Early life exposure to antibiotics and early onset colorectal cancer

Colorectal cancer (CRC) is the second leading cause of cancer related deaths in the United States and worldwide. Recently, the overall incidence of CRC has been decreasing presumably due to early screening and healthy lifestyles. However, CRC in individuals under 50 years old, known as early-onset colorectal cancer (EOCRC) , has been increasing at an alarming rate in the since the 1980s. It is a growing global epidemic with cases rising from 11% to 20 % between 1995 to 2019 and is expected to increase by 140% by 2030. The underlying causes and mechanisms as to why otherwise healthy young adults are susceptible is poorly understood. Based on our current knowledge of the disease, we hypothesized that EOCRC is caused exposure to exposomes that have been increasing globally in parallel with increases in EOCRC with each birth cohort; that impact the gut microbiome causing dysbiosis and inflammation in the distal colon and rectum, the anatomical site of EOCRC; and those that can affect humans at different development stages from conception to adulthood. Among the potential factors is the use of antibiotics, particularly in the early stages of life.In this study, we hypothesize that there are development windows of susceptibility wherein exposure to commonly prescribed pediatric antibiotics (beta-lactams or macrolides) can increase the risk of developing EOCRC. Using a mouse model of EOCRC, we defined corresponding developmental windows of susceptibility over an individual's lifetime. Here, we test if exposure to a single round of antibiotics at the perinatal and juvenile windows can impact risk of developing EOCRC. A/J mice at the perinatal stage were treated by gavage-feeding lactating dams who then passed the antibiotics to their offspring. After weaning, the offspring were treated with azoxymethane (AOM), a carcinogen, and tumor burden was determined after tumor outgrowth. Four-week-old mice were gavage-fed the antibiotics, exposed to AOM and tumor burden assessed as above. Our findings suggest that the impact of antibiotics on EOCRC risk was affected by exposure at specific developmental windows of susceptibility. Maternal antibiotic administration altered the gut microbiota in offspring which persisted over the long term. This effect was associated with changes in gut microbial structure and abundance, and an increase in pro-inflammatory bacterial strains, which correlated with elevated inflammation and tumor burden in offspring.