Abstract
It has been well documented that cytolethal distending toxin (CDT) from Helicobacter hepaticus (H. hepaticus), Campylobacter jejuni (C. jejuni) and other Gram-negative intestinal pathogens is linked to the inflammatory bowel disease (IBD). However, the mechanisms underlying the progression of H. hepaticus induced colitis remains unclear. In this study, male B6.129P2-IL10tm1Cgn/J mice were infected by H. hepaticus and ΔCdtB H. hepaticus for 6, 12, 18, and 24 weeks. Histopathology, H. hepaticus colonization levels, expression of inflammatory cytokines, signaling pathways, and content of NO in proximal colon were examined. We found that Cytolethal distending toxin subunit B (CdtB) deletion had no influence on colonization ability of H. hepaticus in colon of B6.129P2-IL10tm1cgn /J mice, and there was no significant difference in abundance of colonic H. hepaticus over infection duration. H. hepaticus aggravated rectocele and proximal colonic inflammation, especially at 24 WPI, while ΔCdtB H. hepaticus could not cause significant symptom. Furthermore, mRNA levels of Il-6, Tnf-α, Il-1β, and iNOS significantly increased in the proximal colon of H. hepaticus-infected mice compared to ΔCdtB H. hepaticus infected group from 12 WPI to 24 WPI. In addition, the elevated content of NO and activated Stat3 and Jak2 in colon were observed in H. hepaticus infected mice. These data demonstrated that CdtB promote colitis development in male B6.129P2-IL10tm1Cgn/J mice by induction of inflammatory response and activation of Jak-Stat signaling pathway.
Highlights
Helicobacter hepaticus (H. hepaticus) belongs to Proteobacteria, ε-proteobacteria, Heliobacterium
We examined the abundance of wild type H. hepaticus and Cytolethal distending toxin subunit B (CdtB) mutant H. hepaticus in B6.129P2-IL10tm1Cgn/J mice of this study
H. hepaticus and DCdtB H. hepaticus could be able to colonize in the colon of Il10−/− mice over the infection time (Figure 1), and there was no significant difference between H. hepaticus and DCdtB H. hepaticus colonization levels
Summary
Helicobacter hepaticus (H. hepaticus) belongs to Proteobacteria, ε-proteobacteria, Heliobacterium. H. hepaticus, the prototype of human enterohepatic helicobacters, infection is characterized by colitis (Xu et al, 2018), and induce colon cancer (Falsafi and Mahboubi, 2013) in susceptible mice strains. H. hepaticus can cause IBD in IL-10 deficient mice, but is an enteric symbiotic bacterium in wild-type C57/BL6 mice. These results may be caused by the secretion of a high level anti-inflammatory cytokine by macrophages, which were activated by large polysaccharide secreted from H. hepaticus (Danne et al, 2017). There are contrary studies pointing out that H. hepaticus does not induce or potentiate colitis in IL10 deficient Mice (Dieleman et al, 2000). The mechanism of H. hepaticus inducing to inflammatory bowel disease is complicated, which needs to be further explored
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