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 Probiotics are live microorganisms intended to provide health benefits when consumed, generally by improving or restoring the gut flora. The introduction of a hypothesis similar to the modern concept, but not the term, is generally attributed to Nobel laureate Élie Metchnikoff, who postulated that yogurt-consuming Bulgarian peasants lived longer lives because of that custom. He suggested in 1907 that "the dependence of the intestinal microbes on the food makes it possible to adopt measures to modify the microbiota in our bodies and to replace the harmful microbes by useful microbes".

A growing probiotics market has led to higher requirements for scientific substantiation of putative benefits conferred by probiotic microorganisms. Although there are numerous claimed benefits marketed towards using consumer probiotic products, such as reducing gastrointestinal discomfort, improving immune health, relieving constipation, or avoiding the common cold, such claims are not supported by scientific evidence, and are prohibited as deceptive advertising in the United States by the Federal Trade Commission. However, some probiotics have been found to be useful in treating specific medical conditions, such as antibiotic-associated diarrhea in children and Clostridium difficile infection in adults.

Probiotics are considered generally safe to consume, but may cause bacteria-host interactions and unwanted side effects in rare cases.

 

Etymology

 

Some literature gives the word a full Greek etymology, but it appears to be a composite of the Latin preposition pro ('for') and the Greek adjective βιωτικός (biōtikos), 'fit for life, lively', the latter deriving from the noun βίος (bios, 'life'). The term contrasts etymologically with the term antibiotic.

 

Definition

 

An October 2001 report by the World Health Organization (WHO) defines probiotics as live microorganisms that, "when administered in adequate amounts, confer a health benefit on the host." Following this definition, a working group convened by the Food and Agricultural Organization (FAO)/WHO in May 2002 issued the Guidelines for the Evaluation of Probiotics in Food. A consensus definition of the term probiotics, based on available information and scientific evidence, was adopted after the aforementioned joint expert consultation between the FAO of the United Nations and the WHO. This effort was accompanied by local governmental and supra-governmental regulatory bodies' requirements to better characterize health claims substantiations.

That first global effort was further developed in 2010; two expert groups of academic scientists and industry representatives made recommendations for the evaluation and validation of probiotic health claims. The same principles emerged from those two groups as were expressed in the "Guidelines" of FAO/WHO in 2002. This definition, though widely adopted, is not acceptable to the European Food Safety Authority (EFSA) because it embeds a health claim that is not measurable.

 

A group of scientific experts assembled in London on October 23, 2013, to discuss the scope and appropriate use of the term probiotic. That meeting was motivated by developments in the field that followed the formation of the 2001 definition, and the panel's conclusions were published in June 2014.

 

Guidelines

 

First, probiotics must be alive when administered. One of the concerns throughout the scientific literature resides in the viability and reproducibility on a large scale of observed results for specific studies, as well as the viability and stability during use and storage, and finally the ability to survive in stomach acids and then in the intestinal ecosystem.

Secondly, probiotics must have undergone controlled evaluation to document health benefits in the target host. Only products that contain live organisms shown in reproducible human studies to confer a health benefit can actually claim to be probiotic. The correct definition of health benefit, backed with solid scientific evidence, is a strong element for the proper identification and assessment of the effect of a probiotic. This aspect represents a major challenge for scientific and industrial investigations because several difficulties arise, such as variability in the site for probiotic use (oral, vaginal, intestinal) and mode of application.

Thirdly, the probiotic candidate must be a taxonomically defined microbe or combination of microbes (genus, species, and strain level). It is commonly admitted that most effects of probiotics are strain-specific and cannot be extended to other probiotics of the same genus or species. This calls for a precise identification of the strain, i.e. genotypic and phenotypic characterization of the tested microorganism.

Fourthly, probiotics must be safe for their intended use. The 2002 FAO/WHO guidelines recommend that, though bacteria may be generally recognized as safe (GRAS), the safety of the potential probiotic should be assessed by the minimum required tests:

In Europe, the EFSA has adopted a premarket system for safety assessment of microbial species used in food and feed productions to set priorities for the need of risk assessment. The assessment is made for a selected group of microorganisms, which if favorable, leads to a “Qualified Presumption of Safety” status.

Fifthly and finally, probiotics must be supplied in adequate numbers, which may be defined as the number able to trigger the targeted effect on the host. It depends on strain specificity, process, and matrix, as well as the targeted effect. Most of the reported benefits demonstrated with the traditional probiotics have been observed after ingestion of a concentration around 107 to 108 probiotic cells per gram, with a serving size around 100 to 200 mg per day.

 

Availability

 

Live probiotic cultures are part of fermented dairy products, other fermented foods, and probiotic-fortified foods. Some fermented products contain lactic acid bacteria, including pickled vegetables, tempeh, miso, kefir, buttermilk or karnemelk, kimchi, pao cai, sauerkraut, and soy sauce.

 

Commercial probiotics

 

Labeling

 

The US National Yogurt Association gives a Live & Active Cultures Seal to refrigerated yogurt products that contain 100 million cultures per gram or frozen yogurt products containing 10 million cultures per gram at the time of manufacture. In 2002, the US Food and Drug Administration (FDA) and World Health Organization recommended that “the minimum viable numbers of each probiotic strain at the end of the shelf-life” be reported on labeling, but most companies that give a number report the viable cell count at the date of manufacture, a number probably much higher than existing at the moment of consumption. Because of variability in storage conditions and time before eating, it is difficult to tell exactly how much active culture remains at the time of consumption.

Due to these ambiguities, the European Commission placed a ban on putting the word "probiotic" on the packaging of products because such labeling misleads consumers to believe a health benefit is provided by the product when no scientific proof exists to demonstrate that health effect.

In the United States, the FDA and Federal Trade Commission have issued warning letters and imposed punishment on various manufacturers of probiotic products whose labels claim to treat a disease or condition.

 

Global consumption

 

In 2015, the global retail market value for probiotics was US$41 billion, including sales of probiotic supplements, fermented milk products, and yogurt, which alone accounted for 75% of total consumption. Innovation in probiotic products in 2015 was mainly from supplements, which produced US$4 billion and was projected to grow 37% globally by 2020. Consumption of yogurt products in China has increased by 20% per year since 2014.

 

Scientific reviews and regulatory actions

 

The European Food Safety Authority has rejected all petitions by commercial manufacturers for health claims on probiotic products in Europe due to insufficient research, and thus inconclusive proof of effectiveness. Occurring over many years, the scientific reviews established that a cause-and-effect relationship had not been sufficiently proven in the products submitted.

In the United States, where food product labeling requires language approval by the Food and Drug Administration, probiotic manufacturers have received warning letters for making disease or treatment claims. The Federal Trade Commission has taken punitive actions, including a US$21 million fine coordinated by 39 different state governments against a major probiotic manufacturer for deceptive advertising and exaggerated claims of health benefits for a yogurt and probiotic dairy drink.

 

History

 

Probiotics have received renewed attention in the 21st century from product manufacturers, research studies, and consumers. The history of probiotics can be traced to the first use of cheese and fermented products, that were well known to the Greeks and Romans who recommended their consumption. The fermentation of dairy foods represents one of the oldest techniques for food preservation.

Élie Metchnikoff first suggested the possibility of colonizing the gut with beneficial bacteria in the early 20th century.

The original modern hypothesis of the positive role played by certain bacteria was first introduced by Russian scientist and Nobel laureate Élie Metchnikoff, who in 1907 suggested that it would be possible to modify the gut microbiota and to replace harmful microbes with useful microbes. Metchnikoff, at that time a professor at the Pasteur Institute in Paris, proposed the hypothesis that the aging process results from the activity of putrefactive (proteolytic) microbes producing toxic substances in the large bowel. Proteolytic bacteria such as clostridia, which are part of the normal gut microbiota, produce toxic substances including phenols, indols, and ammonia from the digestion of proteins. According to Metchnikoff, these compounds were responsible for what he called intestinal autointoxication, which would cause the physical changes associated with old age.

It was at that time known that milk fermented with lactic-acid bacteria inhibits the growth of proteolytic bacteria because of the low pH produced by the fermentation of lactose. Metchnikoff had also observed that certain rural populations in Europe, for example in Bulgaria and the Russian steppes, who lived largely on milk fermented by lactic-acid bacteria were exceptionally long lived. Based on these observations, Metchnikoff proposed that consumption of fermented milk would "seed" the intestine with harmless lactic-acid bacteria and decrease the intestinal pH, and that this would suppress the growth of proteolytic bacteria. Metchnikoff himself introduced in his diet sour milk fermented with the bacteria he called "Bulgarian Bacillus" and believed his health benefited. Friends in Paris soon followed his example and physicians began prescribing the sour-milk diet for their patients.

 Bifidobacteria were first isolated from a breast-fed infant by Henry Tissier, who also worked at the Pasteur Institute. The isolated bacterium named Bacillus bifidus communis was later renamed to the genus Bifidobacterium. Tissier found that bifidobacteria are dominant in the gut microbiota of breast-fed babies and he observed clinical benefits from treating diarrhea in infants with bifidobacteria.

During an outbreak of shigellosis in 1917, German professor Alfred Nissle isolated a strain of Escherichia coli from the feces of a soldier who was not affected by the disease. Methods of treating infectious diseases were needed at that time when antibiotics were not yet available, and Nissle used the E. coli Nissle 1917 strain in acute gastrointestinal infectious salmonellosis and shigellosis.

In 1920, Rettger and Cheplin reported that Metchnikoff's "Bulgarian Bacillus", later called Lactobacillus delbrueckii subsp. bulgaricus, could not live in the human intestine. They conducted experiments involving rats and humans volunteers, feeding them with Lactobacillus acidophilus. They observed changes in composition of fecal microbiota, which they described as "transformation of the intestinal flora". Rettger further explored the possibilities of L. acidophilus, and reasoned that bacteria originating from the gut were more likely to produce the desired effect in this environment. In 1935 certain strains of L. acidophilus were found very active when implanted in the human digestive tract. Trials were carried out using this organism, and encouraging results were obtained, especially in the relief of chronic constipation.

Contrasting antibiotics, probiotics were defined as microbially derived factors that stimulate the growth of other microorganisms. In 1989 Roy Fuller suggested a definition of probiotics that has been widely used: "A live microbial feed supplement which beneficially affects the host animal by improving its intestinal microbial balance." Fuller's definition emphasizes the requirement of viability for probiotics and introduces the aspect of a beneficial effect on the host.

The term "probiotic" originally referred to microorganisms that have effects on other microorganisms. The conception of probiotics involved the notion that substances secreted by one microorganism stimulated the growth of another microorganism. The term was used again to describe tissue extracts that stimulated microbial growth. The term probiotics was taken up by Parker, who defined the concept as, "Organisms and substances that have a beneficial effect on the host animal by contributing to its intestinal microbial balance." Later, the definition was greatly improved by Fuller, whose explanation was very close to the definition used today. Fuller described probiotics as a "live microbial feed supplement which beneficially affects the host animal by improving its intestinal microbial balance." He stressed two important claims for probiotics: the viable nature of probiotics and the capacity to help with intestinal balance.

In the following decades, intestinal lactic acid bacterial species with alleged health beneficial properties were introduced as probiotics, including Lactobacillus rhamnosus, Lactobacillus casei, and Lactobacillus johnsonii.

 

Research

 

As food products or dietary supplements, probiotics are under preliminary research to evaluate if they provide any effect on health. In all cases proposed as health claims to the European Food Safety Authority, the scientific evidence remains insufficient to prove a cause-and-effect relationship between consumption of probiotic products and any health benefit. There is no scientific basis for extrapolating an effect from a tested strain to an untested strain. Improved health through gut flora modulation appears to be directly related to long-term dietary changes. According to the National Center for Complementary and Integrative Health, "Although some probiotics have shown promise in research studies, strong scientific evidence to support specific uses of probiotics for most health conditions is lacking."

Claims that some lactobacilli may contribute to weight gain in some humans remain controversial.

Allergies

Probiotics are ineffective in preventing allergies in children, with the possible exception of eczema.

Antibiotic-associated diarrhea

Antibiotics are a common treatment for children, with 11% to 40% of antibiotic-treated children developing diarrhea. Antibiotic-associated diarrhea (AAD) results from an imbalance in the colonic microbiota caused by antibiotic therapy. These microbial community alterations result in changes in carbohydrate metabolism, with decreased short-chain fatty acid absorption and osmotic diarrhea as a result. A 2015 Cochrane review concluded that a protective effect of some probiotics existed for AAD in children. In adults, some probiotics showed a beneficial role in reducing the occurrence of AAD.

Probiotic treatment might reduce the incidence and severity of AAD as indicated in several meta-analyses. For example, treatment with probiotic formulations including L. rhamnosus may reduce the risk of AAD, improve stool consistency during antibiotic therapy, and enhance the immune response after vaccination.

The potential efficacy of probiotics to treat AAD depends on the probiotic strains and dosage. One review recommended for children L. rhamnosus or Saccharomyces boulardii at 5 to 40 billion colony forming units/day, given the modest number need to treat and the likelihood that adverse events are very rare. The same review stated that probiotic use should be avoided in pediatric populations at risk for adverse events, such as severely debilitated or immune-compromised children.

Bacterial vaginosis

Probiotic treatment of bacterial vaginosis is the application or ingestion of bacterial species found in the healthy vagina to cure the infection of bacteria causing bacterial vaginosis. This treatment is based on the observation that 70% of healthy females have a group of bacteria in the genus Lactobacillus that dominate the population of organisms in the vagina. Currently, the success of such treatment has been mixed since the use of probiotics to restore healthy populations of Lactobacillus has not been standardized. Often, standard antibiotic treatment is used at the same time that probiotics are being tested. In addition, some groups of women respond to treatment based upon ethnicity, age, number of sexual partners, pregnancy, and the pathogens causing bacterial vaginosis. In 2013 researchers found that administration of hydrogen peroxide producing strains, such as L. acidophilus and L. rhamnosus, were able to normalize vaginal pH and rebalance the vaginal microbiota, preventing and alleviating bacterial vaginosis.

Blood pressure

The consumption of probiotics may modestly help to control high blood pressure.

Cholesterol

Preliminary human and animal studies have demonstrated the efficacy of some strains of lactic acid bacteria (LAB) for reducing serum cholesterol levels, presumably by breaking down bile in the gut, thus inhibiting its reabsorption (where it enters the blood as cholesterol).

A meta-analysis that included five double-blind trials examining the short-term (2–8 weeks) effects of a yogurt with probiotic strains on serum cholesterol levels found a minor change of 8.5 mg/dL (0.22 mmol/L) (4% decrease) in total cholesterol concentration, and a decrease of 7.7 mg/dL (0.2 mmol/L) (5% decrease) in serum LDL concentration.

Diarrhea

Some probiotics are suggested as a possible treatment for various forms of gastroenteritis, and a Cochrane Collaboration meta-analysis on the use of probiotics to treat acute infectious diarrhea based on a comprehensive review of medical literature through 2010 (35 relevant studies, >4500 participants) reported that use of any of the various tested probiotic formulations appeared to reduce the duration of diarrhea by a mean of 25 hours (vs. control groups, 95% confidence interval, 16–34 hours), also noting, however, that "the differences between the studies may be related to other unmeasured and unexplored environmental and host factors" and that further research was needed to confirm reported benefits.

Eczema

Probiotics are commonly given to breast-feeding mothers and their young children to prevent eczema, but some doubt exists over the strength of evidence supporting this effect.

Helicobacter pylori

Some strains of lactic acid bacteria may affect Helicobacter pylori infections (which may cause peptic ulcers) in adults when used in combination with standard medical treatments, but no standard in medical practice or regulatory approval exists for such treatment.

Immune function and infections

Some strains of lactic acid bacteria (LAB) may affect pathogens by means of competitive inhibition (i.e., by competing for growth) and some evidence suggests they may improve immune function by increasing the number of IgA-producing plasma cells and increasing or improving phagocytosis, as well as increasing the proportion of T lymphocytes and natural killer cells. LAB products might aid in the treatment of acute diarrhea, and possibly affect rotavirus infections in children and travelers' diarrhea in adults, but no products are approved for such indications. A large study demonstrated that probiotics may decrease dental caries in children. Two reviews reported reduction of the incidence of respiratory-tract infections in adults.

Inflammatory bowel disease

Probiotics are being studied for their potential to influence inflammatory bowel disease. There is some evidence to support their use in conjunction with standard medications in treating ulcerative colitis and no evidence of their efficacy in treating Crohn's disease.

A live formulation of lyophilized Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus paracasei, Lactobacillus bulgaricus, and Streptococcus thermophilus (VSL#3) has shown effectiveness in the small clinical trials, some of which were not randomized nor double-blinded, that had been done as of 2015; more high-quality clinical trials are needed to determine safety and effectiveness.

Irritable bowel syndrome

Probiotics are under study for their potential to affect irritable bowel syndrome, although uncertainty remains around which type of probiotic works best, and around the size of possible effect.

Lactose intolerance

Ingestion of certain active strains may help lactose-intolerant individuals tolerate more lactose than they would otherwise have tolerated.

Necrotizing enterocolitis

Several clinical studies provide evidence for the potential of probiotics to lower the risk of necrotizing enterocolitis and mortality in premature infants. One meta-analysis indicated that probiotics reduce these risks by more than 50% compared with controls.

Recurrent abdominal pain

A 2017 review based on moderate to low-quality evidences suggests that probiotics may be helpful in relieving pain in the short term in children with recurrent abdominal pain, but the proper strain and dosage are not known.

Urinary tract

There is no good evidence that probiotics are of benefit in the management of infection or inflammation of the urinary tract.

Formulations

However, supplements such as tablets, capsules, powders, and sachets containing the bacteria have been studied. However, probiotics taken orally can be destroyed by the acidic conditions of the stomach. As of 2010, a number of microencapsulation techniques are being developed to address this problem.

 

Side effects

 

The manipulation of the gut microbiota is complex and may cause bacteria-host interactions. Though probiotics are considered safe, some have concerns about their safety in certain cases. Some people, such as those with immunodeficiency, short bowel syndrome, central venous catheters, cardiac valve disease and premature infants, may be at higher risk for adverse events. In severely ill people with inflammatory bowel disease there is a risk of the passage of viable bacteria from the gastrointestinal tract to the internal organs (bacterial translocation) as a consequence of bacteremia, which can cause adverse health consequences. Rarely, consumption of probiotics by children with lowered immune system function or who are already critically ill may result in bacteremia or fungemia (i.e., bacteria or fungi in the blood), which can lead to sepsis, a potentially fatal disease.

It has been suggested that Lactobacillus contributes to obesity in humans, but no evidence of this relationship has been found.

 

Strains

 

There is only preliminary evidence for most probiotic health claims. Even for the most studied probiotic strains, few have been sufficiently developed in basic and clinical research to warrant approval for health claim status by a regulatory agency such as the Food and Drug Administration or European Food Safety Authority, and, as of 2010, no claims had been approved by those two agencies. Some experts are skeptical about the efficacy of different probiotic strains and believe that not all subjects benefit from probiotics.

 

Multiple probiotics

 

Preliminary research is evaluating the potential physiological effects of multiple probiotic strains, as opposed to a single strain. As the human gut may contain several hundred microbial species, one theory indicates that this diverse environment may benefit from consuming multiple probiotic strains, an effect that remains scientifically unconfirmed.