This U01 project leverages our expertise in the epidemiology of colorectal cancer (CRC); disparities; obesity;
metabolic dysregulation, an important manifestation of inflammation; the microbiome; animal CRC models; and
lifestyle intervention trials to address the growing problem of Early-Onset CRC (EOCRC) (i.e., <50 years).
Adiposity and diet drive metabolic dysregulation. So, understanding the interaction between diet and adiposity
are key to understanding the genesis of EOCRC – and an array of other obesity-related cancers). This project
will address the absence of critical clinical trials and mechanistic studies involving lifestyle interventions for
EOCRC. We intend to address this gap; and have the transdisciplinary team representing complementary
backgrounds to do so. We focus on dietary modulation of gut microbes to reduce metaflammation and
subsequent metabolic dysfunction in obesity, with a goal of preventing EOCRC. We will perform 1) an anti-
inflammatory dietary intervention trial in dyads of adults and children at elevated risk for CRC. We also will
conduct a complementary mechanistic animal study that builds on and leverages our expertise in mechanistic
studies on obesity and CRC. This work is supported by infrastructure that we have built over the past decades
in two key centers at the University of South Carolina (UofSC): (1) Center for Colon Cancer Research (CCCR,
2002 - present – which specializes in mouse models of CRC); and (2) the Cancer Prevention and Control
Program (CPCP, 2000 - present – which specializes in the epidemiology of cancer and lifestyle intervention
trials for cancer, with a focus on cancer disparities. The two projects that comprise the proposed grant address
two Specific Aims that are represented by the human study and laboratory animal experiment: i.e. ,1: To
establish the metabolic protective effects of an anti-inflammatory diet in obese, high-risk African-
American (AA) and European-American (EA) adults and children in reducing inflammation as indicated by
Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), IGF-1, Tumor Necrosis Factor alpha
(TNFa), Interleukin 6 (IL-6), and C-Reactive Protein (CRP), and a creating more favorable microbiome
signature; 2: To establish gut microbes as mediators between anti-inflammatory dietary input and
reversal of metabolic dysfunction and associated CRC risk. This complements the human study by
carrying out pre-clinical murine model studies with similar inputs (diet), intermediate endpoints (inflammation,
microbiome), and outcomes (CRC-related). We hypothesize that an anti-inflammatory dietary intervention will
reduce metabolic dysfunction and metainflammation through regulatory effects on gut microbiota.
Results from this work will address the role of metabolic dysregulation in relation to factors that are known to
be important in carcinogenesis, that therefore could have profound effects on EOCRC, have implications for
other obesity-related cancers, and have great promise for moving the field forward by addressing mechanisms
that drive large health-related disparities that consistently disfavor African Americans.
