A great deal has been written about glutamine and the gut (1), its role as an intestinal fuel, its impact on electrolyte and fluid transport and its impact on diarrhea. It is reasonable to ask whether glutamine might benefit malnourished children who often have diarrhea and who are said to have immunodeficiency, increased intestinal permeability to macromolecules and impaired digestive and absorptive functions. In this issue of The Journal of Pediatric Gastroenterology and Nutrition, Lima et al. evaluated the impact of enteral glutamine in childhood malnutrition (2). They studied 80 malnourished, hospitalized Brazilian infants using two outcome measures: weight gain and change in intestinal permeability, measured by the ratio of intestinal lactulose and mannitol absorption (L/M ratio). First, the authors obtained control data from 27 malnourished children from 2 to 60 months of age. They obtained L/M ratios on the children before study. They then fed the infants according to a standard WHO re-feeding protocol for moderate to severe malnutrition, weighing the patients daily. After 10 days they repeated the L/M ratio. Two years later, they enrolled another group containing 53 patients of the same age and degree of malnutrition. They used the same feeding protocol (double blind, random assignment), but they added glutamine or glycine to the formula in equimolar amounts. They monitored weight and obtained L/M ratios before and after 10 days of therapy. Thus, there were two controls for the glutamine supplemented group: an unsupplemented group and a group supplemented with glycine, an amino acid not felt to be conditionally essential in hyper metabolic states or to play a role as an intestinal fuel.
The authors found that weight gain in the three groups was statistically similar. Calorie intake was also similar. There was a statistically significant decrease in L/M ratio after re-nutrition in the glutamine-supplemented group compared with the unsupplemented and the glycine-supplemented control groups. A decrease in L/M ratio is felt to reflect an improvement in the permeability barrier function of the intestine. Since about 70% of the study children had diarrhea on enrollment, the authors looked at the responses of these children separately. They found no difference in weight gain or duration of diarrhea between children receiving glycine and glutamine supplementation. Amount of stool output was not measured.
There are a number of criticisms that can be made of this study. Two very simple measurements and a very short therapeutic intervention were used to study a complex problem. Only 65 of the 80 children had pre- and post-treatment L/M ratios. Two years separated the study of the non-supplemented control group from the supplemented groups. Although the authors stated that they excluded children with serious underlying disease, they included 3 children with celiac disease, one with cystic fibrosis and one who developed varicella on the last day of the intervention. The conditions in these 5 children would very likely have had an impact on weight gain and permeability measurements. Since these 5 children account for 8% of the children with complete L/M ratio data, their inclusion leaves questions about significance of the conclusions about the impact of glutamine on permeability.
Although many writers, including the authors of this paper, refer to the L/M ratio as a measure of intestinal function, an association between the L/M ratio and the most important intestinal function, the digestion and absorption of fat, carbohydrate and protein is uncertain. For example, does the percentage of fat excretion on a quantitative 3-day collection vary directly with the L/M ratio? Does the amount of intact protein absorbed from the intestine vary directly with the L/M ratio? No one has put questions like these to the test. In this study, was the magnitude of the change in the L/M ratio in the glutamine-supplemented children associated with any clinically important aspect of their malnourished state or their recovery there from? This study does not suggest that it was, but more careful assessment of other abnormalities associated with malnutrition besides weight will be needed to answer this question. One thing is clear from this paper. It is premature to consider using glutamine as adjunct therapy in malnourished infants because of its impact on the L/M ratio.
The L/M ratio is often discussed in ways that suggest it is a good measure of global intestinal health or integrity. This is an overstatement. We need specifics on what this easy-to-use measure really reveals about the digestive, absorptive, secretory and permeability functions of the intestine. In the past, the xylose absorption test was similarly said to be a measure of "intestinal function" or "intestinal surface area." It was soon apparent that intestinal function and the disorders causing damage to the intestine were too varied and complex to be confirmed or quantitated by this simple test, and more disease-specific tests were needed. The same criticism applies to the L/M ratio. Does a particular L/M ratio really translate into a quantifiable and predictable pathologic absorption of toxic or immunogenic macromolecules, with a predictable loss of electrolyte and water per cm of intestine, with predictable and consistent abnormalities of immune function, with a particular level of bacterial translocation, or other important intestinal functions? Or is the L/M ratio an overly sensitive test that is likely to be abnormal in whatever disease state you choose to name? Certainly the list of disorders reported to be associated with abnormal L/M ratio is large and includes head injury, cirrhosis, autism, intestinal surgery, infection, malnutrition, intestinal allergy and celiac disease (3-7). Research needs to identify the common thread among these disorders that leads to abnormal test results.
This study asked an important question about a controversial subject and concluded that glutamine supplementation did not improve on the standard WHO re-feeding program for moderate to severe malnutrition in either early weight gain or caloric intake. Although the numbers were small, another important negative finding was that glutamine supplementation did not produce a reduction in duration of diarrhea. This important information, negative though it is, refocuses attention on the fact that the WHO guidelines for re-nutrition of moderately and severely malnourished children without the use of expensive supplements are still appropriate for initial therapy. The authors of this study are to be congratulated for reporting what they saw. Treatment of malnutrition may not be changed by this study, but an important question has been answered about glutamine supplementation, and an attractive sounding, but probably unnecessary, therapy can be confidently avoided.
1. Rhoads M. Glutamine is the gas pedal but not the Ferrari. J Pediatr Gastroenterol Nutr
2. Lima AA, Brito LFB, Ribeiro HB, et al. Intestinal barrier function and weight gain in malnourished children taking glutamine supplemented enteral formula. J Pediatr Gastroenterol Nutr
3. Matejovic M, Krouzecky A, Rokyta R, et al. Effects of intestinal surgery on pulmonary, glomerular, and intestinal permeability and its relation to the hemodynamics and oxidative stress. Surg Today
4. Arvola T, Moilanen E, Vuento R, Isolauri E. Weaning to hypoallergenic formula improves gut barrier function in breastfed infants with atopic eczema. J Pediatr Gastroenterol Nutr
5. Hang CH, Shi JXZ, Li JS, Wu W, Yin HX. Alterations of intestinal mucosa structure and barrier function following traumatic brain injury in rats. World J Gastroenterol
6. Pascual S, Such J, Esteban A, et al. Intestinal permeability is increased in patients with advanced cirrhosis. Hepatogastroenterology
7. D'Eufimia P, Celli M, Finocchiara R, et al. Abnormal intestinal permeability in children with autism. Acta Pediatrr