Hyodeoxycholic acid relieves neuropathic pain by activating farnesoid X receptor signaling

Neuropathic pain, is a chronic condition stemming from nervous system injuries. The farnesoid X receptor (FXR), primarily expressed in the liver and intestines, plays a crucial role in regulating bile acids and lipids metabolism. Emerging evidence suggests that bile acids might influence neural function through FXR modulation. To investigate the specific role of intestinal FXR in the modulation of neuropathic pain. A neuropathic pain model was established in mice through ligation of the lumbar 4 spinal nerve (SNL). FXR expression was detected in the distal ileum and spinal cord. The baseline pain threshold and pain-related behaviors were evaluated in FXR gene knockout (Fxr -/-) mice. To examine the pharmacological role of FXR activation, obeticholic acid (INT-747, 10 mg/kg/day for 14 days) and HDCA (20 mg/kg/day for 21 days) were administered via intragastric gavage, and changes in pain behaviors were monitored. Additionally, the bile acid profiles of Fxr -/- mice and SNL mice were also analyzed. Furthermore, the effects of FXR on intestinal barrier function, gut microbiota composition, and systemic inflammation regulation were systematically evaluated. Neuropathic pain was associated with reduced FXR levels in the gut and spinal cord, accompanied by decreased bile acid levels, especially HDCA. FXR deficiency lowered the pain threshold, whereas treatment with INT-747 or HDCA relieved pain in SNL mice. Activation of FXR restored intestinal barrier integrity, balanced microbiota, reduced inflammation, and decreased microglial activation. HDCA alleviated pain by modulating FXR activity, increasing peroxisome proliferator-activated receptor gamma (PPAR-γ) expression and reducing abnormal matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-2 (MMP-9) activation. This research highlights a critical link between FXR levels and neuropathic pain. Manipulating FXR activity with INT-747 or HDCA not only reduced pain severity but also strengthened intestinal barriers and dampened inflammatory responses, suggesting the potential of FXR-targeted therapies in effectively managing neuropathic pain.