Su1798 Glucagon-Like Peptides Ameliorate Total Prenteral Nutrition Associated Gut Atrophy

Background: Total parenteral nutrition (TPN) is a life-saving therapy in critically ill patients. Unfortunately, it is associated with significant morbidity and mortality, including gut atrophy and Parenteral Nutrition Associated Liver Disease. A lack of enteral feeding during TPN, disrupts key signaling molecules and the enterohepatic circulation, which appears to be a major contributor to disease pathology. Our group previously demonstrated thatenterally administeredbile acid,oleanolic acid (OA)significantly improved gut density andmorphology. OAis a ligand for the G-protein coupled receptor TGR-5. TGR-5 is known to induce transcription of glucagon-like peptide (GLP)-1 and GLP-2. While GLP-1 regulates hepatic steatosis and inflammation, GLP2 is involved in gut growth and motility.Hypothesis: We hypothesize that TPN infusion disrupts the TGR5-GLP axis and exogenous GLP-1, GLP-2 infusion will ameliorate TPN induced injury. Methods: Seven to ten day old piglets were implanted with jugular venous (JVC) and duodenal catheters (DC). Animals were randomized to receive Enteral Feeding (EN) or TPN. The TPN group was subdivided into TPN plus GLP-1 and GLP-2 (n=3). Milk was delivered via the DC and TPN was infused via the JVC. GLP-1 and GLP-2 were dosed at3 mcg/kg/day and 30 mcg/kg/day respectively. Results: Mean daily weight gain (grams) for control Enteral Fed (EN) vs TPN animals and standard deviation (±SD) was 102.4±10.8, 91.03±12.1 respectively, p>0.05. Marked gut atrophy was noted with TPN.Mean gut density as measured in grams/cm of gut tissue and standard deviation (±SD) in EN vs TPN was 0.35±0.03, 0.185±0.05, p<0.05. GLP treatment caused a robust increase in gut density(0.28±0.07). Conclusion: GLP treatment improves gut atrophy in TPN infused animals. This result also provides mechanistic validation for effects of OA treatment. We believe that modulation of TPN associated pathology via bile acid regulation of signaling molecules is novel and could bring a paradigm change in current treatment strategies for unfortunatecomplication of a lifesaving therapy.