Functional Foods and Probiotics: Working Group Report of the First World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition

FUNCTIONAL FOODS The principal role of the diet is to provide sufficient nutrients to meet the metabolic requirements of the individual. The role of diet in health and well-being has changed as the science of nutrition has evolved. In modulating specific target functions in the body, additional beneficial physiologic effects may be provided by so-called functional foods. Functional food science evaluates the potential of the diet to promote health and to reduce disease risk (8). With extended priorities in food science and technology, a greater interest has developed in alteration of the structure and composition of dietary products and to increase microbiologic stability. In particular, the current post-genomic age offers huge possibilities for the management of disorders through diet on an individual basis. A food can be regarded as functional if it is shown to affect beneficially one or more target functions in the body, beyond adequate nutritional effects, in a way that is relevant either to the state of well-being and health or to the reduction of the risk of a disease (Table 1). Functional foods must remain as foods (not capsules, etc.), and they must also demonstrate their effects in amounts that can normally be expected to be consumed in the diet.TABLE 1: DefinitionsTable 2 summarizes how foods may have increased functionality. The basis of the concept is that the specific health benefits have to be scientifically proved in well-established and controlled clinical studies. Moreover, the food has to be proved safe. A food may be functional for all members of a population or for particular groups, which may be defined by age or genetic constitution. In the development of functional foods, it is important to identify beneficial interaction(s) between a functional component within a food, both nutritive and non-nutritive, and one or more systems in the body and to obtain evidence for the mechanism(s) of these interactions. The first generation of functional foods largely involved dietary supplementation with vitamins and micronutrients. However, the current generation is centered more on gastrointestinal interactions (2,8).TABLE 2: Production of functional foodsThe infant intestinal microflora, an important constituent of the gut defense barrier, are an obvious target for the development of functional foods, because it has been demonstrated that qualitative differences in the composition of the gut microflora affect immunologic homeostasis of the host. THE CONCEPT OF PROBIOTIC FOODS The colon is the most heavily populated region of the gastrointestinal tract and, because of this resident microbiota, is the most metabolically active organ in the body (2). The generation of the mucosal barrier functions in the gut depends on the establishment of indigenous microflora. In particular, intestinal colonization acts as an important antigenic stimulus for the maturation of the gut-associated lymphoid tissue. The demonstration that the gut microflora are an important constituent of the intestine's nonimmunologic and immunologic barrier has brought about the concept of probiotic therapy: therapeutic application of consumption of cultures of potentially beneficial bacteria (Table 1). The concept of modulating activities directed toward improving gut microbial function has a long history. The most frequently used dietary method of influencing the gut flora composition is that of probiotics, whereby live microbial additions are made to appropriate food vehicles, usually fermented milks. The first recorded deliberate consumption of bacteria goes back to over 2000 years ago. However, the situation was put onto a scientific assessment by the writings of Metchnikoff at the Pasteur Institute. He hypothesized that longevity was associated with elevated intake of soured milks, that is, dairy-based drinks containing live bacteria. This was the basis of what is now recognized as the probiotic concept, whereby an array of dietary ingredients are deliberately supplemented with microorganisms. NORMAL GUT FLORA—SOURCE OF PROBIOTIC BACTERIA The human gastrointestinal tract, principally the colon, is an intense site of microbial activity. From culture-based data, it is thought that at least 500 different microbial species exist, although on a quantitative basis approximately 10 to 20 genera probably predominate (2,8). Examples include Bacteroides, Lactobacillus, Clostridium, Fusobacterium, Bifidobacterium, Eubacterium, Peptococcus, Peptostreptococcus, Escherichia, and Veillonella. Whereas some indigenous bacteria can be pathogenic (e.g., proteolytic clostridia and bacteroides), it is also the case that some species may offer health-promoting attributes. For example, the commonest probiotics are bifidobacteria and lactobacilli. They exert powerful anti-pathogenic capabilities and are mainly responsible for colonization resistance in the gut (1,4–7,11). Moreover, the same genera have other beneficial aspects such as stimulation of the immune response, thereby promoting nonspecific host resistance to microbial pathogens. Although many of the health-promoting aspects have yet to be definitively proven in humans, eliciting a change away from gut flora dominated by potentially harmful bacteria toward a more benign, or beneficial, composition appears to have great value. A resurgence of the probiotic approach is based on demonstrations that diet can have a major effect on gut microflora activities. Infants who are breast-fed may have a natural predominance of bifidobacteria, whereas formula-fed infants may have a profile that is more complex and similar to the adult situation. This higher concentration of beneficial microorganisms in the former group is open to debate. Nevertheless, a general consensus prevails that human milk contains certain bifidogenic factors, which represent a major mechanism whereby breastfeeding protects the infant when gut microflora and gut immunologic defense mechanisms become established (8). Reliable genetic techniques for profiling the human gut microbiota will help elucidate whether such differences do occur. Functional food science has attempted to manipulate this microbiota for improved health. For pediatricians, the approach may provide an efficient way to control or manage gut-related disorders, although the wider approach may be taken for prophylactic measures. PROBIOTIC FOODS AND INTESTINAL INFECTIONS The potential modification of intestinal flora to increase the predominance of specific non-pathogenic bacteria and modify the intestinal milieu seems a reasonable alternative to attain a prophylactic or therapeutic effect against enteric infections and possibly other intestinal inflammatory conditions. Several open trials have reported the resolution of relapsing Clostridium difficile diarrhea with oral supplementation of Lactobacillus GG (ATCC 53103) in adults, as well as children, and with supplementation of Saccharomyces boulardii in adults (10). Several probiotic agents have been used as a prophylactic, with variable success, for traveler's diarrhea in adults, but not in children. Numerous reports, as well as some controlled studies, also mostly in adults, have shown a benefit with several agents in the management of antibiotic associated diarrhea, not associated with Clostridium difficile (7,10). These include bifidobacteria, Enterococcus faecium-SF68, Lactobacillus GG, and Saccharomyces boulardii. In children, recent well-controlled studies and one multi-center study showed that concomitant ingestion of Lactobacillus GG decreased incidence and duration of diarrhea in children who were prescribed antibiotics for several types of acute illnesses (1,11). Finally, several adequately controlled studies are available conclusively, demonstrating a beneficial effect of specific probiotic strains in ameliorating the course of acute diarrheal disease in infants and children. Agents shown to have similar effects include Lactobaccilus GG, Saccharomyces boulardii, Lactobacillus reuterii, and Enterococcus faecium. In general, these studies show that oral supplementation of specific agents, early in the episode of acute diarrhea, shortens the course, with decreases in duration of 1 to 3 days, depending on the definition used for diarrhea (7,10). There also may be a modest to moderate decreases in purging rate. The effect appears to be most significant in diarrheal disease of viral etiology. Bacterial diarrhea has been less well studied in this regard, and no prospective controlled studies are available. However, some reports suggest that Bifidobacterium breve may help eradicate Campylobacter jejuni from stools of children with enteritis, although not as effectively as standard erythromycin therapy and consumption of Lactobaccilus acidophilus milk appears to reduce the carrier state of Salmonella and Shigella. Fewer studies exist regarding the prophylactic effect probiotics may have on diarrheal disease. Two prospective controlled studies, one in the United States using formula supplemented with Streptococcus thermophilus and Bifidobacterium lactis strain Bb12, in chronically hospitalized children and another using Lactobacillus GG as daily dose in an indigent peri-urban Peruvian population of children, demonstrated a protective effect. There was a decrease in incidence of diarrheal disease, decreased shedding of rotavirus, and decreased incidence of adenoviral diarrhea. In the Peruvian study, the benefit was apparent only for non–breast-fed children. From these studies, it appears that specific agents supplemented to children on a daily basis over time can decrease the incidence of diarrheal disease, with benefits being apparently greater in higher-risk populations (7,10). The prophylactic effect also appears to be significant against diarrhea of viral origin. No adequate studies assessing the prophylactic effects on bacterial diarrhea are thus far available. PROBIOTIC FOODS AND ALLERGY The immature gut barrier may lead to aberrant antigen transfer and immune responses, thus explaining increased vulnerability to breakdown of oral tolerance. At an early age, such antigens are frequently derived from food, and allergic reactions to foods are common. The demonstration that the gut microflora contribute to the generation of a T helper population amenable to oral tolerance induction (9) has offered novel therapeutic applications for specific strains of gut microflora as probiotics in hypersensitive disorders. Moreover, the intestinal microflora contribute to the processing of food antigens in the gut, and probiotics have been shown to modify the structure of potentially harmful antigens and reduce their immunogenicity in vitro and in vivo, together with a potential to dampen hypersensitivity reactions (3). These effects are seen as a significant improvement in the clinical course of atopic dermatitis (eczema) in infants given probiotic-supplemented elimination diet, and in parallel, markers of intestinal and systemic allergic inflammation decreased significantly. The beneficial effects of probiotics in allergy have been attributed to their ability to promote the nonimmunologic defense barrier in the gut, that is, normalization of increased intestinal permeability and unbalanced gut microflora frequently encountered in inflammation. Furthermore, probiotics have been shown to improve the intestinal immunologic barrier, particularly intestinal IgA responses, and to alleviate intestinal inflammation. On the basis of these recent studies, a novel target of probiotic therapy may be the development of T helper 2–skewed immune responsiveness of atopy, in normalizing the balance between pro-and anti-inflammatory cytokines and in controlling changes associated with allergic inflammation, also beyond the gut. PROBIOTIC FOODS—THE FUTURE CHALLENGES We have unequivocal evidence that probiotics are useful in viral diarrheal disorders. Probiotics have also been shown to be efficacious in reducing the incidence of or actually preventing diarrheal illness (Table 3). Where, then, does the road for probiotics lead from this point? One possibility may be the potential use of probiotics in reducing the incidence of allergic disease. This, combined with the enhanced immune response to infections, is probably the greatest argument for widespread use of probiotics in normal healthy populations.TABLE 3: Potential future uses of probioticsPreliminary data from several recent studies suggest the possibility of wide-ranging beneficial effects of probiotics. The role of intestinal flora on colon carcinogenesis and, indeed, other forms of cancer is an important area for study. Bacterial metabolism of various dietary constituents results in the production of a number of compounds, some of which may be carcinogenic. The composition of the intestinal flora may have a major impact on the rate of production of such compounds. Altering the composition of the flora with probiotics may change the flora enough to reduce the production of these compounds. In fact, a diet containing Lactobacillus GG fermented milk was shown to reduce the activity of certain hydrolytic enzymes (beta-glucuronidase, glycocholic acid hydrolase, and nitroreductase) in the colon. The possible association between milk consumption, higher counts of lactobacillus species in feces, and decreased incidence of colon cancer has been described. Probiotics might also be useful in the treatment and prevention of a number of inflammatory disorders in the gastrointestinal tract (5). Strains of Lactobacillus reuteri and Lactobacillus plantarum have both been used to prevent inflammatory changes in a methotrexate-induced enterocolitis model in the rat. Administration of lactobacilli decreased the intestinal myeloperoxidase level, often associated with inflammation, and reduced bacterial translocation to extraintestinal sites and plasma endotoxin levels. Whether this animal model is a valid predictor of response in inflammatory disorders of the gastrointestinal tract such as ulcerative colitis and Crohn's disease is open for speculation. Studies using an interleukin-10 knockout mouse model, have shown potential efficacy of Lactobacillus plantarum in reducing inflammation (5). However, only preliminary evidence exists that certain agents may be useful in modulating the inflammatory response in inflammatory bowel disease and necrotizing enterocolitis. Prospective randomized controlled studies are needed to confirm these possible benefits. Probiotics may be useful in the treatment in inflammatory diseases associated with small bowel bacterial overgrowth. Pouchitis, or inflammation of an ileal pouch created after a total colectomy for ulcerative colitis, also may respond to probiotic therapy. Administration of multiple organisms, predominantly Lactobacillus strains, has been shown to be effective in ameliorating pouchitis. Probiotics also may be of benefit in extraintestinal disease; specific strains of probiotics were shown to reduce severe pneumonia in children with cystic fibrosis and the incidence of respiratory disease in children in day care centers, and to modulate inflammation in rheumatoid arthritis. Insight into possible mechanisms for these findings is beginning to appear. First, intraluminal bacteria predictably and uniformly can induce chronic inflammatory changes in the gastrointestinal tract. Aberrant antigen transfer across the inflamed mucosa and impaired gut barrier functions might serve as a link between inflammatory diseases of the gut and extraintestinal inflammatory disorders. Changing the composition of the gut microflora by probiotics may thus control the inflammatory process, in the gut milieu and beyond the gut. Second, upregulation of mucin genes in cell culture systems by probiotics has been documented. Finally, specific probiotics have been associated with stimulation of immune response. They have been shown to enhance humoral immune responses, and control the balance of proinflammatory and anti-inflammatory cytokines. SUMMARY Strong evidence exists for the beneficial role that probiotic foods offer in infants. A number of important intestinal, and systemic, conditions may be managed more effectively through their use. However, it is important that these are consolidated on a mechanistic basis with a thorough understanding of host–microbe interactions. For the field to progress adequately, robust technologies such as molecular tracking of microbiota changes should be applied to well-controlled human studies. Various disciplines including microbiology, nutrition, immunology, and pediatrics have the potential to contribute toward the multidisciplinary approach required to ensure that the full potential of probiotics in infant nutrition can be realized.