哌啶酸通过促进TNF-a分泌介导溃疡性结肠炎发生的机制研究

溃疡性结肠炎（Ulcerative colitis, UC）的发病机制与基因、环境、肠道菌群及免疫系统异常激活相关。UC发病率在国内逐年升高，饮食结构转变所造成的代谢组变化及代谢重编程可能是原因之一。免疫系统异常激活被认为是造成UC发病的关键步骤，其中巨噬细胞功能异常发挥重要作用。我们前期通过代谢组学发现UC与健康人代谢谱差异巨大。通过体外筛选发现早期未被阐明功能的赖氨酸代谢产物哌啶酸潜在参与了巨噬细胞功能调控。体外实验证实哌啶酸促进巨噬细胞TNF-a分泌，并能够促进P105蛋白磷酸化。因此，哌啶酸可能通过直接活化NF-kB信号通路，进而影响巨噬细胞功能，促进UC发病。本课题将从临床，动物、细胞及分子机制三个层次，深入研究哌啶酸促进TNF-a分泌介导UC的机制。我们相信这些研究成果有助于深入了解UC发病机制，为基于氨基酸代谢的UC个体化精准治疗甚至饮食干预治疗提供新的理论依据。

The pathogenesis of ulcerative colitis (UC) is considered to be involved in genetics, environment, microbiome and dysfunctional immune system. Recently, the incidence of UC was increased in China, which caused by metabolome change and metabolic reprograming due to the change of daily diet. Dysfunction of immune system is considered as one of the critical factors for UC, especially including dysfunctional macrophage. Our preliminary data revealed huge differences of metabolome especially amino acid metabolism between the patient with UC and healthy donors, characterized by metabolome analysis. By screening in vitro, we identified an unexpected function of lysine metabolic intermediate pipecolic acid potentially involved in the regulation of macrophage function. We demonstrated that macrophage secreted more TNF-a under LPS with pipecolic acid stimulation, and the phosphorylation of P105 increased. Therefore, we believe that pipecolic acid affects macrophage function through NF-kB signaling might play an essential role in the pathogenesis of UC. From the perspectives of clinical, animal, cellular and molecular levels, our proposal will focus on the function and underlying mechanism of pipecolic acid in macrophage of the patients with UC. Our study will provide novel ideas for the immune therapeutic treatment of UC.