title: Preserved Gut Microbial Diversity Accompanies Upregulation of TGR5 and Hepatobiliary Transporters in Bile Acid-Treated Animals Receiving Parenteral Nutrition.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors: 1 Department of Pediatrics, Saint Louis University School of Medicine, Cardinal Glennon Children's Medical Center, St. Louis, Missouri, USA.
authors: Ajay Kumar
authors: AK
authors: Jain
authors: 2 Children's Hospital of Wisconsin, Milwaukee, Wisconsin, USA.
authors: Abhineet
authors: A
authors: Sharma
authors: 1 Department of Pediatrics, Saint Louis University School of Medicine, Cardinal Glennon Children's Medical Center, St. Louis, Missouri, USA.
authors: Sumit
authors: S
authors: Arora
authors: 1 Department of Pediatrics, Saint Louis University School of Medicine, Cardinal Glennon Children's Medical Center, St. Louis, Missouri, USA.
authors: Keith
authors: K
authors: Blomenkamp
authors: 1 Department of Pediatrics, Saint Louis University School of Medicine, Cardinal Glennon Children's Medical Center, St. Louis, Missouri, USA.
authors: Ik Chan
authors: IC
authors: Jun
authors: 1 Department of Pediatrics, Saint Louis University School of Medicine, Cardinal Glennon Children's Medical Center, St. Louis, Missouri, USA.
authors: Robert
authors: R
authors: Luong
authors: 1 Department of Pediatrics, Saint Louis University School of Medicine, Cardinal Glennon Children's Medical Center, St. Louis, Missouri, USA.
authors: David John
authors: DJ
authors: Westrich
authors: 3 Wayne State University, Detroit, Michigan, USA.
authors: Aayush
authors: A
authors: Mittal
authors: 4 Center for Outcomes Research, Saint Louis University, St. Louis, Missouri, USA.
authors: Paula M
authors: PM
authors: Buchanan
authors: 5 Department of Pathology, Saint Louis University School of Medicine, St. Louis, Missouri, USA.
authors: Miguel A
authors: MA
authors: Guzman
authors: 6 Department of Comparative Medicine, Saint Louis University School of Medicine, St. Louis, Missouri, USA.
authors: John
authors: J
authors: Long
authors: 7 Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, Missouri, USA.
authors: Brent A
authors: BA
authors: Neuschwander-Tetri
authors: 1 Department of Pediatrics, Saint Louis University School of Medicine, Cardinal Glennon Children's Medical Center, St. Louis, Missouri, USA.
authors: Jeffery
authors: J
authors: Teckman
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11 / Q000235:genetics*; D000818:Animals; D000831:Animals, Newborn; D001284:Atrophy / Q000209:etiology / Q000517:prevention & control; D001439:Bacteroides / Q000254:growth & development; D001647:Bile Acids and Salts / Q000008:administration & dosage*; D002779:Cholestasis / Q000209:etiology / Q000517:prevention & control; D000069196:Gastrointestinal Microbiome / Q000502:physiology*; D007410:Intestinal Diseases / Q000209:etiology / Q000517:prevention & control; D007413:Intestinal Mucosa; D007422:Intestines / Q000382:microbiology / Q000473:pathology; D009828:Oleanolic Acid / Q000494:pharmacology; D010288:Parenteral Nutrition / Q000009:adverse effects*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D034421:Sus scrofa; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D001647:Bile Acids and Salts; C473772:GPBAR1 protein, human; D043562:Receptors, G-Protein-Coupled; D009828:Oleanolic Acid
keywords: TGR5; bile acid transporters; gut microbiota; oleanolic acid; parenteral nutrition