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Background and aims This study aimed to investigate the impact of fish oil-based lipid emulsion (FO) on enterohepatic injuries and intestinal microbiota in piglets of total parenteral nutrition (TPN). Methods Newborn piglets were divided into three groups, including enteral diet (the controls), TPN with 100% FO and TPN with MCT/LCT-based lipid emulsion (MCT/LCT) for 14 days. Serum biochemical indicators, hepatic and intestinal histology, and expression of genes associated with inflammation, oxidative stress, and lipid metabolism were measured. The bile acid profiles in serum and the taxonomic composition of the gut microbiome in different intestinal segments were analyzed. Results Compared to MCT/LCT-piglets, FO reduced inflammation, promoted fatty acid oxidation and decreased oxidative stress in the liver. In the intestine, FO decreased intestinal inflammation and intestinal permeability, leading to reduce lipopolysaccharide entry into the blood circulation relative to MCT/LCT-piglets. TPN groups have dominant contents of Proteobacteria and Bacteroides, while the control group have Firmicutes at the phylum level. FO altered the taxonomic compositions of the gut microbiome in different segments, increased the relative abundance of Bacteroidaceae in ileum, and Rikenellaceae and Ruminococcaceae in the colon. FO treatment shifted bile acids (BAs) composition ratio in serum and had a lower ratio of secondary BAs to primary BAs. Conclusion FO alleviates PNLAD and intestinal injury by regulating the homeostasis of BAs' enterohepatic circulation and altering microbiota composition in different intestinal segments. This article is protected by copyright. All rights reserved.

Enterocyte apoptosis induced by lipid emulsions is a key cause of intestinal atrophy under total parenteral nutrition (TPN) support, and our previous work demonstrated that olive oil lipid emulsion (OOLE) could induce enterocyte apoptosis via CUGBP, Elav‐like family member 1 (CELF1)/ apoptosis‐inducing factor (AIF) pathway. As TPN‐associated complications are partially related to choline deficiency, we aimed to address whether choline supplementation could attenuate OOLE‐induced enterocyte apoptosis. Herein we present evidence that supplementary choline exhibits protective effect against OOLE‐induced enterocyte apoptosis both in vivo and in vitro. In a rat model of TPN, substantial reduction in apoptotic rate along with decreased expression of CELF1 was observed when supplementary choline was added to OOLE. In cultured Caco‐2 cells, supplementary choline attenuated OOLE‐induced apoptosis and mitochondria dysfunction by suppressing CELF1/AIF pathway. Compared to OOLE alone, the expression of CELF1 and AIF was significantly decreased by supplementary choline, whereas the expression of Bcl‐2 was evidently increased. No obvious alterations were observed in Bax expression and caspase‐3 activation. Mechanistically, supplementary choline repressed the expression of CELF1 by increasing the recruitment of CELF1 mRNA to processing bodies, thus resulting in suppression of its protein translation. Taken together, our data suggest that supplementary choline exhibits effective protection against OOLE‐induced enterocyte apoptosis, and thus, it has the potential to be used for the prevention and treatment of TPN‐induced intestinal atrophy.

Phosphatidylinositol 3-kinase (PI3K), one member of lipid kinase family, has been demonstrated to play a key role in regulating cell proliferation, adhesion, survival, and motility. Recent studies indicate that PI3K related signaling pathway is one of the most commonly activated pathways in human cancers. Accordingly, pharmacological inhibition of key nodes in this signaling cascade has been a focus in developmental therapeutics. To date, Inhibitors targeting PI3K or nodes in this pathway, AKT and mTOR, are best studied and have reached clinical trials. In this review, we will focus on recent progress on understanding of PI3Ks signaling pathway and the development of PI3K inhibitors.