Center, Tainan, Taiwan
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49
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Blanke EN, Holmes GM, Besecker EM. Altered physiology of gastrointestinal vagal afferents following neurotrauma. Neural Regen Res 2021; 16:254-263. [PMID: 32859772 PMCID: PMC7896240 DOI: 10.4103/1673-5374.290883] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The adaptability of the central nervous system has been revealed in several model systems. Of particular interest to central nervous system-injured individuals is the ability for neural components to be modified for regain of function. In both types of neurotrauma, traumatic brain injury and spinal cord injury, the primary parasympathetic control to the gastrointestinal tract, the vagus nerve, remains anatomically intact. However, individuals with traumatic brain injury or spinal cord injury are highly susceptible to gastrointestinal dysfunctions. Such gastrointestinal dysfunctions attribute to higher morbidity and mortality following traumatic brain injury and spinal cord injury. While the vagal efferent output remains capable of eliciting motor responses following injury, evidence suggests impairment of the vagal afferents. Since sensory input drives motor output, this review will discuss the normal and altered anatomy and physiology of the gastrointestinal vagal afferents to better understand the contributions of vagal afferent plasticity following neurotrauma.
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Affiliation(s)
- Emily N Blanke
- Department of Neural and Behavioral Sciences, Penn State University College of Medicine, Hershey, PA, USA
| | - Gregory M Holmes
- Department of Neural and Behavioral Sciences, Penn State University College of Medicine, Hershey, PA, USA
| | - Emily M Besecker
- Department of Health Sciences, Gettysburg College, Gettysburg, PA, USA
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50
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Weaver JL. The brain-gut axis: A prime therapeutic target in traumatic brain injury. Brain Res 2020; 1753:147225. [PMID: 33359374 DOI: 10.1016/j.brainres.2020.147225] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 11/27/2020] [Accepted: 12/01/2020] [Indexed: 01/10/2023]
Abstract
Traumatic brain injury (TBI) is a significant cause of morbidity and mortality in trauma patients. The primary focus of treating TBI is to prevent additional injury to the damaged brain tissue, known as secondary brain injury. This treatment can include treating the body's inflammatory response. Despite promise in animal models, anti-inflammatory therapy has failed to improve outcomes in human patients, suggesting a more targeted and precise approach may be needed. There is a bidirectional axis between the intestine and the brain that contributes to this inflammation in acute and chronic injury. The mechanisms for this interaction are not completely understood, but there is evidence that neural, inflammatory, endocrine, and microbiome signals all participate in this process. Therapies that target the intestine as a source of inflammation have potential to lessen secondary brain injury and improve outcomes in TBI patients, but to develop these treatments we need to better understand the mechanisms behind this intestinal inflammatory response.
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Affiliation(s)
- Jessica L Weaver
- Division of Trauma, Surgical Critical Care, Burns, and Acute Care Surgery, Department of Surgery, University of California, San Diego School of Medicine, 200 W Arbor Drive #8896, San Diego, CA 92103-8896, United States.
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