Deng Jiaxin, Zhang Jiawei, Su Mingli, Li Juan, Su Yuping, Zhong Qinghua, Hu Jiancong, Chen Yongcheng, Liao Sen, Lin Dezheng, Guo Xuefeng
Department of Endoscopic Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Gut Microbes. 2025 Dec;17(1):2502138. doi: 10.1080/19490976.2025.2502138. Epub 2025 May 8.
Colorectal cancer (CRC) is one of the most prevalent cancers worldwide, with high incidence and mortality rates. An increasing body of research suggests that obesity is a significant risk factor for the development of CRC. Moreover, recent findings have highlighted the close association between the gut microbiota and both obesity and CRC. Despite this, the specific mechanisms by which the gut microbiota influences obesity and CRC remain unclear. This study aims to explore the role of the gut bacterium Fusobacterium mortiferum and its metabolite 5-aminovaleric acid (5-AVA) in the development of obesity and CRC. Our study found that the metabolite 5-aminovaleric acid produced by Fusobacterium mortiferum significantly inhibits the expression of the tumor suppressor DKK2. This inhibition leads to enhanced proliferation of CRC cells. Furthermore, we discovered that Fusobacterium mortiferum and 5-AVA can activate the Wnt/β-catenin signaling pathway by inhibiting DKK2, thereby promoting tumor growth. This finding was validated in CRC mouse models and in vitro experiments. Additional mechanistic studies revealed that 5-AVA interacts with the demethylase KDM6B, affecting the demethylation process of DKK2 and subsequently activating the Wnt/β-catenin signaling pathway. Our study retrospectively collected fecal samples from patients who underwent gastrointestinal endoscopy at the Sixth Affiliated Hospital of Sun Yat-sen University over the past five years. Participants were stratified into a healthy control group and an adenoma group based on the outcomes of their colonoscopies. Following this, we conducted metagenomic analysis to identify differential bacteria, and based on the results, we performed bacterial cultivation and metabolomic profiling. The roles of the targeted bacteria and their metabolites were further validated through animal models and cellular assays, employing techniques such as Western Blot, qPCR, immunohistochemistry, molecular docking simulations, and gene overexpression studies. This study uncovers the potential carcinogenic effects of Fusobacterium mortiferum and 5-AVA in the development of obesity and CRC. Our research emphasizes the complex interplay between the gut microbiota and host metabolism and suggests new directions for future research to explore how modulation of the gut microbiota could prevent and treat CRC.
结直肠癌(CRC)是全球最常见的癌症之一,发病率和死亡率都很高。越来越多的研究表明,肥胖是CRC发生的一个重要危险因素。此外,最近的研究结果突出了肠道微生物群与肥胖和CRC之间的密切关联。尽管如此,肠道微生物群影响肥胖和CRC的具体机制仍不清楚。本研究旨在探讨死亡梭杆菌及其代谢产物5-氨基戊酸(5-AVA)在肥胖和CRC发生发展中的作用。我们的研究发现,死亡梭杆菌产生的代谢产物5-氨基戊酸显著抑制肿瘤抑制因子DKK2的表达。这种抑制导致CRC细胞增殖增强。此外,我们发现死亡梭杆菌和5-AVA可以通过抑制DKK2激活Wnt/β-连环蛋白信号通路,从而促进肿瘤生长。这一发现已在CRC小鼠模型和体外实验中得到验证。进一步的机制研究表明,5-AVA与去甲基化酶KDM6B相互作用,影响DKK2的去甲基化过程,随后激活Wnt/β-连环蛋白信号通路。我们的研究回顾性收集了中山大学附属第六医院过去五年接受胃肠内镜检查患者的粪便样本。根据结肠镜检查结果,将参与者分为健康对照组和腺瘤组。随后,我们进行了宏基因组分析以鉴定差异细菌,并根据结果进行细菌培养和代谢组学分析。通过动物模型和细胞实验,利用蛋白质免疫印迹、定量聚合酶链反应、免疫组织化学、分子对接模拟和基因过表达研究等技术,进一步验证了靶向细菌及其代谢产物的作用。本研究揭示了死亡梭杆菌和5-AVA在肥胖和CRC发生发展中的潜在致癌作用。我们的研究强调了肠道微生物群与宿主代谢之间的复杂相互作用,并为未来探索如何通过调节肠道微生物群预防和治疗CRC的研究提出了新方向。
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