We conducted a controlled, randomized trial to study the effect of minimal enteral feeding on leucine uptake by splanchnic tissues, as an indicator of maturation of these tissues, in preterm infants in the first week of life. Within a few hours after birth, while receiving only glucose, a primed constant infusion of [1-13 C]-leucine was started and continued for 5 h via the nasogastric tube, whereas 5,5,5 D3-leucine was infused intravenously (for both tracers, priming dose 2 mg/kg, continuous infusion 2 mg/kg/h). Patients were thereafter randomized to receive solely parenteral nutrition (C), parenteral nutrition and 20 mL breast milk/kg/d (BM), or parenteral nutrition and 20 mL formula/kg/d (F). On d 7, the measurements were repeated, after discontinuing the oral intake for 5 h. Fourteen infants were included in group C, 12 in group BM, and 12 in group F. There was no difference in energy intake or nitrogen balance at any time. On d 1, plasma enrichment for the nasogastric tracer was lower than for the intravenous tracer for all three groups, both for leucine and for ␣-keto-isocaproic acid. On d 7, the enrichment for leucine and ␣-keto-isocaproic acid for the nasogastric tracer was lower than for the intravenous tracer for the groups BM and F (BM: 3.65 Ϯ 1.20 nasogastric versus 4.64 Ϯ 0.64 i.v.; F: 4.37 Ϯ 1.14 nasogastric versus 5.21 Ϯ 0.9 i.v.). In the control group, there was no difference between tracers. The lower plasma enrichment for the nasogastric tracer compared with the intravenous tracer suggests uptake of leucine by the splanchnic tissues. We conclude that minimal enteral feeding-even in low volumes of 20 mL/kg/dincreases the leucine uptake by the splanchnic tissue. We speculate that this reflects a higher protein synthesis of splanchnic tissues in the groups receiving enteral nutrition. Advances in perinatal care have lead to a significant increase in survival of preterm infants. There has been an increasing recognition that nutrition plays an important role in the survival and subsequent growth and development of VLBW infants. Parenteral nutrition is used extensively in clinical care of preterm infants. The timing of initiation of enteral feeding in VLBW infants is still controversial. On one hand, anxiety about necrotizing enterocolitis has prompted neonatologists to delay enteral feeding in VLBW infants. On the other hand, animal studies have shown a negative effect of replacing enteral with total parenteral nutrition on gut morphology and function (1-5). Minimal enteral feeding has been shown to improve gut maturation, as evidenced by improved motility (6, 7). The effect of minimal enteral feeding on protein metabolism of splanchnic tissues, an indicator of anabolism of splanchnic tissues, is unknown. Recently, a model using stable isotopes was described that measures the uptake of leucine administered to the GI tract by splanchnic tissues (8,9). In adult human subjects, 17-25% of orally administered leucine is removed by the splanchnic tissues on first pass (8,10,11). Studies show that 13-40% o...