Induction of Persistent Colitis by a Human Commensal, Enterotoxigenic Bacteroides fragilis , in Wild-Type C57BL/6 Mice

Abstract

Enterotoxigenic Bacteroides fragilis (ETBF) causes diarrhea and is implicated in inflammatory bowel diseases and colorectal cancer. The only known ETBF virulence factor is the Bacteroides fragilis toxin (BFT), which induces E-cadherin cleavage, interleukin-8 secretion, and epithelial cell proliferation. A murine model for ETBF has not been characterized. Specific pathogen-free (SPF) C57BL/6J or germfree 129S6/SvEv mice were orally inoculated with wild-type ETBF (WT-ETBF) strains, a nontoxigenic WT strain of B. fragilis (WT-NTBF), WT-NTBF overexpressing bft (rETBF), or WT-NTBF overexpressing a biologically inactive mutated bft (rNTBF). In SPF and germfree mice, ETBF caused colitis but was lethal only in germfree mice. Colonic histopathology demonstrated mucosal thickening with inflammatory cell infiltration, crypt abscesses, and epithelial cell exfoliation, erosion, and ulceration. SPF mice colonized with rETBF mimicked WT-ETBF, whereas rNTBF caused no histopathology. Intestinal epithelial E-cadherin was rapidly cleaved in vivo in WT-ETBF-colonized mice and in vitro in intestinal tissues cultured with purified BFT. ETBF mice colonized for 16 months exhibited persistent colitis. BFT did not directly induce lymphocyte proliferation, dendritic cell stimulation, or Toll-like receptor activation. In conclusion, WT-ETBF induced acute then persistent colitis in SPF mice and rapidly lethal colitis in WT germfree mice. Our data support the hypothesis that chronic colonization with the human commensal ETBF can induce persistent, subclinical colitis in humans.

Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis -induced colon tumorigenesis

“…In addition, inhibition of SMO by MDL 72527 in ETBF-infected mice was shown to (i) reduce chronic intestinal inflammation and proliferation; (ii) decrease the chronic up-regulation of cytokines associated with the Th17 immune response; and, most importantly, (iii) significantly inhibit colon tumorigenesis in Min mice. The results of these studies are particularly intriguing because, in contrast to other published models of intestinal carcinogenesis that rely on chemical irritants, mutagens, and/or immunocompromised mice, the ETBF model used for these experiments incorporates a genetic defect, a bacterial pathogen, and disease physiology that have direct importance in and therefore should be more applicable to human intestinal inflammation and colorectal cancer (12,13,16).…”

“…Recent studies have demonstrated that ETBF infection alone is necessary and sufficient to induce acute and persistent colitis in wild-type C57BL/6 mice (12,13). On the basis of these results, Wu and colleagues (14) studied the effect of ETBF on tumor formation in multiple intestinal neoplasia (Min) mice.…”

The Roles of MicroRNAs in the Cancer Invasion-Metastasis Cascade

“…miR-126 expression is often downregulated in cancers and is able to decrease leukocyte and possibly cancer cell adherence to endothelial cells by targeting VCAM-1 on endothelial cells [83]. Additionally, a number of miRNAs have been discovered to play critical roles in modulation of T and B lymphocytes activation, innate and adaptive immune responses [96,97]. For example, miR-155 is required in conventional and regulatory T lymphocyte differentiation/activation, B lymphocyte development, mac-rophage response and toll-like receptors (TLR) response through targeting suppressor of cytokine signaling 1 (SOCS1), activation-induced cytidine deaminase (AID) and transcription factor c-Maf [96][97][98].…”

“…Additionally, a number of miRNAs have been discovered to play critical roles in modulation of T and B lymphocytes activation, innate and adaptive immune responses [96,97]. For example, miR-155 is required in conventional and regulatory T lymphocyte differentiation/activation, B lymphocyte development, mac-rophage response and toll-like receptors (TLR) response through targeting suppressor of cytokine signaling 1 (SOCS1), activation-induced cytidine deaminase (AID) and transcription factor c-Maf [96][97][98]. miR-223 is found to have crucial roles in regulating granulocyte proliferation and activation by regulating myeloid ELF-1-like factor (Mef2c) [99].…”

“…Cancer suppressing miR-146a can regulate TLR and cytokine signaling through a negative feedback regulation of TNF receptor-associated factor 6 (TRAF6) and IL-1 receptor-associated kinase 1 (IRAK1) genes [100]. miR-181, miR-17∼92 cluster and miR-150 are important regulators of the immune system and therefore could participate in cell survival and arrest in circulation [96,97].…”