Abstract 5299: Impact of gut microbial metabolites on colon epithelium
Authors: Bhasin Nobel , Senavirathna Lakmini Herath , Bresson Madeline , Zhe Lyu , Poplaski Victoria B. , Lami Zahraa A. , Brentnall Teresa A. , Opekun Antone R. , Valentine John F. , Britton Britton A. , Sheng Pan , Chen Ru 
Published: June 2023

Abstract
Inflammatory bowel disease (IBD) is a major risk factor for colorectal cancer (CRC) development. Dysbiosis of the gut microbiome has been implicated in the pathogenesis of IBD and CRC. The gut microbiome and its interaction with the colon may play a significant role in enabling tumor permissive state in an inflammatory environment. However, the functional impact of colon microbiome on epithelial cells that enables neoplastic transformation under inflammatory condition is not clear. This study seeks to examine the impact of mucosa-adherent microbiota on colon epithelial cells. We used in vitro mini-bioreactor arrays to cultivate mucosa-adherent microbiota from colon biopsies, including biopsies from IBD patients with dysplasia (progressors) and without dysplasia (non-progressors). Paired dysplastic and non-dysplastic tissue from progressors was included in the study. HCT116 cells were exposed to the metabolites derived from the cultivation of microbial communities. Cell lysate and secretome were collected after the treatment of microbial metabolites and analyzed by LC-MS/MS. The differentially expressed proteins were identified using Limma. Over-representation analysis was performed using Reactome in Grofiler. Pathways relating to cell division, mitosis and cell proliferation were enriched in cells treated with microbiome metabolites from progressors. Pathways reflecting a proliferative phenotype were also found enriched in the cell secretomes after treatment with microbiome metabolites from progressors. We functionally verified the proliferative phenotype in cells using BRDU incorporation assay. Microbial metabolites from non-dysplastic biopsy from progressor showed significantly higher cell proliferation compared to non-dysplastic biopsy from non-progressors (p&lt;0.05). Furthermore, microbial metabolites from dysplastic tissue showed a significantly higher proliferation compared to non-dysplastic tissue from the same patient (p&lt;0.01) and patients without dysplasia (p&lt;0.0001). A significantly higher degree of DNA damage was induced by microbial metabolites derived from IBD progressors than non-progressors (p&lt;0.05). Together, our findings suggest that microbial metabolites in the dysplastic tissue alter the colon microenvironment to induce higher cellular proliferation and DNA damage, which may contribute to colon neoplastic progression in the IBD patients.
Citation Format: Nobel Bhasin, Lakmini Herath Senavirathna, Madeline Bresson, Lyu Zhe, Victoria B. Poplaski, Zahraa A. Lami, Teresa A. Brentnall, Antone R. Opekun, John F. Valentine, Britton A. Britton, Pan Sheng, Ru Chen. Impact of gut microbial metabolites on colon epithelium. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5299.