Targeting the Intestinal Barrier to Regulate Mucosal Immunity in IBD and Infectious Enterocolitis
Abstract
This application is in the topic area of Inflammatory Bowel Disease (IBD). IBD is an umbrella term describing Crohn’s disease and ulcerative colitis, affecting over 3 million Americans. Rare cases of IBD in the very young can be caused by single gene mutations. However, the majority of patients develop IBD in their teens or early 20s. Many carry genetic changes, i.e., risk genes, that are found within the general population but occur with increased frequency in IBD patients and their families. These genetics define the hereditary component of IBD. They do not, however, explain why some individuals with the same genes as those with IBD do not develop disease or why disease usually develops at older ages. Poorly understood environmental factors are thought to explain differences between individuals with identical genes, e.g., identical twins, as well as sudden development of IBD after years of health. These environmental influences include the gut microbiome, a vast microbial population that lives within us and contributes to disease initiation and progression. The means by which the microbiome modifies health and disease are only now being discovered, but include effects on the immune system, much of which is educated within the gastrointestinal tract by exposure to bacterial products, food, and other ingested substances. These interactions are limited by the gut lining, which prevents intestinal contents from freely accessing the remainder of the body. However, unlike the skin, this “inner skin” cannot form an absolute barrier; the intestines must absorb nutrients, salts, vitamins, and water while eliminating waste products and other noxious substances. Excessive permeability, or leakiness, of the intestinal barrier has been referred to as leaky gut syndrome in the press. While many claims related to leaky gut syndrome are unproven, abundant data confirm that intestinal barrier defects can contribute to development and enhance the severity of diseases including IBD, celiac disease (gluten sensitivity), and irritable bowel syndrome (IBS). Moreover, increases in intestinal permeability, i.e., barrier defects, are associated with many systemic diseases, including diabetes, multiple sclerosis, rheumatoid arthritis, AIDS, and graft-versus-host disease (a complication of bone marrow transplantation). Conversely, many intestinal diseases cause barrier dysfunction. These include acute gastroenteritis, e.g., intestinal infections, that often resolve after several days of diarrhea. Despite complete clinical recovery, these transient disruptions may have lasting impacts, as the risk of developing IBD is increased following some gastrointestinal infections. Thus, dysregulation of the intestinal barrier is both a cause and effect of disease. Despite this, there are no effective therapies to regulate or restore the gut barrier. This failure primarily reflects the absence of detailed understanding at all levels, from molecules to people (or animals), of how the intestinal barrier is regulated and, in turn, regulates essential life functions. Our exciting new results show that a specific form of intestinal barrier regulation caused by a single protein has dramatic impact on disease. This protein, named claudin-2, creates channels that allow extremely small molecules, such as sodium and water, to cross between gut-lining cells to exchange freely between internal organs the gut. We have developed fundamental knowledge that allows us to inhibit these channels (using a drug that is U.S. Food and Drug Administration-approved for other indications). This drug was profoundly beneficial in experimental IBD. While this might be taken as evidence that clinical trials should begin immediately, our other data emphasize that caution is required. For example, in contrast to IBD, we found that claudin-2 inhibition exacerbated infectious enteritis and increased channel function reduced disease severity and duration. In trying to
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910261
Entities
People
- Jerrold R Turner
Organizations
- Brigham and Women's Hospital
- United States Army