Total parenteral nutrition (TPN), a lifesaving therapy, involves providing nutrition by bypassing the gut. Unfortunately it is associated with significant complications including gut atrophy and parenteral nutrition associated liver disease (PNALD). PNALD includes steatosis, cholestasis, disrupted glucose metabolism, disrupted lipid metabolism, cirrhosis, and liver failure. The etiopathogenesis remains poorly defined; however, an altered enterohepatic circulation, disrupting nuclear receptor signaling, is emerging as a promising mechanism. Rodent models and our piglet TPN model have shown that, during regular feeding, bile acids activate farnesoid X receptor (FXR) in the gut and enhance fibroblast growth factor 19 (FGF19) level. FGF19 regulates bile acid, lipid, and glucose metabolism. We noted reduced FGF19 with TPN use and substantial improvement in FGF19, bilirubin, and metabolic profiles with the FXR agonist chenodeoxycholic acid (CDCA). Additionally, CDCA caused gut growth and enhanced expression of glucagon like peptides (GLPs). GLPs regulate gut trophic effects, insulin, glucose homeostasis, and hepatic steatosis. GLP secretion is regulated by the CDCA activated receptor TGR5. This leads to an important conclusion that, in addition to a disrupted FXR-FGF19 axis, a disrupted TGR5-GLP axis may contribute to TPN related pathologies. Thus modulators of FXR-FGF19 and the TGR5-GLP axis could help bring forward novel treatment strategies. 1. Introduction Parenteral nutrition has been in use since the 1960s [1, 2]. Total parenteral nutrition (TPN) involves providing all of patient’s nutritional needs intravenously and is lifesaving in clinical settings in which adequate enteral based delivery of such nutrition is not possible. It has been one of the most promising modalities of nutrition in neonates, older pediatric patients, and adults with lost or impaired gut function. TPN infusion therapy has grown enormously over the last few decades. There are tens of thousands of patients worldwide permanently dependent on parenteral nutrition (PN) for survival [3]. In addition, there are several fold higher numbers of patients requiring PN for varying duration during hospital stay or home care. Unfortunately, it is also associated with important complications and significant morbidity and mortality, including the well-recognized parenteral nutrition associated liver disease (PNALD) which includes steatosis, cholestasis, disrupted glucose metabolism, disrupted lipid metabolism, cirrhosis, development of portal hypertension, and ultimately liver failure [4, 5]. The
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