Project Summary/Abstract Short bowel syndrome (SBS) is often due to the loss of large amounts of small intestine that compromises digestive absorption. The treatments include a high-calorie diet and feeding through the vein (i.e., parenteral nutrition or PN), among others. Many patients cannot wean from PN due to reduced intestinal length or function. Patients on long-term PN frequently experience serious metabolic complications, sepsis, hepatic biliary disorders including cholestasis, and fibrosis and can progress to liver failure. Full intestinal feeding (enteral nutrition) without PN is the optimal way to prevent the above complications. Enterally administered long chain triglycerides in patients with SBS, especially those with hepatic dysfunction, are not well tolerated due to bile acid malabsorption, which leads to decreased micelle formation and fat digestion. The dietary fat is unable to be emulsified by the bile acids and acted on by lipases before exiting the patient as stool. Switching to other forms of fat such as medium-chain triglycerides (MCTs) that do not require micelles for absorption may be better tolerated in patients with bile acid or pancreatic insufficiency but are not optimal as they increase the osmotic load in the intestine. This may increase the chance of stool dumping; moreover, MCTs do not contain essential fatty acids (FAs). The ability to provide the essential FAs such as those present in enteral formulas in a form that does not require the formation of micelles for absorption, would allow patients with SBS and those who are no longer PN dependent to receive adequate nutrition and continue to maintain the same growth trajectory as when they received the majority of their nutrition parenterally. RELiZORB is an enzyme cartridge connected in-line with enteral feed tubing sets designed to mimic the function of pancreatic lipase. It is hypothesized that by using this external lipase device, enteral nutrition will be better absorbed, and PN dependence reduced as enteral autonomy is increased. This product eliminates the need for intestinal emulsification and eliminates the risk of drugs, including lipases, allowing absorption at the time the diet enters the gut. The device has been shown to digest >90% of fat in most enteral formulas. This is a phase 3, open label single center clinical trial to determine the safety, tolerability, and bioavailability of the RELiZORB enzyme cartridge with enteral nutrition when used daily for 90 days in pediatric subjects with SBS, aged 2 years – 18 years, who are PN dependent. The change in PN calories from baseline, assessed weekly, will be evaluated by area under the curve as a mean percentage increase or decrease and presented with a 95% confidence interval. The number (percent) of treatment-emergent adverse events, grade 2 or above, as well as the incidence of abnormalities in vital signs, changes in stool amount/frequency, ostomy output, the need to decrease enteral feeds, changes...