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Dysregulation of bile acid homeostasis in parenteral nutrition mouse model.

ABSTRACT: Long-term parenteral nutrition (PN) administration can lead to PN-associated liver diseases (PNALD). Although multiple risk factors have been identified for PNALD, to date, the roles of bile acids (BAs) and the pathways involved in BA homeostasis in the development and progression of PNALD are still unclear. We have established a mouse PN model with IV infusion of PN solution containing soybean oil-based lipid emulsion (SOLE). Our results showed that PN altered the expression of genes involved in a variety of liver functions at the mRNA levels. PN increased liver gene expression of Cyp7a1 and markedly decreased that of Cyp8b1, Cyp7b1, Bsep, and Shp. CYP7A1 and CYP8B1 are important for synthesizing the total amount of BAs and regulating the hydrophobicity of BAs, respectively. Consistently, both the levels and the percentages of primary BAs as well as total non-12?-OH BAs increased significantly in the serum of PN mice compared with saline controls, whereas liver BA profiles were largely similar. The expression of several key liver-X receptor-? (LXR?) target genes involved in lipid synthesis was also increased in PN mouse livers. Retinoid acid-related orphan receptor-? (ROR?) has been shown to induce the expression of Cyp8b1 and Cyp7b1, as well as to suppress LXR? function. Western blot showed significantly reduced nuclear migration of ROR? protein in PN mouse livers. This study shows that continuous PN infusion with SOLE in mice leads to dysregulation of BA homeostasis. Alterations of liver ROR? signaling in PN mice may be one of the mechanisms implicated in the pathogenesis of PNALD.

SUBMITTER: Zhan L

PROVIDER: S-EPMC4719060 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Dysregulation of bile acid homeostasis in parenteral nutrition mouse model.

Zhan Le L Yang Ill I Kong Bo B Shen Jianliang J Gorczyca Ludwik L Memon Naureen N Buckley Brian T BT Guo Grace L GL

American journal of physiology. Gastrointestinal and liver physiology 20151112 2

Long-term parenteral nutrition (PN) administration can lead to PN-associated liver diseases (PNALD). Although multiple risk factors have been identified for PNALD, to date, the roles of bile acids (BAs) and the pathways involved in BA homeostasis in the development and progression of PNALD are still unclear. We have established a mouse PN model with IV infusion of PN solution containing soybean oil-based lipid emulsion (SOLE). Our results showed that PN altered the expression of genes involved i ...[more]

PMID: 26564717

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Project description:BackgroundParenteral nutrition (PN) has been a life-saving treatment in infants intolerant of enteral feedings. However, PN is associated with liver injury (PN Associated Liver Injury: PNALI) in a significant number of PN-dependent infants. We have previously reported a novel PNALI mouse model in which PN infusion combined with intestinal injury results in liver injury. In this model, lipopolysaccharide activation of toll-like receptor 4 signaling, soy oil-derived plant sterols, and pro-inflammatory activation of Kupffer cells (KCs) played key roles. The objective of this study was to explore changes in the intestinal microbiome associated with PNALI.Methodology and principal findingsMicrobiome analysis in the PNALI mouse identified specific alterations within colonic microbiota associated with PNALI and further association of these communities with the lipid composition of the PN solution. Intestinal inflammation or soy oil-based PN infusion alone (in the absence of enteral feeds) caused shifts within the gut microbiota. However, the combination resulted in accumulation of a specific taxon, Erysipelotrichaceae (23.8% vs. 1.7% in saline infused controls), in PNALI mice. Moreover, PNALI was markedly attenuated by enteral antibiotic treatment, which also was associated with significant reduction of Erysipelotrichaceae (0.6%) and a Gram-negative constituent, the S24-7 lineage of Bacteroidetes (53.5% in PNALI vs. 0.8%). Importantly, removal of soy oil based-lipid emulsion from the PN solution resulted in significant reduction of Erysipelotrichaceae as well as attenuation of PNALI. Finally, addition of soy-derived plant sterol (stigmasterol) to fish oil-based PN restored Erysipelotrichaceae abundance and PNALI.ConclusionsSoy oil-derived plant sterols and the associated specific bacterial groups in the colonic microbiota are associated with PNALI. Products from these bacteria may directly trigger activation of KCs and promote PNALI. Furthermore, the results indicate that lipid modification of PN solutions may alter specific intestinal bacterial species associated with PNALI, and thus suggest strategies for management of PNALI.

Dataset Information

Dysregulation of bile acid homeostasis in parenteral nutrition mouse model.

Publications

Dysregulation of bile acid homeostasis in parenteral nutrition mouse model.

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