Abstract P010: Molecular mediators of the energy balance-colorectal cancer link: evaluating the gut microbiome and pro-inflammatory biomarkers

Background: Physical activity and BMI are convincingly associated with colorectal cancer risk, yet the underlying molecular mediators and their interplay in the energy balance-cancer link remain unclear. Possible counteracting effects of physical activity on obesity-induced metabolic changes, including systemic inflammation and changes in the gut microbiome, have yet to be studied. Here, we investigated associations of several combinations of physical activity and BMI with pro-inflammatory biomarkers and the gut microbiome and relationships between these two mediators among patients with colorectal cancer. Methods: N=579 patients with newly diagnosed colorectal cancer (stages I-IV) were included. Physical activity at baseline was assessed using an adapted International Physical Activity Questionnaire (IPAQ) and participants were classified as being ‘active’ or ‘inactive’ based on physical activity guidelines. BMI at baseline was abstracted from medical records and categorized into ‘normal weight’ and ‘overweight/obese’. Pro-inflammatory biomarkers (CRP, SAA, IL-6, IL-8, and TNF-α) were measured in pre-surgery serum samples. In a subset of patients (n=179), 16S rRNA gene sequencing was additionally performed in pre-surgery stool samples. Relative abundances were determined for each taxonomic level and used to calculate diversity metrics. Analyses were adjusted for sex, stage at diagnosis, neoadjuvant treatment, and study site. Results: ‘Obese’ patients had 88% and 17% higher CRP and TNF-α levels compared to ‘normal weight’ patients (p=0.03 and 0.02, respectively). Highest CRP levels were observed among ‘overweight or obese/inactive’ compared to ‘normal weight/active’ patients (p=0.03). Lower gut microbial diversity was observed among ‘inactive’ vs. ‘active’ patients (Shannon index: p=0.01, Simpson: p=0.03), ‘obese’ vs. ‘normal weight’ patients (Shannon index, Simpson, and Observed species: p=0.02, respectively), and ‘overweight or obese/inactive’ vs. ‘normal weight/active’ patients (Shannon index: p=0.02, Observed species: p=0.04). Two phyla and 12 genera (e.g., Actinobacteria and Fusobacteria, and Ruminococcus, Succinivibrio, Succiniclasticum) were differentially abundant across physical activity and BMI groups. High CRP and TNF-α levels were statistically significantly associated with lower alpha diversity metrics (p=0.02-0.05). Conclusions: This is the first evidence indicating that the gut microbiome may be a molecular mediator of the energy balance-col