Department of Anesthesiology and Surgery, Jining No. 1 People's Hospital, Jining, 272011, Shandong, China.
Inflammation. 2019 Dec;42(6):2257-2266. doi: 10.1007/s10753-019-01090-2.
Gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) has recently been shown to promote inflammation in peripheral tissues and the central nervous system (CNS), contributing to the pathogenesis of various human diseases. Here, we examined whether the presence of high levels of circulating TMAO would influence central and peripheral inflammation and inflammatory hyperalgesia in a carrageenan (CG)-induced rat model of inflammation. Rats were treated with vehicle or TMAO in drinking water. After 2 weeks of treatment, rats received intraplantar injection of saline or CG into the hind paw. Acute nociception was unaltered in TMAO-treated rats that had elevated plasma TMAO. Following CG injection, TMAO-treated rats were significantly more sensitive to thermal and mechanical stimulation of the inflamed paw and displayed greater paw edema. Molecular studies revealed that CG injection induced increases in recruitment of neutrophils/macrophages in the paw and activation of microglia in the spinal cord, along with increased activation of nuclear factor (NF)-kB and production of proinflammatory mediators in both vehicle-treated rats and TMAO-treated rats. However, the increases in the above parameters were more pronounced in TMAO-treated rats. Moreover, TMAO treatment decreased protein levels of anti-inflammatory mediator regulator of G protein signaling (RGS)-10 in both saline-injected rats and CG-injected rats. These findings suggest that the presence of high levels of circulating TMAO downregulates anti-inflammatory mediator RGS10 in both peripheral tissues and the CNS, which may increase the susceptibility to inflammatory challenge-induced NF-kB activity, leading to greater increase in production of inflammatory mediators and consequent exacerbation of peripheral inflammation and inflammatory hyperalgesia.
肠道微生物衍生代谢物三甲胺 N-氧化物（TMAO）最近被证明可促进外周组织和中枢神经系统（CNS）的炎症反应，从而导致各种人类疾病的发病机制。在这里，我们研究了循环 TMAO 水平升高是否会影响角叉菜胶（CG）诱导的炎症大鼠模型中的中枢和外周炎症以及炎症性痛觉过敏。大鼠用载体或 TMAO 处理饮用水。治疗 2 周后，大鼠将盐水或 CG 注射到后爪的足底。 TMAO 处理的大鼠血浆 TMAO 水平升高，但急性痛觉无变化。 CG 注射后，TMAO 处理的大鼠对炎性爪的热和机械刺激更为敏感，并且爪肿胀更大。分子研究表明，CG 注射诱导爪中中性粒细胞/巨噬细胞的募集和脊髓中小胶质细胞的激活增加，同时在载体处理的大鼠和 TMAO 处理的大鼠中核因子（NF）-kB 的激活和促炎介质的产生增加。然而，在 TMAO 处理的大鼠中，这些参数的增加更为明显。此外，TMAO 处理降低了抗炎介质 G 蛋白信号调节蛋白（RGS）-10 的蛋白水平，无论是在盐水注射的大鼠还是 CG 注射的大鼠中。这些发现表明，循环 TMAO 水平升高会下调外周组织和中枢神经系统中的抗炎介质 RGS10，这可能会增加对炎症挑战诱导的 NF-kB 活性的易感性，导致炎症介质产生的增加，并导致外周炎症和炎症性痛觉过敏的加剧。
