Multiple Exposures to Antibiotics Affect Tumor Development in a Mouse Model of Early-Onset Colorectal Cancer
Niti Jani, Valerie Hinsch, Mia Joseph, Ryan Ball, Kenny Johnson, Vitali Sikirzzhytski, Varsha Gowda, Lydia Ebel, Shyam Ganesh Babu, Ibrahim Hasnie, Hannah Villanueva, Maredith Baird, Kristen Hogan, Lorne Hofseth, Jason Kubinak, Maria Marjorette O PeñaAbstract
Early-onset colorectal cancer (EOCRC), defined as colorectal cancer in individuals under 50 years old, is a growing global epidemic, with incidence and mortality rates steadily increasing over the past several decades. Although EOCRC has been linked to established colorectal cancer risk factors, its underlying causes remain poorly understood. We propose that EOCRC may result from exposure to environmental factors, collectively known as the exposome, that have increased globally across EOCRC birth cohorts. Based on our current knowledge of EOCRC, the use of antibiotics is a potential exposome that may increase the risk for EOCRC.
We hypothesized that exposure to antibiotics alters the gut microbiota resulting in dysbiosis that promotes inflammation in the distal colon and rectum, leading to increased risk of developing EOCRC. To test this, we examined the effects of repeated exposure to two commonly prescribed classes of pediatric antibiotics on gut microbiome composition, colonic inflammation, and tumor development following exposure to a carcinogen in a mouse model of EOCRC. A/J mice were subjected to multiple rounds of antibiotics followed by treatment with azoxymethane (AOM) to initiate tumor development, and assessment of colon tumor development. Antibiotic treatment induced dysbiosis and both local and systemic inflammation. Subsequent exposure to AOM showed that the two classes of antibiotics had different effects on tumor development in the distal colon and influenced the risk for EOCRC development in different ways.