Abstract
Recent epidemiological evidence suggests that exposure to antibiotics in early‐to‐middle adulthood is associated with an increased risk of colorectal adenoma. However, mechanistic studies in established preclinical cancer to examine these claims are extremely limited. Therefore, we investigated the effect of long‐term exposure of an antibiotic cocktail composed of Vancomycin, Neomycin, and Streptomycin, on tumor development and progression in the Apc Min/+ mouse, an established genetic model for familial adenomatous polyposis. Clinical pathologies related to tumor development as well as intestinal and colon tissue histopathology were studied at ages 8, 12, and 16 weeks of age, which correspond to the approximate ages of development of neoplasia, gut inflammation with polyposis, and cancer progression, respectively, in this animal model. We show that the antibiotics significantly increase the severity of clinical symptoms, including effects on intestinal histology and goblet cell numbers. In addition, they promote small intestinal polyposis. Finally, metagenomic analysis of fecal samples demonstrated that antibiotic exposure is associated with a significant but nonuniform depletion of the animal's natural gut flora. Overall, these findings support the premise that long‐term antibiotic exposure mediates the selected depletion of gut microbial communities and the concomitant thinning of the protective mucus layer, resulting in an increase in tumor development.
Highlights
The gut microbiome is integral to gastrointestinal tract function and is connected to a variety of health issues [1,2,3]
The functional link between gut microbial dysbiosis and colorectal cancer is supported by preclinical studies with animal models [18,19,20,21] and by clinical investigations with patients predisposed to colorectal cancer [22,23,24,25,26]
We emphasize that the significance of our findings expands beyond colorectal cancer, as a number of recent studies have shown that disruption of the innate microbiota by low-dose antibiotic exposures, even if limited to transient perturbations early in life, can have long-term metabolic alterations and affect ileal expression of genes involved in immunity [59]
Summary
The gut microbiome is integral to gastrointestinal tract function and is connected to a variety of health issues [1,2,3]. The functional link between gut microbial dysbiosis and colorectal cancer is supported by preclinical studies with animal models [18,19,20,21] and by clinical investigations with patients predisposed to colorectal cancer [22,23,24,25,26]. The significant increase in the use of antibiotics among adults and children in the United States [27,28,29,30,31] is a public health concern. Accumulating evidence supports the notion that long-term antibiotic exposure alters the functional capacity of the gut microbiota [32, 33] resulting in an increased risk of chronic gut diseases such as inflammatory bowel disease [34] and celiac disease [35] as well as activation of the biological mechanisms that initiate or promote colorectal carcinogenesis [36]
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