Is there a requirement for glutamine catabolism in the small intestine?

A search for ‘glutamine’ will yield over 20 000 hits on the World Wide Web, many related to the use of glutamine as a dietary supplement. Although glutamine is not, in the traditional sense, an essential amino acid, its use in clinical settings and by the general public has steadily increased over the past 10 years. The rationale for dietary glutamine supplements is based, in part, on its role as a fuel for the gastrointestinal tract and the immune system, and the perceived need to maintain high levels of glutamine in skeletal muscle to minimize proteolysis and maximize protein synthesis. In addition, glutamine is a major substrate for renal NH3 production, hepatic urea synthesis, and both renal and hepatic gluconeogenesis, and the amide N of glutamine is required for the synthesis of purines, pyrimidines and glucosamine. The results of glutamine supplementation in pathological states have not always been unequivocal but significant benefits have been reported in patients undergoing bone marrow transplantation, in patients with various gastrointestinal tract disorders, and in the critically ill (Griffiths et al. 1997; Furst, 1998). Given the explosion of reports involving the use of glutamine it is perhaps surprising how little we really know regarding whole-body glutamine homeostasis in species other than the rat. In this issue of the British Journal of Nutrition, Gateet al. (1999) describe the utilization, and fate, of arterial glutamine metabolized by the portal-drained viscera (PDV) of lambs starved for 24 h. Their results are interesting and provocative, not only in terms of ruminant biology, but also with regard to our understanding of glutamine homeostasis in general. The requirement for high levels of glutamine by certain cell types, such as mammalian cells in culture, the smallintestinal epithelium and immune cells has often been explained by a need for large amounts of glutamine for macromolecule synthesis but this accounts for , 4 % glutamine utilized (Newsholme t al. 1985). The realization that glutamine was the principal respiratory fuel of the rat small-intestinal mucosa (Neptune, 1965; Windmueller & Spaeth, 1974) explained the purpose of high rates of glutamine metabolism but did not answer the question, why glutamine? However, based on the data from the rat, it soon became dogma that the small-intestine epithelial mucosa had an absolute requirement for high rates of glutamine catabolism. Interestingly, in their original papers Windmueller and colleagues (Windmueller & Spaeth, 1974; Pinkus & Windmueller, 1977) showed that although there was net glutamine use by the PDV of the rat, dog and some other species, there was net glutamine output across the gut of guinea-pig and chicken. Similar species differences were seen in the intestinal expression of phosphate-activated glutaminase ( EC 3.5.1.2) (Pinkus & Windmueller, 1977; Wuet al. 1998). Despite the early recognition of species differences in small-intestine glutamine metabolism little attention has been paid to what such differences mean. Similarly, the suitability of inferring patterns of glutamine metabolism in one species from data obtained in other species has not been widely questioned. In ruminants the elegant chronic catherization studies of Bergman and colleagues (Heitmann & Bergman, 1978) demonstrated net glutamine uptake by sheep PDV. Although these results were never directly compared with those for other species, on examination they do suggest lower rates of glutamine utilization by the PDV of ruminants. Gate t al. (1999) have used a double catheterization technique (portal vein and mesenteric vein) combined with the use of 5N-labelled glutamine to follow the fate of glutamine metabolized by lamb PDV. Their results clearly show that the rate of turnover of plasma glutamine is lower in the lamb than in single-stomached species such as man, pig and rat (see van Acker et al. 1998). In keeping with previous reports they did find net glutamine uptake across the PDV and this accounted for 45 % of the total plasma turnover. However, most of the glutamine was used by non-mesenteric-vein drained tissues, not the small intestine. Although interpretation of the results is limited due to a small release of glutamine which could be due tode novo synthesis or absorption from the lumen, this study nevertheless indicates relatively low reliance on glutamine metabolism by ruminant PDV. Perhaps the most interesting finding of the work of Gate et al. (1999) is the fate of the glutamine taken up by lamb PDV. Windmueller & Spaeth (1974) accounted for all of the glutamine N utilized by intact rat small intestine by the production of NH3 and various amino acid end-products. Although this left no room for glutamine incorporation into macromolecules it probably reflects the limits of accuracy of the methodology in the rat, given such large differences in flux between energy production and biosynthetic pathways. In the lamb Gate et al. (1999) found that only 24 % of the glutamine amide N taken up across the mesenteric-drained viscera (small intestine) was released as NH3 (a crude estimate of the amount of glutamine used for energy provision). The majority of the glutamine taken up was found in protein (84 %), RNA (3 ⋅6 %) and DNA (2⋅1 %), with less as NH3 and more as macromolecules in the non-mesenteric-drained tissues. Thus, in the 24-hstarved lamb, arterial glutamine is utilized by the British Journal of Nutrition(1999),81, 261–262 261