Inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, affect more than 1 million people in the United States. IBD is a frequent cause of hospitalization among US military veterans. IBD increases the risk factor for other diseases such as colorectal cancer and atherosclerosis. Polarized epithelia in the intestine play an important role in inflammation by serving as a barrier between an invading pathogen and the immune system of the host. Damage to the epithelia compromises absorption of nutrients and mineral, often leading to malnutrition in patients with IBD. Hence, the ability to maintain the epithelial barrier integrity is critical in protecting the host from a hostile environment in the intestinal lumen. Intestinal epithelial proliferation and migration are requirements in wound healing, a process disrupted in IBD. Lysophosphatidic acid (LPA) is a lipid mediator with diverse growth factor-like effects. Extracellular LPA is produced by hydrolysis of circulating lysophospholipid by a lysophospholipase D known as autotaxin (ATX). The effects of LPA are mediated through a family of G protein- coupled receptors: LPA1R-LPA5R. LPA1R is the most abundant LPA receptor in the small intestine and colon, and yet the functional significance of LPA1R is poorly understood. The impetus of this application came from our recent findings that loss of LPA1R in the intestine results increased susceptibility to dextran sulfate sodium (DSS)- induced colitis by delaying the recovery process.
We aim to further define the importance of LPA1R in chronic inflammation and determine how LPA1R regulates intestinal epithelial homeostasis (Aim 1). LPA is often regarded as a pro-inflammatory agent. We found that the expression level of LPA-producing ATX was increased in DSS- mediated colitis, and mice deficient in ATX expression showed resistance to DSS-induced colitis. However, deletion of ATX or chemical inhibition of ATX significantly delayed recovery from DSS-induced injury. Hence, LPA appear to have opposing effects during the onset of inflammation and recovery. We propose to investigate whether ATX is a potential target in treatment of intestinal inflammation. We will use genetic deletion and chemical inhibition of ATX to assess the effects on acute and chronic inflammation (Aim 2). Individuals with IBD and, particularly, those with Crohn's disease are at risk for a variety of nutritional deficiencies because of decreased nutrient absorption and/or increased losses of macronutrients. Deletion or inhibition of LPA1R decreased expression of several transporters of nutrients and electrolytes. On the contrary, treating mice with spontaneous ileitis with LPA increased transporter expression, suggesting a beneficial role of LPA on the intestinal absorptive function. We propose evaluate whether LPA could be used to enhance epithelial absorptive functions associated with IBD (Aim 3). The overarching goal of this application is to investigate the importance of LPA in maintenance of intestinal epithelial homeostasis and regulation of the epithelial barrier and absorptive functions. Successful completion of the proposed work should provide a better understanding of the LPA1R- mediated effects, which together with the proposed study on the major LPA-producing ATX, will benefit maintenance of healthy intestine and provide potential therapeutic modality for treatment of inflammatory diseases.
Inflammatory diseases, including Crohn's disease and ulcerative colitis, are frequent causes of morbidity and hospitalization of US veterans. Chronic inflammation increases the risk factors for other diseases such as colorectal cancer and atherosclerosis. Epithelial cells lining the intestinal lumen form a barrier that separate the external from interna environments. Maintenance of the epithelial layer is critical for absorption of solutes and nutrients and protection of the host from harmful agents. Our preliminary study demonstrates that LPA facilitates intestinal epithelial repair and increases nutrient transporter expression via LPA1 receptor. On the other hand, inhibition of the major LPA producing enzyme, autotaxin, provides protection against chemically induced colitis. The goal of this project is to determine the roles of LPA1 receptor and autotaxin in maintenance of the epithelial barrier and absorptive functions in the intestine, and to understand how these can be targeted to modulate epithelial injury and repair processes.
