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When We Eat, Which Bacteria Should We Be Feeding? Probiotics and prebiotics to alter the gut flora might usefully curtail metabolic activities of problematic gut pathogens Glenn R. Gibson and Robert A. Rastall he human digestive tract, particuditions, including obstetric techniques, whether larly the colon, is one of the most a delivery is vaginal or caesarean, and the type of microbially active ecosystems in exfeeding the newborns receive affect the level, istence, containing a massive variety frequency, and varieties of species that colonize of bacteria, viruses, yeasts, and other a newborn’s gut. fungi. One novel approach to combating disease When microorganisms are transferred into revolves around diet, using foods with novel the infant gut, the initial colonizers are facultaingredients to stimulate indigetive anaerobes that rapidly remove nous bacteria while avoiding nontraces of oxygen, rendering the gut indigenous microbial species along strictly anaerobic within one week Shortly after with the diseases that they someof birth. Soon, breast- and formutimes provoke. Indeed, this conla-fed infants develop differences birth, an array cept is known as the prebiotic efin microflora profiles, with of bacteria fect. Meanwhile, probiotics bifidobacteria dominating the begin to represent a more traditional apformer while the latter tend to decolonize the proach to altering gut flora— one velop a more complicated commuformerly sterile that entails individuals consuming nity structure. gut live microorganisms with the exHuman milk contains a compectation that those microbes will plex mixture of glycoproteins and remain intact and will interact oligosaccharides that stimulate biwith the resident gut flora to make it more fidobacteria. Because they have powerful inhibbenign. itory properties against various gastrointestinal Virtually everyone experiences a gastrointespathogens, the predominance of the bifidobactinal complaint that relatively harmless prebiotteria more than likely accounts for the “breast is ics and probiotics might help to redress. Even best” hypothesis. In general, bottle-fed infants ignoring the benefits of a flora that is rich in experience higher infection rates than those who lactic acid-producing bacteria, using them to are breast fed. Hence, infant-formula manufacdisplace a distinctly pathogenic flora is surely an turers are seeking to alter their products to more approach worthy of consideration. effectively stimulate bifidobacteria. Once weaned from an exclusive milk or forThe Gastrointenstinal Tract Acquires Flora mula diet, children consume increasingly varied Soon after Birth foods, leading microbial gut populations toward greater complexity. When children reach Shortly after birth, an array of bacteria begin to about 2 years of age, the gut microbial populacolonize the formerly sterile gut. Newborns tyption assumes an adult-like composition, conically first contact bacteria when they move taining at least 500 bacterial species. through the birth canal and are exposed to miThe numbers of bacteria in the human stomcrobial flora within the genital tract. Other con- T Glenn R. Gibson is Professor of Food Microbiology and Robert A. Rastall is Senior Lecturer in Food Biotechnology in the School of Food Biosciences, The University of Reading, Whiteknights Reading, United Kingdom. 224 Y ASM News / Volume 70, Number 5, 2004 FIGURE 1 Bacterial and physicochemical interactions in different areas of the human gut. ach typically remain low, approximately 103 per ml of contents, because their transit time is rapid and stomach acidity is high (Fig. 1). One notorious occupant, Helicobacter pylori, resides in the gastric mucosal layer and is associated with type B gastritis, dyspepsia, and stomach carcinomas. Extensive studies of this microorganism lend support to the idea that carriage of this or other pathogens can predispose individuals towards particular illnesses. Such studies also continue to raise the profile of gut microbiology, emphasizing its important health consequences. The small intestine provides a very different story because it is a compartment where microbial numbers rise to 1 million per ml. A brief transit in the ileum and jejunum plus inputs of bile salts and pancreatic enzymes maintain the flora at this higher level. The human adult colon is about 150 cm in length with a typical transit time of 24 –72 hours, providing a significant period for bacteria to reach extremely high numbers. Moreover, nutrients are plentiful at around 100 g of dietary residues, including carbohydrates, proteins, amino acids, and lipids, entering the colon daily and fortifying endogenous nutrient sources such as mucus and epithelial cells (Fig. 2). Here, bacterial numbers can soar to 1012 per ml of contents—in other words, probably as many bacteria as can be contained in 1 ml— of which several hundred types exist in an adult. This microbial mass makes the colon one of the most metabolically active organs in the body and certainly the most heavily colonized. Indeed, about 95% of the total cells in the body are bacteria within the large intestine, making humans manyfold more microbial in composition than mammalian. In considering what types and numbers of bacteria are being fed when an individual eats dinner, it is easy to imagine the impact that gut bacteria can exert in health and disease. Appreciating the Role of Gut Flora in Health and Disease Through their metabolic activities, the colonic microbiota have a significant impact upon host welfare. For example, the principal end products of anaerobic fermentations are organic acids. Some of these are absorbed from the gut to be metabolized systemically, providing perhaps 10% of an individual’s daily energy requirement. Volume 70, Number 5, 2004 / ASM News Y 225 Prebiotics versus Probiotics in the Lab, and during a Cricket Match Glenn R. Gibson envisions a day when people will have their own designer diets, consuming meals based on their personal genotypes—a health strategy that will work only if food also continues to be fun, he says. “Food is something social and enjoyable, so perhaps we should not be too prescriptive. There has to be some enjoyment too. Hence, the best functional foods will also taste good.” Gibson, professor of food microbiology at the University of Reading in the United Kingdom, leads a multidisciplinary research program on how gut microbiology affects human health and disease. His research includes projects on pro- and prebiotics, molecular genotyping of gut bacteria, diet and cancer, the molecular biology of bifidobacteria, colonic gas metabolism and hydrogen sulfide production, the role of gut bacteria in lipid reduction, and colonic homeostasis. “I think that foods that target gut bacteria have the ability to help a lot of people with acute or chronic ailments,” Gibson says. “Maybe with big moves in individual genotyping, the same may be done for gut flora—that is, sequence and quantify all the bacteria present and predict susceptibility to disorder and define a food intervention to protect. Using diet to reduce disease risk is user-friendly and relatively free of side effects.” But for this strategy to be successful, individuals and health professionals will need to learn a great deal more about microbiology, nutrition, and related subjects, he says. That educational process is beginning to happen, at least in his country, he adds. “Awareness is increasing quite rapidly now in the United Kingdom,” Gibson says. “Family doctors are becoming more and more interested, especially as many gut disorders are not ef- Thus, the microbiota in the colon can affect mood and other markers of well-being. For instance, dietary fiber that is readily metabolized by gut flora has positive effects upon energy, stress, and cognitive performance, according to Andrew Smith and colleagues at the University of Wales, Cardiff, United Kingdom. Meanwhile, other, more specific end products of gut bacterial metabolism, such as propionic acid, are thought to interfere with cholesterol synthesis in the liver and may therefore be useful for protecting against coronary heart disease. Moreover, the gut serves as a major immune organ of the body, in part through the antigenic status of its resident microbiota. Building upon research with H. pylori, several digestive disorders are being researched for their link with specific gut flora components, with some of these associations more tentative than others: 226 Y ASM News / Volume 70, Number 5, 2004 fectively dealt with by pharmaceuticals. This is impressive, as diet and health is not part of the normal training. It takes some effort.” Gibson, 42, grew up in the coalmining village of Horden in County Durham, which is in the northeast of England, very similar, he says, to the town portrayed in the film Billy Elliot. The older of two children— he has a sister— Gibson remembers his hometown as a “great place and a tight-knit community.” His late father worked as a sawmill operator in nearby Hartlepool, and his mother was an occupational therapist and served for a time as the director of a home for the elderly. Gibson credits failure with sending him on the path to microbiology—more specifically, the fact that he flunked his school exams at the age of 18. “I made a real blunder in my first scientific exams, my ‘A’ levels in 1979,” he says. “But I found my subsequent • Ulcerative colitis (UC), a disorder principally of Western origin that typically first appears among young adults, is one example of an inflammatory bowel disorder (IBD). UC, which is confined to the colon, cannot be induced in animal models lacking a gut flora. Our research and that of others implicate sulfate-reducing bacteria, which are virtually always present in the colitic gut but are rarely present in the gut of healthy individuals. These bacteria produce sulfide, which is a cell toxin and also interferes with butyric acid oxidation in colonocytes. Our group is currently conducting a dietary intervention study designed to curtail sulfate-reducing bacterial activity in UC patients. • The etiology for Crohn’s disease, a form of IBD that can affect any area of the alimentary tract, is far from certain. However, several investigators suspect mycobacteria. exams progressively easier, perhaps because my focus narrowed. In fact, to become a professor there are no exams involved!” Despite the momentary setback, he graduated from the University of Dundee in 1983. He received his Ph.D. there three years later, and conducted postdoctoral work there as well, studying the genetics of sulfate-reducing bacteria. From 1987 until 1995, he served as a research microbiologist at the Medical Research Council Dunn Clinical Nutrition Centre in Cambridge, then headed the microbiology department of the Biotechnology and Biological Sciences Research Council Institute of Food Research in Reading. He was awarded a personal chair at the university in 1999. He also heads the Food Microbial Sciences Unit in the school of food biosciences. The unit has about 50 researchers working on gut microbiology and microbial food safety. In 1991, he received the W. H. Pierce memorial prize, which is awarded for microbiology by the Society for Applied Bacteriology and Unipath. Perhaps it is no wonder that Gibson’s wife sometimes tells their dinner guests that he is a painter or decorator. She claims that this deception makes for more tasteful mealtime conversation than would discussing what he really does for a living. Gibson and his wife, who is studying for a degree at Open University, United Kidngom, have two children, a girl, 12, and a boy, 9, both athletes. “Because England won the rugby World Cup last December and beat arch-rival Australia in the final, my son has just taken the game up,” he says. “And my daughter is a very good swimmer indeed.” Gibson plays squash and badminton, and likes to swim and bowl with his family. “I play a lot • Irritable bowel syndrome (IBS), a prevalent disorder affecting up to 20% of individuals in some countries, such as the United States, United Kingdom, France, and Germany, is often related to stress. IBS symptoms include diarrhea or constipation, and attacks occur unpredictably. Candida albicans, which is involved in recurrent vaginal thrush, is suspected as a trigger factor for IBS. We have isolated a probiotic Lactobacillus plantarum with potent anticandida activity that is being evaluated in a clinial trial involving IBS patients. • Bowel cancer—specifically, colorectal tumors—is considered the second most prevalent form of cancer in humans and is responsible for one in five fatalities in the United States. Components of the gut flora have the capacity to produce carcinogens and tumor promoters, including nitrosamines, heterocy- of squash and am in a league system in the university here,” he says. “You don’t know your opponent until they turn up—and my heart sinks when it is a young, fit student. I used to play football, but my knees are past it now.” He also recalls one memorable cricket match among microbiologists on a very hot August afternoon in Reading during a break from an international scientific conference. “The teams were the probiotics versus the prebiotics,” he says, failing to mention which team was his. “I’m not sure who won, as the rules seemed to be mostly ignored. It was great watching the Americans bowl a very hard cricket ball like they would fast-pitch a baseball. There were no hospital cases, but a few bruises did ensue.” Marlene Cimons Marlene Cimons is a freelance writer in Bethesda, Md. clic amines, ammonia, diacylglycerols, IQ, and fecapentenes. • Antibiotic-associated diarrhea occurs when homeostasis in the gut is disturbed through use of broad-spectrum antimicrobials. For example, pseudomembranous colitis may occur when the usual suppressant effect of gut bacteria against Clostridium difficile fails, and it proliferates and also produces damaging amounts of two types of toxin. • Translocations can occur following trauma, such as intensive surgery, leading the gut to become “leaky” and some of its bacterial contents to migrate into sites, such as the liver, where microbially produced toxins can act destructively. • Pneumatosis cystoides intestinalis (PCI) is characterized by gas-filled cysts lining the colon. Clostridia may generate this gas, al- Volume 70, Number 5, 2004 / ASM News Y 227 dietary origin. What about featuring nutrients whose effects might be more benign and perhaps even beneficial? Can diets be fortified to prevent specific disorders? If so, what would be a reliable mechanism? These questions have special relevance because so many of these gut disorders lack effective treatments. However, probiotics and prebiotics, which rely on dietary means to alter the gut flora, could provide a safe and cost-effective approach for reducing the metabolic activities of problematic gut pathogens. This approach thus might be considered a benign approach to “germ warfare.” FIGURE 2 The Probiotic Approach Entails Adding Microorganisms to the Gut Ecosytem Typical food sources for various genera of colonic bacteria. though bacteria capable of metabolizing hydrogen, including sulfate-reducing bacteria, methanogens, and acetogens, may be absent from the PCI gut. • Autistic spectrum disorders (ASDs) might also have bacterial origins, including from toxins that are generated in the gut but have systemic effects. According to investigators from an earlier era, including William ArbuthnottLane (late 19th century) and Elie Metchnikoff (early 20th century), the gut flora can exert nonlocal effects, such as migraine. Our own studies have recently found that, some autistic individuals have high levels of clostridia in their stools; perhaps toxins from these gut bacteria are absorbed into the bloodstream and exert effects elsewhere. These examples of diseases associated with excesses of specific gut bacteria (or other microorganisms) represent instances where one would not want to expand particular microbial populations by supplying them particular nutrients of 228 Y ASM News / Volume 70, Number 5, 2004 Humans have been ingesting probiotics in the form of soured milks for thousands of years. Nowadays, many such products, including fermented milks, yogurts, and cheeses, are plentiful and popular. Among them, however, yogurt is manufactured using Lactobacillus bulgaricus and Streptococcus thermophilus, neither of which is recognized as probiotics, which would entail adding strains to supplement the fermentation-based manufacturing procedure. The most commonly used probiotic or bioactive microorganisms include lactic acid-excreting bacteria such as L. casei, L. acidophilus, L. fermentum, L. johnsonii, L. plantarum, and L. rhamnosus, or bifidobacteria such as Bifidobacterium longum, B. infantis, and B. bifidum. Other microorganisms used in probiotic products include lactococci, streptocococci, the gram-negative Nissle Escherichia coli, and also yeasts such as Saccharomyces species. Delivery vehicles besides milk-based products for probiotics include fruit juices and lyophilized versions in powders, capsules, tablets, and sprays. Probiotics have been used for the past 40 years to treat animals on farms, where these products are said to reduce the risk of infection, to increase yield and feed conversion, improve digestion, and to improve products such as eggs, meat, and milk. The mechanisms behind these effects are not fully understood but are linked to decreased pathogen load in the guts of animals being treated. Pur- chases of probiotics for farm animals in FIGURE 3 the United States have increased fivefold during the past decade, and over 50% of dairy producers are using probiotics. For human use the market is even larger, with a profit income of several billion Euros in Europe. If anything, the situation is even more advanced in Asia, principally Japan. A survey indicates more than 50 recently published scientific reports of humans treated with probiotics having positive results. Principally these trials involved intestinal problems such as gastroenteritis and IBS, but some of them were conducted on patients with urinary tract infections or with chronic conditions such as cancer, coronary heart disease, and IBD. Despite reports of benefits, the data The effects of prebiotic-containing biscuits on the predominant gut flora components of 31 typically are variable, perhaps reflecting healthy adults. Study was of a crossover nature, doubly blind, placebo controlled. Microbiology was carried out using fluorescent in situ hybridization. Courtesy of K. M. Tuohy. probiotic strain variability, poor survival of some strains in products being evaluated, and the varying ability to influence competitive gut ecosystems. Nonetheoligosaccharides resist digestion or absorption in less, in the aggregate, these data suggest that the upper gut and then are selectively metabolized altering gut flora shows promise both prophyby gut flora. For instance, some oligosaccharides, lactically and therapeutically. often called prebiotics, serve as nutrients that favor indigenous bifidobacteria and lactobacilli, stimulating their replication in a way that matches what Prebiotics Are Nutrients That occurs when these microbes are provided as proAlter the Gut Ecosystem biotics. Oligosaccharides considered as prebiotics Many different factors, including age, stress, include the fructooligosaccharides (FOS), inulin, antimicrobial intake, immune status, transit galactooligosaccharides (GOS), and lactulose. time, and availability of substrate, can alter the Bifidobacteria produce several enzymes that gut microbiota. However, the last of these, are particularly suited to metabolizing oligosacwhich could be a major determinant of gut charides, including a -fructanfuranosidase that microbial composition, is one in which the condigests FOS. Meanwhile, other commensal bacsumer can exert considerable control through teria, notably Bacteroides thetaiotaomicron, diet. can signal the host to produce fucosylated glyGenerally, when gut flora metabolize dietary cans via a molecular sensor. Hence, this microbe proteins and lipids, they generate toxins, wherecan engineer its own niche within this ecosysas metabolizing carbohydrates yields harmless tem. Perhaps additional molecular messages are or beneficial organic acids. Meanwhile, metabeing sent by pathogens that prebiotics may bolically resistant starches and fiber are simiinterfere with and thus act as anti-infective larly considered beneficial because they provide agents. fecal bulk, improving digestion and transit time while reducing the risk of colorectal cancer and Prebiotic Oligosaccharides Are Being diverticulitis. Used Extensively Oligosaccharides represent perhaps the most interesting group of nutrients when they enPrebiotics, which were defined in 1995, are noncounter the gut microflora. Distinct from dietary digestible food ingredients with the capacity to fibers such as pectin, celluloses, and xylan, various improve health when selectively metabolized by Volume 70, Number 5, 2004 / ASM News Y 229 FIGURE 4 Fluorescent image of gut bacteria. colonic bacteria. Typically, to achieve a prebiotic effect, producers will add enough of a prebiotic to a food product to deliver a daily dose of at least 5 g. However, although higher daily doses of up to 30 g yield no adverse affects, introducing too high a prebiotic dose may compromise microbial selectivity and would risk generating gas, which is not a problem associated with bifidobacteria or lactobacilli buildups. In Europe, several prebiotic oligosaccharides are being added to foods on a commercial scale. In Japan, food producers are using an even wider range of such materials, including isomaltooligosaccharides, soyaoligosaccharides, gentiooligosaccharides, glucooligosaccharides, lactosucrose, polydextrose, and xylooligosaccharides. What are the health consequences of consuming foods containing prebiotics? Clinical and preclinical studies are under way to assess the value of prebiotics for improving mineral bioavailability and for countering obesity, bowel cancer, IBD, IBS, coronary heart disease, autism, necrotizing enterocolitis, vaginal thrush, and other infectious processes. For instance, volunteers in one of our studies consumed FOScontaining biscuits, which stimulated gut bi- 230 Y ASM News / Volume 70, Number 5, 2004 fidobacteria to a level resembling that in breast-fed infants (Fig. 3). When it comes to analyzing how prebiotics affect the complexity of gut flora populations, researchers are using a variety of molecular techniques, including fluorescent in situ hybridization (Fig. 4), 16S rRNA profiling, temperature/density gradient gel electrophoresis, direct community analysis, ribotyping, pulsed-field gel electrophoresis, expression arrays, detection genes that affect function, microchips, proteomics, metabolomics, and transcription studies. A major advantage of prebiotics over probiotics is that product integrity, viability, or stability are not issues for concern. Hence, prebiotics can be added to many food vehicles, including dairy products, beverages and health drinks, spreads, infant formula and weaning foods, cereals, bakery products, confectionery chocolates, chewing gum, soups, sauces and dressings, processed meats, dried instant foods, canned foods, and sports supplements. They can also be used as powdered or syrup supplements. New product developments are occurring at a rapid pace. In terms of how best to feed your gut bacteria, a balanced high fruit and vegetable intake is key. Foods such as onions, garlic, asparagus, chicory, milk, artichoke, leeks, and bananas contain natural prebiotics. Consuming specially supplemented foods should not be viewed as replacing a healthy diet but rather as an adjunct. As the advantages of prebiotics become more apparent, steps may be needed to ensure that they do not become overpriced. Prebiotics also may contribute to food safety by protecting against food- and waterborne pathogens. For example, a gut flora dominated by bifidobacteria or lactobacilli that produce organic acids, compete for nutrients, improve overall immune status, and sometime secrete antimicrobial agents might better withstand the effects of such pathogens. Our studies with Bo Lönnerdal and his colleagues at the University of California, Davis, show that newborn primates fed prebiotics can resist becoming infected when challenged with enteropathogenic E. coli. In some cases, these protective effects were as robust as those offered by breast milk. Human population groups who are especially suited to pre- and probiotic treatments include the elderly who are prone to gastrointestinal infection, weaning children, formula-fed infants, global travellers, persons who are taking antibiotics, and others who are prone to chronic gastrointestinal complaints. Moreover, such approaches may also be suited to those living in developing countries where conventional medical interventions are prohibitively costly. SUGGESTED READING Brück, W. M., S. L. Kelleher, B. Lönnerdal, K. E. Nielsen, D. Chatterton, and G. R. Gibson. 2002. Fermentation studies on selected infant milk components using in vitro models of the human gut and rhesus monkeys. J. Paediatr. Res. 37:273–280. Gibson, G. R., P. Berry Ottaway, and R. A. Rastall. 2000. Prebiotics: new developments in functional foods. Chandos Publishing Limited, Oxford. Gibson, G. R., and M. B. Roberfroid. 1995. Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J. Nutrition 125:1401–1412. Perdigon, G., and R. Fuller. (ed.) 2003. Gut flora, nutrition, immunity and health. Blackwell Publishing, Oxford. Tannock, G. (ed.). 2002. Probiotics and prebiotics. Caister Academic Press, Norfolk. Tuohy, K. M., S. Kolida, A. Lustenberger, and G. R. Gibson. 2001. The prebiotic effects of biscuits containing partially hydrolyzed guar gum and fructooligosaccharides—a human volunteer study. Br. J. Nutrition 86:341–348. www.isapp.net. Website of a new international scientific association dedicated to probiotic and prebiotic research. www.vtt.fi/virtual/proeuhealth. A collection of European Union-funded research projects on probiotics and prebiotics. Clinical Laboratory Management Volume Editor: Lynne Shore Garcia, LSG and Associates Clinical Laboratory Management is a comprehensive volume presenting authoritative information on the management challenges facing today’s clinical laboratories. Dramatic changes in the fields of medicine and healthcare require an increased level of expertise of all laboratory personnel. An invaluable resource for laboratory directors, managers, and supervisors, Clinical Laboratory Management will also teach healthcare practitioners at all levels how to hear, speak, and thoroughly understand the operational language of healthcare administration. Written by practicing laboratorians and edited by seasoned professionals, this publication details the core requirements for effective laboratory management, including personnel management, communication, data management, point-of-care testing, test management, selection and implementation of tests and instruments, safety and emergency preparedness, and regulatory requirements. A comprehensive overview of management principles is presented, with in-depth analyses of financial challenges encountered in the clinical laboratory. Contained here is an array of administrative tools, including numerous appendices providing guidelines for relevant documentation, information on regulatory requirements, and managerial tools pertaining to personnel, financial, and technical issues, as well as checklists, worksheets, forms, Web addresses, and a complete glossary of specialized terms. Clinical Laboratory Management is the essential resource for all clinical laboratories, from the physician’s office to hospital clinical labs, to the largest commercial reference laboratories, providing practical information in the fields of medicine and healthcare, clinical pathology, and clinical laboratory management, for practitioners, managers, and individuals training to enter these fields. May 2004. Hardcover. ISBN 1-55581-279-1, 888 pages, illustrations, index List price: $149.95 ASM member price: $129.95 ASM accepts VISA, Mastercard, American Express, EuroCard, purchase orders, and checks drawn on U.S. banks in U.S. currency. Canadian orders must include appropriate GST/HST. WRITE TO: ASM Press, P. O. Box 605, Herndon, VA 20172, USA • CALL: 1-800-546-2416 or 703-661-1593 • FAX: 703-661-1501 • WEB: www.asmpress.org Volume 70, Number 5, 2004 / ASM News Y 231