Microbial-derived Hyodeoxycholic Acid Ameliorates Painful Diabetic Neuropathy by Modulating Dorsal Root Ganglion TLR4-Mediated Neuroinflammation Signaling Pathway

ABSTRACT:

BACKGROUND: Painful diabetic neuropathy (PDN) is characterized by hyperalgesia and neuronal hyperexcitability. Although gut microbiota dysbiosis have been found in PDN, how microbiota influences PDN remains largely unexplored. RESULTS: Gut microbiota and its metabolites impacted PDN was investigated with multi-omics analyses in a rat model of high-fat diet/low-dose streptozotocin-induced type 2 diabetes. A significant decrease of the gut microbiota, including Clostridium, Lactobacillus and Bifidobacterium, as well as serum hyodeoxycholic acid (HDCA) was found in the PDN rats through 16S rRNA gene sequencing and metabolomics assessment, respectively. Transplantation of fecal microbiota from the PDN to normal rats resulted in the PDN phenotype, verified with the pain withdrawal threshold test and the whole-cell patch-clamp recordings of the dorsal root ganglion (DRG). Additionally, HDCA treatment was able to improve the hyperalgesia of PDN. RNA sequencing analysis, qRT-PCR, ELISA, Western blot and immunofluorescence revealed that HDCA mitigated neuroinflammation by inhibiting the TLR4/MyD88/NF-kappaB signaling pathway and reducing the production of proinflammatory cytokines in the DRG, thereby alleviating pain. CONCLUSIONS: Our data demonstrated that the microbiome-derived metabolite, HDCA, facilitated PDN through neuroinflammation inhibition. Overall, these findings provided a novel mechanism of PDN, and suggested that HDCA may have a therapeutic potential for PDN.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - reverse phase

PROVIDER: MTBLS12087 | MetaboLights | 2026-08-24

REPOSITORIES: MetaboLights