The influence of gut microbiota dysbiosis to the efficacy of 5-Fluorouracil treatment on colorectal cancer

Abstract

Colorectal cancer is one of the most frequently diagnosed cancers worldwide. Gut flora can modulate the host response to chemotherapeutic drugs. However, the understanding regarding the relationship between the gut microbiota and the antitumor efficacy of 5- Fluorouracil (5-FU) treatment is limited. Therefore, we compared the tumor size and profiled the gut microbiota of mice treated with 5-FU, combined with probiotics or ABX (an antibiotic cocktail of antibiotics) by using the Colorectal Cancer (CRC) mouse model and high-throughput sequencing. The results elucidated that ABX administration diminished the antitumor efficacy of 5-FU in mice and supplementation of probiotics upon 5-FU treatment could not significantly increase the efficacy of 5-FU treatment, despite improving mice body weight at day 33. There were significant differences in fecal bacteria community among the four groups (ANOSIM p < 0.05). ABX administration reduced microbiota biodiversity and altered microbiota community. The pathogenic bacteria included Escherichia shigella and Enterobacter significantly increased, while other commensal bacterial decreased unidentified Firmicutes increased and the opportunistic pathogens decreased after the administration of Probiotics. In addition, 5-FU treatment also changed the diversity and the community composition of the gut mirobiota. The relative abundance of genus Lachnospiracea_NK4 A136, Bacteroides, Odoribacter, Mucispirillum, and Blautia were significantly increased compared to the control group. Additionally, functional capacity analysis of gut microbiota using PICRUSt showed that genes involved in amino acid metabolism, replication and repair translation, nucleotide metabolism expressed much lower in FU.ABX group than the other groups. The current results suggest that ABX administration disrupted the gut microbiota in mice, which contributed to the reduction of antitumor efficacy of 5-FU.

Keywords: 16S rRNA gene; 5-Fluorouracil; Antibiotics; Antitumor efficacy; Gut flora; Probiotics.