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1
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Ohara TE, Hsiao EY. Microbiota-neuroepithelial signalling across the gut-brain axis. Nat Rev Microbiol 2025; 23:371-384. [PMID: 39743581 DOI: 10.1038/s41579-024-01136-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/25/2024] [Indexed: 01/04/2025]
Abstract
Research over the past two decades has established a remarkable ability of the gut microbiota to modulate brain activity and behaviour. Conversely, signals from the brain can influence the composition and function of the gut microbiota. This bidirectional communication across the gut microbiota-brain axis, involving multiple biochemical and cellular mediators, is recognized as a major brain-body network that integrates cues from the environment and the body's internal state. Central to this network is the gut sensory system, formed by intimate connections between chemosensory epithelial cells and sensory nerve fibres, that conveys interoceptive signals to the central nervous system. In this Review, we provide a broad overview of the pathways that connect the gut and the brain, and explore the complex dialogue between microorganisms and neurons at this emerging intestinal neuroepithelial interface. We highlight relevant microbial factors, endocrine cells and neural mechanisms that govern gut microbiota-brain interactions and their implications for gastrointestinal and neuropsychiatric health.
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Affiliation(s)
- Takahiro E Ohara
- Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA.
| | - Elaine Y Hsiao
- Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA.
- UCLA Goodman-Luskin Microbiome Center, Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, UCLA David Geffen School of Medicine, Los Angeles, CA, USA.
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2
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Costa DVS, Thomasi B, Brito GAC, Gulbransen BD, Warren CA. The role of the enteric nervous system in the pathogenesis of Clostridioides difficile infection. Nat Rev Gastroenterol Hepatol 2025:10.1038/s41575-025-01071-x. [PMID: 40404838 DOI: 10.1038/s41575-025-01071-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/16/2025] [Indexed: 05/24/2025]
Abstract
Clostridioides difficile is the leading cause of antibiotic-associated diarrhoea worldwide. In the USA, C. difficile infection (CDI) is the eighth leading cause for hospital readmission and seventh for mortality among all gastrointestinal disorders. Gastrointestinal dysmotility and/or diarrhoea occurs after the acute phase of CDI, but persistent gastrointestinal dysfunction post-infection supports contributions of neuroplasticity in the enteric nervous system (ENS), which has a key role in regulating intestinal motility and secretion, in the natural course of CDI. Here, our goal is to provide an up-to-date summary of how the ENS and extrinsic innervation of the gut are affected by CDI and how ENS responses contribute to CDI pathogenesis and outcomes. Enteric neurons and glia are targets of C. difficile toxins in humans and in preclinical model, and changes to the ENS and extrinsic innervation contribute to intestinal inflammation, damage and secretory diarrhoea. These findings suggest possible bidirectional interaction between CDI and the ENS. More studies focusing on understanding how various neurotransmitters and mediators released by the ENS and extrinsic neurons modulate immune responses to CDI could provide insight into novel pharmacological approaches to balance the host response, improve the management of CDI and prevent gastrointestinal dysfunction post-infection.
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Affiliation(s)
- Deiziane V S Costa
- Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, USA.
| | - Beatriz Thomasi
- Department of Physiology, Michigan State University, East Lansing, MI, USA
| | - Gerly A C Brito
- Department of Morphology, School of Medicine, Federal University of Ceará, Fortaleza, Brazil
| | - Brian D Gulbransen
- Department of Physiology, Michigan State University, East Lansing, MI, USA
| | - Cirle A Warren
- Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, USA.
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3
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Hunjan G, Shah SS, Kosey S, Aran KR. Gut microbiota and the tryptophan-kynurenine pathway in anxiety: new insights and treatment strategies. J Neural Transm (Vienna) 2025:10.1007/s00702-025-02938-8. [PMID: 40369368 DOI: 10.1007/s00702-025-02938-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Accepted: 04/28/2025] [Indexed: 05/16/2025]
Abstract
Anxiety disorders are mental health disorders characterized by long-lasting fear, worry, nervousness, and alterations in gut microbiota (GM). The GM is a vital modulator of brain function through the gut-brain axis, which acts as the neural pathway between the central and peripheral nervous systems. Dysbiosis of GM plays an essential role in anxiety development because of alterations in the vagus nerve, increased intestinal permeability, and altered breakdown of tryptophan (TRP). The Kynurenine (KYN) pathway plays a crucial role in the pathogenesis of anxiety disorders, primarily through its neuroprotective (KYNA) and neurotoxic (QUIN) metabolites. Higher ratios of KYNA/QUIN result in neuroprotection, whereas higher KYN/TRP ratios indicate increased QUIN production causing neuroinflammation. Studies on germ-free models exhibit higher plasma TRP levels, which interrupt the metabolic balance of TRP-derived compounds, thus causing brain impairment. A key issue in anxiety disorders is the dysregulation of GM, which disrupts TRP metabolism and neuroinflammatory pathways, however, remains poorly understood. Hence, the proper understanding of these mechanisms is crucial for future therapeutic advancements. Here, we highlight the significance of the TRP-KYN pathway and the potential of modulating KYN pathway enzymes, such as kynurenine aminotransferases (KATs), to adjust KYNA levels and restore neurotransmitter balance. It further discusses new therapeutic methods with a particular focus on probiotics that may restore GM and modulate TRP metabolism. Advancing our understanding of the intricate relationship between GM and anxiety disorders may facilitate novel, microbiota-targeted interventions. This ultimately contributes to precision medicine approaches in mental health care, thereby enhancing treatment efficacy and patient outcomes.
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Affiliation(s)
- Garry Hunjan
- Department of Pharmacy Practice, ISF College of Pharmacy, Moga, 142001, Punjab, India
| | - Shiv Shankar Shah
- Krupanidhi College of Pharmacy, Carmelaram Gunjur Road, Hobli, off Sarjapur Road, Varthur, Bengaluru, 560035, Karnataka, India
| | - Sourabh Kosey
- Department of Pharmacy Practice, ISF College of Pharmacy, Moga, 142001, Punjab, India
| | - Khadga Raj Aran
- Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, 142001, Punjab, India.
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4
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Interino N, Vitagliano R, D’Amico F, Lodi R, Porru E, Turroni S, Fiori J. Microbiota-Gut-Brain Axis: Mass-Spectrometry-Based Metabolomics in the Study of Microbiome Mediators-Stress Relationship. Biomolecules 2025; 15:243. [PMID: 40001546 PMCID: PMC11853089 DOI: 10.3390/biom15020243] [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: 12/12/2024] [Revised: 01/26/2025] [Accepted: 02/04/2025] [Indexed: 02/27/2025] Open
Abstract
The microbiota-gut-brain axis is a complex bidirectional communication system that involves multiple interactions between intestinal functions and the emotional and cognitive centers of the brain. These interactions are mediated by molecules (metabolites) produced in both areas, which are considered mediators. To shed light on this complex mechanism, which is still largely unknown, a reliable characterization of the mediators is essential. Here, we review the most studied metabolites in the microbiota-gut-brain axis, the metabolic pathways in which they are involved, and their functions. This review focuses mainly on the use of mass spectrometry for their determination, reporting on the latest analytical methods, their limitations, and future perspectives. The analytical strategy for the qualitative-quantitative characterization of mediators must be reliable in order to elucidate the molecular mechanisms underlying the influence of the above-mentioned axis on stress resilience or vulnerability.
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Affiliation(s)
- Nicolò Interino
- IRCCS Institute of Neurological Sciences of Bologna, 40139 Bologna, Italy; (N.I.); (R.V.); (R.L.)
| | - Rosalba Vitagliano
- IRCCS Institute of Neurological Sciences of Bologna, 40139 Bologna, Italy; (N.I.); (R.V.); (R.L.)
| | - Federica D’Amico
- Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy;
| | - Raffaele Lodi
- IRCCS Institute of Neurological Sciences of Bologna, 40139 Bologna, Italy; (N.I.); (R.V.); (R.L.)
| | - Emanuele Porru
- Occupational Medicine Unit, Department of Medical and Surgical Science, Alma Mater Studiorum, University of Bologna, 40138 Bologna, Italy;
| | - Silvia Turroni
- Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy;
| | - Jessica Fiori
- IRCCS Institute of Neurological Sciences of Bologna, 40139 Bologna, Italy; (N.I.); (R.V.); (R.L.)
- Department of Chemistry “G. Ciamician”, University of Bologna, 40126 Bologna, Italy
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5
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Bellés A, Abad I, Buey B, Vergara C, Mesonero JE, Sánchez L, Grasa L. Buttermilk and Whey as Functional Foods to Ameliorate Clindamycin-Induced Changes in Mouse Intestine: Modulation of Intestinal Motility and Toll-like Receptors Expression. J Med Food 2025; 28:205-211. [PMID: 39509172 DOI: 10.1089/jmf.2024.0155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2024] Open
Abstract
Antibiotic treatment is one of the main causes of intestinal dysbiosis, leading, in turn, to other intestinal alterations given the multiple relationships of the microbiota with gut health. Whey and buttermilk are two by-products from the dairy industry with numerous bioactive components. This study aimed to assess the potential of two formulas, containing a mixture of lactoferrin, milk fat globule membrane (MFGM), and whey or buttermilk, to reverse the negative effects of clindamycin on gut motility, Toll-like receptors (TLRs) expression, and oxidative stress in the intestine. For this purpose, a murine model of intestinal dysbiosis was established by clindamycin treatment. Male C57BL/6 mice were treated with saline (Control), clindamycin (Clin), a formula containing whey (F1), or buttermilk (F2) supplemented with lactoferrin and MFGM, Clin+F1, or Clin+F2. Clin delayed the whole gut transit, reduced the response to acetylcholine, decreased TLR2 expression, and increased TLR4 expression in the intestine. F1 and F2 formulas reversed the effects of Clin, restoring TLR2 receptor levels and normalizing intestinal dysmotility. These results indicate that whey- and buttermilk-based formulas supplemented with lactoferrin and MFGM could be used as functional foods to prevent or treat motility disorders and restore some components of the immune system after antibiotic treatment.
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Affiliation(s)
- Andrea Bellés
- Departamento de Farmacología, Fisiología y Medicina Legal y Forense. Facultad de Veterinaria, Universidad de Zaragoza, Zaragoza, Spain
- Instituto Agroalimentario de Aragón IA2 (UNIZAR-CITA), Zaragoza, Spain
| | - Inés Abad
- Instituto Agroalimentario de Aragón IA2 (UNIZAR-CITA), Zaragoza, Spain
- Departamento de Producción Animal y Tecnología de los Alimentos, Facultad de Veterinaria, Universidad de Zaragoza, Zaragoza, Spain
| | - Berta Buey
- Departamento de Farmacología, Fisiología y Medicina Legal y Forense. Facultad de Veterinaria, Universidad de Zaragoza, Zaragoza, Spain
- Instituto Agroalimentario de Aragón IA2 (UNIZAR-CITA), Zaragoza, Spain
- Instituto de Investigación Sanitaria de Aragón (IIS Aragón), Zaragoza, Spain
| | - Claudia Vergara
- Departamento de Farmacología, Fisiología y Medicina Legal y Forense. Facultad de Veterinaria, Universidad de Zaragoza, Zaragoza, Spain
| | - José Emilio Mesonero
- Departamento de Farmacología, Fisiología y Medicina Legal y Forense. Facultad de Veterinaria, Universidad de Zaragoza, Zaragoza, Spain
- Instituto Agroalimentario de Aragón IA2 (UNIZAR-CITA), Zaragoza, Spain
- Instituto de Investigación Sanitaria de Aragón (IIS Aragón), Zaragoza, Spain
| | - Lourdes Sánchez
- Instituto Agroalimentario de Aragón IA2 (UNIZAR-CITA), Zaragoza, Spain
- Departamento de Producción Animal y Tecnología de los Alimentos, Facultad de Veterinaria, Universidad de Zaragoza, Zaragoza, Spain
| | - Laura Grasa
- Departamento de Farmacología, Fisiología y Medicina Legal y Forense. Facultad de Veterinaria, Universidad de Zaragoza, Zaragoza, Spain
- Instituto Agroalimentario de Aragón IA2 (UNIZAR-CITA), Zaragoza, Spain
- Instituto de Investigación Sanitaria de Aragón (IIS Aragón), Zaragoza, Spain
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6
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Alam M, Abbas K, Mustafa M, Usmani N, Habib S. Microbiome-based therapies for Parkinson's disease. Front Nutr 2024; 11:1496616. [PMID: 39568727 PMCID: PMC11576319 DOI: 10.3389/fnut.2024.1496616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Accepted: 10/21/2024] [Indexed: 11/22/2024] Open
Abstract
The human gut microbiome dysbiosis plays an important role in the pathogenesis of Parkinson's disease (PD). The bidirectional relationship between the enteric nervous system (ENS) and central nervous system (CNS) under the mediation of the gut-brain axis control the gastrointestinal functioning. This review article discusses key mechanisms by which modifications in the composition and function of the gut microbiota (GM) influence PD progression and motor control loss. Increased intestinal permeability, chronic inflammation, oxidative stress, α-synuclein aggregation, and neurotransmitter imbalances are some key factors that govern gastrointestinal pathology and PD progression. The bacterial taxa of the gut associated with PD development are discussed with emphasis on the enteric nervous system (ENS), as well as the impact of gut bacteria on dopamine production and levodopa metabolism. The pathophysiology and course of the disease are associated with several inflammatory markers, including TNF-α, IL-1β, and IL-6. Emerging therapeutic strategies targeting the gut microbiome include probiotics, prebiotics, synbiotics, postbiotics, and fecal microbiota transplantation (FMT). The article explored how dietary changes may affect the gut microbiota (GM) and the ways that can affect Parkinson's disease (PD), with a focus on nutrition-based, Mediterranean, and ketogenic diets. This comprehensive review synthesizes current evidence on the role of the gut microbiome in PD pathogenesis and explores its potential as a therapeutic target. Understanding these complex interactions may assist in the development of novel diagnostic tools and treatment options for this neurodegenerative disorder.
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Affiliation(s)
- Mudassir Alam
- Indian Biological Sciences and Research Institute (IBRI), Noida, India
| | - Kashif Abbas
- Department of Zoology, Faculty of Life Sciences, Aligarh Muslim University, Aligarh, India
| | - Mohd Mustafa
- Department of Biochemistry, J.N. Medical College, Aligarh Muslim University, Aligarh, India
| | - Nazura Usmani
- Department of Zoology, Faculty of Life Sciences, Aligarh Muslim University, Aligarh, India
| | - Safia Habib
- Department of Biochemistry, J.N. Medical College, Aligarh Muslim University, Aligarh, India
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7
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Alexander SN, Green AR, Debner EK, Ramos Freitas LE, Abdelhadi HMK, Szabo-Pardi TA, Burton MD. The influence of sex on neuroimmune communication, pain, and physiology. Biol Sex Differ 2024; 15:82. [PMID: 39439003 PMCID: PMC11494817 DOI: 10.1186/s13293-024-00660-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 10/02/2024] [Indexed: 10/25/2024] Open
Abstract
With the National Institutes of Health's mandate to consider sex as a biological variable (SABV), there has been a significant increase of studies utilizing both sexes. Historically, we have known that biological sex and hormones influence immunological processes and now studies focusing on interactions between the immune, endocrine, and nervous systems are revealing sex differences that influence pain behavior and various molecular and biochemical processes. Neuroendocrine-immune interactions represent a key integrative discipline that will reveal critical processes in each field as it pertains to novel mechanisms in sex differences and necessary therapeutics. Here we appraise preclinical and clinical literature to discuss these interactions and key pathways that drive cell- and sex-specific differences in immunity, pain, and physiology.
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Affiliation(s)
- Shevon N Alexander
- Neuroimmunology and Behavior Laboratory, Department of Neuroscience, School of Behavioral and Brain Sciences, Center for Advanced Pain Studies, University of Texas at Dallas, 800 W. Campbell Road, BSB 10.537, Richardson, TX, 75080, USA
| | - Audrey R Green
- Neuroimmunology and Behavior Laboratory, Department of Neuroscience, School of Behavioral and Brain Sciences, Center for Advanced Pain Studies, University of Texas at Dallas, 800 W. Campbell Road, BSB 10.537, Richardson, TX, 75080, USA
| | - Emily K Debner
- Neuroimmunology and Behavior Laboratory, Department of Neuroscience, School of Behavioral and Brain Sciences, Center for Advanced Pain Studies, University of Texas at Dallas, 800 W. Campbell Road, BSB 10.537, Richardson, TX, 75080, USA
| | - Lindsey E Ramos Freitas
- Neuroimmunology and Behavior Laboratory, Department of Neuroscience, School of Behavioral and Brain Sciences, Center for Advanced Pain Studies, University of Texas at Dallas, 800 W. Campbell Road, BSB 10.537, Richardson, TX, 75080, USA
| | - Hanna M K Abdelhadi
- Neuroimmunology and Behavior Laboratory, Department of Neuroscience, School of Behavioral and Brain Sciences, Center for Advanced Pain Studies, University of Texas at Dallas, 800 W. Campbell Road, BSB 10.537, Richardson, TX, 75080, USA
| | - Thomas A Szabo-Pardi
- Neuroimmunology and Behavior Laboratory, Department of Neuroscience, School of Behavioral and Brain Sciences, Center for Advanced Pain Studies, University of Texas at Dallas, 800 W. Campbell Road, BSB 10.537, Richardson, TX, 75080, USA
| | - Michael D Burton
- Neuroimmunology and Behavior Laboratory, Department of Neuroscience, School of Behavioral and Brain Sciences, Center for Advanced Pain Studies, University of Texas at Dallas, 800 W. Campbell Road, BSB 10.537, Richardson, TX, 75080, USA.
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8
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Araldi D, Staurengo-Ferrari L, Bogen O, Bonet IJM, Green PG, Levine JD. Mu-Opioid Receptor (MOR) Dependence of Pain in Chemotherapy-Induced Peripheral Neuropathy. J Neurosci 2024; 44:e0243242024. [PMID: 39256047 PMCID: PMC11484550 DOI: 10.1523/jneurosci.0243-24.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 08/06/2024] [Accepted: 09/02/2024] [Indexed: 09/12/2024] Open
Abstract
We recently demonstrated that transient attenuation of Toll-like receptor 4 (TLR4) in dorsal root ganglion (DRG) neurons, can both prevent and reverse pain associated with chemotherapy-induced peripheral neuropathy (CIPN), a severe side effect of cancer chemotherapy, for which treatment options are limited. Given the reduced efficacy of opioid analgesics to treat neuropathic, compared with inflammatory pain, the cross talk between nociceptor TLR4 and mu-opioid receptors (MORs), and that MOR and TLR4 agonists induce hyperalgesic priming (priming), which also occurs in CIPN, we determined, using male rats, whether (1) antisense knockdown of nociceptor MOR attenuates CIPN, (2) and attenuates the priming associated with CIPN, and (3) CIPN also produces opioid-induced hyperalgesia (OIH). We found that intrathecal MOR antisense prevents and reverses hyperalgesia induced by oxaliplatin and paclitaxel, two common clinical chemotherapy agents. Oxaliplatin-induced priming was also markedly attenuated by MOR antisense. Additionally, intradermal morphine, at a dose that does not affect nociceptive threshold in controls, exacerbates mechanical hyperalgesia (OIH) in rats with CIPN, suggesting the presence of OIH. This OIH associated with CIPN is inhibited by interventions that reverse Type II priming [the combination of an inhibitor of Src and mitogen-activated protein kinase (MAPK)], an MOR antagonist, as well as a TLR4 antagonist. Our findings support a role of nociceptor MOR in oxaliplatin-induced pain and priming. We propose that priming and OIH are central to the symptom burden in CIPN, contributing to its chronicity and the limited efficacy of opioid analgesics to treat neuropathic pain.
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Affiliation(s)
- Dionéia Araldi
- Department of Oral and Maxillofacial Surgery, UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco, California 94143
| | - Larissa Staurengo-Ferrari
- Department of Oral and Maxillofacial Surgery, UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco, California 94143
| | - Oliver Bogen
- Department of Oral and Maxillofacial Surgery, UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco, California 94143
| | - Ivan J M Bonet
- Department of Oral and Maxillofacial Surgery, UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco, California 94143
| | - Paul G Green
- Department of Oral and Maxillofacial Surgery, UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco, California 94143
- Department of Preventative and Restorative Dental Sciences, Division of Neuroscience, University of California at San Francisco, San Francisco, California 94143
| | - Jon D Levine
- Department of Oral and Maxillofacial Surgery, UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco, California 94143
- Department of Medicine, Division of Neuroscience, University of California at San Francisco, San Francisco, California 94143
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9
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Rodríguez-Palma EJ, Huerta de la Cruz S, Islas-Espinoza AM, Castañeda-Corral G, Granados-Soto V, Khanna R. Nociplastic pain mechanisms and toll-like receptors as promising targets for its management. Pain 2024; 165:2150-2164. [PMID: 38595206 DOI: 10.1097/j.pain.0000000000003238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Accepted: 02/29/2024] [Indexed: 04/11/2024]
Abstract
ABSTRACT Nociplastic pain, characterized by abnormal pain processing without an identifiable organic cause, affects a significant portion of the global population. Unfortunately, current pharmacological treatments for this condition often prove ineffective, prompting the need to explore new potential targets for inducing analgesic effects in patients with nociplastic pain. In this context, toll-like receptors (TLRs), known for their role in the immune response to infections, represent promising opportunities for pharmacological intervention because they play a relevant role in both the development and maintenance of pain. Although TLRs have been extensively studied in neuropathic and inflammatory pain, their specific contributions to nociplastic pain remain less clear, demanding further investigation. This review consolidates current evidence on the connection between TLRs and nociplastic pain, with a specific focus on prevalent conditions like fibromyalgia, stress-induced pain, sleep deprivation-related pain, and irritable bowel syndrome. In addition, we explore the association between nociplastic pain and psychiatric comorbidities, proposing that modulating TLRs can potentially alleviate both pain syndromes and related psychiatric disorders. Finally, we discuss the potential sex differences in TLR signaling, considering the higher prevalence of nociplastic pain among women. Altogether, this review aims to shed light on nociplastic pain, its underlying mechanisms, and its intriguing relationship with TLR signaling pathways, ultimately framing the potential therapeutic role of TLRs in addressing this challenging condition.
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Affiliation(s)
- Erick J Rodríguez-Palma
- Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, FL, United States
- Neurobiology of Pain Laboratory, Departamento de Farmacobiología, Cinvestav, South Campus, Mexico City, Mexico
| | | | - Ana M Islas-Espinoza
- Neurobiology of Pain Laboratory, Departamento de Farmacobiología, Cinvestav, South Campus, Mexico City, Mexico
| | | | - Vinicio Granados-Soto
- Neurobiology of Pain Laboratory, Departamento de Farmacobiología, Cinvestav, South Campus, Mexico City, Mexico
| | - Rajesh Khanna
- Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, FL, United States
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10
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Vashishth S, Ambasta RK, Kumar P. Deciphering the microbial map and its implications in the therapeutics of neurodegenerative disorder. Ageing Res Rev 2024; 100:102466. [PMID: 39197710 DOI: 10.1016/j.arr.2024.102466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 08/19/2024] [Accepted: 08/19/2024] [Indexed: 09/01/2024]
Abstract
Every facet of biological anthropology, including development, ageing, diseases, and even health maintenance, is influenced by gut microbiota's significant genetic and metabolic capabilities. With current advancements in sequencing technology and with new culture-independent approaches, researchers can surpass older correlative studies and develop mechanism-based studies on microbiome-host interactions. The microbiota-gut-brain axis (MGBA) regulates glial functioning, making it a possible target for the improvement of development and advancement of treatments for neurodegenerative diseases (NDDs). The gut-brain axis (GBA) is accountable for the reciprocal communication between the gastrointestinal and central nervous system, which plays an essential role in the regulation of physiological processes like controlling hunger, metabolism, and various gastrointestinal functions. Lately, studies have discovered the function of the gut microbiome for brain health-different microbiota through different pathways such as immunological, neurological and metabolic pathways. Additionally, we review the involvement of the neurotransmitters and the gut hormones related to gut microbiota. We also explore the MGBA in neurodegenerative disorders by focusing on metabolites. Further, targeting the blood-brain barrier (BBB), intestinal barrier, meninges, and peripheral immune system is investigated. Lastly, we discuss the therapeutics approach and evaluate the pre-clinical and clinical trial data regarding using prebiotics, probiotics, paraprobiotics, fecal microbiota transplantation, personalised medicine, and natural food bioactive in NDDs. A comprehensive study of the GBA will felicitate the creation of efficient therapeutic approaches for treating different NDDs.
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Affiliation(s)
- Shrutikirti Vashishth
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University (Formerly DCE), Delhi 110042, India
| | - Rashmi K Ambasta
- Department of Medicine, School of Medicine, VUMC, Vanderbilt University, TN, USA
| | - Pravir Kumar
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University (Formerly DCE), Delhi 110042, India.
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11
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Jamka JR, Gulbransen BD. Mechanisms of enteric neuropathy in diverse contexts of gastrointestinal dysfunction. Neurogastroenterol Motil 2024:e14870. [PMID: 39038157 DOI: 10.1111/nmo.14870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 06/11/2024] [Accepted: 07/10/2024] [Indexed: 07/24/2024]
Abstract
The enteric nervous system (ENS) commands moment-to-moment gut functions through integrative neurocircuitry housed in the gut wall. The functional continuity of ENS networks is disrupted in enteric neuropathies and contributes to major disturbances in normal gut activities including abnormal gut motility, secretions, pain, immune dysregulation, and disrupted signaling along the gut-brain axis. The conditions under which enteric neuropathy occurs are diverse and the mechanistic underpinnings are incompletely understood. The purpose of this brief review is to summarize the current understanding of the cell types involved, the conditions in which neuropathy occurs, and the mechanisms implicated in enteric neuropathy such as oxidative stress, toll like receptor signaling, purines, and pre-programmed cell death.
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Affiliation(s)
- Julia R Jamka
- Department of Physiology, Michigan State University, East Lansing, Michigan, USA
| | - Brian D Gulbransen
- Department of Physiology, Michigan State University, East Lansing, Michigan, USA
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12
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Yip JLK, Balasuriya GK, Hill-Yardin EL, Spencer SJ. The gut-brain and gut-macrophage contribution to gastrointestinal dysfunction with systemic inflammation. Brain Behav Immun 2024; 119:867-877. [PMID: 38750700 DOI: 10.1016/j.bbi.2024.05.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 04/24/2024] [Accepted: 05/12/2024] [Indexed: 05/19/2024] Open
Abstract
The gastrointestinal tract is one of the main organs affected during systemic inflammation and disrupted gastrointestinal motility is a major clinical manifestation. Many studies have investigated the involvement of neuroimmune interactions in regulating colonic motility during localized colonic inflammation, i.e., colitis. However, little is known about how the enteric nervous system and intestinal macrophages contribute to dysregulated motility during systemic inflammation. Given that systemic inflammation commonly results from the innate immune response against bacterial infection, we mimicked bacterial infection by administering lipopolysaccharide (LPS) to rats and assessed colonic motility using ex vivo video imaging techniques. We utilized the Cx3cr1-Dtr rat model of transient depletion of macrophages to investigate the role of intestinal macrophages in regulating colonic motility during LPS infection. To investigate the role of inhibitory enteric neurotransmission on colonic motility following LPS, we applied the nitric oxide synthase inhibitor, Nω-nitro-L-arginine (NOLA). Our results confirmed an increase in colonic contraction frequency during LPS-induced systemic inflammation. However, neither the depletion of intestinal macrophages, nor the suppression of inhibitory enteric nervous system activity impacted colonic motility disruption during inflammation. This implies that the interplay between the enteric nervous system and intestinal macrophages is nuanced, and complex, and further investigation is needed to clarify their joint roles in colonic motility.
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Affiliation(s)
- Jackson L K Yip
- School of Health and Biomedical Sciences, RMIT University, Bundoora, Melbourne, VIC, Australia
| | - Gayathri K Balasuriya
- School of Health and Biomedical Sciences, RMIT University, Bundoora, Melbourne, VIC, Australia; Department of Physiology and Cell Biology, Kobe University School of Medicine, Kobe, Japan
| | - Elisa L Hill-Yardin
- School of Health and Biomedical Sciences, RMIT University, Bundoora, Melbourne, VIC, Australia
| | - Sarah J Spencer
- School of Health and Biomedical Sciences, RMIT University, Bundoora, Melbourne, VIC, Australia.
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13
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Li HY, Yan WX, Li J, Ye J, Wu ZG, Hou ZK, Chen B. Global research status and trends of enteric glia: a bibliometric analysis. Front Pharmacol 2024; 15:1403767. [PMID: 38855748 PMCID: PMC11157232 DOI: 10.3389/fphar.2024.1403767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 05/08/2024] [Indexed: 06/11/2024] Open
Abstract
Background Enteric glia are essential components of the enteric nervous system. Previously believed to have a passive structural function, mounting evidence now suggests that these cells are indispensable for maintaining gastrointestinal homeostasis and exert pivotal influences on both wellbeing and pathological conditions. This study aimed to investigate the global status, research hotspots, and future directions of enteric glia. Methods The literature on enteric glia research was acquired from the Web of Science Core Collection. VOSviewer software (v1.6.19) was employed to visually represent co-operation networks among countries, institutions, and authors. The co-occurrence analysis of keywords and co-citation analysis of references were conducted using CiteSpace (v6.1.R6). Simultaneously, cluster analysis and burst detection of keywords and references were performed. Results A total of 514 publications from 36 countries were reviewed. The United States was identified as the most influential country. The top-ranked institutions were University of Nantes and Michigan State University. Michel Neunlist was the most cited author. "Purinergic signaling" was the largest co-cited reference cluster, while "enteric glial cells (EGCs)" was the cluster with the highest number of co-occurring keywords. As the keyword with the highest burst strength, Crohns disease was a hot topic in the early research on enteric glia. The burst detection of keywords revealed that inflammation, intestinal motility, and gut microbiota may be the research frontiers. Conclusion This study provides a comprehensive bibliometric analysis of enteric glia research. EGCs have emerged as a crucial link between neurons and immune cells, attracting significant research attention in neurogastroenterology. Their fundamental and translational studies on inflammation, intestinal motility, and gut microbiota may promote the treatment of some gastrointestinal and parenteral disorders.
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Affiliation(s)
- Huai-Yu Li
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Guangdong Clinical Research Academy of Chinese Medicine, Guangzhou, China
| | - Wei-Xin Yan
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Guangdong Clinical Research Academy of Chinese Medicine, Guangzhou, China
| | - Jia Li
- The First Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jing Ye
- School of Clinical Medicine, Jiangxi University of Chinese Medicine, Nanchang, China
| | - Zhi-Guo Wu
- Clinical Medical College of Acupuncture, Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zheng-Kun Hou
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Guangdong Clinical Research Academy of Chinese Medicine, Guangzhou, China
| | - Bin Chen
- Department of Gastroenterology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Guangdong Clinical Research Academy of Chinese Medicine, Guangzhou, China
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14
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Wanyi Z, Jiao Y, Wen H, Bin X, Xuefei W, Lan J, Liuyin Z. Bidirectional communication of the gut-brain axis: new findings in Parkinson's disease and inflammatory bowel disease. Front Neurol 2024; 15:1407241. [PMID: 38854967 PMCID: PMC11157024 DOI: 10.3389/fneur.2024.1407241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 05/13/2024] [Indexed: 06/11/2024] Open
Abstract
Parkinson's disease (PD) and inflammatory bowel disease (IBD) are the two chronic inflammatory diseases that are increasingly affecting millions of people worldwide, posing a major challenge to public health. PD and IBD show similarities in epidemiology, genetics, immune response, and gut microbiota. Here, we review the pathophysiology of these two diseases, including genetic factors, immune system imbalance, changes in gut microbial composition, and the effects of microbial metabolites (especially short-chain fatty acids). We elaborate on the gut-brain axis, focusing on role of gut microbiota in the pathogenesis of PD and IBD. In addition, we discuss several therapeutic strategies, including drug therapy, fecal microbiota transplantation, and probiotic supplementation, and their potential benefits in regulating intestinal microecology and relieving disease symptoms. Our analysis will provide a new understanding and scientific basis for the development of more effective therapeutic strategies for these diseases.
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Affiliation(s)
- Zhang Wanyi
- Department of Neurology, Chongqing Emergency Medical Center, Chongging University Central Hospital, Chongqing, China
| | - Yan Jiao
- Department of Nursing, Chongqing Emergency Medical Center, Chongging University Central Hospital, Chongqing, China
| | - Huang Wen
- Department of Neurology, Chongqing Emergency Medical Center, Chongging University Central Hospital, Chongqing, China
| | - Xu Bin
- Outpatient Department, Chongqing Emergency Medical Center, Chongging University Central Hospital, Chongqing, China
| | - Wang Xuefei
- Department of Neurology, Chongqing Emergency Medical Center, Chongging University Central Hospital, Chongqing, China
| | - Jiang Lan
- Outpatient Department, Chongqing Emergency Medical Center, Chongging University Central Hospital, Chongqing, China
| | - Zhou Liuyin
- Department of Respiratory Medicine, Chongqing Emergency Medical Center, Chongging University Central Hospital, Chongqing, China
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15
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Cho DE, Hong JP, Kim Y, Sim JY, Kim HS, Kim SR, Lee B, Cho HS, Cho IH, Shin S, Yeom M, Kwon SK, Lee IS, Park H, Kim K, Hahm DH. Role of gut-derived bacterial lipopolysaccharide and peripheral TLR4 in immobilization stress-induced itch aggravation in a mouse model of atopic dermatitis. Sci Rep 2024; 14:6263. [PMID: 38491103 PMCID: PMC10942979 DOI: 10.1038/s41598-024-56936-z] [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: 11/13/2023] [Accepted: 03/12/2024] [Indexed: 03/18/2024] Open
Abstract
Psychological stress and intestinal leakage are key factors in atopic dermatitis (AD) recurrence and exacerbation. Here, we demonstrate the mechanism underlying bacterial translocation across intestinal epithelial barrier damaged due to stress and further aggravation of trimellitic anhydride (TMA)-induced itch, which remain unclear, in AD mice. Immobilization (IMO) stress exacerbated scratching bouts and colon histological damage, and increased serum corticosterone and lipopolysaccharide (LPS). Orally administered fluorescein isothiocyanate (FITC)-dextran and surgically injected (into the colon) Cy5.5-conjugated LPS were detected in the serum and skin after IMO stress, respectively. The relative abundance of aerobic or facultative anaerobic bacteria was increased in the colon mucus layer, and Lactobacillus murinus, E. coli, Staphylococcus nepalensis, and several strains of Bacillus sp. were isolated from the spleens and mesenteric lymph nodes. Oral antibiotics or intestinal permeability blockers, such as lubiprostone (Lu), 2,4,6-triaminopyrimidine (TAP) and ML-7, inhibited IMO stress-associated itch; however, it was reinduced through intradermal or i.p. injection of LPS without IMO stress. I.p. injection of TAK-242 (resatorvid), a TLR4 inhibitor, abrogated IMO stress-associated itch, which was also confirmed in TLR4-KO mice. IMO stress alone did not cause itch in naïve mice. IMO stress-induced itch aggravation in TMA-treated AD mice might be attributed to the translocation of gut-derived bacterial cells and LPS, which activates peripheral TLR4 signaling.
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Affiliation(s)
- Da-Eun Cho
- Department of Biomedical Sciences, Graduate School, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Joon-Pyo Hong
- Department of Biomedical Sciences, Graduate School, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Yoongeun Kim
- Department of Biomedical Sciences, Graduate School, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Ju Yeon Sim
- Department of Biomedical Sciences, Graduate School, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Heenam Stanley Kim
- Division of Biosystems and Biomedical Sciences, College of Health Sciences, Korea University, Seoul, 02841, Republic of Korea
| | - Song-Rae Kim
- Chuncheon Center, Korea Basic Science Institute (KBSI), Chuncheon, 24341, Republic of Korea
| | - Bombi Lee
- Acupuncture and Meridian Science Research Center, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Hyo-Sung Cho
- Department of Korean Medical Science, Graduate School, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Ik-Hyun Cho
- Department of Korean Medical Science, Graduate School, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Sooan Shin
- ACCURIEBIO Co., IRIS Lab., 6th Floor, Sangwon 12-gil 34, Seongdong-gu, Seoul, 04790, Republic of Korea
| | - Mijung Yeom
- Acupuncture and Meridian Science Research Center, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Soon-Kyeong Kwon
- Division of Applied Life Science (Brain Korea 21 PLUS), Gyeongsang National University, Jinju, 52828, Republic of Korea
| | - In-Seon Lee
- Acupuncture and Meridian Science Research Center, Kyung Hee University, Seoul, 02447, Republic of Korea
- Department of Korean Medical Science, Graduate School, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Hijoon Park
- Acupuncture and Meridian Science Research Center, Kyung Hee University, Seoul, 02447, Republic of Korea
- Department of Korean Medical Science, Graduate School, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Kyuseok Kim
- Department of Ophthalmology, Otorhinolaryngology and Dermatology of Korean Medicine, College of Korean Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Dae-Hyun Hahm
- Department of Biomedical Sciences, Graduate School, Kyung Hee University, Seoul, 02447, Republic of Korea.
- Acupuncture and Meridian Science Research Center, Kyung Hee University, Seoul, 02447, Republic of Korea.
- Department of Physiology, College of Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea.
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16
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Whitaker EE, Mecum NE, Cott RC, Goode DJ. Expression of MHC II in DRG neurons attenuates paclitaxel-induced cold hypersensitivity in male and female mice. PLoS One 2024; 19:e0298396. [PMID: 38330029 PMCID: PMC10852343 DOI: 10.1371/journal.pone.0298396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Accepted: 01/23/2024] [Indexed: 02/10/2024] Open
Abstract
Chemotherapy is often a life-saving treatment, but the development of intractable pain caused by chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting toxicity that restricts cancer survival rates. Recent reports demonstrate that paclitaxel (PTX) robustly increases anti-inflammatory CD4+ T cells in the dorsal root ganglion (DRG), and that T cells and anti-inflammatory cytokines are protective against CIPN. However, the mechanism by which CD4+ T cells are activated, and the extent cytokines released by CD4+ T cells target DRG neurons are unknown. Here, we are the first to detect major histocompatibility complex II (MHCII) protein in mouse DRG neurons and to find CD4+ T cells breaching the satellite glial cell barrier to be in close proximity to neurons, together suggesting CD4+ T cell activation and targeted cytokine release. MHCII protein is primarily expressed in small nociceptive neurons in male and female mouse DRG but increased after PTX in small nociceptive neurons in only female DRG. Reducing one copy of MHCII in small nociceptive neurons decreased anti-inflammatory IL-10 and IL-4 producing CD4+ T cells in naïve male DRG and increased their hypersensitivity to cold. Administration of PTX to male and female mice that lacked one copy of MHCII in nociceptive neurons decreased anti-inflammatory CD4+ T cells in the DRG and increased the severity of PTX-induced cold hypersensitivity. Collectively, our results demonstrate expression of MHCII protein in mouse DRG neurons, which modulates cytokine producing CD4+ T cells in the DRG and attenuates cold hypersensitivity during homeostasis and after PTX treatment.
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Affiliation(s)
- Emily E. Whitaker
- Department of Biomedical Sciences, College of Osteopathic Medicine, University of New England, Biddeford, Maine, United States of America
| | - Neal E. Mecum
- Department of Biomedical Sciences, College of Osteopathic Medicine, University of New England, Biddeford, Maine, United States of America
| | - Riley C. Cott
- Department of Biomedical Sciences, College of Osteopathic Medicine, University of New England, Biddeford, Maine, United States of America
| | - Diana J. Goode
- Department of Biomedical Sciences, College of Osteopathic Medicine, University of New England, Biddeford, Maine, United States of America
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17
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Elangovan A, Dahiya B, Kirola L, Iyer M, Jeeth P, Maharaj S, Kumari N, Lakhanpal V, Michel TM, Rao KRSS, Cho SG, Yadav MK, Gopalakrishnan AV, Kadhirvel S, Kumar NS, Vellingiri B. Does gut brain axis has an impact on Parkinson's disease (PD)? Ageing Res Rev 2024; 94:102171. [PMID: 38141735 DOI: 10.1016/j.arr.2023.102171] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 12/04/2023] [Accepted: 12/13/2023] [Indexed: 12/25/2023]
Abstract
Parkinson's Disease (PD) is becoming a growing global concern by being the second most prevalent disease next to Alzheimer's Disease (AD). Henceforth new exploration is needed in search of new aspects towards the disease mechanism and origin. Evidence from recent studies has clearly stated the role of Gut Microbiota (GM) in the maintenance of the brain and as a root cause of various diseases and disorders including other neurological conditions. In the case of PD, with an unknown etiology, the GM is said to have a larger impact on the disease pathophysiology. Although GM and its metabolites are crucial for maintaining the normal physiology of the host, it is an undeniable fact that there is an influence of GM in the pathophysiology of PD. As such the Enteroendocrine Cells (EECs) in the epithelium of the intestine are one of the significant regulators of the gut-brain axis and act as a communication mediator between the gut and the brain. The communication is established via the molecules of neuroendocrine which are said to have a crucial part in neurological diseases such as AD, PD, and other psychiatry-related disorders. This review is focused on understanding the proper role of GM and EECs in PD. Here, we also focus on some of the metabolites and compounds that can interact with the PD genes causing various dysfunctions in the cell and facilitating the disease conditions using bioinformatical tools. Various mechanisms concerning EECs and PD, their identification, the latest studies, and available current therapies have also been discussed.
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Affiliation(s)
- Ajay Elangovan
- Human Cytogenetics and Stem Cell Laboratory, Department of Zoology, School of Basic Sciences, Central University of Punjab, Bathinda 151401, Punjab, India
| | - Bhawna Dahiya
- Human Cytogenetics and Stem Cell Laboratory, Department of Zoology, School of Basic Sciences, Central University of Punjab, Bathinda 151401, Punjab, India
| | - Laxmi Kirola
- Department of Biotechnology, School of Health Sciences and Technology (SoHST), UPES University, Dehradun, Uttarakhand 248007, India
| | - Mahalaxmi Iyer
- Department of Microbiology, Central University of Punjab, Bathinda 151401, Punjab, India; Department of Biotechnology, Karpagam Academy of Higher Education (Deemed to be University), Coimbatore 641021, Tamil Nadu, India
| | - Priyanka Jeeth
- Department of Computational Sciences, Central University of Punjab, Bathinda 151401, Punjab, India
| | - Sakshi Maharaj
- Department of Zoology, School of Basic Sciences, Central University of Punjab, Bathinda 151401, Punjab, India
| | - Nikki Kumari
- Department of Zoology, School of Basic Sciences, Central University of Punjab, Bathinda 151401, Punjab, India
| | - Vikas Lakhanpal
- Department of Neurology, All India Institute of Medical Sciences, Bathinda 151005, Punjab, India
| | - Tanja Maria Michel
- Research Unit of Psychiatry, Dept. of Psychiatry Odense, Clinical Institute, University of Southern Denmark, J.B. Winslowsvej 20, Indg. 220B, Odense, Denmark
| | - K R S Sambasiva Rao
- Mangalayatan University - Jabalpur, Jabalpur - 481662, Madhya Pradesh, India
| | - Ssang-Goo Cho
- Department of Stem Cell and Regenerative Biotechnology, Molecular & Cellular Reprogramming Center and Institute of Advanced Regenerative Science, Konkuk University, 120 Neungdong-ro Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Mukesh Kumar Yadav
- Department of Microbiology, Central University of Punjab, Bathinda 151401, Punjab, India
| | - Abilash Valsala Gopalakrishnan
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology, Vellore 632 014, India
| | - Saraboji Kadhirvel
- Department of Computational Sciences, Central University of Punjab, Bathinda 151401, Punjab, India
| | - Nachimuthu Senthil Kumar
- Department of Biotechnology, Mizoram University (A Central University), Aizawl, 796 004 Mizoram, India
| | - Balachandar Vellingiri
- Human Cytogenetics and Stem Cell Laboratory, Department of Zoology, School of Basic Sciences, Central University of Punjab, Bathinda 151401, Punjab, India.
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18
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Lataro RM, Brognara F, Iturriaga R, Paton JFR. Inflammation of some visceral sensory systems and autonomic dysfunction in cardiovascular disease. Auton Neurosci 2024; 251:103137. [PMID: 38104365 DOI: 10.1016/j.autneu.2023.103137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 11/15/2023] [Accepted: 12/04/2023] [Indexed: 12/19/2023]
Abstract
The sensitization and hypertonicity of visceral afferents are highly relevant to the development and progression of cardiovascular and respiratory disease states. In this review, we described the evidence that the inflammatory process regulates visceral afferent sensitivity and tonicity, affecting the control of the cardiovascular and respiratory system. Some inflammatory mediators like nitric oxide, angiotensin II, endothelin-1, and arginine vasopressin may inhibit baroreceptor afferents and contribute to the baroreflex impairment observed in cardiovascular diseases. Cytokines may act directly on peripheral afferent terminals that transmit information to the central nervous system (CNS). TLR-4 receptors, which recognize lipopolysaccharide, were identified in the nodose and petrosal ganglion and have been implicated in disrupting the blood-brain barrier, which can potentiate the inflammatory process. For example, cytokines may cross the blood-brain barrier to access the CNS. Additionally, pro-inflammatory cytokines such as IL-1β, IL-6, TNF-α and some of their receptors have been identified in the nodose ganglion and carotid body. These pro-inflammatory cytokines also sensitize the dorsal root ganglion or are released in the nucleus of the solitary tract. In cardiovascular disease, pro-inflammatory mediators increase in the brain, heart, vessels, and plasma and may act locally or systemically to activate/sensitize afferent nervous terminals. Recent evidence demonstrated that the carotid body chemoreceptor cells might sense systemic pro-inflammatory molecules, supporting the novel proposal that the carotid body is part of the afferent pathway in the central anti-inflammatory reflexes. The exact mechanisms of how pro-inflammatory mediators affects visceral afferent signals and contribute to the pathophysiology of cardiovascular diseases awaits future research.
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Affiliation(s)
- R M Lataro
- Department of Physiological Sciences, Center of Biological Sciences, Federal University of Santa Catarina, Florianópolis, Santa Catarina, Brazil.
| | - F Brognara
- Department of Nursing, General and Specialized, Nursing School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - R Iturriaga
- Facultad de Ciencias Biológicas, Pontificia Universidad Catolica de Chile, Santiago, Chile; Centro de Investigación en Fisiología y Medicina en Altura - FIMEDALT, Universidad de Antofagasta, Antofagasta, Chile
| | - J F R Paton
- Manaaki Manawa - The Centre for Heart Research, Department of Physiology, Faculty of Medical & Health Sciences, University of Auckland, Grafton, Auckland, New Zealand
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19
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Mohamed AA, al-Ramadi BK, Fernandez-Cabezudo MJ. Interplay between Microbiota and γδ T Cells: Insights into Immune Homeostasis and Neuro-Immune Interactions. Int J Mol Sci 2024; 25:1747. [PMID: 38339023 PMCID: PMC10855551 DOI: 10.3390/ijms25031747] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 01/03/2024] [Accepted: 01/04/2024] [Indexed: 02/12/2024] Open
Abstract
The gastrointestinal (GI) tract of multicellular organisms, especially mammals, harbors a symbiotic commensal microbiota with diverse microorganisms including bacteria, fungi, viruses, and other microbial and eukaryotic species. This microbiota exerts an important role on intestinal function and contributes to host health. The microbiota, while benefiting from a nourishing environment, is involved in the development, metabolism and immunity of the host, contributing to the maintenance of homeostasis in the GI tract. The immune system orchestrates the maintenance of key features of host-microbe symbiosis via a unique immunological network that populates the intestinal wall with different immune cell populations. Intestinal epithelium contains lymphocytes in the intraepithelial (IEL) space between the tight junctions and the basal membrane of the gut epithelium. IELs are mostly CD8+ T cells, with the great majority of them expressing the CD8αα homodimer, and the γδ T cell receptor (TCR) instead of the αβ TCR expressed on conventional T cells. γδ T cells play a significant role in immune surveillance and tissue maintenance. This review provides an overview of how the microbiota regulates γδ T cells and the influence of microbiota-derived metabolites on γδ T cell responses, highlighting their impact on immune homeostasis. It also discusses intestinal neuro-immune regulation and how γδ T cells possess the ability to interact with both the microbiota and brain.
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Affiliation(s)
- Alaa A. Mohamed
- Department of Biochemistry and Molecular Biology, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain P.O. Box 15551, United Arab Emirates
| | - Basel K. al-Ramadi
- Department of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain P.O. Box 15551, United Arab Emirates
- Zayed Center for Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Maria J. Fernandez-Cabezudo
- Department of Biochemistry and Molecular Biology, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain P.O. Box 15551, United Arab Emirates
- Zayed Center for Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
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20
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Khomula EV, Araldi D, Green PG, Levine JD. Sensitization of human and rat nociceptors by low dose morphine is toll-like receptor 4-dependent. Mol Pain 2024; 20:17448069241227922. [PMID: 38195088 PMCID: PMC10851754 DOI: 10.1177/17448069241227922] [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: 12/23/2023] [Accepted: 01/06/2024] [Indexed: 01/11/2024] Open
Abstract
While opioids remain amongst the most effective treatments for moderate-to-severe pain, their substantial side effect profile remains a major limitation to broader clinical use. One such side effect is opioid-induced hyperalgesia (OIH), which includes a transition from opioid-induced analgesia to pain enhancement. Evidence in rodents supports the suggestion that OIH may be produced by the action of opioids at Toll-like Receptor 4 (TLR4) either on immune cells that, in turn, produce pronociceptive mediators to act on nociceptors, or by a direct action at nociceptor TLR4. And, sub-analgesic doses of several opioids have been shown to induce hyperalgesia in rodents by their action as TLR4 agonists. In the present in vitro patch-clamp electrophysiology experiments, we demonstrate that low dose morphine directly sensitizes human as well as rodent dorsal root ganglion (DRG) neurons, an effect of this opioid analgesic that is antagonized by LPS-RS Ultrapure, a selective TLR4 antagonist. We found that low concentration (100 nM) of morphine reduced rheobase in human (by 36%) and rat (by 26%) putative C-type nociceptors, an effect of morphine that was markedly attenuated by preincubation with LPS-RS Ultrapure. Our findings support the suggestion that in humans, as in rodents, OIH is mediated by the direct action of opioids at TLR4 on nociceptors.
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Affiliation(s)
- Eugen V Khomula
- Department of Oral & Maxillofacial Surgery, University of California at San Francisco, San Francisco, CA, USA
| | - Dionéia Araldi
- Department of Oral & Maxillofacial Surgery, University of California at San Francisco, San Francisco, CA, USA
| | - Paul G Green
- Department of Oral & Maxillofacial Surgery, University of California at San Francisco, San Francisco, CA, USA
- Department of Preventative & Restorative Dental Sciences, and Division of Neuroscience, University of California at San Francisco, San Francisco, CA, USA
| | - Jon D Levine
- Department of Oral & Maxillofacial Surgery, University of California at San Francisco, San Francisco, CA, USA
- Department of Medicine, Division of Neuroscience, and UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco, CA, USA
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21
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Willits AB, Kader L, Eller O, Roberts E, Bye B, Strope T, Freudenthal BD, Umar S, Chintapalli S, Shankar K, Pei D, Christianson J, Baumbauer KM, Young EE. Spinal cord injury-induced neurogenic bowel: A role for host-microbiome interactions in bowel pain and dysfunction. NEUROBIOLOGY OF PAIN (CAMBRIDGE, MASS.) 2024; 15:100156. [PMID: 38601267 PMCID: PMC11004406 DOI: 10.1016/j.ynpai.2024.100156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 04/04/2024] [Accepted: 04/04/2024] [Indexed: 04/12/2024]
Abstract
Background and aims Spinal cord injury (SCI) affects roughly 300,000 Americans with 17,000 new cases added annually. In addition to paralysis, 60% of people with SCI develop neurogenic bowel (NB), a syndrome characterized by slow colonic transit, constipation, and chronic abdominal pain. The knowledge gap surrounding NB mechanisms after SCI means that interventions are primarily symptom-focused and largely ineffective. The goal of the present studies was to identify mechanism(s) that initiate and maintain NB after SCI as a critical first step in the development of evidence-based, novel therapeutic treatment options. Methods Following spinal contusion injury at T9, we observed alterations in bowel structure and function reflecting key clinical features of NB. We then leveraged tissue-specific whole transcriptome analyses (RNAseq) and fecal 16S rRNA amplicon sequencing in combination with histological, molecular, and functional (Ca2+ imaging) approaches to identify potential mechanism(s) underlying the generation of the NB phenotype. Results In agreement with prior reports focused on SCI-induced changes in the skin, we observed a rapid and persistent increase in expression of calcitonin gene-related peptide (CGRP) expression in the colon. This is suggestive of a neurogenic inflammation-like process engaged by antidromic activity of below-level primary afferents following SCI. CGRP has been shown to disrupt colon homeostasis and negatively affect peristalsis and colon function. As predicted, contusion SCI resulted in increased colonic transit time, expansion of lymphatic nodules, colonic structural and genomic damage, and disruption of the inner, sterile intestinal mucus layer corresponding to increased CGRP expression in the colon. Gut microbiome colonization significantly shifted over 28 days leading to the increase in Anaeroplasma, a pathogenic, gram-negative microbe. Moreover, colon specific vagal afferents and enteric neurons were hyperresponsive after SCI to different agonists including fecal supernatants. Conclusions Our data suggest that SCI results in overexpression of colonic CGRP which could alter colon structure and function. Neurogenic inflammatory-like processes and gut microbiome dysbiosis can also sensitize vagal afferents, providing a mechanism for visceral pain despite the loss of normal sensation post-SCI. These data may shed light on novel therapeutic interventions targeting this process to prevent NB development in patients.
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Affiliation(s)
- Adam B. Willits
- Department of Anesthesiology, Pain and Perioperative Medicine, University of Kansas Medical Center, Kansas City, KS, United States
| | - Leena Kader
- Department of Anesthesiology, Pain and Perioperative Medicine, University of Kansas Medical Center, Kansas City, KS, United States
| | - Olivia Eller
- Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, United States
| | - Emily Roberts
- Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, United States
| | - Bailey Bye
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS
| | - Taylor Strope
- Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS, United States
| | - Bret D. Freudenthal
- Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS, United States
| | - Shahid Umar
- Department of Surgery, University of Kansas Medical Center, Kansas City, KS, United States
| | - Sree Chintapalli
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Kartik Shankar
- Department of Pediatrics, Section of Nutrition, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Dong Pei
- Department of Biostatistics & Data Science, University of Kansas Medical Center, Kansas City, KS, United States
| | - Julie Christianson
- Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, United States
| | - Kyle M. Baumbauer
- Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, United States
| | - Erin E. Young
- Department of Anesthesiology, Pain and Perioperative Medicine, University of Kansas Medical Center, Kansas City, KS, United States
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22
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Beurel E. Stress in the microbiome-immune crosstalk. Gut Microbes 2024; 16:2327409. [PMID: 38488630 PMCID: PMC10950285 DOI: 10.1080/19490976.2024.2327409] [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: 10/17/2023] [Accepted: 03/04/2024] [Indexed: 03/19/2024] Open
Abstract
The gut microbiota exerts a mutualistic interaction with the host in a fragile ecosystem and the host intestinal, neural, and immune cells. Perturbations of the gastrointestinal track composition after stress have profound consequences on the central nervous system and the immune system. Reciprocally, brain signals after stress affect the gut microbiota highlighting the bidirectional communication between the brain and the gut. Here, we focus on the potential role of inflammation in mediating stress-induced gut-brain changes and discuss the impact of several immune cells and inflammatory molecules of the gut-brain dialogue after stress. Understanding the impact of microbial changes on the immune system after stress might provide new avenues for therapy.
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Affiliation(s)
- Eléonore Beurel
- Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL, USA
- Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL, USA
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23
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Koukoulis TF, Beauchamp LC, Kaparakis-Liaskos M, McQuade RM, Purnianto A, Finkelstein DI, Barnham KJ, Vella LJ. Do Bacterial Outer Membrane Vesicles Contribute to Chronic Inflammation in Parkinson's Disease? JOURNAL OF PARKINSON'S DISEASE 2024; 14:227-244. [PMID: 38427502 PMCID: PMC10977405 DOI: 10.3233/jpd-230315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 01/16/2024] [Indexed: 03/03/2024]
Abstract
Parkinson's disease (PD) is an increasingly common neurodegenerative disease. It has been suggested that the etiology of idiopathic PD is complex and multifactorial involving environmental contributions, such as viral or bacterial infections and microbial dysbiosis, in genetically predisposed individuals. With advances in our understanding of the gut-brain axis, there is increasing evidence that the intestinal microbiota and the mammalian immune system functionally interact. Recent findings suggest that a shift in the gut microbiome to a pro-inflammatory phenotype may play a role in PD onset and progression. While there are links between gut bacteria, inflammation, and PD, the bacterial products involved and how they traverse the gut lumen and distribute systemically to trigger inflammation are ill-defined. Mechanisms emerging in other research fields point to a role for small, inherently stable vesicles released by Gram-negative bacteria, called outer membrane vesicles in disease pathogenesis. These vesicles facilitate communication between bacteria and the host and can shuttle bacterial toxins and virulence factors around the body to elicit an immune response in local and distant organs. In this perspective article, we hypothesize a role for bacterial outer membrane vesicles in PD pathogenesis. We present evidence suggesting that these outer membrane vesicles specifically from Gram-negative bacteria could potentially contribute to PD by traversing the gut lumen to trigger local, systemic, and neuroinflammation. This perspective aims to facilitate a discussion on outer membrane vesicles in PD and encourage research in the area, with the goal of developing strategies for the prevention and treatment of the disease.
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Affiliation(s)
- Tiana F. Koukoulis
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - Leah C. Beauchamp
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
- Ann Romney Center for Neurologic Diseases, Brighamand Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Maria Kaparakis-Liaskos
- Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Melbourne, VIC, Australia
| | - Rachel M. McQuade
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
- Department of Medicine, Gut-Axis Injury and Repair Laboratory, Western Centre for Health Research and Education (WCHRE), The University of Melbourne, Sunshine Hospital, St Albans, VIC, Australia
- Australian Institute of Musculoskeletal Science (AIMSS), Western Centre for Health Research and Education (WCHRE), Sunshine Hospital, St Albans, VIC, Australia
| | - Adityas Purnianto
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - David I. Finkelstein
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - Kevin J. Barnham
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - Laura J. Vella
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
- Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital, Parkville, VIC, Australia
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24
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Khomula EV, Levine JD. Sensitization of Human and Rat Nociceptors by Low Dose Morphine is TLR4-dependent. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.12.19.572472. [PMID: 38187676 PMCID: PMC10769211 DOI: 10.1101/2023.12.19.572472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2024]
Abstract
While opioids remain amongst the most effective treatments for moderate-to-severe pain, their substantial side effect profile remains a major limitation to broader clinical use. One such side effect is opioid-induced hyperalgesia (OIH), which includes a transition from opioid-induced analgesia to pain enhancement. Evidence in rodents supports the suggestion that OIH may be produced by the action of opioids at Toll-like Receptor 4 (TLR4) either on immune cells that, in turn, produce pronociceptive mediators to act on nociceptors, or by a direct action at nociceptor TLR4. And, sub-analgesic doses of several opioids have been shown to induce hyperalgesia in rodents by their action as TLR4 agonists. In the present in vitro patch-clamp electrophysiology experiments, we demonstrate that low dose morphine directly sensitizes human as well as rodent dorsal root ganglion (DRG) neurons, an effect of this opioid analgesic that is antagonized by LPS-RS Ultrapure, a selective TLR4 antagonist. We found that morphine (100 nM) reduced rheobase in human (by 36%) and rat (by 26%) putative C-type nociceptors, an effect of morphine that was markedly attenuated by preincubation with LPS-RS Ultrapure. Our findings support the suggestion that in humans, as well as in rodents, OIH is mediated by the direct action of opioids at TLR4 on nociceptors.
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25
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Bai X, De Palma G, Boschetti E, Nishiharo Y, Lu J, Shimbori C, Costanzini A, Saqib Z, Kraimi N, Sidani S, Hapfelmeier S, Macpherson AJ, Verdu EF, De Giorgio R, Collins SM, Bercik P. Vasoactive Intestinal Polypeptide Plays a Key Role in the Microbial-Neuroimmune Control of Intestinal Motility. Cell Mol Gastroenterol Hepatol 2023; 17:383-398. [PMID: 38061549 PMCID: PMC10825443 DOI: 10.1016/j.jcmgh.2023.11.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 11/24/2023] [Accepted: 11/27/2023] [Indexed: 12/24/2023]
Abstract
BACKGROUND & AIMS Although chronic diarrhea and constipation are common, the treatment is symptomatic because their pathophysiology is poorly understood. Accumulating evidence suggests that the microbiota modulates gut function, but the underlying mechanisms are unknown. We therefore investigated the pathways by which microbiota modulates gastrointestinal motility in different sections of the alimentary tract. METHODS Gastric emptying, intestinal transit, muscle contractility, acetylcholine release, gene expression, and vasoactive intestinal polypeptide (VIP) immunoreactivity were assessed in wild-type and Myd88-/-Trif-/- mice in germ-free, gnotobiotic, and specific pathogen-free conditions. Effects of transient colonization and antimicrobials as well as immune cell blockade were investigated. VIP levels were assessed in human full-thickness biopsies by Western blot. RESULTS Germ-free mice had similar gastric emptying but slower intestinal transit compared with specific pathogen-free mice or mice monocolonized with Lactobacillus rhamnosus or Escherichia coli, the latter having stronger effects. Although muscle contractility was unaffected, its neural control was modulated by microbiota by up-regulating jejunal VIP, which co-localized with and controlled cholinergic nerve function. This process was responsive to changes in the microbial composition and load and mediated through toll-like receptor signaling, with enteric glia cells playing a key role. Jejunal VIP was lower in patients with chronic intestinal pseudo-obstruction compared with control subjects. CONCLUSIONS Microbial control of gastrointestinal motility is both region- and bacteria-specific; it reacts to environmental changes and is mediated by innate immunity-neural system interactions. By regulating cholinergic nerves, small intestinal VIP plays a key role in this process, thus providing a new therapeutic target for patients with motility disorders.
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Affiliation(s)
- Xiaopeng Bai
- Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Ontario, Canada; Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Giada De Palma
- Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Elisa Boschetti
- Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy
| | - Yuichiro Nishiharo
- Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Jun Lu
- Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Chiko Shimbori
- Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Anna Costanzini
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Zarwa Saqib
- Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Narjis Kraimi
- Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Sacha Sidani
- Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | | | - Andrew J Macpherson
- Department of Biomedical Research, University Hospital of Bern, Bern, Switzerland
| | - Elena F Verdu
- Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Roberto De Giorgio
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
| | - Stephen M Collins
- Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Premysl Bercik
- Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
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26
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Geng ZH, Zhu Y, Chen WF, Fu PY, Xu JQ, Wang TY, Yao L, Liu ZQ, Li XQ, Zhang ZC, Wang Y, Ma LY, Lin SL, He MJ, Zhao C, Li QL, Zhou PH. The role of type II esophageal microbiota in achalasia: Activation of macrophages and degeneration of myenteric neurons. Microbiol Res 2023; 276:127470. [PMID: 37574627 DOI: 10.1016/j.micres.2023.127470] [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: 06/11/2023] [Revised: 07/31/2023] [Accepted: 08/02/2023] [Indexed: 08/15/2023]
Abstract
OBJECTIVE The gut microbiota plays a critical role in the appropriate development and maintenance of the enteric nervous system (ENS). Esophageal achalasia (EA) is a rare motility disorder characterized by the selective degeneration of inhibitory neurons in the esophageal myenteric plexus. This study aimed to evaluate the composition of the esophageal microbiota in achalasia and explore the potential microbial mechanisms involved in its pathogenesis. DESIGN The lower esophageal mucosal microbiota was analyzed in patients with achalasia and control participants using 16 S rRNA sequencing. The association between the esophageal microbiota and achalasia was validated by inducing esophageal dysbiosis in C57BL/10 J and C57BL/10ScNJ (TLR4KO) mice via chronic exposure to ampicillin sodium in their drinking water. RESULTS The esophageal microbiota in EA patients had lower diversity and a predominance of Gram-negative bacteria (Type II microbiota) compared to that in the healthy controls. Additionally, the relative abundance of Rhodobacter decreased significantly in patients with achalasia, which correlated with an enrichment of lipopolysaccharide (LPS) biosynthesis based on the COG database. Antibiotic-treated mice showed an esophageal microbiota characterized by increased abundance of Gram-negative bacteria (Type II microbiome), decreased abundance of Rhodobacter, and enriched LPS biosynthesis. Compared to the control and TLR4KO mice, the antibiotic-treated wild-type mice had higher LES resting pressure, increased LES contraction rate after carbachol stimulation, and decreased relaxation response to L-arginine. Moreover, the number of myenteric neurons decreased, while the number of lamina propria macrophages (LpMs) increased after antibiotic exposure. Furthermore, the TLR4-MYD88-NF-κB pathway was up-regulated, and the production of TNF-α, IL-1β, and IL-6 increased in the antibiotic-treated mice. CONCLUSIONS Patients with achalasia exhibit esophageal dysbiosis, which may induce aberrant esophageal motility.
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Affiliation(s)
- Zi-Han Geng
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Collaborative Innovation Center of Endoscopy, Shanghai, China
| | - Yan Zhu
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Collaborative Innovation Center of Endoscopy, Shanghai, China
| | - Wei-Feng Chen
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Collaborative Innovation Center of Endoscopy, Shanghai, China
| | - Pei-Yao Fu
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Collaborative Innovation Center of Endoscopy, Shanghai, China
| | - Jia-Qi Xu
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Collaborative Innovation Center of Endoscopy, Shanghai, China
| | - Tong-Yao Wang
- Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences & National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Lu Yao
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Collaborative Innovation Center of Endoscopy, Shanghai, China
| | - Zu-Qiang Liu
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Collaborative Innovation Center of Endoscopy, Shanghai, China
| | - Xiao-Qing Li
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Collaborative Innovation Center of Endoscopy, Shanghai, China
| | - Zhao-Chao Zhang
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Collaborative Innovation Center of Endoscopy, Shanghai, China
| | - Yun Wang
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Collaborative Innovation Center of Endoscopy, Shanghai, China
| | - Li-Yun Ma
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Collaborative Innovation Center of Endoscopy, Shanghai, China
| | - Sheng-Li Lin
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Collaborative Innovation Center of Endoscopy, Shanghai, China
| | - Meng-Jiang He
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Collaborative Innovation Center of Endoscopy, Shanghai, China
| | - Chao Zhao
- Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences & National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China.
| | - Quan-Lin Li
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Collaborative Innovation Center of Endoscopy, Shanghai, China.
| | - Ping-Hong Zhou
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Collaborative Innovation Center of Endoscopy, Shanghai, China.
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27
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Craig CF, Finkelstein DI, McQuade RM, Diwakarla S. Understanding the potential causes of gastrointestinal dysfunctions in multiple system atrophy. Neurobiol Dis 2023; 187:106296. [PMID: 37714308 DOI: 10.1016/j.nbd.2023.106296] [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: 08/03/2023] [Revised: 09/12/2023] [Accepted: 09/13/2023] [Indexed: 09/17/2023] Open
Abstract
Multiple system atrophy (MSA) is a rare, progressive neurodegenerative disorder characterised by autonomic, pyramidal, parkinsonian and/or cerebellar dysfunction. Autonomic symptoms of MSA include deficits associated with the gastrointestinal (GI) system, such as difficulty swallowing, abdominal pain and bloating, nausea, delayed gastric emptying, and constipation. To date, studies assessing GI dysfunctions in MSA have primarily focused on alterations of the gut microbiome, however growing evidence indicates other structural components of the GI tract, such as the enteric nervous system, the intestinal barrier, GI hormones, and the GI-driven immune response may contribute to MSA-related GI symptoms. Here, we provide an in-depth exploration of the physiological, structural, and immunological changes theorised to underpin GI dysfunction in MSA patients and highlight areas for future research in order to identify more suitable pharmaceutical treatments for GI symptoms in patients with MSA.
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Affiliation(s)
- Colin F Craig
- Gut Barrier and Disease Laboratory, Department of Anatomy & Physiology, The University of Melbourne, Parkville, VIC 3010, Australia
| | - David I Finkelstein
- Parkinson's Disease Laboratory, The Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3052, Australia
| | - Rachel M McQuade
- Gut Barrier and Disease Laboratory, Department of Anatomy & Physiology, The University of Melbourne, Parkville, VIC 3010, Australia; Australian Institute for Musculoskeletal Science (AIMSS), Western Centre for Health Research and Education (WCHRE), Sunshine Hospital, St Albans, VIC 3021, Australia
| | - Shanti Diwakarla
- Gut Barrier and Disease Laboratory, Department of Anatomy & Physiology, The University of Melbourne, Parkville, VIC 3010, Australia; Australian Institute for Musculoskeletal Science (AIMSS), Western Centre for Health Research and Education (WCHRE), Sunshine Hospital, St Albans, VIC 3021, Australia.
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28
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Whitaker EE, Mecum NE, Cott RC, Goode DJ. Novel expression of major histocompatibility complex II in dorsal root ganglion neurons attenuates paclitaxel-induced cold hypersensitivity in male and female mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.31.535136. [PMID: 37066176 PMCID: PMC10103942 DOI: 10.1101/2023.03.31.535136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
Chemotherapy is often a life-saving treatment, but the development of intractable pain caused by chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting toxicity that restricts survival rates. Recent reports demonstrate that paclitaxel (PTX) robustly increases anti-inflammatory CD4+ T cells in the dorsal root ganglion (DRG), and that T cells and anti-inflammatory cytokines are protective against CIPN. However, the mechanism by which CD4+ T cells are activated, and the extent cytokines released by CD4+ T cells target DRG neurons are unknown. Here, we found novel expression of functional major histocompatibility complex II (MHCII) protein in DRG neurons, and CD4+ T cells in close proximity to DRG neurons, together suggesting CD4+ T cell activation and targeted cytokine release. MHCII protein is primarily expressed in small nociceptive neurons in male mouse DRG regardless of PTX, while MHCII is induced in small nociceptive neurons in female DRG after PTX. Accordingly, reducing MHCII in small nociceptive neurons increased hypersensitivity to cold only in naive male mice, but increased severity of PTX-induced cold hypersensitivity in both sexes. Collectively, our results demonstrate expression of MHCII on DRG neurons and a functional role during homeostasis and inflammation.
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29
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Shu LZ, Ding YD, Xue QM, Cai W, Deng H. Direct and indirect effects of pathogenic bacteria on the integrity of intestinal barrier. Therap Adv Gastroenterol 2023; 16:17562848231176427. [PMID: 37274298 PMCID: PMC10233627 DOI: 10.1177/17562848231176427] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Accepted: 05/01/2023] [Indexed: 06/06/2023] Open
Abstract
Bacterial translocation is a pathological process involving migration of pathogenic bacteria across the intestinal barrier to enter the systemic circulation and gain access to distant organs. This phenomenon has been linked to a diverse range of diseases including inflammatory bowel disease, pancreatitis, and cancer. The intestinal barrier is an innate structure that maintains intestinal homeostasis. Pathogenic infections and dysbiosis can disrupt the integrity of the intestinal barrier, increasing its permeability, and thereby facilitating pathogen translocation. As translocation represents an essential step in pathogenesis, a clear understanding of how barrier integrity is disrupted and how this disruption facilitates bacterial translocation could identify new routes to effective prophylaxis and therapy. In this comprehensive review, we provide an in-depth analysis of bacterial translocation and intestinal barrier function. We discuss currently understood mechanisms of bacterial-enterocyte interactions, with a focus on tight junctions and endocytosis. We also discuss the emerging concept of bidirectional communication between the intestinal microbiota and other body systems. The intestinal tract has established 'axes' with various organs. Among our regulatory systems, the nervous, immune, and endocrine systems have been shown to play pivotal roles in barrier regulation. A mechanistic understanding of intestinal barrier regulation is crucial for the development of personalized management strategies for patients with bacterial translocation-related disorders. Advancing our knowledge of barrier regulation will pave the way for future research in this field and novel clinical intervention strategies.
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Affiliation(s)
- Lin-Zhen Shu
- Medical College, Nanchang University, Nanchang,
Jiangxi Province, China
| | - Yi-Dan Ding
- Medical College, Nanchang University, Nanchang,
Jiangxi Province, China
| | - Qing-Ming Xue
- Medical College, Nanchang University, Nanchang,
Jiangxi Province, China
| | - Wei Cai
- Medical College, Nanchang University, Nanchang,
Jiangxi Province, China
- Department of Pathology, the Fourth Affiliated
Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Huan Deng
- Department of Pathology, The Fourth Affiliated
Hospital of Nanchang University, No. 133 South Guangchang Road, Nanchang
330003, Jiangxi Province, China
- Tumor Immunology Institute, Nanchang
University, Nanchang, China
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30
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Calabrò S, Kankowski S, Cescon M, Gambarotta G, Raimondo S, Haastert-Talini K, Ronchi G. Impact of Gut Microbiota on the Peripheral Nervous System in Physiological, Regenerative and Pathological Conditions. Int J Mol Sci 2023; 24:ijms24098061. [PMID: 37175764 PMCID: PMC10179357 DOI: 10.3390/ijms24098061] [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: 04/03/2023] [Revised: 04/21/2023] [Accepted: 04/25/2023] [Indexed: 05/15/2023] Open
Abstract
It has been widely demonstrated that the gut microbiota is responsible for essential functions in human health and that its perturbation is implicated in the development and progression of a growing list of diseases. The number of studies evaluating how the gut microbiota interacts with and influences other organs and systems in the body and vice versa is constantly increasing and several 'gut-organ axes' have already been defined. Recently, the view on the link between the gut microbiota (GM) and the peripheral nervous system (PNS) has become broader by exceeding the fact that the PNS can serve as a systemic carrier of GM-derived metabolites and products to other organs. The PNS as the communication network between the central nervous system and the periphery of the body and internal organs can rather be affected itself by GM perturbation. In this review, we summarize the current knowledge about the impact of gut microbiota on the PNS, with regard to its somatic and autonomic divisions, in physiological, regenerative and pathological conditions.
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Affiliation(s)
- Sonia Calabrò
- Department of Molecular Medicine, University of Padova, Via Ugo Bassi 58/B, 35131 Padova, Italy
- Department of Biology, University of Padova, Viale G. Colombo 3, 35131 Padova, Italy
| | - Svenja Kankowski
- Hannover Medical School, Institute of Neuroanatomy and Cell Biology, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Matilde Cescon
- Department of Molecular Medicine, University of Padova, Via Ugo Bassi 58/B, 35131 Padova, Italy
| | - Giovanna Gambarotta
- Department of Clinical and Biological Sciences & Neuroscience Institute Cavalieri Ottolenghi (NICO), University of Torino, Regione Gonzole 10, Orbassano, 10043 Torino, Italy
| | - Stefania Raimondo
- Department of Clinical and Biological Sciences & Neuroscience Institute Cavalieri Ottolenghi (NICO), University of Torino, Regione Gonzole 10, Orbassano, 10043 Torino, Italy
| | - Kirsten Haastert-Talini
- Hannover Medical School, Institute of Neuroanatomy and Cell Biology, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
- Center for Systems Neuroscience Hannover (ZSN), Buenteweg 2, 30559 Hannover, Germany
| | - Giulia Ronchi
- Department of Clinical and Biological Sciences & Neuroscience Institute Cavalieri Ottolenghi (NICO), University of Torino, Regione Gonzole 10, Orbassano, 10043 Torino, Italy
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Shahbazi A, Sepehrinezhad A, Vahdani E, Jamali R, Ghasempour M, Massoudian S, Sahab Negah S, Larsen FS. Gut Dysbiosis and Blood-Brain Barrier Alteration in Hepatic Encephalopathy: From Gut to Brain. Biomedicines 2023; 11:1272. [PMID: 37238943 PMCID: PMC10215854 DOI: 10.3390/biomedicines11051272] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Revised: 03/20/2023] [Accepted: 03/28/2023] [Indexed: 05/28/2023] Open
Abstract
A common neuropsychiatric complication of advanced liver disease, hepatic encephalopathy (HE), impacts the quality of life and length of hospital stays. There is new evidence that gut microbiota plays a significant role in brain development and cerebral homeostasis. Microbiota metabolites are providing a new avenue of therapeutic options for several neurological-related disorders. For instance, the gut microbiota composition and blood-brain barrier (BBB) integrity are altered in HE in a variety of clinical and experimental studies. Furthermore, probiotics, prebiotics, antibiotics, and fecal microbiota transplantation have been shown to positively affect BBB integrity in disease models that are potentially extendable to HE by targeting gut microbiota. However, the mechanisms that underlie microbiota dysbiosis and its effects on the BBB are still unclear in HE. To this end, the aim of this review was to summarize the clinical and experimental evidence of gut dysbiosis and BBB disruption in HE and a possible mechanism.
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Affiliation(s)
- Ali Shahbazi
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran 1449614535, Iran; (A.S.); (S.M.)
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran 1449614535, Iran;
| | - Ali Sepehrinezhad
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran 1449614535, Iran; (A.S.); (S.M.)
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran 1449614535, Iran;
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad 9919191778, Iran
| | - Edris Vahdani
- Department of Microbiology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari 4815733971, Iran;
| | - Raika Jamali
- Research Development Center, Sina Hospital, Tehran University of Medical Sciences, Tehran 1417653761, Iran
- Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran 1417653761, Iran
| | - Monireh Ghasempour
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran 1449614535, Iran;
| | - Shirin Massoudian
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran 1449614535, Iran; (A.S.); (S.M.)
| | - Sajad Sahab Negah
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad 9919191778, Iran
- Department of Neuroscience, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad 9919191778, Iran
- Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran 9815733169, Iran
| | - Fin Stolze Larsen
- Department of Intestinal Failure and Liver Diseases, Rigshospitalet, Inge Lehmanns Vej 5, 2100 Copenhagen, Denmark
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Pirzgalska RM, Veiga-Fernandes H. Type 2 neuroimmune circuits in the shaping of physiology. Immunity 2023; 56:695-703. [PMID: 37044060 DOI: 10.1016/j.immuni.2023.03.016] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/12/2023] [Accepted: 03/16/2023] [Indexed: 04/14/2023]
Abstract
Type 2 immune responses drive a broad range of biological processes including defense from large parasites, immunity to allergens, and non-immunity-related functions, such as metabolism and tissue homeostasis. The symptoms provoked by type 2 immunity, such as vomiting, coughing or itching, encompass nervous system triggering. Here, we review recent findings that place type 2 neuroimmune circuits at the center stage of immunity at barrier surfaces. We emphasize the homeostatic functions of these circuitries and how deregulation may drive pathology and impact disease outcomes, including in the context of cancer. We discuss a paradigm wherein type 2 neuroimmune circuits are central regulators of organismal physiology.
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Affiliation(s)
- Roksana M Pirzgalska
- Champalimaud Foundation, Champalimaud Centre for the Unknown, Champalimaud Research, Lisbon, Portugal.
| | - Henrique Veiga-Fernandes
- Champalimaud Foundation, Champalimaud Centre for the Unknown, Champalimaud Research, Lisbon, Portugal.
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Sharkey KA, Mawe GM. The enteric nervous system. Physiol Rev 2023; 103:1487-1564. [PMID: 36521049 PMCID: PMC9970663 DOI: 10.1152/physrev.00018.2022] [Citation(s) in RCA: 138] [Impact Index Per Article: 69.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 12/12/2022] [Accepted: 12/15/2022] [Indexed: 12/23/2022] Open
Abstract
Of all the organ systems in the body, the gastrointestinal tract is the most complicated in terms of the numbers of structures involved, each with different functions, and the numbers and types of signaling molecules utilized. The digestion of food and absorption of nutrients, electrolytes, and water occurs in a hostile luminal environment that contains a large and diverse microbiota. At the core of regulatory control of the digestive and defensive functions of the gastrointestinal tract is the enteric nervous system (ENS), a complex system of neurons and glia in the gut wall. In this review, we discuss 1) the intrinsic neural control of gut functions involved in digestion and 2) how the ENS interacts with the immune system, gut microbiota, and epithelium to maintain mucosal defense and barrier function. We highlight developments that have revolutionized our understanding of the physiology and pathophysiology of enteric neural control. These include a new understanding of the molecular architecture of the ENS, the organization and function of enteric motor circuits, and the roles of enteric glia. We explore the transduction of luminal stimuli by enteroendocrine cells, the regulation of intestinal barrier function by enteric neurons and glia, local immune control by the ENS, and the role of the gut microbiota in regulating the structure and function of the ENS. Multifunctional enteric neurons work together with enteric glial cells, macrophages, interstitial cells, and enteroendocrine cells integrating an array of signals to initiate outputs that are precisely regulated in space and time to control digestion and intestinal homeostasis.
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Affiliation(s)
- Keith A Sharkey
- Hotchkiss Brain Institute and Snyder Institute for Chronic Diseases, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Gary M Mawe
- Department of Neurological Sciences, Larner College of Medicine, University of Vermont, Burlington, Vermont
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Li Z, Zhang F, Sun M, Liu J, Zhao L, Liu S, Li S, Wang B. The modulatory effects of gut microbes and metabolites on blood–brain barrier integrity and brain function in sepsis-associated encephalopathy. PeerJ 2023; 11:e15122. [PMID: 37009158 PMCID: PMC10064995 DOI: 10.7717/peerj.15122] [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: 01/17/2023] [Accepted: 03/03/2023] [Indexed: 03/30/2023] Open
Abstract
Background
Intestinal microbiota homeostasis and the gut-brain axis are key players associated with host health and alterations in metabolic, inflammatory, and neurodegenerative disorders. Sepsis-associated encephalopathy (SAE), which is closely associated with bacterial translocation, is a common secondary organ dysfunction and an urgent, unsolved problem affecting patient quality of life. Our study examined the neuroprotective effects of the gut microbiome and short-chain fatty acid (SCFA) metabolites on SAE.
Methods
Male C57BL/6 mice were administered SCFAs in drinking water, then subjected to cecal ligation and puncture (CLP) surgery to induce SAE. 16S rRNA sequencing was used to investigate gut microbiome changes. The open field test (OFT) and Y-maze were performed to evaluate brain function. The permeability of the blood–brain barrier (BBB) was assessed by Evans blue (EB) staining. Hematoxylin and eosin (HE) staining was used to examine intestinal tissue morphology. The expression levels of tight junction (TJ) proteins and inflammatory cytokines was assessed by western blots and immunohistochemistry. In vitro, bEND.3 cells were incubated with SCFAs and then with lipopolysaccharide (LPS). Immunofluorescence was used to examine the expression of TJ proteins.
Results
The composition of the gut microbiota was altered in SAE mice; this change may be related to SCFA metabolism. SCFA treatment significantly alleviated behavioral dysfunction and neuroinflammation in SAE mice. SCFAs upregulated occludin and ZO-1 expression in the intestine and brain in SAE mice and LPS-treated cerebromicrovascular cells.
Conclusions
These findings suggested that disturbances in the gut microbiota and SCFA metabolites play key roles in SAE. SCFA supplementation could exert neuroprotective effects against SAE by preserving BBB integrity.
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Affiliation(s)
- Zhaoying Li
- Department of Anesthesiology, Guizhou Provincial People’s Hospital, Guiyang, Guizhou Province, China
- Institute of Anesthesiology, Guizhou Medical University, Guiyang, Guizhou Province, China
| | - Fangxiang Zhang
- Department of Anesthesiology, Guizhou Provincial People’s Hospital, Guiyang, Guizhou Province, China
| | - Meisha Sun
- Department of Anesthesiology, Guizhou Provincial People’s Hospital, Guiyang, Guizhou Province, China
| | - Jia Liu
- Department of Anesthesiology, Guizhou Provincial People’s Hospital, Guiyang, Guizhou Province, China
| | - Li Zhao
- Department of Anesthesiology, Guizhou Provincial People’s Hospital, Guiyang, Guizhou Province, China
| | - Shuchun Liu
- Department of Anesthesiology, Guizhou Provincial People’s Hospital, Guiyang, Guizhou Province, China
| | - Shanshan Li
- Department of Anesthesiology, Guizhou Provincial People’s Hospital, Guiyang, Guizhou Province, China
| | - Bin Wang
- Department of Anesthesiology, Guizhou Provincial People’s Hospital, Guiyang, Guizhou Province, China
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Microbiota-dependent presence of murine enteric glial cells requires myeloid differentiation primary response protein 88 signaling. J Biosci 2023. [DOI: 10.1007/s12038-023-00325-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/12/2023]
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Neag MA, Craciun AE, Inceu AI, Burlacu DE, Craciun CI, Buzoianu AD. Short-Chain Fatty Acids as Bacterial Enterocytes and Therapeutic Target in Diabetes Mellitus Type 2. Biomedicines 2022; 11:72. [PMID: 36672580 PMCID: PMC9855839 DOI: 10.3390/biomedicines11010072] [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: 10/31/2022] [Revised: 12/10/2022] [Accepted: 12/23/2022] [Indexed: 12/29/2022] Open
Abstract
Diabetes mellitus is a disease with multiple gastrointestinal symptoms (diarrhea or constipation, abdominal pain, bloating) whose pathogenesis is multifactorial. The most important of these factors is the enteric nervous system, also known as the "second brain"; a part of the peripheral nervous system capable of functioning independently of the central nervous system. Modulation of the enteric nervous system can be done by short-chain fatty acids, which are bacterial metabolites of the intestinal microbiota. In addition, these acids provide multiple benefits in diabetes, particularly by stimulating glucagon-like peptide 1 and insulin secretion. However, it is not clear what type of nutraceuticals (probiotics, prebiotics, and alimentary supplements) can be used to increase the amount of short-chain fatty acids and achieve the beneficial effects in diabetes. Thus, even if several studies demonstrate that the gut microbiota modulates the activity of the ENS, and thus, may have a positive effect in diabetes, further studies are needed to underline this effect. This review outlines the most recent data regarding the involvement of SCFAs as a disease modifying agent in diabetes mellitus type 2. For an in-depth understanding of the modulation of gut dysbiosis with SCFAs in diabetes, we provide an overview of the interplay between gut microbiota and ENS.
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Affiliation(s)
- Maria-Adriana Neag
- Department of Pharmacology, Toxicology and Clinical Pharmacology, Iuliu Hatieganu University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | - Anca-Elena Craciun
- Department of Diabetes and Nutrition Diseases, Iuliu Hatieganu University of Medicine and Pharmacy, 400006 Cluj-Napoca, Romania
| | - Andreea-Ioana Inceu
- Department of Pharmacology, Toxicology and Clinical Pharmacology, Iuliu Hatieganu University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | - Diana-Elena Burlacu
- Faculty of Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Cristian-Ioan Craciun
- Department of Pharmacology, Toxicology and Clinical Pharmacology, Iuliu Hatieganu University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | - Anca-Dana Buzoianu
- Department of Pharmacology, Toxicology and Clinical Pharmacology, Iuliu Hatieganu University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
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Sterling KG, Dodd GK, Alhamdi S, Asimenios PG, Dagda RK, De Meirleir KL, Hudig D, Lombardi VC. Mucosal Immunity and the Gut-Microbiota-Brain-Axis in Neuroimmune Disease. Int J Mol Sci 2022; 23:13328. [PMID: 36362150 PMCID: PMC9655506 DOI: 10.3390/ijms232113328] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 10/27/2022] [Accepted: 10/28/2022] [Indexed: 07/30/2023] Open
Abstract
Recent advances in next-generation sequencing (NGS) technologies have opened the door to a wellspring of information regarding the composition of the gut microbiota. Leveraging NGS technology, early metagenomic studies revealed that several diseases, such as Alzheimer's disease, Parkinson's disease, autism, and myalgic encephalomyelitis, are characterized by alterations in the diversity of gut-associated microbes. More recently, interest has shifted toward understanding how these microbes impact their host, with a special emphasis on their interactions with the brain. Such interactions typically occur either systemically, through the production of small molecules in the gut that are released into circulation, or through signaling via the vagus nerves which directly connect the enteric nervous system to the central nervous system. Collectively, this system of communication is now commonly referred to as the gut-microbiota-brain axis. While equally important, little attention has focused on the causes of the alterations in the composition of gut microbiota. Although several factors can contribute, mucosal immunity plays a significant role in shaping the microbiota in both healthy individuals and in association with several diseases. The purpose of this review is to provide a brief overview of the components of mucosal immunity that impact the gut microbiota and then discuss how altered immunological conditions may shape the gut microbiota and consequently affect neuroimmune diseases, using a select group of common neuroimmune diseases as examples.
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Affiliation(s)
| | - Griffin Kutler Dodd
- Department of Microbiology and Immunology, University of Nevada, Reno School of Medicine, Reno, NV 89557, USA
| | - Shatha Alhamdi
- Clinical Immunology and Allergy Division, Department of Pediatrics, King Abdullah Specialist Children’s Hospital, King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh 11426, Saudi Arabia
| | | | - Ruben K. Dagda
- Department of Pharmacology, School of Medicine, University of Nevada, Reno, NV 89557, USA
| | | | - Dorothy Hudig
- Department of Microbiology and Immunology, University of Nevada, Reno School of Medicine, Reno, NV 89557, USA
| | - Vincent C. Lombardi
- Department of Microbiology and Immunology, University of Nevada, Reno School of Medicine, Reno, NV 89557, USA
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Schneider KM, Kim J, Bahnsen K, Heuckeroth RO, Thaiss CA. Environmental perception and control of gastrointestinal immunity by the enteric nervous system. Trends Mol Med 2022; 28:989-1005. [PMID: 36208986 DOI: 10.1016/j.molmed.2022.09.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 05/25/2022] [Accepted: 09/07/2022] [Indexed: 12/12/2022]
Abstract
The enteric nervous system (ENS) forms a versatile sensory system along the gastrointestinal tract that interacts with most cell types in the bowel. Herein, we portray host-environment interactions at the intestinal mucosal surface through the lens of the enteric nervous system. We describe local cellular interactions as well as long-range circuits between the enteric, central, and peripheral nervous systems. Additionally, we discuss recently discovered mechanisms by which enteric neurons and glia respond to biotic and abiotic environmental changes and how they regulate intestinal immunity and inflammation. The enteric nervous system emerges as an integrative sensory system with manifold immunoregulatory functions under both homeostatic and pathophysiological conditions.
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Affiliation(s)
- Kai Markus Schneider
- Microbiology Department, Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, PA, USA; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, PA, USA
| | - Jihee Kim
- Microbiology Department, Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, PA, USA; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, PA, USA
| | - Klaas Bahnsen
- Microbiology Department, Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, PA, USA; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, PA, USA
| | - Robert O Heuckeroth
- Department of Pediatrics, Children's Hospital of Philadelphia Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Christoph A Thaiss
- Microbiology Department, Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, PA, USA; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, PA, USA.
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Reyes EY, Shinohara ML. Host immune responses in the central nervous system during fungal infections. Immunol Rev 2022; 311:50-74. [PMID: 35672656 PMCID: PMC9489659 DOI: 10.1111/imr.13101] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Revised: 04/24/2022] [Accepted: 05/18/2022] [Indexed: 12/19/2023]
Abstract
Fungal infections in the central nervous system (CNS) cause high morbidity and mortality. The frequency of CNS mycosis has increased over the last two decades as more individuals go through immunocompromised conditions for various reasons. Nevertheless, options for clinical interventions for CNS mycoses are still limited. Thus, there is an urgent need to understand the host-pathogen interaction mechanisms in CNS mycoses for developing novel treatments. Although the CNS has been regarded as an immune-privileged site, recent studies demonstrate the critical involvement of immune responses elicited by CNS-resident and CNS-infiltrated cells during fungal infections. In this review, we discuss mechanisms of fungal invasion in the CNS, fungal pathogen detection by CNS-resident cells (microglia, astrocytes, oligodendrocytes, neurons), roles of CNS-infiltrated leukocytes, and host immune responses. We consider that understanding host immune responses in the CNS is crucial for endeavors to develop treatments for CNS mycosis.
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Affiliation(s)
- Estefany Y. Reyes
- Department of Immunology, Duke University School of Medicine, Durham, NC 27705, USA
| | - Mari L. Shinohara
- Department of Immunology, Duke University School of Medicine, Durham, NC 27705, USA
- Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27705, USA
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40
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Layunta E, Forcén R, Grasa L. TLR2 and TLR4 Modulate Mouse Ileal Motility by the Interaction with Muscarinic and Nicotinic Receptors. Cells 2022; 11:cells11111791. [PMID: 35681486 PMCID: PMC9180263 DOI: 10.3390/cells11111791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 05/25/2022] [Accepted: 05/27/2022] [Indexed: 11/16/2022] Open
Abstract
Irritable bowel syndrome (IBS) is a chronic functional bowel disorder characterized by intestinal dysmotility. Changes in intestinal microbiota (dysbiosis) can lead to alterations in neuro-muscular functions in the gut. Toll-like receptors (TLRs) 2 and 4 recognize intestinal bacteria and are involved in the motor response induced by gastrointestinal (GI) neurotransmitters. Acetylcholine (ACh) is a well-known neurotransmitter involved in the regulation of GI motility. This study aimed to evaluate the role of TLR2 and TLR4 in the intestinal motor-response induced by ACh in the mouse ileum, as well as the expression and function of the muscarinic and nicotinic ACh receptors. Muscle contractility studies showed that the contractions induced by ACh were significantly lower in TLR2−/− and TLR4−/− with respect to WT mice. In WT mice, the contractions induced by ACh were reduced in the presence of AF-DX AF-DX 116 (a muscarinic ACh receptor (mAChR) M2 antagonist), 4-DAMP (a mAChR M3 antagonist), mecamylamine (a nicotinic AChR receptor (nAChR) α3β4 antagonist) and α-bungarotoxin (a nAChR α7 antagonist). In TLR2−/− mice, the contractions induced by ACh were increased by AF-DX 116 and mecamylamine. In TLR4−/− mice, the contractions induced by ACh were reduced by α-bungarotoxin and 4-DAMP. The mRNA and protein expressions of M3 and α3 receptors were diminished in the ileum from TLR2−/− and TLR4−/− with respect to WT mice. However, the levels of mRNA and protein of β4 were diminished only in TLR4−/− but not in TLR2−/− mice. In conclusion, our results show that TLR2 and TLR4 modulates the motor responses to ACh in the mouse ileum. TLR2 acts on muscarinic M2 and M3 and nicotinic α3β4 ACh receptors, while TLR4 acts on muscarinic M3 and nicotinic α3β4 and α7 ACh receptors.
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Affiliation(s)
- Elena Layunta
- Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Medicinaregatan 9C, 41390 Gothenburg, Sweden;
| | - Raquel Forcén
- Departamento de Farmacología, Fisiología y Medicina Legal y Forense, Facultad de Veterinaria, Universidad de Zaragoza, 50013 Zaragoza, Spain;
| | - Laura Grasa
- Departamento de Farmacología, Fisiología y Medicina Legal y Forense, Facultad de Veterinaria, Universidad de Zaragoza, 50013 Zaragoza, Spain;
- Instituto de Investigación Sanitaria de Aragón (IIS Aragón), 50009 Zaragoza, Spain
- Instituto Agroalimentario de Aragón—IA2—(Universidad de Zaragoza-CITA), 50013 Zaragoza, Spain
- Correspondence:
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Zhu Y, Duan S, Wang M, Deng Z, Li J. Neuroimmune Interaction: A Widespread Mutual Regulation and the Weapons for Barrier Organs. Front Cell Dev Biol 2022; 10:906755. [PMID: 35646918 PMCID: PMC9130600 DOI: 10.3389/fcell.2022.906755] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 04/26/2022] [Indexed: 12/12/2022] Open
Abstract
Since the embryo, the nervous system and immune system have been interacting to regulate each other’s development and working together to resist harmful stimuli. However, oversensitive neural response and uncontrolled immune attack are major causes of various diseases, especially in barrier organs, while neural-immune interaction makes it worse. As the first defense line, the barrier organs give a guarantee to maintain homeostasis in external environment. And the dense nerve innervation and abundant immune cell population in barrier organs facilitate the neuroimmune interaction, which is the physiological basis of multiple neuroimmune-related diseases. Neuroimmune-related diseases often have complex mechanisms and require a combination of drugs, posing challenges in finding etiology and treatment. Therefore, it is of great significance to illustrate the specific mechanism and exact way of neuro-immune interaction. In this review, we first described the mutual regulation of the two principal systems and then focused on neuro-immune interaction in the barrier organs, including intestinal tract, lungs and skin, to clarify the mechanisms and provide ideas for clinical etiology exploration and treatment.
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Affiliation(s)
- Yan Zhu
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, China
| | - Shixin Duan
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, China
| | - Mei Wang
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, China
| | - Zhili Deng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Zhili Deng, ; Ji Li,
| | - Ji Li
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Aging Biology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Zhili Deng, ; Ji Li,
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Liu C, Yang J. Enteric Glial Cells in Immunological Disorders of the Gut. Front Cell Neurosci 2022; 16:895871. [PMID: 35573829 PMCID: PMC9095930 DOI: 10.3389/fncel.2022.895871] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 04/07/2022] [Indexed: 11/13/2022] Open
Abstract
Enteric glial cells (EGCs) are one of the major cell types of neural crest lineage distributed in the gastrointestinal tract. EGCs represent an integral part of the enteric nervous system (ENS) and significantly outnumber ENS neurons. Studies have suggested that EGCs would exert essential roles in supporting the survival and functions of the ENS neurons. Notably, recent evidence has begun to reveal that EGCs could possess multiple immune functions and thereby may participate in the immune homeostasis of the gut. In this review article, we will summarize the current evidence supporting the potential involvement of EGCs in several important immunological disorders, including inflammatory bowel disease, celiac disease, and autoimmune enteropathy. Further, we highlight critical questions on the immunological aspects of EGCs that warrant future research attention.
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Affiliation(s)
- Chang Liu
- Center for Life Sciences, Peking University, Beijing, China
- Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
- College of Life Sciences, Wuhan University, Wuhan, China
| | - Jing Yang
- Center for Life Sciences, Peking University, Beijing, China
- State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, China
- IDG/McGovern Institute for Brain Research, Peking University, Beijing, China
- Chinese Institute for Brain Research, Beijing, China
- Institute of Molecular Physiology, Shenzhen Bay Laboratory, Shenzhen, China
- *Correspondence: Jing Yang
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Geng ZH, Zhu Y, Li QL, Zhao C, Zhou PH. Enteric Nervous System: The Bridge Between the Gut Microbiota and Neurological Disorders. Front Aging Neurosci 2022; 14:810483. [PMID: 35517052 PMCID: PMC9063565 DOI: 10.3389/fnagi.2022.810483] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Accepted: 01/17/2022] [Indexed: 12/12/2022] Open
Abstract
The gastrointestinal (GI) tract plays an essential role in food digestion, absorption, and the mucosal immune system; it is also inhabited by a huge range of microbes. The GI tract is densely innervated by a network of 200-600 million neurons that comprise the enteric nervous system (ENS). This system cooperates with intestinal microbes, the intestinal immune system, and endocrine systems; it forms a complex network that is required to maintain a stable intestinal microenvironment. Understanding how gut microbes influence the ENS and central nervous system (CNS) has been a significant research subject over the past decade. Moreover, accumulating evidence from animal and clinical studies has revealed that gut microbiota play important roles in various neurological diseases. However, the causal relationship between microbial changes and neurological disorders currently remains unproven. This review aims to summarize the possible contributions of GI microbiota to the ENS and CNS. It also provides new insights into furthering our current understanding of neurological disorders.
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Affiliation(s)
- Zi-Han Geng
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yan Zhu
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Quan-Lin Li
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Collaborative Innovation Center of Endoscopy, Shanghai, China
| | - Chao Zhao
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences & National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Ping-Hong Zhou
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Collaborative Innovation Center of Endoscopy, Shanghai, China
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Wachsmuth HR, Weninger SN, Duca FA. Role of the gut-brain axis in energy and glucose metabolism. Exp Mol Med 2022; 54:377-392. [PMID: 35474341 PMCID: PMC9076644 DOI: 10.1038/s12276-021-00677-w] [Citation(s) in RCA: 114] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 07/01/2021] [Accepted: 07/08/2021] [Indexed: 12/12/2022] Open
Abstract
The gastrointestinal tract plays a role in the development and treatment of metabolic diseases. During a meal, the gut provides crucial information to the brain regarding incoming nutrients to allow proper maintenance of energy and glucose homeostasis. This gut-brain communication is regulated by various peptides or hormones that are secreted from the gut in response to nutrients; these signaling molecules can enter the circulation and act directly on the brain, or they can act indirectly via paracrine action on local vagal and spinal afferent neurons that innervate the gut. In addition, the enteric nervous system can act as a relay from the gut to the brain. The current review will outline the different gut-brain signaling mechanisms that contribute to metabolic homeostasis, highlighting the recent advances in understanding these complex hormonal and neural pathways. Furthermore, the impact of the gut microbiota on various components of the gut-brain axis that regulates energy and glucose homeostasis will be discussed. A better understanding of the gut-brain axis and its complex relationship with the gut microbiome is crucial for the development of successful pharmacological therapies to combat obesity and diabetes.
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Affiliation(s)
| | | | - Frank A Duca
- School of Animal and Comparative Biomedical Sciences, College of Agricultural and Life Sciences, University of Arizona, Tucson, AZ, USA. .,BIO5, University of Arizona, Tucson, AZ, USA.
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Exercise Reduces Pain Behavior and Pathological Changes in Dorsal Root Ganglia Induced by Systemic Inflammation in Mice. Neurosci Lett 2022; 778:136616. [DOI: 10.1016/j.neulet.2022.136616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 03/11/2022] [Accepted: 04/01/2022] [Indexed: 11/23/2022]
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Wang J, Zhu F, Huang W, Chen Z, Zhao P, Lei Y, Liu Y, Liu X, Sun B, Li H. Therapeutic Effect and Mechanism of Acupuncture in Autoimmune Diseases. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2022; 50:639-652. [PMID: 35282807 DOI: 10.1142/s0192415x22500252] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Autoimmune diseases (AIDs) are conditions arising from abnormal immune reactions to autoantigens, which can be defined as the loss of immune tolerance to autoantigens, causing the production of autoantibodies and subsequent inflammation and tissue injury. The etiology of AIDs remains elusive, which may involve both genetic and environmental factors, such as diet, drugs, and infections. Despite rapid progress in the treatment of autoimmune diseases over the past few decades, there is still no approach that can cure AIDs. As an alternative approach, traditional Chinese medicine (TCM) such as acupuncture has been used in an attempt to treat AIDs including multiple sclerosis (MS), rheumatoid arthritis (RA), and inflammatory bowel disease (IBD), and the results have proven to be quite promising, despite the fact that its mechanism is still not fully understood. In this review, the present knowledge regarding mechanisms of acupuncture in the treatment of AIDs has been summarized, and deeper insights will be provided in order to better understand how acupuncture may regulate immune responses during AIDs.
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Affiliation(s)
- Jing Wang
- Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University Harbin, Heilongjiang 150081, P. R. China
| | - Fangyi Zhu
- Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University Harbin, Heilongjiang 150081, P. R. China
| | - Wei Huang
- Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University Harbin, Heilongjiang 150081, P. R. China
| | - Zhengyi Chen
- Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University Harbin, Heilongjiang 150081, P. R. China
| | - Ping Zhao
- Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University Harbin, Heilongjiang 150081, P. R. China
| | - Yanting Lei
- Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University Harbin, Heilongjiang 150081, P. R. China
| | - Yumei Liu
- Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University Harbin, Heilongjiang 150081, P. R. China
| | - Xijun Liu
- Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University Harbin, Heilongjiang 150081, P. R. China
| | - Bo Sun
- Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University Harbin, Heilongjiang 150081, P. R. China
| | - Hulun Li
- Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University Harbin, Heilongjiang 150081, P. R. China
- The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education Harbin, Heilongjiang 150081, P. R. China
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Wang N, Feng BN, Hu B, Cheng YL, Guo YH, Qian H. Neuroprotection of chicoric acid in a mouse model of Parkinson's disease involves gut microbiota and TLR4 signaling pathway. Food Funct 2022; 13:2019-2032. [PMID: 35103734 DOI: 10.1039/d1fo02216d] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Chicoric acid (CA), a polyphenolic acid obtained from chicory and purple coneflower (Echinacea purpurea), has been regarded as a nutraceutical to combat inflammation, viruses and obesity. Parkinson's disease (PD) is a common neurodegenerative disorder, and the microbiota-gut-brain axis might be the potential mechanism in the pathogenesis and development of PD. The results obtained in this study demonstrated that oral pretreatments of CA significantly prevented the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced motor dysfunctions and death of nigrostriatal dopaminergic neurons along with the inhibition of glial hyperactivation and the increment in striatal neurotrophins. 16S rRNA sequence results showed that CA significantly reduced MPTP-induced microbial dysbiosis and partially restored the composition of the gut microbiota to normal, including decreased phylum Bacteroidetes and genera Parabacteroide, as well as increased phylum Firmicutes, genera Lactobacillus and Ruminiclostridium. Besides, CA promoted colonic epithelial integrity and restored normal SCFA production. We also observed that proinflammatory cytokines such as TNF-α and IL-1β in the serum, striatum and colon were reduced by CA, indicating that CA prevented neuroinflammation and gut inflammation, in which the suppression of the TLR4/MyD88/NF-κB signaling pathway might be the underlying molecular mechanism. These findings demonstrated that CA had neuroprotective effects on MPTP-induced PD mice possibly via modulating the gut microbiota and inhibiting inflammation throughout the brain-gut axis.
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Affiliation(s)
- Ning Wang
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China.
| | - Bai-Nian Feng
- School of Pharmaceutical Science, Jiangnan University, Wuxi 214122, China
| | - Bin Hu
- School of Biotechnology, Jiangnan University, Wuxi 214122, China
| | - Yu-Liang Cheng
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China.
| | - Ya-Hui Guo
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China.
| | - He Qian
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China.
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Chandramowlishwaran P, Raja S, Maheshwari A, Srinivasan S. Enteric Nervous System in Neonatal Necrotizing Enterocolitis. Curr Pediatr Rev 2022; 18:9-24. [PMID: 34503418 DOI: 10.2174/1573396317666210908162745] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 02/26/2021] [Accepted: 06/08/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND The pathophysiology of necrotizing enterocolitis (NEC) is not clear, but increasing information suggests that the risk and severity of NEC may be influenced by abnormalities in the enteric nervous system (ENS). OBJECTIVE The purpose of this review was to scope and examine the research related to ENS-associated abnormalities that have either been identified in NEC or have been noted in other inflammatory bowel disorders (IBDs) with histopathological abnormalities similar to NEC. The aim was to summarize the research findings, identify research gaps in existing literature, and disseminate them to key knowledge end-users to collaborate and address the same in future studies. METHODS Articles that met the objectives of the study were identified through an extensive literature search in the databases PubMed, EMBASE, and Scopus. RESULTS The sources identified through the literature search revealed that: (1) ENS may be involved in NEC development and post-NEC complications, (2) NEC development is associated with changes in the ENS, and (3) NEC-associated changes could be modulated by the ENS. CONCLUSION The findings from this review identify the enteric nervous as a target in the development and progression of NEC. Thus, factors that can protect the ENS can potentially prevent and treat NEC and post-NEC complications. This review serves to summarize the existing literature and highlights a need for further research on the involvement of ENS in NEC.
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Affiliation(s)
- Pavithra Chandramowlishwaran
- Department of Medicine, Emory University School of Medicine, Decatur, GA, USA.,Gastroenterology Research, Atlanta VA Medical Center, Decatur, GA, USA
| | - Shreya Raja
- Department of Medicine, Emory University School of Medicine, Decatur, GA, USA.,Gastroenterology Research, Atlanta VA Medical Center, Decatur, GA, USA
| | - Akhil Maheshwari
- Department of Pediatrics, Johns Hopkins University, Baltimore, MD, USA
| | - Shanthi Srinivasan
- Department of Medicine, Emory University School of Medicine, Decatur, GA, USA.,Gastroenterology Research, Atlanta VA Medical Center, Decatur, GA, USA
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New Concepts of the Interplay Between the Gut Microbiota and the Enteric Nervous System in the Control of Motility. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1383:55-69. [PMID: 36587146 DOI: 10.1007/978-3-031-05843-1_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Propulsive gastrointestinal (GI) motility is critical for digestive physiology and host defense. GI motility is finely regulated by the intramural reflex pathways of the enteric nervous system (ENS). The ENS is in turn regulated by luminal factors: diet and the gut microbiota. The gut microbiota is a vast ecosystem of commensal bacteria, fungi, viruses, and other microbes. The gut microbiota not only regulates the motor programs of the ENS but also is critical for the normal structure and function of the ENS. In this chapter, we highlight recent research that has shed light on the microbial mechanisms of interaction with the ENS involved in the control of motility. Toll-like receptor signaling mechanisms have been shown to maintain the structural integrity of the ENS and the neurochemical phenotypes of enteric neurons, in part through the production of trophic factors including glia-derived neurotrophic factor. Microbiota-derived short-chain fatty acids and/or single-stranded RNA regulates the synthesis of serotonin in enterochromaffin cells, which are involved in the initiation of enteric reflexes, among other functions. Further evidence suggests a crucial role for microbial modulation of serotonin in maintaining the integrity of the ENS through enteric neurogenesis. Understanding the microbial pathways of enteric neural control sheds new light on digestive health and provides novel treatment strategies for GI motility disorders.
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Enteric neuroimmune interactions coordinate intestinal responses in health and disease. Mucosal Immunol 2022; 15:27-39. [PMID: 34471248 PMCID: PMC8732275 DOI: 10.1038/s41385-021-00443-1] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 08/02/2021] [Accepted: 08/05/2021] [Indexed: 02/04/2023]
Abstract
The enteric nervous system (ENS) of the gastrointestinal (GI) tract interacts with the local immune system bidirectionally. Recent publications have demonstrated that such interactions can maintain normal GI functions during homeostasis and contribute to pathological symptoms during infection and inflammation. Infection can also induce long-term changes of the ENS resulting in the development of post-infectious GI disturbances. In this review, we discuss how the ENS can regulate and be regulated by immune responses and how such interactions control whole tissue physiology. We also address the requirements for the proper regeneration of the ENS and restoration of GI function following the resolution of infection.
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