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A bottle of Yakult, a probiotic drink containing Lactobacillus paracasei

Probiotics are live microorganisms in foods intended to improve or restore microbiota in the gut.[1][2] Probiotic products include yogurt, cheese, some fermented foods, such as sourdough bread and nattō, dietary supplements, and clinical capsules containing a specific probiotic strain.

Probiotics are considered generally safe to consume, but may cause bacteria–host interactions and unwanted side effects in some cases.[3][4][5][6] Many claimed health benefits, such as treating eczema or curing vaginal infections, lack substantial scientific support.[1][7]

The first discovered probiotic was a certain strain of bacillus in Bulgarian yoghurt, called Lactobacillus bulgaricus. The discovery was made in 1905 by Bulgarian physician and microbiologist Stamen Grigorov. The modern-day theory is generally attributed to Russian Nobel Prize laureate Élie Metchnikoff, who postulated around 1907 that yoghurt-consuming Bulgarian peasants lived longer.[8]

A growing probiotics market has led to the need for stricter requirements for scientific substantiation of putative benefits conferred by microorganisms claimed to be probiotic.[9] Although some evidence claimed benefits are marketed towards using probiotic, such as reducing gastrointestinal discomfort, improving immune health,[10] relieving constipation, or avoiding the common cold, such claims are strain-specific and cannot be extrapolated to other strains.[9][11][12] As of 2019, numerous applications for approval of health claims by European manufacturers of probiotic dietary supplements have been rejected by the European Food Safety Authority for insufficient evidence of beneficial mechanism or efficacy.[10][13]

Definition

[edit]

An October 2001 report by the World Health Organization (WHO) defines probiotics as "live microorganisms which when administered in adequate amounts confer a health benefit on the host."[14][15] Following this definition, a working group convened by the Food and Agriculture Organization (FAO)/WHO in May 2002 issued the Guidelines for the Evaluation of Probiotics in Food.[16] 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.[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.[17][18] 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 because it embeds a health claim that is not measurable.[9]

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."[19]

In food

[edit]

Live probiotic cultures are part of fermented dairy products, other fermented foods, and probiotic-fortified foods.[20]

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.[21]

Fermented products that contain lactic acid bacteria include vegetables such as pickled vegetables,[22] kimchi,[22][23] pao cai,[24] and sauerkraut;[25] sourdough bread or bread-like products made without wheat or rye flour, amino acid/peptide meat-flavored sauces and pastes produced by fermentation of cereals and legumes; fermented cereal-fish-shrimp mixtures and fermented meats;[21] soy products such as tempeh,[26] miso,[27] and soy sauce;[28] dairy products such as yogurt, kefir,[29] buttermilk;[30] and non-dairy products such as bee pollen.[31]

More precisely, sauerkraut contains the bacteria Leuconostoc mesenteroides, Lactobacillus plantarum, Pediococcus pentosaceus, Lactobacillus brevis, Leuconostoc citreum, Leuconostoc argentinum, Lactobacillus paraplantarum, Lactobacillus coryniformis, and Weissella spp.[32] Kimchi contains the bacteria Leuconostoc spp., Weissella spp., and Lactobacillus spp. Pao cai contains L. pentosus, L. plantarum , Leuconostoc mesenteroides , L. brevis, L. lactis, and L. fermentum. A list of many other bacteria found in several Asian fermented fruits and vegetables also is available.[33][34] Kefir contains Lactobacillus acidophilus, Bifidobacterium bifidum, Streptococcus thermophilus, Lactobacillus delbrueckii subsp. bulgaricus, Lactobacillus helveticus, Lactobacillus kefiranofaciens, Lactococcus lactis, and Leuconostoc species.[35][36] Buttermilk contains either Lactococcus lactis or L. bulgaricus. Other acidic bacteria, said to be probiotic,[37][38] can be found in kombucha, including Gluconacetobacter xylinus,[39][40] Zygosaccharomyces sp., Acetobacter pasteurianus, Acetobacter aceti, and Gluconobacter oxydans.[41]

Dosage

[edit]

A high count of colony forming units in probiotic products may not correspond to providing efficacy in clinical conditions; rather, potential efficacy is unique to the microbial strain and to the disease.[3]

Side effects

[edit]

The manipulation of the gut microbiota is complex and may cause bacteria-host interactions.[6] Though probiotics are considered safe, some have concerns about their safety in certain cases.[6][42] Some people, such as those with immunodeficiency, short bowel syndrome, central venous catheters, and cardiac valve disease, and premature infants, may be at higher risk for adverse events.[4] In severely ill people with inflammatory bowel disease, a risk exists for 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.[6] 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.[5]

Probiotic supplements typically contain between one and ten billion colony-forming units per dose.[43] 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.[43][44]

Lactobacillus species have been suggested to contribute to obesity in humans, but no evidence of this relationship has been found.[45]

Consumption

[edit]

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.[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]

Regulation

[edit]

As of 2019, the European Food Safety Authority has rejected all petitions by commercial manufacturers for health claims on probiotic products in Europe due to insufficient evidence for a cause-and-effect mechanism for benefit, thus inconclusive proof of effectiveness.[9][10][13] 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.[9][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, the Food and Drug Administration (FDA) and Federal 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.[12][52][53] Food product labeling requires language approved by the FDA, so probiotic manufacturers have received warning letters for making disease or treatment claims.[12][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]

In Vietnam, the Vietnam Food Administration (VFA) under the Ministry 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]

Yogurt labeling

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The National 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]

History

[edit]

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 of fermented foods being a common practice across various civilizations. Different types of fermented milk products were invented in different generations, such as Kefir in 5000 BC and Yeast usage in 5000 BC. Their history can be traced to the first use of cheese and fermented products, which were well-known to the Greeks and Romans who recommended their consumption.[63] The fermentation of dairy foods represents one of the oldest techniques for food 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 by Russian scientist and Nobel Prize 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.[65] 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.[66]

Bifidobacteria was first isolated from a breastfed infant by Henry Tissier, who also worked at the Pasteur Institute. The isolated bacterium named Bacillus bifidus communis[67] was later renamed to the genus Bifidobacterium.[68] Tissier found that bifidobacteria are dominant in the gut microbiota of breast-fed babies and he observed clinical benefits from treating infant diarrhea 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.[69] 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.[70]

In 1920, Rettger and Cheplin reported that Metchnikoff's "Bulgarian Bacillus", later called Lactobacillus delbrueckii subsp. bulgaricus, could not live in the human intestine.[71] They conducted experiments involving rats and humans volunteers, feeding them with Lactobacillus acidophilus. They observed the disappearance of the pathogenic protist Balantidium coli as well as of other gas-producing bacteria.[72] 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.[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.

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.[78]

Etymology

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Some literature gives the word a Greek etymology,[79][80] but it appears to be a composite of the Latin preposition pro, 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]

Research

[edit]

As food products or dietary supplements, probiotics are under preliminary research to evaluate if they provide any effect on health.[2][9][83] 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.[9][84] There is no scientific basis for extrapolating an effect from a tested strain to an untested strain.[2][85][86] Improved health through gut flora modulation appears to be directly related to long-term dietary changes.[9][87] Claims that some lactobacilli may contribute to weight gain in some humans[88][89] remain controversial.[90]

Acute otitis media

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There is inconsistency in the results of different groups of 3488 children as reported in a Cochrane review.[91] Also, it shows no significant difference regarding the adverse effects between probiotic and the other comparators.[91]

Allergies

[edit]

Only limited, low-quality evidence exists to indicate that probiotics are helpful for treating people with milk allergy.[92] A 2015 review showed low-quality evidence that probiotics given directly to infants with eczema, or in infants whose mothers used probiotics during the last trimester of pregnancy and breastfeeding, had lower risk of eczema.[93]

Asthma

[edit]

It is unclear whether probiotic supplementation helps with childhood asthma, as the quality of research evidence is low.[94]

Antibiotic-associated diarrhea

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Antibiotics are a common treatment for children, with 11% to 40% of antibiotic-treated children developing diarrhea.[95] Antibiotic-associated diarrhea (AAD) results from an imbalance in the colonic microbiota caused by antibiotic therapy.[95] 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.[95] The known risks of using probiotics for treating Clostridioides difficile outweigh the uncertain benefits.[96]

Probiotic treatment might reduce the incidence and severity of AAD as indicated in several meta-analyses.[97][98][99] 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.[100]

The potential efficacy of probiotics to treat AAD depends on the probiotic strains and dosage.[101][102] One review recommended for children L. rhamnosus or Saccharomyces 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.[95] 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.[citation needed]

Bacterial vaginosis

[edit]

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. Specific strains of lactobacilli inhibit the growth of bacteria causing BV by producing H2O2, lactic acid, and/or bacteriocins, and/or inhibit the adherence of Gardnerella vaginalis to the vaginal epithelium, which prevents the infection from occurring in the vagina.[103] Currently, the success of probiotic 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.[104] 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.[105]

Blood pressure

[edit]

As of 2017, only limited evidence indicated any direct link between high blood pressure and gut microbiota.[106]

Cholesterol

[edit]

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) in total cholesterol concentration, and a decrease of 7.7 mg/dL (0.2 mmol/L) (5% decrease) in serum LDL concentration.[107]

Depression and anxiety

[edit]

A 2019 meta-analysis found low-quality evidence for probiotics having a small improvement in depression and anxiety.[108] A 2020 review found probiotics might improve depression, but more studies are needed.[109]

Diarrhea

[edit]

Some probiotics are suggested as a possible treatment for various forms of gastroenteritis.[110] 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.[111]

Dermatitis

[edit]

Probiotics are commonly given to breastfeeding mothers and their young children to prevent eczema (dermatitis), but no good evidence shows efficacy for this purpose.[112] There is little evidence to support the use of probiotics to treat atopic dermatitis, and some risk of adverse effects.[113] The American 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".[114]

Glycemic control

[edit]

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 becomes hypoglycemic; caution and glucose monitoring are necessary to avoid this.[115]

Helicobacter pylori

[edit]

Some strains of lactic acid bacteria (LAB) 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.[116] The only peer-reviewed treatments for H. pylori to date all include various Antibiotic Regimens.[117]

Immune function and infections

[edit]

Some strains of 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.[118][119] LAB products might aid in the treatment of acute diarrhea and possibly affect rotavirus infections in children and travelers' diarrhea in adults,[118][119] 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.[120]

Probiotics do not appear to change the risk of infection in older people.[121]

Inflammatory bowel disease

[edit]

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.[122]

For ulcerative colitis, there is low-certainty evidence that probiotic supplements may increase the probability of clinical remission.[123] 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.[123] Although there was no clear evidence of greater remission when probiotic supplements were compared with 5‐aminosalicylic acid treatment as a monotherapy, the likelihood of remission was 22% higher if probiotics were used in combination with 5-aminosalicylic acid therapy.[123] Whereas in people who are already in remission, it is unclear whether probiotics help to prevent future relapse, either as a monotherapy or combination therapy.[124]

Irritable bowel syndrome

[edit]

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.[125][126]

Necrotizing enterocolitis

[edit]

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 but that further, large, high-quality trials were needed to inform policy and practice.[127]

Pregnancy

[edit]

A Cochrane systematic review found no good evidence that probiotics were of benefit in reducing the risk of gestational diabetes, but good evidence that they increased the risk of pre-eclampsia. For this reason, the use of probiotics in pregnancy was advised against.[128]

Recurrent abdominal pain

[edit]

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.[129]

Dry eye

[edit]

A clinical study investigating the impact of probiotics in relieving the signs and symptoms of dry eye revealed promising results for the ophthalmic formulation of Latilactobacillus sakei, while the oral probiotic demonstrated no discernible benefits.[130]

Urinary tract

[edit]

There is limited evidence indicating probiotics are of benefit in the management of infection or inflammation of the urinary tract.[131] One literature review found Lactobacillus probiotic supplements appeared to increase vaginal lactobacilli levels, thus reducing the incidence of vaginal infections in otherwise healthy adult women.[132]

General research

[edit]

Formulations

[edit]

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 of microencapsulation techniques were being developed to address this problem.[133]

Multiple probiotics

[edit]

Preliminary research is evaluating the potential physiological effects of multiple probiotic strains, as opposed to a single strain.[134][135] 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]

Strains

[edit]

Only preliminary evidence exists 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 FDA or EFSA, and as of 2010, no claims had been approved by those two agencies.[9] Some experts are skeptical about the efficacy of different probiotic strains and believe that not all subjects benefit from probiotics.[9][136]

Storage temperature

[edit]

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).[137]

Scientific guidelines for testing

[edit]

First, probiotics must be alive when administered.[74][138][139] 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.[9][failed verification]

Second, 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 may claim to be probiotic.[9][140][141] 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.[138] This calls for precise identification of the strain, i.e. genotypic and phenotypic characterization of the tested microorganism.[17]

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 the minimum required tests:[142]

  • 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.[143]
  • If the strain under evaluation belongs to a species with known hemolytic 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.[144]

See also

[edit]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Probiotic

View on Grokipedia
from Grokipedia
Probiotics are live microorganisms, primarily and yeasts, that, when administered in adequate amounts, confer a health benefit on the host. This definition, established by the and in , emphasizes their role in modulating the to support physiological functions. The concept of probiotics traces its origins to the early , when Russian Nobel laureate Élie Metchnikoff proposed that consuming fermented milk containing could promote longevity by altering gut , based on observations of long-lived populations in regions with high consumption. The term "probiotic," meaning "for life," was coined in by microbiologists Vernon Lilly and Rosalie Stillwell to describe substances produced by microorganisms that stimulate microbial growth. Over the decades, research has evolved from empirical observations to clinical trials demonstrating strain-specific effects, with probiotics now recognized as a key component of . Common probiotic strains belong to genera such as (e.g., L. acidophilus, L. rhamnosus GG), (e.g., B. bifidum, B. longum), and the yeast . These are naturally found in fermented foods like , , , , and , as well as in dietary supplements available in capsules, powders, or liquids. Strain selection is critical, as benefits are often specific to individual isolates rather than the broader species. Probiotics exert health benefits primarily through gut microbiota modulation, including inhibition of pathogens, enhancement of the intestinal barrier, and regulation. Evidence supports their use in preventing and treating antibiotic-associated diarrhea, acute infectious diarrhea, and symptoms, with some strains also showing potential in reducing levels and supporting immune responses. However, benefits vary by strain, dosage, and individual health status, and not all probiotics are effective for every condition. In the United States, probiotics are regulated as under the Dietary Supplement Health and Education Act of 1994, meaning they do not require pre-market approval by the unless making disease treatment claims, which would classify them as drugs. for healthy individuals, probiotics carry low risk of adverse effects, though rare infections have been reported in immunocompromised patients or premature infants. Consumers should select products with verified live cultures and consult healthcare providers for targeted use.

Definition and Terminology

Definition

Probiotics are defined as live microorganisms which, when administered in adequate amounts, confer a benefit on the host. This definition was established by a joint expert consultation of the of the (FAO) and the (WHO) in 2001, specifically in the context of evaluating properties of probiotics in fermented milks. This definition was reaffirmed with a slight grammatical revision by the International Scientific Association for Probiotics and Prebiotics (ISAPP) in 2014. Key criteria for qualifying microorganisms as probiotics include their viability at the time of consumption, the ability to reach sufficient numbers in the —typically on the order of 10^9 to 10^10 colony-forming units (CFU) per serving—and demonstration of strain-specific health benefits through . Viability ensures that the microorganisms remain active throughout the product's and upon , while the CFU threshold supports effective or modulation of the host's . Benefits are inherently strain-specific, meaning that effects observed with one strain of a cannot be extrapolated to others without targeted validation. Probiotics are distinct from prebiotics, which are non-viable substrates—such as selectively fermented fibers—that are utilized by host microorganisms to confer health benefits, and from synbiotics, which are combinations of probiotics and prebiotics designed for synergistic effects, though synbiotics represent an emerging category outside the core probiotic definition. Common probiotic strains include various species of and .

Etymology

The term "probiotic" derives from the Greek prefix pro- meaning "for" or "in favor of," combined with bios, meaning "life," to signify something "for life." This etymological root emphasizes concepts of vitality and support for living organisms, contrasting with "antibiotic," which means "against life." The word was first coined in 1953 by German scientist Werner Kollath, who introduced "Probiotika" (in German) to describe non-antibiotic organic and inorganic supplements intended to restore and revitalize health in weakened individuals, positioning it as the opposite of antibiotics. In 1965, researchers Daniel M. Lilly and Rosalie H. Stillwell repurposed the term in a microbiological context, defining probiotics as "growth-promoting factors produced by microorganisms" that stimulate the growth of other microbes. By 1974, expanded the concept further, redefining probiotics as "organisms and substances which contribute to intestinal microbial balance," thereby linking it more explicitly to host and microbial in animals. This evolution culminated in 1989 when Roy Fuller refined the term to emphasize live entities, describing probiotics as "a live microbial feed supplement which beneficially affects the host animal by improving its intestinal microbial balance," marking a decisive shift from inanimate substances to viable microorganisms.

History

Early Concepts

The use of fermented milk products for digestive health dates back to ancient civilizations, where fermentation served both preservation and therapeutic purposes. In ancient Egypt, tomb murals from around 2000 BCE depict the production of fermented dairy, such as yogurt-like zabady, which was consumed to aid digestion by reducing lactose content and inhibiting spoilage microbes. Similarly, the Greeks and Romans employed fermented milk to treat intestinal disorders; Roman naturalist Pliny the Elder (23–79 CE) specifically recommended it for gastrointestinal ailments, attributing benefits to its souring process. In the , Louis Pasteur's , developed through his studies on fermentation in the 1850s–1880s, revolutionized by demonstrating that microbes drive both harmful infections and beneficial processes like production in milk, laying the conceptual groundwork for recognizing some as allies rather than universal pathogens. This shifted perspectives from viewing all microbes as deleterious to appreciating their diverse roles in health. Early 20th-century scientific inquiry built on these foundations, with Élie Metchnikoff's 1908 hypothesis proposing that , particularly species in , could extend human lifespan by suppressing harmful gut and promoting intestinal harmony; he advocated daily consumption of based on observations of long-lived Bulgarian peasants. Concurrently, in 1900, pediatrician Henry Tissier isolated Y-shaped bacteria (later classified as ) from the feces of healthy breastfed infants at the , noting their absence in children with and suggesting their administration could restore gut balance by outcompeting pathogens. Initial experiments in the early 1900s applied these ideas clinically, with Tissier pioneering the use of "bifidus milk"—fermented milk enriched with —to treat gastrointestinal disturbances in infants and children, reporting reduced incidence through microbial replacement in the gut. Metchnikoff's collaborators similarly trialed fermented milk for adult digestive and renal issues, observing improved intestinal function.

Modern Advancements

The term "probiotic" was first introduced in 1953 by German scientist Werner Kollath, who used it to describe certain organic and inorganic dietary factors capable of promoting health and restoring balance in the intestinal flora. This marked an early conceptual shift toward viewing beneficial microbes as therapeutic agents, building on prior observations of fermented foods but formalizing the idea in . During the and , probiotics gained traction through international expert consultations and commercial expansion. The (FAO) and (WHO) convened panels that culminated in the 2001 definition of probiotics as "live microorganisms which when administered in adequate amounts confer a health benefit on the host," establishing a global standard for identification and evaluation. Concurrently, products like , originally developed in 1935 with the casei Shirota strain, saw significant international growth, entering markets such as the in 1990 and expanding production facilities worldwide, which popularized probiotic beverages among consumers. In the 2000s, advancements in revolutionized probiotic research, with the first complete genome sequences of key strains published, such as Lactobacillus plantarum WCFS1 in 2001 and Lactobacillus acidophilus NCFM in 2005, enabling detailed analysis of their genetic mechanisms and safety profiles. Regulatory frameworks also evolved, notably with the European Union's Regulation (EC) No 1924/2006, which imposed stringent requirements for substantiating health claims on probiotic products, limiting approvals to those backed by robust clinical evidence and influencing global standards. From the 2010s to 2025, the field progressed toward next-generation probiotics (NGPs), defined as well-characterized, non-traditional microbial strains with targeted therapeutic potential, exemplified by , which has shown promise in modulating gut barrier function and metabolic health in preclinical and early clinical studies. Synbiotic formulations, combining probiotics with prebiotics to enhance microbial survival and efficacy, became increasingly prevalent in product development. The global probiotics market expanded rapidly, reaching an estimated $86 billion by 2025, driven by consumer demand for gut health solutions and innovations in delivery formats. In 2024 and 2025, personalized probiotics emerged as a key , leveraging advances in sequencing and analysis to tailor strains to individual gut profiles, with early applications in managing inflammatory conditions through precision modulation of microbial communities. This approach integrates multi-omics data to predict responses, marking a shift from one-size-fits-all supplements to bespoke therapies.

Types of Probiotics

Bacterial Strains

Bacterial strains constitute the majority of probiotics, with and genera being the most prevalent due to their historical use and demonstrated safety in humans. These strains are typically Gram-positive, lactic acid-producing selected for their ability to survive gastrointestinal transit and confer health benefits when administered in adequate amounts. The genus includes several well-characterized species used in probiotics, valued for their acid tolerance and antimicrobial properties. , for instance, thrives in low-pH environments like the stomach, enabling survival rates of up to 50% after simulated gastric exposure, and produces such as acidophilin that inhibit like . Similarly, Lactobacillus casei exhibits robust acid resistance and contributes to modulation through production. A prominent example is Lactobacillus rhamnosus GG (ATCC 53103), isolated from the intestinal tract of a healthy in by Sherwood Gorbach and Barry Goldin, which has been extensively studied for its adhesion to intestinal cells and production of that support mucosal barrier function. Bifidobacterium species are anaerobic, Gram-positive rods that predominate in the of breastfed , where they can comprise up to 90% of the fecal bacteria. ferments human milk oligosaccharides and prebiotics like galactooligosaccharides, producing that lower intestinal pH and inhibit pathogens. shares these fermentative capabilities, efficiently utilizing prebiotics such as and fructooligosaccharides to promote bifidogenic growth in the colon, and is particularly abundant in infant microbiomes due to its to early-life carbohydrates. Other bacterial genera include , a thermophilic bacterium commonly paired with Lactobacillus bulgaricus in fermentation, where it enhances breakdown and exhibits probiotic traits like tolerance. , a spore-forming Gram-positive bacterium, provides exceptional stability in probiotic formulations, as its endospores resist heat, acidity, and , maintaining viability through manufacturing and storage for up to two years at . Spore-forming strains such as B. coagulans and B. clausii are frequently discussed in probiotic contexts due to their unique sporulation, which confers superior resilience to processing, heat, and compared to non-spore-forming lactobacilli. B. coagulans forms -producing spores that germinate in the intestine, while B. clausii exhibits immunomodulatory effects and oxygen consumption in the gut, aiding in flora balance. These gram-positive rods survive manufacturing stresses better, enabling longer in formulations. Probiotic efficacy is inherently strain-specific, meaning benefits are linked to precise genetic and phenotypic profiles rather than the species alone; for example, Lactobacillus reuteri DSM 17938 has been shown to reduce crying time in breastfed infants with by an average of 50 minutes per day after three weeks of supplementation. Research has demonstrated applications for strains like , particularly the BNR17 variant, which has shown reductions in body weight and visceral fat in adults through mechanisms involving modulation and fat absorption inhibition.

Non-Bacterial Strains

Non-bacterial probiotics primarily encompass yeast and fungal strains, which offer distinct advantages over bacterial counterparts due to their resilience in harsh environmental conditions. , a of , is the most well-established yeast probiotic, first isolated in the 1920s from the peels of and fruits by French scientist Henri Boulard during studies on traditional remedies for . This heat-stable strain survives temperatures up to 50°C and maintains viability through and , making it suitable for oral administration in treating gastrointestinal disturbances. Other yeasts, such as Kluyveromyces marxianus, have gained recognition for their probiotic potential, particularly in fermented dairy products like certain cheeses where they contribute to flavor development and exhibit properties. Isolated from sources including artisanal sourdoughs and traditional fermented foods, K. marxianus demonstrates thermotolerance, rapid growth, and the ability to utilize diverse sugars, enhancing its survival in the gut and potential benefits for lactose-intolerant individuals. These non-Saccharomyces yeasts often produce extracellular enzymes that support modulation, distinguishing them from more fragile bacterial strains like lactobacilli. Emerging research as of 2025 highlights engineered fungal probiotics for enhanced targeted delivery, such as genetically modified designed to bind intestinal proteins, improving localization in the gut for precise therapeutic release. These innovations underscore the growing role of resilient non-bacterial strains in overcoming limitations of traditional probiotics.

Formulations and Production

Probiotic production typically involves the of microorganisms in nutrient-rich media under controlled conditions, followed by harvesting via or , and subsequent formulation to ensure viability.

Delivery Systems

Probiotics are formulated in various delivery systems to ensure their viability and effective administration, with common formats including capsules, powders, and liquids. Capsules and powders, often produced via freeze-drying, encapsulate dried bacterial cells in moisture-resistant packaging to maintain stability under ambient conditions, targeting doses of 10^9 colony-forming units (CFU) per serving as recommended by regulatory guidelines in regions like and . Liquids, such as those in beverages or suspensions, provide an alternative for easier consumption but typically require refrigeration to preserve bacterial integrity, as higher can accelerate viability loss. Microencapsulation represents a key strategy to protect probiotics from gastrointestinal stressors, particularly stomach acid. Materials like alginate form insoluble hydrogels in acidic environments ( < 4), shielding encased bacteria during gastric passage, while chitosan coatings add an additional layer of protection by stabilizing the microcapsules against low and enzymatic degradation, resulting in up to 1-2 log higher survival rates in simulated digestion compared to free cells. Innovations from 2024-2025 have advanced targeted delivery, including nanoencapsulation techniques that achieve over 95% efficiency and enhance gastric survival by 1.4 log CFU/mL for strains like Lactiplantibacillus plantarum. Double emulsions using biopolymers enable pH-responsive release in the intestines, improving viability under gastrointestinal conditions compared to free cells. Aerosol delivery via nebulizers or dry powder inhalers is also emerging for respiratory applications, allowing direct lung deposition of probiotics like Lacticaseibacillus rhamnosus GG to modulate airway microbiota, with particle sizes of 4–5.5 μm achieving fine-particle fractions up to 20.5%, suitable for lung delivery. Synbiotics integrate probiotics with prebiotics like to boost survival, as inulin serves as a fermentable substrate that lowers colonic pH through short-chain fatty acid production, promoting bacterial implantation and growth while overcoming transit-related viability challenges. Overall, these systems prioritize maintaining probiotic viability above 10^6 CFU/g at the end of shelf life, a threshold established by international standards to guarantee therapeutic benefits upon consumption.

Stability and Encapsulation

Probiotics exhibit high sensitivity to environmental stressors, including heat, oxygen, and pH fluctuations, which compromise their viability during manufacturing, storage, and passage through the gastrointestinal tract. Non-encapsulated strains can lose 3–4 log CFU/g under these conditions, with heat from processes like spray drying causing rapid cell membrane damage and oxygen exposure leading to oxidative stress that reduces metabolic activity. Acidic pH in the stomach further exacerbates losses, often resulting in 1–2 log CFU reductions during simulated gastric transit due to proton influx and enzyme degradation. Optimal storage conditions emphasize refrigeration at 4°C to preserve cell integrity, as this temperature minimizes metabolic slowdown and extends shelf life, with strains like Lactobacillus plantarum maintaining 9.15 log CFU/g viability for up to 90 days. Room temperature storage (around 20–25°C), however, accelerates viability decline, potentially halving counts within weeks due to increased enzymatic activity and desiccation. Spore-forming probiotics, such as Bacillus subtilis, offer greater resilience, retaining stability at ambient temperatures through their dormant endospores, which resist dehydration and thermal stress. Encapsulation techniques address these challenges by creating protective barriers around probiotic cells. Spray drying, which involves atomizing a probiotic suspension into hot air streams (inlet temperatures of 110–160°C), achieves high survival rates when combined with cryoprotectants like or , forming microcapsules that shield against heat and oxygen. Complex coacervation, utilizing electrostatic interactions between polymers such as whey protein and gum arabic, encapsulates cells with improved viability, enhancing acid tolerance during gastric exposure. Recent innovations in nanocellulose-based encapsulation have demonstrated improved survival rates in simulated gastrointestinal conditions by forming nanofibril networks that control release and prevent aggregation. As of 2025, advancements include hydrogel matrices incorporating probiotics for targeted applications like wound healing, where Lactobacillus paracasei-embedded gels maintain microbial stability while promoting angiogenesis and reducing inflammation in rat models. Viability in these formulations is routinely assessed via plate count methods, which involve serial dilution and incubation on selective agar to enumerate colony-forming units (CFU), adhering to standards like ISO 29981 for accurate quantification of culturable cells. In multi-strain formulations, interspecies interactions—such as quorum sensing synergies or antagonistic bacteriocin production—can influence overall stability, potentially reducing efficacy by 1–2 log CFU if strains like L. plantarum inhibit companions; proper screening and balanced ratios during formulation mitigate these effects.

Sources

Fermented Foods

Fermented foods have played a significant historical role in promoting gut health, with empirical observations of benefits such as improved digestion and reduced gastrointestinal ailments dating back to ancient civilizations, including the use of yogurt-like products in early 20th-century studies linking them to better intestinal flora balance. Traditional fermentation processes relied on naturally occurring microorganisms to preserve food and inadvertently support microbial diversity in the human gut, as evidenced by longstanding cultural practices across Asia, Europe, and Africa. Among dairy-based fermented foods, yogurt stands out as a primary probiotic source, produced through the fermentation of milk by Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus thermophilus, which must contain at least 10^6 colony-forming units (CFU) per gram of live cultures to qualify as containing active probiotics. To ensure probiotic viability, consumers should select refrigerated yogurt or products labeled with live active cultures, as some shelf-stable varieties undergo post-fermentation heat treatment that reduces or eliminates live bacteria. This symbiotic bacterial interaction during production enhances lactose breakdown and generates bioactive compounds that aid gut colonization. Similarly, kefir is crafted from milk fermented with a complex consortium of lactic acid bacteria, yeasts, and acetic acid bacteria—often comprising up to 61 strains—forming a symbiotic matrix that yields a tangy, effervescent beverage rich in viable probiotics. Non-dairy fermented foods provide accessible probiotic options, particularly for those avoiding animal products. Sauerkraut, made by lacto-fermenting cabbage, features early dominance by Leuconostoc mesenteroides strains that initiate acidification and pave the way for subsequent Lactobacillus species, contributing to its tangy profile and microbial benefits. Kimchi, a Korean staple of fermented vegetables like cabbage and radish, is enriched with Lactobacillus strains such as L. plantarum, which thrive during the anaerobic process and exhibit robust survival in gastrointestinal conditions. Miso, a Japanese paste from fermented soybeans, involves initial saccharification by Aspergillus oryzae mold followed by bacterial fermentation with lactic acid producers like Lactobacillus and Tetragenococcus, yielding a umami-rich product with probiotic potential when unpasteurized. Kombucha, a fermented tea beverage produced using a symbiotic culture of bacteria and yeast (SCOBY), contains probiotics and organic acids that may support digestion and gut health, with optimal benefits from low-sugar, live-culture varieties. For a food to qualify as probiotic, it must contain live, viable cultures at sufficient levels—generally at least 10^6 to 10^7 CFU per gram at consumption—to exert health effects, as viability is essential for microbial activity in the gut. Pasteurization, while extending shelf life, eliminates these live bacteria by heating, rendering the product non-probiotic despite retained flavor or nutrients. Recent trends from 2024 to 2025 highlight the rise of plant-based fermented alternatives, such as oat and soy yogurts fortified with added probiotic strains like Lactobacillus and Bifidobacterium, catering to vegan consumers and projected to drive market growth through enhanced nutritional profiles and sustainability. These innovations maintain traditional fermentation principles while adapting to dietary preferences, often achieving comparable CFU levels to dairy counterparts.

Dietary Supplements

Dietary supplements containing probiotics are commercially available in various forms, including tablets, capsules, powders, and gummies, which allow for convenient consumption and targeted delivery of live microorganisms. These products often feature multi-strain formulations, typically incorporating 5 to 10 different bacterial species such as Lactobacillus and Bifidobacterium, to provide a broader spectrum of potential benefits compared to single-strain options. The composition of probiotic supplements is standardized by labeling colony-forming units (CFU), with most products specifying 1 to 50 billion CFU per serving to indicate the viable bacterial count at the time of manufacture. Many formulations also include added prebiotics, such as or fructooligosaccharides, to support bacterial growth, along with vitamins like or for enhanced nutritional value. The global market for probiotic dietary supplements reached approximately USD 13.3 billion in 2025, driven by increasing consumer awareness of gut health and demand for immune support products. Key players in this sector include Nestlé, Danone, and Procter & Gamble, which invest heavily in research and strain-specific innovations to capture market share. Probiotic supplements offer advantages over fermented food sources, such as delivering higher, more consistent doses of specific strains and enabling customization for particular health needs. However, a notable disadvantage is their variable quality, as supplements are not as rigorously regulated as pharmaceuticals, potentially leading to inconsistencies in viability and potency. Recent advancements include personalized probiotic supplements, developed from 2024 onward, which use at-home gut microbiome testing to tailor formulations to an individual's microbial profile for optimized efficacy.

Consumption and Dosage

Recommended dosages for probiotics lack a universal recommended daily allowance (RDA), as effective intake varies by bacterial strain, targeted health condition, and individual factors rather than a one-size-fits-all standard. Instead, guidelines emphasize strain-specific dosing derived from clinical trials demonstrating benefits. For adults, the general range is 108 to 1010 colony-forming units (CFU) per day, with many over-the-counter supplements providing 1 to 10 billion CFU per dose. Strain-specific examples include Lactobacillus rhamnosus GG at 109 CFU per day, which has shown efficacy in supporting gut health based on viability and studies. These dosages are calculated to ensure sufficient live microbes survive gastric transit and reach the intestines for potential , as determined by and human viability assessments. Duration of probiotic intake depends on the purpose, with 1 to 4 weeks commonly recommended for addressing acute issues like transient digestive discomfort, while chronic conditions may require ongoing use for months under medical supervision. The 2023 Gastroenterology Organisation (WGO) guidelines highlight that effective durations align with those proven in randomized controlled trials, avoiding arbitrary extensions. Exceeding recommended doses offers minimal additional benefits and is generally unnecessary, though risks remain low in healthy individuals. Dosage should be adjusted based on age, health status, and vulnerability; for example, infants and immunocompromised individuals require lower starting doses to minimize any potential imbalance in . The 2023 European Society for Paediatric , and Nutrition (ESPGHAN) position paper specifies doses of 5 × 109 CFU per day or higher for select pediatric strains, underscoring the need for tailored approaches across life stages. Overall, these evidence-based parameters from WGO and ESPGHAN prioritize safety and efficacy without overgeneralization.

Administration Methods

Probiotics are primarily administered orally, through capsules, powders, or fortified foods, allowing the microorganisms to transit through the where they can interact with the host . Emerging delivery methods include s and aerosols, particularly for targeting respiratory health; for instance, spore probiotics delivered via have shown potential in preventing in children by localizing beneficial in the upper airways. To optimize survival during gastric transit, probiotics are often recommended to be taken with meals, as food can buffer stomach acid and raise gastric , reducing exposure to the low environment that may inactivate sensitive strains. Specifically, consumption with milk (especially low-fat or at room temperature) or dairy products like yogurt can enhance probiotic survival through stomach acid and improve efficacy. Acidic foods such as oranges or citrus juices should be avoided around the time of intake, as they can temporarily increase stomach acidity, potentially reducing survival of non-acid-resistant probiotic strains before reaching the intestines; for these strains, acid-resistant formulations or enteric coatings are recommended, or pairing with less acidic mediums. Conversely, hot beverages or foods should be avoided immediately after consumption, as temperatures above 40–50°C can kill live microbial cells, compromising viability. Research on the optimal timing of probiotic intake is limited and mixed, with no universal "best" time applicable to everyone, as it depends on the specific strain and individual factors. Some evidence suggests taking probiotics on an empty stomach (e.g., first thing in the morning or before bed) may help more bacteria survive passage through stomach acid. Other studies indicate taking them with a meal (especially one containing some fat) can protect the bacteria and improve delivery to the intestines. Consistency in daily intake is more important than precise timing. It is advisable to follow the supplement label instructions or consult a healthcare provider. Interactions with other substances can influence probiotic efficacy; antibiotics may reduce viability by targeting both pathogenic and beneficial , so administration should be spaced at least 2 hours apart to minimize interference. , acting as a prebiotic, can enhance probiotic effects by providing substrates for microbial growth and improving in the gut. For compliance, non-spore-forming probiotics require at 2–8°C to maintain viability over time, as elevated temperatures accelerate in vegetative strains, whereas spore-formers are more stable at . Daily intake is generally advised for sustained benefits, though intermittent dosing may suffice for specific applications, depending on the strain and health goal. In infants, probiotics are commonly delivered via oral drops mixed with or formula, facilitating safe administration from birth; breastfeeding mothers may also consume probiotics, potentially transferring benefits through milk oligosaccharides that support microbial growth.

Mechanisms of Action

Core Mechanisms

Probiotics exert their beneficial effects through several core mechanisms at the cellular and physiological levels, primarily within the . These mechanisms include enhancing the intestinal barrier, antimicrobial actions against pathogens, modulation of the , competition for adhesion sites, and emerging evidence of epigenetic modifications. These processes are strain-specific, with variations in efficacy depending on the probiotic species and individual host factors. One key mechanism is the enhancement of the intestinal . Probiotic , such as certain strains of and , ferment dietary fibers to produce (SCFAs), including butyrate, which serve as primary energy sources for colonocytes. Butyrate promotes the expression of proteins like zonula occludens-1 (ZO-1) and , thereby strengthening the gut mucosa and reducing permeability to harmful substances. This barrier reinforcement helps prevent the translocation of pathogens and toxins into the bloodstream. Probiotics also demonstrate antimicrobial actions by producing inhibitory compounds. They secrete bacteriocins, which are ribosomally synthesized that target and disrupt the cell membranes of pathogenic bacteria such as and . Additionally, probiotics generate organic acids like , which lower the intestinal , creating an acidic environment unfavorable for growth and survival. These actions collectively inhibit colonization and proliferation in the gut. Immune modulation represents another fundamental mechanism, where probiotics interact directly with immune cells in the . They stimulate the production of cytokines, such as interleukin-10 (IL-10), which dampens excessive immune responses and promotes tolerance. Probiotics also influence T-cell , enhancing the differentiation and activity of regulatory T-cells (Tregs) that maintain immune and suppress pro-inflammatory pathways. This modulation helps balance Th1/Th2 responses without overstimulating the . Through adhesion, probiotics compete with pathogens for binding sites on epithelial cells. Probiotic strains adhere to mucus layers and host cell receptors via surface proteins, such as pili and adhesins, thereby occupying sites that would otherwise be available to harmful bacteria. This competitive exclusion limits pathogen attachment and invasion of the intestinal epithelium. Recent research as of 2025 highlights probiotics' role in inducing epigenetic changes, particularly through histone modifications. SCFAs like butyrate, produced by probiotics, act as histone deacetylase (HDAC) inhibitors, leading to increased histone acetylation and altered gene expression in intestinal cells. These modifications enhance anti-inflammatory pathways and barrier gene transcription, offering a novel layer of probiotic influence on host physiology.

Microbiome Interactions

Probiotics exert a profound influence on the by modulating its composition, particularly through the enhancement of beneficial bacterial taxa and the alleviation of . Strains such as and species have been shown to increase the relative abundance of beneficial microbes, including , in certain models of high-fat diet-induced , thereby restoring microbial balance and reducing the proliferation of pathogenic bacteria like . This modulation helps counteract , a state of microbial imbalance associated with various conditions, by competitively excluding harmful taxa and promoting a more stable ecosystem. For instance, administration of multi-strain probiotics in obese individuals has been observed to reverse dysbiotic patterns, leading to decreased and improved gut barrier integrity. Regarding microbial diversity, probiotics typically achieve transient colonization of the gut, lasting from days to weeks, rather than permanent engraftment, which allows them to temporarily bolster the resident community without displacing it. This short-term presence promotes the growth of short-chain (SCFA)-producing bacteria, such as certain Bifidobacterium and Faecalibacterium species, enhancing the production of metabolites like , propionate, and butyrate that support epithelial health and immune regulation. Studies indicate that in probiotics stimulate the intrinsic expansion of these SCFA producers, contributing to overall resilience without long-term dominance. Probiotics also interact with the gut-brain axis, influencing neurological functions through microbial signaling pathways. Via the , probiotic-derived metabolites can modulate serotonin production, as strains like Lactobacillus and enhance metabolism, leading to increased serotonin synthesis in the gut, which constitutes about 90% of the body's total serotonin. This bidirectional communication helps regulate mood and stress responses by altering availability. Recent metagenomic studies from 2024 and 2025 underscore the strain-specific nature of probiotic-induced shifts in the , revealing targeted alterations in community structure that vary by individual baseline . For example, precision interventions combining metagenomic profiling with strain-specific probiotics have demonstrated significant enhancements in microbial diversity and function in non-alcoholic patients, highlighting personalized efficacy. In post-antibiotic recovery, probiotics aid in restoring composition by preserving diversity and accelerating the rebound of beneficial taxa, though effects differ by strain—some accelerate recovery while others may delay it, emphasizing the need for tailored selection to minimize disruptions. A key aspect of probiotic function involves cross-feeding interactions with resident microbes, which underpin synbiotic effects when combined with prebiotics. Probiotic strains release metabolites that nourish commensal , fostering mutualistic networks; for instance, Bifidobacterium-derived can be utilized by butyrate producers like prausnitzii, amplifying SCFA output and enhancing overall community stability. This cross-feeding promotes synbiotic synergy, where prebiotics selectively stimulate probiotic growth, leading to amplified benefits for host health through improved microbial .

Clinical Applications and Research

Gastrointestinal Disorders

Probiotics have demonstrated efficacy in managing various gastrointestinal disorders, particularly through strain-specific interventions supported by clinical trials and meta-analyses. In the context of antibiotic-associated diarrhea (AAD), strains such as and Lactobacillus rhamnosus GG (LGG) have been shown to significantly reduce incidence and duration. Reviews and meta-analyses, including those cited in a article, indicate that these probiotics lower AAD risk by approximately 48-60% in both adults and children, with S. boulardii exhibiting strain-specific benefits in preventing antibiotic-induced disruptions to the . For infectious diarrhea, particularly rotavirus-related cases in children, Lactobacillus reuteri DSM 17938 at doses around 10^8-10^9 colony-forming units (CFU) per day has preventive and therapeutic effects. A 2023 meta-analysis indicated that supplementation with this strain shortens diarrhea duration by 0.5-1 day and reduces stool frequency, aiding in the management of acute gastroenteritis including rotavirus infections. In (IBS), multi-strain probiotics targeting symptoms like and show promising results, especially in trials using Rome IV diagnostic criteria. A 2024 of randomized controlled trials reported symptom improvement in up to 70% of patients, with multi-strain formulations (e.g., combinations of and species) reducing global IBS severity scores by 20-30% compared to , though evidence certainty remains moderate. For (IBD), including and (UC), the multi-strain probiotic VSL#3 supports remission maintenance. Clinical studies demonstrate that VSL#3 at high doses (e.g., 3.6 × 10^12 CFU/day) helps sustain endoscopic remission in mild-to-moderate UC, with reductions in markers of inflammation such as fecal calprotectin. Other applications include adjunctive use in Helicobacter pylori eradication and prevention of necrotizing enterocolitis (NEC) in preterm infants. L. reuteri supplementation alongside standard triple therapy improves eradication rates by 10-15% and reduces side effects like diarrhea, as per a 2024 meta-analysis of 12 trials. For NEC, a 2025 large-scale study of over 32,000 preterm infants found no significant reduction in incidence with multi-strain probiotics such as Bifidobacterium and Lactobacillus combinations (aOR 0.92, 98.3% CI: 0.78–1.09), though it was associated with reduced mortality without increasing sepsis risk; earlier meta-analyses had suggested benefits, highlighting ongoing debate.

Immune Function and Infections

Probiotics have been shown to enhance general immune function by promoting the production of (IgA), a key in mucosal immunity that helps protect against pathogens at entry points such as the respiratory and urogenital tracts. Specific strains, including those from the genus, stimulate B cells in the to increase secretory IgA levels, thereby strengthening barrier defenses without overactivating . This immunomodulatory effect contributes to reduced susceptibility to extra-intestinal infections. In the context of upper respiratory tract infections (URTIs), supplementation with Lactobacillus casei strains, such as Shirota, has demonstrated efficacy in lowering incidence and duration among healthy adults and children. A of randomized controlled trials reported a (RR) of 0.83 for URTI occurrence with probiotic fermented products containing L. casei, corresponding to approximately a 17% reduction, with greater benefits observed in subgroups like the elderly. Broader probiotic use, including L. casei, has been associated with symptom reductions of up to 27% in self-reported URTI severity, particularly in individuals over 45 years or with higher . For allergies, early-life exposure to Lactobacillus rhamnosus during the perinatal period significantly lowers the risk of eczema in infants. A 2022 and of randomized trials, updated with 2024 data, found an RR of 0.60 (95% CI: 0.47–0.75) for atopic eczema incidence up to age 2 years, with sustained effects to 6–7 years (RR: 0.62, 95% CI: 0.50–0.75), attributed to modulation of Th1/Th2 immune balance and reduced allergen sensitization. Probiotics also reduce the recurrence of acute (AOM) in children, with Bifidobacterium lactis Bb-12 playing a notable role. In a randomized, double-blind, -controlled trial of formula-fed infants, daily supplementation with B. lactis Bb-12 combined with L. rhamnosus GG decreased AOM incidence from 50% in the group to 22% in the probiotic group (RR: 0.44, 95% CI: 0.21–0.90), alongside lower needs. This protective effect is linked to enhanced nasopharyngeal stability and reduced adhesion. In urinary tract infections (UTIs), Lactobacillus rhamnosus GR-1 supports vaginal recolonization to prevent cystitis, particularly in women prone to recurrence. Oral or vaginal administration of L. rhamnosus GR-1, often with L. reuteri RC-14, restores lactobacilli dominance in the vaginal , inhibiting uropathogen and reducing UTI episodes by competing for epithelial sites and producing compounds like . Clinical evidence indicates this approach lowers recurrence rates by up to 50% compared to in randomized trials. As of 2025, emerging research highlights probiotics' role in modulating respiratory sequelae post-COVID-19 infection. Probiotic strains such as and species help restore associated with , alleviating persistent respiratory symptoms like dyspnea through regulation and immune normalization. Additionally, probiotics serve as adjuvants by enhancing mucosal and systemic responses; for instance, supplementation improves and efficacy by boosting IgA production and T-cell activation, with meta-analyses showing up to 20% higher rates in supplemented groups.

Metabolic and Cardiovascular Health

Probiotics have shown potential in modulating metabolic and cardiovascular health through interactions with the gut microbiota, influencing lipid metabolism, glycemic control, blood pressure regulation, and body weight management. Specific strains, such as Lactobacillus acidophilus, Lactobacillus helveticus, Akkermansia muciniphila, and Lactobacillus gasseri, have been investigated in clinical trials and meta-analyses for their targeted effects on components of metabolic syndrome. These benefits are often linked to alterations in gut-derived metabolites and hormones, contributing to reduced cardiovascular disease (CVD) risk factors like dyslipidemia, hypertension, insulin resistance, and obesity. Recent research, including 2025 updates, highlights emerging roles in lowering trimethylamine N-oxide (TMAO) levels and improving non-alcoholic fatty liver disease (NAFLD) outcomes via synbiotics. In lipid metabolism, Lactobacillus acidophilus supplementation has been associated with reductions in (LDL) cholesterol levels by approximately 5-10% in hypercholesterolemic individuals, primarily through the production of bile salt hydrolase enzymes that promote deconjugation and increased fecal excretion of . This mechanism enhances hepatic conversion to s, thereby lowering circulating LDL without significantly affecting (HDL) in most studies. Meta-analyses of randomized controlled trials confirm these effects are more pronounced in patients with baseline elevations in total . Probiotics also contribute to blood pressure management, with Lactobacillus helveticus-containing formulations demonstrating modest reductions in systolic by 3-5 mmHg among hypertensive adults. A 2024 meta-analysis of 26 trials involving over 1,600 participants reported that probiotic interventions, including L. helveticus strains, significantly lowered office systolic , with greater effects observed in those with elevated baseline values (>130 mmHg). These changes are attributed to enhanced production of bioactive peptides from fermented and improvements in endothelial function, though diastolic pressure reductions are typically smaller (1-2 mmHg). For glycemic control in , meta-analyses of randomized controlled trials indicate that probiotics improve insulin sensitivity, reduce fasting blood glucose levels, and lower inflammation markers, particularly in individuals with insulin resistance. Supplementation with has improved insulin sensitivity, as evidenced by a 12-week randomized trial in overweight patients showing enhanced , though HbA1c levels were not significantly changed. This next-generation probiotic strengthens the gut mucosal barrier and modulates inflammatory pathways, leading to better insulin signaling in metabolic tissues; pasteurized forms were equally effective and well-tolerated. Earlier studies corroborate these findings, with daily doses of 10^10 improving indices without adverse gastrointestinal effects. Regarding obesity and weight management, strains, such as BNR17 and SBT2055, have reduced (BMI) by 1-2 points in and obese individuals over 12 weeks, alongside decreases in visceral fat and waist circumference. These effects involve modulation of gut hormones, including increased (GLP-1) secretion, which promotes and inhibits , as well as reductions in serum leptin and insulin levels. Clinical trials indicate these changes are sustained with consistent dosing and are more effective when combined with dietary interventions. As of 2025, emerging evidence supports probiotics' role in CVD risk reduction by lowering TMAO, a gut-derived linked to and ; interventions with strains like and Lactobacillus plantarum decreased serum TMAO by up to 20% in high-risk patients, potentially mitigating plaque formation. Similarly, synbiotic combinations (probiotics plus prebiotics) have shown benefits in NAFLD , with a 2025 reporting improvements in liver enzymes, , and hepatic fat content across multiple randomized trials, though effects on and lipids were inconsistent. These microbiome shifts in parallel broader interactions detailed elsewhere.

Mental Health and Neurological Conditions

Probiotics have shown potential in modulating mental health and neurological conditions primarily through the gut-brain axis, a bidirectional communication pathway linking the gastrointestinal microbiome to central nervous system function. This axis influences neurotransmitter production, immune responses, and neural signaling, with dysbiosis implicated in disorders such as depression, anxiety, autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), and post-stroke recovery. Emerging research highlights specific probiotic strains that may alleviate symptoms by restoring microbial balance and mitigating neuroinflammation. In clinical trials for depression and anxiety, the combination of R0052 and R0175 has demonstrated efficacy in reducing symptoms. A reported a 25% reduction in total scores on the Hospital Anxiety and Depression Scale (HADS) after 30 days of supplementation in healthy volunteers experiencing . A 2024 meta-analysis of multiple studies confirmed substantial reductions in depression symptoms (effect size ≈0.6) and moderate improvements in anxiety, particularly with multi-strain formulations including these species, though effects were more pronounced in individuals with baseline mild-to-moderate symptoms. These probiotics exert effects via the gut-brain axis by enhancing production of key neurotransmitters and curbing inflammation. Supplementation increases central levels of gamma-aminobutyric acid (GABA) and serotonin, which regulate mood and stress responses, while decreasing peripheral inflammatory markers such as (CRP). For instance, L. helveticus and B. longum strains have been shown to elevate serotonin synthesis in the gut, with downstream signaling to the brain reducing anxiety-like behaviors in preclinical models. Concurrently, they lower CRP by modulating gut permeability and systemic immune activation, thereby attenuating neuroinflammatory pathways linked to mood disorders. For neurodevelopmental conditions like ASD and ADHD, Bacteroides fragilis has emerged as a promising strain. In animal models of ASD, oral administration of B. fragilis improved social behaviors, reduced repetitive actions, and restored gut barrier integrity, effects attributed to decreased gut-derived toxins reaching the brain. Human pilot studies support these findings; a 2024 randomized, double-blind trial in children with ASD found that B. fragilis BF839 supplementation for 12 weeks significantly improved core behavioral symptoms on the Autism Behavior Checklist, with no adverse effects reported. Preliminary evidence in ADHD suggests similar microbiome-targeted interventions may address associated gut dysbiosis, though strain-specific data remain limited. Recent advancements as of 2025 explore probiotics in neurological recovery contexts. For post- rehabilitation, multi-strain probiotics including and species have reduced infection incidence and enhanced functional outcomes in clinical trials, with a ongoing study evaluating impacts on and anxiety in stroke survivors. In PTSD, personalized probiotic formulations tailored to individual profiles show promise; a 2024 trial in combat trauma patients demonstrated symptom relief through targeted restoration of beneficial taxa, reducing anxiety and depression via gut-brain modulation. Animal models further indicate that probiotics increase beneficial abundance, alleviating PTSD-like fear responses. Overall, evidence for probiotics in and neurological conditions is promising yet mixed, with consistent benefits in smaller trials but variability across populations and strains. Larger randomized controlled trials are essential to establish optimal dosing, long-term efficacy, and mechanisms beyond the gut-brain axis.

Dermatological and Other Conditions

Probiotics have shown potential in managing various dermatological conditions, particularly and eczema. Oral administration of Lactobacillus rhamnosus strains, often in combination with other lactobacilli, has been associated with significant reductions in disease severity. In a involving children and adolescents with , a probiotic mixture including L. rhamnosus HN001 led to a mean SCORAD reduction of approximately 28 percentage points compared to , with effects persisting up to three months post-treatment. Topical applications of L. rhamnosus have also demonstrated efficacy, serving as adjuncts to standard therapies by modulating local immune responses and reducing inflammation, though larger studies are needed to confirm optimal formulations. Emerging research supports the use of probiotics for ocular conditions such as . Recent 2024 clinical trials indicate that formulations containing Lactobacillus plantarum improve symptoms by enhancing tear production and reducing ocular surface damage. Two randomized controlled trials specifically highlighted the superiority of probiotic over oral administration alone in alleviating dryness and discomfort, with measurable improvements in and scores. In reproductive health, probiotics play a role in mitigating risks during and treating vaginal . Supplementation with multi-strain probiotics, including species, has been linked to a 27% reduction in risk among pregnant women, particularly those under 30 years with lower BMI, by improving glycemic control and metabolic parameters. Vaginal probiotics during show promise in preventing bacterial vaginosis (BV), with studies demonstrating a trend toward restored normal and reduced preterm delivery risk in women with intermediate . For established BV, Lactobacillus crispatus strains effectively restore post-treatment, increasing the proportion of healthy Nugent scores and supporting long-term microbial balance, even when administered orally alongside antibiotics. Beyond these areas, probiotics address miscellaneous conditions like recurrent in children and . In pediatric populations, probiotic interventions increase the odds of pain improvement by 63% in the short term compared to , with strains such as Lactobacillus reuteri showing sustained benefits in functional abdominal disorders. For , 2025 innovations include chitosan-based hydrogels incorporating metabolites from , which accelerate and diabetic closure by up to 90% through antibacterial activity and enhanced tissue regeneration. Injectable living hydrogels with embedded L. plantarum further combat infections by reducing bacterial loads by 3-7 logs while promoting compatibility.

Oncology Applications

Probiotics have garnered attention in for their potential roles in , adjunctive therapy during treatment, and management of therapy-related side effects. Research indicates that certain probiotic strains can influence carcinogenesis and tumor progression by modulating the and producing bioactive metabolites that inhibit malignant cell growth. In preventive contexts, has been shown to reduce the risk of through the generation of anti-carcinogenic and other metabolites that suppress tumor initiation in preclinical models. During chemotherapy, probiotics offer supportive benefits, particularly in mitigating gastrointestinal toxicities, including potential roles in managing gastric ulcers. For instance, administration of probiotic consortia has been associated with a reduction in irinotecan-induced by decreasing intestinal activity, which otherwise reactivates the drug's toxic metabolites; phase II trials reported up to a 20% decrease in moderate-to-severe incidence compared to . Specific strains such as Lactobacillus rhamnosus GG and Bifidobacterium species may aid in chemotherapy-related gastric ulcer management when white blood cell counts are normal and immunity is adequate, though standard treatments like proton pump inhibitors are prioritized for acute phases; probiotics should be avoided during periods of immunosuppression such as chemotherapy nadir and used only under medical supervision. Similarly, probiotics can enhance the efficacy of agents like PD-1 inhibitors. Strains such as species promote maturation and T-cell activation in the , leading to improved response rates in preclinical and early-phase human studies of colorectal and other solid tumors. Emerging innovations as of 2025 highlight targeted delivery approaches. Aerosolized probiotics have demonstrated promise in preclinical models by altering pulmonary to boost anti-tumor immunosurveillance and reduce metastatic burden in the lungs, with studies showing enhanced infiltration of cytotoxic T cells following intranasal administration. In models, Bifidobacterium breve engineered strains have inhibited HER2-positive tumor growth both and by colonizing tumor sites and eliciting localized immune responses, marking a shift toward strain-specific, tumor-homing probiotics. At the mechanistic level, probiotics exert anti-oncogenic effects by inducing in cancer cells through activation of intrinsic pathways involving caspase-3 and modulation, as observed in gastric and cell lines. They also remodel the by reducing immunosuppressive regulatory T cells and myeloid-derived suppressor cells while promoting pro-inflammatory profiles that favor anti-tumor immunity. Preclinical evidence is robust, with consistent demonstrations of tumor growth inhibition across models, but human data remain preliminary. Ongoing phase II and III trials, including those evaluating multi-strain probiotics alongside or , report symptom reductions such as 15-25% lower rates of treatment-related and , alongside trends toward prolonged ; however, larger randomized studies are needed to confirm and optimal strains.

Safety Profile

Adverse Effects

Probiotics are generally well-tolerated in healthy individuals, with the most common adverse effects being mild gastrointestinal symptoms such as and gas. These effects typically occur in approximately 5-10% of users and resolve within a few days as the body adjusts to the microbial introduction. Rare but more serious adverse effects include systemic infections, such as bacteremia or , primarily observed in immunocompromised patients. The incidence of such infections is extremely low, estimated at less than 1 case per 1 million doses in the general population, though risks may increase in vulnerable groups due to translocation of probiotic strains from the gut. Allergic reactions to probiotics are uncommon, but they can occur with yeast-based strains like , manifesting as skin rashes or in sensitized individuals. Such events are documented in isolated case reports and affect a very small fraction of users. As of 2025, extensive reviews confirm no significant long-term risks associated with probiotic use in healthy adults, with studies showing sustained safety over periods exceeding one year. The potential for resistance gene transfer from probiotics to remains minimal in clinical settings, supported by regulatory assessments and data. Adverse events related to probiotics can be reported through the FDA's MedWatch program, which facilitates post-market surveillance of dietary supplements.

Special Populations

In infants, particularly preterm neonates, administration of multi-strain probiotics has been associated with a reduced incidence of (NEC) and all-cause mortality in very infants, though ongoing monitoring for potential is recommended due to rare reports of probiotic-related bacteremia in vulnerable neonates. As of 2023, the U.S. (FDA) has warned against the use of certain unregulated probiotic products in hospitalized preterm infants due to risks leading to severe infections, including and deaths. In 2025, the (AAP) reviewed evidence indicating that probiotics can reduce NEC and mortality in preterm infants when using high-quality, regulated preparations, with benefits generally outweighing risks in controlled settings. For the elderly, probiotics may require adjusted lower dosing regimens when addressing conditions like (IBS), as age-related changes in gut motility and diversity can influence efficacy and absorption. In frail older adults, the benefits of probiotics in modulating and reducing generally outweigh potential risks, with studies showing improvements in immune function and cognitive health without significant adverse events. During , certain probiotic strains, such as various species, are considered safe for maternal use based on available studies and have been linked to a reduced of spontaneous preterm delivery when consumed habitually through dairy products. These strains support vaginal and balance, potentially mitigating preterm birth associated with , though supplementation should align with individual health assessments. In immunocompromised individuals, should be avoided due to documented risks of and severe infections, particularly in those with central venous catheters or critical illness. Spore-forming probiotics, such as , warrant cautious use in this population, as they have been implicated in bloodstream infections among those with compromised intestinal barriers. For patients undergoing chemotherapy, primary risks include infections such as bacteremia and sepsis due to neutropenia and low white blood cell counts, as live bacteria in probiotics can translocate and cause serious issues; risks are heightened in those with gastric ulcers due to fragile mucosa or bleeding. Probiotics may be considered when white blood cell counts are normal and immune function is adequate, as determined by a healthcare provider, but administration should be avoided during neutropenic periods (chemotherapy nadir) to reduce infection risks. Specific strains such as Lactobacillus rhamnosus GG or Bifidobacterium species may support management of chemotherapy-induced gastrointestinal issues, including gastric ulcers, under medical guidance and after prioritizing standard treatments like proton pump inhibitors for acute phases. As of 2025, emerging research highlights tailored probiotic interventions targeting HIV-associated gut to reduce persistent and support immune recovery, with microbiome-modulating therapies showing promise in clinical trials. Pediatric guidelines for probiotic use have been updated to emphasize strain-specific recommendations for gastrointestinal disorders, incorporating higher doses like 5 × 10^9 CFU/day of Lactobacillus rhamnosus GG for conditions such as antibiotic-associated , while prioritizing safety in preterm and vulnerable infants.

Regulation and Quality Control

Regulatory Frameworks

In the United States, the (FDA) regulates probiotics primarily as ingredients or dietary supplements under the Federal , Drug, and Cosmetic Act, with many strains classified as (GRAS) based on scientific evidence or historical use in prior to 1958. GRAS status allows probiotics to be added to foods without pre-market approval, provided they meet safety criteria through expert consensus or common use, but if a product makes therapeutic claims—such as treating or preventing a —it is reclassified as a drug requiring rigorous pre-market demonstration of safety and efficacy via an application. Unlike additives, dietary supplements containing probiotics face no mandatory pre-market review, though manufacturers must ensure safety and substantiate structure/function claims like "supports digestive " without implying treatment. In the , the (EFSA) oversees probiotic regulation under Regulation (EC) No 1924/2006 for health claims and Regulation (EU) 2015/2283 for novel foods, requiring pre-market authorization for strains not historically consumed in significant amounts within the EU before May 1997. Health claims must be scientifically substantiated, with EFSA evaluating for general function, disease risk reduction, or child health benefits; to date, few probiotic-specific claims have been approved, though a qualified claim exists for live cultures (e.g., certain and strains) stating they improve in individuals with difficulty digesting . Unauthorized use of terms like "probiotic" on labels is prohibited if implying unsubstantiated health benefits, emphasizing strain-specific over genus-level generalizations. Globally, the (WHO) and (FAO) provide foundational guidelines established in 2002 for evaluating probiotics in food, defining them as "live microorganisms which when administered in adequate amounts confer a health benefit on the host" and outlining criteria for strain identification, safety assessment, and efficacy testing through in vitro, animal, and human trials. These guidelines, referenced in ongoing work, emphasize minimum viable counts at end-of-shelf-life and proper labeling of genus, species, and strain; efforts to update them for were shelved by the Codex Committee on Nutrition and Foods for Special Dietary Uses at its 44th session in October 2024, with the decision reported in November 2024, pending a that has extended into 2025 and beyond as of November 2025. In Asia, regulations are often stricter, as exemplified by Japan's Foods for Specified Health Uses (FOSHU) system, introduced in 1991, which requires rigorous pre-market approval from the Consumer Affairs Agency for probiotic-containing products, including scientific evidence of efficacy, safety, and targeted health benefits like improved gut function, with more than 1,000 approvals granted as of 2019 but limited to specific strains. Distinctions between probiotics as dietary supplements versus drugs hinge on intended use and claims: structure/function or general wellness statements keep products under lighter food/supplement oversight, while therapeutic claims—such as mitigating infections or metabolic disorders—trigger pharmaceutical regulations demanding clinical proof of and worldwide. As of 2025, harmonization efforts for next-generation probiotics (NGPs), which include non-traditional strains like engineered for targeted therapies, remain fragmented, with evolving frameworks in the , , and prioritizing drug-like scrutiny to address and gaps in these advanced biotherapeutics.

Testing and Guidelines

Testing probiotics for , , and involves a multi-tiered approach that begins with precise strain identification to ensure reproducibility and specificity in research and manufacturing. Strain identification typically relies on gene sequencing, which targets conserved regions of the bacterial gene to classify probiotics at the species level with high accuracy, often using universal primers like 27F and 1492R for amplification and comparison against databases such as NCBI BLAST. For more granular strain-level differentiation, whole-genome sequencing (WGS) is employed, providing comprehensive genetic profiles that reveal polymorphisms, virulence factors, and functional genes, surpassing the limitations of in resolving closely related strains. WGS has become increasingly accessible due to advances in next-generation sequencing technologies, enabling detailed to confirm probiotic identity and exclude contaminants. In vitro assessments evaluate a probiotic strain's potential to survive gastrointestinal conditions and interact with host cells, serving as initial screens before more resource-intensive in vivo studies. Acid tolerance tests simulate gastric passage by exposing strains to low pH (typically 2.0–3.0) with or without for 1–3 hours, measuring viable cell counts via colony-forming units (CFU)—which enumerate only culturable bacteria capable of forming visible colonies on agar plates, potentially underestimating total viability by excluding viable but non-culturable (VBNC) cells—or through flow cytometry assessing active fluorescent units (AFU), which use fluorescent staining to detect all membrane-intact viable cells, including VBNC states common in stressed probiotics, for a more comprehensive viability assessment especially in multi-strain formulations. Survival rates should exceed 10^6 CFU/mL (or equivalent AFU) for promising candidates. tolerance assays mimic small intestinal conditions using 0.3–0.5% salts for 4–24 hours, evaluating deconjugation and resistance mechanisms like salt activity. Adhesion assays, often using human intestinal cell lines such as or HT-29, quantify bacterial attachment through or plate counts, with adherent strains demonstrating exclusion of pathogens like by competitive binding to mucus or epithelial receptors. These tests prioritize strains with robust survival (e.g., >50% viability post-exposure) and adhesion (>10^5 bacteria per cell monolayer), though results must be validated in vivo due to model simplifications. In vivo evaluation through randomized controlled trials (RCTs) in humans provides direct evidence of probiotic viability and health impacts, with key endpoints including fecal recovery of administered strains to confirm engraftment. In RCTs, probiotics are dosed at 10^8–10^10 CFU/day, and fecal samples are analyzed via culture or qPCR for strain-specific CFU recovery, often detecting 10^4–10^7 CFU/g in responders after 1–4 weeks, indicating transient without permanent alteration of the . Animal models, such as gnotobiotic mice or piglets, elucidate mechanisms like or inhibition, with endpoints measuring levels or load reduction following . These studies emphasize strain-specific outcomes, as efficacy varies; for instance, Lactobacillus rhamnosus GG has shown consistent fecal recovery and reduction in pediatric RCTs. The International Scientific Association for Probiotics and Prebiotics (ISAPP) provides authoritative guidelines emphasizing strain-specific evidence for probiotic claims, as outlined in their 2014 consensus statement, which requires clinical trials demonstrating benefits for the exact strain and dose used. Updated perspectives in 2021 reinforce that benefits cannot be extrapolated from genus or levels, mandating rigorous, well-controlled RCTs with appropriate controls and statistical power. For ongoing monitoring, ISAPP advocates post-market through pharmacovigilance systems to track rare adverse events and long-term safety, particularly for vulnerable populations, integrating real-world data from registries and consumer reporting. Quality control protocols ensure probiotic products maintain viability, purity, and safety throughout the , adhering to Good Manufacturing Practices (GMP) as defined by regulatory bodies like the FDA, which mandate controlled environments, validated processes, and batch testing for contaminants. Third-party verification, such as the (USP) program, independently audits manufacturers for label accuracy, potency (e.g., ≥10^9 CFU at expiration), and absence of pathogens, using standardized microbial assays and stability challenges. resistance screening is critical, involving (MIC) tests against clinically relevant antibiotics per EFSA or FDA breakpoints, to detect transferable resistance genes via PCR or WGS, ensuring strains do not contribute to resistance dissemination. Products passing these verifications display USP seals, enhancing consumer trust and .

Labeling and Standards

Probiotic product labels must include essential information to inform consumers about the composition and viability of the microbes. This typically encompasses the , , and strain designation, such as Lactobacillus rhamnosus GG, to specify the exact microbial identity, as recommended by industry best practices for transparency and efficacy assessment. Labels are also required to declare the quantity of live microbes in colony-forming units (CFU), often expressed as a range or specific count like 1 × 10^9 CFU per serving at the end of , enabling consumers to evaluate potency. Storage instructions, such as to maintain microbial viability, must be provided to ensure the product delivers the intended benefits throughout its . Regulatory frameworks distinguish between permissible claims on probiotic labels, with structure-function claims—such as "supports gut health" or "promotes digestive balance"—allowed on dietary supplements without pre-market approval, provided they are truthful and not misleading. In contrast, disease-related claims, like treating or preventing specific illnesses, are prohibited unless substantiated by authorized s backed by significant scientific evidence, as these fall under stricter drug-like oversight. For and similar cultured products , the International Dairy Foods Association (IDFA) offers a voluntary "Live and Active Cultures" (LAC) seal, certifying that the product contains at least 100 million viable cultures per gram at manufacturing, verified through independent testing to assure probiotic activity. In the , labeling requires proof of microbial viability to support any claims related to live cultures, with the term "probiotic" restricted unless approved under regulations, emphasizing strain-specific substantiation. As of 2025, mandatory disclosure on probiotic labels aligns with broader updates, requiring clear listing of major like derivatives in dairy-based formulations to protect sensitive , in line with FDA guidance on labeling. Emerging practices include the use of QR codes on labels to provide detailed strain-specific data, such as genomic profiles or clinical study links, enhancing access to beyond space-limited , though this remains voluntary in most jurisdictions. Recent audits have revealed that a significant percentage of probiotic supplements do not meet their labeled CFU counts by the , often due to inadequate viability preservation or inaccurate initial declarations, underscoring the need for rigorous quality controls.

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