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Purpose: Total Parenteral Nutrition (TPN) involves delivering all nutritional requirements via the intravenous route. Though TPN therapy has grown enormously over the last few decades; it is associated with significant clinical complications including gut atrophy and liver injury. Amelioration of side effects remains a major research focus. We have previously published improvement in TPN associated pathologies with enteral chenodeoxycholic acid a dual Farnesoid X Receptor (FXR) and TGR5 agonist. We have hypothesized that gut growth is regulated via TGR5 activation. We describe role of the pure TGR5 specific agonist, Oleanolic Acid (OA) in animals receiving TPN.

Methods: Neonatal pigs were implanted jugular vein (JV) and duodenal catheters (DC). Isocaloric swine milk (n=3) was provided via the DC. Continuous TPN solution was infused via the JV. A subset of TPN animals (n=3) received the enteral TGR5 agonist, oleanolic acid at 50mg/kg/day via the DC.

Results: TPN caused marked gut atrophy in comparison to EN fed control animals. Oleanolic acid treatment led to a robust preservation of gut mass. This was evident grossly and on histology. The mean gut weight as a percent of body weight and (±SD) was 4.30±0.26 for EN, 1.92±0.06 for TPN (p<0.05) and 3.39±0.79 for OA, (p<0.05). Markedly decreased villous to crypt ratio (v/c) was noted with TPN. OA significantly improved the v/c ratio. Mean v/c ratio and (±SD) was 3.51±0.59 for EN, 1.69±0.1 for TPN (p<0.05) and 2.9±0.23 for OA, (p<0.05). TGR5 expression was significantly elevated with OA; however no changes in FXR were noted with OA treatment. Catheter sites and surgical wounds healed well.

Conclusions: Oleanolic acid improves gut atrophy in TPN infused animals, via the bile acid regulated G-protein coupled receptor TGR5. Modulation of TPN associated pathology via bile acid regulation of gut receptors is novel and could bring a paradigm change in current treatment strategies for these unfortunate complication of a lifesaving therapy.