Mechanism of dietary indole-mediated attenuation Helicobacter-induced inflammation and colitis

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Project Summary/Abstract Inflammatory bowel disease (IBD) afflicts over one million Americans, causing considerable suffering and lost work time. The direct and indirect costs of IBD were estimated to be between $14.6 and $31.6 billion in 2014. Furthermore, IBD greatly increases the risk of developing colorectal cancer. Bacteria are now believed to be key players in both IBD and colorectal cancer. A number of Helicobacter species infect the human colon and are known to cause colitis and colon cancer in colitis-prone mouse strains. We have exciting data showing that H. muridarum exacerbates dextran sulfate sodium (DSS) induced colitis in wild-type mice. There are no studies on the immune response triggered by H. muridarum. Thus, this EHH species offers a unique experimental model to understand how colitis is triggered in an immunologically normal animal following a chemical insult. Recent studies have shown that dietary indoles, such as Indole-3-carbinol (I3C), derived from cruciferous vegetables, have a number of anti-inflammatory and anti-carcinogenic properties. Our preliminary studies showed that I3C attenuates H. muridarum+DSS-mediated exacerbation of colitis and inflammation in the colon. Furthermore, we noted that I3C treatment decreases the expression of miR-874, which targets FOXP3, and increases that of miR- 30b which targets for RORC (RORγt) as well as increases miR-5112 that targets IL-17. Based on these data, in the current study, we will test the central hypothesis that I3C attenuates colitis and inflammation induced by H. muridarum through alterations in the expression of miRs that promote a switch in T cell differentiation from Th17 to Tregs. The mechanisms of colitis exacerbation involving inflammation by H. muridarum are also not known. Thus, it is critical to understand the nature of immune response against Helicobacter species in IBD. To that end, we will simultaneously explore immunological and regulatory changes induced by these two agents. First, we will examine the T cell responses occurring during DSS-mediated colitis with and without H. muridarum infection and with and without I3C treatment. Our primary focus will be regulatory T cells (Treg), which are critical for intestinal homeostasis. Next, we will determine whether H. muridarum can trigger colitis in Aryl hydrocarbon receptor (AhR)-deficient mice which fail to generate enough Tregs and are more susceptible to colitis. These mice will also be used to test the efficacy of I3C, which has been known to act as an AhR ligand. Finally, we will determine whether specific microRNA species induced by I3C contribute to the Treg response by changing FoxP3 expression both in vitro and in vivo. Together, the insights gained from these experiments will be essential for understanding the mechanisms of action of I3C and could lead to additional highly targeted treatments. This project will not only characterize the nature of immune response triggered by H. muridarum during DSS-induced colitis but also test the mode of action of I3C on H. muridarum-associated colitis. These data will support future explorations to investigate the role of other Helicobacter species in clinical IBD and the potential use of I3C in the treatment of IBD.