Enterotoxigenic Bacteroides fragilis infection exacerbates tumorigenesis in AOM/DSS mouse model

Abstract

The azoxymethane (AOM)/dextran sulfate sodium (DSS) murine model is commonly used to study colitis-associated cancer. The human commensal bacterium, enterotoxigenic Bacteroides fragilis (ETBF) secretes the Bacteroides fragilis toxin (BFT) which is necessary and sufficient to cause colitis. We report that BALB/c mice infected with WT-ETBF and administered three cycles of AOM/DSS developed numerous, large-sized polyps predominantly in the colorectal region. In addition, AOM/DSS-treated BALB/c mice orally inoculated with wild-type nontoxigenic Bacteroides fragilis (WT-NTBF) overexpressing bft (rETBF) developed numerous polyps whereas mice infected with WT-NTBF overexpressing a biologically inactive bft (rNTBF) did not promote polyp formation. Unexpectedly, the combination of AOM+ETBF did not induce polyp formation whereas ETBF+DSS did induce polyp development in a subset of BALB/c mice. In conclusion, WT-ETBF promoted polyp development in AOM/DSS murine model with increased colitis in BALB/c mice. The model described herein provides an experimental platform for understanding ETBF-induced colonic tumorigenesis and studying colorectal cancer in wild-type mice.

Protective Effects of Zerumbone on Colonic Tumorigenesis in Enterotoxigenic Bacteroides fragilis (ETBF)-Colonized AOM/DSS BALB/c Mice

“…Specifically, the proportion of polyps in the 2-4 mm 2 size range was decreased in ETBF-colonized AOM/DSS group administered with zerumbone (30 and 60 mg/kg; Figure 2C). As previously reported, ETBF infection promotes AOM/DSS-mediated tumorigenesis as well as enhanced colon inflammation, decreased colon length and increased colon weight/colon length ratio [16]. Consistent with the observation, we also found a decrease in colon length and increase in colon weight/colon length ratio in ETBF/AOM/DSS mice ( Figure 2D,E).…”

“…Previously, we demonstrated that ETBF infection promoted AOM/DSS-induced tumorigenesis in BALB/c mice with increased serum cytokines related to Th17 immune response [16]. However, there exist no clinical or animal studies investigating the potential natural products to prevent ETBF-promoted colonic tumorigenesis.…”

“…In the ETBF/AOM/DSS model, mice exhibited an aggravated pathology manifested by colitis in association with body weight loss and clinical symptoms such as ruffled fur, lethargy and bloody diarrhea [16]. To assess the chemopreventive effect of zerumbone on the ETBF-mediated CRC, BALB/c mice were injected with AOM (10 mg/kg) once and provided with distilled water containing clindamycin and gentamicin 2 days later for a total of 12 days ( Figure 1A).…”

“…Additionally, we have demonstrated that ETBF infection also promotes azoxymethane (AOM)/dextran sulfate sodium (DSS)-mediated colitis-associated cancer in wild-type mice [16]. ETBF infection in AOM/DSS-treated mice demonstrates the rapid formation of high-grade adenomas in the distal colon [16].…”

Quorum Sensing System in Bacteroides thetaiotaomicron Strain Identified by Genome Sequence Analysis

“…This widespread but highly variable ability to form biofilms is observed in many aerobic bacteria, including Escherichia coli , 33 Staphylococcus epidermidis , 34 and Bacteroides fragilis , which also show a variable biofilm formation capacity caused by sigma factor RpoQ. 35 Biofilm formation by pathogenic bacteria is a major cause of chronic and recurring infections. The pathogenicity and abscess formation of B. fragilis are associated with the biofilm and adhesion to the peritoneal epithelium.…”