S42 Gut 1994; supplement 1: S42-S45 Can arginine and omithine support gut functions? Gut: first published as 10.1136/gut.35.1_Suppl.S42 on 1 January 1994. Downloaded from L Cynober Abstract Metabolism of arginine and related Arginine and ornithine are precursors of compounds in the gut nitric oxide and polyamines, respectively. Arginine synthesis and catabolism in specific These metabolites intimately participate in tissues is conditioned by the presence of permeability and adaptive responses ofthe arginosuccinase and arginase respectively, but gut. The liver possesses high arginase only periportal hepatocytes and, to some activity as an intrinsic part of urea synthe- extent, certain brain areas, possess all the sis and would consume most of the portal enzymes required for arginine recycling and supply ofdietary arginine. The gut reduces urea synthesis.' The gut acts as a user of this possibility by converting dietary arginine because it possesses arginase (isoen- arginine to citrulline, which effectively zyme II) and ornithine carbamoyltransferase.4 bypass the liver and is resynthesised to The gut thus releases urea and citrulline.5 arginine in the kidney. Dietary ornithine In addition, enterocytes express omithine supplementation, in the form of ornithine decarboxylase6 and an NADPH2 dependent a-ketoglutarate (OKG) can be considered arginine deiminase78 which respectively lead to as an arginine precursor. Several supple- local production of aliphatic polyamines and ment studies have shown both amino acids nitric oxide. to promote growth hormone and insulin Despite the high omithine decarboxylase secretion with anabolic effects in post- activity in enterocytes, however, most of the operative patients. Their intermediary omithine produced from arginine is released metabolites (for example, glutamine, pro- into the portal blood stream, and polyamine line) may also be of benefit in trauma formation accounts for a small part of arginine metabolism. Specific effects of either consumption.8 amino acid on the gut are poorly reported. After 14C-ornithine is given by the enteral One recent animal study showed improved route, 14C-proline, '4C-glutamate, and 14C- morphology after OKG administration, polyamines are detected,9 as expected, but, in perhaps through increased polyamine contrast with arginine administration, no secretion. Generation of nitric oxide from citrulline is produced. This could suggest a arginine has two facets. Excess production degree of metabolic compartmentalisation, from high dose arginine potentiated the arginine flux being directed preferentially http://gut.bmj.com/ effects of experimentally induced sepsis, towards ornithine and citrulline production. whereas low doses improved survival. Indeed, omithine translocase, omithine These considerations suggest that the role carbamoyltransferase, and citrulline trans- of enteral diet supplementation with locase function as a multienzyme complex' arginine or OKG should be urgendy exam- (Fig 1). Figure 2 summarises arginine and ined for any benefits it may have on omithine pathways in the gut. mucosal barrier function. on September 27, 2021 by guest. Protected copyright. (Gut 1994; supplement 1: S42-S45) Arginine and related compounds in artificial nutrition For many years, arginine and related com- Arginine has multiple biological properties, pounds (omithine and citrulline) have been including the ability to stimulate anabolic considered solely as intermediate metabolites hormone secretion: intravenous and enteral in the process of nitrogen detoxification - that arginine administration increases both insulin is, in the context of ureagenesis. There is and human growth hormone secretion.'2 renewed interest, however, in these amino Several studies (reviewed in references 2 and Laboratoire de acids because ureagenesis may have an 13) show that arginine given to patients as well Biochimie, Groupe de role in homeostasis' Recherche en important pH and also as in various experimental stress models, acts Nutrition because arginine becomes an essential amino by improving nitrogen balance, accelerating Exp6rimentale et acid during growth and catabolic states.2 wound healing, and restoring depressed Metabolisme Hepatique, H6pital Ornithine is not a constituent of proteins, but immunity (Table). These effects are seen 15 Saint - Antoine, Paris, is clearly important in the regulation of nutri- whether arginine is given orally'4 or paren- France, and Centre de tional state as a precursor of aliphatic terally. 16 Recherche en In in the form of the a Nutrition Humaine, polyamines. addition, Omithine shares with arginine the ability to Clermont-Ferrand, ketoglutarate salt, omithine generates multiple stimulate human growth hormone secretion.3 France metabolic effects, which do not result solely In addition, omithine as its ao-ketoglutarate salt L Cynober to the additive action of the two moieties (OKG) generates various molecules (for Correspondence to: of this molecule.3 There is, however, a paucity example, glutamine) 17 which play a key part in Professor L Cynober, of data on the role of or its metabolites Laboratoire de Biochimie, arginine the control of protein metabolism.'8 OKG has Faculte de Pharmacie, 28 in the maintenance of gut function and been shown to improve nitrogen balance in Place H Dunant, BP38, this 63001 Clermont-Ferrand morphology; indicates possible future various acute and chronic malnutrition states Cedex, France. research directions. (see reference 3 for a review). OKG increases Can arginine and ornithine support gutfunctions? S43 53 Nitric oxide Cytoplasm Mitochondria arginine -..4citruiline Gut: first published as 10.1136/gut.35.1_Suppl.S42 on 1 January 1994. Downloaded from urea I AKU rT- Ia Polyamines ornithine carbamoyl P CIT .putrescine glutamate P5C proline spermidine a ketoglutarate Polyamines GLU spermine Co2 PRO Figure 2: Arginine and ornithine metabolic pathways in the enterocyte. Adaptedfrom Blachier et al.8, Seiler et al,'O Figure 1: Arginine (ARG) and ornithine (ORN) fluxes andJones. 1 1 (I Arginase (EC 3.5.3. 1); 2 ornithine compared. ASe=arginase; OT=ornithine translocase; decarboxylase (EC 4.1.1.17); (a ornithine CT=citrulline translocase; OCT=ornithine carbamoyl- carbamoyltransferase (EC 2.1.3.3); (v) arginine deiminase; transferase; GLU=glutamate; PRO=proline. () ornithine aminotransferase (EC 2.6.1.13). muscle protein anabolism in moderate cata- citrulline in the gut can also be seen as a means bolic states'9 and reduces protein catabolism of protecting this amino acid from excessive in hypercatabolic states.20 degradation in the liver. Finally, arginine and ornithine metabolism in enterocytes could par- ticipate in the support of gut morphology and Arginine and ornithine in the support of function by the synthesis of polyamines and gut functions nitric oxide, as will be discussed. FUNCTIONS OF ARGININE AND ORNITHINE Arginine from dietary proteins is thus actively ACTIONS OF ARGININE AND ORNITHINE metabolised in the enterocyte and supports Surprisingly, published works contain few several gut functions. Firstly, arginine metabo- studies dealing with the effects of arginine on http://gut.bmj.com/ lism in the enterocyte serves to remove excess gut function and morphology. With regard to arginine, although the liver also has a high ornithine, only one recent study is available capacity for arginine transport and metabol- (F Raul, personal communication). Rats were ism.21 It has been shown22 that portal arginine starved for three days and then fed for four concentrations rise with the percentage of pro- days by continuous enteral nutrition, with or tein in the diet, with a parallel increase in urea without supplementation with ornithine (032 synthesis. In fact, arginine acts in the hepato- g/kg/day) as the oa-ketoglutarate salt. Rats were on September 27, 2021 by guest. Protected copyright. cyte as a positive modulator of N-acetylgluta- then killed and intestinal morphology and mate synthesis, which is the allosteric enzyme content were studied. Ornithine led to obligatory activator of carbamoyl phosphate a significantly higher crypt height in the synthetase, the enzyme participating in the first jejunum and ileum and a higher total villous step of urea synthesis.1 Thus, arginine metabo- height in the ileum. In addition, sucrase and lism in the gut should be seen as a means of lactase contents were higher in the ileum of limiting arginine supply to the liver, thereby ornithine supplemented rats. limiting ureagenesis when protein intake is low. It is noteworthy that the intestine also contains significant concentrations ofN-acetylglutamate POSSIBLE MECHANISMS OF ACTION (IF ANY) (20% ofliver content),23 which must play a part As described, enterocytes are well equipped to in favouring citrulline formation from omithine convert arginine into ornithine and to after food intake. Interestingly, citrulline metabolise ornithine into putrescine and other uptake by the liver is low, and citrulline is aliphatic polyamines. Alternatively, arginine extensively converted into arginine in the kid- is the precursor of nitric oxide by arginine ney (Figure 3). Thus, arginine metabolism into desiminase. Effects ofarginine supplementation in enteral nutrition The polyamine pathway _ protein catabolism in trauma (humans/rats) Ornithine is converted into putrescine by t immune response after trauma (humans/rats) Tthymic weight ornithine decarboxylase (EC 4.1.1.17), which tthymic lymphocyte content is the rate limiting enzyme in polyamine Tlymphocyte mitotic