Fusobacterium mortiferum and its metabolite 5-aminovaleric acid promote the development of colorectal cancer in obese individuals through Wnt/β-catenin pathway by DKK2

作者：J. S. Deng, Jiawei Zhang, Mingli Su, Juan Li, Yuping Su, Qinghua Zhong, Jiancong Hu, Yongcheng Chen, Sen Liao, Dezheng Lin, Xuefeng Guo · 发表于：Gut Microbes · 年份：2025 · DOI：10.1080/19490976.2025.2502138 · 被引用次数：18 · 研究领域：Gut microbiota and health、Pancreatic and Hepatic Oncology Research、Diet and metabolism studies

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 i...