Next Article in Journal
Effect of Diet and Dietary Components on the Composition of the Gut Microbiota
Next Article in Special Issue
Therapeutic Potential of Various Plant-Based Fibers to Improve Energy Homeostasis via the Gut Microbiota
Previous Article in Journal
Vitamin D and Hashimoto’s Thyroiditis: Observations from CROHT Biobank
Previous Article in Special Issue
The Western Dietary Pattern Combined with Vancomycin-Mediated Changes to the Gut Microbiome Exacerbates Colitis Severity and Colon Tumorigenesis
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Nutrients
Volume 13
Issue 8
10.3390/nu13082794
nutrients-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Citrulline, Biomarker of Enterocyte Functional Mass and Dietary Supplement. Metabolism, Transport, and Current Evidence for Clinical Use

by
Stefano Maric
1,†,
Tanja Restin
2,3,*,†,
Julian Louis Muff
1,
Simone Mafalda Camargo
2,
Laura Chiara Guglielmetti
4,
Stefan Gerhard Holland-Cunz
5,
Pascal Crenn
6 and
Raphael Nicolas Vuille-dit-Bille
2,5
1
School of Medicine, University of Basel, 4001 Basel, Switzerland
2
Institute of Physiology, University of Zurich, 8091 Zurich, Switzerland
3
Newborn Research Zurich, Department of Neonatology, University Hospital Zürich and University of Zurich, 8091 Zurich, Switzerland
4
Department of Visceral und Thoracic Surgery, Cantonal Hospital of Winterthur, 8400 Winterthur, Switzerland
5
Department of Pediatric Surgery, University Children’s Hospital of Basel, 4001 Basel, Switzerland
6
Hepato-gastroenterology and Nutrition, Hôpital Ambroise Paré, Boulogne Billancourt, APHP-Université Paris Saclay, 92100 Boulogne-Billancourt, France
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Nutrients 2021, 13(8), 2794; https://doi.org/10.3390/nu13082794
Submission received: 22 June 2021 / Revised: 28 July 2021 / Accepted: 28 July 2021 / Published: 15 August 2021
(This article belongs to the Special Issue Nutritional Interventions to Shift the Gut Microbiome for Gut and Systemic Health)
Browse Figures
Review Reports Versions Notes

Abstract

:
L-Citrulline is a non-essential but still important amino acid that is released from enterocytes. Because plasma levels are reduced in case of impaired intestinal function, it has become a biomarker to monitor intestinal integrity. Moreover, oxidative stress induces protein citrullination, and antibodies against anti-citrullinated proteins are useful to monitor rheumatoid diseases. Citrullinated histones, however, may even predict a worse outcome in cancer patients. Supplementation of citrulline is better tolerated compared to arginine and might be useful to slightly improve muscle strength or protein balance. The following article shall provide an overview of L-citrulline properties and functions, as well as the current evidence for its use as a biomarker or as a therapeutic supplement.

1. Introduction

L-Citrulline is a non-essential and non-proteinogenic amino acid (AA), which has first been isolated by Koga out of water melon juice [1]. The presence in human proteins has been suspected for a long time [2], and it has been shown that posttranslational modification, called citrullination or deamination, plays a major role and is associated with inflammatory disease [3,4]. Citrulline has antioxidant and vasodilation properties and belongs to the human nitric oxide system [5]. In addition, both for undernourished and sarcopenic aged patients [6] and for sports purposes [7], possible anabolic effects after oral supplementation are suggested. Circulating citrulline is released from small intestinal enterocytes, predominantly in its proximal sections of jejunum and duodenum [8], where it is synthesized de novo from precursor AAs deriving from either nutritional proteins or systemic circulation [9,10]. Because the kidney is the main organ to metabolize citrulline into arginine, high plasma citrulline levels may reflect kidney failure [11]. Most nutrients do not contain relevant amounts of citrulline; however, there are about 7–14 mg citrulline per g dry weight of watermelon and 1.9 mg per g fresh weight [12]. In order to know more about the physiological properties of citrulline we performed a structured literature research and hereby summarize the signaling pathways of citrulline and the current evidence for its clinical use.
Literature research has been performed in April 2021 with the terms “citrulline” AND (“clinical trials” OR “trials”) mentioned in the abstract or title. The research databases Pubmed, EMBASe, and Cochrane Library were accessed, and case reports and animal studies have been excluded. Afterwards, doubles were erased, and the remaining literature was clustered by T.R. and J.L.M. and summarized in the following review. Important animal data that were repetitively cited in these studies retrieved above are also summarized in this review.
The structured research found 389 articles, the same search on EMBASE explicitly excluding case reports or animal studies found 301 hits, and the Cochrane Library retrieved 263 articles. A total of 184 records were at least reported twice and erased. However, 153 published articles referred to rheumatological diseases where citrullinated proteins are mainly used as biological markers for disease severity. A total of 52 articles assess the effect of citrulline supplementation on sportive executive functions. These studies show small but positive effects of citrulline supplementation on high-intensity strength that are summarized within the review by Trexler et al. [13]. A total of 44 articles deal with the potential effect of citrulline on hypertension and its effect on vessel tone. However, a meta-analysis published in 2018 analyzed the potential effect of citrulline supplementation on blood pressure but has not found any significant effect [14]. In 19 articles, citrulline as a marker for intestinal function or as a potential supplement in cases of intestinal diseases is discussed. The remaining articles either just mentioned citrulline related to certain diseases or assessed protein status and metabolics after citrulline supplementation in different persons or were unrelated to the topic. The PRISMA flow diagram is displayed in Figure 1. A summary of the included studies can be found in the Appendix A, Appendix B, Appendix C and Appendix D.

2. Results

2.1. Citrulline Precursors, Metabolism and Inter-Organ Relationship

Glutamate represents a crossroad between AA and carbohydrate metabolism. It can serve as a source of all known precursors for intestinal citrulline synthesis, which are glutamine [15,16,17], arginine [18,19], proline [20], and ornithine [9,18,21]. Glutamine has generally been considered as the main precursor of intestinal citrulline synthesis [10,17], and glutamine supplementation was shown to increase intestinal citrulline and renal arginine synthesis [17,19]. Glutamine depletion from the diet was correlated with decreased plasma citrulline levels in humans [22]. However, some studies suggest glutamine to be a nonspecific nitrogen (and carbon) donor [23]. This discrepancy results from the kind of precursors used in metabolic studies. When oral 15N-glutamine was used as a precursor, an enrichment in 15N-citrulline can be observed, and it is responsible for approximately 5% of the nitrogen of circulating citrulline [24]. When 13C-glutamine was used, a negligible (0.4%) incorporation into circulating citrulline was detected. Orally administered U-13C-arginine or U-13C-proline accounted for 40% and 3.4% of the circulating citrulline, respectively [20,25]. Therefore, the relative contribution of each precursor to plasma citrulline synthesis in humans remains controversial [26].
The citrulline production, metabolism, reabsorption, and turnover involve the intestines, the liver (for ureagenesis), and the kidneys, as displayed in Figure 2. Citrulline in enterocytes, as in hepatocytes, is made from ornithine in the mitochondrial matrix by the enzyme ornithine carbamyltransferase (OCT), one of the key enzymes in citrulline synthesis and in the urea cycle [21]. In contrast to hepatocytes, where the synthesized citrulline is compartmentalized as an intermediate of the urea cycle and does not contribute to systemic (circulating) citrulline flux, enterocytes show only a low expression of argininosuccinate synthetase (ASS) [27] and argininosuccinate lyase (ASL), the two enzymes that subsequentially interconvert citrulline to arginine. Citrulline, following synthesis in small intestinal enterocytes, is released across the basolateral membrane into portal circulation [10,21,28]. Unlike other AAs, citrulline is poorly taken up by hepatocytes, therefore bypassing liver metabolism and entering systemic circulation at a level of 10.4–13.6 µmol per kg and hour [21,29]. It has been shown that citrulline uptake into renal epithelial cells can occur both apically from primary urine [30] as well as basolaterally from the capillary system [30]. After filtration (at the glomeruli in the kidney) most of the citrulline is reabsorbed by proximal tubule kidney cells [31]. The almost complete reabsorption of plasma AAs prevents their urinary loss and helps to maintain homeostasis [32]. Proximal kidney tubule cells hereby use a similar set of luminal and basolateral amino acid transporters (AATs) for AA reabsorption from the primary urine as the small intestine for absorption of digested dietary proteins [32]. In the proximal kidney tubule cells, citrulline is converted by ASS and ASL into arginine, which is released into systemic circulation for use by peripheral tissues. Citrulline delivery to the kidney (and therefore circulating plasma citrulline concentration) represents the rate-limiting step of renal arginine synthesis [33]. Pharmacokinetic studies with oral citrulline supplementation have shown a dose-dependent increase in plasma citrulline, arginine, and ornithine levels [34]. Furthermore, plasma citrulline has been shown to be augmented following oral citrulline supplementation [22].
This metabolic interaction between the small intestine and the kidneys is known as the intestinal-renal axis and is believed to provide arginine supply to peripheral tissues, which would otherwise be taken up by the liver and induce ureagenesis and hence AA catabolism [35]. Citrulline is therefore seen as a form to avoid excessive hepatic metabolism of AAs. This mechanism is mainly activated in conditions with low protein intake, as in a post-absorptive (fasting) state [36]. However, in very preterm children, citrulline might be converted into arginine directly by the gut in situ [37]. Citrulline may serve to support protein anabolism in states of low protein intake [38,39]; this way, citrulline helps to limit the plasmatic arginine decrease [40,41]. Moreover, endogenous arginine and citrulline production is increased in the case of lowgrade inflammation with increased NO production rates such as chronic obstructive lung disease [42]. The intestinal-renal axis underlies a maturation process because kidneys produce arginine from citrulline in the presence of ASS and ASL, which is differentially expressed depending on age [43]. Consequently, plasma citrulline concentration is lower in neonates compared to adult individuals and increases during development [21,44]. If the kidneys are dysfunctional, citrulline is directly metabolized to arginine in the enterocytes, which show a high expression of ASS and ASL, but low arginase expression [15,36].

2.2. Causes for High and Low Plasma Citrulline Levels

Normal plasma citrulline concentrations in healthy adults have been defined as 40 (±10) µmol/L [45,46]. Both elevations and reductions in citrulline levels can either be inherited or acquired and are summarized in Table 1. Increased citrulline levels can be caused by rare inborn errors of disease such as citrullinemia, which is caused by a deficiency of ASS that leads to elevated levels of blood citrulline and ammonia, ending in hyperammonemic coma and early death [47,48]. Likewise, the deficiency of ASL accumulates argininosuccinic acid with deficient endogenous arginine production and high levels of ammonia and neurocognitive decline [49]. If ASS and ASL activity are reduced due to kidney failure, citrulline elevations may be noticed, too [50]. The adult-onset type II citrullinemia is caused by a defect in the mitochondrial aspartate-glutamate carrier [51]. Unlike the disease conditions described above, a physiological increase in citrulline has been described after improvement of the intestinal absorption capacity, such as after intestinal lengthening [52], bariatric surgery [53], or after enterotrophic treatment with teduglutide (glucagon-like peptide 2), which increases intestinal mucosal growth and trophic function [54,55]. In contrast, lowered citrulline levels have been detected due to deficiencies in carbamoyl phosphate synthetase 1 (CPS1) [56] and OTC [57] because they limit the turnover from ornithine to citrulline in mitochondria. It seems that prematurity can potentially be associated with lowered citrulline levels [58], but it is difficult to differentiate this lowering from lower levels due to any inflammatory process. Any condition that is associated with a reduced absorptive intestinal capacity has been associated with reduced citrulline levels and will be discussed in detail (see below).
The importance of intestinal nutrient absorption becomes evident in situations of intestinal failure. Intestinal failure reflects the reduction in functional small bowel below the minimum necessary for digestion and absorption to maintain growth in children and/or homeostasis in children and adults. The most common etiology is short bowel syndrome (SBS), which describes a reduction in anatomical and functional bowel length [64,65,66,67]. Several diseases of the gastrointestinal tract, including necrotizing enterocolitis (NEC), intestinal atresia [68], midgut volvulus, and long-segment Hirschsprungs’ disease in children, as well as mesenteric ischemia, Crohn’s disease, and irradiation in adults [65], may lead to extensive damage and/or intestinal resections ending in SBS [69]. Patients with chronic intestinal failure can be dependent on long-term parenteral nutrition with its inherent morbidity and mortality, including (repeated) catheter-associated sepsis, cirrhosis, and liver failure [69]. While many factors seem to play a role, the length of the remnant intestine and the type of digestive anastomosis reflects a major determinant of patient survival and nutritional prognosis [67,70,71].
Significant reduction in plasma citrulline concentration has been shown in various pathologies of the digestive tract [46], including NEC [72], SBS [73,74,75,76,77,78], villous atrophy including celiac disease [8], acute mucosal enteropathy of various etiology such as mucositis after antineoplastic treatment, chemotherapy and/or radiotherapy [79,80], HIV enteropathy [81] and acute enteric infection or graft rejection after short bowel transplantation [82,83]. Plasma citrulline can also be decreased in critically ill patients with intestinal dysfunction in the intensive care unit [63,84]. Interestingly, early antibiotic use seems to be associated with lower citrulline levels and lower performance and survival rates in patients with non-small-cell lung cancer, which might possibly be associated with the changed microbial profile [85]. In post-surgical conditions (SBS) the threshold, for the parenteral nutrition autonomy is 20 mol/L, whereas, in medical conditions, the threshold is 10 mol/L [8,45,46,86] . Some of these studies also suggested a correlation between plasma citrulline and intestinal adaptation after small bowel resection, the dependence of nutritional support, and absorptive function of the intestine [73,74,75,76]. Finally, plasma citrulline was elevated in animal models and pediatric patients following intestinal lengthening using serial transverse enteroplasty (STEP) [87,88]. Consequently, citrulline is a potential sensitive biomarker for small intestinal absorptive function [45,86,89]. It can be clinically useful to monitor citrulline levels of patients before and after intestinal surgery and to predict absorption even before enteral feeds are started [61].
Surgical treatments aim to elongate the small intestine in order to increase its absorptive capacity, especially in pediatric patients. Among different surgical treatment options, longitudinal intestinal lengthening and tailoring (LILT), first described by Bianchi in 1980 [90], and STEP are the most commonly used [87]. Unfortunately, both procedures reconfigure the intestinal morphology (making a long thin tube out of a short thick tube) without creating more luminal surface area. As the LILT procedure is technically very demanding and more prone to complications, the outcomes following STEP seem to be more favorable and can potentially be repeated [88].

2.3. Citrulline and Cancer

In nine children with AML, citrulline was significantly lower after chemotherapy (27 plasma samples) and positively correlated with scores for mucosal integrity [91]. Hepatocellular carcinoma, which often lacks ASS, is commonly dependent on arginine metabolism. Consequently, several studies assessed arginine-depleting strategies such as treatment via pegylated arginine deiminase [92] or arginase [93]. Both treatment strategies led to higher plasma levels of citrulline. There is a debate whether arginine depletion might also be useful in other ASS deficient cancer types. In a study including 68 patients with ASS1 deficient mesothelioma, Szlosarek demonstrated a prolonged progression-free survival and a reciprocal increase in citrulline after treatment with pegylated arginine deiminase [94]. When this medicament was used against glioma-, melanoma- or other ASS1 deficient malignancies, a similar rise of citrulline has been noted [95,96]. Likewise, parenteral glutamine substitution has been associated with higher citrulline levels [97]. However, in melanoma patients, a decrease in citrulline levels after treatment with pegylated interferone y was noted, which has been attributed to lower NO production [98]. The largest study of citrulline assessment in cancer patients involves 957 patients where citrullinated histone, an accepted marker for neutrophil extracellular trap (NET) formation, was shown to correlate with patient mortality [99].

2.4. Intestinal Amino Acid Transporters and Transport Mechanisms—Application to Citrulline

AAs are polar molecules and therefore rely on a variety of transport proteins to cross the lipid bilayer of cell membranes (such as small intestinal enterocytes or proximal kidney tubule cells). AATs are a heterogeneous group of transmembrane proteins that vary in terms of substrate specificity, transport mechanism, transport kinetics, tissue-specific expression, cellular distribution within a cell, and dependence on protein subunits [100]. In this review, we will focus on apical membrane transporters involved in the uptake of L-citrulline and especially its precursors. At the basolateral membrane, we will discuss transporters involved in citrulline efflux from cells. More information about AAT in epithelial cells (not restricted to citrulline and its precursors) can be found elsewhere [100,101,102,103].

2.5. Brush-Border Membrane Transporters for Citrulline Precursors in Small Intestinal Enterocytes

Transport of almost all neutral AA across the apical enterocyte (and proximal tubule) membrane is largely mediated by the transporter B0AT1 (SLC6A19), a broad specificity sodium-dependent symporter using the sodium gradient created by the basolateral Na-K-ATPase as driving force [104,105,106]. Heterodimeric AAT b0,+AT-rBAT (SLC7A9-SLC3A1) functions as an obligatory AA exchanger providing transport (exchange) of cationic (such as arginine) and neutral AAs [107]. b0,+AT-rBAT is composed of two subunits, a type II membrane protein (heavy chain; b0,+AT) and a polytopic membrane protein (light chain; rBAT) bound together via a disulfide bridge [108,109]. Other luminal membrane transporters such as IMINO transporter SIT1 (SLC6A20) and the proton-dependent AA transporter PAT1 (SLC36A1) provide transport of proline, glycine, and some other neutral AAs to some extent [32]. Interestingly, both neutral AATs, B0AT1 and SIT1 (but not the other transporters mentioned) depend on the presence of accessory proteins for being expressed in the luminal cellular membrane, whereas the B0AT1 and SIT1 expression in kidney proximal tubule cells’ brush-border membrane depends on co-expression of type I membrane protein collectrin (TMEM27) [110], expression of the same transporters in small intestinal enterocytes depends on the presence of its structural homolog ACE2 (as shown in ACE2 knock-out mice) [32,111]; ACE2 (angiotensin-converting enzyme 2) is a membrane-bound monocarboxypeptidase that hydrolyzes luminal peptides and provides AAs for transmembrane transport. Moreover, ACE2 has also been identified as a functional receptor for the SARS coronavirus (SARS-CoV) in 2003 and more recently for SARS-CoV-2 [68,112,113,114,115]. Finally, the proton-dependent peptide transporter PEPT1 (SLC15A1) transports citrulline precursors (including glutamine, arginine, glutamate, and proline) as di- or tripeptides [116]. PEPT1 seems to be important to provide sufficient AA uptake when AATs become saturated after high dietary protein intake [117].

2.6. Citrulline Transport—Luminal Membrane

As previously indicated, citrulline is a non-proteinogenic AA. Therefore, it is not incorporated in human protein biosynthesis, nor does it appear in nutritional proteins in substantial quantities, except essentially in watermelon [12]. Citrulline transport across the luminal enterocyte membrane hence seems to be of minor importance. As a functional characterization of AA transporters (i.e., testing substrate specificities of different AAs for a certain transporter) mainly focused on proteinogenic AA, transport of citrulline has not been shown yet and remains unknown (to the best of our knowledge). Based on transported substrates and their structural similarity with citrulline, it has been suggested that citrulline transport across the luminal membrane of proximal tubule kidney cells (and small intestinal enterocytes) is mediated by AATs B0AT1 (SLC6A19) and b0,+AT (SLC7A9) [31,118,119].

2.7. Amino Acid Transport—Basolateral Membrane

Basolateral AA efflux from small intestinal enterocytes is mediated by two different types of transporters: uniporters and heterodimeric AA exchangers. To enable net efflux of all proteinogenic AAs from small intestinal enterocytes, a functional interaction between these different transport types is necessary. Equilibration of essential neutral AAs along their concentration gradients between enterocytes and the extracellular space is mediated by the two low-affinity uniporters for essential AAs, LAT4 (SLC43A2) and TAT1 (SLC16A10). LAT4 belongs to the sodium-independent large neutral AA transporter family “system L” and acts as low-affinity facilitated diffusion protein for branched-chain AAs (leucine, isoleucine, valine) [120], as well as for phenylalanine and methionine [121]. TAT1 transports aromatic AAs (tyrosine, tryptophan, phenylalanine) [122,123].
Neutral and cationic AAs are transported by the exchangers LAT1 (SLC7A5), LAT2 (SLC7A8), y+LAT1 (SLC7A7), and y+LAT2 (SLC7A6), with LAT2 and y+LAT1 being expressed primarily and at a much higher level in resorbing epithelia such as the small intestine and the renal tubular cells [124,125]. The heavy chain 4F2 (SLC3A2) hereby binds to different light chains in the basolateral membrane, including LAT1, LAT2, y+LAT1, and y+LAT2 [108,109].

2.8. Citrulline Transport—Basolateral Membrane

As for B0AT1 and b0,+AT in the luminal membrane, transport of citrulline across the basolateral membrane remains unknown from the literature, as mainly proteinogenic AAs were tested as putative transporter candidates in the past (to the best of our knowledge). Reviewing transport specificities and structural similarities of proteinogenic AAs (to citrulline) accepted by the named transporters makes LAT2 and y+LAT1 the most valuable candidates for basolateral citrulline transport [109,119,126]. As these AA exchangers exchange AAs in a 1:1 ratio, they rely on the co-expression of uniporters such as LAT4 and TAT1. As LAT4 has a quite narrow substrate specificity [120,121], citrulline transport by LAT4 seems unlikely. Nevertheless, citrulline levels in amniotic fluid and plasma were reduced in LAT4 knock-out mice, indicating LAT4 as a functional partner providing extracellular substrates for LAT2/y+LAT1-mediated citrulline exchange [28,121].

2.9. Citrulline and Intensive Care Treatment

The review found 11 articles that referred to ICU treatment; however, most of them deal with arginine or protein supplementation. In six studies, citrulline is men-tioned in detail: in these patients. Three studies measured serum citrulline in these patients. Ware et al. analyzed 135 patients with severe sepsis and found out that those 44 with ARDS at ICU entrance had lower citrulline levels (mean 6, IQR 3.3–10.4 µmol/L) compared to those without ARDS (mean 10.1 (6.2–16.6 µmol/L)). Piton analyzed the effect of 3 days of enteral nutrition in patients with severe sepsis and found that those with enteral nutrition rose from 12.2 to 18.7 µmol/L while those on parenteral nutrition who started with 13.3 had a citrulline level of 15.3 µmol/L. In patients with severe sepsis, only low levels of citrulline were found, but no significant difference between survivors and non-survivors. Groups differed concerning their glutamine level, which was higher in those who died.

2.10. Citrulline in Intestinal Development

Preterm infants are often dependent on parenteral nutrition at least for one week until their enteral feds are established. Bourdon found only weak correlations with post-conceptional age, parenteral amino acid supply, and daily volume of enteral mixture administered. They found that urinary citrulline cannot predict GI tolerance, but the major determinant of urinary citrulline may be arginine produced by NO-synthase [37].

2.11. Citrulline and Intestinal Microbiota

Citrulline changes are associated with microbial changes in the gut, for example, after chemotherapy [127]. Gut bacteria are known to use AAs, including arginine, for both protein synthesis and the production of arginine-derived metabolites such as polyamines or nitric oxide, as reviewed by Baier et al. [128]. Interestingly, Indian women, especially those with very light babies, had lower citrulline and arginine flux compared with Jamaican or American women, which has been associated with microbial dysbiosis [129]. In addition, the bacterium Porphyromonas gingivalis, which is associated with the development of periodontitis, is also able to convert arginine to citrulline with the aid of the peptidylarginine deiminase, a process called “citrullination” [130]. This protein, which contains the AA citrulline, is recognized by the anti-citrullinated protein antibodies, which are highly specific for rheumatoid arthritis [131,132].

2.12. Clinical and Therapeutical Implications

With its diverse biological functions, citrulline suggests several therapeutic applications, as summarized in Table 2. As a precursor of arginine [126], it might be useful when the arginine turnover is high such as during hemolysis or liver damage. As a precursor of nitric oxide (NO), it might support the treatment of pulmonary hypertension [133]. Improved arginine recycling by citrulline [134] might improve T cell function [135].

2.13. Safety of Oral Citrulline Supplementation

Whereas some studies indicate gastrointestinal side effects from oral L-arginine supplementation, including nausea, abdominal cramping, and diarrhea [149], no side effects were seen when oral citrulline was administered [22,116]. Indeed, no toxicity was identified when oral citrulline had been administered to infants and children in doses up to 3.8 g/m2 per day (in five doses of 1.9 g/m2 every 12 h) [116] and in doses up to 15 g in healthy human adults [34]. Due to its limited degradation in the placenta [150], it seems to be a promising supplement for pregnant women. Animal data suggest that it might be beneficial for the prevention of intrauterine growth restriction [151,152]. In 24 obese pregnant women, citrulline has been used at a dose of 3 g/day for 3 weeks, which has been associated with improved vascular function and blood pressure without any side effects [153].
Furthermore, long-term citrulline administration in patients with urea cycle defects was without any side effects [154]. Finally, citrulline administration via the intravenous route has been performed in infants and young children without any side effects (including severe systemic hypotension) [155].

2.14. Oral AA Supplements to Induce Nitric Oxide-Mediated Vasodilation

Nitric oxide (NO) is a vasoactive gaseous signaling molecule that induces vasodilation in both arterial and venous blood vessels [156]. In endothelial cells, NO is synthesized from arginine by eNOS (endothelial-nitric oxide synthase). Reduced eNOS synthesis associated with aging contributes to endothelial dysfunction. Decreased NO bioavailability impairs blood flow and increases the risk of hypertension, atherosclerosis, insulin resistance, and cardiovascular disease [133]. As arginine and its precursor citrulline are intermediates in the urea cycle and substrates for nitric oxide production, their supplementation has been investigated, at various doses, in the treatment of endothelial dysfunction and related diseases (including arterial hypertension, pulmonary arterial hypertension, pressure sores, erectile dysfunction, arteriosclerosis, some mitochondrial disorders, and necrotizing enterocolitis) [116,157,158]. Arginine has a relatively high first-pass extraction in the intestine and the liver (as arginases 1 and 2 metabolize arginine to ornithine and urea). Furthermore, oral arginine supplementation may cause (dose-dependent) gastrointestinal distress (unlike citrulline), resulting in higher activity and bioavailability of citrulline as compared to arginine [133]. Different animal studies have shown a protective effect of dietary citrulline supplementation by preserving eNOS synthesis and NO production against an atherogenic diet [159,160]. Furthermore, oral citrulline shows antioxidant effects by reducing reactive oxygen species (ROS) (NO-dependent and NO-independent), thereby preventing platelet aggregation and pathological vascular remodeling [133]. By increasing endogenous arginine and hence NO synthesis, citrulline was shown to reduce arterial stiffness and also had anti-hypertensive effects: oral citrulline or watermelon extract supplementation for a few weeks resulted in blood pressure reductions in pre-hypertensive and hypertensive patients [161]. It is to note that a recent meta-analysis did not find any significant beneficial effect of citrulline on arterial, systolic or diastolic, blood pressure [14], but this area needs further rigorous clinical trials. In a randomized controlled trial of 40 children randomized to five perioperative doses (1.9 g/m2/dose), oral citrulline or placebo found that either children with naturally elevated citrulline or citrulline due to supplementation did not develop postoperative pulmonary hypertension [162]. Moreover, in obese asthmatics with low or normal fractional excretion of NO L-citrulline treatment (15 g/d for 2 weeks) improved asthma control [163].

2.15. Oral L-Citrulline Supplementation to Improve Exercise Performance in Healthy Athletes

Oral citrulline supplementation has been shown to increase pulmonary oxygen uptake and exercise performance in healthy human probands and athletes [7,164]. Nevertheless, results from different studies were not uniform as others could not show an effect on exercise performance upon oral citrulline supplementation [165]. Furthermore, oral citrulline was supplemented as a malate salt, possibly biasing obtained results. It hence remains unclear if citrulline itself or the Krebs cycle intermediate malate improved exercise performance.

2.16. Citrulline Supplementation in Children

Citrulline supplementation has shown to be safe in children, the group of Marealle and Cox used 0.1 mg/kg/day in ready to use supplementary food (RUSF) [166,167], while Silvera Ruiz calculated 3 g/m2/day [154] for long term supplementation (4 months). Citrulline can be a marker for intestinal function which is reduced in malnourished children [168], in those with necrotizing enterocolitis [169] or in case of severe mucositis [170]. Citrulline may increase with gluten free diet in children with celiac disease [171]. However, it is not a marker of gastrointestinal tolerance [37] and has shown to be higher in a group of children formerly born preterm compared to their term counterparts [172], while shortly after delivery preterm citrulline levels have shown to be very low [173]. As it improves the supply with NO, it has been used to lower pulmonary hypertension [162,174]. As in adults, severely ill children have lower amounts of serum citrulline than healthy children [175]. A more detailed overview is shown in Appendix A [162]

2.17. Citrulline Supplementation and Exercise Performance in Sarcopenic Elderly Patients

Sarcopenia refers classically to the loss of skeletal muscle mass, power, and strength due to aging and/or immobility [176]. Sarcopenia may lead to disability and reduced quality of life and is considered to be part of frailty syndrome, which refers to the progressing decline in health and function typically occurring in geriatric patients [177]. Moreover, sarcopenia is possible in all chronic conditions such as inflammatory diseases, chronic liver and intestinal diseases, undernutrition of various causes, and cancers [178]. In addition to loss of muscle mass and strength, mitochondrial oxidative capacity likewise deteriorates as humans age, resulting in reduced exercise performance [179,180]. Oral citrulline supplementation has shown anabolic effects on muscle protein synthesis in malnourished animals [181] as well as higher systemic AA availability, but has no significant effect, with an oral dose of 10 g per day during 3 weeks, on protein synthesis in sarcopenic malnourished patients of more than 80 years [6]. However, in this last study, citrulline supplementation was associated with a higher systemic AA availability, and in the subgroup of women, citrulline supplementation increased lean mass and appendicular skeletal muscle mass and decreased fat mass. Inconsistent findings were also found when citrulline effects on protein synthesis in healthy humans were assessed [39,182]. In nine adult SBS patients in suitable nutritional status, in the late phase of intestinal adaptation and with near-normal baseline citrulline homeostasis, oral citrulline supplementation (0.18 g/kg/d during 7 days) enhanced citrulline and arginine bioavailability but did not have any anabolic effect on whole-body protein metabolism [183]. Whether oral citrulline would impact whole-body protein anabolism in severely malnourished SBS patients in the early adaptive period, and with baseline plasma citrulline below 20 μmol/L, is not known. In addition, the mechanism of citrulline action on muscle protein synthesis (anabolic effect but not anti-catabolic) is hereby not completely understood and may involve the mTOR (mammalian/mechanistic target of rapamycin) pathway, iNOS, insulin secretion, and vasodilation effects [5,133] and/or reallocating ATP consumption [143]. Major surgical procedures (tumor resections, etc.) are frequently necessary for the elderly and often lead to a further decline in frailty in these patients. As physical fitness, mood, and nutritional status have been shown to affect outcome following major surgical procedures, especially in sarcopenic and/or frail patients, not only the post- but also the presurgical period has been recognized as an important time span to improve exercise tolerance, optimize the nutritional status, as well as psychological wellbeing of the patients, which is referred to as multimodal prehabilitation [184,185]. Evidence is currently not sufficient to recommend citrulline supplementation in frail patients, but possible anabolic effects warrant further investigation.

2.18. Oral Citrulline Supplementation to Improve Non-Alcoholic Fatty Liver Disease

Another situation of the potential interest of citrulline, due to its anti-inflammatory and antioxidant actions with reduction in hypertriglyceridemia and liver fat accumulation induced by diet (mainly fructose), is metabolic liver disease (NAFLD, i.e., steatosis), but at the present time, after animal preclinical data in rats with fructose-induced non-alcoholic liver disease [146,148], there is only one clinical promising study with a low dose of 2 g/d during 3 months [186].

3. Conclusions

Citrulline appears to be a suitable functional biomarker for severe intestinal disease, no matter whether the intestinal dysfunction developed because of surgical, chemotherapeutical, or radiological intervention or due to a medical condition. It can be used as a marker for the intestinal function as a follow-up under adapted care such as nutritional care, surgery, or pharmacological treatments. Citrulline is a potential therapeutic tool, which may be used as a dietary supplement and as a NO donor bypassing the metabolism of arginine. The optimal dose, application route (either intravenous or oral), and timing for citrulline supplementation need further investigation.

Author Contributions

Conceptualization, T.R., S.M., R.N.V.-d.-B. and S.M.C.; methodology, T.R. and R.N.V.-d.-B.; formal analysis, J.L.M. and T.R.; resources T.R., R.N.V.-d.-B., P.C. and S.G.H.-C.; data curation, T.R., R.N.V.-d.-B. and J.L.M.; writing—original draft preparation, T.R., S.M.C., P.C., R.N.V.-d.-B. and L.C.G. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No public data storage available.

Conflicts of Interest

The authors declare no conflict of interest.

Appendix A

Appendix Tables summarizing the data on citrulline.
Table
Table A1. Publications concerning citrulline in children.
Table A1. Publications concerning citrulline in children.
Study
First Author and Year of Publication		N and Patient
Characteristics Median
(Interquartile Range, IQR)		InterventionControlOutcomeCitrulline Level
Median (IQR)
Bourdon, 2012 [37]47 Preterm infants <1500 g
29 weeks [27,28,29]		Measurement of citrulline and analysis of potential influencing factorsNoneGastrointestinal (GI) tolerance
(citrulline is no predictor of GI tolerance in this age group)		Urinary: 24·7 (14·5–38·6) μmol/mmol creatinine
Cox, 2018 [167]119 children with sickle cell disease age 8–12,
Double blind random order crossover trial		Ready-to-use supplementary food (RUSF) with supplementation of arginine and citrulline (arginine, 0.2 g/kg/day; citrulline, 0.1 g/kg/day)
4 months		RUSF (4 months) and baseline before supplementation
washout phases were 4 months		mean
height-for-age Z-score and body-mass index-for-age Z-score for both interventions		Baseline 24.53 (23.41–25.70) RUSF with arginine and citrulline 25.52 (22.91–28.41) RUSF alone 21.59 (20.68–22.53)
Gosselin, 2014 [170]26 children at mean age of 14.9 years undergoing hematopoietic stem cell therapyPeak mucositis score 2–4Peak mucositis score 0–1Citrulline was lower when severe mucositis was present. Graft versus host disease preferentially occurred in those patients with very low citrulline levelsCitrulline with severe mucositis 6.7 (95% CI 3.4–13.1) µmol/L-citrulline without severe oral
mucositis 11.9 (95% CI 5.8–24.4) µmol/L, p = 0.003
Ioannou, 2010 [171]73 children
Age 7.6 ± 1.6 years		Citrulline levels according to disease group (celiac disease with or without diet)Citrulline levels in healthy controls Patients with celiac disease: 24.5 ± 4.9 μmol/L
patients with celiac disease on gluten-free diet: 31.2 ± 6.7 μmol/L
patients with gastrointestinal symptoms but normal mucosa: 30.3 ± 4.7 μmol/L
healthy controls: 32.4 ± 7.5 μmol/L
Ioannou, 2012 [169]41 preterm at a gestational age of 30.8 ± 2Preterms with necrotizing enterocolitis (NEC)
(n = 17)		Control preterms
(n = 24)		Citrulline cut-off distinguishing NEC patient from controls was 17.75 µmol/L (sensitivity 76%, specificity 87%)At day 7: 16.85 ± 4.2 vs. 20.5 ± 4.5 μmol/L, p < 0.05
Lanyero, 2019 [168]430 children aged 21.6 ± 6.5 monthsSevere acute malnutrition (n = 400)Children with normal nutrition
(n = 30)		Citrulline levels with severe acute malnutrition were significantly lower compared to normal nutritionChildren with severe acute malnutrition had citrulline levels of 5.14 vs. 27.4 μmol/L in children with normal nutrition
Marealle, 2018 [187]29 children with sickle cell disease at age 9–11Ready-to-use supplementary food with arginine and citrulline
(arginine, 0.2 g/kg/day; ci-trulline, 0.1 g/kg/day for 10.7 weeks)		Ready-to-use supplementary food(Arginine, 0.2 g/kg/day; ci-trulline, 0.1 g/kg/day)48.19 ± 62.66 versus 22.18 ± 6.02 μmol/L, p = 0.07
Posod, 2016 [172]108 children at 5–7 years of ageFormerly born preterm (n = 79)Formerly born at term (n = 29)Amino acid profilesElevated in preterm group
31.72 ± 6.8 versus 26.89 ± 7.24 μmol/L, p < 0.01
Raphael, 2011 [188]10 children 30.3 ± 30.5 months of age with cisapride use for gastrointestinal rehabilitationObservational study-Amino acid profiles14.5 μmol/L (10.5–31.3 μmol/L)
Ruiz, 2020 [174]15 children at 3–48 months undergoing reconstructive heart surgeryCitrulline supplementation 5 doses a 3 g/m2 eachPlacebo administrationPulmonary artery pressure was lower in intervention group
67 mmHg IQR 63–73 vs. 81 mmHg IQR 75–82, p = 0.025, treated group vs. placebo		17.93 (10–27) μmol/L
Smith, 2006 [162]40 children aged 8.5 (4–29) months5 doses of oral citrulline 1.9 g/m2 per dose (n = 20)5 doses of placebo(n = 20)If the citrulline level was higher than 37µmol/L, no pulmonary hypertension occurred36 [28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48] µmol/L vs. 26 (24–35) µmol/L p = 0.012
Steinbach, 2007 [173]122 preterms at a gestational age of 27 (25–28)Observational study with cholestasis (n = 13)Without cholestasis (n = 109)Amino acid profiles8.2 [6.6–9.7] vs. 11.4 (7.7–14.3) μmol/L, p = 0.021

Appendix B

Table
Table A2. Publications dealing with cancer and citrulline.
Table A2. Publications dealing with cancer and citrulline.
First Author and YearnCharacteristicsInterventionControlOutcomeCitrulline Level
Blijlevens, 2004 [80]32Patients admitted to receive an HLA-matched T-cell-depleted sibling graft, provided they were between 18 and 65 years of ageAminomix in which a portion of the amino acids were replaced by 200 mL glutamine-dipeptide, L-alanyl-L-glutamine (Dipeptiven, Fresenius-Kabi)Standard Aminomix (Fresenius-Kabi, Nederland BV‘s-Hertogen- bosch, The Netherlands) parenterallySignificant differences in citrulline, albumin, and CRP apparent on SCT day +21 favoring glutamine-dipeptide supplementationCitrulline was 18 ± 6 μmol/L with the glutamine-dipeptide and 12 ± 3 μmol/L with the placebo (p = 0.03)
Fekkes, 2007 [98]40Patients participating in a trial of the European Organization for Research and Treatment of Cancer (EORTC 18991), evaluating the efficacy and toxicity of PEG-IFN-a-2b versus controls in high-risk melanoma patients8 weeks induction with 6 mg/kg/wk s.c., followed by a five years maintenance with 3 mg/kg/wk s.cObservation onlyThe concentrations of citrulline decreased significantly at all time points in the patients treated with PEG-IFN-a during the whole study period. Both compared to baseline and to non-treated controls. No changes in citrulline levels were observed in the non-treated controlsTreatment group
Baseline: 26.5 ± 6.0 μmol/L
Change in % after 3 Months: −19.4 μmol/L (−31.0/−5.8) (p < 0.05)
Control group
Baseline: 27.4 ± 7.3 μmol/L Change in % after 3 Months: 5.7 μmol/L (−8.6/22.4)
(95% confidence interval)
Grilz, 2019 [99]957Adult patients (aged ≥ 18 years) with a newly diagnosed cancer or a progression of disease after complete or partial remission//Univariable association between two biomarkers of NET formation, H3Cit and cfDNA, and the risk of mortality in patients with cancerOnly data on citrullinated histone
Kim, 2016 [189]41Patients who received intensity-modulated radiotherapy (IMRT)Whole pelvic (WP) IMRTSmall field (SF) IMRTPlasma citrulline levels did not show a serial decrease by radiotherapy volume difference (WP versus SF) and were not relevant to the irradiated dosesWP
Baseline: 30.9 ± 13.6 μmol/L
At 30 Gy: 38.2 ± 21.8 μmol/L
At 60 Gy: 31.6 ± 16.0 μmol/L
p-Value: 0.95
SF
Baseline: 30.1 ± 10.5 μmol/L
At 30 Gy: 24.1 ± 10.5 μmol/L
At 60 Gy: 34.4 ± 16.7 μmol/L
p-Value: 0.66
Patiroglu, 2015 [190]27Patients aged 4–17 years receiving chemotherapy regimens with strong mucotoxic effectsSecond chemotherapy course given standard oral care (SOC) plus Ankaferd Blood Stopper (ABS)First chemotherapy course given SOC aloneStages of oral mucositis were found lower in the second chemotherapy course given SOC plus ABS when compared to first chemotherapy course given SOC alone (p = 0.007)Control: 44.08 (before) to 23.99 (after) μmol/L
(p < 0.001)
Intervention: 38.67 (before) to 26.78 (after) μmol/L
Vidal-Casarieg [191]69Patients who needed RT because of pelvic or abdominal malignanciesGlutamine (30 g/d)Placebo (casein, 30 g/d)Final citrulline levels were similar between groups. Citrulline concentration was reduced during RT with placebo but remained unchanged with glutamineGlutamine group: 26.31 (10.29) μmol/L Placebo group: 27.69 (12.31) μmol/L
p = 0.639
Vliet, 2009 [91]9Children newly diagnosed with acute myeloid leucemiaPatients were monitored for the presence of oral (mucosal barrier injury) MBI using two different clinical indices for MBI: the NCI symptomatic scale for oral MBI and the daily mouth score (DMS)/A significant decrease in plasma citrulline was seen in the post-samples compared to the pre-samples in all chemotherapy cycles1.0–29.4 μmol/L

Appendix C

Table
Table A3. Publications dealing with citrulline in patients needing intensive care treatment.
Table A3. Publications dealing with citrulline in patients needing intensive care treatment.
First Author and Year of PublicationnCharacteristicsInterventionControlOutcomeCitrulline Level
in Μmol/Liter
[Interquartile Range]
de Betue, 2011 [192]51Patients from the Medicosurgical Department of Intensive Care, Erasme University Hospital, who required artificial enteral Nutrition support and were over 18 years of ageFormula enriched with free arginine (6.3 g/L)Isocaloric and isonitrogenous control solutionThe time course of the plasma citrulline concentration was unaffected by the type of enteral solution administered/
de Betue, 2013 [175]8Critically ill infants with respiratory failure because of viral bronchiolitisProtein-energy–enriched enteral formulasStandard infant formula
(S-formula)		The intake of a PE-formula in critically ill infants resulted in an increased arginine appearance and NO synthesis, whereas citrulline production and plasma arginine con- centrations were unaffected/
Gills, 2021 [193]28Recreationally active males12 g dextrose + 8 g Citrulline-malate (CM)Placebo
(12 g dextrose)		Acute CM supplementation in recreationally active males provides no ergogenic benefit in aerobic cycling performance followed by an anaerobic cycling test./
Piton, 2011 [194]165Ventilated adults with shockEnteral nutritionParenteral nutritionPlasma citrulline concentration was higher after 3 days of enteral nutrition than after 3 days of parenteral nutrition. This result raises the question of the possibility that enteral nutrition is associated with more rapid restoration of enterocyte mass than parenteral nutrition18.7 [13.4; 29.2] enteral nutrition
15.3 [9.8; 21.2] in parenteral nutrition
Viana, 2020 [195]37 Critically ill patients (ITT), on mechanical ventilation, with full treatment and a functional gastrointestinal tract Enteral hydroxymethylbutyrate (HMB) twice 1.5 g/day Placebo There was no significant difference in production of essential amino acids and branched-chain amino acids over time (p = 0.1148 and p = 0.1758, respectively) and also no interaction between groups (p = 0.2163 and p = 0.2144, respectively.) However, the HMB group had significant higher conversions over time of arginine to citrulline (nitric oxide synthesis: p = 0.0093) and glutamate to glutamine (p = 0.038). In addition, the HMB group showed over time a higher citrulline production (0.0026) /
Ware, 2013 [196]135Patients with severe sepsisAnalysis of potential association between citrulline levels and end organ damage/Plasma citrulline levels were below normal in all patients and were significantly lower in acute respiratory distress syndrome (ARDS) compared to the no ARDS group. The rate of ARDS was 50% in the lowest citrulline quartile compared to 15% in the highest citrulline quartile (p = 0.002). In multivariable analyses, citrulline levels were associated with ARDS even after adjustment for covariates, including severity of illnessMedian 9.2
(5.2–14.4)
ARDS: 6 (3.3–10.4)
No ARDS 10.1(6.2–16.6)

Appendix D

Table
Table A4. Citrulline in patients with gastrointestinal diseases.
Table A4. Citrulline in patients with gastrointestinal diseases.
Study
First Author and Year of Publication		N
and Patient Characteristics
Median (Interquartile Range, IQR)		InterventionControlOutcomeCitrulline Level
Median (IQR)
Jirka, 2019 [197]9 adults with short bowel syndrome7 day oral citrulline supplementation 0.18 g/kg/d7-day placebo supplementationIncreased citrulline level and no effect on protein metabolism25 ± 9 vs. 384 ± 95 μmol/L
Van der Velden, 2013 [59]106 patients with stem cell transplantationTime course measurement of citrulline and albumin with different stem cell transplant conditioning regimens Reduced citrulline may be a suitable marker to monitor GI mucositis and precedes the disease courseBelow 10 µmol/L was associated with severe GI mucositis
Picot, 2009 [198]26 patients with small bowel disruption and double enterostomyAssessment before chyme reinfusionAssessment after start of chyme reinfusion 30 ± 33 days (range 8–186 days)Assessment citrulline level in each patient17.0 ± 10.0 vs. 31.0 ± 12.0 μmol/L; p = 0.0001
Luo, 2007 [77]24 patientsGrowth hormone treatment (n = 15)Placebo treatment (n = 9)Correlation of 0.47, p = 0.028 between bowel length and citrulline levels24 ± 2 µmol/L
Hyšpler, 2015 [199]117 patients undergoing colorectal surgerySerial measurements of citrulline 24.9 (19.1–32.0) µmol/L on day 4 after surgery, a value below 20 µmol/L achieved a sensitivity and specificity of 75% and 76% in the diagnosis of prolonged

References

  1. Koga, Y. Study report on the constituents of squeezed watermelon. Tokyo Kagaku Kaishi J. Tokyo Chem. Soc. 1914, 35, 519–528. [Google Scholar]
  2. Fearon, W.R. The carbamido diacetyl reaction: A test for citrulline. Biochem. J. 1939, 33, 902–907. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Rogers, G.E.; Harding, H.W.; Llewellyn-Smith, I.J. The origin of citrulline-containing proteins in the hair follicle and the chemical nature of trichohyalin, an intracellular precursor. Biochim. et Biophys. Acta (BBA) Protein Struct. 1977, 495, 159–175. [Google Scholar] [CrossRef]
  4. Vossenaar, E.R.; Zendman, A.J.; van Venrooij, W.J.; Pruijn, G.J. PAD, a growing family of citrullinating enzymes: Genes, features and involvement in disease. BioEssays 2003, 25, 1106–1118. [Google Scholar] [CrossRef]
  5. Papadia, C.; Osowska, S.; Cynober, L.; Forbes, A. Citrulline in health and disease. Review on human studies. Clin. Nutr. 2018, 37, 1823–1828. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  6. Bouillanne, O.; Melchior, J.-C.; Faure, C.; Paul, M.; Canoui-Poitrine, F.; Boirie, Y.; Chevenne, D.; Forasassi, C.; Guery, E.; Herbaud, S.; et al. Impact of 3-week citrulline supplementation on postprandial protein metabolism in malnourished older patients: The Ciproage randomized controlled trial. Clin. Nutr. 2018, 38, 564–574. [Google Scholar] [CrossRef] [PubMed]
  7. Suzuki, T.; Morita, M.; Kobayashi, Y.; Kamimura, A. Oral L-citrulline supplementation enhances cycling time trial performance in healthy trained men: Double-blind randomized placebo-controlled 2-way crossover study. J. Int. Soc. Sports Nutr. 2016, 13, 6. [Google Scholar] [CrossRef] [Green Version]
  8. Crenn, P.; Vahedi, K.; Lavergne-Slove, A.; Cynober, L.; Matuchansky, C.; Messing, B. Plasma citrulline: A marker of enterocyte mass in villous atrophy-associated small bowel disease. Gastroenterol. 2003, 124, 1210–1219. [Google Scholar] [CrossRef]
  9. Curis, E.; Crenn, P.; Cynober, L. Citrulline and the gut. Curr. Opin. Clin. Nutr. Metab. Care 2007, 10, 620–626. [Google Scholar] [CrossRef]
  10. Windmueller, G.H.; Spaeth, A.E. Source and fate of circulating citrulline. Am. J. Physiol. -Endocrinol. Metab. 1981, 241, E473–E480. [Google Scholar] [CrossRef]
  11. Lau, T.; Owen, W.; Yu, Y.M.; Noviski, N.; Lyons, J.; Zurakowski, D.; Tsay, R.; Ajami, A.; Young, V.R.; Castillo, L. Arginine, citrulline, and nitric oxide metabolism in end-stage renal disease patients. J. Clin. Investig. 2000, 105, 1217–1225. [Google Scholar] [CrossRef] [Green Version]
  12. Rimando, M.A.; Perkins-Veazie, P.M. Determination of citrulline in watermelon rind. J. Chromatogr. A 2005, 1078, 196–200. [Google Scholar] [CrossRef]
  13. Trexler, E.T.; Persky, A.; Ryan, E.D.; Schwartz, T.; Stoner, L.; Smith-Ryan, A.E. Acute Effects of Citrulline Supplementation on High-Intensity Strength and Power Performance: A Systematic Review and Meta-Analysis. Sports Med. 2019, 49, 707–718. [Google Scholar] [CrossRef] [PubMed]
  14. Mirenayat, M.S.; Moradi, S.; Mohammadi, H.; Rouhani, M.H. Effect of L-Citrulline Supplementation on Blood Pressure: A Systematic Review and Meta-Analysis of Clinical Trials. Curr. Hypertens. Rep. 2018, 20, 98. [Google Scholar] [CrossRef] [PubMed]
  15. Wu, G. Intestinal Mucosal Amino Acid Catabolism. J. Nutr. 1998, 128, 1249–1252. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  16. Fujita, T.; Yanaga, K. Association between glutamine extraction and release of citrulline and glycine by the human small intestine. Life Sci. 2007, 80, 1846–1850. [Google Scholar] [CrossRef]
  17. van de Poll, M.; Ligthart-Melis, G.C.; Boelens, P.G.; Deutz, N.; Van Leeuwen, P.A.M.; DeJong, C.H.C. Intestinal and hepatic metabolism of glutamine and citrulline in humans. J. Physiol. 2007, 581, 819–827. [Google Scholar] [CrossRef]
  18. Marini, J.C.; Keller, B.; Didelija, I.C.; Castillo, L.; Lee, B. Enteral arginase II provides ornithine for citrulline synthesis. Am. J. Physiol. Metab. 2011, 300, E188–E194. [Google Scholar] [CrossRef] [Green Version]
  19. Buijs, N.; Brinkmann, S.J.; Oosterink, J.E.; Luttikhold, J.; Schierbeek, H.; Wisselink, W.; Beishuizen, A.; van Goudoever, J.; Houdijk, A.P.; Van Leeuwen, P.A.; et al. Intravenous glutamine supplementation enhances renal de novo arginine synthesis in humans: A stable isotope study. Am. J. Clin. Nutr. 2014, 100, 1385–1391. [Google Scholar] [CrossRef] [Green Version]
  20. Tomlinson, C.; Rafii, M.; Ball, R.O.; Pencharz, P.B. Arginine Can Be Synthesized from Enteral Proline in Healthy Adult Humans. J. Nutr. 2011, 141, 1432–1436. [Google Scholar] [CrossRef]
  21. Curis, E.; Nicolis, I.; Moinard, C.; Osowska, S.; Zerrouk, N.; Bénazeth, S.; Cynober, L. Almost all about citrulline in mammals. Amino Acids 2005, 29, 177–205. [Google Scholar] [CrossRef]
  22. Rougé, C.; Robert, C.D.; Robins, A.; LE Bacquer, O.; Volteau, C.; De La Cochetière, M.-F.; Darmaun, D. Manipulation of citrulline availability in humans. Am. J. Physiol. Liver Physiol. 2007, 293, G1061–G1067. [Google Scholar] [CrossRef] [Green Version]
  23. Marini, J.C.; Didelija, I.C.; Castillo, L.; Lee, B. Glutamine: Precursor or nitrogen donor for citrulline synthesis? Am. J. Physiol. Metab. 2010, 299, E69–E79. [Google Scholar] [CrossRef] [Green Version]
  24. Marini, J.C.; Didelija, I.C.; Castillo, L.; Lee, B. Plasma Arginine and Ornithine Are the Main Citrulline Precursors in Mice Infused with Arginine-Free Diets. J. Nutr. 2010, 140, 1432–1437. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Marini, J.C.; Agarwal, U.; Didelija, I.C.; Azamian, M.; Stoll, B.; Nagamani, S.C. Plasma Glutamine Is a Minor Precursor for the Synthesis of Citrulline: A Multispecies Study. J. Nutr. 2017, 147, 549–555. [Google Scholar] [CrossRef] [Green Version]
  26. Ligthart-Melis, C.G.; Deutz, N.E.P. Is glutamine still an important precursor of citrulline? Am. J. Physiol.Endocrinol. Metab. 2011, 301, E264–E266. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  27. Haines, R.J.; Pendleton, L.C.; Eichler, D.C. Argininosuccinate synthase: At the center of arginine metabolism. Int. J. Biochem. Mol. Boil. 2010, 2, 8–23. [Google Scholar]
  28. Maric, S.; Flüchter, P.; Guglielmetti, L.C.; Staerkle, R.F.; Sasse, T.; Restin, T.; Schneider, C.; Holland-Cunz, S.G.; Crenn, P.; Vuille-Dit-Bille, R.N. Plasma citrulline correlates with basolateral amino acid transporter LAT4 expression in human small intestine. Clin. Nutr. 2020, 40, 2244–2251. [Google Scholar] [CrossRef]
  29. Castillo, L.; Sánchez, M.; Vogt, J.; Chapman, T.E.; Derojas-Walker, T.C.; Tannenbaum, S.R.; Ajami, A.M.; Young, V.R. Plasma arginine, citrulline, and ornithine kinetics in adults, with observations on nitric oxide synthesis. Am. J. Physiol. Content 1995, 268, E360–E367. [Google Scholar]
  30. Nakakariya, M.; Shima, Y.; Shirasaka, Y.; Mitsuoka, K.; Nakanishi, T.; Tamai, I. Organic anion transporter OAT1 is involved in renal handling of citrulline. Am. J. Physiol. Physiol. 2009, 297, F71–F79. [Google Scholar] [CrossRef] [PubMed]
  31. Mitsuoka, K.; Shirasaka, Y.; Fukushi, A.; Sato, M.; Nakamura, T.; Nakanishi, T.; Tamai, I. Transport characteristics of L-citrulline in renal apical membrane of proximal tubular cells. Biopharm. Drug Dispos. 2009, 30, 126–137. [Google Scholar] [CrossRef] [PubMed]
  32. Verrey, F.; Singer, D.; Ramadan, T.; Vuille-Dit-Bille, R.; Mariotta, L.; Camargo, S. Kidney amino acid transport. Pflügers Arch. J. Physiol. 2009, 458, 53–60. [Google Scholar] [CrossRef] [Green Version]
  33. Dhanakoti, S.N.; Brosnan, J.T.; Herzberg, G.R.; Brosnan, M.E. Renal arginine synthesis: Studies in vitro and in vivo. Am. J. Physiol. Metab. 1990, 259, E437–E442. [Google Scholar] [CrossRef] [PubMed]
  34. Moinard, C.; Nicolis, I.; Neveux, N.; Darquy, S.; Bénazeth, S.; Cynober, L. Dose-ranging effects of citrulline administration on plasma amino acids and hormonal patterns in healthy subjects: The Citrudose pharmacokinetic study. Br. J. Nutr. 2007, 99, 855–862. [Google Scholar] [CrossRef] [PubMed]
  35. Morris, J.S. Regulation of enzymes of the urea cycle and arginine metabolism. Annu. Rev. Nutr. 2002, 22, 87–105. [Google Scholar] [CrossRef] [PubMed]
  36. Cynober, L.; Le Boucher, J.; Vasson, M.-P. Arginine metabolism in mammals. J. Nutr. Biochem. 1995, 6, 402–413. [Google Scholar] [CrossRef]
  37. Bourdon, A.; Rougé, C.; Legrand, A.; Robert, C.D.; Piloquet, H.; Vodovar, M.; Voyer, M.; Rozé, J.-C.; Darmaun, D. Urinary citrulline in very low birth weight preterm infants receiving intravenous nutrition. Br. J. Nutr. 2011, 108, 1150–1154. [Google Scholar] [CrossRef] [Green Version]
  38. Osowska, S.; Moinard, C.; Loï, C.; Neveux, N.; Cynober, L. Citrulline increases arginine pools and restores nitrogen balance after massive intestinal resection. Gut 2004, 53, 1781–1786. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  39. Jourdan, M.; Nair, K.S.; Carter, R.E.; Schimke, J.; Ford, G.C.; Marc, J.; Aussel, C.; Cynober, L. Citrulline stimulates muscle protein synthesis in the post-absorptive state in healthy people fed a low-protein diet—A pilot study. Clin. Nutr. 2014, 34, 449–456. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  40. Ventura, G.; Moinard, C.; Sinico, F.; Carrière, V.; Lasserre, V.; Cynober, L.; De Bandt, J.P. Evidence for a role of the ileum in the control of nitrogen homeostasis via the regulation of arginine metabolism. Br. J. Nutr. 2011, 106, 227–236. [Google Scholar] [CrossRef] [Green Version]
  41. Castillo, L.; Chapman, T.E.; Sanchez, M.; Yu, Y.M.; Burke, J.F.; Ajami, A.M.; Vogt, J.; Young, V.R. Plasma arginine and citrulline kinetics in adults given adequate and arginine-free diets. Proc. Natl. Acad. Sci. USA 1993, 90, 7749–7753. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Jonker, R.; Deutz, N.E.; Erbland, M.L.; Anderson, P.J.; Engelen, M.P. Alterations in whole-body arginine metabolism in chronic obstructive pulmonary disease. Am. J. Clin. Nutr. 2016, 103, 1458–1464. [Google Scholar] [CrossRef] [Green Version]
  43. Marini, J.C.; Agarwal, U.; Robinson, J.L.; Yuan, Y.; Didelija, I.C.; Stoll, B.; Burrin, D. The intestinal-renal axis for arginine synthesis is present and functional in the neonatal pig. Am. J. Physiol. Metab. 2017, 313, E233–E242. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Ioannou, H.; Avgoustides-Savvopoulou, P.; Diamanti, E.; Tsampoura, Z.; Drosou-Agakidou, V. Age-related serial plasma citrulline levels in preterm neonates. Pediatrics 2008, 121, S137–S138. [Google Scholar] [CrossRef] [Green Version]
  45. Crenn, P.; Hanachi, M.; Neveux, N.; Cynober, L. Circulating citrulline levels: A biomarker for intestinal functionality assessment. Ann. Biol. Clin. 2011, 69, 513–521. [Google Scholar] [CrossRef]
  46. Crenn, P.; Messing, B.; Cynober, L. Citrulline as a biomarker of intestinal failure due to enterocyte mass reduction. Clin. Nutr. 2008, 27, 328–339. [Google Scholar] [CrossRef] [PubMed]
  47. Ratner, S.; Petrack, B. Biosynthesis of urea. III. Further studies on arginine synthesis from citrulline. J. Biol. Chem. 1951, 191, 693–705. [Google Scholar] [CrossRef]
  48. McMurray, W.C. Biochemical Genetics and Mental Retardation. Can. Med Assoc. J. 1962, 87, 486–490. [Google Scholar]
  49. Allan, J.; Cusworth, D.; Dent, C.; Wilson, V. A disease, probably hereditary, characterised by severe mental deficiency and a constant gross abnormality of aminoacid metabolism. Lancet 1958, 271, 182–187. [Google Scholar] [CrossRef]
  50. Chen, G.-F.; Baylis, C. In vivo renal arginine release is impaired throughout development of chronic kidney disease. Am. J. Physiol. Physiol. 2010, 298, F95–F102. [Google Scholar] [CrossRef] [Green Version]
  51. Saheki, T.; Kobayashi, K. Mitochondrial aspartate glutamate carrier (citrin) deficiency as the cause of adult-onset type II citrullinemia (CTLN2) and idiopathic neonatal hepatitis (NICCD). J. Hum. Genet. 2002, 47, 333–341. [Google Scholar] [CrossRef]
  52. Booth, C.; Dowling, R.H. Functional compensation after small-bowel resection in man: Demonstration by Direct Measurement. Lancet 1966, 288, 146–147. [Google Scholar] [CrossRef]
  53. Mifsud, F.; Czernichow, S.; Carette, C.; Levy, R.; Ravaud, P.; Cynober, L.; Neveux, N.; Rives-Lange, C.; Eustache, F.; Coupaye, M.; et al. Behaviour of plasma citrulline after bariatric surgery in the BARIASPERM cohort. Clin. Nutr. 2020, 40, 505–510. [Google Scholar] [CrossRef]
  54. Seidner, D.L.; Joly, F.; Youssef, N.N. Effect of Teduglutide, a Glucagon-like Peptide 2 Analog, on Citrulline Levels in Patients With Short Bowel Syndrome in Two Phase III Randomized Trials. Clin. Transl. Gastroenterol. 2015, 6, e93. [Google Scholar] [CrossRef] [PubMed]
  55. Jeppesen, P.B.; Pertkiewicz, M.; Messing, B.; Iyer, K.; Seidner, D.L.; O’Keefe, S.; Forbes, A.; Heinze, H.; Joelsson, B. Teduglutide Reduces Need for Parenteral Support Among Patients with Short Bowel Syndrome with Intestinal Failure. Gastroenterology 2012, 143, 1473–1481.e3. [Google Scholar] [CrossRef] [PubMed]
  56. Funghini, S.; Thusberg, J.; Spada, M.; Gasperini, S.; Parini, R.; Ventura, L.; Meli, C.; De Cosmo, L.; Sibilio, M.; Mooney, S.; et al. Carbamoyl Phosphate Synthetase 1 deficiency in Italy: Clinical and genetic findings in a heterogeneous cohort. Gene 2011, 493, 228–234. [Google Scholar] [CrossRef] [PubMed]
  57. Tuchman, M.; Tsai, M.Y.; Holzknecht, R.A.; Brusilow, S.W. Carbamyl Phosphate Synthetase and Ornithine Transcarbamylase Activities in Enzyme-Deficient Human Liver Measured by Radiochromatography and Correlated with Outcome. Pediatr. Res. 1989, 26, 77–82. [Google Scholar] [CrossRef] [Green Version]
  58. Robinson, J.L.; Smith, V.; Stoll, B.; Agarwal, U.; Premkumar, M.H.; Lau, P.; Cruz, S.M.; Manjarin, R.; Olutoye, O.; Burrin, D.; et al. Prematurity reduces citrulline-arginine-nitric oxide production and precedes the onset of necrotizing enterocolitis in piglets. Am. J. Physiol. Liver Physiol. 2018, 315, G638–G649. [Google Scholar] [CrossRef] [Green Version]
  59. Van Der Velden, W.J.F.M.; Herbers, A.H.E.; Brüggemann, R.J.M.; Feuth, T.; Donnelly, J.P.; Blijlevens, N.M.A. Citrulline and albumin as biomarkers for gastrointestinal mucositis in recipients of hematopoietic SCT. Bone Marrow Transplant. 2013, 48, 977–981. [Google Scholar] [CrossRef]
  60. Lutgens, L.; Lambin, P. Biomarkers for radiation-induced small bowel epithelial damage: An emerging role for plasma Citrulline. World J. Gastroenterol. 2007, 13, 3033–3042. [Google Scholar] [CrossRef]
  61. Fitzgibbons, S.; Ching, Y.A.; Valim, C.; Zhou, J.; Iglesias, J.; Duggan, C.; Jaksic, T. Relationship between serum citrulline levels and progression to parenteral nutrition independence in children with short bowel syndrome. J. Pediatr. Surg. 2009, 44, 928–932. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  62. Pappas, P.A.; Tzakis, A.G.; Gaynor, J.J.; Carreno, M.R.; Ruiz, P.; Huijing, F.; Kleiner, G.; Rabier, D.; Kato, T.; Levi, D.M.; et al. An Analysis of the Association between Serum Citrulline and Acute Rejection among 26 Recipients of Intestinal Transplant. Arab. Archaeol. Epigr. 2004, 4, 1124–1132. [Google Scholar] [CrossRef]
  63. Piton, G.; Manzon, C.; Monnet, E.; Cypriani, B.; Barbot, O.; Navellou, J.-C.; Carbonnel, F.; Capellier, G. Plasma citrulline kinetics and prognostic value in critically ill patients. Intensiv. Care Med. 2010, 36, 702–706. [Google Scholar] [CrossRef]
  64. Batra, A.; Keys, S.C.; Johnson, M.; Wheeler, R.A.; Beattie, R.M. Epidemiology, management and outcome of ultrashort bowel syndrome in infancy. Arch. Dis. Child. Fetal Neonatal Ed. 2017, 102, F551–F556. [Google Scholar] [CrossRef] [Green Version]
  65. Pironi, L. Definitions of intestinal failure and the short bowel syndrome. Best Pr. Res. Clin. Gastroenterol. 2016, 30, 173–185. [Google Scholar] [CrossRef] [PubMed]
  66. Pironi, L.; Goulet, O.; Buchman, A.; Messing, B.; Gabe, S.; Candusso, M.; Bond, G.; Gupte, G.; Pertkiewicz, M.; Steiger, E.; et al. Outcome on home parenteral nutrition for benign intestinal failure: A review of the literature and benchmarking with the European prospective survey of ESPEN. Clin. Nutr. 2012, 31, 831–845. [Google Scholar] [CrossRef]
  67. Choudhury, R.A.; Yoeli, D.; Hoeltzel, G.; Moore, H.B.; Prins, K.; Kovler, M.; Goldstein, S.; Holland-Cunz, S.G.; Adams, M.; Roach, J.; et al. STEP improves long-term survival for pediatric short bowel syndrome patients: A Markov decision analysis. J. Pediatr. Surg. 2020, 55, 1802–1808. [Google Scholar] [CrossRef] [PubMed]
  68. Dewberry, L.C.; Hilton, S.A.; Vuille-dit-Bille, R.N.; Liechty, K.W. Is Tapering Enteroplasty an Alternative to Resection of Dilated Bowel in Small Intestinal Atresia? J. Surg. Res. 2020, 246, 1–5. [Google Scholar] [CrossRef]
  69. Mangalat, N.; Teckman, J. Pediatric Intestinal Failure Review. Child. 2018, 5, 100. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  70. Vantini, I.; Benini, L.; Bonfante, F.; Talamini, G.; Sembenini, C.; Chiarioni, G.; Maragnolli, O.; Benini, F.; Capra, F. Survival rate and prognostic factors in patients with intestinal failure. Dig. Liver Dis. 2004, 36, 46–55. [Google Scholar] [CrossRef]
  71. Messing, B.; Crenn, P.; Beau, P.; Boutron-Ruault, M.C.; Rambaud, J.-C.; Matuchansky, C. Long-term survival and parenteral nutrition dependence in adult patients with the short bowel syndrome. Gastroenterology 1999, 117, 1043–1050. [Google Scholar] [CrossRef]
  72. Celik, I.H.; Demirel, G.; Canpolat, F.E.; Dilmen, U. Reduced Plasma Citrulline Levels in Low Birth Weight Infants With Necrotizing Enterocolitis. J. Clin. Lab. Anal. 2013, 27, 328–332. [Google Scholar] [CrossRef]
  73. Crenn, P.; Coudray–Lucas, C.; Thuillier, F.; Cynober, L.; Messing, B. Postabsorptive plasma citrulline concentration is a marker of absorptive enterocyte mass and intestinal failure in humans. Gastroenterology 2000, 119, 1496–1505. [Google Scholar] [CrossRef]
  74. Diamanti, A.; Panetta, F.; Gandullia, P.; Morini, F.; Noto, C.; Torre, G.; Lezo, A.; Goffredo, B.; Daniele, A.; Gambarara, M. Plasma citrulline as marker of bowel adaptation in children with short bowel syndrome. Langenbeck’s Arch. Surg. 2011, 396, 1041–1046. [Google Scholar] [CrossRef]
  75. Rhoads, J.M.; Plunkett, E.; Galanko, J.; Lichtman, S.; Taylor, L.; Maynor, A.; Weiner, T.; Freeman, K.; Guarisco, J.L.; Wu, G.Y. Serum citrulline levels correlate with enteral tolerance and bowel length in infants with short bowel syndrome. J. Pediatr. 2005, 146, 542–547. [Google Scholar] [CrossRef]
  76. JianFeng, G.; Weiming, Z.; Ning, L.; Fangnan, L.; Li, T.; Nan, L.; Jieshou, L. Serum Citrulline Is a Simple Quantitative Marker for Small Intestinal Enterocytes Mass and Absorption Function in Short Bowel Patients. J. Surg. Res. 2005, 127, 177–182. [Google Scholar] [CrossRef] [PubMed]
  77. Luo, M.; Fernández-Estívariz, C.; Manatunga, A.K.; Bazargan, N.; Gu, L.H.; Jones, D.P.; Klapproth, J.M.; Sitaraman, S.V.; Leader, L.M.; Galloway, J.R.; et al. Are plasma citrulline and glutamine biomarkers of intestinal absorptive function in patients with short bowel syndrome? J. Parenter. Enteral Nutr. 2007, 31, 1–7. [Google Scholar] [CrossRef]
  78. Jeppesen, P.B.; Gabe, S.M.; Seidner, D.L.; Lee, H.-M.; Olivier, C. Citrulline correlations in short bowel syndrome–intestinal failure by patient stratification: Analysis of 24 weeks of teduglutide treatment from a randomized controlled study. Clin. Nutr. 2020, 39, 2479–2486. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  79. Barzał, J.A.; Szczylik, C.; Rzepecki, P.; Jaworska, M.; Anuszewska, E. Plasma citrulline level as a biomarker for cancer therapy-induced small bowel mucosal damage. Acta Biochim. Pol. 2014, 61, 615–631. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  80. Blijlevens, N.M.A.; Lutgens, L.C.H.W.; Schattenberg, A.V.M.B.; Donnelly, J.P. Citrulline: A potentially simple quantitative marker of intestinal epithelial damage following myeloablative therapy. Bone Marrow Transplant. 2004, 34, 193–196. [Google Scholar] [CrossRef]
  81. Crenn, P.; De Truchis, P.; Neveux, N.; Galpérine, T.; Cynober, L.; Melchior, J.C. Plasma citrulline is a biomarker of enterocyte mass and an indicator of parenteral nutrition in HIV-infected patients. Am. J. Clin. Nutr. 2009, 90, 587–594. [Google Scholar] [CrossRef] [Green Version]
  82. Pironi, L.; Guidetti, M.; Lauro, A.; Zanfi, C.; Agostini, F.; D’Errico, A.; Altimari, A.; Pinna, A.D. Plasma citrulline after small bowel transplantation: Effect of time from transplantation, acute cellular rejection, and renal failure. Clin. Transplant. 2015, 29, 1039–1046. [Google Scholar] [CrossRef] [PubMed]
  83. Vecino Lopez, R.; Andrés Moreno, A.M.; Ramos Boluda, E.; Martinez-Ojinaga Nodal, E.; Hernanz Macías, A.; Prieto Bozano, G.; Lopez Santamaria, G.; Tovar Larrucea, J.A. Plasma citrulline concentration as a biomarker of intestinal function in short bowel syndrome and in intestinal transplant. An. Pediatr. 2013, 79, 218–223. [Google Scholar]
  84. Crenn, P.; Neveux, N.; Chevret, S.; Jaffray, P.; Cynober, L.; Melchior, J.-C.; Annane, D. Plasma l-citrulline concentrations and its relationship with inflammation at the onset of septic shock: A pilot study. J. Crit. Care 2014, 29, 315.e1–315.e6. [Google Scholar] [CrossRef] [Green Version]
  85. Krief, J.O.; De Tauriers, P.H.; Dumenil, C.; Neveux, N.; Dumoulin, J.; Giraud, V.; Labrune, S.; Tisserand, J.; Julie, C.; Emile, J.-F.; et al. Role of antibiotic use, plasma citrulline and blood microbiome in advanced non-small cell lung cancer patients treated with nivolumab. J. Immunother. Cancer 2019, 7, 176. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Fragkos, K.C.; Forbes, A. Citrulline as a marker of intestinal function and absorption in clinical settings: A systematic review and meta-analysis. United Eur. Gastroenterol. J. 2018, 6, 181–191. [Google Scholar] [CrossRef] [PubMed]
  87. Chang, R.W.; Javid, P.J.; Oh, J.-T.; Andreoli, S.; Kim, H.B.; Fauza, D.; Jaksic, T. Serial Transverse Enteroplasty Enhances Intestinal Function in a Model of Short Bowel Syndrome. Ann. Surg. 2006, 243, 223–228. [Google Scholar] [CrossRef]
  88. Frongia, G.; Kessler, M.; Weih, S.; Nickkholgh, A.; Mehrabi, A.; Holland-Cunz, S. Comparison of LILT and STEP procedures in children with short bowel syndrome—A systematic review of the literature. J. Pediatr. Surg. 2013, 48, 1794–1805. [Google Scholar] [CrossRef]
  89. Amiot, A.; Messing, B.; Corcos, O.; Panis, Y.; Joly, F. Determinants of home parenteral nutrition dependence and survival of 268 patients with non-malignant short bowel syndrome. Clin. Nutr. 2012, 32, 368–374. [Google Scholar] [CrossRef]
  90. Bianchi, A. Intestinal loop lengthening—A technique for increasing small intestinal length. J. Pediatr. Surg. 1980, 15, 145–151. [Google Scholar] [CrossRef]
  91. van Vliet, M.J.; Tissing, W.J.; Rings, E.H.; Koetse, H.A.; Stellaard, F.; Kamps, W.A.; de Bont, E.S. Citrulline as a marker for chemotherapy induced mucosal barrier injury in pediatric patients. Pediatr. Blood Cancer 2009, 53, 1188–1194. [Google Scholar] [CrossRef] [PubMed]
  92. Abou-Alfa, G.; Qin, S.; Ryoo, B.-Y.; Lu, S.-N.; Yen, C.-J.; Feng, Y.-H.; Lim, H.; Izzo, F.; Colombo, M.; Sarker, D.; et al. Phase III randomized study of second line ADI-PEG 20 plus best supportive care versus placebo plus best supportive care in patients with advanced hepatocellular carcinoma. Ann. Oncol. 2018, 29, 1402–1408. [Google Scholar] [CrossRef] [PubMed]
  93. Cheng, P.; Leung, Y.; Lo, W.; Tsui, S.M.; Lam, K. Remission of hepatocellular carcinoma with arginine depletion induced by systemic release of endogenous hepatic arginase due to transhepatic arterial embolisation, augmented by high-dose insulin: Arginase as a potential drug candidate for hepatocellular carcinoma. Cancer Lett. 2005, 224, 67–80. [Google Scholar] [CrossRef]
  94. Szlosarek, P.W.; Steele, J.P.; Nolan, L.; Gilligan, D.; Taylor, P.; Spicer, J.; Lind, M.; Mitra, S.; Shamash, J.; Phillips, M.M.; et al. Arginine Deprivation with Pegylated Arginine Deiminase in Patients with Argininosuccinate Synthetase 1-Deficient Malignant Pleural Mesothelioma: A Randomized Clinical Trial. JAMA Oncol. 2017, 3, 58–66. [Google Scholar] [CrossRef]
  95. Hall, P.E.; Lewis, R.; Syed, N.; Shaffer, R.; Evanson, J.; Ellis, S.; Williams, M.; Feng, X.; Johnston, A.; Thomson, J.A.; et al. A Phase I Study of Pegylated Arginine Deiminase (Pegargiminase), Cisplatin, and Pemetrexed in Argininosuccinate Synthetase 1-Deficient Recurrent High-grade Glioma. Clin. Cancer Res. 2019, 25, 2708–2716. [Google Scholar] [CrossRef] [Green Version]
  96. Yao, S.; Janku, F.; Subbiah, V.; Stewart, J.; Patel, S.P.; Kaseb, A.; Westin, S.N.; Naing, A.; Tsimberidou, A.M.; Hong, D.; et al. Phase 1 trial of ADI-PEG20 plus cisplatin in patients with pretreated metastatic melanoma or other advanced solid malignancies. Br. J. Cancer 2021, 124, 1533–1539. [Google Scholar] [CrossRef]
  97. Blijlevens, N.M.A.; Donnelly, J.P.; Naber, A.H.J.; Schattenberg, A.V.M.B.; Depauw, B.E. A randomised, double-blinded, placebo-controlled, pilot study of parenteral glutamine for allogeneic stem cell transplant patients. Support. Care Cancer 2005, 13, 790–796. [Google Scholar] [CrossRef] [PubMed]
  98. Fekkes, D.; Bannink, M.; Kruit, W.H.J.; Van Gool, A.R.; Mulder, P.G.H.; Sleijfer, S.; Eggermont, A.M.M.; Stoter, G. Influence of pegylated interferon-α therapy on plasma levels of citrulline and arginine in melanoma patients. Amino Acids 2006, 32, 121–126. [Google Scholar] [CrossRef]
  99. Grilz, E.; Mauracher, L.; Posch, F.; Königsbrügge, O.; Zöchbauer-Müller, S.; Marosi, C.; Lang, I.; Pabinger, I.; Ay, C. Citrullinated histone H3, a biomarker for neutrophil extracellular trap formation, predicts the risk of mortality in patients with cancer. Br. J. Haematol. 2019, 186, 311–320. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  100. Broer, S.; Fairweather, S.J. Amino Acid Transport. Across the Mammalian Intestine. Compr. Physiol. 2018, 9, 343–373. [Google Scholar] [PubMed]
  101. Bröer, S. Amino Acid Transport Across Mammalian Intestinal and Renal Epithelia. Physiol. Rev. 2008, 88, 249–286. [Google Scholar] [CrossRef] [PubMed]
  102. Bröer, S. Amino Acid Transporters as Disease Modifiers and Drug Targets. SLAS Discov. Adv. Life Sci. R&D 2018, 23, 303–320. [Google Scholar] [CrossRef] [Green Version]
  103. Fleck, C.; Schwertfeger, M.; Taylor, P.M. Regulation of renal amino acid (AA) transport by hormones, drugs and xenobiotics—A review. Amino Acids 2003, 24, 347–374. [Google Scholar] [CrossRef] [PubMed]
  104. Rudnick, G.; Krämer, R.; Blakely, R.D.; Murphy, D.L.; Verrey, F. The SLC6 transporters: Perspectives on structure, functions, regulation, and models for transporter dysfunction. Pflügers Arch. Eur. J. Physiol. 2013, 466, 25–42. [Google Scholar] [CrossRef] [Green Version]
  105. Camargo, S.M.; Singer, D.; Makrides, V.; Huggel, K.; Pos, K.M.; Wagner, C.A.; Kuba, K.; Danilczyk, U.; Skovby, F.; Kleta, R.; et al. Tissue-specific amino acid transporter partners ACE2 and collectrin differentially interact with hartnup mutations. Gastroenterology 2009, 136, 872–882. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  106. Singer, D.; Camargo, S.M.; Ramadan, T.; Schäfer, M.; Mariotta, L.; Herzog, B.; Huggel, K.; Werner, S.; Penninger, J.M.; Verrey, F.; et al. Defective intestinal amino acid absorption in Ace2 null mice. Am. J. Physiol. Gastrointest. Liver Physiol. 2012, 303, G686–G695. [Google Scholar]
  107. Camargo, S.M.R.; Vuille-Dit-Bille, R.; Mariotta, L.; Ramadan, T.; Huggel, K.; Singer, D.; Götze, O.; Verrey, F. The Molecular Mechanism of Intestinal Levodopa Absorption and Its Possible Implications for the Treatment of Parkinson’s Disease. J. Pharmacol. Exp. Ther. 2014, 351, 114–123. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  108. Palacín, M.; Nunes, V.; Font-Llitjós, M.; Jiménez-Vidal, M.; Fort, J.; Gasol, E.; Pineda, M.; Feliubadaló, L.; Chillarón, J.; Zorzano, A. The Genetics of Heteromeric Amino Acid Transporters. Physiology 2005, 20, 112–124. [Google Scholar] [CrossRef]
  109. Wagner, C.A.; Lang, F.; Broer, S. Function and structure of heterodimeric amino acid transporters. Am. J. Physiol. Physiol. 2001, 281, C1077–C1093. [Google Scholar] [CrossRef]
  110. Danilczyk, U.; Sarao, R.; Remy, C.; Benabbas, C.; Stange, G.; Richter, A.; Arya, S.; Pospisilik, J.A.; Singer, D.; Camargo, S.; et al. Essential role for collectrin in renal amino acid transport. Nat. Cell Biol. 2006, 444, 1088–1091. [Google Scholar] [CrossRef]
  111. Camargo, S.M.; Vuille-Dit-Bille, R.N.; Meier, C.F.; Verrey, F. ACE2 and gut amino acid transport. Clin. Sci. 2020, 134, 2823–2833. [Google Scholar] [CrossRef]
  112. Hamming, I.; Timens, W.; Bulthuis, M.L.; Lely, A.T.; Navis, G.; van Goor, H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J. Pathol. 2004, 203, 631–637. [Google Scholar] [CrossRef]
  113. To, K.F.; Lo, A.W. Exploring the pathogenesis of severe acute respiratory syndrome (SARS): The tissue distribution of the coronavirus (SARS-CoV) and its putative receptor, angiotensin-converting enzyme 2 (ACE2). J. Pathol. 2004, 203, 740–743. [Google Scholar] [CrossRef] [Green Version]
  114. Hoffmann, M.; Kleine-Weber, H.; Schroeder, S.; Krüger, N.; Herrler, T.; Erichsen, S.; Schiergens, T.S.; Herrler, G.; Wu, N.H.; Nitsche, A.; et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 2020, 181, 271–280. [Google Scholar] [CrossRef] [PubMed]
  115. Walls, A.C.; Park, Y.J.; Tortorici, M.A.; Wall, A.; McGuire, A.T.; Veesler, D. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell 2020, 181, 281–292. [Google Scholar] [CrossRef] [PubMed]
  116. Vig, B.S.; Stouch, T.R.; Timoszyk, J.K.; Quan, Y.; Wall, D.A.; Smith, R.L.; Faria, T.N. Human PEPT1 Pharmacophore Distinguishes between Dipeptide Transport and Binding. J. Med. Chem. 2006, 49, 3636–3644. [Google Scholar] [CrossRef]
  117. Nässl, A.-M.; Rubio-Aliaga, I.; Fenselau, H.; Marth, M.K.; Kottra, G.; Daniel, H. Amino acid absorption and homeostasis in mice lacking the intestinal peptide transporter PEPT1. Am. J. Physiol. Liver Physiol. 2011, 301, G128–G137. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  118. Böhmer, C.; Bröer, A.; Munzinger, M.; Kowalczuk, S.; Rasko, J.E.J.; Lang, F.; Bröer, S. Characterization of mouse amino acid transporter B0AT1 (slc6a19). Biochem. J. 2005, 389, 745–751. [Google Scholar] [CrossRef] [Green Version]
  119. Bröer, S.; Bröer, A. Amino acid homeostasis and signalling in mammalian cells and organisms. Biochem. J. 2017, 474, 1935–1963. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  120. Vuille-Dit-Bille, R.; Ha-Huy, R.; Stover, J.F. Changes in plasma phenylalanine, isoleucine, leucine, and valine are associated with significant changes in intracranial pressure and jugular venous oxygen saturation in patients with severe traumatic brain injury. Amino Acids 2011, 43, 1287–1296. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  121. Guetg, A.; Mariotta, L.; Bock, L.; Herzog, B.; Fingerhut, R.; Camargo, S.; Verrey, F. Essential amino acid transporter Lat4 (Slc43a2) is required for mouse development. J. Physiol. 2015, 593, 1273–1289. [Google Scholar] [CrossRef] [Green Version]
  122. Vilches, C.; Boiadjieva-Knöpfel, E.; Bodoy, S.; Camargo, S.; De Heredia, M.L.; Prat, E.; Ormazabal, A.; Artuch, R.; Zorzano, A.; Verrey, F.; et al. Cooperation of Antiporter LAT2/CD98hc with Uniporter TAT1 for Renal Reabsorption of Neutral Amino Acids. J. Am. Soc. Nephrol. 2018, 29, 1624–1635. [Google Scholar] [CrossRef] [PubMed]
  123. Boiadjieva, E.; Vilches, C.; Bodoy, S.; Oparija, L.; Jando, J.; Nunes, V.; Verrey, F.; Palacin, M. Cooperation of Basolateral Epithelial Amino Acid Transporters TAT1 and LAT2 Investigated in a Double Knockout Mouse Model. FASEB J. 2015, 29, 969.4. [Google Scholar] [CrossRef]
  124. Verrey, F.; Christian, M.; Grégoire, R.; Lukas, C.K. Glycoprotein-associated amino acid exchangers: Broadening the range of transport specificity. Pflügers Archiv. 2000, 440, 503–512. [Google Scholar] [CrossRef] [PubMed]
  125. Vuille-Dit-Bille, R.N.; Camargo, S.M.; Emmenegger, L.; Sasse, T.; Kummer, E.; Jando, J.; Hamie, Q.M.; Meier, C.F.; Hunziker, S.; Forras-Kaufmann, Z.; et al. Human intestine luminal ACE2 and amino acid transporter expression increased by ACE-inhibitors. Amino Acids 2015, 47, 693–705. [Google Scholar] [CrossRef] [Green Version]
  126. Pineda, M.; Fernández, E.; Torrents, D.; Estevez, R.; López, C.; Camps, M.; Lloberas, J.; Zorzano, A.; Palacín, M. Identification of a Membrane Protein, LAT-2, That Co-expresses with 4F2 Heavy Chain, an L-type Amino Acid Transport Activity with Broad Specificity for Small and Large Zwitterionic Amino Acids. J. Biol. Chem. 1999, 274, 19738–19744. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  127. Hueso, T.; Ekpe, K.; Mayeur, C.; Gatse, A.; Curt, M.J.-C.; Gricourt, G.; Rodriguez, C.; Burdet, C.; Ulmann, G.; Neut, C.; et al. Impact and consequences of intensive chemotherapy on intestinal barrier and microbiota in acute myeloid leukemia: The role of mucosal strengthening. Gut Microbes 2020, 12. [Google Scholar] [CrossRef]
  128. Baier, J.; Gänsbauer, M.; Giessler, C.; Arnold, H.; Muske, M.; Schleicher, U.; Lukassen, S.; Ekici, A.B.; Rauh, M.; Daniel, C.; et al. Arginase impedes the resolution of colitis by altering the microbiome and metabolome. J. Clin. Investig. 2020, 130, 5703–5720. [Google Scholar] [CrossRef] [PubMed]
  129. Kao, C.C.; Cope, J.L.; Hsu, J.W.; Dwarkanath, P.; Karnes, J.M.; Luna, R.A.; Hollister, E.B.; Thame, M.M.; Kurpad, A.V.; Jahoor, F. The Microbiome, Intestinal Function, and Arginine Metabolism of Healthy Indian Women Are Different from Those of American and Jamaican Women. J. Nutr. 2015, 146, 706–713. [Google Scholar] [CrossRef]
  130. Wegner, N.; Wait, R.; Sroka, A.; Eick, S.; Nguyen, K.-A.; Lundberg, K.; Kinloch, A.; Culshaw, S.; Potempa, J.; Venables, P.J. Peptidylarginine deiminase from Porphyromonas gingivalis citrullinates human fibrinogen and α-enolase: Implications for autoimmunity in rheumatoid arthritis. Arthritis Rheum. 2010, 62, 2662–2672. [Google Scholar] [CrossRef]
  131. Gabarrini, G.; De Smit, M.; Westra, J.; Brouwer, E.; Vissink, A.; Zhou, K.; Rossen, J.; Stobernack, T.; Van Dijl, J.M.; Van Winkelhoff, A.J. The peptidylarginine deiminase gene is a conserved feature of Porphyromonas gingivalis. Sci. Rep. 2015, 5, 13936. [Google Scholar] [CrossRef] [PubMed]
  132. Curran, A.M.; Naik, P.; Giles, J.T.; Darrah, E. PAD enzymes in rheumatoid arthritis: Pathogenic effectors and autoimmune targets. Nat. Rev. Rheumatol. 2020, 16, 301–315. [Google Scholar] [CrossRef] [PubMed]
  133. Allerton, T.D.; Proctor, D.N.; Stephens, J.M.; Dugas, T.R.; Spielmann, G.; Irving, B.A. l-Citrulline Supplementation: Impact on Cardiometabolic Health. Nutrients 2018, 10, 921. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  134. Hecker, M.; Sessa, W.C.; Harris, H.J.; Anggard, E.E.; Vane, J.R. The metabolism of L-arginine and its significance for the biosynthesis of endothelium-derived relaxing factor: Cultured endothelial cells recycle L-citrulline to L-arginine. Proc. Natl. Acad. Sci. USA 1990, 87, 8612–8616. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  135. Werner, A.; Koschke, M.; Leuchtner, N.; Luckner-Minden, C.; Habermeier, A.; Rupp, J.; Heinrich, C.; Conradi, R.; Closs, E.I.; Munder, M. Reconstitution of T Cell Proliferation under Arginine Limitation: Activated Human T Cells Take Up Citrulline via L-Type Amino Acid Transporter 1 and Use It to Regenerate Arginine after Induction of Argininosuccinate Synthase Expression. Front. Immunol. 2017, 8, 864. [Google Scholar] [CrossRef] [Green Version]
  136. Urschel, K.L.; Shoveller, A.K.; Uwiera, R.R.E.; Pencharz, P.B.; Ball, R.O. Citrulline Is an Effective Arginine Precursor in Enterally Fed Neonatal Piglets1,2. J. Nutr. 2006, 136, 1806–1813. [Google Scholar] [CrossRef]
  137. Morris, S.M. Arginases and arginine deficiency syndromes. Curr. Opin. Clin. Nutr. Metab. Care 2012, 15, 64–70. [Google Scholar] [CrossRef]
  138. Gramaglia, I.; Velez, J.; Chang, Y.-S.; Caparros-Wanderley, W.; Combes, V.; Grau, G.; Stins, M.F.; Van Der Heyde, H.C. Citrulline protects mice from experimental cerebral malaria by ameliorating hypoargininemia, urea cycle changes and vascular leak. PLoS ONE 2019, 14, e0213428. [Google Scholar] [CrossRef] [Green Version]
  139. Kim, I.-Y.; Schutzler, S.E.; Schrader, A.; Spencer, H.J.; Azhar, G.; Deutz, N.E.P.; Wolfe, R.R. Acute ingestion of citrulline stimulates nitric oxide synthesis but does not increase blood flow in healthy young and older adults with heart failure. Am. J. Physiol. Metab. 2015, 309, E915–E924. [Google Scholar] [CrossRef] [Green Version]
  140. Dikalova, A.; Aschner, J.L.; Kaplowitz, M.R.; Cunningham, G.; Summar, M.; Fike, C.D. Combined L-citrulline and tetrahydrobiopterin therapy improves NO signaling and ameliorates chronic hypoxia-induced pulmonary hypertension in newborn pigs. Am. J. Physiol. Lung Cell. Mol. Physiol. 2020, 318, L762–L772. [Google Scholar] [CrossRef]
  141. Fike, C.D.; Summar, M.; Aschner, J.L. L-citrulline provides a novel strategy for treating chronic pulmonary hypertension in newborn infants. Acta Paediatr. 2014, 103, 1019–1026. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  142. Hotta, Y.; Shiota, A.; Kataoka, T.; Motonari, M.; Maeda, Y.; Morita, M.; Kimura, K. Oral L-citrulline supplementation improves erectile function and penile structure in castrated rats. Int. J. Urol. 2014, 21, 608–612. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  143. Goron, A.; Lamarche, F.; Blanchet, S.; Delangle, P.; Schlattner, U.; Fontaine, E.; Moinard, C. Citrulline stimulates muscle protein synthesis, by reallocating ATP consumption to muscle protein synthesis. J. Cachex Sarcopenia Muscle 2019, 10, 919–928. [Google Scholar] [CrossRef] [Green Version]
  144. Le Plénier, S.; Walrand, S.; Noirt, R.; Cynober, L.; Moinard, C. Effects of leucine and citrulline versus non-essential amino acids on muscle protein synthesis in fasted rat: A common activation pathway? Amino Acids 2011, 43, 1171–1178. [Google Scholar] [CrossRef]
  145. Kaore, S.N.; Amane, H.S.; Kaore, N.M. Citrulline: Pharmacological perspectives and its role as an emerging biomarker in future. Fundam. Clin. Pharmacol. 2012, 27, 35–50. [Google Scholar] [CrossRef]
  146. Ouelaa, W.; Jegatheesan, P.; M’Bouyou-Boungou, J.; Vicente, C.; Nakib, S.; Nubret, E.; De Bandt, J.P. Citrulline decreases hepatic endotoxin-induced injury in fructose-induced non-alcoholic liver disease: An ex vivo study in the isolated perfused rat liver. Br. J. Nutr. 2017, 117, 1487–1494. [Google Scholar] [CrossRef] [Green Version]
  147. Ginguay, A.; Regazzetti, A.; Laprevote, O.; Moinard, C.; De Bandt, J.-P.; Cynober, L.; Billard, J.-M.; Allinquant, B.; Dutar, P. Citrulline prevents age-related LTP decline in old rats. Sci. Rep. 2019, 9, 1–10. [Google Scholar] [CrossRef] [PubMed]
  148. Jegatheesan, P.; Beutheu, S.; Ventura, G.; Sarfati, G.; Nubret, E.; Kapel, N.; Waligora-Dupriet, A.-J.; Bergheim, I.; Cynober, L.; De-Bandt, J.-P. Effect of specific amino acids on hepatic lipid metabolism in fructose-induced non-alcoholic fatty liver disease. Clin. Nutr. 2015, 35, 175–182. [Google Scholar] [CrossRef] [PubMed]
  149. Grimble, G.K. Adverse Gastrointestinal Effects of Arginine and Related Amino Acids. J. Nutr. 2007, 137, 1693S–1701S. [Google Scholar] [CrossRef] [Green Version]
  150. Lassala, A.; Bazer, F.W.; Cudd, T.A.; Li, P.; Li, X.; Satterfield, M.C.; Spencer, T.E.; Wu, G. Intravenous Administration of L-Citrulline to Pregnant Ewes Is More Effective Than L-Arginine for Increasing Arginine Availability in the Fetus. J. Nutr. 2009, 139, 660–665. [Google Scholar] [CrossRef] [Green Version]
  151. Tran, N.; Amarger, V.; Bourdon, A.; Misbert, E.; Grit, I.; Winer, N.; Darmaun, D. Maternal citrulline supplementation en-hances placental function and fetal growth in a rat model of IUGR: Involvement of insulin-like growth factor 2 and angio-genic factors. J. Matern. Fetal Neonatal Med. 2017, 30, 1906–1911. [Google Scholar] [CrossRef]
  152. Bourdon, A.; Parnet, P.; Nowak, C.; Tran, N.-T.; Winer, N.; Darmaun, D. L-Citrulline Supplementation Enhances Fetal Growth and Protein Synthesis in Rats with Intrauterine Growth Restriction. J. Nutr. 2016, 146, 532–541. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  153. Powers, R. L-citrulline administration increases the arginine /ADMA ratio, decxrases blood pressure and improves vascular function in obese pregnant women. Prenancy Hypertens. Int. J. Women’s Cardiovasc. Health. 2015, 5, 4. [Google Scholar]
  154. Häberle, J.; Boddaert, N.; Burlina, A.; Chakrapani, A.; Dixon, M.; Huemer, M.; Karall, D.; Martinelli, D.; Crespo, P.S.; Santer, R.; et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J. Rare Dis. 2012, 7, 32. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  155. Barr, F.E.; Tirona, R.G.; Taylor, M.B.; Rice, G.; Arnold, J.; Cunningham, G.; Smith, H.A.; Campbell, A.; Canter, J.A.; Christian, K.G.; et al. Pharmacokinetics and safety of intravenously administered citrulline in children undergoing congenital heart surgery: Potential therapy for postoperative pulmonary hypertension. J. Thorac. Cardiovasc. Surg. 2007, 134, 319–326. [Google Scholar] [CrossRef] [Green Version]
  156. Schwedhelm, E.; Maas, R.; Freese, R.; Jung, D.; Lukacs, Z.; Jambrecina, A.; Spickler, W.; Schulze, F.; Böger, R.H. Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: Impact on nitric oxide metabolism. Br. J. Clin. Pharmacol. 2008, 65, 51–59. [Google Scholar] [CrossRef]
  157. Khalaf, D.; Krüger, M.; Wehland, M.; Infanger, M.; Grimm, D. The Effects of Oral l-Arginine and l-Citrulline Supplementation on Blood Pressure. Nutrients 2019, 11, 1679. [Google Scholar] [CrossRef] [Green Version]
  158. Rashid, J.; Kumar, S.S.; Job, K.M.; Liu, X.; Fike, C.D.; Sherwin, C.M.T. Therapeutic Potential of Citrulline as an Arginine Supplement: A Clinical Pharmacology Review. Pediatr. Drugs 2020, 22, 279–293. [Google Scholar] [CrossRef]
  159. Xuan, C.; Lun, L.-M.; Zhao, J.-X.; Wang, H.-W.; Wang, J.; Ning, C.-P.; Liu, Z.; Zhang, B.-B.; He, G.-W. L-citrulline for protection of endothelial function from ADMA–induced injury in porcine coronary artery. Sci. Rep. 2015, 5, srep10987. [Google Scholar] [CrossRef] [Green Version]
  160. Hayashi, T.; Juliet, P.A.R.; Matsui-Hirai, H.; Miyazaki, A.; Fukatsu, A.; Funami, J.; Iguchi, A.; Ignarro, L.J. L-citrulline and L-arginine supplementation retards the progression of high-cholesterol-diet-induced atherosclerosis in rabbits. Proc. Natl. Acad. Sci. USA 2005, 102, 13681–13686. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  161. Barkhidarian, B.; Khorshidi, M.; Shab-Bidar, S.; Hashemi, B. Effects of L-citrulline supplementation on blood pressure: A systematic review and meta-analysis. Avicenna J. Phytomed. 2019, 9, 10–20. [Google Scholar] [PubMed]
  162. Smith, H.A.; Canter, J.A.; Christian, K.G.; Drinkwater, D.C.; Scholl, F.G.; Christman, B.W.; Rice, G.D.; Barr, F.E.; Summar, M. Nitric oxide precursors and congenital heart surgery: A randomized controlled trial of oral citrulline. J. Thorac. Cardiovasc. Surg. 2006, 132, 58–65. [Google Scholar] [CrossRef] [Green Version]
  163. Holguin, F.; Grasemann, H.; Sharma, S.; Winnica, D.; Wasil, K.; Smith, V.; Cruse, M.H.; Perez, N.; Coleman, E.; Scialla, T.J.; et al. L-Citrulline increases nitric oxide and improves control in obese asthmatics. JCI Insight 2019, 4. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  164. Bailey, S.; Blackwell, J.R.; Lord, T.; Vanhatalo, A.; Winyard, P.; Jones, A.M. l-Citrulline supplementation improves O2 uptake kinetics and high-intensity exercise performance in humans. J. Appl. Physiol. 2015, 119, 385–395. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  165. Cutrufello, P.T.; Gadomski, S.J.; Zavorsky, G.S. The effect of l-citrulline and watermelon juice supplementation on anaerobic and aerobic exercise performance. J. Sports Sci. 2015, 33, 1459–1466. [Google Scholar] [CrossRef]
  166. Marealle, A.I.; Siervo, S.M.; Wassel, L.; Bluck, A.M.; Prentice, O.; Minzi, P.; Sasi, A.; Kamuhabwa, D.; Soka, J.; Makani, S.E. A Pilot Study of a Non-Invasive Oral Nitrate Stable Isotopic Method Suggests That Arginine and Citrulline Supplementation Increases Whole-Body No Production in Tanzanian Children with Sickle Cell Disease. Nitric Oxide. 2018, 74, 532–541. [Google Scholar] [CrossRef]
  167. Cox, S.E.; Ellins, E.A.; Marealle, A.I.; Newton, C.R.; Soka, D.; Sasi, P.; di Tanna, G.L.; Johnson, W.; Makani, J.; Prentice, A.M.; et al. Ready-to-Use Food Supplement, with or without Arginine and Citrulline, with Daily Chloroquine in Tanzanian Children with Sickle-Cell Disease: A Double-Blind, Random Order Crossover Trial. Lancet Haematol 2018, 5, e147–e160. [Google Scholar] [CrossRef] [Green Version]
  168. Lanyero, B.; Grenov, B.; Barungi, N.N.; Namusoke, H.; Michaelsen, K.F.; Mupere, E.; Mølgaard, C.; Jiang, P.; Frøkiær, H.; Wiese, M.; et al. Correlates of Gut Function in Children Hospitalized for Severe Acute Malnutrition, a Cross-sectional Study in Uganda. J. Pediatr. Gastroenterol. Nutr. 2019, 69, 292–298. [Google Scholar] [CrossRef]
  169. Ioannou, H.P.; Diamanti, E.; Piretzi, K.; Drossou-Agakidou, V.; Augoustides-Savvopoulou, P. Plasma citrulline levels in preterm neonates with necrotizing enterocolitis. Early Hum. Dev. 2012, 88, 563–566. [Google Scholar] [CrossRef] [PubMed]
  170. Gosselin, K.B.; Feldman, H.A.; Sonis, A.; Bechard, L.J.; Kellogg, M.; Gura, K.; Venick, R.; Gordon, C.M.; Guinan, E.C.; Duggan, C. Serum Citrulline as a Biomarker of Gastrointestinal Function During Hematopoietic Cell Transplantation in Children. J. Pediatr. Gastroenterol. Nutr. 2014, 58, 709–714. [Google Scholar] [CrossRef] [Green Version]
  171. Ioannou, H.P.; Fotoulaki, M.; Pavlitou, A.; Efstratiou, I.; Augoustides-Savvopoulou, P. Plasma citrulline levels in paediatric patients with celiac disease and the effect of a gluten-free diet. Eur. J. Gastroenterol. Hepatol. 2011, 23, 245–249. [Google Scholar] [CrossRef] [PubMed]
  172. Posod, A.; Komazec, I.O.; Kager, K.; Peglow, U.P.; Griesmaier, E.; Schermer, E.; Würtinger, P.; Baumgartner, D.; Kiechl-Kohlendorfer, U. Former Very Preterm Infants Show an Unfavorable Cardiovascular Risk Profile at a Preschool Age. PLoS ONE 2016, 11, e0168162. [Google Scholar] [CrossRef] [PubMed]
  173. Steinbach, M.; Clark, R.H.; Kelleher, A.S.; Flores, C.; White, R.; Chace, D.H.; Spitzer, A.R.; For the Pediatrix Amino-Acid Study Group. Demographic and nutritional factors associated with prolonged cholestatic jaundice in the premature infant. J. Perinatol. 2007, 28, 129–135. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  174. Silvera Ruiz, S.; Grosso, C.L.; Tablada, M.; Cabrera, M.; de Kremer, R.D.; Juaneda, E.; Laróvere, L.E. Efficacy of oral citrulline supplementation to decrease the risk of pulmonary hypertension after congenital heart disease surgery. Rev. Fac. Cienc. Med. 2020, 77, 249–253. [Google Scholar]
  175. de Betue, C.T.; Joosten, K.F.; Deutz, N.E.; Vreugdenhil, A.C.; van Waardenburg, D.A. Arginine appearance and nitric oxide synthesis in critically ill infants can be increased with a protein-energy-enriched enteral formula. Am. J. Clin. Nutr. 2013, 98, 907–916. [Google Scholar] [CrossRef] [Green Version]
  176. Roubenoff, R. Sarcopenia: A major modifiable cause of frailty in the elderly. J. Nutr. Heal. Aging 2000, 4, 140–142. [Google Scholar]
  177. Manini, T.M.; Clark, B.C. Dynapenia and Aging: An Update. J. Gerontol. Ser. A 2011, 67, 28–40. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  178. Cruz-Jentoft, A.J.; Baeyens, J.P.; Bauer, J.M.; Boirie, Y.; Cederholm, T.; Landi, F.; Martin, F.C.; Michel, J.-P.; Rolland, Y.; Schneider, S.; et al. Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age Ageing 2010, 39, 412–423. [Google Scholar] [CrossRef] [Green Version]
  179. Short, K.R.; Bigelow, M.L.; Kahl, J.; Singh, R.; Coenen-Schimke, J.; Raghavakaimal, S.; Nair, K.S. Decline in skeletal muscle mitochondrial function with aging in humans. Proc. Natl. Acad. Sci. USA 2005, 102, 5618–5623. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  180. Lanza, I.; Short, D.K.; Short, K.; Raghavakaimal, S.; Basu, R.; Joyner, M.J.; McConnell, J.P.; Nair, K.S. Endurance Exercise as a Countermeasure for Aging. Diabetes 2008, 57, 2933–2942. [Google Scholar] [CrossRef] [Green Version]
  181. Faure, C.; Raynaud-Simon, A.; Ferry, A.; Daugé, V.; Cynober, L.; Aussel, C.; Moinard, C. Leucine and citrulline modulate muscle function in malnourished aged rats. Amino Acids 2011, 42, 1425–1433. [Google Scholar] [CrossRef]
  182. Thibault, R.; Flet, L.; Vavasseur, F.; Lemerle, M.; Ferchaud-Roucher, V.; Picot, D.; Darmaun, D. Oral citrulline does not affect whole body protein metabolism in healthy human volunteers: Results of a prospective, randomized, double-blind, cross-over study. Clin. Nutr. 2011, 30, 807–811. [Google Scholar] [CrossRef]
  183. Jirka, A.; Layec, S.; Picot, D.; Bernon-Ferreira, S.; Grasset, N.; Flet, L.; Thibault, R.; Darmaun, D. Effect of oral citrulline supplementation on whole body protein metabolism in adult patients with short bowel syndrome: A pilot, randomized, double-blind, cross-over study. Clin. Nutr. 2019, 38, 2599–2606. [Google Scholar] [CrossRef]
  184. Weimann, A.; Braga, M.; Carli, F.; Higashiguchi, T.; Hübner, M.; Klek, S.; Laviano, A.; Ljungqvist, O.; Lobo, D.N.; Martindale, R.; et al. ESPEN guideline: Clinical nutrition in surgery. Clin. Nutr. 2017, 36, 623–650. [Google Scholar] [CrossRef] [Green Version]
  185. Scheede-Bergdahl, C.; Minnella, E.M.; Carli, F. Multi-modal prehabilitation: Addressing the why, when, what, how, who and where next? Anaesthesia 2019, 74, 20–26. [Google Scholar] [CrossRef] [Green Version]
  186. Darabi, Z.; Darand, M.; Yari, Z.; Hedayati, M.; Faghihi, A.; Agah, S.; Hekmatdoost, A. Inflammatory markers response to citrulline supplementation in patients with non-alcoholic fatty liver disease: A randomized, double blind, placebo-controlled, clinical trial. BMC Res. Notes 2019, 12, 1–5. [Google Scholar] [CrossRef]
  187. Marealle, A.; Makani, J.; Prentice, A.; Kamuhabwa, A.; Sasi, P.; Minzi, O.; Siervo, M.; Cox, S.; Wassell, S. Systemic Nitric Oxide (NO) Production is Increased in Children with Sickle Cell Disease (SCD) Receiving Fortified Supplementary Food. FASEB J. 2015, 29, LB276. [Google Scholar] [CrossRef]
  188. Raphael, B.P.; Nurko, S.; Jiang, H.; Hart, K.; Kamin, D.S.; Jaksic, T.; Duggan, C. Cisapride Improves Enteral Tolerance in Pediatric Short-bowel Syndrome With Dysmotility. J. Pediatr. Gastroenterol. Nutr. 2011, 52, 590–594. [Google Scholar] [CrossRef] [Green Version]
  189. Kim, Y.J.; Park, J.H.; Yun, I.H.; Kim, Y.S. A prospective comparison of acute intestinal toxicity following whole pelvic versus small field intensity-modulated radiotherapy for prostate cancer. Onco Targets Ther. 2016, 9, 1319–1325. [Google Scholar] [CrossRef]
  190. Patiroglu, T.; Sahin, N.; Unal, E.; Kendirci, M.; Ozdemir, M.A.; Karakukcu, M. Effectiveness of ankaferd blood stopper in prophylaxis and treatment of oral mucositis seen in childhood cancers and correlation with plasma citrulline levels. Pediatric Blood Cancer 2015, 62, S336–S337. [Google Scholar]
  191. Vidal-Casariego, A.; Calleja-Fernández, A.; De Urbina-González, J.J.O.; Cano-Rodríguez, I.; Cordido, F.; Ballesteros-Pomar, M.D. Efficacy of glutamine in the prevention of acute radiation enteritis: A randomized controlled trial. J. Parenter. Enter. Nutr. 2014, 38, 205–213. [Google Scholar] [CrossRef] [Green Version]
  192. de Betue, C.T.; van Waardenburg, D.A.; Deutz, N.E.; van Eijk, H.M.; van Goudoever, J.B.; Luiking, Y.C.; Zimmermann, L.J.; Joosten, K.F. Increased protein-energy intake promotes anabolism in critically ill infants with viral bronchiolitis: A double-blind randomised controlled trial. Arch. Dis. Child. 2011, 96, 817–822. [Google Scholar] [CrossRef] [PubMed]
  193. Gills, J.L.; Glenn, J.M.; Gray, M.; Romer, B.; Lu, H. Acute citrulline-malate supplementation is ineffective during aerobic cycling and subsequent anaerobic performance in recreationally active males. Eur. J. Sport Sci. 2020, 21, 77–83. [Google Scholar] [CrossRef]
  194. Piton, G.; Manzon, C.; Cypriani, B.; Carbonnel, F.; Capellier, G. Acute intestinal failure in critically ill patients: Is plasma citrulline the right marker? Intensive Care Med. 2011, 37, 911–917. [Google Scholar] [CrossRef] [PubMed]
  195. Viana, M.; Becce, F.; Schmidt, S.; Bagnoud, G.; Berger, M.; Deutz, N. Beta-hydroxy-beta-methylbutyrate (HMB) modifies amino acid metabolism in critically ill patients. a RCT. Clin. Nutr. ESPEN 2020, 40, 428. [Google Scholar] [CrossRef]
  196. Ware, L.B.; Magarik, J.A.; Wickersham, N.; Cunningham, G.; Rice, T.W.; Christman, B.W.; Wheeler, A.P.; Bernard, G.R.; Summar, M.L. Low plasma citrulline levels are associated with acute respiratory distress syndrome in patients with severe sepsis. Crit. Care 2013, 17, R10. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  197. Jirka, A.; Layec, S.; Picot, D.; Bernon-Ferreira, S.; Darmaun, D. SUN-P234: Effect of Citrulline Supplementation on Protein Metabolism in Patients with Short Bowel Syndrome: A Stable Isotope Study. Clin. Nutr. 2016, 35, S131. [Google Scholar] [CrossRef]
  198. Picot, D.; Garin, L.; Trivin, F.; Kossovsky, M.P.; Darmaun, D.; Thibault, R. Plasma citrulline is a marker of absorptive small bowel length in patients with transient enterostomy and acute intestinal failure. Clin. Nutr. 2010, 29, 235–242. [Google Scholar] [CrossRef]
  199. Hyšpler, R.; Tichá, A.; Kaska, M.; Žaloudková, L.; Plíšková, L.; Havel, E.; Zadak, Z. Markers of Perioperative Bowel Complications in Colorectal Surgery Patients. Dis. Markers 2015, 2015, 428535. [Google Scholar] [CrossRef] [Green Version]
Nutrients 13 02794 g001 550
Figure 1. Literature research adapted from [15], table licensed under creative commons.
Figure 1. Literature research adapted from [15], table licensed under creative commons.
Nutrients 13 02794 g001
Nutrients 13 02794 g002 550
Figure 2. This image demonstrates how citrulline is synthesized, converted, and degraded. Abbreviations: ASL argininosuccinate lyase, ASS argininosuccinate synthetase, GLNase glutaminase, OAT ornithine aminotransferase, OTC ornithine trans-carbamylase, NOS nitric oxygen synthase.
Figure 2. This image demonstrates how citrulline is synthesized, converted, and degraded. Abbreviations: ASL argininosuccinate lyase, ASS argininosuccinate synthetase, GLNase glutaminase, OAT ornithine aminotransferase, OTC ornithine trans-carbamylase, NOS nitric oxygen synthase.
Nutrients 13 02794 g002
Table
Table 1. Main conditions that induce or decrease plasma citrulline concentration.
Table 1. Main conditions that induce or decrease plasma citrulline concentration.
Elevated CitrullineDecreased Citrulline
  • Rare metabolic deficiencies: argininosuccinate synthase (ASS) [47,48]; argininosuccinic acid lyase (ASL) [49]; mitochondrial aspartate-glutamate carrier [51]
  • Intestinal lengthening [54]
  • Enterotrophic treatment with teduglutide (glucagon-like peptide 2) [37]
  • Bariatric surgery [36]
  • Renal insufficiency [11]
  • Rare metabolic deficiencies: carbamoyl phosphate synthetase 1 (CPS1) [56];
  • Ornithine transcarbamylase (OTC) 57
  • Prematurity/before weaning [58]
  • Mucositis due to chemo- or radiotherapy [59,60]
  • Short bowel/gut syndrome (intestinal failure) [61]
  • Villous atrophy: celiac disease, various intestinal diseases [45]
  • Graft rejection after small bowel transplantation [62]
  • Intestinal dysfunction in intensive care conditions [63]
Table
Table 2. Physiological function and potential medical use of citrulline as suggested by animal experiments.
Table 2. Physiological function and potential medical use of citrulline as suggested by animal experiments.
Physiological FunctionPotential Medical Use
  • Precursor of arginine [136]
Counteracts arginine deficiency such as during conditions of increased arginase activity (hemolysis, liver damage) [137]
Protects against cerebral malaria [138]
  • Precursor of nitric oxide (NO) [139]
Reduces blood pressures in hypertension [133]
Vasodilator for pulmonary hypertension [140,141]
Improvement of erectile dysfunction [142]
  • Improvement of arginine recycling [134]
Improved T cell function [135]
  • Increased protein synthesis [143]
Counteracts sarcopenia state [6,144]
  • Hydroxyl radical scavenger [145]
  • Reduction in LPS-induced inflammation [146]
improves the capacity of neuronal networks during aging [147]
Attenuates fructose-induced non-alcoholic fatty liver disease [148]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Maric, S.; Restin, T.; Muff, J.L.; Camargo, S.M.; Guglielmetti, L.C.; Holland-Cunz, S.G.; Crenn, P.; Vuille-dit-Bille, R.N. Citrulline, Biomarker of Enterocyte Functional Mass and Dietary Supplement. Metabolism, Transport, and Current Evidence for Clinical Use. Nutrients 2021, 13, 2794. https://doi.org/10.3390/nu13082794

AMA Style

Maric S, Restin T, Muff JL, Camargo SM, Guglielmetti LC, Holland-Cunz SG, Crenn P, Vuille-dit-Bille RN. Citrulline, Biomarker of Enterocyte Functional Mass and Dietary Supplement. Metabolism, Transport, and Current Evidence for Clinical Use. Nutrients. 2021; 13(8):2794. https://doi.org/10.3390/nu13082794

Chicago/Turabian Style

Maric, Stefano, Tanja Restin, Julian Louis Muff, Simone Mafalda Camargo, Laura Chiara Guglielmetti, Stefan Gerhard Holland-Cunz, Pascal Crenn, and Raphael Nicolas Vuille-dit-Bille. 2021. "Citrulline, Biomarker of Enterocyte Functional Mass and Dietary Supplement. Metabolism, Transport, and Current Evidence for Clinical Use" Nutrients 13, no. 8: 2794. https://doi.org/10.3390/nu13082794

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop