Systematic review and meta-analysis of microbiota-gut-astrocyte axis perturbation in neurodegeneration, brain injury, and mood disorders

Astrocytes are essential for preserving homeostasis, maintaining the blood-brain barrier, and they are a key element of the tripartite neuronal synapse. Despite such multifaceted roles, their importance as contributors to the microbiota-gut-brain axis studies, which typically focus on microglia and neurons, has been largely overlooked. This meta-analysis provides the first systematic review of the microbiota-gut-astrocyte (MGA) axis in vivo, integrating findings across distinct neurological diseases. A systematic narrative review was conducted per PRISMA guidelines. The search term employed for PubMed was "Microbiota"[MeSH] AND (astrocyte OR glial) NOT (Review[Publication Type]) and for Web of Science, Embase, and Scopus, “Microbio* AND (astrocyte OR glial)” with filters applied to exclude review articles. Searches were completed by May 9 th 2024. Data extracted included study models, interventions, and outcomes related to astrocyte biology and rodent behaviour. SYRCLE’s risk of bias tool was used to assess individual study designs. 53 studies met the inclusion criteria, covering rodent models of stroke and traumatic (acute) brain injury, chronic neurodegenerative diseases including Alzheimer’s and Parkinson’s disease and other heterogeneous models of cognitive impairment and affective disorders. Significant heterogeneity in methodology was observed between studies. Five studies had a high risk of bias, and 15 were low risk. Astrocyte biology, typically measured by GFAP expression, was increased in neurodegeneration and acute brain injury models but varied significantly in mood disorder models, depending on the source of stress. Common findings across diseases included altered gut microbiota, particularly an increased Bacteroidetes/Firmicutes ratio and compromised gut barrier integrity, linked to increased GFAP expression. Faecal microbiota transplants and microbial metabolite analyses suggested a direct impact of the gut microbiota on astrocyte biology and markers of neuroinflammation. This review and meta-analysis describes the impact of the gut microbiota on astrocyte biology, and argues that the MGA axis is a promising therapeutic target for neurological disorders. However, it is clear that our understanding of the relationship between the gut microbiota and astrocyte behaviour is incomplete, including how different subtypes of astrocytes may be affected. Future studies must adopt new, multi-dimensional studies of astrocyte function and dysfunction, to elucidate their role in disease and explore the therapeutic potential of gut microbiota modulation. • Astrocyte Biology and MGA Axis : The review highlights how changes to astrocyte biology, indicated by variable GFAP expression, is associated with different neurological conditions, including acute brain injury, neurodegeneration (especially Alzheimer's and Parkinson's diseases), and mood disorders. • Type of Stress Affects Astrocyte Function: Through meta-analysis of GFAP expression, we identify for the first time that the source of stress that contributes to depressive-like behaviour in rodents variably affects astrocyte biology. Physiological stressors increase GFAP expression, whereas psychological stressors tend to reduce GFAP expression. • Common Mechanisms of Gut Dysbiosis : Despite disease-specific variations, common patterns such as reduced gut barrier integrity and increased Bacteroidetes/Firmicutes ratio were identified across various neuropathologies, suggesting shared mechanisms in MGA axis perturbation. • Impact of Microbiota Manipulation : The therapeutic potential of microbiota manipulation, such as the use of probiotics and faecal microbiota transplants, are identified as promising methods for restoring BBB integrity and reducing neuroinflammation. • Sex and Age Bias in Research : The review identifies a significant bias towards male and younger rodent models in existing studies, calling for future research to include more female and older animals to better understand sex-specific and age-related effects on astrocyte biology and MGA axis interactions. Whereas traumatic brain injury and depression are less age-dependent, neurodegenerative diseases and stroke are more common in late life, and depression has a female preponderance.

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