Abstract 3733: Increased risk of EOCRC after multiple exposures to antibiotics in A/J mice

Abstract Colorectal cancer (CRC) is the fourth most common cancer and the second leading cause of cancer-related deaths in the United States and globally. When diagnosed in individuals under 55 years of age, it is referred to as early onset colorectal cancer (EOCRC). EOCRC has been increasing in incidence and mortality since the 1990’s with an 11% to 20% increase from 1995 to 2019 and projected to rise by 140% by 2030. Although EOCRC has been associated with known risk factors for CRC, the exact causes and mechanisms remain unclear. Based on current knowledge, we propose that EOCRC may be driven by exposure to internal and external factors (collectively known as exposomes) that have been on the rise over the past four decades, potentially affecting the microbiome and leading to dysbiosis and inflammation in the distal colon and rectum. One significant contributing factor may be the use of antibiotics (Abx), especially in infants and young children. In this study, we hypothesized that early life exposure to Abx could lead to dysbiosis and inflammation in the distal colon and rectum, which in turn may cause increased mutations and epigenetic changes that promote development of EOCRC. To test this hypothesis, we investigated the impact of commonly prescribed pediatric Abx on the gut microbiota and inflammatory environment in the colon, and their potential role in tumor development when exposed to a carcinogen. A/J mice were treated with several rounds of Abx and then exposed to azoxymethane (AOM), a known carcinogen, to assess their effect on tumor formation. The results revealed that Abx exposure induced dysbiosis and inflammation in the colon, along with systemic inflammation in the treated mice. When AOM was introduced in the presence of Abx-induced dysbiosis, this led to increased tumor burden in the distal colon. These findings suggest that Abx may play a role in elevating the risk of EOCRC. Future studies are aimed at examining age-dependent effects of Abx on EOCRC risk and in combination with other common exposomes. Citation Format: Niti Jani, Maredith Richardson, Kristen Hogan, Maria M. Pena. Increased risk of EOCRC after multiple exposures to antibiotics in A/J mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3733.