硫胺素缺乏通过糖代谢重编程促进M1巨噬细胞极化在溃疡性结肠炎中的作用研究

M1 macrophage polarization is intrinsically associated with ulcerative colitis (UC) pathogenesis, and M1 macrophage polarization is regulated by “TCA cycle/glycolysis” metabolic reprogramming. Our study found that thiamine, as a key coenzyme of pyruvate dehydrogenase (PDH), its deficiency leads to a glucose metabolic switch from TCA cycle towards glycolysis, resulting in lactate accumulation and intestinal inflammation. Accordingly, we hypothesize that thiamine deficiency may drive the onset of UC by promoting M1 macrophage polarization through glucose metabolic reprogramming. To verify this hypothesis, the metabonomics and gene overexpression and silencing techniques will be used both in vivo and in vitro, to clarify the following three questions: (1) the correlationship between thiamine deficiency and the UC incidence in mice; (2) the modulatory effects of thiamine deficiency on M1 macrophage polarization and UC lesion; (3) the mechanisms of thiamine deficiency on M1 macrophage polarization and associated UC exacerbation based on “PDH-Lactate-NFκB” pathway analysis. The implementation of this project will provide a direct evidence for the involvement of thiamine deficiency in M1 macrophage polarization and UC pathogenesis, and ulteriorly provide theoretic reference and technical guidance for intervening UC by nutritional support in diet.

M1巨噬细胞极化与溃疡性结肠炎(UC)密切相关，而“三羧酸循环/糖酵解”糖代谢重编程在M1巨噬细胞极化过程发挥关键作用。申请人前期研究发现，硫胺素作为丙酮酸脱氢酶(PDH)的关键辅酶，其缺乏引起糖代谢由三羧酸循环转变为糖酵解为主，导致乳酸堆积及肠道炎症。据此，硫胺素缺乏可能通过糖代谢重编程影响M1巨噬细胞极化而在UC发病过程中发挥重要角色。本项目拟在小鼠和细胞水平，应用代谢组学和基因过表达/沉默技术研究：①明确硫胺素缺乏与UC发病的关联性；②阐明硫胺素缺乏对M1巨噬细胞极化以及UC发病的作用；③基于“PDH-乳酸-核因子κB”途径，揭示硫胺素缺乏调控M1巨噬细胞极化影响UC发病的分子机制。本项目的实施将提供硫胺素缺乏促进UC发病的直接证据，为UC防治的营养素干预提供理论依据和新策略。

M1巨噬细胞极化在溃疡性结肠炎(Ulcerative colitis, UC)的发生中起重要作用，且其极化受“三羧酸循环/糖酵解”糖代谢重编程调控。硫胺素作为糖代谢丙酮酸脱氢酶(PDH)的关键辅酶，其缺乏引起糖代谢由三羧酸循环转变为糖酵解为主。然而，硫胺素缺乏是否通过糖代谢重编程影响M1巨噬细胞极化进而加重UC发病尚不明确。本项目研究发现，硫胺素缺乏加重UC发病及结肠组织M1巨噬细胞的炎性浸润及促炎性细胞因子（TNF-α，IL-1β，IL-6）的分泌，表明硫胺素缺乏与UC发病存在关联性。利用体外BMDM细胞模型及小鼠结肠炎模型，我们进一步揭示了硫胺素缺乏通过“PDH-Lactate-NFκB”途径促进M1巨噬细胞极化加重UC发病的分子机制。本项目的实施提供了硫胺素缺乏促进UC发病的直接证据，为UC防治的营养素干预提供理论依据和新策略。