Probiotics and prebiotics

1.1 History and definitions

Over a century ago, Elie Metchnikoff (a Russian scientist, Nobel laureate, and professor at the Pasteur Institute in Paris) postulated that lactic acid bacteria (LAB) offered health benefits capable of promoting longevity. He suggested that “intestinal auto-intoxication” and the resultant aging could be suppressed by modifying the gut microbiota and replacing proteolytic microbes—which produce toxic substances including phenols, indoles, and ammonia from the digestion of proteins—with useful microbes. He developed a diet with milk fermented with a bacterium that he called “Bulgarian bacillus.”

Other early developments of this concept ensued. Disorders of the intestinal tract were frequently treated with viable nonpathogenic bacteria to change or replace the intestinal microbiota. In 1917, before Sir Alexander Fleming’s discovery of penicillin, the German scientist Alfred Nissle isolated a nonpathogenic strain of Escherichia coli from the feces of a First World War soldier who did not develop enterocolitis during a severe outbreak of shigellosis. The resulting Escherichia coli strain Nissle 1917 is one of the few examples of a non-LAB probiotic.

Henry Tissier (of the Pasteur Institute) isolated a Bifidobacterium from a breast-fed infant with the goal of administering it to infants suffering from diarrhea. He hypothesized that it would displace proteolytic bacteria that cause diarrhea. In Japan, Dr. Minoru Shirota isolated Lactobacillus casei strain Shirota to battle diarrheal outbreaks. A probiotic product with this strain has been marketed since 1935.

These were early predecessors in a scientific field that has blossomed. Today, a search of PubMed for human clinical trials shows that over 1500 trials have been published on probiotics and close to 350 on prebiotics. Although these studies are heterogeneous with regard to strain(s), prebiotics tested, and populations included, accumulated evidence supports the view that benefits are measurable across many different outcomes.

Probiotics are live microorganisms that confer a health benefit on the host when administered in adequate amounts [1] (Table 1). Species of Lactobacillus (Fig. 1) and Bifidobacterium are most commonly used as probiotics, but the yeast Saccharomyces boulardii and some E. coli and Bacillus species are also used. Newcomers include also Clostridium butyricum, recently approved as a novel food in European Union. Lactic acid bacteria, including Lactobacillus species, which have been used for preservation of food by fermentation for thousands of years, can act as agents for food fermentation and, in addition, potentially impart health benefits. Strictly speaking, however, the term “probiotic” should be reserved for live microbes that have been shown in controlled human studies to impart a health benefit. Fermentation is globally applied in the preservation of a range of raw agricultural materials (cereals, roots, tubers, fruit and vegetables, milk, meat, fish, etc.).

 

 

Fig. 1  Electron micrograph of Lactobacillus salivarius UCC118 adhering to Caco-2 cells. Reproduced with permission of Blackwell Publishing Ltd.

 

1.2  Prebiotics and synbiotics

The prebiotic concept is a more recent one than probiotics and was first proposed by Gibson and Roberfroid in 1995 [2]. The key aspects of a prebiotic are that it is not digestible by the host and that it leads to health benefits for the individual through a positive influence on native beneficial microbes. The administration or use of prebiotics or probiotics is intended to influence the gut environment, which is dominated by trillions of commensal microbes, for the benefit of human health. Both probiotics and prebiotics have been shown to have beneficial effects that extend beyond the gut, but this guideline will focus on gut effects.

Prebiotics are dietary substances (mostly consisting of nonstarch polysaccharides and oligosaccharides). Most prebiotics are used as food ingredients—in biscuits, cereals, chocolate, spreads, and dairy products, for example. Commonly known prebiotics are:

• Oligofructose
• Inulin
• Galacto-oligosaccharides
• Lactulose
• Breast milk oligosaccharides

Lactulose is a synthetic disaccharide used as a drug for the treatment of constipation and hepatic encephalopathy. The prebiotic oligofructose is found naturally in many foods, such as wheat, onions, bananas, honey, garlic, and leeks. Oligofructose can also be isolated from chicory root or synthesized enzymatically from sucrose.

Fermentation of oligofructose in the colon results in a large number of physiologic effects, including:

• Increasing the numbers of bifidobacteria in the colon
• Increasing calcium absorption
• Increasing fecal weight
• Shortening gastrointestinal transit time
• Possibly lowering blood lipid levels

The increase in colonic bifidobacteria has been assumed to benefit human health by producing compounds to inhibit potential pathogens, by reducing blood ammonia levels, and by producing vitamins and digestive enzymes.

Synbiotics are appropriate combinations of prebiotics and probiotics. A synbiotic product exerts both a prebiotic and probiotic effect.

1.3  Genera, species, and strains used as probiotics

A probiotic strain is identified by the genus, species, subspecies (if applicable) and an alphanumeric designation that identifies a specific strain. In the scientific community, there is an agreed nomenclature for microorganisms—for example, Lactobacillus casei DN-114 001 or Lactobacillus rhamnosus GG. Marketing and trade names are not controlled by the scientific community. According to WHO/FAO guidelines (http://www.fao.org/3/a-a0512e.pdf), probiotic manufacturers should register their strains with an international depository. Depositories will give an additional designation to strains. Table 2 shows a few examples of commercial strains and the names associated with them.

Using strain designations for probiotics is important, since the most robust approach to probiotic evidence is to link benefits (such as the specific gastrointestinal targets discussed in this guideline) to specific strains or strain combinations of probiotics at the effective dose.

Recommendations of probiotics, especially in a clinical setting, should tie specific strains to the claimed benefits based on human studies. Some strains will have unique properties that may account for certain neurological, immunological, and antimicrobial activities. However, an emerging concept in the field of probiotics is to recognize that some mechanisms of probiotic activity are likely shared among different strains, species, or even genera. Many probiotics may function in a similar manner with regard to their ability to foster colonization resistance, regulate intestinal transit, or normalize perturbed microbiota. For example, the ability to enhance short-chain fatty acid production or reduce luminal pH in the colon may be a core benefit expressed by many different probiotic strains. Some probiotic benefits may therefore be delivered by many strains of certain well-studied species of Lactobacillus and Bifidobacterium. If the goal of probiotic consumption is to support digestive health, perhaps many different probiotic preparations containing adequate numbers of well-studied species will be sufficient.

It is now common in the field of probiotics for systematic reviews and meta-analyses to include multiple strains. Such an approach is valid if shared mechanisms of action among the different strains included are demonstrated to be responsible for the benefit being assessed.

1.4  Colonizing microbiota

The functions of both probiotics and prebiotics are interwoven with the microbes that colonize humans. Prebiotics serve as a food source for beneficial members of the commensal microbial community, thereby promoting health. Cross-talk between probiotics and host cells, or probiotics and resident microbes, provides a key means of influencing host health.

The intestine contains a large number of microbes, located mainly in the colon, and comprising hundreds of species (Table 3). Estimates suggest that over 40 trillion bacteria cells are harbored in the colon of an adult human being (including a small proportion of archaea, less than 1%). Fungi and protists are also present, with a negligible contribution in terms of cell numbers, whereas viruses/phages may outnumber bacteria cells. Altogether, gut microbes add an average of 600,000 genes to each human being.

At the level of species and strains, the microbial diversity between individuals is quite remarkable: each individual harbors his or her own distinctive pattern of bacterial composition, determined partly by the host genotype, by initial colonization at birth via vertical transmission, and by dietary habits.

In healthy adults, the fecal composition is stable over time. In the human gut ecosystem, two bacterial divisions predominate—Bacteroidetes and Firmicutes—and account for more than 90% of microbes. The rest are Actinobacteria, Proteobacteria, Verrucomicrobia, and Fusobacteria.

The normal interaction between gut bacteria and their host is a symbiotic relationship. An important influence of intestinal bacteria on immune function is suggested by the presence of a large number of organized lymphoid structures in the mucosa of the small intestine (Peyer’s patches) and large intestine (isolated lymphoid follicles). The epithelium over these structures is specialized for the uptake and sampling of antigens and contains lymphoid germinal centers for induction of adaptive immune responses. In the colon, microorganisms proliferate by fermenting available substrates from the diet or endogenous secretions and contribute to host nutrition.

Many studies have shown that populations of colonizing microbes differ between healthy individuals and others with disease or unhealthy conditions. However, researchers are still not able to define the composition of a healthy human microbiota. Certain commensal bacteria (such as Roseburia, Akkermansia, Bifidobacterium, and Faecalibacterium prausnitzii) appear to be associated more commonly with health, but it is a current active area of research to determine whether supplementation with these bacteria may improve health or reverse disease.

 

1.5  Mechanisms of action of probiotics

Prebiotics affect intestinal bacteria by increasing the numbers of beneficial anaerobic bacteria and decreasing the population of potentially pathogenic microorganisms. Probiotics affect the intestinal ecosystem by impacting mucosal immune mechanisms, by interacting with commensal or potential pathogenic microbes, by generating metabolic end products such as short-chain fatty acids, and by communicating with host cells through chemical signaling (Fig. 2; Table 4). These mechanisms can lead to antagonism of potential pathogens, an improved intestinal environment, bolstering the intestinal barrier, down-regulation of inflammation, and up-regulation of the immune response to antigenic challenges. These phenomena are thought to mediate most beneficial effects, including a reduction in the incidence and severity of diarrhea, which is one of the most widely recognized uses of probiotics.

 

 

2.1  Understanding the marketplace

Probiotic-containing products have been successful in many regions of the world. A range of product types—from conventional food through prescription drugs—is available commercially (Table 5).

The claims that can be made about these types of product differ depending on regulatory oversight in each region. Most commonly, probiotics and prebiotics are sold as foods or supplement-type products. Typically, no mention of disease or illness is allowed, claims tend to be general, and products are targeted for the generally healthy population. “Natural health products” is a category specific to Canada, where the regulatory authorities approve claims and the use of the product to manage diseases is permitted.

From a scientific perspective, a suitable description of a probiotic product as reflected on the label should include:

• Genus and species identification, with nomenclature consistent with current scientifically recognized names
• Strain designation
• Viable count of each strain at the end of shelf-life
• Recommended storage conditions
• Safety under the conditions of recommended use
• Recommended dose, which should be based on induction of the claimed physiological effect
• An accurate description of the physiological effect, as far as is allowable by law
• Contact information for post-market surveillance

The global market for probiotics was valued at US $32.06 billion in 2013, according to a 2015 Grand View Research report. Wading through the multitude of foods, supplements, and pharmaceutical products on the market is a daunting task. Some guidance is provided by the documents listed in Table 6.

 

2.2  Products: dosages and quality

The quality of probiotic products depends on the manufacturer concerned. Since most are not made to pharmaceutical standards, the regulatory authorities may not oversee adherence to quality standards. The issues that are important specifically for probiotic quality include maintenance of viability (as indicated by colony-forming units, or CFU) through the end of the product’s shelf-life and using the current nomenclature to identify the genus, species, and strain of all organisms included in the product.

The dose needed for probiotics varies greatly depending on the strain and product. Although many over-the-counter products deliver in the range of 1–10 billion CFU/dose, some products have been shown to be efficacious at lower levels, while some require substantially more. It is not possible to state a general dose that is needed for probiotics; the dosage should be based on human studies showing a health benefit.

Because probiotics are alive, they are susceptible to die-off during product storage. Responsible manufacturers build in overages so that at the end of the product’s shelf-life, it does not fall below the potency declared on the label. Spore-forming probiotic strains, although not as well studied as others, do have the advantage of superior resistance to environmental stress during shelf-life. Probiotic products on the market have been shown in some cases to fail to meet label claims regarding the numbers and types of viable microbes present in the product.

Note: A specified range of permissible colony-forming units should perhaps be required in order to minimize the risks of toxicity as well as loss of effect between production and the end of shelf-life [3,4].

 

2.3  Product safety

Most probiotics in use today are derived either from fermented foods or from the microbes colonizing a healthy human and have been used in products for decades. On the basis of the prevalence of lactobacilli in fermented food, as normal colonizers of the human body, and the low level of infection attributed to them, their pathogenic potential is deemed to be quite low by experts in the field. Bifidobacterium species enjoy a similar safety record. Most products are designed for the generally healthy population, so use in persons with compromised immune function or serious underlying disease is best restricted to the strains and indications with proven efficacy, as described in section 4. Microbiological quality standards should meet the needs of at-risk patients, as reviewed by Sanders et al. [4]. Testing or use of newly isolated probiotics in other disease indications is only acceptable after approval by an independent ethics committee. Traditional lactic acid bacteria, long associated with food fermentation, are generally considered safe for oral consumption as part of foods and supplements for the generally healthy population and at levels traditionally used.

 

Current insights into the clinical applications for various probiotics or prebiotics in gastroenterology are summarized below. Specific recommendations for different indications are based on levels of graded evidence (Table 7) and are summarized in Tables 8 and 9.

3.1 Colorectal cancer prevention

• Although diet is thought to contribute to the onset of colorectal cancer, and both probiotics and prebiotics have been shown to improve biomarkers associated with colorectal cancer, there are limited data in humans showing any benefit of probiotics or prebiotics in the prevention of colorectal cancer.

3.2  Diarrhea treatment and prevention

3.2.1  Treatment of acute diarrhea

• Some probiotic strains are useful in reducing the severity and duration of acute infectious diarrhea in children. Oral administration shortens the duration of acute diarrheal illness in children by approximately 1 day. Several meta-analyses of controlled clinical trials testing other probiotic strains have been published that show consistent results suggesting that probiotics are likely to be safe and effective. However, the mechanisms of action may be strain-specific.

3.2.2  Prevention of acute diarrhea

• In the prevention of adult and childhood diarrhea, there is evidence that certain probiotics can be effective in some specific settings.

3.2.3  Prevention of antibiotic-associated diarrhea

• In the prevention of antibiotic-associated diarrhea, there is strong evidence of efficacy in adults or children who are receiving antibiotic therapy.

3.2.4  Prevention of Clostridium difficile diarrhea

• A 2016 meta-analysis [5] concluded that probiotics can reduce the risk of developing C. difficile–associated diarrhea in patients receiving antibiotics. However, the authors caution that additional studies are needed in order to determine the best dosage and strain.

3.2.5  Prevention of radiation-induced diarrhea

• The gut microbiota may play an important role in radiation-induced diarrhea by reinforcing intestinal barrier function, improving innate immunity, and stimulating intestinal repair mechanisms. A 2013 meta-analysis [6] concluded that probiotics may be beneficial in the prevention and possibly in the treatment of radiation-induced diarrhea.

3.3  Helicobacter pylori eradication

• The 2016 Maastricht V/Florence Consensus Report on management of H. pylori infection concluded that probiotics and prebiotics show promise in reducing side effects of treatment for H. pylori. However, the quality of the evidence and the grade of recommendation were low. A 2014 meta-analysis of randomized trials [7] suggests that supplementation of anti–H. pylori antibiotic regimens with certain probiotics may also be effective in increasing eradication rates and may be considered helpful for patients with eradication failure. There is no evidence to support the concept that a probiotic alone, without concomitant antibiotic therapy, would be effective.

3.4  Hepatic encephalopathy prevention and treatment

• Prebiotics such as lactulose are commonly used for the prevention and treatment of hepatic encephalopathy. Evidence for one probiotic mixture suggests that it can reverse minimal hepatic encephalopathy.

3.5  Immune response

• There is suggestive evidence that several probiotic strains and the prebiotic oligofructose are useful in improving the immune response. Evidence suggestive of enhanced immune responses has been obtained in studies aimed at preventing acute infectious disease (nosocomial diarrhea in children, influenza episodes in winter) and studies that tested antibody responses to vaccines.

3.6  Inflammatory bowel disease (IBD)

3.6.1  Pouchitis

• There is good evidence for the usefulness of certain probiotics in preventing an initial attack of pouchitis, and in preventing further relapse of pouchitis after the induction of remission with antibiotics. Probiotics can be recommended to patients with pouchitis of mild activity, or as maintenance therapy for those in remission.

3.6.2  Ulcerative colitis

• Certain probiotics have been found to be safe and as effective as conventional therapy in achieving higher response and remission rates in mild to moderately active ulcerative colitis in both adult and pediatric populations.

3.6.3  Crohn’s disease

• Studies of probiotics in Crohn’s disease have indicated that there is no evidence to suggest that probiotics are beneficial for maintenance of remission of Crohn’s disease.

3.7  Irritable bowel syndrome (IBS)

• A reduction in abdominal bloating and flatulence as a result of probiotic treatments is a consistent finding in published studies; some strains may ameliorate pain and provide global relief. The literature suggests that certain probiotics may alleviate symptoms and improve the quality of life in patients with functional abdominal pain.

3.8  Colic

• Certain probiotic strains have been shown to reduce crying time in breastfed infants with colic.

3.9  Lactose malabsorption

• Streptococcus thermophilus and Lactobacillus delbrueckii subsp. bulgaricus improve lactose digestion and reduce symptoms related to lactose intolerance. This was confirmed in a number of controlled studies with individuals consuming yogurt with live cultures.

3.10  Necrotizing enterocolitis

• Probiotic supplementation reduces the risk of necrotizing enterocolitis in preterm neonates. Meta-analyses of randomized controlled trials have also shown a reduced risk of death in probiotic-treated groups, although not all probiotic preparations tested are effective. The number needed to treat to prevent one death from all causes by treatment with probiotics is 20.

3.11  Nonalcoholic fatty liver disease

• The usefulness of certain probiotics as a treatment option to mitigate steatohepatitis has been proven through a number of randomized clinical trials in adults and children. Probiotics provided improvements in the outcomes of homeostasis model of assessment (HOMA) scores, blood cholesterol, tumor necrosis factor-α (TNF-α), and liver function tests—alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Further studies are needed to confirm long-term benefits.

3.12  Prevention of systemic infections

• There is insufficient evidence to support the use of probiotics and synbiotics in critically ill adult patients in intensive-care units.

 

Although it is outside the scope of this guideline, it may be of interest to readers to note that probiotics and prebiotics have been shown to affect several clinical outcomes that are outside the normal spectrum of gastrointestinal disease. Emerging evidence suggests that gut microbiota may affect several non-gastrointestinal conditions, thereby establishing a link between these conditions and the gastrointestinal tract. Numerous studies have shown that probiotics can reduce bacterial vaginosis, prevent atopic dermatitis in infants, reduce oral pathogens and dental caries, and reduce the incidence and duration of common upper respiratory tract infections. The net benefit of probiotics during the perinatal period in preventing allergic disease has lead to a World Allergy Organization recommendation on probiotic use during pregnancy, breastfeeding, and weaning in families with a high risk of allergic disease. Probiotics and prebiotics are also being tested for the prevention of some manifestations of the metabolic syndrome, including excess weight, type 2 diabetes, and dyslipidemia.

Tables 8 and 9 summarize a number of gastrointestinal conditions for which there is evidence from at least one well-designed clinical trial that oral administration of a specific probiotic strain or a prebiotic is effective. The purpose of these tables is to inform the reader about the existence of studies that support the efficacy and safety of the products listed, as some other products for sale on the market may not have been tested.

The list may not be complete, as the publication of new studies is ongoing. The level of evidence may vary between the different indications. The doses shown are those used in the randomized controlled trials. The order of the products listed is random.

There is no evidence from comparative studies to rank the products in terms of efficacy. The tables do not provide grades of recommendation, but only levels of evidence in accordance with the Oxford Centre for Evidence-Based Medicine criteria (Table 7). Recommendations by medical associations are also shown.

 

 

5.1  General references

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Gibson GR, Roberfroid MB. Dietary modulation of the colonic microbiota: introducing the concept of prebiotics. J Nutr 1995;125:1401–12.

Goldenberg JZ, Lytvyn L, Steurich J, Parkin P, Mahant S, Johnston BC. Probiotics for the prevention of pediatric antibiotic-associated diarrhea. Cochrane Database Syst Rev 2015;(12):CD004827. doi:10.1002/14651858.CD004827.pub4. PubMed PMID: 26695080.

Goldenberg JZ, Ma SS, Saxton JD, Martzen MR, Vandvik PO, Thorlund K, et al. Probiotics for the prevention of Clostridium difficile–associated diarrhea in adults and children. Cochrane Database Syst Rev 2013;CD006095. doi: 10.1002/14651858.CD006095.pub3. PubMed PMID: 23728658.

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5.2  References in the text

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