Impact of total parenteral nutrition and antibiotics on hepatic and intestinal homeostasis in pediatric murine model

Abstract

Parenteral nutrition (PN) prevents starvation and supports metabolic requirements intravenously when patients are unable to feed enterally. Adult rodents and piglets have been used in PN research for decades, while almost no research has used adolescent mice. Clinically, human neonates are frequently provided PN in intensive care settings along with exposure to antibiotics (ABX) to minimize infection during care. Since PN bypasses the intestine, intravenous alimentation impacts metabolism and may alter organ growth and programming during critical early life developmental windows. Utilizing our newly established adolescent murine PN model, we first administered ABX or controlled drinking water to time pregnant dams to disrupt maternal microbiome. Resulting pups (post-natal day 9, n=6-8/group) were then randomized to PN or sham surgery controls for 72 hours with or without prior ABX exposure. ABX or PN decreased liver and brain organ weights, intestinal length, and mucosal architecture compared with controls. PN significantly elevated hepatic proinflammatory cytokine expression, neutrophils, macrophages, and bacterial colony forming units, which was blocked by ABX. However, PN+ABX uniquely elevated metabolic regulatory genes, FXR, CYP27A1, SPEBP1, and FASN, resulting in accumulation of hepatocyte lipid vesicles and altered circulating bile acid pools. Within the gut, PN elevated the relative abundance of Akkermansia, Coprococcus and decreased Lactobacillus compared with enteral controls, while ABX enriched Enterobacteriaceae and Adlercrutzia. We conclude that even brief PN feeding elevates hepatic inflammatory stress in an early life model. While concurrent ABX exposure protects against PN associated inflammatory responses, the dual therapy modulates bile acid and lipid metabolism, which may contribute to the progressive hepatic dysfunction observed in human neonates unable to wean from PN. This study serves as the first demonstration of PN and ABX exposures upon hepatic metabolism and inflammation in an early life murine model. Institutional Start Up Funding This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.