BASIC SCIENCE ARTICLE Intestinal resection affects whole-body arginine synthesis in neonatal piglets Marihan Lansing 1 , George Slim 1 , Pamela Wizzard 1 , Mahroukh Rafii 2 , Paul B. Pencharz 3 , Patrick N. Nation 4 , Megan R. Beggs 5 , R. Todd Alexander 1,5 , Paul W. Wales 1,2,6 , Justine M. Turner 1 and Ron O. Ball 7 BACKGROUND: Previous studies in piglets show a direct relationship between intestinal mass and arginine (Arg) synthesis. We aimed to study the effects of 75% intestinal resection on whole-body Arg synthesis. METHODS: Piglets were allocated to sham or jejunocolic (JC) surgery and to enteral nutrition (EN) at 20% [sham (n = 8), JC (n = 10)], or 40% [sham (n = 4), JC (n = 5)]. A gastric tube was placed for EN and a venous catheter for parenteral nutrition and blood sampling. On day 6, a primed bolus and constant infusion of Arg m + 2 label and proline m + 1 label was delivered. In addition, 40% EN piglets received a citrulline (Cit) m + 3 tracer. Blood sampling was undertaken and whole-body Arg synthesis was calculated. On day 7, intestinal length was measured, and samples were collected for gene expression (PCR quantification) and histopathology. RESULTS: On Day 7, sham piglets showed intestinal lengthening compared to JC (p = 0.02). Whole-body Arg synthesis was similar between groups (p = 0.50). Adjusting for absolute small intestinal length, JC piglets had greater Arg synthesis (p = 0.01). Expression of arginosuccinase was upregulated in the jejunum of JC compared to sham on 20% EN (p = 0.03). CONCLUSION: This demonstrates for the first-time adaptive changes in intestinal Arg synthesis following intestinal resection. Pediatric Research (2021) 89:1420–1426; https://doi.org/10.1038/s41390-020-01139-1 IMPACT: ● The intestine makes a critical contribution to whole-body arginine synthesis, particularly in neonates, a human population at risk for short bowel syndrome. Therefore, we studied intestinal arginine synthesis in a neonatal piglet model of short bowel syndrome and demonstrated adaptive changes in the intestine that may preserve whole-body arginine synthesis, despite loss of intestinal mass. ● This research adds new information to our understanding of the effects a massive intestinal resection has on amino acid metabolism during neonatal development. INTRODUCTION Short bowel syndrome (SBS) is the leading cause of intestinal failure (IF) in children. IF results in the inability to absorb sufficient nutrients for normal growth and survival. 1 Preterm infants are the most vulnerable, having an increased risk of developing necrotizing enterocolitis (NEC), a leading cause of SBS in this population. 1 One accepted definition of SBS comes from the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, and states that SBS is defined as a parenteral nutrition (PN) requirement for more than 60 days following intestinal resection, or when the remnant intestine is less than 25% of what is expected for age. 2 Following significant intestinal resection, the residual intestine undergoes both structural and functional changes that allow for independence from PN—a process called intestinal adaptation. 3 In growing neonates and infants it has been shown that adaptation can take many years. 4 The intestine is an important site for whole-body amino acid metabolism, particularly for glutamine (Gln), arginine (Arg), methionine, glycine, lysine, threonine, and citrulline (Cit). 5 The small intestine contributes up to 60% of whole-body Arg synthesis and in the TPN-fed piglet model, mucosal mass and Arg synthesis are directly related. 6 In preterm infants, growing children, and critically ill adults, Arg is considered a conditionally essential amino acid. 7 It has important roles in immune function, ammonia detoxification, synthesis of polyamines, nitric oxide (NO) produc- tion, and creatine synthesis. 8 Further, preterm infants with NEC have lower plasma Arg and Arg supplementation decreases the incidence of NEC in this population. 9,10 The dietary precursors for intestinal Arg synthesis include proline (Pro), Gln, and Cit. We have shown in piglets that first pass intestinal metabolism of an enterally fed diet is responsible for 40–60% of Arg synthesis from Pro. 11 The orally administered Gln increases synthesis of Cit and Arg more than the parenteral Received: 4 June 2020 Revised: 1 August 2020 Accepted: 6 August 2020 Published online: 13 September 2020 1 Department of Pediatrics, University of Alberta, Edmonton, AB, Canada; 2 Research Institute, The Hospital for Sick Children, Toronto, ON, Canada; 3 Departments of Pediatrics and Nutritional Sciences, University of Toronto, Toronto, ON, Canada; 4 Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada; 5 Department of Physiology at the University of Alberta, Edmonton, AB, Canada; 6 Division of General and Thoracic Surgery, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada and 7 Department of Agricultural, Life & Environmental Sciences, University of Alberta, Edmonton, AB, Canada Correspondence: Justine M. Turner (Justine.turner@albertahealthservices.ca) www.nature.com/pr © International Pediatric Research Foundation, Inc 2020 1234567890();,: