Probiotics are livemicroorganisms in that are intended to support or improve the health and wellbeing of a host organism.[1] They are commonly used in both humans and animals. Although the term refers to the microorganisms themselves, probiotics can be consumed through a range of products includingyogurt,cheese, certainfermented foods (such asnattō), as well ascapsules containing a single strain or a defined mixture of strains.
Probiotics are regarded asgenerally recognised as safe (GRAS) by theU.S. Food and Drug Administration (FDA), which supports their safety when used as intended, although this designation does not establish their effectiveness or specific health benefits.[2][3][4] Many claimed health benefits, such as treating eczema or curing vaginal infections, lack substantial scientific support.[5][6]
A growing probiotics market has led to the need for stricter requirements forscientific substantiation of putative benefits conferred by microorganisms claimed to be probiotic.[8] Although some evidence claimed benefits are marketed towards using probiotic, such as reducinggastrointestinal discomfort, improvingimmune health,[9] relievingconstipation, or avoiding thecommon cold, such claims are strain-specific and cannot be extrapolated to other strains.[8][10][11] As of 2019, numerous applications for approval ofhealth claims by European manufacturers of probioticdietary supplements have been rejected by theEuropean Food Safety Authority for insufficient evidence of beneficial mechanism or efficacy.[9][12]
An October 2001 report by theWorld Health Organization (WHO) defines probiotics as "live microorganisms which when administered in adequate amounts confer a health benefit on the host."[13][14] Following this definition, aworking group convened by theFood and Agriculture Organization (FAO)/WHO in May 2002 issued theGuidelines for the Evaluation of Probiotics in Food.[15] A consensus definition of the termprobiotics, based on available information and scientific evidence, was adopted after the aforementioned joint expert consultation between theFAO of theUnited Nations and the WHO. This effort was accompanied by local governmental and supra-governmental regulatory bodies' requirements to better characterize health claims substantiations.[citation needed]
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.[16][17] 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 theEuropean Food Safety Authority because it embeds a health claim that is not measurable.[8]
A group of scientific experts assembled in Canada in October 2013 to discuss the scope and appropriate use of the term "probiotic", adjusting the definition to be "live microorganisms that, when administered in adequate amounts, confer a health benefit on the host."[1]
Lactic acid bacteria (LAB), which are food fermenting bacteria, have the ability to prevent food spoilage and can improve the nutritive value of the foods they inhabit. Acid fermentation (as well as salting), remains one of the most practical methods of preservation of fresh vegetables, cereal gruels, and milk-cereal mixtures due to its low cost and energy requirements.[19]
Probiotics are measured incolony forming units (CFU), which indicates the number of viable microorganisms in a product. The effective dose depends on the intended use with typical amounts ranging from 1 - 10 billion CFU/dose.[3] It is important to note that products with higher CFU counts are not necessarily more effective than those with lower counts.[3][40]
The manipulation of the gut microbiota is complex and may cause bacteria-host interactions.[41] Though probiotics are considered safe, some have concerns about their safety in certain cases.[41][42] Some people, such as those withimmunodeficiency,short bowel syndrome,central venous catheters, andcardiac valve disease, and premature infants, may be at higher risk for adverse events.[4] In severely ill people withinflammatory bowel disease, a risk exists for the passage of viable bacteria from the gastrointestinal tract to the internal organs (bacterial translocation) as a consequence ofbacteremia, which can cause adverse health consequences.[41] Rarely, consumption of probiotics by children with lowered immune system function or who are already critically ill may result in bacteremia orfungemia (i.e., bacteria or fungi in the blood), which can lead tosepsis, a potentially fatal disease.[43]
Probiotic supplements typically contain between one and ten billion colony-forming units per dose.[44] A higher number of CFUs does not provide additional probiotic effects, but may have unintended consequences of causing digestive discomfort, such as bloating, gas, and diarrhea.[44]
Lactobacillus species have been suggested to contribute to obesity in humans, but no evidence of this relationship has been found.[45]
In 2015, the global retail market value for probiotics was US$41 billion, including sales of probioticsupplements, fermented milk products, and yogurt, which alone accounted for 75% of total consumption.[46] Innovation in probiotic products in 2015 was mainly from supplements, which produced US$4 billion and was projected to grow 37% globally by 2020.[46] Consumption of yogurt products in China has increased by 20% per year since 2014.[47]
As of 2019[update], theEuropean Food Safety Authority has rejected all petitions by commercial manufacturers for health claims on probiotic products in Europe due to insufficient evidence for acause-and-effect mechanism for benefit, thus inconclusive proof of effectiveness.[8][9][12] TheEuropean 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.[8][48][49][50]
For food labeling in Canada, the federal government requires product labels using the term "probiotic" to have a government-approved health claim about the live specific microorganism(s) contained in the food.[51]
In the United States, theFood and Drug Administration (FDA) andFederal Trade Commission (FTC) have issued warning letters and imposed punishment on various manufacturers of probiotic products whose labels claim to treat a disease or condition.[11][52][53]Food product labeling requires language approved by the FDA, so probiotic manufacturers have received warning letters for making disease or treatment claims.[11][53] The FTC 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 yogurt and a probiotic dairy drink.[52]
InVietnam, the Vietnam Food Administration (VFA) under theMinistry of Health, in collaboration with other relevant authorities, oversees and addresses violations related to probiotic products. This includes issuing warnings, imposing administrative penalties,[54] demanding product recalls[55][56] and coordinating with other agencies.[57][58]
TheNational Yogurt Association (NYA) of the United States gives a "Live & Active Cultures Seal" to refrigerated yogurt products that contain 100 million cells per gram, or frozen yogurt products that contain 10 million cells per gram at the time of manufacture.[59] In 2002, the FDA and WHO recommended that "the minimum viable numbers of each probiotic strain at the end of the shelf-life" be reported on labeling,[60] but most companies that give a number report the viable cell count at the date of manufacture, a number that could be much higher than that which exists at consumption.[61] Because of the variability in storage conditions and time before eating, exactly how many active culture cells remain at the time of consumption is difficult to determine. The survival of probiotics was strongly dependent on the storage temperature and remarkable viability loss occurred in room temperature compared to refrigerated storage.[62]
Probiotics have received renewed attention in the 21st century from product manufacturers, research studies, and consumers. The history of probiotics dates back to ancient times, with the consumption offermented foods being a common practice across variouscivilizations. Different types offermented milk products were invented in differentgenerations, such asKefir in 5000 BC andYeast usage in 5000 BC. Their history can be traced to the first use of cheese and fermented products, which were well-known to theGreeks andRomans who recommended their consumption.[63] Thefermentation of dairy foods represents one of the oldest techniques forfood preservation.[64]
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 byRussian scientist andNobel Prize laureateÉlie Metchnikoff, who in 1907 suggested that it would be possible to modify thegut microbiota and to replace harmful microbes with useful microbes.[65] Metchnikoff proposed that consumption offermented milk would "seed" theintestine with harmless lactic-acid bacteria and decrease the intestinal pH, and that this would suppress the growth of proteolytic bacteria.[66]
Bifidobacteria was first isolated from a breastfed infant by Henry Tissier, who also worked at thePasteur Institute. The isolated bacterium namedBacillus bifidus communis[67] was later renamed to the genusBifidobacterium.[68] Tissier found that bifidobacteria are dominant in the gut microbiota ofbreast-fed babies and he observed clinical benefits from treating infant diarrhea with bifidobacteria.
During an outbreak ofshigellosis in 1917, German professor Alfred Nissle isolated a strain ofEscherichia coli from the feces of a soldier who was not affected by the disease.[69] Methods of treating infectious diseases were needed at that time when antibiotics were not yet available, and Nissle used theE. coli Nissle 1917 strain in acute gastrointestinal infectioussalmonellosis andshigellosis.[70]
In 1920, Rettger and Cheplin reported that Metchnikoff's "Bulgarian Bacillus", later calledLactobacillus delbrueckiisubsp. bulgaricus, could not live in the human intestine.[71] They conducted experiments involving rats and humans volunteers, feeding them withLactobacillus acidophilus. They observed the disappearance of the pathogenic protistBalantidium coli as well as of other gas-producing bacteria.[72] Rettger further explored the possibilities ofL. acidophilus, and reasoned that bacteria originating from the gut were more likely to produce the desired effect in this environment. In 1935, certain strains ofL. acidophilus were found very active when implanted in the human digestive tract.[73]
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 have been widely used: "A live microbial feed supplement which beneficially affects the host animal by improving its intestinal microbial balance."[74] 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.[75] The concept of probiotics involved the notion that substances secreted by one microorganism stimulated the growth of another microorganism. The term was used again[76] to describe tissue extracts that stimulated microbial growth. The term probiotics was taken up by Parker,[77] 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 improved by Fuller,[74] whose explanation was similar to the Fuller description of 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.
Some literature gives the word a Greeketymology,[79][80] but it appears to be a composite of the Latin prepositionpro, meaning 'for', and the Greek adjective βιωτικός (biōtikos), meaning 'fit for life, lively',[81] the latter deriving from the noun βίος (bios), meaning 'life'.[82]
As food products or dietary supplements, probiotics are under preliminary research to evaluate if they provide any effect on health.[83][8][84] In all cases proposed as health claims to theEuropean Food Safety Authority, the scientific evidence remains insufficient to prove a cause-and-effect relationship between consumption of probiotic products and any health benefit.[8][85] There is no scientific basis for extrapolating an effect from a tested strain to an untested strain.[83][86][87] Improved health through gut flora modulation appears to be directly related to long-term dietary changes.[8][88] Claims that some lactobacilli may contribute toweight gain in some humans[89][90] remain controversial.[91]
There is inconsistency in the results of different groups of 3488 children as reported in a Cochrane review.[92] Also, it shows no significant difference regarding the adverse effects between probiotic and the other comparators.[92]
Only limited, low-quality evidence exists to indicate that probiotics are helpful for treating people withmilk allergy.[93] A 2015 review showed low-quality evidence that probiotics given directly to infants witheczema, or in infants whose mothers used probiotics during thelast trimester of pregnancy and breastfeeding, had lower risk of eczema.[94]
Antibiotics are a common treatment for children, with 11% to 40% of antibiotic-treated children developingdiarrhea.[96]Antibiotic-associated diarrhea (AAD) results from an imbalance in the colonic microbiota caused by antibiotic therapy.[96] These microbial community alterations result in changes incarbohydrate metabolism, with decreasedshort-chain fatty acid absorption and osmotic diarrhea as a result. A 2015Cochrane review concluded that a protective effect of some probiotics existed for AAD in children.[96] The known risks of using probiotics for treatingClostridioides difficile outweigh the uncertain benefits.[97]
Probiotic treatment might reduce the incidence and severity of AAD as indicated in severalmeta-analyses.[98][99][100] For example, treatment with probiotic formulations includingL. rhamnosus may reduce the risk of AAD, improve stool consistency during antibiotic therapy, and enhance the immune response after vaccination.[101]
The potential efficacy of probiotics to treat AAD depends on the probiotic strains and dosage.[102][103] One review recommended for childrenL. rhamnosus orSaccharomyces boulardii at 5 to 40 billion colony-forming units/day, given the modest number needed to treat and the likelihood that adverse events are very rare.[96] The same review stated that probiotic use should be avoided in pediatric populations at risk foradverse events, such as severely debilitated orimmune-compromised children.[citation needed]
Probiotic treatment of bacterial vaginosis is the application or ingestion ofbacterial species found in the healthy vagina to cure the infection of bacteria causingbacterial vaginosis. This treatment is based on the observation that 70% of healthy females have a group of bacteria in the genusLactobacillus that dominate the population of organisms in the vagina. Specific strains of lactobacilli inhibit the growth of bacteria causing BV by producing H2O2, lactic acid, and/or bacteriocins, and/or inhibit the adherence ofGardnerella vaginalis to the vaginal epithelium, which prevents the infection from occurring in the vagina.[104] Currently, the success of probiotic treatment has been mixed, since the use of probiotics to restore healthy populations ofLactobacillus 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.[105] In 2013, researchers found that administration ofhydrogen peroxide-producing strains, such asL. acidophilus andL. rhamnosus, were able to normalize vaginal pH and rebalance thevaginal microbiota, preventing and alleviating bacterial vaginosis.[106]
A 2002 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 little effect of 8.5 mg/dL (0.22 mmol/L) (4% decrease) intotal cholesterol concentration, and a decrease of 7.7 mg/dL (0.2 mmol/L) (5% decrease) in serumLDL concentration.[108]
A 2019 meta-analysis found low-quality evidence for probiotics having a small improvement indepression andanxiety.[109] A 2020 review found probiotics might improve depression, but more studies are needed.[110]
Some probiotics are suggested as a possible treatment for various forms ofgastroenteritis.[111] As a treatment for infectious diarrhea, probiotics are of no benefit to people who have the condition for more than two days, and there is no evidence they lessen the duration of diarrhea overall.[112]
Probiotics are commonly given to breastfeeding mothers and their young children to prevent eczema (dermatitis), but no good evidence shows efficacy for this purpose.[113] There is little evidence to support the use of probiotics to treatatopic dermatitis, and some risk ofadverse effects.[114] TheAmerican Academy of Dermatology stated: "The use of probiotics/prebiotics for the treatment of patients with established atopic dermatitis is not recommended due to inconsistent evidence".[115]
According to an umbrella review of meta-analyses of randomized controlled trials, probiotics supplementation reduces glucose homeostasis. This can be an effective therapy for lowering high blood sugar levels unless the body becomeshypoglycemic; caution and glucose monitoring are necessary to avoid this.[116]
Some strains of lactic acid bacteria (LAB) may affectHelicobacter pylori infections (which may causepeptic ulcers) in adults when used in combination with standard medical treatments, but no standard in medical practice or regulatory approval exists for such treatment.[117] The only peer-reviewed treatments forH. pylori to date all include various Antibiotic Regimens.[118]
Some strains of LAB may affectpathogens by means ofcompetitive inhibition (i.e., by competing for growth) and some evidence suggests they may improve immune function by increasing the number ofIgA-producing plasma cells and increasing or improvingphagocytosis, as well as increasing the proportion ofT lymphocytes and natural killer cells.[119][120] LAB products might aid in the treatment of acute diarrhea and possibly affectrotavirus infections in children and travelers' diarrhea in adults,[119][120] but no products are approved for such indications. There are weak evidence probiotics might lower the incidence of acute upper respiratory tract infections in adults, they were better than placebo or no treatment.[121]
Probiotics do not appear to change the risk of infection in older people.[122]
The use of oral probiotic supplements to modify the composition and behavior of the microbiome has been considered as a possible therapy for both induction and maintenance of remission in people with Crohn's disease and ulcerative colitis. A Cochrane review in 2020 did not find clear evidence of improved remission likelihood, nor lower adverse events, in people with Crohn's disease, following probiotic treatment.[123]
For ulcerative colitis, there is low-certainty evidence that probiotic supplements may increase the probability of clinical remission.[124] People receiving probiotics were 73% more likely to experience disease remission and over 2x as likely to report improvement in symptoms compared to those receiving a placebo, with no clear difference in minor or serious adverse effects.[124] Although there was no clear evidence of greater remission when probiotic supplements were compared with5‐aminosalicylic acid treatment as amonotherapy, the likelihood of remission was 22% higher if probiotics were used in combination with 5-aminosalicylic acid therapy.[124] Whereas in people who are already in remission, it is unclear whether probiotics help to prevent future relapse, either as a monotherapy orcombination therapy.[125]
Probiotics are under study for their potential to affectirritable bowel syndrome, although uncertainty remains around which type of probiotic works best, and around the size of possible effect.[126][127]
Several clinical studies provide evidence for the potential of probiotics to lower the risk ofnecrotizing enterocolitis and mortality in premature infants. One meta-analysis indicated that probiotics reduce these risks by more than 50% compared with controls but that further, large, high-quality trials were needed to inform policy and practice.[128]
A Cochrane systematic review found no good evidence that probiotics were of benefit in reducing the risk ofgestational diabetes, but good evidence that they increased the risk ofpre-eclampsia. For this reason, the use of probiotics in pregnancy was advised against.[129]
A 2017 review based on moderate to low-quality evidence 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.[130]
A clinical study investigating the impact of probiotics in relieving the signs and symptoms ofdry eye revealed promising results for the ophthalmic formulation ofLatilactobacillus sakei, while the oral probiotic demonstrated no discernible benefits.[131]
There is limited evidence indicating probiotics are of benefit in the management of infection or inflammation of theurinary tract.[132] One literature review foundLactobacillus probiotic supplements appeared to increase vaginal lactobacilli levels, thus reducing the incidence of vaginal infections in otherwise healthy adult women.[133]
Supplements such as tablets, capsules, powders, and sachets containing bacteria have been studied. However, probiotics taken orally can be destroyed by the acidic conditions of the stomach. As of 2010, a number ofmicroencapsulation techniques were being developed to address this problem.[134]
Preliminary research is evaluating the potentialphysiological effects of multiple probiotic strains, as opposed to a single strain.[135][136] As the human gut may contain tens of thousands of microbial species, one theory indicates that this diverse environment may benefit from consuming multiple probiotic strains, an effect that remains scientifically unconfirmed.[citation needed]
Only preliminary evidence exists for most probiotic health claims. Even for the most studied probioticstrains, few have been sufficiently developed in basic and clinical research to warrant approval forhealth claim status by a regulatory agency such as the FDA or EFSA, and as of 2010[update], no claims had been approved by those two agencies.[8] Some experts are skeptical about the efficacy of different probiotic strains and believe that not all subjects benefit from probiotics.[8][137]
Multiple studies have shown that there is a significant difference in the survival rate of Lactobacillus and Bifidobacterium under refrigerated (4 °C) and room temperature (25 °C) storage conditions. At room temperature (25±1 °C), the number of probiotics decreased by 5 to 6 logarithmic units (down to 1/100,000) after 90 days of storage. In contrast, no significant change in the number of probiotics was observed under refrigerated conditions (4 ± 1 °C).[138]
First, probiotics must be alive when administered.[74][139][140] One of the concerns throughout thescientific 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.[8][failed verification]
Second, probiotics must have undergone controlled evaluation to documenthealth benefits in the target host. Only products that contain live organisms shown in reproducible human studies to confer a health benefit may claim to be probiotic.[8][141][142] 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 is a 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.[74]
Third, 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.[139] This calls for precise identification of the strain, i.e.genotypic andphenotypic characterization of the tested microorganism.[16]
Fourth, 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 be assessed by theminimum required tests:[143]
Assessment of certain metabolic activities (e.g. D-lactate production, bile salt deconjugation)
Assessment of side effects in human studies
Determination of antibiotic resistance patterns
Epidemiological surveillance of adverse incidents in consumers (aftermarket)
If the strain under evaluation belongs to a species known to produce toxins in mammals, it must be tested for toxin production. One possible scheme for testing toxin production has been recommended by the EU Scientific Committee on Animal Nutrition.[144]
If the strain under evaluation belongs to a species with knownhemolytic potential, determination of hemolytic activity is required.
In Europe, EFSA adopted a premarket system for the safety assessment of microbial species used in food and feed productions to set priorities for the need for risk assessment. The assessment is made for certain microorganisms; if the result is favorable, it leads to "Qualified Presumption of Safety" status.[145]
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