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; Table 1) 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 saccharolytic microbes. He developed a diet with milk fermented with a bacterium 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 professor 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 an example 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 Lacticaseibacillus paracasei strain Shirota to battle diarrheal outbreaks. A probiotic product with this strain has been commercially available since 1935.

These were early predecessors in a scientific field that has flourished. Today, a search of human clinical trials in PubMed shows that over 1500 trials have been published on probiotics. Although these studies are heterogeneous with regard to the strains and populations included, accumulated evidence supports the view that benefits are measurable across many different outcomes that have been assessed.

Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host [1] (Table 1). Lactobacilli, along with species of Bifidobacterium, have historically been common probiotics. In 2020, the genus Lactobacillus underwent a major restructuring to better address the wide diversity of microbes assigned to the genus. Twenty-three new genera were defined, including some with well-studied probiotic species (Table 2).

The yeast Saccharomyces boulardii and some E. coli and Bacillus species are also used. Newcomers to the probiotic ranks include Clostridium butyricum, recently approved as a novel food in the European Union. LAB, which have been used for preservation of food by fermentation (Table 1) for thousands of years, may also potentially impart health benefits. 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, such as cereals, roots, tubers, fruit and vegetables, milk, meat, and fish.

1.2  Prebiotics and synbiotics

The prebiotic concept, first proposed by Gibson and Roberfroid in 1995 [2], is a more recent one than probiotics. The key aspects of a prebiotic are that it is nondigestible by the host and that it leads to health benefits for the consumer through a positive influence on the resident beneficial microbes (Table 1). The administration or use of prebiotics or probiotics is intended to influence the gut environment, which is inhabited by trillions of 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 typically consist of nonstarch polysaccharides and oligosaccharides, although other substances are being studied as candidate prebiotics—such as resistant starch, conjugated linoleic acid, and polyphenols. Most prebiotics are used as food ingredients, in foods such as biscuits, cereals, chocolate, spreads, and dairy products. Commonly known prebiotics are:

• Oligofructose (fructooligosaccharide, FOS)
• Inulin
• Galactooligosaccharides (GOSs)
• Lactulose

• Breast milk oligosaccharides (human milk oligosaccharides or HMOs)

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 may result in several physiologic effects, including:

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

However, the extent to which these physiological effects may be experienced by a consumer varies due to a number of factors, including baseline gut microbiota and diet.

It has been hypothesized that the increase in colonic bifidobacteria benefits human health by producing compounds that inhibit potential pathogens, by reducing blood ammonia levels, and by producing vitamins and digestive enzymes.

Synbiotics were originally described as appropriate combinations of prebiotics and probiotics. More recently, the concept of synbiotics has evolved to include both complementary and synergistic synbiotics (Table 1). A complementary synbiotic is defined simply as a mixture of probiotic(s) and prebiotic(s), where the two components meet the criteria defined for each, including proper characterization, and are used at a dose shown to provide a health benefit. However, a synergistic synbiotic has been described as a mixture of a live microbe selected to utilize a coadministered substrate, which together lead to a documented health benefit. The components of a synergistic synbiotic do not need to independently meet the criteria for a probiotic or prebiotic.

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 (Table 3). In the scientific community, there is an agreed nomenclature for genus, species, and subspecies names. Strain designations, product names, and trade names are not controlled by the scientific community. According to the guidelines of the World Health Organization (WHO) and Food and Agriculture Organization (FAO); http://www.fao.org/3/a-a0512e.pdf), probiotic manufacturers should deposit their strains in an internationally recognized culture collection. Such depositories will give an additional designation to strains. Table 3 shows a few examples of commercial strains and the names associated with them.

Strain designations for probiotics are important, because 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. Thus, some probiotic benefits may be delivered by different strains of certain well-studied species of probiotic genera.

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. Otherwise, such efforts should focus on strain-specific evidence.

1.4  Colonizing microbiota

The functions of both probiotics and prebiotics for gastrointestinal end points are interwoven with the microbes that reside in the human gut. Prebiotics are utilized by beneficial members of the commensal microbial community, thereby promoting health. Crosstalk between probiotics and host cells or probiotics and resident microbes provides a key mechanism for influencing the host’s health.

The intestine contains a large number of microbes, located mainly in the colon and comprising hundreds of species (Table 4). Estimates suggest that over 40 trillion bacterial 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. Gut microbes add an average of 600,000 genes to each human being [4].

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, the two bacterial divisions Bacteroidetes and Firmicutes predominate 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 those structures is specialized for the uptake and sampling of antigens, and they contain lymphoid germinal centers for induction of adaptive immune responses. In the colon, microorganisms proliferate by fermenting available substrates from diet or endogenous secretions and thereby 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 not able to define the composition of healthy human microbiota. Certain commensal bacteria (such as Roseburia, Akkermansia, Bifidobacterium, and Faecalibacterium prausnitzii) seem to be associated more commonly with health, but it is a current active area of research to determine whether supplementation with these bacteria will improve health or reverse disease.

1.5  Mechanisms of action of probiotics and prebiotics

Prebiotics affect intestinal bacteria by enhancing the numbers or activities of beneficial bacteria. This may result in decreasing the population of potentially pathogenic microorganisms or reducing potentially deleterious metabolic activities of host microbiota. Prebiotics may also impact immune function.

Probiotic strains may mediate health effects through one or more of several identified mechanisms. Probiotics may 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. 3; Table 5). 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 reduction of 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 successfully marketed in many regions of the world. A range of product types—from conventional food through prescription drugs—is available commercially (Table 6).

The claims that can be made on these types of products differ, depending on regulatory oversight in the 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 represent a specific category in Canada, where the regulatory authorities approve claims and the labeling of the product for use in managing diseases is allowed.

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

• Genus, species (and subspecies, if applicable) 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
• Recommended dose, which should be based on induction of the claimed physiological effect
• An accurate description of the physiological effect, as allowable by law
• Contact information for post-market surveillance

2.2  Products: dosages and quality

The global market for probiotics was valued at US$ 32.1 billion in 2013, according to a 2015 Grand View Research report. It is predicted that the worldwide probiotic market will progress rapidly at an annual growth rate of 8.1% to reach US$ 85.4 billion by 2027 (“Probiotics Market,” https://www.marketsandmarkets.com/). Wading through the multitude of foods, supplements, and pharmaceutical products on the market is a daunting task. Most guidance from medical organizations is based on strains rather than product names, which can differ depending on the geographical region. It can be difficult to match probiotic strains to specific products, and not all products are suitably labeled. One effort to do this for Canada and the United States, funded by unrestricted grants from commercial entities, does link products to available evidence (see http://www.probioticchart.ca/ and http://usprobioticguide.com/).

The quality of probiotic products depends on the manufacturer concerned. Since most are not made to pharmaceutical standards, regulatory authorities may not oversee adherence to quality standards. The issues that are important specifically to probiotic quality include assurance of potency (maintenance of viability, typically indicated by colony-forming units, through the end of shelf-life), purity (manufacturing processes that sufficiently reduce any pathogens of concern), and identity (current nomenclature used to specify the genus, species, and subspecies, if applicable, and a strain designation for each strain in the product).

The dose needed for probiotics varies 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. For example, Bifidobacterium longum subsp. longum 35624 was effective in alleviating the symptoms of IBS at 100 million cfu/day, whereas the effective dose of other probiotic products is 300–450 billion cfu three times daily. 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. Manufacturers typically 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. Responsible manufacturers will indicate the dose expected at the use-by date (not at the time of manufacture). Spore-forming probiotic strains have an advantage of superior resistance to environmental stress during shelf-life. However, robust evidence of the efficacy of spore-formers lags behind that for non–spore-forming probiotics. 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. Purchasing products from reliable manufacturers is therefore essential.

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 intended by design for the generally healthy population, so use in persons with compromised immune function or serious underlying disease should be restricted to the strains and indications with proven safety and efficacy for these target patient populations, as described in section 4 below. Microbiological quality standards should meet the needs of at-risk patients, as reviewed by Sanders et al. [5]. Testing or use of newly isolated probiotics or known probiotics for new disease indications is only acceptable after scrutiny and approval by an independent ethics committee. Traditional LAB, 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 (in alphabetical order) for probiotics or prebiotics in gastroenterology are summarized below. It should be noted that the description provides a general overview of clinical efficacy. However, the effects of probiotics are strain-specific and dose-specific, and for prebiotics the effects are based on the particular formulation. For specific recommendations for different indications on the basis of levels of graded evidence, Tables 8 and 9 should be consulted. Meta-analyses are regarded as providing the highest level of evidence for evaluating clinical efficacy. However, applying meta-analysis to clinical trials with probiotics is fraught with problems due to the heterogeneity of trial designs, the heterogeneity of the probiotic interventions used, the heterogeneity of the populations studied, and the relatively small numbers included in each clinical trial. Such issues can plague meta-analyses conducted on any intervention, but the strain-specificity of effects needs to be carefully taken into account with meta-analyses on probiotics. Combining data on different probiotic strains without a rationale that similar underlying mechanisms of action are driving the effects observed should be avoided when using the results to make medical recommendations. While this section therefore deals with an overview of probiotic efficacy in clinical situations, Tables 8 and 9 detail individual probiotic preparations and clinical situations in which they have been found effective.

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 in animal models, there are limited data in humans showing any benefit of probiotics or prebiotics in 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.

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. A Cochrane meta-analysis based only on large trials with a low risk of bias [6] concluded that probiotics probably make little or no difference with diarrhea lasting 48 hours or longer. Early administration of probiotics may therefore be needed.

3.2.3  Prevention of antibiotic-associated diarrhea

• In the prevention of antibiotic-associated diarrhea, there is evidence of efficacy in adults or children who are receiving antibiotic therapy. Meta-analyses concluded that probiotics may provide a moderate effect for preventing antibiotic-associated diarrhea in children [7], adults [8], and elderly adults [9].

3.2.4  Prevention of C. difficile diarrhea

• A 2017 meta-analysis concluded with moderate certainty that probiotics are effective for preventing C. difficile–associated diarrhea in patients receiving antibiotics [10]. Probiotic use in patients who are not immunocompromised or severely debilitated appeared to be safe. The authors also cited the need for further research, but concluded that the data indicate that patients who are at high risk of developing C. difficile–associated diarrhea would benefit from being informed of the potential benefits and harms of probiotics.

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 concluded that probiotics may be beneficial in the prevention and possibly in the treatment of radiation-induced diarrhea [11].

3.3  Helicobacter pylori eradication

• The 2022 Maastricht VI/Florence Consensus Report on management of H. pylori infection concluded that certain probiotics have been shown to be effective in reducing gastrointestinal side effects caused by Helicobacter pylori eradication therapies and thus have a beneficial effect on the treatment. However, the quality of the evidence was weak, and the grade of recommendation was moderate [12]. There is no evidence to support the concept that a probiotic alone, without concomitant antibiotic therapy, would be effective. Instead, probiotics appear to increase the H. pylori eradication rate by reducing side effects related to eradication therapy, rather than through direct effects on H. pylori.

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. A 2017 Cochrane meta-analysis found that evidence from three studies on the benefits of probiotics for people with hepatic encephalopathy was of low quality [13]. Although no difference in the mortality rate was observed, the authors concluded that probiotics may improve recovery, quality of life, and plasma ammonia concentrations.

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 in studies that tested antibody responses to vaccines.

3.6  Inflammatory bowel disease (IBD)

3.6.1  Pouchitis

• There is evidence for the usefulness of a probiotic mix in preventing an initial attack of pouchitis and in preventing further relapse after the induction of remission with antibiotics. The probiotic mix is recommended for adults and children with pouchitis of mild activity, or as maintenance therapy for those in remission [14].

3.6.2  Ulcerative colitis

• Individual studies show that certain probiotics may be safe and as effective as conventional therapy in response and remission rates in mild to moderately active ulcerative colitis in both adult and pediatric populations. However, a 2020 Cochrane meta-analysis concluded that evidence for induction of remission in mild to moderate ulcerative colitis was of low certainty, and there was no evidence that probiotics were effective in more severe disease [15].

3.6.3  Crohn’s disease

• Studies of probiotics in Crohn’s disease have indicated that there is no evidence to suggest that they are beneficial for induction or 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 persons with functional abdominal pain. Strain-specific effects of certain probiotics on IBS symptoms are shown in Tables 8 and 9.

3.8  Colic

• L. reuteri DSM17938 and B. animalis ssp. lactis BB12 have been shown to reduce crying time in breastfed infants with colic (Table 9).

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 [16].

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. Special attention to adequate quality in the probiotic product is important for this vulnerable group of patients [17]. There was moderate certainty for reduction of the mortality rate and late-onset invasive infection, but no effect was observed on severe neurodevelopmental impairment [18].

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 assessment (HOMA), blood cholesterol, TNF-α, and liver function tests (ALT and 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 or synbiotics in critically ill adult patients in intensive-care units.

Although it is beyond 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 nongastrointestinal 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 led to a World Allergy Organization recommendation on probiotic use during pregnancy, breastfeeding, and weaning in families with a high risk of allergic disease [19]. 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.

 

We have comprehensively evaluated the evidence for gastrointestinal conditions. Table 7 lists the criteria used to establish the level of evidence.

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 on sale in the market may not have been tested. The column headed “Comments” includes the most recent (2020–2022) recommendations from major pediatric gastroenterology societies such as the European Society for Paediatric Gastroenterology, Hepatology and Nutrition and the American Gastroenterological Association.

For Tables 8 and 9, probiotics had to be described by genus, species, and strain designations in studies reporting the benefit. If the strain was not given, the strain designation was not included. Only positive studies (i.e., studies showing statistically significant results for its main outcome) were included. Negative (null) studies were not included (i.e., studies in which the results for the main outcome were not statistically significant). For each condition, a list of the probiotic strains or prebiotics found to have a beneficial effect is presented.

For clinical decisions, however, only evidence related to a specific probiotic strain and/or prebiotic is relevant. Each study should be considered within the context of the totality of the relevant evidence. The risk of bias in the included trials was not assessed.

The list may not be complete, as the publication of new studies is ongoing. Locally, other probiotics and/or prebiotics evaluated in randomized controlled trials (RCTs) may be available. The level of evidence may vary among the different indications. Doses shown are those used in the RCTs. 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 according to evidence-based medicine criteria.

 

 

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