2. Academic Validation
  3. Exercise-induced Metabolite N-lactoyl-phenylalanine Ameliorates Colitis by Inhibiting M1 Macrophage Polarization Via the Suppression of the NF-κB Signaling Pathway

Exercise-induced Metabolite N-lactoyl-phenylalanine Ameliorates Colitis by Inhibiting M1 Macrophage Polarization Via the Suppression of the NF-κB Signaling Pathway

  • Cell Mol Gastroenterol Hepatol. 2025 Jun 23:101558. doi: 10.1016/j.jcmgh.2025.101558.
Runfeng Yu 1,  Chi Zhang 1,  Ming Yuan 1,  Shubiao Ye 1,  Tuo Hu 1,  Shaopeng Chen 1,  Guanzhan Liang 1,  Jiaqi Liu 2,  Haoxian Ke 3,  Junfeng Huang 3,  Ping Lan 4,  Xiaosheng He 5,  Xianrui Wu 6
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China.
  • 4 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 Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China. Electronic address: lanping@mail.sysu.edu.cn.
  • 5 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. Electronic address: hexsheng@mail.sysu.edu.cn.
  • 6 Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China. Electronic address: wuxianr5@mail.sysu.edu.cn.
PMID: 40562095 DOI: 10.1016/j.jcmgh.2025.101558
Abstract

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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords

Exercise; Inflammatory Bowel Disease; Lac-Phe; Macrophage Polarization.

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