Pub Date : 2024-10-01DOI: 10.1016/j.neurot.2024.e00462
Adam M. Hamilton , Ian N. Krout , Alexandria C. White , Timothy R. Sampson
Recent experimental and clinical data demonstrate a significant dysregulation of the gut microbiome in individuals with Parkinson's disease (PD). With an immense influence on all aspects of physiology, this dysregulation has potential to directly or indirectly contribute to disease pathology. Experimental models have bridged these associations toward defined contributions, identifying various microbiome-dependent impacts to PD pathology. These studies have laid the foundation for human translation, examining whether certain members of the microbiome and/or whole restoration of the gut microbiome community can provide therapeutic benefit for people living with PD. Here, we review recent and ongoing clinically-focused studies that use microbiome-targeted therapies to limit the severity and progression of PD. Fecal microbiome transplants, prebiotic interventions, and probiotic supplementation are each emerging as viable methodologies to augment the gut microbiome and potentially limit PD symptoms. While still early, the data in the field to date support continued cross-talk between experimental systems and human studies to identify key microbial factors that contribute to PD pathologies.
{"title":"Microbiome-based therapeutics for Parkinson's disease","authors":"Adam M. Hamilton , Ian N. Krout , Alexandria C. White , Timothy R. Sampson","doi":"10.1016/j.neurot.2024.e00462","DOIUrl":"10.1016/j.neurot.2024.e00462","url":null,"abstract":"<div><div>Recent experimental and clinical data demonstrate a significant dysregulation of the gut microbiome in individuals with Parkinson's disease (PD). With an immense influence on all aspects of physiology, this dysregulation has potential to directly or indirectly contribute to disease pathology. Experimental models have bridged these associations toward defined contributions, identifying various microbiome-dependent impacts to PD pathology. These studies have laid the foundation for human translation, examining whether certain members of the microbiome and/or whole restoration of the gut microbiome community can provide therapeutic benefit for people living with PD. Here, we review recent and ongoing clinically-focused studies that use microbiome-targeted therapies to limit the severity and progression of PD. Fecal microbiome transplants, prebiotic interventions, and probiotic supplementation are each emerging as viable methodologies to augment the gut microbiome and potentially limit PD symptoms. While still early, the data in the field to date support continued cross-talk between experimental systems and human studies to identify key microbial factors that contribute to PD pathologies.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 6","pages":"Article e00462"},"PeriodicalIF":5.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.neurot.2024.e00469
Megha Kaul, Debanjan Mukherjee, Howard L. Weiner, Laura M. Cox
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss of motor neurons. While there has been significant progress in defining the genetic contributions to ALS, greater than 90 % of cases are sporadic, which suggests an environmental component. The gut microbiota is altered in ALS and is an ecological factor that contributes to disease by modulating immunologic, metabolic, and neuronal signaling. Depleting the microbiome worsens disease in the SOD1 ALS animal model, while it ameliorates disease in the C9orf72 model of ALS, indicating critical subtype-specific interactions. Furthermore, administering beneficial microbiota or microbial metabolites can slow disease progression in animal models. This review discusses the current state of microbiome research in ALS, including interactions with different ALS subtypes, evidence in animal models and human studies, key immunologic and metabolomic mediators, and a path toward microbiome-based therapies for ALS.
肌萎缩性脊髓侧索硬化症（ALS）是一种以运动神经元丧失为特征的进行性神经退行性疾病。虽然在确定 ALS 的遗传因素方面取得了重大进展，但 90% 以上的病例为散发性，这表明其中存在环境因素。ALS 患者的肠道微生物群发生了改变，这是一种通过调节免疫、新陈代谢和神经元信号转导而导致疾病的生态因素。消耗微生物群会加重 SOD1 ALS 动物模型的病情，而改善 C9orf72 ALS 模型的病情，这表明亚型特异性相互作用至关重要。此外，在动物模型中施用有益微生物群或微生物代谢物可减缓疾病进展。本综述讨论了 ALS 微生物组研究的现状，包括与不同 ALS 亚型的相互作用、动物模型和人体研究中的证据、关键的免疫学和代谢组学介质，以及基于微生物组的 ALS 治疗方法。
{"title":"Gut microbiota immune cross-talk in amyotrophic lateral sclerosis","authors":"Megha Kaul, Debanjan Mukherjee, Howard L. Weiner, Laura M. Cox","doi":"10.1016/j.neurot.2024.e00469","DOIUrl":"10.1016/j.neurot.2024.e00469","url":null,"abstract":"<div><div>Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss of motor neurons. While there has been significant progress in defining the genetic contributions to ALS, greater than 90 % of cases are sporadic, which suggests an environmental component. The gut microbiota is altered in ALS and is an ecological factor that contributes to disease by modulating immunologic, metabolic, and neuronal signaling. Depleting the microbiome worsens disease in the SOD1 ALS animal model, while it ameliorates disease in the C9orf72 model of ALS, indicating critical subtype-specific interactions. Furthermore, administering beneficial microbiota or microbial metabolites can slow disease progression in animal models. This review discusses the current state of microbiome research in ALS, including interactions with different ALS subtypes, evidence in animal models and human studies, key immunologic and metabolomic mediators, and a path toward microbiome-based therapies for ALS.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 6","pages":"Article e00469"},"PeriodicalIF":5.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142605716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.neurot.2024.e00458
Hyung-Joo Chung , Thy N.C. Nguyen , Ji Won Lee , Youngbuhm Huh , Seungbeom Ko , Heejin Lim , Hyewon Seo , Young-Geun Ha , Jeong Ho Chang , Jae-Sung Woo , Ji-Joon Song , So-Woon Kim , Jin San Lee , Jung-Soon Mo , Boyoun Park , Kyung-Won Min , Je-Hyun Yoon , Min-Sik Kim , Junyang Jung , Na Young Jeong
Peripheral neuropathies (PNs) are common diseases in elderly individuals characterized by Schwann cell (SC) dysfunction and irreversible Wallerian degeneration (WD). Although the molecular mechanisms of PN onset and progression have been widely studied, therapeutic opportunities remain limited. In this study, we investigated the pharmacological inhibition of Mammalian Ste20-like kinase 1/2 (MST1/2) by using its chemical inhibitor, XMU-MP-1 (XMU), against WD. XMU treatment suppressed the proliferation, dedifferentiation, and demyelination of SCs in models of WD in vitro, in vivo, and ex vivo. As a downstream mediator of canonical and noncanonical Hippo/MST1 pathway activation, the mature microRNA (miRNA) let-7b and its binding partners quaking homolog (QKI)/nucleolin (NCL) modulated miRNA-mediated silencing of genes involved in protein transport. Hence, direct phosphorylation of QKI and NCL by MST1 might be critical for WD onset and pathogenesis. Moreover, p38α/mitogen-activated protein kinase 14 (p38α) showed a strong affinity for XMU, and therefore, it may be an alternative XMU target for controlling WD in SCs. Taken together, our findings provide new insights into the Hippo/MST pathway function in PNs and suggest that XMU is a novel multitargeted therapeutic for elderly individuals with PNs.
{"title":"Targeting the Hippo pathway in Schwann cells ameliorates peripheral nerve degeneration via a polypharmacological mechanism","authors":"Hyung-Joo Chung , Thy N.C. Nguyen , Ji Won Lee , Youngbuhm Huh , Seungbeom Ko , Heejin Lim , Hyewon Seo , Young-Geun Ha , Jeong Ho Chang , Jae-Sung Woo , Ji-Joon Song , So-Woon Kim , Jin San Lee , Jung-Soon Mo , Boyoun Park , Kyung-Won Min , Je-Hyun Yoon , Min-Sik Kim , Junyang Jung , Na Young Jeong","doi":"10.1016/j.neurot.2024.e00458","DOIUrl":"10.1016/j.neurot.2024.e00458","url":null,"abstract":"<div><div>Peripheral neuropathies (PNs) are common diseases in elderly individuals characterized by Schwann cell (SC) dysfunction and irreversible Wallerian degeneration (WD). Although the molecular mechanisms of PN onset and progression have been widely studied, therapeutic opportunities remain limited. In this study, we investigated the pharmacological inhibition of Mammalian Ste20-like kinase 1/2 (MST1/2) by using its chemical inhibitor, XMU-MP-1 (XMU), against WD. XMU treatment suppressed the proliferation, dedifferentiation, and demyelination of SCs in models of WD <em>in vitro</em>, <em>in vivo</em>, and <em>ex vivo</em>. As a downstream mediator of canonical and noncanonical Hippo/MST1 pathway activation, the mature microRNA (miRNA) let-7b and its binding partners quaking homolog (QKI)/nucleolin (NCL) modulated miRNA-mediated silencing of genes involved in protein transport. Hence, direct phosphorylation of QKI and NCL by MST1 might be critical for WD onset and pathogenesis. Moreover, p38α/mitogen-activated protein kinase 14 (p38α) showed a strong affinity for XMU, and therefore, it may be an alternative XMU target for controlling WD in SCs. Taken together, our findings provide new insights into the Hippo/MST pathway function in PNs and suggest that XMU is a novel multitargeted therapeutic for elderly individuals with PNs.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 6","pages":"Article e00458"},"PeriodicalIF":5.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142392052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.neurot.2024.e00464
Qingbiao Song , Sihan E , Zhiyu Zhang , Yingxia Liang
Acute pain is a transient sensation that typically serves as part of the body's defense mechanism. However, in certain patients, acute pain can evolve into chronic pain, which persists for months or even longer. Neuroplasticity refers to the capacity for variation and adaptive alterations in the morphology and functionality of neurons and synapses, and it plays a significant role in the transmission and modulation of pain. In this paper, we explore the molecular mechanisms and signaling pathways underlying neuroplasticity during the transition of pain. We also examine the effects of neurotransmitters, inflammatory mediators, and central sensitization on neuroplasticity, as well as the potential of neuroplasticity as a therapeutic strategy for preventing chronic pain. The aims of this article is to clarify the role of neuroplasticity in the transformation from acute pain to chronic pain, with the hope of providing a novel theoretical basis for unraveling the pathogenesis of chronic pain and offering more effective strategies and approaches for its diagnosis and treatment.
{"title":"Neuroplasticity in the transition from acute to chronic pain","authors":"Qingbiao Song , Sihan E , Zhiyu Zhang , Yingxia Liang","doi":"10.1016/j.neurot.2024.e00464","DOIUrl":"10.1016/j.neurot.2024.e00464","url":null,"abstract":"<div><div>Acute pain is a transient sensation that typically serves as part of the body's defense mechanism. However, in certain patients, acute pain can evolve into chronic pain, which persists for months or even longer. Neuroplasticity refers to the capacity for variation and adaptive alterations in the morphology and functionality of neurons and synapses, and it plays a significant role in the transmission and modulation of pain. In this paper, we explore the molecular mechanisms and signaling pathways underlying neuroplasticity during the transition of pain. We also examine the effects of neurotransmitters, inflammatory mediators, and central sensitization on neuroplasticity, as well as the potential of neuroplasticity as a therapeutic strategy for preventing chronic pain. The aims of this article is to clarify the role of neuroplasticity in the transformation from acute pain to chronic pain, with the hope of providing a novel theoretical basis for unraveling the pathogenesis of chronic pain and offering more effective strategies and approaches for its diagnosis and treatment.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 6","pages":"Article e00464"},"PeriodicalIF":5.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.neurot.2024.e00447
Xiaxin Yang , Jianhang Zhang , Zhihao Wang , Zhong Yao , Xue Yang , Xingbang Wang , Xiuhe Zhao , Shuo Xu
Temporal lobe epilepsy (TLE) is the most prevalent type of focal epilepsy in adults. While comprehensive bioinformatics analyses have facilitated the identification of novel biomarkers in animal models, similar efforts are limited for TLE patients. In the current study, a comprehensive analysis using human transcriptomics datasets GSE205661, GSE190451, and GSE186334 was conducted to reveal differentially expressed genes related to mitochondria (Mito-DEGs). Protein-protein interaction (PPI) network and Least Absolute Shrinkage and Selection Operator (LASSO) regression analyses were performed to identify hub genes. Additional GSE127871 and GSE255223 were utilized to establish the association with hippocampal sclerosis (HS) and seizure frequency, respectively. Single-cell RNA analysis, functional investigation, and clinical verification were conducted. Herein, we reported that the Mito-DEGs in human TLE were significantly enriched in metabolic processes. Through PPI and LASSO analysis, HSDL2 was identified as the hub gene, of which diagnostic potential was further confirmed using independent datasets, animal models, and clinical validation. Subsequent single-cell and functional analyses revealed that HSDL2 expression was enriched and upregulated in response to excessive lipid accumulation in astrocytes. Additionally, the diagnostic efficiency of blood HSDL2 was verified in Qilu cohort. Together, our findings highlight the translational potential of HSDL2 as a biomarker and provide a novel therapeutic perspective for human TLE.
{"title":"Mitochondria-related HSDL2 is a potential biomarker in temporal lobe epilepsy by modulating astrocytic lipid metabolism","authors":"Xiaxin Yang , Jianhang Zhang , Zhihao Wang , Zhong Yao , Xue Yang , Xingbang Wang , Xiuhe Zhao , Shuo Xu","doi":"10.1016/j.neurot.2024.e00447","DOIUrl":"10.1016/j.neurot.2024.e00447","url":null,"abstract":"<div><div>Temporal lobe epilepsy (TLE) is the most prevalent type of focal epilepsy in adults. While comprehensive bioinformatics analyses have facilitated the identification of novel biomarkers in animal models, similar efforts are limited for TLE patients. In the current study, a comprehensive analysis using human transcriptomics datasets GSE205661, GSE190451, and GSE186334 was conducted to reveal differentially expressed genes related to mitochondria (Mito-DEGs). Protein-protein interaction (PPI) network and Least Absolute Shrinkage and Selection Operator (LASSO) regression analyses were performed to identify hub genes. Additional GSE127871 and GSE255223 were utilized to establish the association with hippocampal sclerosis (HS) and seizure frequency, respectively. Single-cell RNA analysis, functional investigation, and clinical verification were conducted. Herein, we reported that the Mito-DEGs in human TLE were significantly enriched in metabolic processes. Through PPI and LASSO analysis, HSDL2 was identified as the hub gene, of which diagnostic potential was further confirmed using independent datasets, animal models, and clinical validation. Subsequent single-cell and functional analyses revealed that HSDL2 expression was enriched and upregulated in response to excessive lipid accumulation in astrocytes. Additionally, the diagnostic efficiency of blood HSDL2 was verified in Qilu cohort. Together, our findings highlight the translational potential of HSDL2 as a biomarker and provide a novel therapeutic perspective for human TLE.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 6","pages":"Article e00447"},"PeriodicalIF":5.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142154673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.neurot.2024.e00442
Naoto Kawakami , Hartmut Wekerle
Brain antigen-specific autoreactive T cells seem to play a key role in inducing inflammation in the central nervous system (CNS), a characteristic feature of human multiple sclerosis (MS). These T cells are generated within the thymus, where they escape negative selection and become integrated into the peripheral immune repertoire of immune cells. Typically, these autoreactive T cells rest in the periphery without attacking the CNS. When autoimmune T cells enter gut-associated lymphatic tissue (GALT), they may be stimulated by the microbiota and its metabolites. After activation, the cells migrate into the CNS through the blood‒brain barrier, become reactivated upon interacting with local antigen-presenting cells, and induce inflammatory lesions within the brain parenchyma. This review describes how microbiota influence autoreactive T cells during their life, starting in the thymus, migrating through the periphery and inducing inflammation in their target organ, the CNS.
脑抗原特异性自反应 T 细胞似乎在诱发中枢神经系统（CNS）炎症中发挥着关键作用，这是人类多发性硬化症（MS）的一个特征。这些 T 细胞在胸腺中产生，它们在胸腺中逃脱了负选择，并融入了外周免疫细胞的免疫程序组中。通常情况下，这些自身反应性 T 细胞停留在外周，不会攻击中枢神经系统。当自身免疫 T 细胞进入肠道相关淋巴组织（GALT）时，可能会受到微生物群及其代谢产物的刺激。激活后，这些细胞通过血脑屏障迁移到中枢神经系统，与当地抗原递呈细胞相互作用后重新激活，并诱发脑实质内的炎症病变。这篇综述描述了微生物群如何在自反应 T 细胞的一生中对其产生影响，从胸腺开始，迁移到外周，并在其目标器官--中枢神经系统中诱发炎症。
{"title":"Life history of a brain autoreactive T cell: From thymus through intestine to blood-brain barrier and brain lesion","authors":"Naoto Kawakami , Hartmut Wekerle","doi":"10.1016/j.neurot.2024.e00442","DOIUrl":"10.1016/j.neurot.2024.e00442","url":null,"abstract":"<div><div>Brain antigen-specific autoreactive T cells seem to play a key role in inducing inflammation in the central nervous system (CNS), a characteristic feature of human multiple sclerosis (MS). These T cells are generated within the thymus, where they escape negative selection and become integrated into the peripheral immune repertoire of immune cells. Typically, these autoreactive T cells rest in the periphery without attacking the CNS. When autoimmune T cells enter gut-associated lymphatic tissue (GALT), they may be stimulated by the microbiota and its metabolites. After activation, the cells migrate into the CNS through the blood‒brain barrier, become reactivated upon interacting with local antigen-presenting cells, and induce inflammatory lesions within the brain parenchyma. This review describes how microbiota influence autoreactive T cells during their life, starting in the thymus, migrating through the periphery and inducing inflammation in their target organ, the CNS.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 6","pages":"Article e00442"},"PeriodicalIF":5.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142140642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.neurot.2024.e00473
Miles Berger , David Ryu , Melody Reese , Steven McGuigan , Lisbeth A. Evered , Catherine C. Price , David A. Scott , M. Brandon Westover , Roderic Eckenhoff , Laura Bonanni , Aoife Sweeney , Claudio Babiloni
{"title":"Corrigendum to “A real-time neurophysiologic stress test for the aging brain: Novel perioperative and ICU applications of EEG in older surgical patients” Neurotherapeutics 20 (4) (2023) 975–1000","authors":"Miles Berger , David Ryu , Melody Reese , Steven McGuigan , Lisbeth A. Evered , Catherine C. Price , David A. Scott , M. Brandon Westover , Roderic Eckenhoff , Laura Bonanni , Aoife Sweeney , Claudio Babiloni","doi":"10.1016/j.neurot.2024.e00473","DOIUrl":"10.1016/j.neurot.2024.e00473","url":null,"abstract":"","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 6","pages":"Article e00473"},"PeriodicalIF":5.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.neurot.2024.e00445
Gergana Mincheva , Vicente Felipo , Victoria Moreno-Manzano , Alfonso Benítez-Páez , Marta Llansola
Gut microbiota perturbation and motor dysfunction have been reported in steatosis patients. Rats with mild liver damage (MLD) show motor dysfunction mediated by neuroinflammation and altered GABAergic neurotransmission in the cerebellum. The extracellular vesicles (EV) from mesenchymal stem cells (MSC) have emerged as a promising therapeutic proxy whose molecular basis relies partly upon TGFβ action. This study aimed to assess if MSC-EVs improve motor dysfunction in rats with mild liver damage and analyze underlying mechanisms, including the role of TGFβ, cerebellar neuroinflammation and gut microbiota. MLD in rats was induced by carbon tetrachloride administration and EVs from normal (C-EVs) or TGFβ-siRNA treated MSCs (T-EV) were injected. Motor coordination, locomotor gait, neuroinflammation and TNF-α-activated pathways modulating GABAergic neurotransmission in the cerebellum, microbiota composition in feces and microbial-derived metabolites in plasma were analyzed. C-EVs reduced glial and TNFα-P2X4-BDNF-TrkB pathway activation restoring GABAergic neurotransmission in the cerebellum and improving motor coordination and all the altered gait parameters. T-EVs also improved motor coordination and some gait parameters, but the mechanisms involved differed from those of C-EVs. MLD rats showed increased content of some Bacteroides species in feces, correlating with decreased kynurenine aside from motor alterations. These alterations were all normalized by C-EVs, whereas T-EVs only restored kynurenine levels. Our results support the value of MSC-EVs on improving motor dysfunction in MLD and unveil a possible mechanism by which altered microbiota may contribute to neuroinflammation and motor impairment. Some of the underlying mechanisms are TGFβ-dependent.
{"title":"Extracellular vesicles from mesenchymal stem cells alter gut microbiota and improve neuroinflammation and motor impairment in rats with mild liver damage","authors":"Gergana Mincheva , Vicente Felipo , Victoria Moreno-Manzano , Alfonso Benítez-Páez , Marta Llansola","doi":"10.1016/j.neurot.2024.e00445","DOIUrl":"10.1016/j.neurot.2024.e00445","url":null,"abstract":"<div><div>Gut microbiota perturbation and motor dysfunction have been reported in steatosis patients. Rats with mild liver damage (MLD) show motor dysfunction mediated by neuroinflammation and altered GABAergic neurotransmission in the cerebellum. The extracellular vesicles (EV) from mesenchymal stem cells (MSC) have emerged as a promising therapeutic proxy whose molecular basis relies partly upon TGFβ action. This study aimed to assess if MSC-EVs improve motor dysfunction in rats with mild liver damage and analyze underlying mechanisms, including the role of TGFβ, cerebellar neuroinflammation and gut microbiota. MLD in rats was induced by carbon tetrachloride administration and EVs from normal (C-EVs) or TGFβ-siRNA treated MSCs (T-EV) were injected. Motor coordination, locomotor gait, neuroinflammation and TNF-α-activated pathways modulating GABAergic neurotransmission in the cerebellum, microbiota composition in feces and microbial-derived metabolites in plasma were analyzed. C-EVs reduced glial and TNFα-P2X4-BDNF-TrkB pathway activation restoring GABAergic neurotransmission in the cerebellum and improving motor coordination and all the altered gait parameters. T-EVs also improved motor coordination and some gait parameters, but the mechanisms involved differed from those of C-EVs. MLD rats showed increased content of some <em>Bacteroides</em> species in feces, correlating with decreased kynurenine aside from motor alterations. These alterations were all normalized by C-EVs, whereas T-EVs only restored kynurenine levels. Our results support the value of MSC-EVs on improving motor dysfunction in MLD and unveil a possible mechanism by which altered microbiota may contribute to neuroinflammation and motor impairment. Some of the underlying mechanisms are TGFβ-dependent.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"21 6","pages":"Article e00445"},"PeriodicalIF":5.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142146045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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