调控Th17/Treg细胞平衡在改善衰弱综合征中的作用及机制

Frailty is an age-related medical syndrome with no effective treatments. Early identification and intervention of frailty can prevent the occurrence of worse clinical outcomes, such as death, and improve the quality of life in the elderly. Immunosenescence, characterized by a high inflammatory level caused by the imbalance of Th17/Treg cells, have been found in patients of frailty. The applicant found that reducing the ratio of Th17/Treg cells by using F. prausnitzii, a commensal bacterium in the gut, could ameliorate colitis. Therefore, the hypothesis of this study is that the increase of Th17/Treg ratio is an important factor in the occurrence of frailty, and reversing the imbalance of Th17/Treg can inhibit inflammation thus alleviating frailty. In this study, firstly, the level of Th17/Treg cells will be detected in mice and patients with frailty. Then, naive T cells will be extracted to be knockout or overexpressed related proteins, and added with F. prausnitzii products in the process of differentiation in vitro, to explore the pathways for regulating the differentiation of Th17 and Treg cells. Finally, F. prausnitzii products will be administrated in mice and patients with frailty, to figure out the effects and mechanisms of Th17/Treg cell balance in frailty. This study has great significance in theory and application in revealing the pathogenesis and clinical interventions of frailty from a perspective of immune cell imbalance.

衰弱综合征与年龄正相关，尚无有效治疗手段，因此早期识别和干预衰弱可预防老年人包括死亡在内的临床不良事件的发生，提高生活质量。衰弱患者体内存在免疫衰老，其中Th17/Treg细胞失衡导致的高炎症状态是免疫衰老的特征之一。申请人发现，使用肠道中的普拉梭菌来降低Th17/Treg细胞比例可抑制肠炎。故本研究提出假说：Th17/Treg比例升高是衰弱发生的重要因素，逆转Th17/Treg失衡可抑制炎症，改善衰弱。为此，本研究首先将检测衰弱小鼠和衰弱人群体内Th17/Treg细胞水平；然后提取原代初始T细胞敲除或过表达相关信号蛋白，在体外分化过程中加入普拉梭菌产物，探索调控Th17、Treg细胞分化的信号通路；最后对衰弱小鼠和衰弱人群使用普拉梭菌产物干预，研究降低Th17/Treg细胞比例对衰弱的改善作用和机制。本研究从免疫细胞失衡的角度揭示衰弱的发病机制和临床干预方法，有重大的理论和应用价值。

背景：衰弱综合征与年龄正相关，尚无有效治疗手段，因此早期识别和干预衰弱可预防老年人包括死亡在内的临床不良事件的发生，提高生活质量。衰弱患者体内存在免疫衰老，其中Th17/Treg细胞失衡导致的高炎症状态是免疫衰老的特征之一。.方法：本研究首先检测了衰弱个体中普拉梭菌和Th17/Treg水平。然后使用普拉梭菌和丁酸钠对老龄小鼠灌胃，观察衰弱评分和Th17/Treg细胞比例。然后提取原代T细胞体外分化，过表达或抑制Sirt1，过程中加入普拉梭菌产物，研究Th17/Treg分化比例。最后对衰弱小鼠使用丁酸钠和Sirt1干预。.结果：本研究发现衰弱小鼠和衰弱人群体内均存在普拉梭菌降低和Th17/Treg细胞比例升高；普拉梭菌上清液和丁酸钠均可降低衰弱小鼠Th17/Treg细胞比例和衰弱指数评分。体外T细胞分化实验证实，普拉梭菌通过抑制Sirt1抑制Th17细胞、促进Treg细胞分化。动物实验进一步证实，Sirt1抑制剂降低Th17/Treg细胞比例，对小鼠具有改善衰弱的作用。.结论：普拉梭菌可以通过抑制Sirt1降低Th17/Treg细胞比例，从而改善衰弱。研究从免疫细胞失衡的角度揭示衰弱的发病机制和临床干预方法，有重大的理论和应用价值。