Ajay Kumar Jain1, Abhineet Sharma2, Sumit Arora1, Keith Blomenkamp1, Ik Chan Jun1, Robert Luong1, David John Westrich1, Aayush Mittal3, Paula M Buchanan4, Miguel A Guzman5, John Long6, Brent A Neuschwander-Tetri7, Jeffery Teckman1. 1. 1 Department of Pediatrics, Saint Louis University School of Medicine, Cardinal Glennon Children's Medical Center, St. Louis, Missouri, USA. 2. 2 Children's Hospital of Wisconsin, Milwaukee, Wisconsin, USA. 3. 3 Wayne State University, Detroit, Michigan, USA. 4. 4 Center for Outcomes Research, Saint Louis University, St. Louis, Missouri, USA. 5. 5 Department of Pathology, Saint Louis University School of Medicine, St. Louis, Missouri, USA. 6. 6 Department of Comparative Medicine, Saint Louis University School of Medicine, St. Louis, Missouri, USA. 7. 7 Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, Missouri, USA.
Abstract
BACKGROUND: Parenteral nutrition (PN) is a lifesaving therapy but is associated with gut atrophy and cholestasis. While bile acids (BAs) can modulate intestinal growth via gut receptors, the gut microbiome likely influences gut proliferation and inflammation. BAs also regulate the bile salt export pump (BSEP) involved in cholestasis. We hypothesized that the BA receptor agonist oleanolic acid (OA) regulates gut TGR5 receptor and modulates gut microbiota to prevent PN-associated injury. MATERIALS AND METHODS: Neonatal piglets were randomized to approximately 2 weeks of isocaloric enteral nutrition (EN), PN, or PN + enteral OA. Serum alanine aminotransferase, bilirubin, BAs, hepatic BSEP, gut TGR5, gut, liver morphology, and fecal microbiome utilizing 16S rRNA sequencing were evaluated. Kruskal-Wallis test, pairwise Mann-Whitney U test, and multilevel logistic regression analysis were performed. RESULTS: PN support resulted in gut atrophy substantially prevented by OA. The median (interquartile range) for villous/crypt ratio was as follows: EN, 3.37 (2.82-3.80); PN, 1.73 (1.54-2.27); and OA, 2.89 (2.17-3.34; P = .006). Pairwise comparisons yielded P = .002 (EN vs PN), P = .180 (EN vs OA), P = .026 (PN vs OA). OA upregulated TGR5 and BSEP without significant improvement in serum bilirubin ( P = .095). A decreased microbial diversity and shift toward proinflammatory phylum Bacteroidetes were seen with PN, which was prevented by OA. CONCLUSIONS: OA prevented PN-associated gut mucosal injury, Bacterioides expansion, and the decreased microbial diversity noted with PN. This study demonstrates a novel relationship among PN-associated gut dysfunction, BA treatment, and gut microbial changes.
BACKGROUND: Parenteral nutrition (PN) is a lifesaving therapy but is associated with gut atrophy and cholestasis. While bile acids (BAs) can modulate intestinal growth via gut receptors, the gut microbiome likely influences gut proliferation and inflammation. BAs also regulate the bile salt export pump (BSEP) involved in cholestasis. We hypothesized that the BA receptor agonist oleanolic acid (OA) regulates gut TGR5 receptor and modulates gut microbiota to prevent PN-associated injury. MATERIALS AND METHODS: Neonatal piglets were randomized to approximately 2 weeks of isocaloric enteral nutrition (EN), PN, or PN + enteral OA. Serum alanine aminotransferase, bilirubin, BAs, hepatic BSEP, gut TGR5, gut, liver morphology, and fecal microbiome utilizing 16S rRNA sequencing were evaluated. Kruskal-Wallis test, pairwise Mann-Whitney U test, and multilevel logistic regression analysis were performed. RESULTS: PN support resulted in gut atrophy substantially prevented by OA. The median (interquartile range) for villous/crypt ratio was as follows: EN, 3.37 (2.82-3.80); PN, 1.73 (1.54-2.27); and OA, 2.89 (2.17-3.34; P = .006). Pairwise comparisons yielded P = .002 (EN vs PN), P = .180 (EN vs OA), P = .026 (PN vs OA). OA upregulated TGR5 and BSEP without significant improvement in serum bilirubin ( P = .095). A decreased microbial diversity and shift toward proinflammatory phylum Bacteroidetes were seen with PN, which was prevented by OA. CONCLUSIONS:OA prevented PN-associated gut mucosal injury, Bacterioides expansion, and the decreased microbial diversity noted with PN. This study demonstrates a novel relationship among PN-associated gut dysfunction, BA treatment, and gut microbial changes.
Entities:
Keywords:
TGR5; bile acid transporters; gut microbiota; oleanolic acid; parenteral nutrition
Authors: Frédéric M Vaz; Coen C Paulusma; Hidde Huidekoper; Minke de Ru; Cynthia Lim; Janet Koster; Kam Ho-Mok; Albert H Bootsma; Albert K Groen; Frank G Schaap; Ronald P J Oude Elferink; Hans R Waterham; Ronald J A Wanders Journal: Hepatology Date: 2014-08-25 Impact factor: 17.425
Authors: Ajay Kumar Jain; Carel W le Roux; Puneet Puri; Ali Tavakkoli; Nana Gletsu-Miller; Blandine Laferrère; Richard Kellermayer; John K DiBaise; Robert G Martindale; Bruce M Wolfe Journal: JPEN J Parenter Enteral Nutr Date: 2018-02 Impact factor: 4.016