Integrative analysis reveals bacterial load as a determinant of molecular and immune phenotypes in colorectal cancer

Colorectal cancer (CRC) ranks as the third most frequently diagnosed cancer and the second leading cause of cancer deaths globally. The incidence and mortality rates vary widely across regions, being highest in developed countries but it is increasing rapidly in low- and middle-income nations due to aging population, urbanization and adoption of Western lifestyles. Phenotypically, CRC can broadly be divided into tumors with microsatellite instability (MSI) and those that are microsatellite stable (MSS). MSI tumors typically arise in the right colon and are driven by hypermutation from loss of function in DNA mismatch repair (MMR) genes, such as MLH1 or MSH2 . We recently found that the overall bacterial load in a tumor, rather than relative abundance of any specific taxa, is the primary driver of microbial-based immunosuppression in head and neck squamous cell carcinoma. However, how bacterial load is associated with clinicopathological features and molecular phenotypes of CRC remains unknown. To address this, we performed a comprehensive analysis of bacterial load in CRC tumors. We found that bacterial load was independently enriched in both MSI tumors and tumors with lymphatic invasion. After controlling for MSI status, tumors with high bacteria were more likely to be TP53 and APC wildtype and exhibited elevated inflammatory signaling at both the gene and protein level. Further analysis of systems-level metabolic rewiring indicated elevated levels of glycoprotein metabolism in high bacterial tumors, which have previously been associated with bacteria adhesion to tumor cells. Together, these findings offer the first landscape of how the bacterial load is associated with clinicopathological and molecular alterations, which may have implications for patient prognosis and treatment strategies.