Probiotics and Functional Foods in Gastrointestinal Disorders Martin H. Floch, MD JoAnn Hong-Curtiss, MD Address Digestive Disease Section, Yale University School of Medicine, Norwalk Hospital, Norwalk, CT 06850, USA. E-mail:
[email protected] Current Treatment Options in Gastroenterology 2002, 5:311–321 Current Science Inc. ISSN 1092-8472 Copyright © 2002 by Current Science Inc.
Opinion statement Probiotics are live microbial food supplements that benefit the host animal by improving intestinal microbial balance. When they are fed in yogurts, they can fall into the category of functional foods. Functional foods include these probiotics, prebiotics, and, to a certain extent, dietary fiber. Prebiotics are nondigestible food ingredients or supplements that alter the intestinal flora and stimulate the growth of healthy bacteria. Dietary fibers are part of plant foods that are nonstarch polysaccharides and are poorly digested or not digested by human enzymes. The physiologic process in which probiotics and functional foods affect the intestinal flora is through the balance of the intestinal microecology. This review looks at the four major components of intestinal microecology and describes the probiotics in use today and their clinical relevance. Although probiotics hold great promise and appear to be useful in some settings, more clinical study is needed to firmly establish the relevance of probiotic therapy.
Introduction Functional foods are substances or supplements that are administered to obtain a specific result. Other names for functional foods are “nutriceuticals” and “biotherapeutics.” Examples of functional foods are probiotics, prebiotics, and, to a certain extent, dietary fiber. Probiotics are live microbial food supplements that benefit the host animal by improving intestinal microbial balance. Prebiotics are nondigestible food ingredients that alter the intestinal flora and stimulate the growth of healthy bacteria. Dietary fiber is that part of plant foods that consists of nonstarch polysaccharides and is poorly digested or not digested by human enzymes. Ordinarily, the broad group of dietary fiber substances are not called functional foods, but in reality many prebiotic substances are part of, or come from, dietary fiber. Numerous foods fall into the category of functional foods and work by exerting a metabolic affect in the host or changing the host’s metabolism. Certainly, in this review, we cannot go into such topics as diets to control cholesterol
metabolism or therapeutic diets for various diseases. We therefore limit the discussion of functional foods to those that contain probiotics or prebiotics and those that affect the microbial balance. It is clear that normal bacteria enhance the health of humans and that these bacteria are nurtured by so-called functional foods. We begin this review with a discussion of intestinal microecology, which is the basic physiology of probiotics and functional food therapy. We then discuss the present use, or abuse, of probiotics in gastrointestinal diseases.
INTESTINAL MICROECOLOGY Luckey [1] popularized the idea that the gastrointestinal tract and organisms within its lumen constitute an ecologic unit. The metabolism and function of this ecologic unit, in turn, affects the host. All of the components of the ecologic unit are important and depend upon each other. If there is any major change in any of the components, the other components are affected.
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Figure 1. Components of the gastrointestinal ecology are depicted. In order to understand the mechanisms by which probiotics maintain the intestinal microbial balance, one must understand intestinal microecology. Microecology of the gastrointestinal tract can be divided into four major components (Fig. 1): 1) the gut wall, which contains the hollow lumen tract; 2) the gastrointestinal secretions that enter the hollow organ; 3) the intestinal microflora that live within the gut [2]; and 4) foods that are fed into the tract. The gut wall The specific functions of the epithelial lining and mucosa vary throughout the gastrointestinal tract. The mouth has its own complete ecology. We will not discuss the importance of the oral cavity in this review. The esophagus, which is lined with a squamous epithelium, functions primarily to allow passage of food to the stomach. Any disturbance in esophageal function results in marked disturbances to the ecologic unit by limiting the delivery of adequate nutrients to the other components of the tract and to the microflora. The stomach lining and motility are essential for normal passage of food and digestion. The epithelium of the small bowel is essential for absorption of all major nutrients. The epithelium of the colon is nurtured by the butyric acid produced by the intestinal microflora and acts as a major absorptive surface for short-chain fatty acids (SCFA) produced by the microflora [3]. The integrity of the epithelium of the eso-
Microflora With the development of anaerobic techniques, several laboratories have defined the aerobic and anaerobic flora of humans [6–8]. There are few indigenous organisms in the esophagus, and few reports of any adherence to the wall. However, yeast and bacterial infections of the esophagus do occur. This implies that, in the normal state, the gut wall is free of infection, but with alteration of the metabolism of the wall, infection can occur. Normal gastric juice of the stomach harbors some gram-positives that do not appear to be pathologic. Normal bacterial counts within the stomach are never more than 102 or 104/mL. However, Helicobacter pylori is now well-known to invade the gastric ecology and adhere to the mucosa surface of the gastric wall, causing both gastritis and ulceration in the stomach and the proximal duodenum. In the jejunum, bacterial counts are still low, at less than 105 /mL. Aerobes have been primarily recovered from the sulcus entericus. When counts are above 105/ mL, bacterial overgrowth becomes apparent. The transitional zone from the jejunum into the ileum occurs somewhere in the middle to distal ileum, where bacterial counts of the indigenous flora rise sharply. At this point, aerobic and anaerobic organisms are evenly distributed. However, in the distal ileum and the right side of the colon, anaerobic organisms are prolific, and bacterial counts rise to greater than 10 12 /mL, with anaerobes outnumbering aerobes by anywhere from 100- to 1000-fold [6–8]. Qualitative and quantitative analyses of the fecal flora have been done most frequently on specimens from the colon. Table 1 lists the major organisms identified from the feces by vigorous aerobic and anaerobic techniques. Recently, RNA and DNA analysis has
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Table 1. Predominant human fecal flora Aerobic organisms
Anaerobic species
Escherichia coli Enterococcus spp Other Streptococcus spp Bacillus spp Citrobacter spp Klebsiella spp
Anaerobic cocci Bacteroides spp Eubacterium spp Bifidobacterium spp Lactobacillus spp Fusobacterium spp
Data from Moore and Holdeman [6], Floch et al. [7], and Feingold et al. [8].
enabled more specific identification [9]. However, these methods have not been used in human clinical studies to date. It is important to note that the fecal flora of breast-fed infants is predominantly composed of bifidobacteria. In contrast, the fecal flora of bottle-fed infants is more complex and heterogeneous. Once infants are fed regular
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foods, bacteria such as Bacteroides, Clostridium, and Streptococcus spp and Escherichia coli increase rapidly. The transition to the adult-type flora occurs in about the second year of life [10]. Foods The fourth major component of the intestinal microecology is food. All of the macro- and micronutrients are important. However, this discussion focuses on specific foods or substances that directly affect the microflora population and ecosystem. The idea of prebiotics developed after the concept of functional foods was established. Gibson and Roberfroid [11] define prebiotics as nondigestible food ingredients that benefit the host by selectively stimulating the growth or activity of one or a number of bacteria in the colon that can improve the health of the host. Whereas prebiotics are supplements, dietary fiber is in our natural foods, as previously defined [5]. Both prebiotics and dietary fiber are important in maintaining the natural microflora, as well as in enhancing the use of probiotics.
Treatment Prebiotics • Criteria for supplements defined as prebiotics have been proposed and established [11]. Prebiotics are substances that are not absorbed or degraded in the upper gastrointestinal tract. They act as substrates for the beneficial bacteria in the colon by stimulating growth of the colonic flora that are beneficial to the host. By beneficially changing the microflora of the gut ecology, they improve the status of the host. The majority of the bacterial species of the intestine are saccharolytic and ferment nutrients [12]. They include species of the genera Bacteroides, Bifidobacterium, Eubacterium, Lactobacillus, and Clostridium. Prebiotics should stimulate the organisms that are most beneficial to the host and, hence, specifically stimulate the bifidiobacteria and lactobacilli. In vitro and in vivo studies show that oligofructose and inulin stimulate the growth of bifidobacteria, whereas they inhibit the growth of E. coli and C. perfringens producing the desired affect [13]. • Prebiotics stimulate bacterial growth, which, in turn, enhances fermentation and production of SCFA. Although increased SCFA is a desired effect, SCFA can produce symptoms that are not desirable to some patients, such as flatulence [13]. Both oligofructose and inulin stimulate bifidobacteria growth and metabolism in humans [14,15]. In a study of constipated elderly patients fed significant amounts of inulin, bifidobacteria counts increased from 7.9 to 9.210/g of dried feces, with a decrease in enterococci and enterobacteria, as well as a trend to higher SCFA production. Stools were soft and more frequent, but there was only mild discomfort [15]. These human experiments clearly demonstrate that prebiotic agents affect the microflora and their chemical activity in the stool.
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Table 2. Prebiotic substances Prebiotic
Country/manufacturer
Fructooligosaccharide Isomaltooligosaccharide Oligomate Palatinose Pyrodextrin Raftiline Soybean oligosaccharide Xylooligosaccharide Fructooligosaccharide Guar Lactulose (Duphalac)
Orafti, Belgium Showa Sangyo, Japan Yakult, Japan Sudzucker, Germany Matsutani, Japan Orafti, Belgium Calpis, Japan Sutory, Japan Ross Laboratories, Columbus, OH (US) Novartis Nutrition, Minneapolis, MN (US) Solvay, Marietta, GA (US)
Adapted from Cummings et al. [13].
• Table 2 lists some prebiotics that are available. The material is modified from Cummings et al. [13] and is by no means complete. However, this list represents the variety of substances and their clinical use in the United States, Europe, and Asia. • Fructooligosaccarides (FOS) promote the growth of bifidobacteria and lactobacilli. They lower the colonic pH, tend to discourage the growth of clostridia, have a low glycemic index, are water soluble, have a low viscosity, and do not bind minerals. FOS are usually pleasantly sweet tasting, add texture to foods, and naturally occur in the artichoke, onion, garlic, chicory, leek, and some cereals. Both raffinose and stachynose are major carbohydrates of beans and peas and can affect the colonic microflora [13]. The major effect of feeding FOS is to increase the population of bifidobacteria. Bifidobacteria readily ferment FOS to SCFA. Bifidobacteria also produce B vitamins and inhibit the growth of pathogenic bacteria as well as restoring the flora after antibiotic use [16]. • Inulin naturally occurs in fruits and vegetables. It is a much more complex compound than the fructooligosaccarides, and it provides a fat-mimicking texture to foods [16]. • Animal studies and anecdotal experience indicate that prebiotics are able to benefit the host’s ecology. However, the lack of clinical trials makes it difficult to establish the animal data that would be relevant to humans and to show that prebiotics can truly prevent colonization resistance of pathogens. The clinical experience in infant diarrhea and the ability to clearly increase the flora of bifidobacteria in infants indicate that prebiotics have clinical importance [12]. Animal research has shown the impact of prebiotics in changing the microflora and the microecology of the gut. This effect has been demonstrated in some disease states, indicating their potential [13,16]. However, controlled clinical studies are needed to establish the full value of prebiotics.
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Dietary fiber • Dietary fiber can be chemically divided into soluble and insoluble fibers, which are fermented at different rates and have varying physiochemical effects in the gut lumen. Their major effects are water holding, ion exchange, binding organic chemicals, forming gels, increasing viscosity, slowing transit, and increasing bulk [5,17]. • The soluble fibers are largely hemicelluloses and gums. The microbial flora ferment the fiber, yielding significant amounts of SCFA, namely butyric acid, acetic acid, and propionic acid. Butyric acid has turned out to be the major nutrient for colonocytes, whereas acetic acid and propionic acid are absorbed by the colonic mucosa and become part of cholesterol metabolism [18]. SCFA appear to be extremely important both in maintaining the health of the colonic mucosa and in serving as an energy source [18]. Depending on dietary intake, the amount of polysaccharide that reaches the colonic flora can be anywhere from 5% to 20% of the oral intake, leading to production of anywhere from 300 to 800 micromoles of SCFA. This can make up as much as 5% to 10% of the basic energy of the host [18]. On the other hand, insoluble fibers are lignin and celluloses, which are found in bran, are not as well fermented, and hold onto water until the fecal mass is excreted [5,17]. • Very few studies have investigated the relationship between the microflora and dietary fiber intake. The studies that have been done are largely epidemiologic. Initially, laboratories working in this area showed significant differences in the aerobic and anaerobic flora with respect to dietary fiber intake [19,20]. However, there have been very few recent studies to relate clinical situations to either soluble or insoluble intake. Nevertheless, clinical studies definitely demonstrate the role of high-fiber diets in improvement and treatment of diabetes, diverticular disease, and hypercholesterolemia [21], but such diets remain controversial, and better physiologic and metabolic studies are needed.
Probiotics • Modern medical history reveals that Metchnikoff [22] established the conceptual importance of intestinal microbial balances. Metchnikoff claimed that the ingestion of yogurt containing lactobacilli reduces the toxic bacteria of the gut and prolongs life. In 1926, Kipeloff [23] began to promulgate the importance of Lactobacillus acidophilus. Rettger et al. [24], working at Yale, began to stress its therapeutic applications. In the second half of the last century, Freter [25] and others began to demonstrate the relationship of enteric pathogens to the normal flora. In 1965, Lilly and Stillwell [26] described the growth-promoting factor produced by microorganisms that stimulated other microorganisms and coined the term “probiotic.” Parker [27] was actually the first to use the term in the clinical sense in which it is now employed. In 1989, Fuller [28] defined probiotics as microbial supplements that benefit the host animal by improving its intestinal microbial balance [28]. • Probiotics are live microbial food supplements. They are usually strains of lactobacilli or bifidobacteria, but yeast such as Saccharomyces species are employed. They are usually administered in yogurt or capsules. The important properties of probiotics are numerous: 1) they are bacteria of human origin; 2) they survive passage through the gut; 3) they resist the secretions of the upper gut, primarily hydrochloric acid and bile acids; 4) they adhere to human intestinal cells, and adherence is a major
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Functional Disorders and Gastrointestinal Motility Dysfunction phenomenon that enables them to protect the cells of the epithelium against invasion by pathogens; 5) they have the ability to colonize the human intestinal tract; 6) they produce antimicrobial substances and antagonize both carcinogenic and pathogenic flora; and, finally, 7) they are safe in clinical use in large amounts [16,29]. Table 3 lists the microorganisms that can be considered as probiotics. By definition, probiotic agents are isolated from human strains.
Clinical relevance • A wide range of claims have been made for probiotics. As outlined by Tannock [45], these claims include increased resistance to infectious diseases, decreased duration of diarrhea, reduced blood pressure, reduced serum cholesterol concentration, reduced allergy, stimulation of phagocytosis by peripheral blood leukocytes, modulation of cytosine gene expression, adjuvant effect, regression of tumors, and reduced carcinogen or co-carcinogen production. As Reid [46] states: “There is a relatively large volume of literature which supports the use of probiotics to prevent and treat intestinal and urogenital infections and other ailments. However, the basis for the claims is often weakened by a lack of proven reliability of the preparations, and an inability to prove conclusively that the contents are safe and efficacious. In addition, not enough emphasis has been placed upon selecting strains which have specific properties shown to be important in colonizing the host and acting antagonistically against pathogens. For probiotic therapy to truly be accepted in general medical practice, it must undergo rigorous clinical trials, and as these are expensive, government agencies and industry partners should, and indeed must, begin to invest in such studies.” Table 4 lists the referenced reports that are clinically relevant in many of the conditions. These studies are often uncontrolled and have the limitations Reid has outlined [46].
Table 3. Probiotic microorganisms Lactobacillus species L. acidophilus L. amylovorus L. casei L. crispatus L. gasseri L. johnsonii L. paracasei L. plantarum L. reuteri L. rhamnosus Non–lactic acid bacteria Bacillus cereus var. toyoi Escherichia coli–strain Nissle Propionibacterium fredenreichii Saccharomyces cerevisiae Saccharomyces boulardii (Adapted from Holzapfel et al. [30].)
Bifidobacterium species B. adolescentis B. animalis B. lectis B. bifidum B. breve B. infantis B. longum
Other lactic acid bacteria Enterococcus faecium Leuconstoc mesenteroides Streptococcus thermophilus
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Table 4. Probiotics and their reported clinical relevance Study or studies
Probiotic
Clinical relevance
Bernet et al. [31]
Lactobacillus acidophilus LC1
Lidbeck et al. [32] and Salminen et al. [33] McDonough et al. [34]
L. acidophilus NCFO1748
Aso and Akazan [35] and Spanhaak et al. [36] Kaila et al. [37,38], Majamaa et al. [39], Gorbach [40•]
L. casei Shirota
Marteau et al. [41]
Bifidobacterium bifidum
Shornikova et al. [42], Wolf et al. [43] Surawicz et al. [44], Tannock [45] Rembacken et al. [52•] Gionchetti et al. [55] Nobaek et al. [56] Hilton et al. [57]
L. reuteri
Adherence to human intestinal cells, balancing of intestinal microflora, and immune enhancing Treatment of constipation, decreased food enzymes, and prevention of radiotherapy-related diarrhea Treatment of lactolose intolerance, production of bacteriocins, decreased fecal enzyme activity, high lactase activity Balancing of intestinal bacteria, decreased fecal enzymes, superficial bladder cancer control Treatment and prevention of rotavirus diarrhea, treatment of relapsing C. difficile colitis, prevention of acute diarrhea, prevention of antibiotic-associated diarrhea, antagonistic against carcinogenic bacteria Treatment of rotavirus and viral diarrhea and balancing of intestinal microflora Colonization of the intestinal tract, shortening of rotavirus diarrhea Prevention and treatment of C. difficile colitis and antibiotic-associated diarrhea Used to maintain remission in IBD Decreased recurrence of pouchitis Decreased IBS symptoms Prevention of recurrent candidal vaginitis
L. acidophilus NFCM
L. rhamnosus GG
Saccharomyces boulardii Escherichia coli–strain Nissle Eight strains; see text and reference L. plantarum L. acidophilus
Immunity From a physiologic point of view, it is clear that probiotics lower the lumenal pH, produce antimicrobial substances, adhere and attach to the epithelium, grow and colonize on the mucus surface, and act as very specific immunomodulators [16]. It is logical to accept that probiotic therapy affects immunity because increased IgA production has been shown, particularly in antirotaviral IgA levels and production of interferon-gamma (IFN-␥), tumor necrosis factor-alpha (TNF-␣), and interleukin-1 (IL-1) by mononuclear cells incubated with lactobacilli [16]. Adherent lactobacilli and bifidobacteria significantly increase phagocytosis, and Lactobacillus GG has been used to treat cow’s milk allergy and atopic eczema [16,40•,47,48].
Infections Because probiotics stimulate an immune response, it is logical that they should be used in treating infections. Surawicz et al. [44] showed that Saccharomyces boulardi is successful in reducing the incidence of recurrent C. difficile colitis. In a prospective, double-blinded, controlled study of 180 patients, they found that S. boulardi administration statistically reduced the incidence of diarrhea in those patients receiving a placebo concurrently with antibiotics from 22% to 9%. Gorbach [40•] also showed that Lactobicillus GG is effective in reducing relapses of C. difficile colitis. It is well known that bifidobacteria reduce the risk of diarrhea when they are added to acidified milk or formula [45]. However, their effectiveness in traveler’s diarrhea is controversial [16].
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Inflammatory bowel disease Increased interest has been shown in the possible role of the bacterial flora and nutrients in inflammatory bowel disease (IBD). The production of butyric acid by colonic bacterial fermentation of polysaccharides, and the treatment of diversion colitis with butyric acid, led to numerous trials of butyric acid in ulcerative colitis [21,49], with varied results. Additionally, the difficulty in administering butyric acid rectally limited its use. Demonstration that IL-10–deficient mice develop patchy colitis under conventional conditions, which is prevented by a germ-free state and by administration of lactobacilli and prebiotics, stimulated interest in the possibility that probiotics could be helpful in the treatment of ulcerative colitis [50,51]. In a clinical trial, nonpathogenic E. coli-strain Nissle used as a probiotic was compared with mesalamine in maintenance therapy for patients with ulcerative colitis [52•]. One hundred and sixteen patients with ulcerative colitis were randomly assigned in this trial, and results suggest that treatment with E. coli was equivalent to treatment with mesalamine in maintaining remission of ulcerative colitis. In a limited study of 32 patients, Guslandi et al. [53] randomly administered either mesalamine or mesalamine plus S. boulardii for 6 months in patients with Crohn’s disease in remission. They found that 37.5% of the mesalamine patients had relapsed, but only 6.25% of those receiving S. boulardii, indicating a protective effect with the probiotic agent [53]. An interesting study by Schultsz et al. [54] demonstrated that the intestinal mucus layer in patients with IBD harbors high numbers of bacteria, compared with results in control subjects. Evaluation of 10 control subjects and six IBD patients indicates that the intestinal mucus in the IBD patients was less protected against the indigenous microflora than in controls, resulting in increased association of lumenal bacteria with the mucus layer. These results may also indicate that only pathogenic bacteria are able to colonize in the mucus layer of patients with IBD. Unfortunately, these investigators did not identify the species of organisms growing in the mucus layer. In a double-blinded, placebo-controlled study, Gionchetti et al. [55•] enrolled patients with an ileorectal anastomosis performed for colitis who had chronic pouchitis. In their study, 40 patients were randomly assigned to receive a placebo or a probiotic that consisted of a mixture of eight strains of organisms (four strains of Lactobacillus, three strains of Bifidobacterium, and one strain of Streptococcus thermophilus). Three patients in the probiotic group (15%) relapsed within 9 months, whereas all of the patients (100%) in the placebo group relapsed. These authors were also were able to identify increased fecal counts of the administered probiotic organisms. They concluded that the probiotic was effective in preventing recurrent pouchitis.
Irritable bowel syndrome The use of probiotics in the treatment of irritable bowel syndrome (IBS) has been controversial [48]. However, a recent study of 60 patients by Nobaek et al. [56•] from Lund University in Sweden indicates a definite decrease in pain and other symptoms of IBS. These patients ingested a solution with L. plantarum, and this probiotic was recovered from their feces [56•]. The mechanism of action is not clear.
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Genitourinary infections Some evidence indicates that probiotic agents can protect the urogenital tract against infection in women. Hilton et al. [57] demonstrated that administration of L. acidophilus decreased incidence of recurrent infections of Candida spp vaginitis and bacterial vaginosis. They compared 11 women treated with yogurt containing the probiotic with 11 women who received placebo. Those on placebo had 36 infections during the trial period, whereas the women who ate the yogurt only had four infections. Other studies have demonstrated the effectiveness of probiotics in genital urinary tract infections, but the literature is not conclusive. In a review article on this topic, Reid [58•] notes that lactobacilli are the major constituents of the normal vaginal flora of premenopausal women. The normal strains are important for their adhesive abilities and production of antimicrobial substances that prevent infection. However, efforts to use lactobacilli and other probiotics have yielded mixed results [58•]. Most recently, McLean and Rosenstein [59] isolated several strains of Lactobacillus with the capacity to inhibit overgrowth by pathogens. This work is encouraging and, as Reid [58•] points out, continued efforts in this area hold great promise for probiotics in prevention of recurrent bacterial vaginosis.
Cancer Although the role of diet in cancer remains unclear, relevant epidemiologic studies have shown that low-fiber diets and high-fat diets appear to increase the risk for cancer. The question of whether probiotics and prebiotics have a protective role in colon cancer remains controversial [60]. However, numerous studies have shown that certain probiotics are effective in deactivating genotoxic substances and in decreasing fecal enzymes that may play a role in carcinogenesis [35,40•,60].
Hepatic encephalopathy It is important to reiterate that the gastrointestinal tract is an ecologic unit. The ecologic unit is significantly affected by the use of probiotics and prebiotics [61•]. A classic example of a prebiotic that is now the main treatment of a disease is lactulose in hepatic encephalopathy [62,63]. Numerous studies have shown that lactulose administration is successful in treating hepatic encephalopathy. Although we know that this agent drops the pH and alters the colonic flora, the exact mechanism is still not clear. More studies are needed to evaluate the combined effects of prebiotics and probiotics. A recently reported study in rats demonstrates that combining a barley foodstuff with a probiotic of C. butyricum could suppress sulfate sodium–induced experimental colitis in rats [64]. Clinical studies in humans combining prebiotics and probiotics are needed to enhance our understanding of the potential benefits of these agents. The future should show that prebiotics as lactulose are helpful in other clinical conditions and that combinations of prebiotics and probiotics may be beneficial
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