Yu Runfeng, Zhang Chi, Yuan Ming, Ye Shubiao, Hu Tuo, Chen Shaopeng, Liang Guanzhan, Liu Jiaqi, Ke Haoxian, Huang Junfeng, Lan Ping, He Xiaosheng, Wu Xianrui
Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China.
Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China; Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, PR China.
Cell Mol Gastroenterol Hepatol. 2025 Jun 23:101558. doi: 10.1016/j.jcmgh.2025.101558.
BACKGROUND & AIMS: Although the anti-inflammatory benefits of exercise are well-documented, the specific mechanisms responsible for these advantages remain uncertain. N-lactoyl-phenylalanine (Lac-Phe), a major metabolite produced during exercise, is synthesized through the condensation of lactic acid and phenylalanine, catalyzed by the CNDP2. However, the potential anti-inflammatory properties of Lac-Phe remain poorly understood. This study aimed to investigate the anti-inflammatory effects of Lac-Phe in the context of inflammatory bowel disease (IBD) and to examine the underlying mechanisms.
The levels of Lac-Phe were measured in both patients and mice with IBD utilizing enzyme-linked immunosorbent assay kits. The anti-inflammatory effects of Lac-Phe were demonstrated through colitis models. The impacts of Lac-Phe on macrophage polarization and the associated mechanisms were determined by flow cytometry, quantitative polymerase chain reaction, RNA sequencing, Western blotting, and immunofluorescence.
Our study revealed a reduction in plasma Lac-Phe content in patients with IBD, in conjunction with a decrease in the expression of CNDP2 in the colon, which exhibited a negative correlation with disease activity scores. Exercise mitigated dextran sulfate sodium-induced colitis in mice by elevating plasma Lac-Phe levels and inhibiting the polarization of M1 macrophages. Mechanistically, Lac-Phe impedes the movement of p65 protein from the cytoplasm into the nucleus, consequently suppressing the activation of the NF-κB signaling pathway and macrophage M1 polarization. Furthermore, the supplementation of phenylalanine, a substrate of Lac-Phe, was observed to enhance the generation of Lac-Phe and to exert a protective effect in the murine colitis model.
Our results suggest that exercise can induce the production of Lac-Phe, which plays a preventive role against dextran sulfate sodium-induced colitis in mice. Lac-Phe mitigates colitis through inhibition of the polarization of M1 macrophage. Adjusting macrophage polarization with Lac-Phe and phenylalanine supplementation may offer a potential therapeutic strategy for managing IBD.
尽管运动的抗炎益处已有充分记录，但其产生这些益处的具体机制仍不明确。N-乳酰苯丙氨酸（Lac-Phe）是运动过程中产生的一种主要代谢产物，由乳酸和苯丙氨酸在CNDP2催化下缩合而成。然而，Lac-Phe潜在的抗炎特性仍知之甚少。本研究旨在探讨Lac-Phe在炎症性肠病（IBD）中的抗炎作用，并研究其潜在机制。
使用酶联免疫吸附测定试剂盒测量IBD患者和小鼠体内Lac-Phe的水平。通过结肠炎模型证明Lac-Phe的抗炎作用。通过流式细胞术、定量聚合酶链反应、RNA测序、蛋白质印迹和免疫荧光确定Lac-Phe对巨噬细胞极化的影响及其相关机制。
我们的研究发现，IBD患者血浆Lac-Phe含量降低，同时结肠中CNDP2的表达减少，且与疾病活动评分呈负相关。运动通过提高血浆Lac-Phe水平和抑制M1巨噬细胞极化减轻小鼠葡聚糖硫酸钠诱导的结肠炎。机制上，Lac-Phe阻碍p65蛋白从细胞质进入细胞核，从而抑制NF-κB信号通路的激活和巨噬细胞M1极化。此外，观察到补充Lac-Phe的底物苯丙氨酸可增加Lac-Phe的生成，并在小鼠结肠炎模型中发挥保护作用。
我们的结果表明，运动可诱导Lac-Phe的产生，其对小鼠葡聚糖硫酸钠诱导的结肠炎具有预防作用。Lac-Phe通过抑制M1巨噬细胞极化减轻结肠炎。用Lac-Phe和补充苯丙氨酸调节巨噬细胞极化可能为IBD的治疗提供一种潜在策略。
