In this issue of the Journal, there is an interesting experimental investigation on oral rehydration solution (ORS) in the whole gut with special reference to amylase-resistant starch (1). What is the meaning of the term “whole gut,” and how can we interpret the results of a whole-gut perfusion in rats?
It is impossible to study an organ in a holistic sense as it does not function in isolation. For example, we are unable to examine an entity such as a single muscle, a pair of lungs or a complete liver without “interference” from adjacent organs. However, the intestine presents a particular case. It is a complex organ shaped like a tube with an entrance at one end and an exit at the other. Practical by design, a solution infused at point A can be collected at point B given any surplus. Therefore, it is feasible to study the whole gut at once. Why is this significant? One good reason is that ORSs have usually been studied using a segment of the intestine, often the jejunum, but this method excludes the colon in the testing of solution made to rehydrate children afflicted with diarrhea. The objective to reduce stool output through the colon, which is largely responsible for processing water and electrolytes, has been without much consideration.
That is, until now. By mentioning the whole intestine, the authors indicate the importance of colonic function. Technically, it is a difficult experiment that requires specific skills. They essentially found that amylase-resistant starch increases water and sodium absorption from iso-osmolar and reduced osmolar solutions.
Rehydration is part of the daily activity of a pediatric center, and there is no question whether ORS rehydrates. Still, occasionally, oral rehydration therapy is not fully satisfactory; it could possibly aggravate the initial condition and may call for additional intravenous treatment. Furthermore, many mothers comment that oral rehydration does not treat the disease because it does not cure diarrhea. In response to such resistance and criticism, it is necessary to better understand the mechanisms of infectious diarrhea and how ORSs act on the whole intestine. This article will benefit readers of the Journal who wish to learn more about innovation and discovery within a well-researched topic.
The treatment of diarrhea is as old as humanity itself, something like 100,000 years back, at least as old as the origin of art, 35,000 years ago. It is common to think that 30 to 40 years ago, the invention of ORS was a major breakthrough because it was based on firm pathophysiological knowledge. However, the efficacy of ORS was not proven by what we would now call a comparative clinical trial. The first studies were not blinded but performed by researchers with wide open eyes (2)! It was through 3 experimental results obtained on a segment of small intestine, which showed that water follows passively the absorption of actively transported sodium, glucose stimulates sodium chloride and water absorption, and cholera toxin does not alter those 2 physiological small intestine functions. Interestingly, these claims were derived from irreversible thermodynamic concepts, including the third law of thermodynamics (3). They were also checked by performing whole-intestine perfusions in adults with cholera (4). Jejunal infusion of an electrolyte solution comparable to watery stools did not reduce stool output, except with the addition of glucose.
Does this mean that results from experiments done on a segment of small intestine could translate into applied therapeutic consequences? Unfortunately, several counterproductive examples from the past indicate otherwise. One of them is the relationship between jejunal lactase activity and lactose-induced diarrhea. Around the same time that ORS was invented, intestinal lactase was a main topic in the very new field of pediatric gastroenterology. It is hard to imagine now the excitement produced by the first measurements of disaccharidase activity on human jejunal capsule biopsies. It generated interesting scientific developments on persistent lactase activity after weaning in some human populations and on the environmental and genetic control of lactase activity. However, the findings also raised concern about lactose as a source of diarrhea. Low lactase activity on a jejunal biopsy was often considered equivalent to lactose malabsorption and lactose-induced diarrhea. During the 1960s and 1970s, breast milk was promoted as the reference food for infants. In this context, it came as a surprise that lactose from breast milk was not fully absorbed in the small intestine. It was as if healthy breast-fed infants had lactose malabsorption! Clearly, the whole gut rather than a 5-mg biopsy sample had to be taken into account. Subsequently, the colon and its fermentative microbial flora were rediscovered. Prebiotics are now tested these days to prevent diarrhea at weaning or after the administration of oral antibiotics (5).
The testing of the whole intestine as demonstrated in the article by Ramkrishna et al. is inspiring. Their experiments definitively show how the intestinal epithelium (in vivo) absorbs or secretes water, in addition to how electrolytes react when the infused solution varies. It explores the result of both small and large intestinal complex epithelium functions. This method is useful to test the hypotheses produced by physicochemical, genetic, cellular and epithelial in vitro techniques where the experimental conditions are best controlled. For example, the transportation of water by the intestinal epithelium is more complicated than initially thought, especially in the distal part of the colon (6). The relationship between glucose and electrolytes, which is typical of the small intestine (7), can be extended to the short-chain fatty acid (SCFA)/electrolyte relationship in the colon (8), and the mechanisms by which infectious agents cause diarrhea are numerous.
The whole-intestine perfusion study is part of an in vivo complex process. In vivo, in physiological conditions, the fluid entering the jejunum is delivered by the stomach at a controlled rate. Osmolarity is also tightly controlled. After 15 cm in the duodenum, the intestinal fluid is approximately 300 mOsm/L. It provides data that are useful for understanding the epithelial function, but that cannot be simply extrapolated for physiological conditions. How the stomach functions in relation to infectious diarrhea has not been extensively studied. At the other end, we know that the ileal fluid in the colon is mixed with a bacterial community; essentially, it is the anaerobic species that create fermentation. The local strains of bifidobacteria and lactobacilli are stimulated by prebiotics, but bifidobacteria and lactobacilli are currently orally given under the name of probiotics. They ferment unabsorbed carbohydrates including amylase-resistant starch under SCFAs that stimulate epithelial water absorption. Technical reasons require that the colon is first washed of its bacterial content before a whole-gut perfusion. However, in vivo, during an episode of diarrhea, carbohydrate fermentation may be present and stimulate water absorption. Thus, a whole-gut perfusion could manifest a function for amylase-resistant starch which is not directly linked with fermentation, except if part of the colonic bacteria is not washed out. It is now established that a pool of bacteria adheres to colonic epithelium. During acute watery diarrhea, little is known on the alteration of the composition and function of colonic bacterial flora. Moreover, there is no reliable method to quantitatively assess SCFA production in vivo during an unsteady period of diarrhea. Recent evidence indicates that cholera is associated with a decrease in the total number of species (M. Shirajum, unpublished data). Yet the functional consequences are unknown.
There is a need for clinical trials to assess the consequences of altering ORS. The amylase-resistant starch which had been tested in a whole-gut perfusion study also proved to decrease stool output in adult patients with cholera (9) and in acute diarrhea in children (10,11), although other carbohydrates in different ORSs have provided little or no effect in children with infectious diarrhea (12). Even if a clinical trial indicates positive rehydration and symptomatic effects, it is not enough for improving the health of children with diarrhea (13). It is a long road from experiment results to potential health care benefits. No doubt then that whole-gut perfusion studies are very useful in the journey to unravel some of the mystery embedded in our complex digestive system.
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