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

Abstract

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

Spinal Cord Injury Management Based on Microglia-Targeting Therapies

“…Studies using various mouse models, including those with limited bacterial colonization or complete microbiome depletion, have demonstrated distinct microglial abnormalities, such as immature phenotype and altered cellular morphology [89]. Fecal microbiota transplantation has shown promise in reducing microglial activation and providing neuroprotection in conditions like Parkinson's disease, potentially via modulation of the TLR4/TBK1/NF-κB/TNF-α signaling pathway [90]. Additionally, microbial-derived tryptophan has been implicated in regulating microglial inflammation through the aryl hydrocarbon receptor-mediated production of TGF-α and VEGF-b [91].…”

The microbiota-gut-brain-immune interface in the pathogenesis of neuroinflammatory diseases: a narrative review of the emerging literature

“…Indeed, transdisciplinary perspectives intersecting neuroscience, psychology, and philosophy are further exploring the role of the gut microbiome in perception and cognition, and posit the idea that the microbiome possesses its own proto-cognition independent of, yet interrelated to the rest of the body ( 11 ). Interestingly, the hormones ghrelin and leptin (involved in hunger and satiety, respectively) have also been tied to cognition ( 12 ). Our microbiome, therefore, may not only affect the quality of our cognition but also how we perceive our internal and external worlds.…”

“…The relationship between the microbiota-gut-brain-immune interface, microbial metabolites, and glia is a potent regulator of GI and actionable target in neuroinflammatory and neurodegenerative disorders ( 12 ). In chronic neuroinflammation, pro-inflammatory cytokines are habitually upregulated and glia are overactive, resulting in damage to neurons, synapse function, cortical tissue, and functional connectivity—commonly observed in neurological disorders ( 57 , 63 ).…”

Exploiting Natural Niches with Neuroprotective Properties: A Comprehensive Review

“…Bidirectional communication between the human gut microbiota and the brain, commonly referred to as the microbiota-gut-brain axis or gut-brain axis, exerts a significant influence on behavior and brain function. The microbiota-gut-brain axis represents an intricate communication network that connects the gastrointestinal tract with the brain and facilitates bidirectional interactions through neural, endocrine, and immune pathways [205]. The investigation into dietary impact on the gut microbiota demonstrates a major impact on the brain, especially on the development and function of microglia and the BBB [206].…”

“…These compounds can influence the local gut physiology and can circulate through the blood to interact with the host immune system, which directly signals the brain and may affect microglial activation [207]. Notably, early microbiome changes were found in patients with preclinical AD and PD, and compelling evidence shows that the altered gut microbiome can drive neurodegenerative disease pathogenesis [205]. Strikingly, changes to the gut microbiome can cause the misfolding and abnormal aggregation of α synuclein, which can be transported from the periphery to the central nervous system (CNS) via the vagus nerve [208].…”