Male-Dependent Promotion of Colitis in 129 Rag2-/- Mice Co-Infected with Helicobacter pylori and Helicobacter hepaticus.

Zhongming Ge,Lili Ge,Yan Feng,Sureshkumar Muthupalani,James G Fox

doi:10.3390/ijms21238886

Abstract

The prevalence of gastric Helicobacter pylori (Hp) infection is ~50% of the world population. However, how Hp infection influences inflammatory bowel disease in humans is not fully defined. In this study, we examined whether co-infection with Hp influenced Helicobacter hepaticus (Hh)–induced intestinal pathology in Rag2−/− mice. Rag2−/− mice of both sexes were infected with Hh, of which a subgroup was followed by infection with Hp two weeks later. Co-infected males, but not females, had significantly higher total colitis index scores in the colon at both 10 and 21 weeks post-Hh infection (WPI) and developed more severe dysplasia at 21 WPI compared with mono-Hh males. There were no significant differences in colonization levels of gastric Hp and colonic Hh between sexes or time-points. In addition, mRNA levels of colonic Il-1β, Ifnγ, Tnfα, Il-17A, Il-17F, Il-18, and Il-23, which play important roles in the development and function of proinflammatory innate lymphoid cell groups 1 and 3, were significantly up-regulated in the dually infected males compared with mono-Hh males at 21 WPI. These data suggest that concomitant Hp infection enhances the inflammatory responses in the colon of-Hh-infected Rag2−/− males, which results in more severe colitis and dysplasia.

Highlights

Helicobacter pylori (Hp) is an important human pathogen that colonizes the stomach
The increased severity of colonic pathology in Helicobacter hepaticus (Hh)+Hp male mice was not related to colonization levels of cecal or colonic Hh or levels of gastric Hp, but instead was associated with enhanced expression of the colonic cytokines including Il-18, Il-23, Il-17, Ifnγ, Il-1β, and Tnfα at 21 weeks post-Hh infection (WPI), all of which play important roles in the development and function of proinflammatory innate lymphoid cell (ILC) 1/natural killer (NK) and 3 [18,21]
More severe colonic pathology in the Hh+Hp males when compared to their mono-Hh counterparts was coupled with significant transcriptional up-regulation of colonic Il-18 (ILC1s) and Il23/Il-1β (IlC3s) but not Il-13 (ILC2s), indicating that co-Hp infection promotes male-dependent Hh induced colonic pathology, likely driven by enhancing the function of ILC1s and ILC3s [18]

Summary

Introduction

Helicobacter pylori (Hp) is an important human pathogen that colonizes the stomach. Despite vigorous efforts to eradicate this bacterium with antibiotic treatments for the past 3 decades, the prevalence of Hp remains high; approximately 17% in developed countries to 85% in some developing countries [1]. Epidemiological findings indicate that Hp infection is associated with the increased risk of the development of colorectal cancer (CRC) [3]. Some epidemiological data suggest that Hp infection is protective in the development of inflammatory bowel disease (IBD) in humans [5]. Such associations were further supported by murine models of gastric Hp infection in which prior Hp infection in female C57BL/6 mice attenuated Salmonella typhimurium enteritis or dextran sodium sulphate-induced colitis [6,7]. Effects of Hp infection and the underlying mechanisms on the development of IBD and CRC still remains unclear

Methods

Results

Conclusion