Exploring the Role of Microglial Cells in the Gut–Brain Axis Communication: A Systematic Review

The gut–brain axis (GBA) is a bidirectional communication system between the gastrointestinal tract and the CNS, playing a key role in neurological function, immune response, and metabolism. Microglia, the resident immune cells in the brain, are crucial regulators of neuroinflammation and synaptic plasticity. Recent studies indicate that the gut microbiota modulates microglial activity through metabolic and immune pathways, with implications for neurodegenerative, neurodevelopmental, and psychiatric disorders. However, the mechanisms underlying microbiota–microglia interactions remain unclear. Following a systematic screening of 4481 studies, 20 preclinical studies met the inclusion criteria and were reviewed in depth to assess microbiota–microglia interactions. These studies were found by searching in PubMed, Science Direct, and Google Scholar. The findings synthesize results from 20 carefully selected studies examining the impact of gut microbiota on microglial function. Experimental models, including fecal microbiota transplantation, dietary interventions, and bacterial supplementation, were analyzed. Microglial activity was assessed through immunohistochemistry, gene expression profiling, and functional assays. Most studies suggest that gut dysbiosis promotes microglial overactivation and neuroinflammation through pathways involving microbial-derived short-chain fatty acids (SCFAs), bile acids, and neuroimmune signaling cascades such as TLR4/NF-κB and the NLRP3 inflammasomes, whereas microbiota-targeted interventions reduce inflammation and support cognitive function. Despite these promising findings, inconsistencies in study methodologies and microbiota analyses limit comparability and clinical translation. This review offers a unique synthesis of studies specifically linking gut microbiota alterations to microglial states, neuroinflammatory signatures, and cognitive outcomes across diverse experimental models. It highlights the therapeutic potential of microbiota-based strategies for modulating microglial function and mitigating neuroinflammatory diseases.