Lay Summary
Proposal No. IBD-0198R
Principal Investigator: Sylvia Daunert, Pharm.D., Ph.D.
Applicant Organization: University of Kentucky Research Foundation (Lexington, U.S.A.)
Project Title: Non-invasive biosensors for the diagnosis and management of Crohn's disease
Period of Award: June 1, 2007 – November 30, 2008
The exact causes of CD are not fully understood. However, the available evidence suggests that a combination of environmental, genetic, immunologic and microbial factors predispose to and induce IBD. Of relevance to our study, it is established, both, in animals and humans that the many bacterial species present in the bowel are essential for, both, its health and disease. Altered bacterial balance in the gut may lead to inflammation such as that occurring in IBD, especially CD. Overall, there is evidence that an overly aggressive immune response mounted by the host to bacterial flora present in the gut can occur in individuals who are genetically predisposed or ‘predestined’ to develop IBD. Altered bacterial balance may not only initiate unrelenting inflammation, but also translate to periodic exacerbations experienced by patients with IBD. Hence, it is suggested that bacterial load and interactions play an important role in Crohn’s disease. Bacterial behavior and colonization depend upon communication between bacteria, of the same or of different species. This ‘conversation’ or communication between bacteria is based on a phenomenon known as quorum sensing (QS). Quorum sensing enables bacteria to communicate with each other and control expression of certain specialized genes by producing and responding to extracellular signals in proportion to cell density. Quorum sensing involves sophisticated and elaborate chemical signaling systems. Given the interplay of bacterial flora and the status of luminal inflammation, we believe that measurement of these quorum sensing signal molecules (QSMs) is an attractive tool in the assessment of the degree of inflammation. Varying levels of quorum sensing molecules may thus be an early predictor of an exacerbation.
We have successfully developed genetically engineered bacteria to act as whole-cell sensing systems that are capable of detecting the presence of QSMs. These systems can also quantify the levels of QSMs. Based upon our prior research, we have established that this is a reliable, rapid and sensitive system to detect changes in QSM levels in human biological samples. This is a novel approach to investigation of CD, in that it proposes to relate bacterial cell-to-cell communication to inflammatory bowel disease, and employ living whole-cell-based biosensors for detection of quorum sensing molecules in saliva and stool of Crohn’s disease patients. In that regard, the overall goal of this project is to clarify that quorum sensing signal molecules are biomarkers to measure intestinal inflammatory activity, and biosensors provide a useful tool to assess the QSM levels in body fluids such as saliva and stool, thus allowing the non-invasive monitoring of inflammatory activity in CD. This simple, non- or minimally invasive fast method for the diagnosis of Crohn’s disease may lead to the future development of a home-based, self-testing tool for disease monitoring. Another relevant outcome of this project is that measurement of bacterial signaling mechanisms in subjects with Crohn’s disease may allow for new understanding of the interplay of gastrointestinal bacterial flora and inflammatory bowel disease, and lead to the design and development of new and more effective therapeutic agents that target bacterial quorum sensing.