Dextran Sulfate Sodium Colitis Facilitates Colonization with Shiga Toxin-Producing Escherichia coli: a Novel Murine Model for the Study of Shiga Toxicosis

Abstract

Shiga toxin-producing (STEC) are globally important gastrointestinal pathogens causing hemorrhagic gastroenteritis with variable progression to potentially fatal Shiga toxicosis. Little is known about potential effects ofderived Shiga-like toxins on host gastrointestinal immune responses during infection in part due to lack of a reproducible, immunocompetent animal model of STEC infection without depleting the commensal microbiota.Here we describe a novel and reproducible murine model utilizing dextran sulfate sodium (DSS) colitis to induce susceptibility to colonization with clinical isolate STEC strains. After exposure to DSS and subsequent oral STEC challenge, all mice were colonized and 66% of STEC-infected mice required early euthanasia. Morbidity during STEC infection, but not with an isogenic toxin-deleted STEC mutant, was associated with increased renal transcripts of injury markers and, histological evidence of renal tubular injury, and increased renal and inflammatory transcripts.Interestingly, the intestinal burden of Shiga toxin-producing STEC during infection was increased compared to its isogenic Shiga toxin deletion strain. Increased bacterial burdens during Shiga toxin production coincided with decreased induction of colonic IL-23 axis transcripts known to be critical for clearance of similar gastrointestinal pathogens in mice, suggesting a previously undescribed role for STEC Shiga toxins in suppressing host immune responses during STEC infection and survival. The DSS+STEC model establishes infection with clinical isolate strains of STEC in immune-competent mice without depleting the gastrointestinal microbiota, enabling characterization of the effects of STXs on the IL-23 axis and other gastrointestinal pathogen-host interactions.

Preventive Effects of Pyungwi-san against Dextran Sulfate Sodium- and Clostridium difficile-Induced Inflammatory Bowel Disease in Mice

“…Several reports have revealed that the relative abundance of E. coli increases as a result of inflammation of the intestinal tract [73][74][75][76]. Furthermore, DSS treatment was shown to promote colonization with Shiga toxin-producing E. coli [77]. Notably, in our study, the relative abundance of E. coli was observed to be lower in the DSS + CD + PWS group than in both the DSS and DSS + CD groups.…”

Effects of phage variation on Shiga toxin 2 (Stx2) production and the virulence of Stx-producingEscherichia coli

“…6B; note that this was also the case for the 112648 strain and its mutants). Then, using germ-free mice treated with dextran sulfate sodium (DSS), which induces colitis [40], we evaluated the virulence of the WT 12E129 strain and its mutants carrying either CI-4 or CI-5 L-Stx2a phage. A 12E129 mutant lacking both phages was also generated and used as a negative control after confirming that it produced no Stx2 (dKO in Figs.…”

Escherichia coli Shiga Toxins and Gut Microbiota Interactions

“…Mice that were fed a high fiber diet (HFD) exhibited a decrease in native Escherichia species and increased colonization of STEC, weight loss, and mortality compared with mice that were fed a low fiber diet (LFD) [45]. A colitis murine model generated using dextran sulfate sodium similarly had an increased risk of STEC infection [46]. These reports indicate that the robustness of the gut microbiota plays an important role in the defense against STEC infection (Figure 2).…”