Dong Yue, Meng Fanyi, Wang Jingyi, Wei Jingge, Zhang Kexin, Qin Siqi, Li Mengfan, Wang Fucheng, Wang Bangmao, Liu Tianyu, Zhong Weilong, Cao Hailong
Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China.
Gut Microbes. 2025 Dec;17(1):2446376. doi: 10.1080/19490976.2024.2446376. Epub 2024 Dec 24.
The initiation and progression of colorectal cancer (CRC) are intimately associated with genetic, environmental and biological factors. (DSV), a sulfate-reducing bacterium, has been found excessive growth in CRC patients, suggesting a potential role in carcinogenesis. However, the precise mechanisms underlying this association remain incompletely understood. We have found was abundant in high-fat diet-induced mice, and DSV, a member of , triggered colonocyte proliferation of germ-free mice. Furthermore, the level of DSV progressively rose from healthy individuals to CRC patients. Flagella are important accessory structures of bacteria, which can help them colonize and enhance their invasive ability. We found that flagellin (DVF) drove the proliferation, migration, and invasion of CRC cells and fostered the growth of CRC xenografts. DVF enriched the epithelial-mesenchymal transition (EMT)-associated genes and characterized the facilitation of DVF on EMT. Mechanistically, DVF induced EMT through a functional transmembrane receptor called leucine-rich repeat containing 19 (LRRC19). DVF interacted with LRRC19 to modulate the ubiquitination of tumor necrosis factor receptor-associated factor (TRAF)6, rather than TRAF2. This interaction drove the ubiquitination of pivotal molecule TAK1, further enhancing its autophosphorylation and ultimately contributing to EMT. Collectively, DVF interacts with LRRC19 to activate the TRAF6/TAK1 signaling pathway, thereby promoting the EMT of CRC. These data shed new light on the role of gut microbiota in CRC and establish a potential clinical therapeutic target.
结直肠癌（CRC）的发生和发展与遗传、环境及生物学因素密切相关。脱硫弧菌属（DSV）这种硫酸盐还原菌在CRC患者中被发现过度生长，提示其在致癌过程中可能发挥作用。然而，这种关联背后的确切机制仍未完全明确。我们发现其在高脂饮食诱导的小鼠中大量存在，并且作为脱硫弧菌属成员之一的DSV可触发无菌小鼠的结肠细胞增殖。此外，从健康个体到CRC患者，DSV水平逐渐升高。鞭毛是细菌重要的附属结构，可帮助它们定殖并增强侵袭能力。我们发现脱硫弧菌鞭毛蛋白（DVF）可驱动CRC细胞的增殖、迁移和侵袭，并促进CRC异种移植瘤的生长。DVF使上皮-间质转化（EMT）相关基因富集，并体现了DVF对EMT的促进作用。机制上，DVF通过一种名为富含亮氨酸重复序列19（LRRC19）的功能性跨膜受体诱导EMT。DVF与LRRC19相互作用以调节肿瘤坏死因子受体相关因子（TRAF）6而非TRAF2的泛素化。这种相互作用促使关键分子TAK1的泛素化，进一步增强其自身磷酸化并最终促成EMT。总体而言，DVF与LRRC19相互作用以激活TRAF6/TAK1信号通路，从而促进CRC的EMT。这些数据为肠道微生物群在CRC中的作用提供了新的见解，并确立了一个潜在的临床治疗靶点。
