Understanding Microbial Sensing in Inflammatory Bowel Disease Using Click Chemistry
Abstract
Only 10% of the cells in our bodies are human; yet, in treating illness, we tend to overlook the roughly 1014 microorganisms that comprise the human body. Just as the organs within an individual must communicate to function as a whole, the communication of this set of bacteria, fungi, and viruses (termed the microbiota) with the host defines local and systemic physiology. When this delicate ecosystem is upset, a "dysbiosis" occurs in which the healthy symbiosis between human and microbe is lost, exacerbating a number of metabolic, inflammatory, and autoimmune diseases. There is mounting evidence that this dysbiosis and the resulting inflammation play a large role in the initiation and progression of inflammatory bowel disease (IBD). This phenomena is exemplified in mice and rats that are genetically susceptible to IBD, which are rendered virtually disease-free in a germ-free environment. In this proposal, we will combine advanced chemical techniques with modern methods in immunology and microscopy to track the intestinal bacterial components that contribute to IBD-related inflammation. Bioorthogonal "click" chemistry (i.e., reactions that can be performed in living organisms) will be used to label and track distinct bacterial molecules that can be sensed by the host. A common bacterial species from the intestine, Bacteroides fragilis, will be labeled in this manner and the live bacteria colonized in mice. We will use state-of-the-art imaging techniques to trace the specific bacterial molecules as they are acquired and sensed by the intestinal tissue of healthy mice versus mice with induced IBD. We will use this new platform to understand the process of microbial sensing as it leads to disease and identify the immunological pathways associated with an inflammatory response. Once developed, this imaging platform may ultimately be used to diagnose patients at various stages of IBD through fluorescence endoscopy of labeled intestinal bacteria. If left untreated, the symptoms of IBD are not only debilitating (recurring diarrhea, fever, fatigue, and abdominal pain) but often require surgical intervention and commonly lead to the development of colorectal cancer (CRC). Currently, military candidates with an inflammatory bowel disease are not eligible for service and will be discharged upon diagnosis. Furthermore, the occurrence of irritable bowel syndrome (IBS) and IBD is increasing in Veterans especially those that served in Gulf War areas. Due to the lack of a defined universal cause in IBD, there is currently no cure. This proposal will aid in understanding the immunological components of the disease especially those pathways that contribute to the aberrant communication between host and microbe. We hope to define specific cells that contribute to inflammation or tolerance so that patients can receive the correct and most effective treatments targeting the proper pathways and immune cells. Furthermore, recent research in active duty personnel has demonstrated that risk of both IBS and IBD increases after infectious gastroenteritis (IGE) and in a defined subset of IBS patients IBD risk was 15 times that of subjects without IBS. By completing studies in both chemically induced colitis that mimics chronic disease versus pathogen-induced colitis, we hope to understand the immunological differences that may define each disease and aid in understanding how IGE may lead to IBD.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510367
Entities
People
- Ulrich von Andrian
Organizations
- Harvard University
- United States Army