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

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.