Research Advancements in Preventing Parenteral Nutrition-Associated Cholestasis

Research study background

Many infants and young children suffering from intestinal failure, including short bowel syndrome and necrotizing enterocolitis, must receive parenteral nutrition (PN) to survive. However, prolonged use of PN increases the risk of developing parenteral nutrition-associated cholestasis (PNAC), a serious complication impacting liver function that can progress to end-stage liver disease or the need for liver transplantation if not treated quickly.

Ronald Sokol, MD, Chief Scientific Officer, Child Health, and his research team in the Digestive Health Institute at Children’s Hospital Colorado have spent years studying PNAC, seeking new ways to treat and prevent the disease in these vulnerable patients. More than a decade ago, the team replicated the human pathophysiology of PNAC to better understand how it develops and progresses. Their model includes key features observed in affected infants, including intestinal microbial imbalance (dysbiosis), activation of liver macrophages and accumulation of bile acids and phytosterols in the liver.

Previously, the team, which included Swati Ghosh, PhD, used the model to investigate the role of a nuclear receptor called liver receptor homolog-1 (LRH-1) in key metabolic and inflammatory pathways. They demonstrated that dilauroylphosphatidylcholine (DLPC), a phospholipid and LRH-1 agonist, could mitigate liver injury, however, the underlying mechanisms of DLPC's protective effects were not known.

The murine model was used again in this study to better understand how DLPC regulates the inflammatory response in macrophages and hepatocytes and offers protection during PNAC. They found LRH-1 expression in macrophages is induced by DLPC via a mechanism dependent on the signal transducer and activator of transcription 6 (STAT6) protein. This led to the inhibition of the complex protein, nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB), which reduced inflammation.

Clinical implications

When PNAC murine models were intravenously treated with DLPC, it prevented liver injury and cholestasis by normalizing blood chemistry levels and restoring the expression of key transporters in liver cells responsible for bile and sterol movement. It also protected the liver by decreasing M1 macrophages, the harmful inflammatory liver cells, and increasing M2 macrophages, the anti-inflammatory cells that promote healing.

The implications of this study are significant, suggesting that therapies activating LRH-1, such as DLPC, could potentially treat or prevent PNAC. Although no studies have yet explored this therapeutic approach in infants, children or adults, these findings indicate its potential viability. Future studies are examining pathways activated by LRH-1 that may explain the beneficial effects of the DLPC and may identify potential additional targets to prevent or treat PNAC.