Fecal Metabolomic Signatures in Colorectal Adenoma Patients Are Associated with Gut Microbiota and Early Events of Colorectal Cancer Pathogenesis

Colorectal adenomas are precancerous lesions of colorectal cancer (CRC) that offer a means of viewing the events key to early CRC development. A number of studies have investigated the changes and roles of gut microbiota in adenoma and carcinoma development, highlighting its impact on carcinogenesis. However, there has been less of a focus on the gut metabolome, which mediates interactions between the host and gut microbes. Here, we investigated metabolomic profiles of stool samples from patients with advanced adenoma (n = 102), matched controls (n = 102), and patients with CRC (n = 36). We found that several classes of bioactive lipids, including polyunsaturated fatty acids, secondary bile acids, and sphingolipids, were elevated in the adenoma patients compared to the controls. Most such metabolites showed directionally consistent changes in the CRC patients, suggesting that those changes may represent early events of carcinogenesis. We also examined gut microbiome-metabolome associations using gut microbiota profiles in these patients. We found remarkably strong overall associations between the microbiome and metabolome data and catalogued a list of robustly correlated pairs of bacterial taxa and metabolomic features which included signatures of adenoma. Our findings highlight the importance of gut metabolites, and potentially their interplay with gut microbes, in the early events of CRC pathogenesis.