The human gastrointestinal tract is home to a diverse microbial community, the gut microbiome, which plays a crucial role in various aspects of human biology, including health maintenance, development, aging, and disease. Recent advancements in sequencing technologies and culture-independent methods have enabled researchers to move beyond correlative studies to mechanistic explorations of the microbiome-host interactions. The bidirectional communication between the gut microbiome and the central nervous system, known as the "microbiota-gut-brain axis," has been identified as an important regulator of glial functions, making it a potential therapeutic target for neurodegenerative diseases. This review discusses the mechanisms of the microbiota-gut-brain axis in neurodegenerative diseases, focusing on the interactions between gut microbiota and glial cells (microglia, astrocytes, and oligodendrocytes). It examines the role of gut microbiota-derived metabolites, neurotransmitters, and hormones in these diseases. The review also explores the potential of targeting the intestinal barrier, blood-brain barrier, meninges, and peripheral immune system to counteract glial dysfunction. Finally, it assesses the pre-clinical and clinical evidence of probiotics, prebiotics, and fecal microbiota transplantation in neurodegenerative diseases. The review highlights the importance of understanding the microbiota-gut-brain axis to develop effective therapeutic interventions for neurodegenerative diseases. It provides a comprehensive overview of the current state of knowledge, emphasizing the complex interplay between the gut microbiome and glial cells in various neurodegenerative conditions, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease.The human gastrointestinal tract is home to a diverse microbial community, the gut microbiome, which plays a crucial role in various aspects of human biology, including health maintenance, development, aging, and disease. Recent advancements in sequencing technologies and culture-independent methods have enabled researchers to move beyond correlative studies to mechanistic explorations of the microbiome-host interactions. The bidirectional communication between the gut microbiome and the central nervous system, known as the "microbiota-gut-brain axis," has been identified as an important regulator of glial functions, making it a potential therapeutic target for neurodegenerative diseases. This review discusses the mechanisms of the microbiota-gut-brain axis in neurodegenerative diseases, focusing on the interactions between gut microbiota and glial cells (microglia, astrocytes, and oligodendrocytes). It examines the role of gut microbiota-derived metabolites, neurotransmitters, and hormones in these diseases. The review also explores the potential of targeting the intestinal barrier, blood-brain barrier, meninges, and peripheral immune system to counteract glial dysfunction. Finally, it assesses the pre-clinical and clinical evidence of probiotics, prebiotics, and fecal microbiota transplantation in neurodegenerative diseases. The review highlights the importance of understanding the microbiota-gut-brain axis to develop effective therapeutic interventions for neurodegenerative diseases. It provides a comprehensive overview of the current state of knowledge, emphasizing the complex interplay between the gut microbiome and glial cells in various neurodegenerative conditions, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease.