Role of the inflammatory dietary pattern in gut and colon tissue microbiomes and impact on survival outcomes among colorectal cancer patients

Colorectal cancer (CRC) is the 3rd most commonly diagnosed cancer and 3rd leading cause of cancer-related deaths in the United States. Poor dietary quality and the gut microbiome are related modifiable factors implicated in the burden of this disease. However, the mechanisms through which they interact to impact CRC development and progression are poorly understood. Our team previously developed the novel Empirical Dietary Inflammatory Pattern (EDIP) score based on plasma inflammatory markers. A higher EDIP score is linked with higher levels of inflammation and a higher risk of developing CRC and dying from the disease. Though diet has been shown to modulate the gut microbiome, the dietary effects that trigger inflammation and dysbiosis in CRC are largely unknown. We have shown that a pro-inflammatory dietary pattern (higher EDIP) is associated with a higher risk of developing CRC in which the tumor is depleted in tumor-infiltrating lymphocytes (TILs) and that among CRC survivors, higher post-diagnosis EDIP also predisposed patients to die from tumors with depleted TILs, but not tumors with high levels of TILs. We further demonstrated that higher EDIP was associated with greater risk of colorectal tumors enriched with a bacterium called Fusobacterium nucleatum but not with tumors negative for F. nucleatum. These findings shed light on a potential mechanism for how diet-related inflammation may influence CRC tumor development and progression. However, our studies were limited to a single bacterium in colon tissue, and we now have the ability and expertise to use more robust methods to identify diverse microbes (bacteria, fungi, viruses, etc) and a wider range of host immune cells within tumors. Based on our preliminary data, we will test the overarching hypothesis that a pro-inflammatory dietary pattern reduces concentrations of important cancer-fighting immune cells in the colon and alters the overall balance of microbes in colon tissue, thereby increasing the risk of developing aggressive CRC that will lead to death. We will leverage data among 291 men and women in the Colocare cohort with diet and stool samples to identify gut microbes associated with EDIP and assess their impact on survival among CRC patients. In addition, we will utilize RNAseq data from the Oncology Information Exchange Network (ORIEN) among 2500 CRC patients to identify microbes and immune cell in CRC tumor tissue linked to EDIP and determine their impact on tumor clinical characteristics (e.g., CRC stage), host factors (e.g., sex, body mass index), and survival outcomes (recurrence, all-cause mortality, CRC mortality). At the completion of our study, we expect to have a) identified the microbes associated with the inflammatory dietary pattern in the gut and within CRC tumor tissue and b) determined how these EDIP-related microbes are linked to survival outcomes among CRC patients for the first time. These results will inform the design of larger studies of dietary strategies for mitigating dysbiosis in the gut and tumor tissue associated with proinflammatory (high-EDIP) dietary patterns and CRC progression. These novel strategies may also serve as adjunct therapies to improve anti-cancer treatment responses while reducing side effects.