Gut microbiome mediates the associations between lifestyle factors and risk of colorectal high-risk adenoma: results from a population-based cohort study

Lifestyle factors exert influence on the risk of colorectal cancer (CRC) and its precursors. However, the interaction between gut microbiota and lifestyle factors concerning colorectal high-risk adenomas (HRAs), as well as the specific microbial taxa implicated, remains underexplored. Here, we aimed to investigate the impact of common lifestyle factors on HRAs and to explore the potential mediating roles of gut microbiota in these effects. A total of 3,827 participants were enrolled from our multicenter CRC screening cohort. Lifestyle factors over the 12 months preceding enrollment were assessed via questionnaires. Fecal samples were collected upon enrollment and analyzed using 16S rRNA sequencing. Multivariate analyses were used to identify lifestyle-related risk factors for HRA, followed by the application of the multivariate association with linear models (MaAsLin2) to explore associations between microbiota and lifestyle risk factors, with causal mediation analysis employed to evaluate the gut microbiota's mediating effect between lifestyle factors and HRA risk. A total of 272 patients with HRA and 1,253 controls were included. Independent risk factors for HRA were identified as high body mass index, number of pack-years smoked >30, alcohol consumption >4 units/week. These lifestyle factors were significantly associated with the relative abundance of various microbial genera. Notably, genus <i>Fusobacterium</i> and <i>Tyzzerella 4</i> were found to partially mediate the increased risk of HRA due to alcohol and cigarette consumption, respectively. These findings provide new insights for microbiota-targeted interventions or lifestyle-based prevention strategies to reduce the risk of CRC, offering a novel and actionable approach to early prevention.IMPORTANCELifestyle choices, such as diet, smoking, and alcohol consumption, are known to influence colorectal cancer risk, but the role of gut bacteria in mediating this process remains underestimated. To address this gap, our study aimed to explore the connections between lifestyle factors, gut microbes, and colorectal precancerous growths, referred to as high-risk adenomas (HRAs). We observed a dual association whereby obesity, heavy smoking, and excessive alcohol consumption were linked to both an increased risk of HRAs and distinct changes in gut bacteria. Importantly, smoking and alcohol consumption are associated with increased cancer risk, in part, through certain bacteria such as genus <i>Fusobacterium</i> and <i>Tyzzerella 4</i>. These findings reveal how gut microbes may act as a hidden bridge between lifestyle and disease development. Our discovery of these microbial mediators reveals novel opportunities for HRA prevention through lifestyle modifications or probiotic interventions targeting this carcinogenic pathway prior to malignant transformation.CLINICAL TRIALSThis study is registered with the Chinese Clinical Trial Registry as ChiCTR1800015506.