Improving the ORS: Does Glutamine have a Role?

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 exeption 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 electroneutral NaCl absorption (22) has generated interest in glutamine as a potentially-useful component in ORS. …