Glycopolymer-Mimicking Polysaccharides to Provide Barrier Function and Restore Gastrointestinal Integrity and Homeostasis in Inflammatory Bowel Diseases
Abstract
Inflammatory bowel disease (IBD) is an overall term used to describe disorders that involve chronic inflammation of the digestive tract. Types of IBD include ulcerative colitis (UC), which causes long-lasting inflammation and sores (ulcers) in the innermost lining of the large intestine and rectum, and Crohn’s disease, which is characterized by inflammation of the lining of the digestive tract. Both ulcerative colitis and Crohn’s disease usually involve severe diarrhea, abdominal pain, fatigue, and weight loss. Although they are separate conditions, they share common features of intestinal inflammation and ulceration. This proposal addresses the topic of Inflammatory Bowel Diseases, specifically studies directed toward understanding how acute infections may trigger chronic bowel diseases with acute and sub-acute inflammatory bowel disease, research on the influence of the microbiome on IBD, and research on treatment strategies for patients with IBD, including those who do not respond to standard care. Infection, genetics, prior infectious gastroenteritis, and stress have been associated with increased risk of inflammatory bowel diseases and syndromes. In a healthy gut, the microenvironment provides homeostasis, which is the body’s ability to auto-regulate and maintain a stable state, with the normal bacterial flora and supports an intact gut barrier. In a damaged/inflamed gut, dysfunction of the mucosal barrier allows penetration of both “good” and “bad” microbes onto and through the intestinal cell wall. This intestinal permeability allows material, bacteria, proteins, and cellular debris, to pass from inside the gastrointestinal tract through the cells lining the gut wall, and into the circulation. The intestine normally has controlled permeability, which allows nutrients to pass through the gut, while also maintaining a barrier function to keep potentially harmful substances from leaving the intestine and migrating more widely into to the body. IBD results in damage to the layers of protection in the gastrointestinal tract, allowing microbes to incite inflammation and cellular shedding, increasing intestinal permeability. This effort is based on newly developed targeted molecules to replace the natural immune functions of the gastrointestinal surface and help to repair damaged, multilayered intestinal barrier in IBD. Under this effort, three different drug molecules will be studied for efficacy in improving outcomes in a model of IBD. Mouse models of UC using dextran sodium sulfate as the disease instigator will be used to determine which of the tested molecules are most effective in replacing the barrier function to reduce inflammation, restore the microflora, minimize bacterial translocation into the circulation, and improve healing. Mechanistic studies will translocation of the bacteria into the bloodstream, thus assessing intestinal integrity (permeability). Histology and endoscopy will assess the physiology of the disease progression; fecal and serum tests of inflammatory markers and fecal measurements of microbiome will assess the relative temporal effects of the candidate molecules on intestinal regeneration, local and systemic inflammation, and microbiome. The goal of the study will be to identify which characteristics of the molecules are most effective in providing the innate barrier function that is lost in a damaged intestine and correlate those observations with the restoration of a healthy gut. The fundamental structure of the gastrointestinal tract is disrupted in IBD; therapeutics that target only the downstream inflammatory component of IBDs have had only modest success. Approximately 1.6 million Americans currently have IBD, and as many as 70,000 new cases of IBD are diagnosed in the United States each year, which highlights the need for new effective therapies. New therapeutics that can target the source of inflammation, i.e., barrier function, barrier damage, and microbiome,
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910165
Entities
People
- Shenda M. Baker
Organizations
- Synedgen (United States)
- United States Army