Wang Dan, Wu Nianbang, Li Pei, Zhang Xiaojuan, Xie Wenshuai, Li Shunkang, Wang Ding, Kuang Yanling, Chen Shaokui, Liu Yulan
Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan 430023, China.
Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan 430023, China.
J Adv Res. 2024 Dec 30. doi: 10.1016/j.jare.2024.12.050.
Inflammatory bowel disease (IBD) is often associated with impaired proliferation and differentiation of intestinal stem cells (ISCs). Eicosapentaenoic acid (EPA), which is predominantly found in fish oil, has been recognized for its intestinal health benefits, although the potential mechanisms are not well understood.
This study aimed to investigate the regulatory role and mechanism of EPA in colonic epithelial regeneration, specifically from the perspective of ISCs.
Wild-type mice whose diet was supplemented with 5% EPA-enriched fish oil were subjected to dextran sulfate sodium (DSS) to induce colitis. We utilized intestinal organoids, ISC-specific lysine-specific demethylase 1 (LSD1) knockout mice, and WNT inhibitor-treated mice to explore how EPA influences ISC proliferation and differentiation. ISC proliferation, differentiation and apoptosis were assessed using tdTomato and propidium iodide tracer testing, histological analyses, and immunofluorescence staining.
EPA treatment significantly mitigated the symptoms of DSS-induced acute colitis, as evidenced by lower body weight loss and decreased disease activity index, histological scores and proinflammatory cytokine levels. Additionally, EPA increased the numbers of proliferative cells, absorptive cells, goblet cells, and enteroendocrine cells, which enhanced the regeneration of intestinal epithelium. Pretreatment with EPA increased ISC proliferation and differentiation, and protected against TNF-α-induced cell death in intestinal organoids. Mechanistically, EPA upregulated G protein-coupled receptor 120 (GPR120) to induce LSD1 expression, which facilitated ISC proliferation and differentiation in organoids. ISC-specific ablation of LSD1 negated the protective effect of EPA on DSS-induced colitis in mice. Moreover, EPA administration activated the WNT signaling pathway downstream of LSD1 in ISCs, while inhibiting WNT signaling abolished the beneficial effects of EPA.
These findings demonstrate that EPA promotes ISC proliferation and differentiation, thereby enhancing colonic epithelial regeneration through the activation of LSD1-WNT signaling. Consequently, dietary supplementation with EPA represents a promising alternative therapeutic strategy for managing IBD.
炎症性肠病（IBD）常与肠道干细胞（ISC）增殖和分化受损相关。二十碳五烯酸（EPA）主要存在于鱼油中，其对肠道健康有益，但其潜在机制尚不清楚。
本研究旨在探讨EPA在结肠上皮再生中的调节作用及机制，特别是从ISC的角度。
给野生型小鼠喂食添加5%富含EPA鱼油的饮食，然后用葡聚糖硫酸钠（DSS）诱导结肠炎。我们利用肠道类器官、ISC特异性赖氨酸特异性去甲基化酶1（LSD1）基因敲除小鼠和经WNT抑制剂处理的小鼠，以探究EPA如何影响ISC增殖和分化。使用tdTomato和碘化丙啶示踪试验、组织学分析和免疫荧光染色评估ISC增殖、分化和凋亡。
EPA治疗显著减轻了DSS诱导的急性结肠炎症状，表现为体重减轻较少、疾病活动指数、组织学评分和促炎细胞因子水平降低。此外，EPA增加了增殖细胞、吸收细胞、杯状细胞和肠内分泌细胞的数量，从而增强了肠上皮的再生。EPA预处理增加了ISC增殖和分化，并保护肠道类器官免受TNF-α诱导的细胞死亡。机制上，EPA上调G蛋白偶联受体120（GPR120）以诱导LSD1表达，这促进了类器官中ISC的增殖和分化。ISC特异性敲除LSD1消除了EPA对小鼠DSS诱导结肠炎的保护作用。此外，EPA给药激活了ISC中LSD1下游的WNT信号通路，而抑制WNT信号通路则消除了EPA的有益作用。
这些发现表明，EPA通过激活LSD1-WNT信号通路促进ISC增殖和分化，从而增强结肠上皮再生。因此，饮食中补充EPA是治疗IBD的一种有前景的替代治疗策略。
