Citrulline (CIT) is an amino acid that is not involved in protein synthesis but that is tightly linked to arginine (ARG) metabolism. CIT displays a very specific metabolism: In the 1980s, Windmuller demonstrated that the small intestine releases CIT, which is mainly taken up by the kidney and metabolized into ARG……..These observations have led to the concept that plasma CIT concentration would be a good marker of intestinal failure in short bowel syndrome. Hence, in massive intestinal resection, citrullinemia is greatly reduced, and this is proportional to the severity of the intestinal disease……. CIT supplementation is able to restore nitrogen balance, generate large amounts of ARG in rats with short bowel syndrome, and increase muscle protein content (+20%) as well as muscle protein synthesis (+90%) in elderly malnourished rats. Finally, recent data indicate that CIT per se could be able to stimulate muscle protein synthesis. Hence, CIT could play a pivotal role in maintaining protein homeostasis, and the determination of the underlying mechanisms involved in its action should be important for the development of new nutritional strategies in malnourished patients with compromised intestinal functions.

o      Moinard, C, & Cynober, L. (2007). Citrulline: a new player in the control of nitrogen homeostasis. J Nutr, 137, 1621S-5S.

Protein energy malnutrition is common in the elderly, especially in hospitalized patients. The development of strategies designed to correct such malnutrition is essential. Our working hypothesis was that poor response to nutrition with advancing age might be related to splanchnic sequestration of amino acids, which implies that fewer amino acids reach the systemic circulation. Administration of citrulline, which is not taken up by the liver, can offer a means of increasing whole body nitrogen availability and, hence, improve nutritional status……… The standard diet did not have any effect on protein synthesis or on the protein content in the muscle. Citrulline supplementation led to higher protein synthesis and protein content in muscle………… For the first time, a realistic therapeutic approach is proposed to improve muscle protein content in muscle in frail state related to malnutrition in aging.

o      Osowska, S et al. (2006). Citrulline modulates muscle protein metabolism in old malnourished rats. Am J Physiol Endocrinol Metab, 291(3), 582-6.

Citrulline, a nonprotein amino acid, is an important source of endogenous arginine. The gut is the main source of citrulline in humans. Hence, citrulline is a potential biomarker of short bowel function. Conversely, citrulline uptake by the gut is important for an oral supply of this amino acid as an alternative to arginine………….Citrulline is easily taken up by the gut, with a broad set of transporters that can remove it from the lumen in the enterocytes. This is confirmed by pharmacokinetic studies and the efficacy is so great that oral complementation with citrulline seems more efficient than complementation with arginine to provide arginine.

 o      Curis, E, Crenn, P, & Cynober, L. (2007). Citrulline and the gut. Curr Opin Clin Nutr Metab Care, 10(5), 620-6.

BACKGROUND: The amino acid arginine plays a key role in many metabolic processes in health and disease. Low arginine concentrations are found in various illnesses in children. OBJECTIVE: The objective was to investigate the relation between plasma concentrations of arginine (and precursor amino acids) and severity of inflammation in critically ill children…………. CONCLUSIONS: Plasma concentrations of arginine and citrulline are low during the acute phase of critical illness in children and normalize again during recovery. Plasma arginine and citrulline are strongly related to the severity of inflammation indicated by plasma CRP concentrations.

 o      van Waardenburg, DA, de Betue, CT, Luiking, YC, Engel, M, & Deutz, NE. (2007). Plasma arginine and citrulline concentrations in critically ill children: strong relation with inflammation. Am J Clin Nutr, 86(5), 1438-44.

BACKGROUND: L-Arginine is an important precursor of nitric oxide (NO) and protein synthesis. Arginine is produced in the body (mainly kidney) by de novo production from citrulline and by protein breakdown. Arginine availability appears to be limited in sepsis. OBJECTIVE: The objective was to compare arginine and citrulline metabolism in septic patients and nonseptic control patients in an intensive care unit (ICU) and in healthy control subjects……… CONCLUSIONS: Citrulline production is severely low in patients with sepsis and is related to diminished de novo arginine and NO production. These metabolic alterations contribute to reduced citrulline and arginine availability, and these findings warrant further studies of therapeutic nutritional interventions to restore arginine metabolism in sepsis.

o      Luiking, YC, Poeze, M, Ramsay, G, & Deutz, NE. (2009). Reduced citrulline production in sepsis is related to diminished de novo arginine and nitric oxide production. Am J Clin Nutr, 89(1), 142-52.

OBJECTIVE: Watermelon is a rich source of citrulline, an amino acid that can be metabolized to arginine, a conditionally essential amino acid for humans. Arginine is the nitrogenous substrate used in the synthesis of nitric oxide and plays an essential role in cardiovascular and immune functions. No detailed studies have been conducted to evaluate plasma arginine response in humans after long-term feeding of citrulline from natural plant sources. This study investigated if watermelon juice consumption increases fasting concentrations of plasma arginine, ornithine, and citrulline in healthy adult humans……… CONCLUSION: The increased fasting plasma concentrations of arginine and ornithine and stable concentrations of plasma citrulline in response to watermelon juice consumption indicated that the citrulline from this plant origin was effectively converted into arginine. These results demonstrate that plasma concentration of arginine can be increased through intake of citrulline from watermelon.

o      Collins, JK et al. (2007). Watermelon consumption increases plasma arginine concentrations in adults. Nutrition, 23(3), 261-6.

Background: Arginine depletion by the enzyme Arginase I, decreases expression of the TCR chain preventing T-cell activation and causing T-cell dysfunction. We hypothesized that citrulline could substitute for arginine under conditions of increased arginase expression. Thus, the goal was to establish a possible mechanism of how citrulline could overcome arginine depletion caused by arginase………….. Conclusions: T cells exhibit the molecular capability of increasing citrulline membrane transport and up-regulating AS expression, thus exhibiting the necessary mechanisms for converting citrulline into arginine and escaping the ill effects of arginine depletion. Therefore, citrulline has the potential to be a substitute for supplemental arginine in diseases associated with arginase-mediated T cell dysfunction.

o      Bansal, V et al. (2004). Citrulline can preserve proliferation and prevent the loss of cd3 chain under conditions of low arginine. Journal of Parenteral and Enteral Nutrition, 28(6), 423-30.