Drugs from Bugs: Developing New Inflammatory Bowel Disease Drugs from Gut Bacteria-Derived Bioactives
Abstract
Rationale: Inflammatory bowel disease (IBD) is a chronic disease, often diagnosed in otherwise healthy people in their twenties and thirties. The symptoms of IBD are painful, debilitating, and embarrassing. IBD is a medical bar to joining the military, and the unpredictability of symptoms can prevent patients from having active service roles. IBD is a priority area for the military as several factors associated with military service can increase the chances of developing this disease. These include intensive training, previous gut infections, and psychological stress – all of which regularly occur in military service. Current treatments for IBD are only effective in ~50% of people, with nearly 25% of patients requiring bowel surgery. In addition, side effects from these medications can pose significant additional burdens on patients. Clearly, there is a need for more effective therapies to control this devastating disease. The bacteria that live in the gut play a crucial role in gut inflammation and the development of IBD in particular. We know now that people with IBD have a different collection of bacteria than healthy people. This is important as the bacteria produce many substances that can prevent or drive the development of IBD. While previous studies have catalogued the changes in the collection of bacteria that is associated with diseases, we still don’t know how these bacteria drive disease. Relation to Discovery Award: In our previous successful Discovery Award project, we hypothesized that stool from healthy people contained bacteria that actively produce anti-inflammatory substances that promote gut health and protect against the inflammation underlying IBD. We screened healthy stool samples and found at least three different bacterial strains that produce chemical compounds that were anti-inflammatory in our laboratory-based tests. When we tested the products from one of these bacteria in an animal model of IBD, we found that it could reduce symptoms and decreased gut inflammation. We went on to purify and identify the likely chemical structure of this substance, which could be synthesized in the lab. Aims of Expansion Award: In this Expansion Award project, we will directly continue the work of our Discovery Award project to find out if the chemicals produced by these three bacteria would be good drug candidates to treat IBD. To do this, we will experiment with small alterations to the structure of the chemicals and determine how this effects their potency. We will test these chemicals in animal models of IBD to find out if they last long enough to be effective, and whether they induce any side effects. We will also learn specifically how these chemicals act to decrease inflammation, since this could lead to even better anti-inflammatory properties. Finally, we will perform experiments that will tell us if these chemicals change the growth or composition of the gut bacteria to either a less or more inflammatory composition, and if gut bacteria alter the chemicals’ structure to make them more or less effective. At the end of these studies, we will have developed three new potential drug candidates that can be taken into early-stage human trials of IBD. Topic Area Addressed: This project spans two priority areas of research. It leverages the microbiome and their metabolites to develop new treatments for IBD, and it specifically examines how the new treatments target epithelial function. Patient Impact: Current therapies for IBD patients don’t work for everyone, are often expensive (including biologics), or have toxic side effects (e.g., steroids), meaning that they can only be taken for a short time. Thus, there is a real need for new therapies that can overcome these limitations. As the three different types of bacteria we isolated were from a healthy person, we expect this will mean that any chemicals derived from them are fairly non-toxic. The long-term (5-10 year) potential clinical applicat
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110481
Entities
People
- Jakob Begun
Organizations
- United States Army