Probiotics and Prebiotics as Modulators of the Gut Microbiota1
Sandra Tejero
Ian R. Rowland
Robert Rastall
Glenn R. Gibson
1Abbreviations: ADD, antibiotic-associated diarrhea; CDI, Clostridium difficile infection; CFU, colony-forming units; DP, degree of polymerization; FISH, fluorescence in situ hybridization; FOS, fructooligosaccharide; GOS, galactooligosaccharide; IBD, inflammatory bowel disease; IBS, irritable bowel syndrome; IMO, isomaltooligosaccharide; LGG, Lactobacillus rhamnosus GG; MOS, mannooligosaccharide; SOS, soy oligosaccharide; TD, traveler’s diarrhea; XOS, xylooligosaccharide.
Driven by the increasing burden of gastrointestinal disease, the functional foods market has moved heavily toward gut-derived events. Specifically, these foods target the human gut to stimulate beneficial microbial genera either directly, by providing growth substrates to promote the growth of an individual’s autochthonous “healthy flora” selectively (prebiotics), or by using live microbial additions (probiotics). Bifidobacteria and lactobacilli are the most common targets for in vivo within the large intestine for such fortification. The use of probiotics and prebiotics carries little to no risk for consumers, but it holds much promise for improved health and well-being. This chapter discusses the main types of probiotics and prebiotics and briefly describes some of the clinical applications of each approach (Table 38.1).
PROBIOTICS
The first widely accepted definition of probiotics was made by Fuller (1): “a live microbial feed supplement which beneficially affects the host by improving its intestinal microbial balance.” A more recent formal definition of probiotics was proposed by the World Health Organization (FAO/WHO): “live microorganisms which, when administrated in adequate amounts, confer a health benefit to the host” (2). Both definitions, as well as others that have been touted, rely on viability of the strains during ingestion and within the product. This requirement is key for probiotic efficacy.
Any health claims associated with a probiotic food product, including claims about disease risk reduction, are strictly regulated by the European Food Safety Authority (EFSA) in the European Union and the Food and Drug Administration (FDA) in the United States. Probiotics must be safe and devoid of any toxic potential and belong to the category of “generally regarded as safe” (GRAS) substances. Current issues are becoming protracted in the legislative arena, driven largely by disagreements on what constitutes a health claim when foods such as probiotics and prebiotics are considered.
Numerous studies have been published on the benefits of oral supplementation with certain probiotics on human health. These studies provide evidence of the important roles of probiotics to prevent, ameliorate, and possibly treat some disorders and diseases (3, 4, 5). It is difficult for legislators to ignore this scientific literature (>7000 PubMed articles on probiotics alone) in their deliberations on claim efficacy. Given the track record of success with probiotics and prebiotics as well as their history of safety, robust claims based on sound scientific evidence are overdue.
Probiotics are usually strains of lactic acid-producing bacteria, in particular members of the Lactobacillus and Bifidobacterium genera. This use is not least the result of the long and safe history of these bacteria in the manufacture of dairy products. Other microorganisms have also been developed as potential probiotics, including Bacillus coagulans, Escherichia coli, and Saccharomyces.
Probiotic Products
The most common delivery system for live microbes is dairy products such as milk, yogurt, and cheese. This use may have historical reasons because the Russian immunologist Elie Metchnikoff proposed in 1907 that lactobacilli present in yogurt played an important role in the prolongation of human life by promoting health (6). This proposal is generally seen as the birth of the probiotic concept. Technologic advances are making it possible to market a novel range of products, such as capsules and tablets, with advantages
of longer shelf life, easier administration, straightforward distribution requirements, and storage at ambient temperatures. These products are based on spray or freeze drying technology, which preserves bacteria for extended periods.
of longer shelf life, easier administration, straightforward distribution requirements, and storage at ambient temperatures. These products are based on spray or freeze drying technology, which preserves bacteria for extended periods.
TABLE 38.1 DESIRED CHARACTERISTICS OF PROBIOTICS AND PREBIOTICS | ||||
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Saarela et al (7) investigated the stability of Bifidobacterium animalis spp. lactis VTT E-D12010 during freeze drying, storage, and acid and bile exposure by using a milk-free culture medium and cryoprotectants to produce cells for non-milk-based applications. These investigators concluded that it was feasible to develop non-milk-based production technologies for probiotic cultures. This would give an advantage for the use of probiotics in individuals with lactose intolerance or in strict vegetarians.
Selection Criteria
Investigators generally agree that, to be effective, probiotics have to survive passage through the upper gastrointestinal tract by exhibiting resistance to the low pH, bile salts, and pancreatic enzymes (12, 13, 14). This is a challenge that some probiotics may not meet. However, given the level of evidence in human studies for positive health outcomes, it is apparent that many strains are able to compensate for the harsh physicochemical conditions of the gastrointestinal tract.
Another important aspect of probiotics is safety, and many investigators have reviewed the different requirements for a probiotic to be regarded as “safe” (15, 16, 17). Furthermore, probiotics need certain technologic properties to be cultured on large scale, in addition to an acceptable shelf life (15).
Probiotics and the Gut
Probiotic bacteria exert their activity mainly in the human gastrointestinal tract. Most health-related studies of probiotics have focused on this activity. This discussion is divided into noninfectious and infectious disorders. Some studies that are important for gauging probiotic success are summarized here. However, probiotics also act prophylactically by reducing the risk of disease. This use should be considered when considering the frequent question on when to use probiotics: Should healthy persons take these products? The answer is “yes” if the consumer wishes to help avoid gut difficulties such as gastroenteritis. The caveat is that the strains should be recognized probiotics and able to meet the various selection criteria that are required. Different strains are almost certain to exert different effects, as noted in the examples given in this discussion.
Noninfectious Disorders
Probiotics are claimed to be effective in a wide range of gastrointestinal disorders, particularly in diarrhea, irritable bowel syndrome (IBS), and inflammatory bowel disease (IBD). The potential of probiotics to alleviate IBS symptoms was shown in several studies carried out since 2000. IBS is a significant challenge because of its ubiquity, difficulty in diagnosis, and lack of therapeutic strategies. Trials have also shown a placebo effect, and this chapter cites studies in which the investigators controlled for this effect.
Evidence for efficacy in IBS has been generated from several studies.
O’Mahony et al (18) reported that further than improvement in symptoms, the consumption of Bifidobacterium infantis was associated with the normalization of the basal ratio of interleukin-10 to interleukin-12 (anti-inflammatory/proinflammatory cytokine). This ratio was lower in patients with IBS than in matched healthy controls, a finding suggesting an immune-modulating ability for this intervention. In a 4-week double-blind study by Whorwell et al (19), 362 adult patients were randomized to receive 1 of 3 different doses of freeze-dried encapsulated B. infantis 35624 or placebo. A dose of 108 colony-forming units (CFU)/mL showed the best scores in relation to abdominal pain, bloating, bowel dysfunction, incomplete evacuation, straining, and the passage of gas (19).
In a more recent double-blind, placebo-controlled study, 298 adults diagnosed with IBS were randomized to receive an E. coli preparation or placebo. Significant improvements in pain relief and typical symptoms were observed in the treatment group (20).
IBDs such as Crohn disease, ulcerative colitis, and pouchitis are recurrent inflammatory disorders of the colon and small intestine with a complex, undefined origin. Microbial involvement has been suggested, and if this is the case, then the potential for probiotic interventions against the culprit microorganisms is feasible.
In relation to maintain remission in Crohn disease, a study of 32 adults that compared the effect of treatment with mesalamine or the yeast Saccharomyces boulardii in combination with mesalamine demonstrated significantly fewer relapses in the second group, a finding supporting
the beneficial effect of S. boulardii (21). In a more recent study of 34 patients with Crohn disease, the group receiving S. boulardii showed an improvement in intestinal permeability compared with a placebo group (22).
the beneficial effect of S. boulardii (21). In a more recent study of 34 patients with Crohn disease, the group receiving S. boulardii showed an improvement in intestinal permeability compared with a placebo group (22).
In active Crohn disease, further research is required because some studies (23, 24) could not show definite conclusions on the efficacy of probiotic therapy. Clinical efficacy of the probiotic mixture VSL #3 (a mixture of 4 species of lactobacilli, 3 species of bifidobacteria, and Streptococcus thermophilus) was assessed in a study of 34 ambulatory patients with active ulcerative colitis. Probiotic organisms were detected in 3 of 11 patients following microbiologic analysis of mucosal biopsies, and an induction of remission or response rate of 77% was observed (25). Another study (26) demonstrated that VSL #3 treatment of patients with ulcerative colitis produced an increase in fecal concentrations of VSL #3 bacteria and helped to maintain remission, because only 4 of 20 patients experienced relapse. Given that VSL #3 is a complex mixture of probiotic strains, it is currently unclear which of the individual constituents was responsible for the effects seen.
In relation to pouchitis, Gionchetti et al (27) assessed a reduction in the incidence of pouchitis in the treated group (10%) compared with the placebo group (40%) in 40 patients after ileal pouch-anal anastomosis for ulcerative colitis. Moreover, Mimura et al (28) later confirmed the effectiveness of this probiotic mixture in antibiotic-introduced remission in 36 patients with recurrent or chronic pouchitis who were randomized to receive either a daily dose of VSL #3 or placebo. Gosselink et al (29) reported a lower rate in episodes of pouchitis after pouch formation in patients receiving Lactobacillus rhamnosus GG (LGG), than in patients not treated with this probiotic.
Infectious Disorders
Probiotics have been shown to be promising for the management of infectious disorders. This approach holds much promise and shows how probiotics may be useful in disease prevention. Frequent travelers, hospitalized persons, and older persons are examples of high-risk populations that may benefit from using effective probiotics.
Increasing evidence shows that probiotic treatment can alleviate acute infectious diarrhea, mainly in infants and children. Several metaanalyses (30, 31, 32, 33) reported some moderate effects in relation to the duration of diarrhea observed after therapeutic treatment with probiotics. The probiotic that has shown the best efficacy, in this regard, to date is LGG. Some of the controlled trials using LGG are discussed here.
In a double-blind, placebo-controlled trial developed by Shornikova et al (34), 123 children aged between 1 and 36 months who had acute diarrhea received oral rehydration and 5 × 109 CFU of LGG or placebo orally. LGG significantly shortened the duration of rotavirus diarrhea, but not of diarrhea with a confirmed bacterial cause. In another study involving 39 children, the group consuming LGG showed a significantly shorter duration in episodes of diarrhea and enhanced immunoglobulin A secretion, considered a parameter of local immune defense (35). Guandalini et al (3) carried out a controlled trial in which 287 children 1 month to 3 years old were randomized to receive either a live preparation of LGG or placebo; a reduction in almost 1 day in the course of the diarrhea was observed in the treatment group.
Probably the most extensively investigated use of probiotics related to infectious disorders is as adjunctive treatment to reduce antibiotic-associated diarrhea (AAD) in patients receiving antibiotic therapy. A metaanalysis by Szajewska et al (36) of data from five randomized-controlled trials showed that S. boulardii significantly reduced the risk of diarrhea in patients (adults and children) treated with antibiotics for any reason (mainly respiratory tract infections). Another metaanalysis also suggested that although S. boulardii and Lactobacillus spp. had the potential to prevent AAD, their efficacy remained to be proven (37).
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