A NUTRITIONAL CHALLENGE REPROGRAMS MICROGLIAL TRANSCRIPTOME AND FUNCTION VIA GUT MICROBIOTA–BRAIN CROSSTALK

High-fat diet (HFD) consumption and obesity are associated with metabolic disturbances that contribute to cognitive impairment, depression, and anxiety. HFD-induced metabolic dysregulation promotes chronic, low-grade systemic inflammation that can extend to the central nervous system, increasing the risk of neuroinflammation. Microglia, the resident immune cells of the brain, are key mediators of neuroimmune interactions and are highly responsive to peripheral metabolic and inflammatory signals. However, how HFD-driven metabolic alterations modulate microglial function remains poorly understood.
In this study, adult CX3CR1^GFP/+ male mice were fed a HFD for 6 weeks to investigate the potential metabolic modulation of microglial activity. Microglia-specific transcriptomic profiling revealed HFD-induced reprogramming, characterized by downregulation of immune-related genes and upregulation of mitochondrial metabolism–associated pathways. Functional analyses using lipopolysaccharide (LPS) challenge showed reduced microglial proliferation in HFD-fed mice compared with chow-fed controls, suggesting impaired neuroimmune responsiveness. In vivo two-photon microscopy revealed increased microglial motility in HFD-fed mice compared to lean controls.
To explore potential mediators, gut microbiota composition was analysed by 16S rRNA sequencing, showing marked HFD-driven alterations. Fecal microbiota transplantation (FMT) partially transferred the phenotype observed in HFD-fed animals, as recipient mice showed increased fat depot weight and microglial transcriptional signatures overlapping with HFD donors. These findings were further supported by LPS challenge and microglial dynamic analyses in FMT recipients.
Our results demonstrate that HFD profoundly reprograms microglial transcriptome and activity, partly through diet-induced gut microbiota remodelling, highlighting the gut–brain–immune axis as a key pathway linking metabolic dysfunction to altered neuroimmune states associated with obesity.