Ulcerative enteropathies, such as nonsteroidal anti-inflammatory drug (NSAID) enteropathy, radiation proctitis or idiopathic inflammatory bowel disease are common among the veteran population. Thus far, the treatments for these conditions is only somewhat satisfactory due to lack of efficacy, cost, and toxicity. The gut contains endocrine cells that secrete hormones in response to ingested nutrients. We have found recently that the intestinotrophic hormones glucagon-like peptide-2 (GLP-2) is secreted in response to amino acids in the intestine. Furthermore, GLP-2 is metabolized principally by the enzyme dipeptidyl peptidase IV (DPPIV), a diabetes drug. We therefore propose to augment GLP-2 systemic concentrations by enhancing its secretion by the ingestion of the appropriate nutrients and by slowing its metabolism with DPPIV inhibition. Recently, several G-protein-coupled receptors (GPCRs) have been identified on enteroendocrine cells that appear to be involved with luminal nutrient sensing. Methods: We will perfuse intestinal segments of rats with ligands of GPCRs implicated in nutrient sensing in order to determine if they elicit GLP-2 secretion. GPCRs will be immunolocalized to the gut. We will also determine if taste GPCR ligands increase mucosal defense mechanism such as mucosal blood flow, mucus secretion, enterocyte alkalinization, and, bicarbonate secretion. Last, we will give GPCR ligands by gavage to rats in a standard refed NSAID enteropathy model in conjunction with DPPIV inhibitors in order to determine if they ameliorate NSAID gastropathy.
We plan to study the mechanisms by which nutrients that are present in the gut after eating stimulate the release of hormones by the gut. It is well known that eating sugars can stimulate hormones that increase insulin secretion. Other hormones however are also secreted, including one called GLP-2 that helps repair the intestine. This hormone is broken down buy an enzyme called DPPIV that also breaks down the hormone GLP-1 that is used to treat diabetes. DPPIV inhibitors are currently approved to treat diabetes. Through a combination of finding the right nutrients that release the hormone and inhibiting its breakdown with a DPPIV inhibitor, we hope to be able to treat ulceration of the colon that can be caused by taking medicines such as Motrin, by radiation, or by inflammatory bowel disease. Since intestinal damage is very common among veterans, we hope that any treatments that are derived from this research will improve veterans health.