Abstract P010: Molecular mediators of the energy balance-colorectal cancer link: evaluating the gut microbiome and pro-inflammatory biomarkers
Authors: Himbert Caroline , Stephens W. Zac , Gigic Biljana , Lin Tengda , Ose Jennifer , Ashworth Anjelica , Warby Christy , Nix David , Jedrzkiewicz Jolanta , Peoples Anita R , Bronner Mary , Pickron Bartley , Scaife Courtney , Cohan Jessica N. , Grady William M. , Cohen Stacey A. , Krane Mukta , Schrotz-King Petra , Figueiredo Jane C. , Toriola Adetunji T. , Siegel Erin M. , Li Christopher I. , Ulrich Alexis , Shibata David , Round June L. , Huang Lyen C. , Schneider Martin , Hardikar Sheetal , Ulrich Cornelia M 
Published: January 2023

Abstract
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-colorectal cancer link. We further provide evidence of associations between physical activity and BMI groups with pro-inflammatory biomarkers. While BMI was identified as the key driver of inflammation, biomarker levels were higher among ‘inactive’ patients across BMI groups. Physical activity may offset obesity-induced inflammation and gut microbiome dysbiosis. Our results further provide new insights into the host-microbiome interactions with respect to systemic inflammation.
Citation Format: Caroline Himbert, W. Zac Stephens, Biljana Gigic, Tengda Lin, Jennifer Ose, Anjelica Ashworth, Christy Warby, David Nix, Jolanta Jedrzkiewicz, Anita R Peoples, Mary Bronner, Bartley Pickron, Courtney Scaife, Jessica N. Cohan, William M. Grady, Stacey A. Cohen, Mukta Krane, Petra Schrotz-King, Jane C. Figueiredo, Adetunji T. Toriola, Erin M. Siegel, Christopher I. Li, Alexis Ulrich, David Shibata, June L. Round, Lyen C. Huang, Martin Schneider, Sheetal Hardikar, Cornelia M Ulrich. Molecular mediators of the energy balance-colorectal cancer link: evaluating the gut microbiome and pro-inflammatory biomarkers. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P010.