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This study evaluated the effects of supplemental dietary glutamine (GLN) on methotrexate sodium concentrations in tumors and serum of sarcoma-bearing rats following the initiation of methotrexate. After randomization to a GLN diet (+GLN) or GLN-free diet (-GLN), tumor-bearing rats received 20 mg/kg of methotrexate sodium by intraperitoneal injection. The provision of supplemental GLN in the diet increased methotrexate concentrations in tumor tissues at 24 and 48 hours (38.0 +/- 0.20 nmol/g for the +GLN group vs 28.8 +/- 0.10 nmol/g for the -GLN group and 35.6 +/- 0.18 nmol/g for the +GLN group vs 32.5 +/- 0.16 nmol/g for the -GLN group, respectively). Arterial methotrexate levels were elevated only at 48 hours (0.147 +/- 0.007 microns/L for the +GLN group vs 0.120 +/- 0.006 microns/L for the -GLN group). Tumor morphometrics were not different between the groups but significantly greater tumor volume loss was seen even at 24 hours (-2.41 +/- 1.3 cm3 for the +GLN group vs -0.016 +/- 0.9 cm3 for the -GLN group). Tumor glutaminase activity was suppressed in both groups at 48 hours, but more so in the +GLN group (0.94 +/- 0.13 mumol/g per hour for the +GLN group vs 1.47 +/- 0.22 mumol/g per hour for the -GLN group). This study suggests that GLN may have therapeutic as well as nutritional benefit in oncology patients.

The healing effects of glutamine given orally for 8 days as a single amino acid nutrient after treatment with whole abdominal radiation (10 Gy) were studied. Rats received isonitrogenous and isovolumic diets containing 3% glutamine or 3% glycine. Control rats were not irradiated but were given identical diets. In irradiated animals, survival was 100% in animals receiving glutamine compared with 45% in animals receiving glycine. Glutamine ingestion diminished bloody diarrhea and the incidence of bowel perforation. Arterial glutamine level was higher in animals receiving glutamine in the diet, as were gut glutamine extraction (35% +/- 8% vs 12% +/- 7%) and intestinal glutaminase activity. These metabolic improvements were associated with a marked increase in villous height, villous number, and the number of mitoses per crypt in rats receiving glutamine. Glutamine was not beneficial in control nonirradiated animals. The data demonstrated that provision of oral glutamine after abdominal radiation supported gut glutamine metabolism, improved mucosal morphometrics, and decreased the morbidity and mortality associated with this abdominal radiation model.

Glutamine may be an essential dietary component, especially for the support of intestinal mucosal growth and function. This study evaluated the effects of a glutamine-enriched elemental diet, administered before whole-abdominal radiation on gut glutamine metabolism, mucosal morphometrics, and bacterial translocation. Rats were randomized to receive a nutritionally complete elemental diet that was glutamine-enriched or glutamine-free for 4 days. The animals were then subjected to a single dose of 1000 cGy x-radiation to the abdomen. After irradiation, all animals received the glutamine-free diet. Four days later the animals underwent laparotomy for sampling of arterial and portal venous blood, culture of mesenteric lymph nodes, and removal of the small intestine for microscopic examination. There was no difference in arterial glutamine or gut glutamine extraction between the two groups, but body weight loss was significantly diminished in the glutamine-fed rats. Rats receiving the glutamine-enriched elemental diet before radiation had a significant increase in jejunal villous number, villous height, and number of metaphase mitoses per crypt. Scanning electron microscopy confirmed the presence of an intact gut epithelium in eight of eight rats receiving prophylactic glutamine compared to one of eight animals in the glutamine-free group. Three of eight rats fed glutamine had culture positive mesenteric lymph nodes compared with five of seven rats receiving the glutamine-free diet. Glutamine exerts a protective effect on the small bowel mucosa by supporting crypt cell proliferation effect on accelerate healing of the acutely radiated bowel.

Although glutamine-supplemented diets appear to be beneficial in the model described here, carefully designed clinical trials must be done before such therapy is recommended in patients receiving XRT. Such studies should examine the efficacy of glutamine-enriched parenteral nutrition as well as enteral feedings. They must address the issue of potential stimulation of tumor growth by glutamine supplementation. In addition, the question has been raised as to whether glutamine will result in the tumor being more refractory to radiation therapy.

The effects of sepsis on gut glutamine (GLN) metabolism were studied to gain further insight into the regulation of the altered glutamine metabolism that characterizes critical illnesses. Studies were done in laboratory rats and in hospitalized patients. The human studies were done in seven healthy surgical patients (controls) and six septic patients who underwent laparotomy. Radial artery and portal vein samples were obtained during operation and were analyzed for GLN and oxygen content. Despite no reduction in arterial glutamine concentration in the septic patients, gut glutamine extraction was diminished by 75% (12.0% +/- 1.6% in controls vs. 2.8% +/- 0.8% in septic patients, p less than 0.01). Similarly gut oxygen extraction was diminished by nearly 50% in the septic patients (p less than 0.05). To further investigate these abnormalities, endotoxin (10 mg/kg intraperitoneally) or saline (controls) was administered to adult rats 12 hours before cannulation of the carotid artery and portal vein. The arterial GLN concentration was increased by 13% in the endotoxin-treated animals (p less than 0.05) but gut glutamine uptake was diminished by 46% (526 +/- 82 nmol/100 g BW/minute in controls vs. 282 +/- 45 in endotoxin, p less than 0.01). Simultaneously gut glutaminase activity was diminished by 30% (p less than 0.01) and intestinal glutamate release fell by two thirds. Blood cultures were negative in control animals (0 of 20), but were positive in 25% of endotoxemic animals (6 of 24) for gram-negative rods (p = 0.019). Sepsis and endotoxemia impair gut glutamine metabolism. This impairment may be etiologic in the breakdown of the gut mucosal barrier and in the development of bacterial translocation.

Glutamine is a principal fuel utilized by rapidly growing tumors. Advanced malignant disease results in muscle glutamine depletion and weight loss. Concern exists about providing dietary glutamine to the host with cancer since it may stimulate tumor growth. This study examined the effects of oral glutamine on muscle glutamine metabolism and tumor growth. Twenty-four rats with large sarcomas were pair fed a glutamine-enriched or glutamine-free elemental diet. Diets were isonitrogenous and isocaloric. After 6 days of feeding, the animals were anesthetized and arterial glutamine, hindquarter glutamine flux, muscle glutamine content, tumor weight, tumor DNA content, tumor glutaminase activity, and number of metaphase mitoses/high power field (HPF) in the tumor were determined. There was no difference in arterial glutamine between the two groups, but provision of a glutamine-enriched diet increased muscle glutamine content by 60% (2.31 +/- 0.21 mumole/g tissue vs 1.44 +/- 0.22 mumol/g tissue, P less than 0.05), which supported muscle glutamine release. There were no differences among tumor DNA content, tumor glutaminase activity, or tumor weight and there was no difference histologically in the number of metaphase mitoses/HPF. Glutamine-enriched oral diets may replete host glutamine stores and support muscle glutamine metabolism without stimulating tumor growth.

In the critically ill surgical patient a variety of therapeutic maneuvers is required to maintain a "healthy gut." Provision of adequate amounts of glutamine to the gastrointestinal mucosa appears to be just one of these maneuvers. Other methods utilized to protect the gut from becoming a wound include: (a) minimizing additional systemic insults (such as hypotension, sepsis, multiple operative procedures); (b) aggressive pulmonary care; (c) the judicious use of antibiotics; and (d) aggressive enteral or parenteral feedings. The concept that the gut is an organ of quiescence following surgical stress merits reconsideration. The intestinal tract plays a central role in interorgan glutamine metabolism and is a key regulator of nitrogen handling following surgical stress. Critically ill patients are susceptible to developing gut-origin sepsis, the incidence of which will be diminished by instituting measures and providing treatments which support intestinal structure, function, and metabolism. Provision of glutamine-enriched diets to such patients may be one of these therapies.

In critically ill surgical patients, a variety of therapeutic maneuvers are required to maintain a healthy GI tract. Provision of adequate amounts of glutamine to the gastrointestinal mucosa appears to be just one of these maneuvers. Other methods used to protect the GI tract from becoming a wound are (1) to avoid additional systemic and local insults (such as hypotension, sepsis, and multiple operative procedures); (2) to provide aggressive pulmonary care; (3) to use antibiotics judiciously; and (4) to provide aggressive enteral or parenteral feedings. The concept that the intestine is an organ of quiescence after surgical stress merits reconsideration. The intestinal tract plays a central role in interorgan glutamine metabolism and is a key regulator of nitrogen handling after surgical stress. Critically ill patients are susceptible to sepsis of GI origin, the incidence of which is diminished by instituting measures that support intestinal structure, function, and metabolism. Clearly, the biochemical and functional importance of the GI tract in surgical stress demands further elucidation of these factors.

Gut glutamine utilization after massive small bowel resection was studied to gain further insight into the alterations and adaptations in intestinal glutamine metabolism that occur during the development of post-resectional hyperplasia. After resection of the middle 60% of the small intestine in the rat, gut glutamine metabolism was studied immediately and 1, 2, and 3 weeks later. Whole gut glutamine extraction was 22% in sham controls and it acutely declined to 12% (p less than 0.01) after bowel resection. Extraction increased to 31% 1 week later (p less than 0.05) and then returned to normal by week 2. Gut ammonia release decreased after massive small bowel resection, whereas intestinal alanine release increased. The increase in gut glutamine extraction at 1 week occurred at a time when jejunal and ileal DNA and protein content were markedly increased (p less than 0.01). Intestinal glutaminase content declined initially and then increased by the third week after bowel resection (p less than 0.01). With time, increases in gut cellularity and glutaminase content are associated with gut glutamine utilization in the shortened small bowel that is equal to that of the intact unresected intestine.

The effect of dietary glutamine on bacterial translocation was studied in rats following administration of a single dose of abdominal radiation (1000 rad) that causes a reproducible mucosal injury and results in a high incidence of culture-positive mesenteric lymph nodes after radiation (XRT). Following XRT, rats received only the amino acid glutamine (3%, +GLN) in their drinking water or a control nonessential amino acid (glycine, -GLN). Diets were isonitrogenous and isovolumetric. Four days after XRT, rats were anesthetized and a laparotomy was performed. Mesenteric lymph nodes were sterilely excised and cultured. Arterial blood was also obtained for whole blood glutamine determination. Control rats received no XRT but received identical diets. In XRT rats who received the GLN-free diet, the incidence of culture-positive mesenteric lymph nodes was 89% (eight of nine rats) while in the radiated rats receiving the GLN-enriched diet, the incidence fell to 20% (P less than 0.05). In non-radiated control rats receiving GLN-enriched and GLN-depleted diets for 4 days, bacterial translocation occurred in zero of eight and one of eight rats, respectively (NS). Provision of glutamine to XRT rats resulted in higher blood levels of glutamine (408 +/- 25 microM in XRT +GLN vs 311 +/- 19 microM in XRT -GLN, P less than 0.05). In addition, provision of GLN maintained mucosal mass and reduced weight loss (P less than 0.05). The data lend further support to the hypothesis that glutamine helps maintain the gut mucosal barrier and thereby decreases the incidence of bacterial translocation following bowel injury.(ABSTRACT TRUNCATED AT 250 WORDS)