Lay Summary
Proposal No. IBD-0227R
Principal Investigator: James M. Mullin, Ph.D.
Applicant Organization: Lankenau Institute for Medical Research (Wynnewood, Pennsylvania, U.S.A.)
Project Title: Improvement in gastrointestinal barrier function and morbidity by restriction of sulfur-containing amino acids in Crohn's disease patients
Period of Award: October 1, 2008 - June 30, 2010
Crohn’s disease (CD) is thought to involve at least in part a failure of the (epithelial cell) lining of the GI tract to act as barrier. This failure results in unregulated movement of noxious agents (such as bacteria, antigens, chemicals normally kept in the lumen or interior of the GI tract) across that lining and into the tissue spaces of the GI tract that communicate directly with blood vessels. The result is thought to then be a virulent inflammatory response that begins the round-robin of events that give rise to CD. If something could interrupt that vicious cycle, significant improvement in a patient’s condition could result.
Over 10 years ago, researchers studying the biology of aging found that when various animals were fed a diet that is low in the amino acids that contain a sulfur atom (SCAA) (methionine, cysteine, cystine), the animal lives as much as 30% longer, with a forestalling of age-related diseases and conditions. This latter observation led our group to wonder what the effects of this low SCAA diet might be on the epithelial linings of the major organs, since their ability to act as a barrier is a major component of our physiology and health. In studies done with kidney epithelial cells grown in our lab, we observed that a low SCAA condition resulted in restructuring and overall improvement in the junction seals between epithelial cells, the seals that constitute the barrier function of the epithelial layer as a whole. Those seals essentially rejuggled their components and their structure, and in the process became less leaky to certain molecules.
We then reasoned that if this dietary approach could be applied to a human disease that is known to be linked to a barrier issue, significant improvement in tissue damage and disease symptoms might result. This approach has never been attempted in inflammatory bowel disease. After consultations with nutritionists we formulated a diet for a study that will involve people with CD lowering their methionine intake by 40% for a period of four weeks. We will evaluate their disease state, and the degree of leakiness in their small and large intestine, at the beginning and end of this diet, to determine if the diet has made a real difference in either parameter. We will simultaneously monitor their nutritional status and the decrease in their internal methionine levels over the next four weeks. We will likewise observe if barrier function and disease status worsens once patients return to a normal diet. If we are successful, a relatively low-cost, drug-free approach to managing CD would be forthcoming.
Over 10 years ago, researchers studying the biology of aging found that when various animals were fed a diet that is low in the amino acids that contain a sulfur atom (SCAA) (methionine, cysteine, cystine), the animal lives as much as 30% longer, with a forestalling of age-related diseases and conditions. This latter observation led our group to wonder what the effects of this low SCAA diet might be on the epithelial linings of the major organs, since their ability to act as a barrier is a major component of our physiology and health. In studies done with kidney epithelial cells grown in our lab, we observed that a low SCAA condition resulted in restructuring and overall improvement in the junction seals between epithelial cells, the seals that constitute the barrier function of the epithelial layer as a whole. Those seals essentially rejuggled their components and their structure, and in the process became less leaky to certain molecules.
We then reasoned that if this dietary approach could be applied to a human disease that is known to be linked to a barrier issue, significant improvement in tissue damage and disease symptoms might result. This approach has never been attempted in inflammatory bowel disease. After consultations with nutritionists we formulated a diet for a study that will involve people with CD lowering their methionine intake by 40% for a period of four weeks. We will evaluate their disease state, and the degree of leakiness in their small and large intestine, at the beginning and end of this diet, to determine if the diet has made a real difference in either parameter. We will simultaneously monitor their nutritional status and the decrease in their internal methionine levels over the next four weeks. We will likewise observe if barrier function and disease status worsens once patients return to a normal diet. If we are successful, a relatively low-cost, drug-free approach to managing CD would be forthcoming.