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Belelli D, Lambert JJ, Wan MLY, Monteiro AR, Nutt DJ, Swinny JD. From bugs to brain: unravelling the GABA signalling networks in the brain-gut-microbiome axis. Brain 2025; 148:1479-1506. [PMID: 39716883 PMCID: PMC12074267 DOI: 10.1093/brain/awae413] [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: 07/30/2024] [Revised: 11/21/2024] [Accepted: 12/01/2024] [Indexed: 12/25/2024] Open
Abstract
Convergent data across species paint a compelling picture of the critical role of the gut and its resident microbiota in several brain functions and disorders. The chemicals mediating communication along these sophisticated highways of the brain-gut-microbiome (BGM) axis include both microbiota metabolites and classical neurotransmitters. Amongst the latter, GABA is fundamental to brain function, mediating most neuronal inhibition. Until recently, GABA's role and specific molecular targets in the periphery within the BGM axis had received limited attention. Yet, GABA is produced by neuronal and non-neuronal elements of the BGM, and recently, GABA-modulating bacteria have been identified as key players in GABAergic gut systems, indicating that GABA-mediated signalling is likely to transcend physiological boundaries and species. We review the available evidence to better understand how GABA facilitates the integration of molecularly and functionally disparate systems to bring about overall homeostasis and how GABA perturbations within the BGM axis can give rise to multi-system medical disorders, thereby magnifying the disease burden and the challenges for patient care. Analysis of transcriptomic databases revealed significant overlaps between GABAAR subunits expressed in the human brain and gut. However, in the gut, there are notable expression profiles for a select number of subunits that have received limited attention to date but could be functionally relevant for BGM axis homeostasis. GABAergic signalling, via different receptor subtypes, directly regulates BGM homeostasis by modulating the excitability of neurons within brain centres responsible for gastrointestinal (GI) function in a sex-dependent manner, potentially revealing mechanisms underlying the greater prevalence of GI disturbances in females. Apart from such top-down regulation of the BGM axis, a diverse group of cell types, including enteric neurons, glia, enteroendocrine cells, immune cells and bacteria, integrate peripheral GABA signals to influence brain functions and potentially contribute to brain disorders. We propose several priorities for this field, including the exploitation of available technologies to functionally dissect components of these GABA pathways within the BGM, with a focus on GI and brain-behaviour-disease. Furthermore, in silico ligand-receptor docking analyses using relevant bacterial metabolomic datasets, coupled with advances in knowledge of GABAAR 3D structures, could uncover new ligands with novel therapeutic potential. Finally, targeted design of dietary interventions is imperative to advancing their therapeutic potential to support GABA homeostasis across the BGM axis.
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Affiliation(s)
- Delia Belelli
- GABA Labs (Research) Ltd., Hemel Hempstead HP2 5HD, UK
- Division of Neuroscience, School of Medicine, Medical Sciences Institute, Dundee University, Dundee DD1 5HL, UK
- School of Medicine, Pharmacy & Biomedical Sciences, University of Portsmouth, Portsmouth PO1 2DT, UK
| | - Jeremy J Lambert
- Division of Neuroscience, School of Medicine, Medical Sciences Institute, Dundee University, Dundee DD1 5HL, UK
| | - Murphy Lam Yim Wan
- School of Medicine, Pharmacy & Biomedical Sciences, University of Portsmouth, Portsmouth PO1 2DT, UK
| | - Ana Rita Monteiro
- School of Medicine, Pharmacy & Biomedical Sciences, University of Portsmouth, Portsmouth PO1 2DT, UK
| | - David J Nutt
- GABA Labs (Research) Ltd., Hemel Hempstead HP2 5HD, UK
- Division of Psychiatry, Department of Brain Sciences, Imperial College London, London W12 0NN, UK
| | - Jerome D Swinny
- School of Medicine, Pharmacy & Biomedical Sciences, University of Portsmouth, Portsmouth PO1 2DT, UK
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Kubota D, Sato M, Udono M, Kohara A, Kudoh M, Ukawa Y, Teruya K, Katakura Y. Activation of the Gut-Brain Interaction by Urolithin A and Its Molecular Basis. Nutrients 2024; 16:3369. [PMID: 39408336 PMCID: PMC11478980 DOI: 10.3390/nu16193369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Revised: 08/29/2024] [Accepted: 10/01/2024] [Indexed: 10/20/2024] Open
Abstract
Background: Urolithin A (Uro-A), a type of polyphenol derived from pomegranate, is known to improve memory function when ingested, in addition to its direct effect on the skin epidermal cells through the activation of longevity gene SIRT1. However, the molI ecular mechanism by which orally ingested Uro-A inhibits cognitive decline via the intestine remains unexplored. Objectives: This study aimed to evaluate the role of Uro-A in improving cognitive function via improved intestinal function and the effect of Uro-A on the inflammation levels and gene expression in hippocampus. Methods: Research to clarify the molecular basis of the functionality of Uro-A was also conducted. Results: The results demonstrated that Uro-A suppressed age-related memory impairment in Aged mice (C57BL/6J Jcl, male, 83 weeks old) by reducing inflammation and altering hippocampal gene expression. Furthermore, exosomes derived from intestinal cells treated with Uro-A and from the serum of Aged mice fed with Uro-A both activated neuronal cells, suggesting that exosomes are promising candidates as mediators of the Uro-A-induced activation of gut-brain interactions. Additionally, neurotrophic factors secreted from intestinal cells may contribute to the Uro-A-induced activation of gut-brain interactions. Conclusions: This study suggests that Uro-A suppresses age-related cognitive decline and that exosomes and other secreted factors may contribute to the activation of the gut-brain interaction. These findings provide new insights into the therapeutic potential of Uro-A for cognitive health.
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Affiliation(s)
- Daiki Kubota
- Graduate School of Bioresources, Bioenvironmental Sciences, Kyushu University, Fukuoka 819-0395, Japan; (D.K.); (M.S.)
| | - Momoka Sato
- Graduate School of Bioresources, Bioenvironmental Sciences, Kyushu University, Fukuoka 819-0395, Japan; (D.K.); (M.S.)
| | - Miyako Udono
- Faculty of Agriculture, Kyushu University, Fukuoka 819-0395, Japan; (M.U.); (K.T.)
| | - Akiko Kohara
- Daicel Corporation, Tokyo 108-8230, Japan (M.K.); (Y.U.)
| | - Masatake Kudoh
- Daicel Corporation, Tokyo 108-8230, Japan (M.K.); (Y.U.)
| | - Yuichi Ukawa
- Daicel Corporation, Tokyo 108-8230, Japan (M.K.); (Y.U.)
| | - Kiichiro Teruya
- Faculty of Agriculture, Kyushu University, Fukuoka 819-0395, Japan; (M.U.); (K.T.)
| | - Yoshinori Katakura
- Faculty of Agriculture, Kyushu University, Fukuoka 819-0395, Japan; (M.U.); (K.T.)
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Ikegami M, Narabayashi H, Nakata K, Yamashita M, Sugi Y, Fuji Y, Matsufuji H, Harata G, Yoda K, Miyazawa K, Nakanishi Y, Takahashi K. Intervention in gut microbiota increases intestinal γ-aminobutyric acid and alleviates anxiety behavior: a possible mechanism via the action on intestinal epithelial cells. Front Cell Infect Microbiol 2024; 14:1421791. [PMID: 39301289 PMCID: PMC11410766 DOI: 10.3389/fcimb.2024.1421791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 08/14/2024] [Indexed: 09/22/2024] Open
Abstract
The role of the gut microbiota in the gut-brain axis has attracted attention in recent years. Some gut microbiota produces γ-aminobutyric acid (GABA), a major inhibitory neurotransmitter in mammals, in vitro, but the correlation between gut microbiota composition and intestinal GABA concentration, as well as the action of intestinal GABA in vivo, are poorly understood. Herein, we found that the intestinal GABA concentration was increased in mice by the intervention of the gut microbiota with neomycin or Bifidobacterium bifidum TMC3115 (TMC3115). Administration of TMC3115 reduced anxiety without affecting serum levels of serotonin, corticosterone, or GABA. We further found that intestinal epithelial cells expressed GABA receptor subunits and mediated mitogen-activated protein kinase signaling upon GABA stimulation. In addition, administration of TMC3115 induced mitogen-activated protein kinase signaling in colonic epithelial cells but not in small intestinal epithelial cells in mice. These results indicate that GABA produced by the gut microbiota, mainly in the colon, may affect host behavioral characteristics via GABA receptors expressed in intestinal epithelial cells without being transferred to the blood. This study suggests a novel mechanism by which intestinal GABA exerts physiological effects, even in the presence of the blood-brain barrier.
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Affiliation(s)
- Mion Ikegami
- Nihon University Graduate School of Bioresource Sciences, Fujisawa, Kanagawa, Japan
| | - Hikari Narabayashi
- Nihon University Graduate School of Bioresource Sciences, Fujisawa, Kanagawa, Japan
| | - Kazuaki Nakata
- Nihon University Graduate School of Bioresource Sciences, Fujisawa, Kanagawa, Japan
| | - Miyu Yamashita
- Nihon University Graduate School of Bioresource Sciences, Fujisawa, Kanagawa, Japan
| | - Yutaka Sugi
- College of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa, Japan
| | - Yushiro Fuji
- Nihon University Graduate School of Bioresource Sciences, Fujisawa, Kanagawa, Japan
| | - Hiroshi Matsufuji
- Nihon University Graduate School of Bioresource Sciences, Fujisawa, Kanagawa, Japan
- College of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa, Japan
| | - Gaku Harata
- Technical Research Laboratory, Takanashi Milk Products Co., Ltd, Yokohama, Kanagawa, Japan
| | - Kazutoyo Yoda
- Technical Research Laboratory, Takanashi Milk Products Co., Ltd, Yokohama, Kanagawa, Japan
| | - Kenji Miyazawa
- Technical Research Laboratory, Takanashi Milk Products Co., Ltd, Yokohama, Kanagawa, Japan
| | - Yusuke Nakanishi
- Nihon University Graduate School of Bioresource Sciences, Fujisawa, Kanagawa, Japan
- College of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa, Japan
| | - Kyoko Takahashi
- Nihon University Graduate School of Bioresource Sciences, Fujisawa, Kanagawa, Japan
- College of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa, Japan
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Fang X, Zhou D, Wang X, Ma Y, Zhong G, Jing S, Huang S, Wang Q. Exosomes: A Cellular Communication Medium That Has Multiple Effects On Brain Diseases. Mol Neurobiol 2024; 61:6864-6892. [PMID: 38356095 DOI: 10.1007/s12035-024-03957-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 01/12/2024] [Indexed: 02/16/2024]
Abstract
Exosomes, as membranous vesicles generated by multiple cell types and secreted to extracellular space, play a crucial role in a range of brain injury-related brain disorders by transporting diverse proteins, RNA, DNA fragments, and other functional substances. The nervous system's pathogenic mechanisms are complicated, involving pathological processes like as inflammation, apoptosis, oxidative stress, and autophagy, all of which result in blood-brain barrier damage, cognitive impairment, and even loss of normal motor function. Exosomes have been linked to the incidence and progression of brain disorders in recent research. As a result, a thorough knowledge of the interaction between exosomes and brain diseases may lead to the development of more effective therapeutic techniques that may be implemented in the clinic. The potential role of exosomes in brain diseases and the crosstalk between exosomes and other pathogenic processes were discussed in this paper. Simultaneously, we noted the delicate events in which exosomes as a media allow the brain to communicate with other tissues and organs in physiology and disease, and compiled a list of natural compounds that modulate exosomes, in order to further improve our understanding of exosomes and propose new ideas for treating brain disorders.
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Affiliation(s)
- Xiaoling Fang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong Province, China
| | - Dishu Zhou
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong Province, China
| | - Xinyue Wang
- Department of Oncology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510405, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, 510405, Guangzhou, China
| | - Yujie Ma
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong Province, China
| | - Guangcheng Zhong
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong Province, China
| | - Shangwen Jing
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong Province, China
| | - Shuiqing Huang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong Province, China.
| | - Qi Wang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong Province, China.
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Cabrera-Pastor A. Extracellular Vesicles as Mediators of Neuroinflammation in Intercellular and Inter-Organ Crosstalk. Int J Mol Sci 2024; 25:7041. [PMID: 39000150 PMCID: PMC11241119 DOI: 10.3390/ijms25137041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 06/20/2024] [Accepted: 06/22/2024] [Indexed: 07/16/2024] Open
Abstract
Neuroinflammation, crucial in neurological disorders like Alzheimer's disease, multiple sclerosis, and hepatic encephalopathy, involves complex immune responses. Extracellular vesicles (EVs) play a pivotal role in intercellular and inter-organ communication, influencing disease progression. EVs serve as key mediators in the immune system, containing molecules capable of activating molecular pathways that exacerbate neuroinflammatory processes in neurological disorders. However, EVs from mesenchymal stem cells show promise in reducing neuroinflammation and cognitive deficits. EVs can cross CNS barriers, and peripheral immune signals can influence brain function via EV-mediated communication, impacting barrier function and neuroinflammatory responses. Understanding EV interactions within the brain and other organs could unveil novel therapeutic targets for neurological disorders.
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Affiliation(s)
- Andrea Cabrera-Pastor
- Departamento de Farmacología, Facultad de Medicina y Odontología, Universitat de València, 46010 Valencia, Spain; or
- Fundación de Investigación del Hospital Clínico Universitario de Valencia, INCLIVA, 46010 Valencia, Spain
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6
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Kashiwagi R, Udono M, Katakura Y. Fructobacillus fructosus OS-1010 strain stimulates intestinal cells to secrete exosomes that activate muscle cells. Cytotechnology 2024; 76:209-216. [PMID: 38495295 PMCID: PMC10940565 DOI: 10.1007/s10616-023-00610-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Accepted: 12/13/2023] [Indexed: 03/19/2024] Open
Abstract
Fructobacillus is a lactic-acid bacterium recently identified in fructose-rich environments. Fructobacillus is also known to exhibit unusual growth characteristics due to an incomplete gene encoding alcohol/acetaldehyde hydrogenase, which results in an imbalance in the nicotinamide adenine mononucleotide (NAD+)/NADN levels. Recently, the addition of d-fructose to the culture medium of Fructobacillus strains increased the intracellular nicotinamide mononucleotide (NMN) content. In the present study, we evaluated the functionality of Fructobacillus that produces high levels of NMN, using one substrain (Fructobacillus fructosus OS-1010). Therefore, in this study, we examined its functionality in the interaction between intestinal cells and muscle cells. The results showed that supernatant derived from intestinal epithelial cells (Caco-2 cells) treated with F. fructosus OS-1010 activated muscle cells (C2C12 cells). Further analysis revealed that Caco-2 cells treated with F. fructosus OS-1010 secreted exosomes known as extracellular vesicles, which activated the muscle cells. Furthermore, pathway analysis of the target genes of miRNA in exosomes revealed that pathways involved in muscle cell activation, including insulin signaling and cardiac muscle regulation, neurotrophic factors, longevity, and anti-aging, can be activated by exosomes. In other words, F. fructosus OS-1010 could activate various cells such as the skin and muscle cells, by secreting functional exosomes from the intestinal tract.
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Affiliation(s)
- Riku Kashiwagi
- Graduate School of Systems Life Sciences, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 813-0395 Japan
| | - Miyako Udono
- Faculty of Agriculture, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 813-0395 Japan
| | - Yoshinori Katakura
- Graduate School of Systems Life Sciences, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 813-0395 Japan
- Faculty of Agriculture, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 813-0395 Japan
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Belelli D, Riva A, Nutt DJ. Reducing the harms of alcohol: nutritional interventions and functional alcohol alternatives. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2024; 175:241-276. [PMID: 38555118 DOI: 10.1016/bs.irn.2024.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/02/2024]
Abstract
The health risks and harm associated with regular alcohol consumption are well documented. In a recent WHO statement published in The Lancet Public Health alcohol consumption has been estimated to contribute worldwide to 3 million deaths in 2016 while also being responsible for 5·1% of the global burden of disease and injury. The total elimination of alcohol consumption, which has been long imbedded in human culture and society, is not practical and prohibition policies have proved historically ineffective. However, valuable strategies to reduce alcohol harms are already available and improved alternative approaches are currently being developed. Here, we will review and discuss recent advances on two main types of approaches, that is nutritional interventions and functional alcohol alternatives.
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Affiliation(s)
- Delia Belelli
- GABALabs Res. Senior Scientific Consultant, United Kingdom
| | - Antonio Riva
- Roger Williams Institute of Hepatology (Foundation for Liver Research), London; Faculty of Life Sciences & Medicine, King's College London, London
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Zhang Z, Tao Q, Bai L, Qin Z, Liu X, Li S, Yang Y, Ge W, Li J. MicroRNA in the Exosomes Mediated by Resveratrol to Activate Neuronal Cells. TOXICS 2024; 12:122. [PMID: 38393218 PMCID: PMC10891859 DOI: 10.3390/toxics12020122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 01/29/2024] [Accepted: 01/29/2024] [Indexed: 02/25/2024]
Abstract
Resveratrol (RSV), a polyphenol, is known to have a wide range of pharmacological properties in vitro. RSV may have therapeutic value for various neurodegenerative diseases via neuroprotective effects. However, it is not yet clear whether RSV can induce intestinal-brain interactions. It is assumed that the intestinal cells may secrete some factors after being stimulated by other substances. These secreted factors may activate nerve cells through gut-brain interaction, such as exosomes. In this study, it was discovered that Caco-2 cells treated with RSV secrete exosomes to activate SH-SY5Y neuronal cells. The results showed that secreted factors from RSV-treated Caco-2 cells activated SH-SY5Y. The exosomes of RSV-treated Caco-2 cells activated SH-SY5Y cells, which was manifested in the lengthening of the nerve filaments of SH-SY5Y cells. The exosomes were characterized using transmission electron microscopy and sequenced using the Illumina NovaSeq 6000 sequencer. The results showed that the miRNA expression profile of exosomes after RSV treatment changed, and twenty-six kinds of miRNAs were identified which expressed differentially between the control group and the RSV-treated group. Among them, three miRNAs were selected as candidate genes for inducing SH-SY5Y neural cell activation. Three miRNA mimics could activate SH-SY5Y neurons. These results suggested that the miRNA in intestinal exocrine cells treated with RSV may play an important role in the activation of SH-SY5Y neurons.
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Affiliation(s)
- Zhendong Zhang
- Key Lab of New Animal Drug of Gansu Province, Key Lab of Veterinary Pharmaceutical Development of Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, Lanzhou 730050, China; (Z.Z.); (Q.T.); (L.B.); (Z.Q.); (X.L.); (S.L.); (Y.Y.); (W.G.)
- College of Life Sciences, South China Agricultural University, Guangzhou 510642, China
| | - Qi Tao
- Key Lab of New Animal Drug of Gansu Province, Key Lab of Veterinary Pharmaceutical Development of Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, Lanzhou 730050, China; (Z.Z.); (Q.T.); (L.B.); (Z.Q.); (X.L.); (S.L.); (Y.Y.); (W.G.)
| | - Lixia Bai
- Key Lab of New Animal Drug of Gansu Province, Key Lab of Veterinary Pharmaceutical Development of Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, Lanzhou 730050, China; (Z.Z.); (Q.T.); (L.B.); (Z.Q.); (X.L.); (S.L.); (Y.Y.); (W.G.)
| | - Zhe Qin
- Key Lab of New Animal Drug of Gansu Province, Key Lab of Veterinary Pharmaceutical Development of Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, Lanzhou 730050, China; (Z.Z.); (Q.T.); (L.B.); (Z.Q.); (X.L.); (S.L.); (Y.Y.); (W.G.)
| | - Xiwang Liu
- Key Lab of New Animal Drug of Gansu Province, Key Lab of Veterinary Pharmaceutical Development of Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, Lanzhou 730050, China; (Z.Z.); (Q.T.); (L.B.); (Z.Q.); (X.L.); (S.L.); (Y.Y.); (W.G.)
| | - Shihong Li
- Key Lab of New Animal Drug of Gansu Province, Key Lab of Veterinary Pharmaceutical Development of Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, Lanzhou 730050, China; (Z.Z.); (Q.T.); (L.B.); (Z.Q.); (X.L.); (S.L.); (Y.Y.); (W.G.)
| | - Yajun Yang
- Key Lab of New Animal Drug of Gansu Province, Key Lab of Veterinary Pharmaceutical Development of Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, Lanzhou 730050, China; (Z.Z.); (Q.T.); (L.B.); (Z.Q.); (X.L.); (S.L.); (Y.Y.); (W.G.)
| | - Wenbo Ge
- Key Lab of New Animal Drug of Gansu Province, Key Lab of Veterinary Pharmaceutical Development of Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, Lanzhou 730050, China; (Z.Z.); (Q.T.); (L.B.); (Z.Q.); (X.L.); (S.L.); (Y.Y.); (W.G.)
| | - Jianyong Li
- Key Lab of New Animal Drug of Gansu Province, Key Lab of Veterinary Pharmaceutical Development of Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, Lanzhou 730050, China; (Z.Z.); (Q.T.); (L.B.); (Z.Q.); (X.L.); (S.L.); (Y.Y.); (W.G.)
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Li H, Yuan Y, Xie Q, Dong Z. Exosomes: potential targets for the diagnosis and treatment of neuropsychiatric disorders. J Transl Med 2024; 22:115. [PMID: 38287384 PMCID: PMC10826005 DOI: 10.1186/s12967-024-04893-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 01/14/2024] [Indexed: 01/31/2024] Open
Abstract
The field of neuropsychiatry is considered a middle ground between neurological and psychiatric disorders, thereby bridging the conventional boundaries between matter and mind, consciousness, and function. Neuropsychiatry aims to evaluate and treat cognitive, behavioral, and emotional disorders in individuals with neurological conditions. However, the pathophysiology of these disorders is not yet fully understood, and objective biological indicators for these conditions are currently lacking. Treatment options are also limited due to the blood-brain barrier, which results in poor treatment effects. Additionally, many drugs, particularly antipsychotic drugs, have adverse reactions, which make them difficult to tolerate for patients. As a result, patients often abandon treatment owing to these adverse reactions. Since the discovery of exosomes in 1983, they have been extensively studied in various diseases owing to their potential as nanocellulators for information exchange between cells. Because exosomes can freely travel between the center and periphery, brain-derived exosomes can reflect the state of the brain, which has considerable advantages in diagnosis and treatment. In addition, administration of engineered exosomes can improve therapeutic efficacy, allow lesion targeting, ensure drug stability, and prevent systemic adverse effects. Therefore, this article reviews the source and biological function of exosomes, relationship between exosomes and the blood-brain barrier, relationship between exosomes and the pathological mechanism of neuropsychiatric disorders, exosomes in the diagnosis and treatment of neuropsychiatric disorders, and application of engineered exosomes in neuropsychiatric disorders.
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Affiliation(s)
- Haorao Li
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China
| | - Yanling Yuan
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China
| | - Qinglian Xie
- Department of Outpatient, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China.
| | - Zaiquan Dong
- Department of Psychiatry and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China.
- Mental Health Center, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China.
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Tamés H, Sabater C, Royo F, Margolles A, Falcón JM, Ruas-Madiedo P, Ruiz L. Mouse intestinal microbiome modulation by oral administration of a GABA-producing Bifidobacterium adolescentis strain. Microbiol Spectr 2024; 12:e0258023. [PMID: 37991375 PMCID: PMC10783132 DOI: 10.1128/spectrum.02580-23] [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: 06/20/2023] [Accepted: 10/15/2023] [Indexed: 11/23/2023] Open
Abstract
IMPORTANCE The gut microbiome-brain communication signaling has emerged in recent years as a novel target for intervention with the potential to ameliorate some conditions associated with the central nervous system. Hence, probiotics with capacity to produce neurotransmitters, for instance, have come up as appealing alternatives to treat disorders associated with disbalanced neurotransmitters. Herein, we further deep into the effects of administering a gamma-aminobutyric acid (GABA)-producing Bifidobacterium strain, previously demonstrated to contribute to reduce serum glutamate levels, in the gut microbiome composition and metabolic activity in a mouse model. Our results demonstrate that the GABA-producing strain administration results in a specific pattern of gut microbiota modulation, different from the one observed in animals receiving non-GABA-producing strains. This opens new avenues to delineate the specific mechanisms by which IPLA60004 administration contributes to reducing serum glutamate levels and to ascertain whether this effect could exert health benefits in patients of diseases associated with high-glutamate serum concentrations.
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Affiliation(s)
- Héctor Tamés
- Department of Microbiology and Biochemistry of Dairy Products, Instituto de Productos Lácteos de Asturias-Consejo Superior de Investigaciones Científicas (IPLA-CSIC), Paseo Río Linares s/n, Villaviciosa, Asturias, Spain
- Functionality and Ecology of Beneficial Microbes (MicroHealth) Group, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Asturias, Spain
| | - Carlos Sabater
- Department of Microbiology and Biochemistry of Dairy Products, Instituto de Productos Lácteos de Asturias-Consejo Superior de Investigaciones Científicas (IPLA-CSIC), Paseo Río Linares s/n, Villaviciosa, Asturias, Spain
- Functionality and Ecology of Beneficial Microbes (MicroHealth) Group, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Asturias, Spain
| | - Félix Royo
- Exosomes Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas Y Digestivas (CIBERehd), Madrid, Spain
- IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - Abelardo Margolles
- Department of Microbiology and Biochemistry of Dairy Products, Instituto de Productos Lácteos de Asturias-Consejo Superior de Investigaciones Científicas (IPLA-CSIC), Paseo Río Linares s/n, Villaviciosa, Asturias, Spain
- Functionality and Ecology of Beneficial Microbes (MicroHealth) Group, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Asturias, Spain
| | - Juan Manuel Falcón
- Exosomes Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas Y Digestivas (CIBERehd), Madrid, Spain
- IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - Patricia Ruas-Madiedo
- Department of Microbiology and Biochemistry of Dairy Products, Instituto de Productos Lácteos de Asturias-Consejo Superior de Investigaciones Científicas (IPLA-CSIC), Paseo Río Linares s/n, Villaviciosa, Asturias, Spain
- Functionality and Ecology of Beneficial Microbes (MicroHealth) Group, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Asturias, Spain
| | - Lorena Ruiz
- Department of Microbiology and Biochemistry of Dairy Products, Instituto de Productos Lácteos de Asturias-Consejo Superior de Investigaciones Científicas (IPLA-CSIC), Paseo Río Linares s/n, Villaviciosa, Asturias, Spain
- Functionality and Ecology of Beneficial Microbes (MicroHealth) Group, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Asturias, Spain
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11
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Tao Q, Zhang ZD, Lu XR, Qin Z, Liu XW, Li SH, Bai LX, Ge BW, Li JY, Yang YJ. Multi-omics reveals aspirin eugenol ester alleviates neurological disease. Biomed Pharmacother 2023; 166:115311. [PMID: 37572635 DOI: 10.1016/j.biopha.2023.115311] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 08/06/2023] [Accepted: 08/07/2023] [Indexed: 08/14/2023] Open
Abstract
BACKGROUND Exosomes play an essential role in maintaining normal brain function due to their ability to cross the blood-brain barrier. Aspirin eugenol ester (AEE) is a new medicinal compound synthesized by the esterification of aspirin with eugenol using the prodrug principle. Aspirin has been reported to have neuroprotective effects and may be effective against neurodegenerative diseases. PURPOSE This study wanted to investigate how AEE affected neurological diseases in vivo and in vitro. EXPERIMENTAL APPROACH A multi-omics approach was used to explore the effects of AEE on the nervous system. Gene and protein expression changes of BDNF and NEFM in SY5Y cells after AEE treatment were detected using RT-qPCR and Western Blot. KEY RESULTS The multi-omics results showed that AEE could regulate neuronal synapses, neuronal axons, neuronal migration, and neuropeptide signaling by affecting transport, inflammatory response, and regulating apoptosis. Exosomes secreted by AEE-treated Caco-2 cells could promote the growth of neurofilaments in SY5Y cells and increased the expression of BDNF and NEFM proteins in SY5Y cells. miRNAs in the exosomes of AEE-treated Caco-2 cells may play an important role in the activation of SY5Y neuronal cells. CONCLUSIONS In conclusion, AEE could play positive effects on neurological-related diseases.
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Affiliation(s)
- Qi Tao
- Key Lab of New Animal Drug Project of Gansu Province, Key Lab of Veterinary Pharmaceutical Development of Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, Lanzhou 730050, China
| | - Zhen-Dong Zhang
- Key Lab of New Animal Drug Project of Gansu Province, Key Lab of Veterinary Pharmaceutical Development of Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, Lanzhou 730050, China
| | - Xiao-Rong Lu
- Key Lab of New Animal Drug Project of Gansu Province, Key Lab of Veterinary Pharmaceutical Development of Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, Lanzhou 730050, China
| | - Zhe Qin
- Key Lab of New Animal Drug Project of Gansu Province, Key Lab of Veterinary Pharmaceutical Development of Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, Lanzhou 730050, China
| | - Xi-Wang Liu
- Key Lab of New Animal Drug Project of Gansu Province, Key Lab of Veterinary Pharmaceutical Development of Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, Lanzhou 730050, China
| | - Shi-Hong Li
- Key Lab of New Animal Drug Project of Gansu Province, Key Lab of Veterinary Pharmaceutical Development of Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, Lanzhou 730050, China
| | - Li-Xia Bai
- Key Lab of New Animal Drug Project of Gansu Province, Key Lab of Veterinary Pharmaceutical Development of Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, Lanzhou 730050, China
| | - Bo-Wen Ge
- Key Lab of New Animal Drug Project of Gansu Province, Key Lab of Veterinary Pharmaceutical Development of Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, Lanzhou 730050, China
| | - Jian-Yong Li
- Key Lab of New Animal Drug Project of Gansu Province, Key Lab of Veterinary Pharmaceutical Development of Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, Lanzhou 730050, China.
| | - Ya-Jun Yang
- Key Lab of New Animal Drug Project of Gansu Province, Key Lab of Veterinary Pharmaceutical Development of Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS, Lanzhou 730050, China.
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12
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Deng Z, Li D, Yan X, Lan J, Han D, Fan K, Chang J, Ma Y. Activation of GABA receptor attenuates intestinal inflammation by modulating enteric glial cells function through inhibiting NF-κB pathway. Life Sci 2023; 329:121984. [PMID: 37527767 DOI: 10.1016/j.lfs.2023.121984] [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: 06/21/2023] [Revised: 07/18/2023] [Accepted: 07/26/2023] [Indexed: 08/03/2023]
Abstract
AIMS Emerging research indicates that γ-aminobutyric acid (GABA) provides substantial benefits during enteritis. Nevertheless, GABA signaling roles on enteric glial cells (EGCs) remain unknown. The study's objective was to evaluate the underlying mechanisms of GABA signaling on EGCs in vitro and in vivo. MAIN METHODS We established LPS-induced mouse models and stimulated EGCs with LPS to mimic intestinal inflammation, and combined GABA, GABAA receptor (GABAAR) or GABAB receptor (GABABR) agonists to explore the exact mechanisms of GABA signaling. KEY FINDINGS EGCs were immunopositive for GAD65, GAD67, GAT1, GABAARα1, GABAARα3, and GABABR1, indicating GABAergic and GABAceptive properties. GABA receptor activation significantly inhibited the high secretions of proinflammatory factors in EGCs upon LPS stimulation. Interestingly, we found that EGCs express immune-related molecules such as CD16, CD32, CD80, CD86, MHC II, iNOS, Arg1, and CD206, thus establishing their characterization of E1 and E2 phenotype. EGCs exposed to LPS mainly acted as E1 phenotype, whereas GABABR activation strongly promoted EGCs polarization into E2 phenotype. Transcriptome analysis of EGCs indicated that GABA, GABAAR or GABABR agonists treatment participated in various biological processes, however all of these treatments exhibit inhibitory effects on NF-κB pathway. Notably, in LPS-induced mice, activation of GABABR mitigated intestinal damage through modulating inflammatory factors expressions, strengthening sIgA and IgG levels, inhibiting NF-κB pathway and facilitating EGCs to transform into E2 phenotype. SIGNIFICANCE These data demonstrate that the anti-inflammatory actions of GABA signaling system offer in enteritis via regulating EGCs-polarized function through impeding NF-κB pathway, thus providing potential targets for intestinal inflammatory diseases.
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Affiliation(s)
- Ziteng Deng
- National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Dan Li
- National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Xue Yan
- New Hope Liuhe Co., Ltd., Key Laboratory of Feed and Livestock and Poultry Products Quality & Safety Control, Ministry of Agriculture, Chengdu, Sichuan, China
| | - Jing Lan
- National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Deping Han
- National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China; Peking University Institute of Advanced Agricultural Sciences, Weifang, Shandong, China
| | - Kai Fan
- National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Jianyu Chang
- National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Yunfei Ma
- National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, China.
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13
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Zhou W, Zhao L, Mao Z, Wang Z, Zhang Z, Li M. Bidirectional Communication Between the Brain and Other Organs: The Role of Extracellular Vesicles. Cell Mol Neurobiol 2023; 43:2675-2696. [PMID: 37067749 PMCID: PMC10106324 DOI: 10.1007/s10571-023-01345-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 04/03/2023] [Indexed: 04/18/2023]
Abstract
A number of substances released by the brain under physiological and pathological conditions exert effects on other organs. In turn, substances produced primarily by organs such as bone marrow, adipose tissue, or the heart may have an impact on the metabolism and function and metabolism of the healthy and diseased brain. Despite a mounting amount of evidence supports such bidirectional communication between the brain and other organs, research on the function of molecular mediators carried by extracellular vesicles (EVs) is in the early stages. In addition to being able to target or reach practically any organ, EVs have the ability to cross the blood-brain barrier to transport a range of substances (lipids, peptides, proteins, and nucleic acids) to recipient cells, exerting biological effects. Here, we review the function of EVs in bidirectional communication between the brain and other organs. In a small number of cases, the role has been explicitly proven; yet, in most cases, it relies on indirect evidence from EVs in cell culture or animal models. There is a dearth of research currently available on the function of EVs-carrying mediators in the bidirectional communication between the brain and bone marrow, adipose tissue, liver, heart, lungs, and gut. Therefore, more studies are needed to determine how EVs facilitate communication between the brain and other organs.
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Affiliation(s)
- Wu Zhou
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, 17 Yongwai Street, Nanchang, 330006, Jiangxi, China
| | - Lihong Zhao
- Department of Radiotherapy, Jilin Cancer Hospital, 1018 Huguang Street, Changchun, 130012, Jilin, China
| | - Zelu Mao
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, 17 Yongwai Street, Nanchang, 330006, Jiangxi, China
| | - Zhihua Wang
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, 17 Yongwai Street, Nanchang, 330006, Jiangxi, China
| | - Zhixiong Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, 17 Yongwai Street, Nanchang, 330006, Jiangxi, China
| | - Meihua Li
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, 17 Yongwai Street, Nanchang, 330006, Jiangxi, China.
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Gangadaran P, Madhyastha H, Madhyastha R, Rajendran RL, Nakajima Y, Watanabe N, Velikkakath AKG, Hong CM, Gopi RV, Muthukalianan GK, Valsala Gopalakrishnan A, Jeyaraman M, Ahn BC. The emerging role of exosomes in innate immunity, diagnosis and therapy. Front Immunol 2023; 13:1085057. [PMID: 36726968 PMCID: PMC9885214 DOI: 10.3389/fimmu.2022.1085057] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 12/16/2022] [Indexed: 01/17/2023] Open
Abstract
Exosomes, which are nano-sized transport bio-vehicles, play a pivotal role in maintaining homeostasis by exchanging genetic or metabolic information between different cells. Exosomes can also play a vital role in transferring virulent factors between the host and parasite, thereby regulating host gene expression and the immune interphase. The association of inflammation with disease development and the potential of exosomes to enhance or mitigate inflammatory pathways support the notion that exosomes have the potential to alter the course of a disease. Clinical trials exploring the role of exosomes in cancer, osteoporosis, and renal, neurological, and pulmonary disorders are currently underway. Notably, the information available on the signatory efficacy of exosomes in immune-related disorders remains elusive and sporadic. In this review, we discuss immune cell-derived exosomes and their application in immunotherapy, including those against autoimmune connective tissue diseases. Further, we have elucidated our views on the major issues in immune-related pathophysiological processes. Therefore, the information presented in this review highlights the role of exosomes as promising strategies and clinical tools for immune regulation.
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Affiliation(s)
- Prakash Gangadaran
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Harishkumar Madhyastha
- Department of Cardiovascular Physiology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Radha Madhyastha
- Department of Cardiovascular Physiology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Ramya Lakshmi Rajendran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Yuichi Nakajima
- Department of Cardiovascular Physiology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Nozomi Watanabe
- Department of Cardiovascular Physiology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Anoop Kumar G. Velikkakath
- Center for System Biology and Molecular Medicine, Yenepoya Research center, Yenepoya (Deemed to be University), Mangaluru, Karnataka, India
| | - Chae Moon Hong
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Rahul Velikkakath Gopi
- Department of Tissue Engineering and Regeneration Technologies, Sree Chitra Thirunal Institute of Medical Sciences and Technology, Thiruvananthapuram, India
| | | | | | - Madhan Jeyaraman
- Department of Orthopaedics, Faculty of Medicine, Sri Lalithambigai Medical College and Hospital, Dr MGR Educational and Research Institute, Chennai, Tamil Nadu, India
| | - Byeong-Cheol Ahn
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
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Feng T, Zhang W, Li Z. Potential Mechanisms of Gut-Derived Extracellular Vesicle Participation in Glucose and Lipid Homeostasis. Genes (Basel) 2022; 13:1964. [PMID: 36360201 PMCID: PMC9689624 DOI: 10.3390/genes13111964] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 10/24/2022] [Accepted: 10/26/2022] [Indexed: 01/19/2023] Open
Abstract
The intestine participates in the regulation of glucose and lipid metabolism in multiple facets. It is the major site of nutrient digestion and absorption, provides the interface as well as docking locus for gut microbiota, and harbors hormone-producing cells scattered throughout the gut epithelium. Intestinal extracellular vesicles are known to influence the local immune response, whereas their roles in glucose and lipid homeostasis have barely been explored. Hence, this current review summarizes the latest knowledge of cargo substances detected in intestinal extracellular vesicles, and connects these molecules with the fine-tuning regulation of glucose and lipid metabolism in liver, muscle, pancreas, and adipose tissue.
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Affiliation(s)
- Tiange Feng
- Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100191, China
| | - Weizhen Zhang
- Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100191, China
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
| | - Ziru Li
- MaineHealth Institute for Research, MaineHealth, Scarborough, ME 04074, USA
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16
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Singh S, Somvanshi RK, Kumar U. Somatostatin-Mediated Regulation of Retinoic Acid-Induced Differentiation of SH-SY5Y Cells: Neurotransmitters Phenotype Characterization. Biomedicines 2022; 10:biomedicines10020337. [PMID: 35203546 PMCID: PMC8961784 DOI: 10.3390/biomedicines10020337] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 01/27/2022] [Accepted: 01/29/2022] [Indexed: 02/04/2023] Open
Abstract
During brain development, neurite formation plays a critical role in neuronal communication and cognitive function. In the present study, we compared developmental changes in the expression of crucial markers that govern the functional activity of neurons, including somatostatin (SST), choline acetyltransferase (ChAT), tyrosine hydroxylase (TH), brain nitric oxide synthase (bNOS), gamma-aminobutyric acid (GABA), glutamic acid decarboxylase (GAD-65) and synaptic vesicle protein synaptophysin (SYP) in non-differentiated and retinoic acid (RA)-induced differentiated SH-SY5Y cells. We further determined the role of SST in regulating subcellular distribution and expression of neurotransmitters. Our results indicate that SST potentiates RA-induced differentiation of SH-SY5Y cells and involves regulating the subcellular distribution and expression of neurotransmitter markers and synaptophysin translocation to neurites in a time-dependent manner, anticipating the therapeutic implication of SST in neurodegeneration.
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17
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Investigating the Molecular Mechanism of Xijiao Dihuang Decoction for the Treatment of SLE Based on Network Pharmacology and Molecular Docking Analysis. BIOMED RESEARCH INTERNATIONAL 2022; 2022:5882346. [PMID: 35097123 PMCID: PMC8794658 DOI: 10.1155/2022/5882346] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 11/01/2021] [Accepted: 12/27/2021] [Indexed: 12/30/2022]
Abstract
Objective To elucidate the main mechanism of Xijiao Dihuang decoction (XJDHT) for the treatment of systemic lupus erythematosus (SLE). Methods TCMSP, BATMAN-TCM, ETCM, and TCMID databases and literature search were used to screen the potential active compounds of XJDHT, and TCMSP and SwissProt databases were searched to predict the targets of the compounds. The targets of SLE were obtained from Genegards, OMIM, and DisGeNET databases, and Venn online platform was used to obtain the intersection targets of XJDHT and SLE. Afterwards, the PPI network was constructed by using the STRING database, and the core targets were identified by network topology analysis. GO and KEGG enrichment analyses were performed through R software, and molecular docking of the top three core targets and their corresponding compounds were accomplished by Autodock Vina and Pymol softwares. Results There were 30 potential active ingredients, 289 potential targets, and 129 intersection targets screened from the above databases. Network topology analysis identified 23 core targets, such as AKT1, TNF, IL6, IL1B, and INS. GO enrichment analysis obtained 2555 terms and mainly clustering on the react to lipopolysaccharide, membrane raft, and ubiquitin-like protein ligase binding. KEGG enrichment analysis obtained 187 signaling pathways, mainly concentrating on the lipid and atherosclerosis, AGE-RAGE signaling pathway in diabetic complications, fluid shear stress, and atherosclerosis. Molecular docking verified that the active compounds of XJDHT have the strong binding activity to the core targets. Conclusion This study preliminarily uncovers the mechanism of XJDHT acting on SLE through a “multicompound, multitarget, and multipathway” manner. XJDHT may achieve the treatment of SLE by inhibiting the proinflammatory factors, inflammatory signal cvtokines, proliferation, injury, and apoptosis processes. In summary, the present study would provide a promising theoretical basis for further clinical and experimental studies.
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18
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Roux-En-Y Gastric Bypass (RYGB) Surgery during High Liquid Sucrose Diet Leads to Gut Microbiota-Related Systematic Alterations. Int J Mol Sci 2022; 23:ijms23031126. [PMID: 35163046 PMCID: PMC8835548 DOI: 10.3390/ijms23031126] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 01/13/2022] [Accepted: 01/17/2022] [Indexed: 12/17/2022] Open
Abstract
Roux-en-Y gastric bypass (RYGB) surgery has been proven successful in weight loss and improvement of co-morbidities associated with obesity. Chronic complications such as malabsorption of micronutrients in up to 50% of patients underline the need for additional therapeutic approaches. We investigated systemic RYGB surgery effects in a liquid sucrose diet-induced rat obesity model. After consuming a diet supplemented with high liquid sucrose for eight weeks, rats underwent RYGB or control sham surgery. RYGB, sham pair-fed, and sham ad libitum-fed groups further continued on the diet after recovery. Notable alterations were revealed in microbiota composition, inflammatory markers, feces, liver, and plasma metabolites, as well as in brain neuronal activity post-surgery. Higher fecal 4-aminobutyrate (GABA) correlated with higher Bacteroidota and Enterococcus abundances in RYGB animals, pointing towards the altered enteric nervous system (ENS) and gut signaling. Favorable C-reactive protein (CRP), serine, glycine, and 3-hydroxybutyrate plasma profiles in RYGB rats were suggestive of reverted obesity risk. The impact of liquid sucrose diet and caloric restriction mainly manifested in fatty acid changes in the liver. Our multi-modal approach reveals complex systemic changes after RYGB surgery and points towards potential therapeutic targets in the gut-brain system to mimic the surgery mode of action.
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19
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Chen M, Ruan G, Chen L, Ying S, Li G, Xu F, Xiao Z, Tian Y, Lv L, Ping Y, Cheng Y, Wei Y. Neurotransmitter and Intestinal Interactions: Focus on the Microbiota-Gut-Brain Axis in Irritable Bowel Syndrome. Front Endocrinol (Lausanne) 2022; 13:817100. [PMID: 35250873 PMCID: PMC8888441 DOI: 10.3389/fendo.2022.817100] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 01/05/2022] [Indexed: 12/12/2022] Open
Abstract
Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder of unknown etiology. IBS is caused by a disruption in the gut-brain axis. Given the importance of the gut microbiota in maintaining local and systemic homeostasis of immunity, endocrine, and other physiological processes, the microbiota-gut-brain axis has been proposed as a key regulator in IBS. Neurotransmitters have been shown to affect blood flow regulation, intestinal motility, nutrient absorption, the gastrointestinal immune system, and the microbiota in recent studies. It has the potential role to play a function in the pathophysiology of the gastrointestinal and neurological systems. Transmitters and their receptors, including 5-hydroxytryptamine, dopamine, γ-aminobutyric acid, and histamine, play an important role in IBS, especially in visceral sensitivity and gastrointestinal motility. Studies in this field have shed light on revealing the mechanism by which neurotransmitters act in the pathogenesis of IBS and discovering new therapeutic strategies based on traditional pharmacological approaches that target the nervous system or novel therapies that target the microbiota.
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Affiliation(s)
- Minjia Chen
- Department of Gastroenterology, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
- Department of Pathogenic Biology and Immunology, School of Basic Medicine, Ningxia Medical University, Yinchuan, China
| | - Guangcong Ruan
- Department of Gastroenterology, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Lu Chen
- Department of Gastroenterology, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Senhong Ying
- Department of Gastroenterology, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Guanhu Li
- Department of Gastroenterology, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Fenghua Xu
- Department of Gastroenterology, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Zhifeng Xiao
- Department of Gastroenterology, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Yuting Tian
- Department of Gastroenterology, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Linling Lv
- Department of Gastroenterology, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Yi Ping
- Department of Gastroenterology, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Yi Cheng
- Department of Gastroenterology, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
- *Correspondence: Yanling Wei, ; Yi Cheng,
| | - Yanling Wei
- Department of Gastroenterology, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
- *Correspondence: Yanling Wei, ; Yi Cheng,
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20
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Organ-on-a-Chip for Studying Gut-Brain Interaction Mediated by Extracellular Vesicles in the Gut Microenvironment. Int J Mol Sci 2021; 22:ijms222413513. [PMID: 34948310 PMCID: PMC8707342 DOI: 10.3390/ijms222413513] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 12/14/2021] [Accepted: 12/15/2021] [Indexed: 12/12/2022] Open
Abstract
Extracellular vesicles (EVs) are a group of membrane vesicles that play important roles in cell-to-cell and interspecies/interkingdom communications by modulating the pathophysiological conditions of recipient cells. Recent evidence has implied their potential roles in the gut–brain axis (GBA), which is a complex bidirectional communication system between the gut environment and brain pathophysiology. Despite the evidence, the roles of EVs in the gut microenvironment in the GBA are less highlighted. Moreover, there are critical challenges in the current GBA models and analyzing techniques for EVs, which may hinder the research. Currently, advances in organ-on-a-chip (OOC) technologies have provided a promising solution. Here, we review the potential effects of EVs occurring in the gut environment on brain physiology and behavior and discuss how to apply OOCs to research the GBA mediated by EVs in the gut microenvironment.
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21
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Inotsuka R, Udono M, Yamatsu A, Kim M, Katakura Y. Exosome-Mediated Activation of Neuronal Cells Triggered by γ-Aminobutyric Acid (GABA). Nutrients 2021; 13:nu13082544. [PMID: 34444704 PMCID: PMC8399553 DOI: 10.3390/nu13082544] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 07/08/2021] [Accepted: 07/23/2021] [Indexed: 02/06/2023] Open
Abstract
γ-Aminobutyric acid (GABA) is a potent bioactive amino acid, and several studies have shown that oral administration of GABA induces relaxation, improves sleep, and reduces psychological stress and fatigue. In a recent study, we reported that exosomes derived from GABA-treated intestinal cells serve as signal transducers that mediate brain–gut interactions. Therefore, the purpose of this study was to verify the functionality of GABA-derived exosomes and to examine the possibility of improving memory function following GABA administration. The results showed that exosomes derived from GABA-treated intestinal cells (Caco-2) activated neuronal cells (SH-SY5Y) by regulating genes related to neuronal cell functions. Furthermore, we found that exosomes derived from the serum of GABA-treated mice also activated SH-SY5Y cells, indicating that exosomes, which are capable of activating neuronal cells, circulate in the blood of mice orally administered GABA. Finally, we performed a microarray analysis of mRNA isolated from the hippocampus of mice that were orally administered GABA. The results revealed changes in the expression of genes related to brain function. Gene Set Enrichment Analysis (GSEA) showed that oral administration of GABA affected the expression of genes related to memory function in the hippocampus.
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Affiliation(s)
- Ryo Inotsuka
- Graduate School of Bioresources and Bioenvironmental Sciences, Kyushu University, Fukuoka 819-0395, Japan;
| | - Miyako Udono
- Faculty of Agriculture, Kyushu University, Fukuoka 819-0395, Japan;
| | - Atsushi Yamatsu
- International GABA Research Center, Kyoto 615-8245, Japan;
- Pharma Foods International Co., Ltd., Kyoto 615-8245, Japan;
| | - Mujo Kim
- Pharma Foods International Co., Ltd., Kyoto 615-8245, Japan;
| | - Yoshinori Katakura
- Graduate School of Bioresources and Bioenvironmental Sciences, Kyushu University, Fukuoka 819-0395, Japan;
- Faculty of Agriculture, Kyushu University, Fukuoka 819-0395, Japan;
- Correspondence:
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22
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Ogawa M, Udono M, Teruya K, Uehara N, Katakura Y. Exosomes Derived from Fisetin-Treated Keratinocytes Mediate Hair Growth Promotion. Nutrients 2021; 13:nu13062087. [PMID: 34207142 PMCID: PMC8234638 DOI: 10.3390/nu13062087] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 06/15/2021] [Accepted: 06/16/2021] [Indexed: 11/17/2022] Open
Abstract
Enhanced telomerase reverse transcriptase (TERT) levels in dermal keratinocytes can serve as a novel target for hair growth promotion. Previously, we identified fisetin using a system for screening food components that can activate the TERT promoter in HaCaT cells (keratinocytes). In the present study, we aimed to clarify the molecular basis of fisetin-induced hair growth promotion in mice. To this end, the dorsal skin of mice was treated with fisetin, and hair growth was evaluated 12 days after treatment. Histochemical analyses of fisetin-treated skin samples and HaCaT cells were performed to observe the effects of fisetin. The results showed that fisetin activated HaCaT cells by regulating the expression of various genes related to epidermogenesis, cell proliferation, hair follicle regulation, and hair cycle regulation. In addition, fisetin induced the secretion of exosomes from HaCaT cells, which activated β-catenin and mitochondria in hair follicle stem cells (HFSCs) and induced their proliferation. Moreover, these results revealed the existence of exosomes as the molecular basis of keratinocyte-HFSC interaction and showed that fisetin, along with its effects on keratinocytes, caused exosome secretion, thereby activating HFSCs. This is the first study to show that keratinocyte-derived exosomes can activate HFSCs and consequently induce hair growth.
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Affiliation(s)
- Mizuki Ogawa
- Graduate School of Bioresources and Bioenvironmental Sciences, Kyushu University, Fukuoka 819-0395, Japan; (M.O.); (K.T.)
| | - Miyako Udono
- Faculty of Agriculture, Kyushu University, Fukuoka 819-0395, Japan;
| | - Kiichiro Teruya
- Graduate School of Bioresources and Bioenvironmental Sciences, Kyushu University, Fukuoka 819-0395, Japan; (M.O.); (K.T.)
- Faculty of Agriculture, Kyushu University, Fukuoka 819-0395, Japan;
| | - Norihisa Uehara
- Department of Molecular Cell Biology and Oral Anatomy, Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan;
| | - Yoshinori Katakura
- Graduate School of Bioresources and Bioenvironmental Sciences, Kyushu University, Fukuoka 819-0395, Japan; (M.O.); (K.T.)
- Faculty of Agriculture, Kyushu University, Fukuoka 819-0395, Japan;
- Correspondence: ; Tel.: +81-92-802-4727
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23
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The Microbiota and the Gut-Brain Axis in Controlling Food Intake and Energy Homeostasis. Int J Mol Sci 2021; 22:ijms22115830. [PMID: 34072450 PMCID: PMC8198395 DOI: 10.3390/ijms22115830] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 05/21/2021] [Accepted: 05/26/2021] [Indexed: 12/12/2022] Open
Abstract
Obesity currently represents a major societal and health challenge worldwide. Its prevalence has reached epidemic proportions and trends continue to rise, reflecting the need for more effective preventive measures. Hypothalamic circuits that control energy homeostasis in response to food intake are interesting targets for body-weight management, for example, through interventions that reinforce the gut-to-brain nutrient signalling, whose malfunction contributes to obesity. Gut microbiota-diet interactions might interfere in nutrient sensing and signalling from the gut to the brain, where the information is processed to control energy homeostasis. This gut microbiota-brain crosstalk is mediated by metabolites, mainly short chain fatty acids, secondary bile acids or amino acids-derived metabolites and subcellular bacterial components. These activate gut-endocrine and/or neural-mediated pathways or pass to systemic circulation and then reach the brain. Feeding time and dietary composition are the main drivers of the gut microbiota structure and function. Therefore, aberrant feeding patterns or unhealthy diets might alter gut microbiota-diet interactions and modify nutrient availability and/or microbial ligands transmitting information from the gut to the brain in response to food intake, thus impairing energy homeostasis. Herein, we update the scientific evidence supporting that gut microbiota is a source of novel dietary and non-dietary biological products that may beneficially regulate gut-to-brain communication and, thus, improve metabolic health. Additionally, we evaluate how the feeding time and dietary composition modulate the gut microbiota and, thereby, the intraluminal availability of these biological products with potential effects on energy homeostasis. The review also identifies knowledge gaps and the advances required to clinically apply microbiome-based strategies to improve the gut-brain axis function and, thus, combat obesity.
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