Restoring Blood Flow to the Neonatal Gut Following IV Feeding: The Roles of Dietary Arginine and Citrulline.

Arginine is a nutritionally and metabolically important amino acid for the neonate that is synthesized in the small intestine (SI) in early life. Deficiency in preterm infants has been associated with severe complications such as necrotizing enterocolitis. Arginine is involved in the synthesis of proteins, creatine, urea and polyamines and is the substrate for nitric oxide synthase to produce nitric oxide (NO); NO inhibits vascular smooth muscle contraction to enhance blood flow. Citrulline may also be used as a precursor for NO synthesis. A high-risk time for feeding preterm neonates occurs during the transition from intravenous (parenteral) nutritional support (PN) to oral (enteral) feeding. We speculated that greater dietary arginine or citrulline will lead to better gut morphology during this transition phase. In piglets with SI atrophy induced by PN-feeding, we hypothesized that supplemental dietary arginine or citrulline would lead to greater NO production, higher blood flow to the intestine and structural and functional improvements in the intestinal mucosa.
Piglets (7-10 d old, n = 20) were implanted with jugular and femoral vein and gastric catheters. An ultrasonic flow probe was secured around the superior mesenteric artery (SMA). Piglets were supported by PN for 3-4 days to induce intestinal atrophy then randomized to enteral re-feeding with one of three elemental formulas: arginine intake equivalent to sow’s milk (low Arg), 2.5 times the sow milk concentration (high Arg) or the difference in the arginine between the low and high Arg groups being replaced with citrulline (Cit group). The PN and enteral diets were infused continuously. SMA blood flow was measured for 10 hours on day 4 starting with the initiation of enteral feeding. On day 5, piglets underwent a 6-hour isotope tracer experiment to measure whole body protein and NO synthesis. Blood flow increased significantly with enteral feeding, with a significantly higher flow after 6 hours of feeding in the Cit group compared to both the high and low Arg groups. Whole body protein synthesis was higher in the high Arg group compared to the low Arg group (P = 0.038). Analysis of NO synthesis is ongoing but will provide a sensitive indicator of the adequacy of arginine or citrulline to maintain intestinal blood flow. Dietary arginine at the concentration in milk may not meet the whole body needs of the neonate with compromised SI function.