Efficacy of Benefiber-Added, Reduced-Osmolarity WHO-ORS in the Treatment of Cholera in Adults

Considerable interest has recently been generated on dietary fibers (DF), and soluble fibers have emerged both as a subject for research and therapeutic applications. The 'fiber hypothesis', put forward by Denis Bukitt and Hugh Trowel (1-4), suggests that consumption of unrefined carbohydrate food protects against many western ailments including colon cancer, diverticular disease, appendicitis, constipation, haemorrhoids, diabetes, heart disease, gall stones, and obesity among others. In the line of this hypothesis, many basic laboratory and clinical works have been done. The term 'dietary fiber' has been used to denote plant polysaccharides and lignin that are resistant to hydrolysis by human digestive enzymes (5,6). The detailed chemistry and metabolism of DF have also been studied (7-10). The classification of fiber is based on their chemical structures (11), and they can be divided into non-polysaccharides and non-starch polysaccharides. Lignin is the only non-polysaccharide fiber, which is a polymer of phenolic alcohol that is water insoluble. The non-starch polysaccharide can be divided into cellulose and non-cellulose fiber. Cellulose consists of un-branched D-glucose chains in 1,4-ß linkage and is water insoluble. Non-cellulose polysaccharides include hemicelluloses, mucillages, gums and pectins, and they consists of various ß linkages of wide variety of hexose and pentose sugars. The polysaccharide chains are heteroglycans (chains with more than one type of monosaccharide). The hemicellulosic materials are polymers of xylose, mannose and glucose with side chains of galactose and arabinose. The pectic substances are polymers of galacturonic acids. Likewise, the gums and mucillages are branched carbohydrate polymers (e.g. gum, which is a linear mannan with galactose side chains). Non-cellulose polysaccharides vary in degree of their water solubilities (7,9,10).

In man, fiber is mainly degraded in the large intestine by the bacterial flora. Many of the effects of fiber on stool output arise from this degradation. The main products of fiber fermentation are short chain fatty acids (SCFAs) including acetate, propionate and butyrate, which are the major anions in the colon. Bacteria utilize SCFAs and proliferate, absorbing water from the colonic epithelium in the course of their metabolism, and thus decrease the free water content in the lumen (11). The SCFAs that are not utilized by the bacteria are largely absorbed by the colon (12). Their transepithelial transport is associated with stimulation of sodium transport from the colon in several species including human (13-15). This effect may be particularly important in acute diarrhoeal diseases where purging, and associated reduced food intake might deplete the colon of SCFAs leading to colonic dysfunction (16, 17). Thus, luminal SCFAs levels in the colon might influence the clinical course of acute diarrhoeal diseases. SCFAs have also been shown to be clinically important in one diarrhoeal disease in animal -transmissible gastroenteritis of swine (18). Animals infected with the virus develop acute enteritis with marked fluid loss from the small intestine. Young animals develop severe diarrhoea as their colonic mucosa is incapable of absorbing fluid, whereas older infected animals has been shown to have increased colonic absorption by about six-folds over the controls. This compensatory response prevents severe diarrhoea and is related to the development of colonic fermentation with the production of SCFAs.

Cholera is a disease of humans affecting the small intestine where fluid and electrolyte secretion is increased while their absorptions are decreased leading to profuse watery diarrhoea. As the human colon has the capacity to absorb water and electrolyte (19), some compensation is expected reducing the diarrhoeal loss. In recent studies (20, 21) SCFAs have been shown to stimulate sodium absorption in the colon, an effect that is not influenced by c-AMP, and additionally they have been found to inhibit cyclic AMP-mediated chloride secretion in the colon.

The SCFA-enhanced colonic absorption of water and electrolytes might be exploited in the treatment of acute diarrhoeal diseases. Oral rehydration therapy has dramatically changed the management of acute diarrhoeal disease. Yet, oral rehydration therapy is in the process of being improved. Cereal-based oral rehydration solutions (ORS) have been shown to reduce the stool volume by about 30% to 40% compared to the WHO-ORS (22, 23). It is possible that, at least a part of their effect on stool volume reduction might be attributed to SCFAs produced by unabsorbed carbohydrate including dietary fiber in the colon. Diversion colitis is an inflammatory process affecting the bypassed colon and rectum following surgical diversion of faecal stream (24). The inflammation disappears after surgical re-anastomosis, where topical steroids are usually ineffective (25). Rectal instillation of SCFAs has resulted in the disappearance of symptoms and endoscopic change over a period of 4-6 weeks; remission has been maintained for over a year by regular rectal SCFAs treatment (26). These findings suggest that SCFAs also play a role in mucosal healing in colitis

The colonic epithelial cells utilize SCFAs as source of energy for their various metabolic activities (27, 28). Human colonocytes use butyrate in preference to glucose, glutamine or ketone bodies as fuel source (27). Thus, in contrast to small intestinal cells, colonic epithelial cells derive the major part of their energy supply from the lumen rather than from the blood. Depriving luminal nutrition of the mucosa has been found to induce fluid secretion (29). The lack of luminal SCFAs in the colon may be involved in special diarrhoeal states such as diversion colitis and antibiotic associated diarrhoea. Diarrhoea is not uncommon after abdominal operations, particularly after closure of a temporary colostomy (30). Although there is no proof, this postoperative diarrhoea might be attributed to lack SCFAs in the colon, which might perhaps be reversed by the intake of fermentable fiber (31). Lengthy preoperative bowel preparation by antibiotic and lavage, and diminished oral nutrition probably contributes to postoperative diarrhoea. Lack of luminal SCFAs can similarly explain the diarrhoea often seen in the terminal stages of malnutrition and starvation. In these conditions, intestinal infections might not always be implicated and it seems likely that diarrhoea is a manifestation of organ-specific malnutrition of the colon (32). Diarrhoea is often associated with the use of broad-spectrum antibiotics, and colonization by toxin producing clostridium difficile accounts for only a third of these cases (33). The use of antibiotics suppresses the formation of SCFAs from fermentable carbohydrate (34), a feature that might also be responsible for diarrhoea. Although there are lots of data suggesting antidiarrhoeal effect of fermentable fibers, their therapeutic application in diarrhoeal disease is yet to be examined. Some recent clinical studies have demonstrated the beneficial effect of dietary fiber in treatment of adult cholera (35) and in the treatment of children with acute diarrhoea (36). In children with acute diarrhoea, Benefiber-added ORS has been observed to reduce the mean duration of diarrhoea by 16 hours, (74 vs. 90 h; p <0.05). Further studies are required to evaluate the effect of Benefiber in reducing severity and duration of cholera, a form of severe dehydrating diarrhoea.