The Journal of Health, Population and Nutrition icddr,b ISSN: 1606-0997 EISSN: 2072-1315 Vol. 25, Num. 3, 2007, pp. 263-266

Journal of Health, Population and Nutrition, Vol. 25, No. 3, September, 2007, pp. 263-266

Editorial

Improving the ORS: Does Glutamine have a Role?

Pradip K. Bardhan

Scientist and Head, Special Care Unit Dhaka Hospital ICDDR,B GPO Box 128, Dhaka 1000 Bangladesh Email: bardhan@icddrb.org

Correspondence and reprint requests should be addressed to: Dr. Pradip K. Bardhan Scientist and Head, Special Care Unit Dhaka Hospital ICDDR,B GPO Box 128, Dhaka 1000 Bangladesh Email: bardhan@icddrb.org

Code Number: hn07035

Diarrhoea continues to be a leading cause of mor­bidity 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 dehydra­tion due to diarrhoea and, for the past three dec­ades, has saved millions of lives, mostly in develop­ing countries. A crucial aspect in this decrease in mortality due to diarrhoea has been the widespread acceptance of ORT for the prevention and treat­ment of dehydration associated with diarrhoeal illnesses (3). However, despite its remarkable suc­cess, 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 mem­brane 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 carbohy­drates, e.g. maltodextrins (8), cooked rice-powder and other cereal powders (9,10). While the clinical trials using glycine, alanine, maltodextrins, and ce­real-based ORSs conducted in the 1970s and 1980s showed promise, results of subsequent large tri­als 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, vol­ume 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 dehy­drated children with acute non-cholera diarrhoea.

The amino acid glutamine is the fundamental res­piratory 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 chemother­apy, 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 immu­noglobulin A levels and to reduce bacterial trans­location (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 intracel­lular kinases, apoptosis, cell proliferation, redox sta­tus, 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 in­terest in glutamine as a potentially-useful compo­nent in ORS. Experiments have clearly shown that glutamine is able to promote the absorption of so­dium 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). In a rat model of secretory diarrhoea induced by cholera toxin (25), glutamine was found to have a significant positive effect upon sodium absorp­tion, 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 avail­ability of glutamine or to a different mechanism. In adult cholera patients, in vivo intestinal perfusion experiments have shown that glutamine-contain­ing 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 effective­ness 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 so­dium absorption and inhibit chloride secretion in both normal and secreting colon (31,32). Short-chain fatty acids are formed in the colon by fer­mentation 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-re­sistant starch had had significantly reduced stool volumes and the duration of illness when com­pared with the group receiving the standard WHO-ORS (33). In non-cholera childhood diarrhoea, two studies reported that the addition of amylase-resist­ant 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 ap­proach, a group of investigators aimed at ex­amining 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 de­crease 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 ex­posed to cholera toxin or the 5-fluorouracil—ORS with partial incorporation of the ORS components into liposomes showed 40-50% increased absorp­tion 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 be­fore 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 com­pared 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, sim­plicity, or ease of use. In future, further enhance­ments of ORT will similarly depend upon a careful balance of clinical effectiveness, cost-effectiveness, safety, public-health benefits, and ease of use.

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© 2007 ICDDR,B: Centre for Health and Population Research