Lin Jiaqi, Zeng Xuejiao, Su Zehua, Li Xin, Yu Yongze, Qian Shuwen, Hou Qianhao, Duan Wenying, Wang Zetian, Liu Chunzheng, Zhang Jinyuan, Huang Changshun, Liao Lijun
Department of Pain Management, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China.
Department of Pain Management, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China; Dalian Medical University, Dalian 116000, China; Department of Pain Management, Shanghai East Hospital of Clinical Medical College, Shanghai 200120, China.
J Adv Res. 2025 Jul 11. doi: 10.1016/j.jare.2025.07.017.
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.
神经性疼痛是一种源于神经系统损伤的慢性疾病。法尼酯X受体（FXR）主要在肝脏和肠道中表达，在调节胆汁酸和脂质代谢中起关键作用。新出现的证据表明，胆汁酸可能通过FXR调节影响神经功能。
研究肠道FXR在神经性疼痛调节中的具体作用。
通过结扎腰4脊髓神经（SNL）在小鼠中建立神经性疼痛模型。检测回肠末端和脊髓中的FXR表达。在FXR基因敲除（Fxr-/-）小鼠中评估基线疼痛阈值和疼痛相关行为。为了研究FXR激活的药理学作用，通过灌胃给予奥贝胆酸（INT-747，10mg/kg/天，共14天）和熊去氧胆酸（HDCA，20mg/kg/天，共21天），并监测疼痛行为的变化。此外，还分析了Fxr-/-小鼠和SNL小鼠的胆汁酸谱。此外，还系统评估了FXR对肠道屏障功能、肠道微生物群组成和全身炎症调节的影响。
神经性疼痛与肠道和脊髓中FXR水平降低有关，同时胆汁酸水平降低，尤其是HDCA。FXR缺乏降低了疼痛阈值，而INT-747或HDCA治疗可缓解SNL小鼠的疼痛。FXR激活可恢复肠道屏障完整性，平衡微生物群，减轻炎症，并减少小胶质细胞激活。HDCA通过调节FXR活性、增加过氧化物酶体增殖物激活受体γ（PPAR-γ）表达和减少异常的基质金属蛋白酶-2（MMP-2）和基质金属蛋白酶-9（MMP-9）激活来减轻疼痛。
本研究突出了FXR水平与神经性疼痛之间的关键联系。用INT-747或HDCA调节FXR活性不仅降低了疼痛严重程度，还加强了肠道屏障并抑制了炎症反应，表明靶向FXR的疗法在有效管理神经性疼痛方面具有潜力。
