Discovery and Functional Validation of a Gut Microbiota-Metabolite-miRNA Axis in Diabetic Encephalopathy

Feb 6, 2026Archives of biochemistry and biophysics

A Gut Microbiome-Metabolite-MicroRNA Link in Brain Problems Related to Diabetes

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Abstract

DE patients exhibited distinct gut microbiota composition with elevated Verrucomicrobiota and Bacteroidota.

No significant differences in overall microbial diversity were found between DE and diabetic control groups.
Metabolomic analysis identified 160 differentially abundant metabolites related to amino acid and lipid metabolism in DE patients.
In vitro exposure to fecal microbiota supernatant from DE patients increased oxidative damage and apoptosis in neuronal cells.
Upregulation of miR-493-3p was associated with neuronal injury, while inhibiting this microRNA reduced damage and restored RAF1 expression.
RAF1 was confirmed to be a direct target of miR-493-3p, highlighting its role in mediating neuronal harm.

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BACKGROUND: Diabetic encephalopathy (DE), a severe neurological complication of diabetes, is characterized by cognitive decline and neuronal damage. While gut microbiota dysbiosis has been implicated in diabetes pathogenesis, its specific role and molecular mechanisms in DE remain unclear.

METHODS: A multi-omics approach integrating 16S rRNA sequencing and untargeted metabolomics was performed on fecal samples from 29 DE patients and 31 diabetic controls (DM). An in vitro DE model was established using high glucose (HG)-treated HT22 cells, which were further incubated with sterile fecal microbiota supernatant (FMS) from DE patients. Neuronal viability, apoptosis, oxidative stress markers (SOD, MDA, ROS), and miR-493-3p expression were assessed. The miR-493-3p/RAF1 interaction was validated using dual-luciferase reporter assays and Western blot.

RESULTS: No significant differences in overall microbial diversity were identified in DE and DM cohorts. However, DE patients exhibited distinct gut microbiota composition, with elevated Verrucomicrobiotaand Bacteroidota, and reduced Proteobacteriaand Firmicutes. Metabolomic analysis revealed 160 differentially abundant metabolites enriched in amino acid and lipid metabolism pathways. In vitro, DE-derived FMS dose-dependently exacerbated HG-induced neuronal oxidative damage and apoptosis, concomitant with miR-493-3p upregulation. Inhibition of miR-493-3p attenuated these damaging effects and restored RAF1 expression. RAF1 was confirmed as a direct target of miR-493-3p, and its downregulation was critical in mediating FMS-induced neuronal injury.

CONCLUSION: This study identified a novel gut-brain axis pathway in DE, whereby gut microbiota dysbiosis and metabolic alterations promote neuronal damage via the miR-493-3p/RAF1 signaling axis. These findings provide new insights into DE pathogenesis and suggest potential therapeutic targets for this debilitating complication.

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Discovery and Functional Validation of a Gut Microbiota-Metabolite-miRNA Axis in Diabetic Encephalopathy

Abstract

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