R.R.W.J. van der Hulst

Glutamine and the preservation of gut integrity

Parenteral glutamine dipeptide improves nitrogen balance in postoperative patients on total parenteral nutrition (TPM). Animal studies show that the structure and function of the gut is preserved by glutamine. It is not known if this is the case in human beings. 20 patients admitted to hospital for total parenteral nutrition were randomly allocated to receive parenteral nutrition enriched with glycyl-L-glutamine (Gln TPN), or standard parenteral nutrition (STPN). Mucosal biopsy specimens were taken from the second part of the duodenum before starting parenteral nutrition, and after two weeks. The ratio between the urine concentrations of lactulose and mannitol after enteral administration was used to measure intestinal permeability. After two weeks of parenteral nutrition in the GlnTPN group, intestinal permeability was unchanged, whereas permeability in the STPN group increased. Villus height was unaltered in the GlnTPN group but in the STPN group it decreased. The addition of glutamine to parenteral nutrition prevents deterioration of gut permeability and preserves mucosal structure.

Effect of Helicobacter pylori eradication on gastritis in relation to cagA: A prospective 1-year follow-up study

BACKGROUND & AIMS Whether Helicobacter pylori eradication resolves intestinal metaplasia and atrophy and whether infection with cagA+ H. pylori is related to a specific clinical outcome are not known. The aim of this study was to investigate the role of H. pylori eradication on the course of intestinal metaplasia (IM) and atrophy in relation to cagA. METHODS In a large prospective study, the cagA status of H. pylori isolated from consecutive dyspeptic patients was related to clinical outcome before and 1 year after successful eradication of H. pylori. At pretreatment and 4-6 weeks and on average 1 year after eradication therapy, the degree of gastritis and the status of H. pylori were assessed by culture and histopathology. RESULTS Specimens of cagA+ H. pylori were recovered from 122 of 155 (79%) patients infected with H. pylori. Pretreatment degrees of gastritis activity, superficial epithelial damage, IM, and atrophy were significantly greater in patients infected with cagA+ H. pylori (P < 0.001). After successful eradication of H. pylori, a significant improvement of activity of gastritis and superficial epithelial damage occurred (P < 0.001), but the degree of IM and atrophy did not change, irrespective of the cagA status. CONCLUSIONS The usefulness of H. pylori eradication to revert precancerous lesions such as IM and atrophy after 1-year follow-up is questionable.

Gut permeability, intestinal morphology, and nutritional depletion.

Nutritional depletion increases the risk for postoperative complications. The intestinal barrier may be important in the underlying pathophysiologic mechanism. In this study, 26 patients were evaluated to determine whether nutritional depletion was related to gut integrity and intestinal morphology. Nutritional depletion was estimated by calculating percentage ideal body weight (PIB) or percentage ideal fat free mass (PIFFM). To assess gut integrity, a lactulose/mannitol (L/M) test was performed. Duodenal biopsies were taken, and villous height, crypt depth, number of IgA-producing plasma cells, intraepithelial lymphocytes (IELs), and proliferating index were determined. The L/M ratio was increased, and villous height was decreased in depleted patients. Depletion was not associated with differences in the number of immune cells or proliferating index. The number of IgA-producing plasma cells was positively correlated with the L/M ratio. This study shows that nutritional depletion is associated with increased intestinal permeability and a decrease in villous height.

Glutamine Depletion and Increased Gut Permeability in Nonanorectic, Non-Weight-Losing Tumor-Bearing Rats

BACKGROUND & AIMS Glutamine is an essential amino acid for rapidly dividing cells such as enterocytes. The progress of cancer is associated with a decrease of arterial and muscle glutamine concentrations. The aim of this study was to test whether increasing tumor loads affect gut intracellular glutamine handling, protein turnover, and gut absorptive and barrier function. METHODS Methylcholantrene-induced tumor-bearing rats were studied with a subcutaneous tumor load of 5%-15% or 15%-30% of body weight. Portal drained visceral net uptake or release of energy substrates, amino acids, and intestinal protein turnover were studied. Gut absorptive capacity and permeability was assessed by the urinary recovery of 3-O-methyl-D-glucose or lactulose-rhamnose ratio after an oral gavage. RESULTS In tumor-bearing rats, the net uptake of energy substrates (ketones and glutamine) and net protein synthesis increased across the portal drained viscera, whereas mucosal glutamine concentrations decreased. Absorptive capacity remained unchanged in both tumor-bearing groups. However, the lactulose-rhamnose ratio increased with increasing tumor load, indicating loss of gut barrier function. This was not related to changes in villus height, crypt depth, or changes in mucosal cell populations but to decreased intracellular polyamine concentrations. CONCLUSIONS The presence of a methylcholantrene tumor leads to altered mucosal glutamine metabolism and loss of gut barrier function possibly related to disturbed proliferation or differentiation of enterocytes.

Free flaps in burn reconstruction

In this paper, we present our experience of free flap reconstructions in burned patients. It allows the preservation of otherwise unsalvageable deep burn injuries and secondary correction of contracted burn scars. We analyse the indications of different free flaps, according to different anatomic regions and defects: depth and width of the loss of tissue, different colour skin, texture and thickness of the receptor area, weight-bearing or not weight-bearing surface. Free flap reconstructions were successful in 50 of 53 cases (94%). They provide good aesthetic and functional results with low morbidity both in acute deep burn injuries as in delayed reconstructions.

Glutamine extraction by the gut is reduced in depleted [corrected] patients with gastrointestinal cancer.

OBJECTIVE AND SUMMARY BACKGROUND DATA Glutamine is an important fuel for the intestinal mucosa. However, glutamine pools may become depleted in the cancer-bearing host as a result of tumor consumption and diminished production due to nutritional depletion. As human data are lacking, the authors investigated glutamine extraction by different sites of the human intestine, including tumor and the potential relation with the degree of nutritional depletion. METHODS Thirty-two patients with gastrointestinal malignancies were studied. Blood from an artery and veins draining jejunum, ileum, colon, or tumor were sampled. Depletion was estimated by the percentage ideal body weight. RESULTS Fractional glutamine extraction rate in the jejunum was 24%, three times higher than in ileum and colon. Percentage ideal body weight correlated with arterial glutamine levels (r = 0.5275, p = 0.003). In addition, arterial glutamine concentrations were correlated with extraction in the ileum (r = -0.8411, p < 0.001). Colon-containing tumor did not extract more glutamine than did nontumor-containing colon. CONCLUSIONS Glutamine is a quantitatively more important substrate for the proximal intestine than for the distal gut. Nutritional depletion results in decreased arterial glutamine concentration, which in turn results in diminished extraction. Colon cancer does not function as a glutamine trap and does not contribute to glutamine depletion.

Glutamine : An essential amino acid for the gut

Glutamine is a non-essential amino acid which is produced in sufficient amount by the healthy human body. From experimental work it is known that glutamine is an important nutrient for rapidly dividing cells such as cells from the immune system and the gut. During several conditions a lack of glutamine may occur. This will result in functional disturbances of the immune system and/or the gut. Glutamine is produced mainly by the muscle tissue. A decrease in muscle mass during nutritional depletion may result in decreased glutamine production capacity. Furthermore during critical illness, there is an increased demand for glutamine probably as a result of an increased utilization by the immune system. In addition, patients receiving standard parenteral nutrition do not receive glutamine, until recently, commercial parenteral nutrition did not contain glutamine because of instability of this amino acid during prolonged storage. One of the important functions of the gut is to prevent migration of bacteria and/or toxins from the gut lumen into the systemic circulation. A lack of glutamine may result in deterioration of this intestinal barrier. Supplementation of glutamine to certain patients could be essential. The relation between glutamine and the gut in several situations (nutritional depletion, critical illness, parenteral nutrition) is discussed in this paper.

Glutamine: The Pivot of Our Nitrogen Economy?

Glutamine serves as a shuttle of useful nontoxic nitrogen, supplying nitrogen from glutamine-producing (eg, muscle) to glutamine-consuming tissues. True production rates of glutamine are difficult to measure, but probably are less than 60 to 100 g/d for a 70-kg man. During catabolic stress increased amounts of glutamine are released from muscle, consisting of protein derived glutamine, newly synthesized glutamine, and glutamine losses from the intramuscular free pool. The large and rapid losses of free muscle glutamine are difficult to restore, presumably as a result of disturbances in the Na+ electrochemical gradient across the cell membrane. Whereas increased amounts of glutamine are released from muscle, glutamine consumption by the immune system (liver, spleen) also is enhanced. Thus, during catabolic stress changes occur in the flow of glutamine between organs. These changes are not necessarily reflected by alterations in the whole-body appearance rate of glutamine. In contrast with the gut, where glutamine is taken up in a concentration dependent manner, the immune system actively takes up glutamine despite decreased plasma concentrations. Supplementation with glutamine influences uptake by both the gut and the immune system, as evidenced by increased mucosal glutamine concentrations and gut glutathione production. There is evidence suggesting that this improves gut barrier function. Although the benefit of glutamine supplementation is most evident from experimental studies, clinical studies on the effect of glutamine do exist and suggest that glutamine supplementation has beneficial effects with regard to patient outcome.

Glutamine and intestinal immune cells in humans.

BACKGROUND Total parenteral nutrition (TPN) is associated with depletion of intestinal immune cells and increased gut permeability (GP). Adding glutamine (GLN) to TPN preserves GP by an unknown mechanism. Intestinal immune cells situated between the enterocytes (intraepithelial lymphocytes, [IEL]) influence GP in vitro. To obtain insight into the underlying mechanism of GLN on GP, we investigated the effects of GLN-supplemented TPN on IEL, immunoglobulin A (IgA) plasma cells and goblet cells, and enterocyte proliferation in intestinal biopsies. METHODS Twenty patients randomly received GLN-enriched TPN (GT) or isonitrogenous standard TPN (ST). Proliferation and number of immune cells were measured in intestinal biopsies obtained before and after 10 days of TPN. RESULTS No change in proliferative activity or in number of IgA plasma cells was observed. Goblet cells increased in the ST group, whereas the change seen in the GT group did not reach significance. In the GT group, IEL decreased, whereas in the ST group, no change in the number of IEL was observed. CONCLUSIONS TPN was not associated with changes in proliferative activity or with depletion of gut immune cells. The data indicate that GLN-supplemented TPN has a different effect on intestinal immune cells compared with standard TPN.

Decrease of mucosal glutamine concentration in the nutritionally depleted patient

A diminished glutamine delivery by peripheral tissues is suggested to play an important role in the etiology of postoperative complications of nutritionally depleted patients. Decreased glutamine supply to the gut mucosa in these nutritionally depleted patients may have important consequences for the integrity of the gut mucosa barrier. To evaluate whether glutamine concentration in the gut mucosa of depleted patients is altered, patients with either a fat-free mass index below 90% or percentage ideal body weight below 90% as a result of weight loss were studied. 22 patients admitted to the University Hospital Maastricht and 14 controls were studied. After an overnight fast, venous blood was sampled and duodenal biopsies were obtained by endoscopy. Plasma and tissue amino acids were measured. Fat-free mass was determined by bioelectrical impedance measurement. In 10 depleted patients glutamine concentration in the duodenal mucosa was 2883 +/- 250 mumol/kg dry weight. Concentration of alanine was 2570 +/- 263 mumol/kg dry weight. In the non-depleted patients glutamine and alanine concentrations were respectively 3463 +/- 171 mumol/kg dry weight and 3540 +/- 315 mumol/kg dry weight. Concentrations in controls were 3296 +/- 176 mumol/kg dry weight for glutamine and 3682 +/- 372 mumol/kg dry weight for alanine. Concentrations for alanine and glutamine were significantly lower in depleted patients compared to non-depleted patients (p < 0.05). Also, alanine and glutamine concentrations were significantly correlated with percentage ideal body weight (r=0.43, p < 0.005 for glutamine and r=0.62, p < 0.001 for alanine) and fat-free mass index (r=0.42, p < 0.05 for glutamine and r=0.48, p < 0.01 for alanine) This study suggests that in patients depletion appears to be related to decreased plasma and mucosa glutamine and alanine concentrations.