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1 From the Division of Nutrition, Harvard Medical School, Boston.
2 Presented at a symposium held at Experimental Biology 2000, in San Diego, April 2000. 3 Address reprint requests to WA Walker, Children's Hospital, 300 Longwood Avenue, Boston, MA 02115. E-mail: walkerwa{at}a1.tch.harvard.edu.
INTRODUCTION
The increasing use of functional foods by the public to improve their general health and prevent the incidence of chronic diseases (eg, cardiovascular disease, diabetes, and cancer) has become a major area of interest within the nutrition community. Of the many functional foods available, probiotics have been best studied with regard to disease prevention and most actively promoted commercially to the American public. Fermented foods containing large quantities of "good" bacteria, or that contain more bacteria than what is usually ingested daily in American diets, have been consumed for a prolonged period of time in Europe to promote good health. Many reviews in the European literature suggest that the probiotics in these foods may aid in preventing major health problems, such as postoperative gram-negative sepsis and other nosocomial infections in hospitalized patients, and in preventing gastroenteritis in daycare centers and retirement homes (1, 2). Because of the increasing interest in functional foods and in probiotics in particular, we organized this symposium as an American Society for Clinical Nutrition event and obtained an educational grant from the Dannon Foundation to have it published as a supplement to the American Journal of Clinical Nutrition. Topics and speakers (authors) were selected to cover important basic and clinical areas of investigation with regard to the mechanisms of interaction between probiotics and the gastrointestinal tract, eg, bacterial-epithelial crosstalk, and to review objective evidence of probiotic benefits in the prevention and treatment of human disease. Finally, we predicted the long-range potential for the clinical uses of this type of functional food for health and disease.
PATHOLOGIC AND PHYSIOLOGIC INTERACTIONS OF BACTERIA WITH THE GASTROINTESTINAL EPITHELIUM
In the first presentation, Lu and Walker (3) review what is currently known of the interaction between pathologic and physiologic bacteria and the gastrointestinal tract. Most of the basic research on the molecular mechanisms of bacterial-epithelial crosstalk was conducted with enteric pathogens and their penetration of the epithelial barrier and exploitation of mucosal host defenses for their own benefit. Three representative pathogens are used to illustrate the various adaptive techniques used to colonize and penetrate the mucosal barrier. Salmonella enterica typhimurium interacts with the physiologic receptor for epidermal growth factor to co-opt the receptor's signal transduction mechanisms for its own purpose. By virtue of its attachment to the microvillus surface, this organism can activate the transcription and translation of inflammatory cytokines. In contrast, enteropathogenic Escherichia coli secretes a receptor (type III secretion) into the microvillus surface of enterocytes that disrupts the microvillus and alters its actin structure to form a dome-like anchoring site. Finally, Shigella flexneri is used to illustrate how pathogens use follicular epithelial cells (M cells), which are the physiologic conduits for antigens to reach gastrointestinal lymphoid tissues, for penetration of the epithelial barrier. In contrast with pathogen–epithelial crosstalk, there has been less basic research to explain the molecular mechanisms by which probiotics communicate with the intestinal epithelium to protect against pathogen invasion. We know from clinical studies that probiotics can strengthen epithelial tight junctions to protect against intercellular invasion by pathogens. Probiotics can prevent pathogen colonization by competing for the same glycoconjugate receptor on lipids and proteins in the enterocyte's microvillus membrane. For example, evidence suggests that probiotic organisms can up-regulate the specific glycosyltransferase enzyme that regulates the glycoconjugate receptor on glycolipid and protein microvillus membrane surface molecules. In addition, probiotics can enhance the mucosal immune response to specific pathogens, thus strengthening the protective effect at the mucosal surface. However, additional molecular studies are needed to define more precisely, at the molecular level, the actual mechanism of probiotic-epithelial crosstalk.
MICROBIAL MODULATION OF INNATE DEFENSE: GOBLET CELLS AND THE INTESTINAL MUCUS LAYER
In their review, Deplancke and Gaskins (4) underscore the importance of mucus in the innate defense of the gastrointestinal tract surface and provide exciting new observations to link microbiota colonizing the gut with the regulation of mucin gene expression, composition, and secretion. Intestinal microbes may affect goblet cell dynamics and the composition of the mucus layer directly by the release of bioactive factors or indirectly by the activation of host immune cells. Goblet cells, 1 of 4 enterocyte lineages derived from common stem cells in the crypt, are primarily responsible for the mucus coat that covers the epithelial layer of the entire gastrointestinal tract and that acts as a medium for protection, lubrication, and transport between luminal contents and the epithelial barrier. Mucus protects the gastrointestinal tract against many potential insults including mechanical damage, pathogens, enzymatic digestion, and potential carcinogens. Mucus, synthesized in goblet cells, consists principally of mucin, large highly glycosylated peptides that rapidly hydrate from the secretion of goblet cells to form a viscous coat on the luminal surface of enterocytes. The nature of the oligosaccharide composition of mucus varies from one region of the intestine to another and is dependent on the regulation of specific glycosyltransferase gene expression in goblet cells. Evidence to support the relation of intestinal flora to mucus production and function comes from studies in germfree rodents. Specific direct effects of microbiota have also been reported. Examples of these effects are the cAMP-mediated increase in mucus secretion in response to cholera toxin's direct interaction with goblet cells and the noted depletion of goblet cells stores of mucus with enteric infestation of the protozoan parasite, Entamoeba histolytica, presumed to trigger mucin release via a protein kinase C–dependent pathway. Of most interest in Deplancke and Gaskin's review is the recent report that the probiotic Lactobacillus rhamnosus GG can activate mucin genes in intestinal cell lines, thereby inhibiting their colonization by intestinal pathogens, eg, extrapathogenic E. coli. This exciting review underscores the complexity of the interaction between both pathogens and commensal flora in one aspect of innate host defense in the gastrointestinal tract, eg, mucus.
PROBIOTICS IN HUMAN DISEASE
In this review of the application of probiotics to prevent and treat human disease, Isolauri (5) summarizes some recent studies, many from her own program, that underscore the potential importance of exposure to probiotic flora in allergic, autoimmune, and inflammatory conditions. She suggests that with the increasing use of antibiotics and the aggressive eradication of infectious diseases in developed countries, the incidence of these diseases, particularly atopic diseases, is increasing. This increase in atopic disease over the past several decades cannot be explained strictly on a genetic basis. Changes in environmental stimuli appear to be an important factor. Isolauri suggests that a decrease in exposure to microorganisms and a modification of commensal gut flora may be an important environmental basis for this increase in disease incidence. This altered environmental stimulus is compounded by the progressive absence of microbes in human nutrients over the same time period. She suggests that the regular use of probiotics to adequately colonize the gut may be helpful in reversing this trend both from a preventive as well as a therapeutic perspective. As mentioned above, commensal bacteria (probiotics) generally activate both the innate and the applied mucosal systems by facilitating the maturation of the mucosal barrier at birth and by maintaining effective protective function thereafter. In this review, recent publications are cited that provide evidence that probiotics help prevent and can be used to treat conditions that are related to the disruption of the ecologic balance of colonizing gut flora, eg, antibiotic-induced infection and nosocomial infections in elderly hospitalized patients. A multicenter trial of probiotic use in rotoviral-infected infants showed a reduction in the severity and longevity of the illness. She also reports the use of L. rhamnosus GG and Bifidobacterium lactis in the down-regulation of allergic hypersensitivity reactions such as atopic dermatitis. Although the mechanism of this modification of allergic disease is not defined, it is likely due to a balancing of the THcell subclass responses from a specific TH2 immune response (allergy prone) to a mixed TH1 and TH3 cellular immune-mediated and oral toleragenic response. Additional clinical studies are needed to clarify this hypothesis.
CLINICAL APPLICATIONS OF PROBIOTIC AGENTS
From a different perspective, Saavedra (6) provides additional evidence, some of which stems from his clinical studies, to suggest the considerable advantages of using probiotics to alter gastrointestinal digestive and protective functions to treat gastrointestinal conditions in pediatric patients. He suggests that a proper balance in colonizing bacteria with an abundance of probiotics can modify such diverse conditions as lactose intolerance and Clostridium difficle diarrhea. Extensive multicenter studies examined the prevention of daycare-center-induced viral gastroenteritis and traveler's diarrhea. He cites evidence that probiotic use can enhance the specific mucosal immune immunoglobulin A response against diverse pathogens such as viruses and bacteria. In addition, Saavedra cites the results of conclusive clinical studies that support the clinical safety and tolerance of probiotics in infants (including premature infants) and young children. Such studies indicate that the use of fermented foods or probiotics should be considered as a treatment for such gastrointestinal disease by pediatricians worldwide.
PROBIOTICS: FUTURE DIRECTIONS
Finally, Vanderhoof (7) provides a perspective on the future use of probiotic therapy in gastrointestinal disease states. He emphasizes the increasing use of such therapy over the past few years to treat diarrheal and allergy-related diseases. As new information from basic research studies is forthcoming (with respect to the specific mechanisms by which probiotics modulate the mucosal immune response, particularly the distribution of TH cells, and strengthen the mucosal barrier to bacterial and antigen penetration), new trials of the use of probiotics in clinical disease can be designed. For example, inflammatory bowel disease, a major clinical problem treated by gastroenterologists, is thought to be caused by a subtle, excessive response to intestinal bacteria, leading to chronic inflammation. On the basis of the observation that probiotics may down-regulate what is considered to be an excessive TH1 response to bacteria in these patients, thus reducing chronic inflammation, studies are in progress to determine whether the use of probiotics can prolong clinical remission induced by initial, aggressive antiinflammatory treatment. Although preliminary in nature and derived largely from animal studies, the use of probiotics may help to prevent the clinical expression of colon cancer. Additional studies are needed before these observations can progress to clinical trials. Vanderhoof strongly emphasizes that a specific probiotic must be studied with regard to its specific effect on a clinical condition before it can be recommended for extensive clinical use. He also suggests that recommendations must depend on prospective, large clinical trials and not on ancedotal observations.
From a basic research and clinical perspective, the articles within this supplement provide strong evidence of the enormous potential of probiotic use as a natural alternative to the modern, perhaps excessive, use of antibiotic therapy and compulsion to establish a sterile environment, which has led to an increase in specific disease states.
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