Antibiotic‐mediated bacteriome depletion in Apc^Min/+ mice is associated with reduction in mucus‐producing goblet cells and increased colorectal cancer progression

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.

Fecal microbiota transplantation in cancer management: Current status and perspectives

“…Accumulating epidemiological evidence supports the opinion that long‐term antibiotic exposures, known to change the composition and decrease the diversity of gut microbiota, increase the risk of CRC, as well as gastric, pancreatic, lung, breast and prostate cancers . Consistent with this, long‐term antibiotic use was highly correlated with increased colorectal tumor progression in the Apc Min/+ mouse, a genetic model for human adenomatous polyposis . However, there is conflicting data about the association between antibiotics and risk of cancer.…”

Modulation of Anti-Tumour Immune Responses by Probiotic Bacteria

“…The detection of species linked with chronic inflammation is important, as this state exacerbates dysbiosis and leads to the accumulation of carcinogenic species [59,60]. In addition, epidemiological and experimental studies support the idea that reduced diversity due to the long-term use of antibiotics or diet increases the risk of CRC [61][62][63][64][65]. Interestingly, the administration of stools from CRC patients to germ-free mice and carcinogen-treated mice resulted in increased tumour formation and distinct pro-tumorigenic immune functions, as compared with stools from healthy individuals, indicating that altered fecal microbiota can promote cancer development [66].…”

Impact of Polypharmacy for Chronic Ailments in Colon Cancer Patients: A Review Focused on Drug Repurposing

“…Kaur et al [ 48 ] showed that long-term antibiotic use may cause depletion of the natural bacterial flora, leading to a reduced number of mucous-producing goblet cells. This can lead to chronic bowel inflammation, which is a crucial factor in tumour development and progression.…”