Enteral and Intravenous Supplementation of Arginine and Citrulline Fail To Prevent Necrotizing Enterocolitis in Preterm Neonatal Pigs

Authors

• Caitlin Vonderohe
• Julia Garcia Mancebo
• Valeria Melendez Hebib
• Barbara Stoll
• Inka Didelija
• Sarah Elefson
• Mahmoud Mohammad
• Brooklynn Earls
• Greg Guthrie
• Doug Burrin

Language

English

Publication Date

2-1-2026

Journal

Journal of Parenteral and Enteral Nutrition

DOI

10.1002/jpen.70031

PMID

41221582

PMCID

PMC12865763

PubMedCentral® Posted Date

11-12-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Background: Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency in preterm infants with a morality rate that approaches 50%. Arginine has been widely studied in the field of clinical nutrition as a supplement for patients experiencing critical illness because it can be metabolized into nitric oxide, an important agent for supporting immunity and microcirculation. Citrulline has received less attention but can be metabolized into arginine and has a much longer plasma half-life than arginine. We used the highly translational preterm pig model to determine the effect of intravenous and enteral supplementation of arginine and citrulline on NEC incidence in preterm neonates.

Methods: A total of 67 pigs were delivered by cesarean on day 105 of 115 (analogous to 30 weeks gestation in humans) and allocated to six treatments: preterm infant formula (control; CTL), donor human milk (DHM), formula with arginine (OG ARG) or citrulline (OG CIT), and formula with intravenous arginine (IV ARG) or citrulline (IV CIT). Pigs were monitored for clinical signs associated with NEC, and tissue was collected for later analysis. NEC diagnosis and severity was quantified using previously validated gross and histologic scales.

Results: Enteral and intravenous supplementation of arginine and citrulline did not impact NEC incidence or severity. NEC incidence tended (P < 0.07) to be lower in the DHM pigs. NEC incidence was highest in the CTL (60%), IV ARG (64%), and OG CIT (62.5%) pigs.

Conclusion: Citrulline and arginine supplementation are not feasible or safe nutrition strategies to prevent NEC in preterm neonates.

Keywords

Animals, Arginine, Enterocolitis, Necrotizing, Citrulline, Swine, Enteral Nutrition, Animals, Newborn, Dietary Supplements, Disease Models, Animal, Female, Milk, Human, Infant Formula, Administration, Intravenous, Humans, Infant, Newborn, critical care, enteral formulas, enteral nutrition, neonates, parenteral nutrition, pediatrics, proteins

Published Open-Access

yes

Recommended Citation

Vonderohe, Caitlin; Garcia Mancebo, Julia; Melendez Hebib, Valeria; et al., "Enteral and Intravenous Supplementation of Arginine and Citrulline Fail To Prevent Necrotizing Enterocolitis in Preterm Neonatal Pigs" (2026). Children’s Nutrition Research Center Staff Publications. 361.
https://digitalcommons.library.tmc.edu/staff_pub/361