Short-chain fatty acids and chronic temporomandibular joint pain

项目总结： 颞下颌关节紊乱病(TMD)是最常见的TMJ疼痛状态； 然而，人们对其潜在机制仍知之甚少。因此，TMJ疼痛长期以来一直令人困惑 医疗和牙科保健提供者，以及目前对慢性TMJ疼痛的治疗往往不令人满意。 我们最近的工作表明，肠道微生物组的扰动和短链脂肪酸(SCFA)的减少 肠道可能参与了TMJ疼痛的发病机制，SCFAs恢复到正常水平可能是 发展成为治疗这种疼痛的新的补充非阿片类药物疗法。我们的初步结果进一步表明 SCFAs可能通过表观遗传机制参与TMJ疼痛的发生。在这个项目中，我们将揭示具体的 SCFAs调控慢性TMJ疼痛的表观遗传学机制。我们的假设是肠道微生物群 扰动产生的SCFA减少通过表观遗传抑制GAD2增强慢性TMJ疼痛 转录，并且补充SCFA通过使表观遗传调节正常化来抑制这种疼痛。至 针对这一中心假设，我们将在三个具体目标下进行研究。在目标1中，我们将 测定补充SCFA治疗慢性TMJ疼痛的疗效。在目标2中，我们将确定 SCFAs在慢性TMJ疼痛中作用的表观遗传学机制。在目标3中，我们将定义 迷走神经在SCFA介导的慢性TMJ痛的表观遗传调节中的作用。我们希望共同揭示一个关键的 SCFAs在TMJ疼痛中作用的表观遗传学机制。拟议的研究具有重要意义，因为 它将演示SCFA是否以及如何调节TMJ疼痛。拟议的研究具有创新性，因为 研究将确定SCFAs在TMJ疼痛的表观遗传调节中以前未被认识到的作用。

Project Summary: Temporomandibular disorders (TMDs) are the most common temporomandibular joint (TMJ) pain condition; however, the underlying mechanisms remain poorly understood. As such, TMJ pain has long confounded medical and dental health care providers, and current treatment of chronic TMJ pain are often unsatisfactory. Our recent work suggests that gut microbiome perturbation and reduction of short-chain fatty acids (SCFAs) in the gut may be involved in the pathogenesis of TMJ pain and recovering SCFAs to normal levels could be developed into a new complementary non-opioid therapy for such pain. Our preliminary results further suggest that SCFAs may contribute to TMJ pain via an epigenetic mechanism. In this project, we will reveal specific epigenetic mechanisms by which SCFAs regulate chronic TMJ pain. Our hypothesis is that gut microbiome perturbation-produced SCFA reduction enhances chronic TMJ pain by epigenetically suppressing Gad2 transcription, and that SCFA supplementation inhibits such pain via normalizing the epigenetic regulation. To address this central hypothesis, we will conduct the studies proposed in three specific aims. In Aim 1, we will determine the therapeutic effect of SCFA supplementation on chronic TMJ pain. In Aim 2, we will identify the epigenetic mechanism that underlies the role of SCFAs in chronic TMJ pain. In Aim 3, we will define the role of vagus nerve in SCFA-mediated epigenetic regulation of chronic TMJ pain. Together, we expect to reveal a critical epigenetic mechanism that underlies the role of SCFAs in TMJ pain. The proposed research is significant since it will demonstrate whether and how SCFAs regulate TMJ pain. The proposed studies are innovative since these studies will identify a previously unrecognized role for SCFAs in the epigenetic regulation of TMJ pain.