Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Фев. 16, 2024

Abstract The human gastrointestinal tract is populated with a diverse microbial community. vast genetic and metabolic potential of the gut microbiome underpins its ubiquity in nearly every aspect biology, including health maintenance, development, aging, disease. advent new sequencing technologies culture-independent methods has allowed researchers to move beyond correlative studies toward mechanistic explorations shed light on microbiome–host interactions. Evidence unveiled bidirectional communication between central nervous system, referred as “microbiota–gut–brain axis”. microbiota–gut–brain axis represents an important regulator glial functions, making it actionable target ameliorate development progression neurodegenerative diseases. In this review, we discuss mechanisms As provides essential cues microglia, astrocytes, oligodendrocytes, examine communications microbiota these cells during healthy states Subsequently, diseases using metabolite-centric approach, while also examining role microbiota-related neurotransmitters hormones. Next, targeting intestinal barrier, blood–brain meninges, peripheral immune system counteract dysfunction neurodegeneration. Finally, conclude by assessing pre-clinical clinical evidence probiotics, prebiotics, fecal transplantation A thorough comprehension will foster effective therapeutic interventions for management

Язык: Английский

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Multiple sclerosis: Neuroimmune crosstalk and therapeutic targeting

Cell, Год журнала: 2023, Номер 186(7), С. 1309 - 1327

Опубликована: Март 1, 2023

Язык: Английский

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Advances in Neurodegenerative Diseases

Journal of Clinical Medicine, Год журнала: 2023, Номер 12(5), С. 1709 - 1709

Опубликована: Фев. 21, 2023

Neurological disorders are the leading cause of physical and cognitive disability across globe, currently affecting approximately 15% worldwide population [...].

Язык: Английский

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Microglia regulation of central nervous system myelin health and regeneration

Nature reviews. Immunology, Год журнала: 2023, Номер 24(1), С. 49 - 63

Опубликована: Июль 14, 2023

Язык: Английский

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Molecular and metabolic heterogeneity of astrocytes and microglia

Cell Metabolism, Год журнала: 2023, Номер 35(4), С. 555 - 570

Опубликована: Март 22, 2023

Язык: Английский

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Aging microglia

Cellular and Molecular Life Sciences, Год журнала: 2023, Номер 80(5)

Опубликована: Апрель 21, 2023

Abstract Microglia are the tissue-resident macrophage population of brain, specialized in supporting CNS environment and protecting it from endogenous exogenous insults. Nonetheless, their function declines with age, ways that remain to be fully elucidated. Given critical role played by microglia neurodegenerative diseases, a better understanding aging phenotype is an essential prerequisite designing preventive therapeutic strategies. In this review, we discuss most recent literature on aging, comparing findings rodent models human subjects.

Язык: Английский

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Microglia maintain structural integrity during fetal brain morphogenesis

Cell, Год журнала: 2024, Номер 187(4), С. 962 - 980.e19

Опубликована: Фев. 1, 2024

Microglia (MG), the brain-resident macrophages, play major roles in health and disease via a diversity of cellular states. While embryonic MG display large heterogeneity distribution transcriptomic states, their functions remain poorly characterized. Here, we uncovered role for maintenance structural integrity at two fetal cortical boundaries. At these boundaries between structures that grow distinct directions, accumulate, state resembling post-natal axon-tract-associated microglia (ATM) prevent progression microcavities into cavitary lesions, part mechanism involving ATM-factor Spp1. Spp1 furthermore contribute to rapid repair collectively highlighting protective preserve brain from physiological morphogenetic stress injury. Our study thus highlights key maintaining during morphogenesis, with implications our understanding development.

Язык: Английский

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Cellular architecture of evolving neuroinflammatory lesions and multiple sclerosis pathology

Cell, Год журнала: 2024, Номер 187(8), С. 1990 - 2009.e19

Опубликована: Март 20, 2024

Multiple sclerosis (MS) is a neurological disease characterized by multifocal lesions and smoldering pathology. Although single-cell analyses provided insights into cytopathology, evolving cellular processes underlying MS remain poorly understood. We investigated the dynamics of modeling temporal regional rates progression in mouse experimental autoimmune encephalomyelitis (EAE). By performing spatial expression profiling using situ sequencing (ISS), we annotated neighborhoods found centrifugal evolution active lesions. demonstrated that disease-associated (DA)-glia arise independently are dynamically induced resolved over course. Single-cell mapping human archival spinal cords confirmed differential distribution homeostatic DA-glia, enabled deconvolution inactive sub-compartments, identified new lesion areas. establishing resource neuropathology at resolution, our study unveils intricate MS.

Язык: Английский

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Role of microglia in stroke

Glia, Год журнала: 2024, Номер 72(6), С. 1016 - 1053

Опубликована: Янв. 4, 2024

Abstract Microglia play key roles in the post‐ischemic inflammatory response and damaged tissue removal reacting rapidly to disturbances caused by ischemia working restore lost homeostasis. However, modified environment, encompassing ionic imbalances, disruption of crucial neuron–microglia interactions, spreading depolarization, generation danger signals from necrotic neurons, induce morphological phenotypic shifts microglia. This leads them adopt a proinflammatory profile heighten their phagocytic activity. From day three post‐ischemia, macrophages infiltrate core while microglia amass at periphery. Further, inflammation prompts metabolic shift favoring glycolysis, pentose‐phosphate shunt, lipid synthesis. These shifts, combined with intake, drive droplet biogenesis, fuel anabolism, enable proliferation. Proliferating release trophic factors contributing protection repair. some accumulate lipids persistently transform into dysfunctional potentially harmful foam cells. Studies also showed that either display impaired apoptotic cell clearance, or eliminate synapses, viable endothelial Yet, it will be essential elucidate viability engulfed cells, features local extent damage, temporal sequence. Ischemia provides rich variety region‐ injury‐dependent stimuli for microglia, evolving time generating distinct phenotypes including those exhibiting traits others showing pro‐repair features. Accurate profiling phenotypes, alongside more precise understanding associated conditions, is necessary step serve as potential foundation focused interventions human stroke.

Язык: Английский

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Therapeutic potential of human microglia transplantation in a chimeric model of CSF1R-related leukoencephalopathy

Neuron, Год журнала: 2024, Номер 112(16), С. 2686 - 2707.e8

Опубликована: Июнь 18, 2024

Microglia replacement strategies are increasingly being considered for the treatment of primary microgliopathies like adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). However, available mouse models fail to recapitulate diverse neuropathologies reduced microglia numbers observed in patients. In this study, we generated a xenotolerant model lacking fms-intronic regulatory element (FIRE) enhancer within Csf1r, which develops nearly all hallmark pathologies associated ALSP. Remarkably, transplantation human induced pluripotent stem cell (iPSC)-derived microglial (iMG) progenitors restores homeostatic signature prevents development spheroids, white matter abnormalities, reactive astrocytosis, brain calcifications. Furthermore, CRISPR-corrected ALSP-patient-derived iMG reverses pre-existing astrogliosis, calcification pathologies. Together accompanying study by Munro colleagues, our results demonstrate utility FIRE mice ALSP provide compelling evidence that could offer promising new therapeutic strategy perhaps other microglia-associated neurological disorders.

Язык: Английский

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