Mechanisms and Therapeutic Implications of the Pregnane X Receptor Targeting Indole Bacterial Metabolites in Inflammatory Bowel Disease
Abstract
This proposal addresses a significant medical problem, namely, infection-triggered inflammation in the intestines (technically called post-infectious inflammatory bowel disease [IBD]) in military personnel. This problem is especially problematic when military personnel are called on active duty and while serving overseas. The magnitude of this ailment has prompted a new consideration by the Department of Defense on the impact of infectious diarrhea during deployment -- that is to develop preventative strategies to reduce the risk of infection and its health complications in military personnel. A serious issue undermining the current strategies (e.g., vaccines, antibiotic prophylaxis) is that over time these infectious agents (e.g., bacteria) do mutate or develop drug resistance, having then to develop newer agents continuously. Our strategy involves focusing on understanding the basic science that leads to uncontrolled inflammation after someone is exposed to a bacterial infection (usually termed a pathogen). Based on published evidence and our own published results, we believe that a very subtle loss of how our intestinal cells are able to sense a “normal” intestinal environment (i.e., the bacteria that live inside us) leads to a loss in protection from the environment (called loss in barrier integrity or function), which then leads to chronic inflammation. Stresses (e.g., intestinal infection) produced during this period can highly exaggerate inflammation in the intestines, which in some individuals who are prone to get spontaneous intestinal inflammation, will lead to IBD. Specifically, we show that there is a direct link between production of indole and its metabolites by intestinal bacteria with maintaining a “sealed” intestine (no leakiness) through a specific pathway involving cell receptors PXR and TLR4. If there is adequate indole production or PXR/TLR4 signaling is intact, the mice are healthy and without inflammation. Loss of indole and/or PXR signals leads to inflammation. In this project, we will test whether indoles (and their metabolites, specifically indole 3 propionic acid) and/or PXR play an important role in disrupting intestinal leakiness during an infection-induced human-like inflammation of the colon in mice. Based on our preliminary data, there is a strong likelihood that bacterial metabolites and PXR would be important in infection-induced colon inflammation in mice and to show this effect, we will engineer mice to have a loss of the PXR only in specific cell types in the intestines. These mice will then be allowed to gain inflammation through infection with a bacterium, and we will study all aspects of the mouse intestinal immunology and define the role of PXR in infection-induced inflammation. Finally, we propose a very novel idea in which we will test small molecules that mimic (behave like) indoles, but these molecules are safe and more potent PXR activators. We call this “bacterial metabolite mimicry” and propose that this method will allow us to build safer more effective PXR based treatments for IBD. Towards this goal, we will test two new molecules that we have discovered with this property, FKK999 and FKK5, in PXR activation assays using cell lines and mice. Eventually, we will test for the ability of FKK999 and FKK5 in protecting against infection-induced intestinal inflammation in genetically altered mice carrying the human PXR receptor. These studies will inform the eventual discovery of novel potent small molecules that could potentially mimic how these bacterial metabolites bind and activate PXR, thus paving a whole new generation of treatments for post-infectious IBD. Together, these studies directly address the Peer Reviewed Medical Research Program Focus Area: “Mechanistic studies in animal models designed to understand how enteric infection may trigger IBD, including genomic, microbiomic, and immune mechanisms.” The proposed studies will also potentially lead to
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710479
Entities
People
- Sridhar Mani
Organizations
- Albert Einstein College of Medicine
- United States Army