Bardhan, Pradip K.

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Improving the ORS: Does Glutamine have a Role?

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Bioline International

J HEALTH POPUL NUTR 2007 Sep;25(3):263-266ISSN 1606-0997 | $ 5.00+0.20©INTERNATIONAL CENTRE FOR DIARRHOEALDISEASE RESEARCH, BANGLADESHImproving the ORS: Does Glutamine have a Role?Correspondence and reprint requests should be addressed to:Dr. Pradip K. BardhanScientist and Head, Special Care UnitDhaka HospitalICDDR,BGPO Box 128, Dhaka 1000BangladeshEmail: bardhan@icddrb.orgEDITORIALDiarrhoea continues to be a leading cause of mor-bidity and mortality around the world, resulting in an estimated 1.5 billion episodes and 1.5 million to 2.2 million deaths annually among children aged less than five years (1,2). Oral rehydration therapy (ORT) effectively treats mild-to-moderate dehydra-tion due to diarrhoea and, for the past three dec-ades, has saved millions of lives, mostly in develop-ing countries. A crucial aspect in this decrease in mortality due to diarrhoea has been the widespread acceptance of ORT for the prevention and treat-ment of dehydration associated with diarrhoeal illnesses (3). However, despite its remarkable suc-cess, the currently-recommended oral rehydration solution (ORS) does not significantly reduce stool volume or duration of diarrhoeal illness. Thus, the search continues for improved formulations of ORS capable of lessening the severity of diarrhoea.The underlying physiologic principle of ORT is neat and simple—transport of sodium-coupled glucose across the small intestinal epithelial mem-brane remains largely intact in secretory diarrhoea and continues to stimulate absorption of water and electrolytes (4). Most attempts towards improving ORS have aimed at optimization of absorption of small intestinal fluid. Searching for an ORS capable of reducing diarrhoeal stool output, many clinical and basic scientists have investigated the role of other sodium co-transport substrates in addition to or instead of glucose. These included adding amino acids, e.g. glycine (5), alanine (6), and glutamine (7), and substitution of glucose by complex carbohy-drates, e.g. maltodextrins (8), cooked rice-powder and other cereal powders (9,10). While the clinical trials using glycine, alanine, maltodextrins, and ce-real-based ORSs conducted in the 1970s and 1980s showed promise, results of subsequent large tri-als and meta-analyses of results of previous trials found no advantage of most of these formulations when compared with the WHO-ORS, with the ex-ception of rice-based ORS (11,12).In the study published in this issue of the Journal of Health, Population and Nutrition, Guiterrez et al. compared the effects of a glutamine-containing glucose-free ORS with WHO-ORS in a double-blind randomized clinical trial among 147 dehydrated children with acute diarrhoea (13). Rotavirus was isolated from 62 of these children. The authors did not observe any significant difference between the two ORS groups in stool output during the first four hours, time taken to rehydrate successfully, vol-ume of ORS needed to rehydrate, vomiting, and urinary output. This was independent of rotavirus-associated illness. The authors concluded that an L-glutamine-containing glucose-free ORS does not seem to offer any clinical benefit compared to the standard WHO-ORS in mild-to-moderately dehy-drated children with acute non-cholera diarrhoea.The amino acid glutamine is the fundamental res-piratory fuel for the small intestine and has been classified as a conditional essential amino acid (14). Supplementation of glutamine has been shown to cause marked improvement in gastrointestinal structure and function after injury by chemother-apy, radiotherapy (15,16), or following prolonged parenteral nutrition (17). Glutamine also helps maintain the intestinal immunologic barrier, since it has been shown to increase the intestinal immu-noglobulin A levels and to reduce bacterial trans-location (18,19), and possibly the mechanism by which it reduces the incidence of bacteraemia and clinical infections (15,20). In addition, glutamine has also been postulated as a regulator of intracel-lular kinases, apoptosis, cell proliferation, redox sta-tus, and heat shock protein expression (21). In addition to being the predominant intestinal epithelial fuel source, the fact that glutamine is able to function as a sodium co-transport substrate in an electrogenic manner and to stimulate elec-troneutral NaCl absorption (22) has generated in-terest in glutamine as a potentially-useful compo-nent in ORS. Experiments have clearly shown that glutamine is able to promote the absorption of so-dium and water, even more effectively than glucose (23,24). In a perfused rabbit ileum model exposed to cholera toxin, a glutamine-based ORS caused a reduction of approximately 90% of cholera toxin-induced net sodium and water secretion (23); these observations are supported by other reports (24). JHPN264Bardhan PKImproving the ORSIn a rat model of secretory diarrhoea induced by cholera toxin (25), glutamine was found to have a significant positive effect upon sodium absorp-tion, but alanine-glutamine-based ORS had an even better effect in sodium absorption.  However, it remains to be explained whether these effects of alanine-glutamine are due only to effective avail-ability of glutamine or to a different mechanism. In adult cholera patients, in vivo intestinal perfusion experiments have shown that glutamine-contain-ing ORS reduced electrolyte and water secretion, although no increased sodium or water absorption was observed when compared with the effects with ORS containing glucose alone (26). In dehydrated infants suffering from non-cholera acute diarrhoea, ORS containing glutamine was found to be well-tolerated and as effective as the standard WHO-ORS (7). In another study conducted among adults with cholera, use of glutamine-supplemented ORS was associated with a 25% reduction in stool volume in the first 24 hours and a 30% reduction in the total faecal loss (27). Glutamine has also been observed to stimulate sodium co-transport in experimental models of rotavirus-associated enteritis and entero-pathogenic Escherichia coli-associated enteritis (28,29), although observations from other animal studies are not suggestive of a substantial effect of glutamine on acute diarrhoea (30).Investigators, in efforts to enhance the effective-ness of ORS, have also pursued pathways other than optimization of small intestinal absorption. One approach has been to use the mechanism of colonic salvage of fluids unabsorbed in the small intestine. Short-chain fatty acids are the major colonic luminal anions and are able to enhance so-dium absorption and inhibit chloride secretion in both normal and secreting colon (31,32). Short-chain fatty acids are formed in the colon by fer-mentation of unabsorbed starch and dietary fibres by the resident anaerobic bacterial flora. Several studies have examined the effects of addition of amylase-resistant starch and soluble dietary fibres to the standard ORS in diarrhoeal patients. In adult cholera patients, the group receiving amylase-re-sistant starch had had significantly reduced stool volumes and the duration of illness when com-pared with the group receiving the standard WHO-ORS (33). In non-cholera childhood diarrhoea, two studies reported that the addition of amylase-resist-ant starch or partially-hydrolyzed guar gum (as the short-chain fatty acid precursors) to the standard glucose-ORS significantly shortened the duration of diarrhoea (34,35), whereas another study using a mixture of non-digestible carbohydrates failed to observe any benefit (36). Taking a different ap-proach, a group of investigators aimed at ex-amining whether bioactive proteins found in breastmilk, when added to the standard ORS, yield any additional advantage. They observed that the addition of recombinant human lactoferrin and lysozyme to a rice-based ORS led to a significant de-crease in the duration of diarrhoea in children with non-cholera acute diarrhoea (37). Yet, in another innovative approach—in an experimental study using in vivo small intestinal perfusion in rats ex-posed to cholera toxin or the 5-fluorouracil—ORS with partial incorporation of the ORS components into liposomes showed 40-50% increased absorp-tion of water when compared with that from hypo-osmolar WHO glucose-ORS (38). To assess the full potential of these various approaches in enhancing ORS, data from carefully-designed and conducted large-scale clinical trials require to be evaluated be-fore deciding upon their effectiveness, practicality, applicability, and acceptability.Among the various factors contributing towards the success of ORS, the critical factors include its low cost, simplicity, and ease of use. Based upon observations that using a reduced-osmolarity ORS caused fewer unscheduled intravenous infusions, lower stool volumes, and less vomiting when com-pared with the standard WHO-ORS (39), the WHO recently recommended a change in the composition of ORS to a low-sodium and low-glucose solution (40). This improvement in the effectiveness of ORS was achieved without compromising the cost, sim-plicity, or ease of use. In future, further enhance-ments of ORT will similarly depend upon a careful balance of clinical effectiveness, cost-effectiveness, safety, public-health benefits, and ease of use.REFERENCES1. Black RE, Morriss SS, Bryce J. Where and why are 10 million children dying every year? Lancet 2003;361:2226-34.2. Kosek M, Bern C, Guerrant RL. The global burden of diarrhoeal disease, as estimated from studies pub-lished between 1992 and 2000. Bull World Health Or-gan 2003;81:197-204.3. Victora CG, Bryce J, Fontaine O, Monasch R. Reduc-ing deaths from diarrhoea through oral rehydration therapy. Bull World Health Organ 2000;78:1246-55.4. Field M. Intestinal ion transport and the pathophysio-logy of diarrhea. J Clin Invest 2003;111:931-43.5. Nalin DR, Cash RA, Rahman M, Yunus M. Effect of glycine and glucose on sodium and water absorption in patients with cholera. Gut 1970;11:768-72.6. Sazawal S, Bhatnagar S, Bhan MK, Saxena SK, Arora Bardhan PKImproving the ORSVolume 25 | Number 3 | September 2007 265NK, Aggarwal SK et al. Alanine-based oral rehydration solution: assessment of efficacy in acute noncholera diarrhea among children. J Pediatr Gastroenterol Nutr 1991;12:461-8.7. Ribeiro H, Jr., Ribeiro T, Mattos A, Palmeira C, Fern-andez D, Sant’Ana I et al. Treatment of acute di-arrhea with oral rehydration solutions containing glutamine. J Am Coll Nutr 1994;13:251-5.8. Santos Ocampo PD, Bravo LC, Rogacion JM, Bat-tad GR. A randomized double-blind clinical trial of a maltodextrin-containing oral rehydration solution in acute infantile diarrhea. J Pediatr Gastroenterol Nutr 1993;16:23-8.9. Molla AM, Molla A, Nath SK, Khatun M. Food-based oral rehydration salt solution for acute childhood di-arrhoea. Lancet 1989;2:429-31.10. Fontaine O, Gore SM, Pierce NF. Rice-based oral rehy-dration solution for treating diarrhea. Cochrane Data-base Syst Rev 2000;(2):CD001264.11. International Study Group on Improved ORS. Impact of glycine-containing ORS solutions on stool output and duration of diarrhoea: a meta-analysis of seven clinical trials. Bull World Health Organ 1991;69:541-8.12. Bhan MK, Mahalanabis D, Fontaine O, Pierce NF. Clinical trials of improved oral rehydration salt formulations: a review. Bull World Health Organ 1994;72:945-55.13. Gutiérrez C, Villa S, Mota FR, Calva JJ. Does an L-glutamine-containing, glucose-free, oral rehydration solution reduce stool output and time to rehydrate in children with acute diarrhoea? A double-blind rand-omized clinical trial. J Health Popul Nutr 2007;25:278-84. 14. Lacey JM, Wilmore DW. Is glutamine a conditionally essential amino acid? Nutr Rev 1990;48:297-309.15. Ziegler TR, Young LS, Benfell K, Scheltinga M, Hortos K, Bye R et al. Clinical and metabolic efficacy of glutamine-supplemented parenteral nutrition af-ter bone marrow transplantation. A randomized, double-blind, controlled study. Ann Intern Med 1992;116:821-8.16. Yoshida S, Matsui M, Shirouzu Y, Fujita H, Yamana H, Shirouzu K. Effects of glutamine supplements and ra-diochemotherapy on systemic immune and gut bar-rier function in patients with advanced esophageal cancer. Ann Surg 1998;227:485-91.17. Tremel H, Kienle B, Weilemann LS, Stehle P, Fürst P. Glutamine dipeptide-supplemented parenteral nutri-tion maintains intestinal function in the critically ill. Gastroenterology 1994;107:1595-601.18. Burke DJ, Alverdy JC, Aoys E, Moss GS. Glutamine-supplemented total parenteral nutrition improves gut immune function. Arch Surg 1989;124:1396-9.19. Ersin S, Tuncyurek P, Esassolak M, Alkanat M, Buke C, Yilmaz M et al. The prophylactic and therapeu-tic effects of glutamine- and arginine-enriched di-ets on radiation-induced enteritis in rats. J Surg Res 2000;89:121-5.20. Wischmeyer PE, Lynch J, Liedel J, Wolfson R, Riehm J, Gottlieb L et al. Glutamine administration reduces Gram-negative bacteraemia in severely burned patients: a prospective, randomized, double-blind trial versus isonitrogenous control. Crit Care Med 2001;29:2075-80.21. Carneiro-Filho BA, Bushen OY, Brito GA, Lima AA, Guerrant RL. Glutamine analogues as adjunctive therapy for infectious diarrhea. Curr Infect Dis Rep 2003;5:114-9.22. Rhoads JM, Keku EO, Bennett LE, Quinn J, Lecce JG. Development of L-glutamine-stimulated electroneu-tral sodium absorption in piglet jejunum. Am J Physi-ol 1990;259:G99-G107.23. Silva AC, Santos-Neto MS, Soares AM, Fonteles MC, Guerrant RL, Lima AA. Efficacy of a glutamine-based oral rehydration solution on the electrolyte and wa-ter absorption in a rabbit model of secretory diarrhea induced by cholera toxin. J Pediatr Gastroenterol Nutr 1998;26:513-9.24. Abely M, Dallet P, Boisset M, Desjeux JF. Effect of chol-era toxin on glutamine metabolism and transport in rabbit ileum. Am J Physiol Gastrointest Liver Physiol 2000;278:G789-96.25. Lima AA, Carvalho GH, Figueiredo AA, Gifoni AR, Soares AM, Silva EA et al. Effects of an alanyl-glutamine-based oral rehydration and nutrition ther-apy solution on electrolyte and water absorption in a rat model of secretory diarrhea induced by cholera toxin. Nutrition 2002;18:458-62.26. van Loon FP, Banik AK, Nath SK, Patra FC, Wahed MA, Darmaun D et al. The effect of L-glutamine on salt and water absorption: a jejunal perfusion study in cholera in humans. Eur J Gastroenterol Hepatol 1996;8:443-8.27. Punjabi NH, Kumala S, Rasidi C, Witham ND, Pu-lungsih SP, Rivai AR  et al. Glutamine supplemented ORS is superior to standard citrate glucose ORS for the maintenance therapy of adult cholera patients in Jakarta (abstract). Am J Trop Med Hyg 1991;45(Sup-pl):114-5.28. Rhoads JM, Keku EO, Quinn J, Woosely J, Lecce JG. L-glutamine stimulates jejunal sodium and chloride absorption in pig rotavirus enteritis. Gastroenterology 1991;100:683-91.29. Nath SK, Dechelotte P, Darmaun D, Gotteland M, JHPN266Bardhan PKImproving the ORSRongier M, Desjeux JF. [15N]- and [14C]glutamine fluxes across rabbit ileum in experimental bacterial diarrhea. Am J Physiol 1992;262:G312-8.30. Naylor JM, Leibel T, Middleton DM. Effect of glutamine or glycine containing oral electrolyte solu-tions on mucosal morphology, clinical and biochem-ical findings, in calves with viral induced diarrhea. Can J Vet Res 1997;61:43-8.31. Rabbani GH, Albert MJ, Rahman H, Chowdhury AK. Short-chain fatty acids inhibit fluid and electrolyte loss induced by cholera toxin in proximal colon of rabbit in vivo. Dig Dis Sci 1999;44:1547-53.32. Vidyasagar S, Ramakrishna BS. Effects of butyrate on active sodium and chloride transport in rat and rab-bit distal colon. J Physiol 2002;539(Pt 1):163-73.33. Ramakrishna BS, Venkataraman S, Srinivasan P, Dash P, Young G, Binder HJ. Amylase-resistant starch plus oral rehydration solution for cholera. N Engl J Med 2000;342:308-13.34. Raghupathy P, Ramakrishna BS, Oommen SP, Ahmed MS, Priyaa G, Dziura J et al. Amylase-resistant starch as adjunct to oral rehydration therapy in children with diarrhea. J Pediatr Gastroenterol Nutr 2006;42:362-8.35. Alam NH, Meier R, Schneider H, Sarker SA, Bardhan PK, Mahalanabis D et al. Partially hydrolysed guar gum-supplemented oral rehydration solution in the treatment of acute diarrhea in children. J Pediatr Gas-troenterol Nutr 2000;31:503-7.36. Hoekstra JH, Szajewska H, Zikri MA, Micetic-Turk D, Weizman Z, Papadopoulou A et al. Oral rehydra-tion solution containing a mixture of non-digestible carbohydrates in the treatment of acute diarrhea: a multicenter randomized placebo-controlled study on behalf of the ESPGHAN Working Group on Intestinal Infections. J Pediatr Gastroenterol Nutr 2004;39:239-45.37. Zavaleta N, Figueroa D, Rivera J, Sanchez J, Alfaro S, Lonnerdal B. Efficacy of rice-based oral rehydration solution containing recombinant human lactoferrin and lysozyme in Peruvian children with acute di-arrhea. J Pediatr Gastroenterol Nutr 2007;44:258-64.38. Bardhan PK, Rahman H, Sack DA. Absorption of wa-ter from a liposomal oral rehydration solution (ORS): an in-vivo perfusion study of rat small intestine (ab-stract). Gastroenterology 2004;126(4 Suppl 2):A-514.39. Hahn S, Kim S, Garner P. Reduced osmolarity oral rehydration solution for treating dehydration caused by acute diarrhea in children. Cochrane Database Syst Rev 2002;(1):CD002847.40. Duggan C, Fontaine O, Pierce NF, Glass RI, Maha-lanabis D, Alam NH et al. Scientific rationale for a change in the composition of oral rehydration solu-tion. JAMA 2004;291:2628-31.Pradip K. BardhanScientist and Head, Special Care UnitDhaka HospitalICDDR,BGPO Box 128, Dhaka 1000BangladeshEmail: bardhan@icddrb.org

A randomized double-blind clinical trial of a maltodextrin-containing oral rehydration solution in acute infantile diarrhea.

Absorption of water from a liposomal oral rehydration solution (ORS): an in-vivo perfusion study of rat small intestine (abstract).

Alanine-based oral rehydration solution: assessment of efficacy in acute noncholera diarrhea among children.

Amylase-resistant starch as adjunct to oral rehydration therapy in children with diarrhea.

Amylase-resistant starch plus oral rehydration solution for cholera.

Clinical and metabolic efficacy of glutamine-supplemented parenteral nutrition after bone marrow transplantation. A randomized, double-blind, controlled study.

Clinical trials of improved oral rehydration salt formulations: a review. Bull World Health Organ

Development of L-glutamine-stimulated electroneutral sodium absorption in piglet jejunum.

Does an Lglutamine-containing, glucose-free, oral rehydration solution reduce stool output and time to rehydrate in children with acute diarrhoea? A double-blind randomized clinical trial.

Effect of cholera toxin on glutamine metabolism and transport in rabbit ileum.

Effect of glutamine or glycine containing oral electrolyte solutions on mucosal morphology, clinical and biochemical findings, in calves with viral induced diarrhea.

Effect of glycine and glucose on sodium and water absorption in patients with cholera.

Effects of an alanylglutamine-based oral rehydration and nutrition therapy solution on electrolyte and water absorption in a rat model of secretory diarrhea induced by cholera toxin.

Effects of butyrate on active sodium and chloride transport in rat and rabbit distal colon.

Effects of glutamine supplements and radiochemotherapy on systemic immune and gut barrier function in patients with advanced esophageal cancer. Ann Surg

Efficacy of a glutamine-based oral rehydration solution on the electrolyte and water absorption in a rabbit model of secretory diarrhea induced by cholera toxin.

Efficacy of rice-based oral rehydration solution containing recombinant human lactoferrin and lysozyme in Peruvian children with acute diarrhea.

fluxes across rabbit ileum in experimental bacterial diarrhea.

Food-based oral rehydration salt solution for acute childhood diarrhoea.

Glutamine administration reduces Gram-negative bacteraemia in severely burned patients: a prospective, randomized, double-blind trial versus isonitrogenous control. Crit Care Med

Glutamine analogues as adjunctive therapy for infectious diarrhea. Curr Infect Dis Rep

Glutamine dipeptide-supplemented parenteral nutrition maintains intestinal function in the critically ill.

Glutamine supplemented ORS is superior to standard citrate glucose ORS for the maintenance therapy of adult cholera patients in Jakarta (abstract).

Glutaminesupplemented total parenteral nutrition improves gut immune function. Arch Surg

Group on Improved ORS. Impact of glycine-containing ORS solutions on stool output and duration of diarrhoea: a meta-analysis of seven clinical trials. Bull World Health Organ

Intestinal ion transport and the pathophysiology of diarrhea.

Is glutamine a conditionally essential amino acid? Nutr Rev

L-glutamine stimulates jejunal sodium and chloride absorption in pig rotavirus enteritis.

Papadopoulou A et al. Oral rehydration solution containing a mixture of non-digestible carbohydrates in the treatment of acute diarrhea: a multicenter randomized placebo-controlled study on behalf of the ESPGHAN Working Group on Intestinal Infections.

Partially hydrolysed guar gum-supplemented oral rehydration solution in the treatment of acute diarrhea in children.

Reduced osmolarity oral rehydration solution for treating dehydration caused by acute diarrhea in children. Cochrane Database Syst Rev

Reducing deaths from diarrhoea through oral rehydration therapy.

Rice-based oral rehydration solution for treating diarrhea. Cochrane Database Syst Rev

Scientific rationale for a change in the composition of oral rehydration solution.

Short-chain fatty acids inhibit fluid and electrolyte loss induced by cholera toxin in proximal colon of rabbit in vivo. Dig Dis Sci

The effect of L-glutamine on salt and water absorption: a jejunal perfusion study in cholera in humans.

The global burden of diarrhoeal disease, as estimated from studies published between

The prophylactic and therapeutic effects of glutamine- and arginine-enriched diets on radiation-induced enteritis in rats.

Treatment of acute diarrhea with oral rehydration solutions containing glutamine.

Where and why are 10 million children dying every year?

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Improving the ORS: Does Glutamine have a Role?

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