Arginine Cools the Inflamed Gut

Abstract

Maintenance of immunophysiological homeostasis and regulation of gut barrier function are essential for the defense of the host. Severe alterations, including infections and chronic inflammation, have been associated with increased intestinal permeability, leading to deregulation of gut function and homeostasis. To establish and reinforce this crucial balance, the intestinal metabolismplaysakeyroleandhastobetightlyregulatedsincein the human intestinal mucosa, the protein fractional synthesis rate is approximately 50% per day. This value is higher than that of other major metabolically active tissues, such as liver and muscle, and depends on the accessibility of the metabolic precursor pool (1). The amino acid L-arginine (L-Arg) is a central intestinal metabolite, both as a constituent of protein synthesis and as a regulatory molecule limiting intestinal alterations and maintaining immunophysiologicalfunctions(1,2).Infection-associated L-Arg deficiency has been shown to contribute to immunopathology, andclinicaltrialsinvolving L-Argadministrationhaveshownsubstantial decreases in inflammation and infectious complications (3). In this issue, Chau and colleagues demonstrate that malariaassociated hypoargininemia impairs intestinal barrier function and predisposes the host to coinfection with Salmonella. Increasingbioavailabilityof L-Argthroughoralsupplementationameliorates intestinal inflammation and pathology, demonstrating that pharmacological intervention at the metabolic-precursor level can be utilized to regulate mucosal immunohomeostasis (4). L-Arg is derived from the diet, turnover of proteins, and endogenous production through synthesis from L-citrulline (L-Cit) and successive actions of argininosuccinate synthetase (AS) and argininosuccinate lyase (AL), the third and fourth enzymes of the urea cycle. The major site of L-Arg metabolism is the liver, where L-Arg generated in the urea cycle is rapidly converted to urea and ornithine by arginases, however, with no net synthesis of L-Arg. Although synthesis of L-Arg from L-Cit can occur in many cell types, a major part of endogenous synthesis occurs via “the intestinal-renal axis,” a postnatally established collaboration between epithelial cells of the small intestine and proximal tubule cells of the kidney. In adult animals, L-Cit is produced primarily by intestinal epithelial cells from NH3 ,C O2, and ornithine by carbamylphosphate synthetase I and ornithine transcarbamylase, the first two enzymes of the urea cycle, and is supplied to the kidney and probably to other tissues for synthesis of L-Arg (2, 5, 6). L-Arg is a crucial amino acid that serves to modulate immune responses through conversion by several intracellular classes of enzymes, with isoforms of arginase and nitric oxide synthase (NOS) being the two major enzyme families exerting key immunological functions (7). However, catabolism of extracellular LArg requires active and regulated uptake via specific cationic amino acid transporters (CAT) or heteromeric amino acid transporters (HAT) that act as H-coupled symporters or antiporters