Helicobacter pylori colonizes the gastric mucosa of more than half of the world's population. Approximately 10-15% of the infected individuals will go on to develop gastroduodenal ulcers and <3% will develop gastric cancer. Universal vaccination has been proposed and yet the impact of eradicating H. pylori in the 85-90% of otherwise asymptomatic individuals has not been emphasized. One potential negative impact is the possible protective role of H. pylori against the development of inflammatory bowel disease (IBD), a chronic debilitating inflammatory condition of the gastrointestinal tract resulting from a dysregulation of host immune response to resident gut microbes. The broad long-term objective of this proposal is to elucidate the mechanisms of how H. pylori may aid in the prevention of IBD. Several reports indicated lower risk of IBD in patients infected with H. pylori and noted a rising incidence of IBD in regions endemic for H. pylori infection. The mechanism of this association, which is important for defining a causal relationship between H. pylori eradication and increased risk of IBD, is currently unknown. The central hypothesis behind the proposed research is that H. pylori colonization induces regulatory T cells (Tregs) by maintaining toleragenic phenotype of myeloid dendritic cells (DCs) thus decreases host susceptibility to the development of IBD. The rationale for this hypothesis is based on the following observations. First, patients with H. pylori infection were found to have higher Treg response than uninfected individuals. Depletion of Tregs reversed the immunosuppression on memory T cells in those infected with H. pylori. Second, Tregs were shown to play a role in suppressing colitis in mice. Third, our preliminary results show that in vitro, H. pylori maintains the toleragenic phenotype of semi-mature DCs and that, in vivo, H. pylori-pulsed myeloid DCs induce H. pylori-specific Tregs. Thus, the overall goal of this proposal is to examine the role of H. pylori infection in modulating IBD susceptibility.
Specific Aims : 1. Study the mechanism of how H. pylori maintains DC toleragenic phenotype. 1.1. To study the role of H. pylori factors (PAI, CagA, VacA) in the maintenance of DC tolerance using knockout strains of H. pylori. C57BL/6 bone marrow-derived DCs will be cocultured with H. pylori mutant strains and TGF-2 production and Tregs induction will be compared. 1.2. To examine the role of TLR-2 signaling and IRAK-M. Using TLR-2 null or IRAK-M siRNA to assess the role of these two pathways in H. pylori-induced DC tolerance. 2. To study the impact of H. pylori-induced Tregs on mouse susceptibility to chronic dextran sulfate sodium (DSS)-colitis. 2.1. To demonstrate the presence of extragastric H. pylori-specific Tregs response induced by H. pylori (oral gavaged H. pylori versus H. pylori-pulsed DC transfer plus oral H. pylori). Mice will be adoptively transferred with PBS-treated DCs or H. pylori-pulsed DCs followed by H. pylori infection. The presence of extragastric H. pylori-specific Tregs will be assessed. 2.2. To study the effect of H. pylori Treg induction on chronic DSS colitis. Mice adoptively transferred with PBS-treated DCs or H. pylori-pulsed DCs followed by H. pylori infection will be treated with DSS to induce chronic colitis. The degree of colitis will be compared to determine the effect of H. pylori-specific Tregs on host susceptibility to colitis. The health relatedness of the project is to understand the impact of H. pylori eradication on the host susceptibility to IBD. The completion of this project will also offer a potential mechanism through which beneficial bacteria (e.g., probiotics) may help to prevent IBD flares. Helicobacter pylori colonizes the gastric mucosa of more than half of the world's population. Approximately 10-15% of the infected individuals will go on to develop gastroduodenal ulcers and <3% will develop gastric cancer. Universal vaccination has been proposed and yet the impact of eradicating H. pylori in the 85-90% of otherwise asymptomatic individuals has not been emphasized. Several reports indicated lower risk of Inflammatory bowel disease (IBD) in patients infected with H. pylori and noted a rising incidence of IBD in regions endemic for H. pylori infection. The mechanism of this association, which is important for defining a causal relationship between H. pylori eradication and increased risk of IBD, is currently unknown. The goals of this proposal are to study how H. pylori may influence the immune system of an individual by inducing suppressive T cells in the host and to show in an animal model of colitis, how H. pylori infection may protect against IBD. The health relatedness of the project is to understand the impact of H. pylori eradication on the host susceptibility to IBD. The completion of this project will also offer a potential mechanism through which beneficial bacteria (e.g., probiotics) may help to prevent IBD flares.
