Invention of a Genetic Toolkit for Immunomodulatory Gut Bacteria to Expedite the Development of New Crohn s Disease Therapeutics
Abstract
This proposed project addresses the Fiscal Year 2016 Peer Reviewed Medical Research Program Topic Area of Inflammatory Bowel Disease, with particular emphasis on the Area of Encouragement "Research on the influence of the microbiome on IBD." Crohn s disease (CD) is a chronic disease that is characterized by episodic and disabling inflammation of the gastrointestinal tract in genetically susceptible individuals. The incidence of CD has a peak in early adulthood (circa 14-30 years), with a second peak in later life (circa 60-80 years), and the disease can affect anywhere along the length of the gastrointestinal tract from mouth to anus, although it most commonly affects the terminal ileum and/or proximal colon. There is no cure for CD, and the current therapeutic strategies aim to decrease the frequency and severity of inflammatory episodes in an effort to prevent progression of bowel damage and avoid disabling disease with the need for surgery. Nonetheless, long-term treatment typically involves surgical intervention, and over 70% of CD patients require at least one surgical intervention during their lifetime, with 39% requiring additional surgery. The incidence and prevalence of CD continues to increase, and there is an urgent need for improved therapeutics to reduce surgery and restrain the individual and public health costs associated with this disease. NF-kappa B (NF-kB) is a master regulator of gut inflammation, and activation of the NF-kB signalling pathway plays a key role in driving the inflammatory response during the onset and progression of CD. Consistent with this, the NF-kB pathway is a recognized and validated therapeutic target, and many of the current CD therapeutics target this pathway at least in part. Unfortunately, the current therapies are suboptimal in terms of compliance, toxicity, and cost, and new therapeutics are required to better target this pathway. It is now increasingly recognized that the microbes resident in the healthy gut (collectively termed the "gut microbiota") play a key role regulating the host inflammatory response and maintaining well-being. The gut microbiota helps maintain the natural balance of the gut environment, and studies have revealed the microbiota differs between the healthy and CD subjects. In particular, several bacteria that are more abundant in the healthy gut produce anti-inflammatory "bioactives" that suppress the NF-kB-mediated inflammatory response and alleviate inflammation in animal models of CD. As these bioactives are naturally present in the healthy gut, they may have specific attributes favorable to the development of new therapeutics, and they may also be well tolerated and cause fewer side effects. We hypothesize that these natural anti-inflammatory bioactives produced by the gut microbiota can be exploited to develop new therapeutics for CD. It is indisputable that techniques in bacterial genetics have been central to deciphering the functional capabilities of the microbial world; however, the vast majority of microbes are considered to be genetically recalcitrant, and genomic and metabolomics-based approaches to bioactive discovery have struggled to identify the anti-inflammatory bioactives produced by the gut microbiota. This challenge could be overcome if it were possible to apply genetic approaches to anti-inflammatory gut bacteria to expedite the identification of their bioactive factors. Our team has applied a recently described approach that supports the rapid and directed isolation of genetically tractable gut bacteria. We have now demonstrated that many of the bacteria recovered produce NF-kB-suppressive bioactives and that the extent of this capability in the healthy gut is more widespread than previously appreciated. The goal of this project is to develop genetic-based approaches and demonstrate they can be used to expedite the discovery of novel natural NF-kB-suppressive bioactives from fastidious gut bacteria and to
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710279
Entities
People
- Paraic O Cuiv
Organizations
- United States Army
- University of Queensland