The arrival of methods that permit the detailed annotation of the individual species and strains that inhabit the gastrointestinal tract, and that have revealed their metabolic activity as well as their multiple and complex interactions with their host, has initiated an explosion of interest in the microbiota in health and disease.1,2 These advances in biology have generated the expectation that the microbiota may provide new avenues for the development of new diagnostic and therapeutic approaches to a number of gastrointestinal and non-gastrointestinal disorders. These scientific advances have also provided some long-needed legitimacy to a group of remedies that have been used widely for decades: prebiotics and probiotics.
Defined as non-digestible, but fermentable, foods, prebiotics beneficially affect the host by selectively stimulating the growth and activity of one species or a limited number of species of bacteria in the colon4 and, especially, but not exclusively, lactobacilli and bifidobacteria.5,6 Prebiotics can be tailored for specific effects: The administration of transgalacto-oligosaccharides, for example, results in an increase in the numbers of bifidobacteria and a rise in actetate and lactate formation, indicating an alteration of colonic fermentation.7
The prebiotics for which most data has been generated are the inulin-type fructans, which are linked by beta (2-1) bonds that limit their digestion by upper intestinal enzymes, and fructo-oligosaccharides. Both are present in significant amounts in many edible fruits and vegetables, including wheat, onion, chicory, garlic, leeks, artichokes and bananas. Because of their chemical structure, prebiotics are not absorbed in the small intestine but are fermented, in the colon, by endogenous bacteria to energy and metabolic substrates, with lactic and short-chain carboxylic acids as end products of the fermentation. It should be noted that fiber and lactulose, widely advocated for the therapy of a number of common gastrointestinal conditions, have, in some instances, been shown to exert prebiotic effects.5,6
Synbiotics, defined as a combination of a probiotic and a prebiotic, aim to increase the survival and activity of proven probioticsin vivo, as well as stimulating indigenous Bifidobacteria and Lactobacilli.
A probiotic, from the Greek and meaning "for life," is defined as a live organisms that, when ingested in adequate amounts, exerts a health benefit to the host. The most commonly used probiotics are lactic acid bacteria and nonpathogenic yeasts. Though dead bacteria, bacterial components, bacterial DNA and substances elaborated by commensal species and strains have been shown to exert anti-bacterial, anti-inflammatory, immunomodulatory and other effects similar to those exhibited by live organisms, the restriction of the term probiotic to preparations containing live organisms persists for now. How do probiotics act? Experimental studies of individual probiotic organisms or probiotic cocktails have revealed a number of potential mechanisms8,9 that range from:
- simple displacement to metabolic interactions with pathogens
- production of chemical products (such as bacteriocins) that directly inhibit other bacteria or viruses
- inhibition of bacterial movement (translocation) across the gut wall
- enhancement of mucosal barrier function10,11
- signaling with the epithelium and immune system to modulate the inflammatory/immune response.
Inflammation is a key point. For example, a number of probiotic organisms have been shown to modify the inflammatory response to a number of pathogens, including salmonella. Bifidobacterium infantis has been shown to prevent NFk-B and IL-8 activation and also inhibit the secretion of the chemokine CCL20 in response to Salmonella typhimurium, Clostridium difficile, Mycobacterium paratuberculosis and, even, bacterial flagellin.12,13
Some strains, indeed, appear to exert potent anti-inflammatory effects: in an experimental animal (IL-10 knockout) model of colitis, for example, both a Lactobacillus and a Bifidobacterium produced a marked reduction in inflammation in the colon and cecum with a parallel suppression of the pro-inflammatory cytokines IFN-γ, TNF-α, and IL-12, while levels of the anti-inflammatory cytokine TGF-Β were maintained.14 These differential cytokine responses to commensals and pathogens have also been demonstrated in man.15 Similar effects have been demonstrated for the probiotic cocktail VSL#3 in experimental models of colitis; these anti-inflammatory effects could, indeed, be transmitted by bacterial DNA alone.16,17 What is very exciting is the observation,again in an animal model, of the ability of orally administered probiotics to exert anti-inflammatory effects at sites well distant from the gut such as in an inflamed joint.18
Non-immunological activities of commensals and, thus, probiotics are now beginning to attract considerable attention. For example, probiotics may also produce other chemicals, including neurotransmitters and neuromodulators, which can modify other gut functions, such as motility or sensation.19,20,21 However, it is the metabolic potential of the microbiota that has really grabbed the headlines. Though the salvage of unabsorbed dietary sugars, such as lactose, and alcohols by bacterial disaccharidases and their conversion into short-chain fatty acids (SCFA’s), the de-conjugation of bile salts, drug metabolism and the synthesis of vitamins, such as folate and vitamin K, have been recognized for some time, it is only recently that the full metabolic potential of the microbiome has come to be recognized and the potential contributions of the microbiota to the metabolic status of the host, in health, and to obesity and related disorders, in disease, appreciated. The application of genomics, metabolomics and transcriptomics can now reveal, in immense detail, the metabolic potential of a given organism.22 That microbe-microbe interaction can also play a critical role in homeostasis and disease in man23 is exemplified by the consumption of hydrogen by methanogenic organisms.24
Most recently and, perhaps, most surprisingly, it has been proposed that the microbiota can influence the development25 and function26 of the central nervous system, thereby, leading to the concept of the microbiota-gut-brain axis.27,28
In the interpretation of results from in vitro and animal experiments, a number of caveats must be raised before we rush to extrapolate these findings to man. Firstly, doses of probiotics used in mouse or rat models are enormous on a per body weight basis in comparison with any used or currently feasible in man. Secondly, for many probiotics, their mechanism(s) of action in a given disease state, or in health, is likely to be multifactorial and, thirdly, not only are probiotic effects highly strain-specific29 but the very manner in which a strain is prepared and presented may profoundly influence its biological response.
Van Baarlen and colleagues studied the immune response to two live (one preparation in the logarithmic phase of growth and the other stationary) and one heat-killed preparation of Lactobacillus plantarum. While the heat-killed preparation induced an inflammatory response featuring up-regulation of expression of TNF-α, for example, consumption of the actively growing organism preferentially induced genes associated with anti-inflammatory activities.30
Evidence for probiotics in digestive disorders
While experimental observations suggest potential benefits for probiotics in a variety of gastrointestinal, pancreatic and liver disorders, as well as such systemic disorders as obesity and allergy that may have gastrointestinal manifestations, the most solid clinical data rests in three main areas: infection, inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). Given the metabolic capacity and impact of the microbiota, it should come as no surprise that probiotics have also been proposed as potential modifiers of such intestinal metabolic functions as fermentation of lactose and production of short chain fatty acids.
Infectious diarrhea: Though probiotics have been proposed to demonstrate some efficacy in the prevention of a variety of community and hospital acquired infections, 31 the most conclusive evidence rests in the area of infectious diarrhea and in relation to rotavirus-associated diarrhea and Clostridium difficile-related diarrhea, in particular32,33. Several studies have reported that probiotics may be effective in rotavirus-induced diarrhea, resulting in a shortening of the duration of this illness, which is a scourge of day care centers and similar environments34,35. Similarly, a meta-analysis of nine double-blind, placebo-controlled trials, suggested that probiotics (Saccharomyces boulardii, Lactobacillus acidophilus and bulgaricus, Enterococus fecium SF68, Bifidobacterium longum, and Lactobacillus GG) appeared to be effective in preventing antibiotic-associated diarrhea.36,37
Inflammatory bowel disease: There is an extensive literature from a variety of experimental models to indicate anti-inflammatory and/or immune modulating effects of a variety of probiotic strains. While several of these have been reviewed already, it should be stressed how very subtle changes in bacterial genetics and physiology can exert profound changes on the immunomodulatory capacity of commensal or probiotic organisms.38,39,40 These findings exemplify how an understanding of the molecular basis for probiotic-host interactions could lead to the development of new therapeutic strategies in IBD. Probiotics may also exert beneficial effects at the epithelial level; by down-regulating the chemokine response to inflammatory stimuli (such as TNF-α), probiotics, and the soluble factors they secrete, can reduce the inflammatory response within the epithelium.41 Here, as in the mucosal and systemic immune responses, dendritic cells appear to play a critical role.42
The rationale for the therapeutic use of probiotics in IBD and variants, such as pouchitis, is derived from the hypothesis that the endogenous intestinal microflora plays a crucial role in the pathogenesis of these disorders43,44 and is supported by the variable efficacy of antibiotics in IBD. Evidence from a number of controlled trials featuring a number of probiotic organisms, including non-pathogenic Escherichia coli, Saccharomyces boulardii and a Bifidobacterium have suggested efficacy for probiotics in maintaining remission in ulcerative colitis and in treating mild to moderate flare-ups; other studies have been less favorable.45
VSL#3, a probiotic cocktail containing eight different strains, has proven effective in the primary prevention and maintenance of remission among patients with pouchitis, an ulcerative colitis variant that occurs in the neo-rectum in ulcerative colitis patients who have undergone a total colectomy and ileo-anal pouch procedure. In one study, remission was maintained in 85 percent of patients on VSL#3 compared to 6 percent in those receiving placebo.46 Remissions were associated with reduced levels of pro-inflammatory cytokines, such as TNFα and IFNγ, and increased levels of the anti-inflammatory cytokine IL-10.44
In contrast to these somewhat encouraging findings in ulcerative colitis, a review of the available literature on the use of probiotics either in the management of acute illness or the maintenance of remission in Crohn’s disease provides little encouragement.47 (Though the precise etiology of the condition remains uncertain, the efficacy of probiotics in the prevention of necrotizing entercolitis (NEC) also needs to be mentioned.48 There is some data to suggest a role for probiotics in radiation-induced enteritis.49
Irritable bowel syndrome: While probiotics have been used on an empiric basis for some time in the management of IBS, several recent developments provide a more logical basis for their use in this context. These include the clear recognition that IBS may be induced by bacterial gastro-enteritis (post-infectious IBS) and that qualitative changes in the flora, as well as immune dysfunction, may be prevalent in IBS in general.50,51,52 Antibiotic-induced symptomatic responses in IBS have, undoubtedly, also stimulated interest in this concept.53
Several experimental observations have provided a scientific basis for the potential efficacy of specific probiotic strains in IBS.54 Thus oral administration of Bifidobacterium infantis 35624 has been shown to attenuate interferon γ (IFN-γ), tumor necrosis factor α (TNF-α) and interleukin 6 responses following mitogen stimulation, increase plasma levels of tryptophan and kynurenic acid and, most strikingly, reduce concentrations of 5-hydroxyindole acetic acid (5-HIAA) and dihydroxyphenylacetic acid (DOPAC) concentrations in the frontal cortex and amygdala, respectively.55
These observations were taken one step further by the same research group by demonstrating, in an animal model of depression (the maternally-separated rat), normalization of immune responses, reversal of behavioral deficits and restoration of basal norepinephrine concentrations in the brainstem.56
While these latter observations could address some of the proposed pathophysiological mechanisms associated with symptom development in IBS, namely, immune activation and disturbances in the brain-gut axis, other studies suggest that a probiotic strain can also modify peripheral mechanisms linked with IBS, such as visceral hypersensitivity,57,58,59 altered intestinal permeability60 or act as visceral analgesics61 or "anti-spasmodics."62
Up to the year 2000, a small number of studies evaluated the response of IBS to probiotic preparations and, while results between studies were difficult to compare because of differences in study design, probiotic dose and strain, there was some, but by no means consistent, evidence of symptom improvement.63 Further studies, since then, have assessed the response to a number of well-characterized organisms and have produced discernible trends.64 While results continue to be variable with a number of organisms, such as Lactobacillus GG, Lactobacillus plantarum, Lactobacillus acidophilus, Lactobacillus casei, the probiotic "cocktail" VSL#3 and Bifidobacterium animalis, as well as others65,66 being shown to alleviate individual IBS symptoms, such as bloating, flatulence and constipation. Only a few products have been shown to affect pain and global symptoms in IBS;67,68,69 others have shown no benefit.70,71
Safety of probiotics
Many different species and strains and preparations of probiotics have been used for decades and by millions of healthy and diseased individuals, yet definitive data on safety is scanty. In a careful and critical review in 2006, Boyle, Robins-Browne and Tang concluded that although probiotics have an excellent overall safety record, they should be used with caution in certain patient groups—particularly newborns born prematurely or with immune deficiency.72,73 They reviewed case reports of instances of abscesses and endocarditis in relation to probiotic use; in many instances the probiotic cultured from the infected tissue was most likely an innocent contaminant rather than the real pathogen. Fears that live probiotic organisms might translocate across the gut and lead to systemic sepsis have also been allayed by the absence of such reports from studies among patients with inflammatory bowel disease and other situations where the intestinal barrier may be compromised.
Two notes of caution must be mentioned.
The first relates to reports of septicemia occurring among infants with short bowel syndrome and the second to instances of increased mortality among patients with severe acute pancreatitis who had been administered a probiotic cocktail through a naso-enteric tube. These deaths were associated not with sepsis, but with intestinal ischemia whose etiology remains unclear.74 In a comprehensive and recent review, Sanders and colleagues list the potential adverse outcomes of probiotic ingestion, expose the limitations of prior safety assessments, and provide a road map for future studies.75
The challenges for the consumer and the physician
Over the years many products have appeared on health food store and supermarket shelves throughout the world that include the term probiotic in their labels. Several barely merit that title. Firstly, they may not contain live organisms, have not been adequately tested to ensure that the organisms will survive in the conditions (e.g. room temperature), or for the length of time (days, weeks, or months), that is claimed, or may not have been shown to survive transit through the human gut.1,2 Secondly, there may be no data to support a claimed health benefit because, either the particular preparation may have never been tested in man, or what studies have been preformed have been inadequate or even negative.
The interpretation of available data on probiotics is further confounded by variability in strain characterization, selection, dose, delivery vehicle and evaluation of viability and efficacy. When some store products have been analyzed, they have found, not only that organisms claimed to be alive were actually dead, but that the product contained organisms (including pathogens) that it was not supposed to contain.3
Eamonn M. Quigley, MD, is professor of medicine and human physiology at the Alimentary Pharmabiotic Centre at the National University of Ireland. He is past president of the World Gastroenterology Organisation.
Select suppliers: probiotics and prebiotics
Inulin and oligofructose prebiotic fibers can be incorporated into any probiotic formulation for increased performance.
Oliggo-Fiber® inulin and oligofructose, known as the "invisible fiber," inulin can be incorporated into almost any food or beverage without affecting taste or texture. It is recognized as a prebiotic ingredient that supports the natural, healthful bacteria in the lower GI tract.
Provides eight branded probiotic strains under the Probio-Tec-brand umbrella. Chr. Hansen’s science-backed strains are marketed for a variety of health-specific applications.
The world’s biggest probiotics supplier, Danisco offers FloraFIT and HOWARU lines of probiotics including both both acidopholis and bifido species. Suitable for beverages, confectionery, dairy, dietary supplements and frozen desserts.
Ganeden Biotech, Inc.
Supplies BC30, an easy to use, kosher, non-GMO, self- affirmed GRAS probiotic ingredient. It’s the only probiotic to survive mixing, shearing, and baking and does not require refrigeration.
Supplies two single branded probiotic strains, DR20 and DR10, the latter of which was used in the world’s first large-scale human study on probiotics conducted on 1,000 children in India.
Vivinal GOS is a prebiotic lactose-derived galacto-oligosaccharide. Vivinal GOS is selectively fermented by the key beneficial probiotic bacteria in the colon, most notably Bifidus and Lactobacilli to increase the populations of these bacterial species, as well as produce short chain fatty acids.
n-Fibre Standard and organic inulin in powder form; In-Oligo oligosaccharide for beverages, nutritional bars, fiber supplements and enrichments, baked goods, cereals, dairy foods, and dry mixes.
BLIS K12 is a safe yet powerful strain of a beneficial bacteria called S. salivarius which normally occurs in the mouth and throat. Marketed for support in oral and ear health.
NutrFlora NutraFlora short-chain fructooligosaccharides (scFOS) and Purimune prebiotic GOS is a highly pure prebiotic derived from lactose containing a minimum of 90 percent galactooligosaccharides (GOS).
FiberAid is a soluble prebiotic fiber with good digestive tolerance and technological properties. It is water soluble, stable against a wide pH and temperature range and forms low-viscosity solutions.
National Starch Food Innovation
Nutriose soluable fiber with prebiotic properties. Applications include beverages, dairy, soups, sauces, extruded snacks, cereals and baked goods. Also supplies Hi-maize resistant starch.
Exclusive supplier of Dr. Shahani’s® custom-manufactured probiotics, founded on the DDS-1 strain of Lactobacillus acidophilus. The full line of microorganisms is available either individually or in combination, and with or without enzymes, colostrum or phytonutrients.
PrimeBiotix Bulk Probiotic Powders, Patented BIO-tract Delivery System Probiotic Caplets, Contract Manufacturing/Private Labeling.
Offers Probiomega® which combines probiotics with omega-3s in a single ingredient.
Roquette America Inc.
NUTRIOSE range of soluble dietary fibres obtained from cereals. NUTRIOSE promotes healthy eating by improving nutrition profile of food while maintaining their original taste. Use NUTRIOSE to increase fiber content to contribute to recommended daily intake; decrease calories intake; bring specific nutritional benefits.
A synbiotic, proprietary composition comprising of beneficial human intestinal microorganism (LactoSpore®, Bacillus coagulans) and dietary fiber (Fenumannan®, Galactomannan) for promoting gastrointestinal health.
UAS Laboratories, Inc.
Supplies DDS® Probiotic Blend 003, a synergistic combination of Lactobacillus acidophilus DDS® 1 superstrain, Bifidobacterium longum, Bifidobacterium bifidum, Bifidobacterium lactis and FOS at a potency of 10 billion CFU/g. The probiotics are human isolates and are acid and bile resistant.