The Bacteroides fragilis toxin gene is prevalent in the colon mucosa of colorectal cancer patients

Abstract

Background: Enterotoxigenic Bacteroides fragilis (ETBF) produces the Bacteroides fragilis toxin, which has been associated with acute diarrheal disease, inflammatory bowel disease, and colorectal cancer (CRC). ETBF induces colon carcinogenesis in experimental models. Previous human studies have demonstrated frequent asymptomatic fecal colonization with ETBF, but no study has investigated mucosal colonization that is expected to impact colon carcinogenesis.

Methods: We compared the presence of the bft gene in mucosal samples from colorectal neoplasia patients (cases, n = 49) to a control group undergoing outpatient colonoscopy for CRC screening or diagnostic workup (controls, n = 49). Single bacterial colonies isolated anaerobically from mucosal colon tissue were tested for the bft gene with touch-down polymerase chain reaction.

Results: The mucosa of cases was significantly more often bft-positive on left (85.7%) and right (91.7%) tumor and/or paired normal tissues compared with left and right control biopsies (53.1%; P = .033 and 55.5%; P = .04, respectively). Detection of bft was concordant in most paired mucosal samples from individual cases or controls (75% cases; 67% controls). There was a trend toward increased bft positivity in mucosa from late- vs early-stage CRC patients (100% vs 72.7%, respectively; P = .093). In contrast to ETBF diarrheal disease where bft-1 detection dominates, bft-2 was the most frequent toxin isotype identified in both cases and controls, whereas multiple bft isotypes were detected more frequently in cases (P ≤ .02).

Conclusions: The bft gene is associated with colorectal neoplasia, especially in late-stage CRC. Our results suggest that mucosal bft exposure is common and may be a risk factor for developing CRC.

Keywords: Bacteroides fragilis toxin; colorectal cancer; enterotoxigenic Bacteroides fragilis; mucosal microbiota.

Figure 1.

Case and control bft status. A, Overall, cases (n = 26; no antibiotics) were more often bft-positive than controls (n = 49; P = .054). bft positivity was present significantly more often in both left- and right-sided colorectal neoplasia cases compared with left and right colon biopsies from controls (Fisher exact test, P = .033 and P = .040, respectively). B, Patients with colorectal cancer (CRC) (n = 23; no antibiotics) were stratified by tumor stage (early, stage I/II; and late, stage III/IV). All 12 late-stage CRC patients (100%) were bft-positive compared with 67.3% of all controls and 71.1% of controls without adenomas (Fisher exact test, P = .026 and P = .046, respectively). Cases with adenomas were excluded from this analysis.