The Journal of Nutrition Effects of Probiotics and Prebiotics Probiotics and Prebiotics: Effects on Diarrhea

Probiotics have preventive as well as curative effects on several types of diarrhea of different etiologies. Prevention and therapy (or alleviation) of diarrhea have been successfully investigated for numerous dietary probiotics to establish probiotic properties and to justify health claims (the medicinal use of probiotic food and the therapy of gastrointestinal diseases itself may not be advertised under current food laws). Other probiotic microorganisms (e.g., Lactobacillus rhamnosus GG, L. reuteri, certain strains of L. casei, L. acidophilus, Escherichia coli strain Nissle 1917, and certain bifidobacteria and enterococci (Enterococcus faecium SF68) as well as the probiotic yeast Saccharomyces boulardii have been investigated with regard to their medicinal use, either as single strains or in mixed-culture probiotics. However, the effects on humans have been assessed mainly in smaller (n , 100) randomized, controlled clinical studies or in open label trials, but large intervention studies and epidemiological investigations of long-term probiotic effects are largely missing. Perhaps with the exception of nosocomial diarrhea or antibiotic-associated diarrhea, the results of these studies are not yet sufficient to give specific recommendations for the clinical use of probiotics in the treatment of diarrhea. J. Nutr. 137: 803S–811S, 2007. Diarrhea (Greek diarroia 1⁄4 flowing through) means the increased liquidity or decreased consistency of stools usually associated with an increased frequency of stools and an increased fecal weight. The WHO defines diarrhea as 3 or more watery stools on 2 or more consecutive days. According to the main mechanisms involved, there are several types of diarrhea, which are summarized in Table 1, together with therapeutic measures. Treatment of diarrhea by administering living or dried bacteria to restore a disturbed intestinal microflora has a long tradition. Interestingly, yogurt had originally been developed in Spain and introduced into the market as an inexpensive, easy to prepare, and easily available remedy against diarrhea in children and was sold in pharmacies. However, earlier reports on the successful use of Enterococcus faecium/faecalis, strains of Escherichia coli, or freshly isolated members of the patients’ own intestinal microflora were mostly case reports and open studies rather than well-documented, randomized, double-blind, controlled clinical studies. But in the last 2 decades, investigations in probiotic microorganisms by in vitro studies, animal experiments, and appropriate well-designed clinical studies have put this ‘‘bacteriotherapy’’ on a more rational basis. Probiotics in prevention and treatment of diarrhea The use of probiotic microorganisms for the prevention or therapy of gastrointestinal disorders is an obvious measure and perhaps the most usual application of probiotics because most health effects attributed to them are related directly or indirectly (i.e., mediated by the immune system) to the gastrointestinal tract. The mechanisms and the efficacy of a probiotic effect often depend on interactions with the specific microflora of the host or immunocompetent cells of the intestinal mucosa. The gut (or its associated lymphoid system, GALT) is the largest immunologically competent organ in the body, and maturation and optimal development of the immune system after birth depend on the development and composition of the indigenous microflora and vice versa. Many strains of probiotic microorganisms have been shown to inhibit growth and metabolic activity as well as the adhesion to intestinal cells of enteropathogenic bacteria (Salmonella, Shigella, enterotoxigenic E. coli, or Vibrio cholerae) (1–3) to modulate (temporarily) the intestinal microflora and to have immunostimulatory or -regulatory properties. Suggested mechanisms for the effects on the intestinal microflora are lowering the intestinal pH, the production of bactericidal substances such as organic acids (lactic, acetic, butyric 1 Published as a supplement to The Journal of Nutrition. The articles included in this supplement are derived from presentations and discussions at the World Dairy Summit 2003 of the International Dairy Federation (IDF) in a joint IDF/FAO symposium entitled ‘‘Effects of Probiotics and Prebiotics on Health Maintenance—Critical Evaluation of the Evidence,’’ held in Bruges, Belgium. The articles in this publication were revised in April 2006 to include additional relevant and timely information, including citations to recent research on the topics discussed. The guest editors for the supplement publication are Michael de Vrese and J. Schrezenmeir. Guest Editor disclosure: M. de Vrese and J. Schrezenmeir have no conflict of interest in terms of finances or current grants received from the IDF. J. Schrezenmeir is the IDF observer for Codex Alimentarius without financial interest. The editors have received grants or compensation for services, such as lectures, from the following companies that market proand prebiotics: Bauer, Danone, Danisco, Ch. Hansen, Merck, Müller Milch, Morinaga, Nestec, Nutricia, Orafti, Valio, and Yakult. 2 Author disclosure: no relationships to disclose. * To whom correspondence should be addressed. E-mail: michael.devrese@ bfel.de. 5 Abbreviations used: AAD, antibiotic-associated diarrhea; GALT, gut-associated lymphoid tissue; IBS, irritable bowel syndrome; LGG, Lactobacillus rhamnosus GG. 0022-3166/07 $8.00 a 2007 American Society for Nutrition. 803S by gest on F ebuary 5, 2015 jn.nition.org D ow nladed fom acid) (4), H2O2 and bacteriocines, agglutination of pathogenic microorganisms, adherence to the cellular surface of the mucosa, andcompetition for fermentable substratesor receptors, strengthening the barrier effect of the intestinal mucosa (5,6), release of gut-protective metabolites (arginine, glutamine, short-chain fatty acids, conjugated linoleic acids), binding and metabolism of toxic metabolites (7–11), immunologic mechanisms (12,13), or regulation of the intestinal motility (14) and mucus production (15). In human and animal experiments, bacterial counts in stool samples and in samples from the small bowel taken from ileostomized patients, have been altered by probiotics. All these methods, however, have drawbacks and only indirectly reflect the real situation in the gastrointestinal tract and its microflora. The interactions between probiotic microrganisms and the GALT or the respective mucosal receptors and signaling pathways as well as the mechanisms of immunomodulation and antiinflammatory probiotic effects are not yet fully understood, but the use of modern techniques such as molecular biology lead to a rapidly growing knowledge of the relations among probiotics, the immune system, and health. Preventive or curative effects of probiotic microorganisms with evidence of the effects on the gastrointestinal microflora and antibacterial, immunostimulatory, and antiinflammatory properties have been investigated in diarrhea caused by (primary) lactose intolerance; acute diarrhea from viral and/or bacterial infections, e.g., nosocomial rotavirus infections in children, gastrointestinal infections in children in day-care centers, and travelers’ diarrhea; antibiotic-associated diarrhea (AAD); Clostridium difficile gastroenteritis; diarrhea in tube-fed patients; chemoor radiotherapy-induced diarrhea; inflammatory bowel diseases (Crohn’s disease, ulcerative colitis, pouchitis); small bowel bacterial overgrowth; and irritable bowel syndrome (IBS) with diarrhea. Reduced diarrhea and other gastrointestinal symptoms in lactose intolerance The most thoroughly investigated health effect of fermented milk products is the enhancement of lactose digestion and the avoidance of intolerance symptoms in lactose malabsorbers, that is, in persons with insufficient activity of the lactose-cleaving enzyme b-galactosidase in the small intestine. This effect is based mainly on the fact that fermented milk products with living bacteria contain microbial b-galactosidase that survives the passage through the stomach to be finally liberated in the small intestine and to support lactose hydrolysis there (16). However, depending on the definition of ‘‘probiotic,’’ this is not a specific probiotic effect because it does not depend on survival of the bacteria in the small intestine. Yogurt is usually more effective (17,18), and, last but not least, primary or adulttype hypolactasia (the reason for lactose malabsorption) is not a disease but actually the normal physiological state. Many probiotic bacteria show either a lower b-galactosidase activity or, because of their high resistance against acid and bile salts, do not release their enzymes in the small intestine (16). There is no strong correlation, however, between lactose malabsorption and the occurrence of intolerance symptoms such as flatulence, bloating, abdominal cramping and pain, or diarrhea in any case. Many persons with alleged nonallergenic milk intolerance can digest lactose, and some truely maldigesting persons live without symptoms of intolerance. Thus, it may be imagined that probiotic bacteria do not significantly improve lactose digestion in the small intestine but rather avoid symptoms of intolerance directly in the large intestine (16,19). The latter effect depends on the specific strain, concentration, and preparation of the probiotic as well as on the subject’s susceptibility to gas and osmotic pressure or, for unknown reasons, the individual responsiveness to probiotics (20). In conclusion, probiotics promote lactose digestion in lactose malabsorbers no better than conventional yogurt. No independent reduction of diarrhea and other gastrointestinal complaints in lactose intolerance has yet been definitely proven. Prevention or alleviation of acute diarrhea caused by viral or bacterial infection Acute diarrhea from viral (mostly rotaviruses) or bacterial infection is still a major health problem worldwide and a frequent cause of death, especially in hospitalized children and in developing countries. But infectious diarrhea is not only a problem of developing countries. Up to 30% of the population in developed countries are affected by food-borne bacterial diarrheas each year. Protection by probiotic bacteria and yeasts with immunostimulatory properties or the alleviation of symptoms and shortening of acute infections are perhaps the best-documented probiotic effects, and these have been demonstrated many times in the past in clinical studies fulfilling scientific requirements. Beneficial effects such as decreased frequency of infections, shortening of the duration of episodes by 1–1.5 d, decreased shedding of rotaviruses or promotion of systemic or local immune response, and an increase in the production of rotavirusspecific antibodies have been demonstrated for a number of food (Lactobacillus rhamnosus GG, L. casei Shirota, L. reuteri, L. acidophilus spec., Bifidobacterium animalis ssp. lactis BB-12, and others) (21–31) and nonfood probiotics (E. coli, Enterococcus faecium SF68, Saccharomyces boulardii) (32–34). In numerous studies probiotics were administered as nonfood preparations, e.g., as a powder or suspended in oral rehydration solutions (35). For reviews see Fonden et al. (9), de Roos and Katan (36), or Marteau et al. (37). Prevention of infectious diarrhea in healthy children and adults In large part, studies demonstrating positive effects on the prevention and alleviation of infectious diarrhea in healthy human populations have been performed in infants and children. Young children may be particularly responsive to probiotics because of the immaturity of their immune system and the greater TABLE 1 Types of diarrhea and therapeutic measures Diarrhea Characterization