The human gastrointestinal tract is home to a diverse microbial community, with the gut microbiome playing a crucial role in various aspects of human biology, including health, development, aging, and disease. Recent advances in sequencing technologies have enabled researchers to explore the microbiome-host interactions in greater depth, revealing the bidirectional communication between the gut microbiome and the central nervous system, known as the microbiota–gut–brain axis. This axis is an important regulator of glial functions and has therapeutic potential in neurodegenerative diseases. The 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 gut hormones in neurodegenerative diseases, as well as the potential of targeting the intestinal barrier, blood–brain barrier, meninges, and peripheral immune system to counteract glial dysfunction. The review also assesses the pre-clinical and clinical evidence of probiotics, prebiotics, and fecal microbiota transplantation in neurodegenerative diseases. The microbiota–gut–brain axis is highlighted as a key target for therapeutic interventions in neurodegenerative diseases. The review also discusses the roles of microglia in neurodegenerative diseases, including their involvement in neuroinflammation and the regulation of microglial activation. The review highlights the importance of the gut microbiome in neurodegenerative diseases, with evidence showing that early microbiome changes are detected in preclinical Alzheimer's disease and prodromal Parkinson's disease patients. The review also discusses the interaction between gut microbiota and microglia, astrocytes, and oligodendrocytes in neurodegenerative diseases, emphasizing the potential of targeting the gut microbiome to modulate glial dysfunction and neurodegeneration. The review concludes by emphasizing the need for further research to understand the complex interactions between the gut microbiome and neurodegenerative diseases.The human gastrointestinal tract is home to a diverse microbial community, with the gut microbiome playing a crucial role in various aspects of human biology, including health, development, aging, and disease. Recent advances in sequencing technologies have enabled researchers to explore the microbiome-host interactions in greater depth, revealing the bidirectional communication between the gut microbiome and the central nervous system, known as the microbiota–gut–brain axis. This axis is an important regulator of glial functions and has therapeutic potential in neurodegenerative diseases. The 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 gut hormones in neurodegenerative diseases, as well as the potential of targeting the intestinal barrier, blood–brain barrier, meninges, and peripheral immune system to counteract glial dysfunction. The review also assesses the pre-clinical and clinical evidence of probiotics, prebiotics, and fecal microbiota transplantation in neurodegenerative diseases. The microbiota–gut–brain axis is highlighted as a key target for therapeutic interventions in neurodegenerative diseases. The review also discusses the roles of microglia in neurodegenerative diseases, including their involvement in neuroinflammation and the regulation of microglial activation. The review highlights the importance of the gut microbiome in neurodegenerative diseases, with evidence showing that early microbiome changes are detected in preclinical Alzheimer's disease and prodromal Parkinson's disease patients. The review also discusses the interaction between gut microbiota and microglia, astrocytes, and oligodendrocytes in neurodegenerative diseases, emphasizing the potential of targeting the gut microbiome to modulate glial dysfunction and neurodegeneration. The review concludes by emphasizing the need for further research to understand the complex interactions between the gut microbiome and neurodegenerative diseases.