Mo1762 A Novel Role of GLP-1 Nanomedicine in Amelioration of Gut Inflammation

Abstract

Glucagon-like peptide-1 (GLP-1) is an important gut hormone, which in intestine is secreted by L-cells. In addition to its beneficial roles in insulin secretion, obesity, cardio and neuro protection, recently GLP-1 has also been shown to act as an anti-inflammatory agent. However, its use in clinical practice has been hampered by its short half-life and by the fact that commercially available analogues have increased risk of immunogenicity. It has recently been shown that novel formulation composed of human GLP-1 self-associated to a sterically stabilized phospholipid micelles (SSM), GLP-1 nanomedicine, increased the stability of circulating GLP-1 in the blood, and the nanomedicine had an anti-inflammatory effect against LPS induced inflammation in lungs. Whether GLP-1 nanomedicine exerts anti-inflammatory effects in intestine is not known. We hypothesized that GLP-1 nanomedicine decreases intestinal inflammation and attenuates the associated diarrhea. To test this hypothesis, we used Dextran Sodium Sulfate (DSS) (3% in drinking water for 7 days) induced colitis mouse as a model for intestinal inflammation. Animals were divided into 4 groups (5 mice/group) and i.p. injections of vehicle (SSMs) or GLP-1 (15 nmole/100μl) were given daily: Group 1(Control): vehicle alone; Group 2 (DSS): vehicle+DSS; Group 3 (GLP-1): GLP-1 alone; Group 4 (GLP-1+DSS). Mucosa was scraped from distal colon on day 8 for qRT-PCR and western blotting. Tissue sections were used for immunostaining. DSS mice showed a significant decrease in body weight as compared to control. However, GLP-1 treatment to DSS mice partially attenuated the weight loss. When colons were harvested from experimental mice and examined, loose fecal pellets were observed in the colon of DSS colitis mice reflecting diarrheal phenotype, which was partly alleviated in GLP-1 treated mice. Further, treatment with GLP-1 alleviated the increase in expression of the pro-inflammatory cytokines in colonic epithelium of DSS mice e.g. IL-1β (Control: 2±0.6; DSS: 201±43; GLP-1: 2±0.3 GLP-1+DSS: 78±20); and CXCL-1 (Control: 1±0.3; DSS: 18.9±7; GLP-1: 1.3±0.9; GLP1+DSS: 12±3). Increased levels of pro-inflammatory cytokines have been implicated in the associated diarrhea by decreased expression of chloride transporter SLC26A3 or down regulated in adenoma (DRA). Western blot results showed that DSS decreased the expression of DRA as compared to control but GLP-1 abrogated this effect of DSS (Control: 0.9±0.1; DSS: 0.3±0.1; GLP-1: 1.2±0.1; GLP-1+DSS: 0.6±0.2). This data was further confirmed by immunostaining. Our data showed that GLP-1 nanomedicine is effective in reducing intestinal inflammation and the associated diarrhea. We speculate that GLP-1 nanomedicine could be used as a novel therapeutic approach to treat patients with Crohn's disease and ulcerative colitis. (Supported by NIDDK and Dept. of Veteran Affairs)