Patients with temporomandibular disorders (TMDs) often experience persistent facial pain. However, the treatment of TMD pain is still inadequate. In recent years, the disturbance of gut microbiota has been shown to play an important role in the pathogenesis of different neurological diseases including chronic pain. In the present study, we investigated the involvement of gut microbiota in the development of temporomandibular joint (TMJ) inflammation. Intra-temporomandibular joint injection of complete Freund's adjuvant (CFA) was employed to induce TMJ inflammation. Resveratrol (RSV), a natural bioactive compound with anti-inflammatory property, was used to treat the CFA-induced TMJ inflammation. We observed that CFA injection not only induces persistent joint pain, but also causes the reduction of short-chain fatty acids (SCFAs, including acetic acid, propionic acid and butyric acid) in the gut as well as decreases relevant gut bacteria Bacteroidetes and Lachnospiraceae. Interestingly, systemic administration of RSV (i.p.) dose-dependently inhibits CFA-induced TMJ inflammation, reverses CFA-caused reduction of SCFAs and these gut bacteria. Moreover, CFA injection causes blood-brain barrier (BBB) leakage, activates microglia and enhances tumor necrosis factor alpha (TNFα) release in the spinal trigeminal nucleus caudalis (Sp5C). The RSV treatment restores the BBB integrity, inhibits microglial activation and decreases the release of TNFα in the Sp5C. Furthermore, fecal microbiota transplantation with feces from RSV-treated mice significantly diminishes the CFA-induced TMJ inflammation. Taken together, our results suggest that gut microbiome perturbation is critical for the development of TMJ inflammation and that recovering gut microbiome to normal levels could be a new therapeutic approach for treating such pain.

中文翻译：

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白藜芦醇通过恢复受干扰的肠道菌群来缓解颞下颌关节炎症性疼痛

患有颞下颌关节紊乱病 (TMD) 的患者经常会出现持续的面部疼痛。然而，TMD疼痛的治疗仍然不足。近年来，肠道微生物群的紊乱已被证明在包括慢性疼痛在内的不同神经系统疾病的发病机制中发挥着重要作用。在本研究中，我们调查了肠道微生物群在颞下颌关节 (TMJ) 炎症发展中的作用。颞下颌关节内注射完全弗氏佐剂 (CFA) 用于诱导 TMJ 炎症。白藜芦醇 (RSV) 是一种具有抗炎特性的天然生物活性化合物，用于治疗 CFA 诱导的 TMJ 炎症。我们观察到 CFA 注射不仅会引起持续性关节疼痛，还会导致短链脂肪酸（SCFAs、包括乙酸、丙酸和丁酸）在肠道中以及减少相关的肠道细菌拟杆菌属和毛螺菌科。有趣的是，RSV (ip) 的全身给药剂量依赖性地抑制 CFA 诱导的 TMJ 炎症，逆转 CFA 引起的 SCFA 和这些肠道细菌的减少。此外，CFA 注射会导致血脑屏障 (BBB) 渗漏，激活小胶质细胞并增强脊髓三叉神经尾核 (Sp5C) 中肿瘤坏死因子 α (TNFα) 的释放。RSV 治疗恢复 BBB 完整性，抑制小胶质细胞活化并减少 Sp5C 中 TNFα 的释放。此外，用 RSV 治疗小鼠的粪便移植粪便微生物群可显着减少 CFA 诱导的 TMJ 炎症。综合起来，