The original theory, similar to the modern concept, but not the term, is generally attributed to Nobel laureateÉlie Metchnikoff, who postulated that yoghurt-consuming Bulgarian peasants lived longer.
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." 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. 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 supragovernmental regulatory bodies' requirements to better characterize health claims substantiations.
That first global effort was further developed in 2010; two expert groups of academic scientists and industry representatives made recommendations for the evaluation and validation of probiotic health claims. The same principles emerged from those two groups as were expressed in the "Guidelines" of FAO/WHO in 2002. This definition, though widely adopted, is not acceptable to the European Food Safety Authority because it embeds a health claim that is not measurable.
A group of scientific experts assembled in London, Canada, on October 23, 2013, to discuss the scope and appropriate use of the term "probiotic". That meeting was motivated by developments in the field that followed the formation of the 2001 definition, and the panel's conclusions were published in June 2014. The panel noted that a more grammatically correct definition would be worded as, "live microorganisms that, when administered in adequate amounts, confer a health benefit on the host."
Lactobacillus spp. have been suggested to contribute to obesity in humans, but no evidence of this relationship has been found.
In 2015, the global retail market value for probiotics was US$41 billion, including sales of probiotic supplements, fermented milk products, and yogurt, which alone accounted for 75% of total consumption. Innovation in probiotic products in 2015 was mainly from supplements, which produced US$4 billion and was projected to grow 37% globally by 2020. Consumption of yogurt products in China has increased by 20% per year since 2014.
As of 2019[update], 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. The European Commission placed a ban on putting the word "probiotic" on the packaging of products because such labeling misleads consumers to believe a health benefit is provided by the product when no scientific proof exists to demonstrate that health effect.
In the United States, the 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.Food product labeling requires language approval by the FDA, so probiotic manufacturers have received warning letters for making disease or treatment claims. 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 a yogurt and probiotic dairy drink.
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. 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, 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 what exists at consumption. 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.
Probiotics have received renewed attention in the 21st century from product manufacturers, research studies, and consumers. Their history can be traced to the first use of cheese and fermented products, that were well known to the Greeks and Romans who recommended their consumption. The fermentation of dairy foods represents one of the oldest techniques for food preservation.
Élie Metchnikoff first suggested the possibility of colonizing the gut with beneficial bacteria in the early 20th century.
The original modern hypothesis of the positive role played by certain bacteria was first introduced by Russian scientist and Nobel laureateÉlie Metchnikoff, who in 1907 suggested that it would be possible to modify the gut microbiota and to replace harmful microbes with useful microbes. Metchnikoff, at that time a professor at the Pasteur Institute in Paris, proposed the hypothesis that the aging process results from the activity of putrefactive (proteolytic) microbes producing toxic substances in the large bowel. Proteolytic bacteria such as clostridia, which are part of the normal gut microbiota, produce toxic substances including phenols, indols, and ammonia from the digestion of proteins. According to Metchnikoff, these compounds were responsible for what he called "intestinal autointoxication", which would cause the physical changes associated with old age.
At that time, milk fermented with lactic-acid bacteria were known to inhibit the growth of proteolytic bacteria because of the low pH produced by the fermentation of lactose. Metchnikoff had also observed that certain rural populations in Europe, for example in Bulgaria and the Russian steppes, who lived largely on milk fermented by lactic-acid bacteria, were exceptionally long-lived. Based on these observations, Metchnikoff proposed that consumption of fermented milk would "seed" the intestine with harmless lactic-acid bacteria and decrease the intestinal pH, and that this would suppress the growth of proteolytic bacteria. Metchnikoff himself introduced in his diet sour milk fermented with the bacteria he called "Bulgarian Bacillus" and believed his health benefited. Friends in Paris soon followed his example and physicians began prescribing the sour-milk diet for their patients.
Bifidobacteria were first isolated from a breast-fed infant by Henry Tissier, who also worked at the Pasteur Institute. The isolated bacterium named Bacillus bifidus communis was later renamed to the genus Bifidobacterium. Tissier found that bifidobacteria are dominant in the gut microbiota of breast-fed babies and he observed clinical benefits from treating 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. Methods of treating infectious diseases were needed at that time when antibiotics were not yet available, and Nissle used the E. coli Nissle 1917 strain in acute gastrointestinal infectious salmonellosis and shigellosis.
In 1920, Rettger and Cheplin reported that Metchnikoff's "Bulgarian Bacillus", later called Lactobacillus delbrueckii subsp. bulgaricus, could not live in the human intestine. They conducted experiments involving rats and humans volunteers, feeding them with Lactobacillus acidophilus. They observed the disappearance of the pathogenic protist Balantidium coli as well as of other gas-producing bacteria. Rettger further explored the possibilities of L. acidophilus, and reasoned that bacteria originating from the gut were more likely to produce the desired effect in this environment. In 1935, certain strains of L. acidophilus were found very active when implanted in the human digestive tract. Trials were carried out using this organism, and encouraging results were obtained, especially in the relief of chronic constipation.
Contrasting antibiotics, probiotics were defined as microbially derived factors that stimulate the growth of other microorganisms. In 1989, Roy Fuller suggested a definition of probiotics that has been widely used: "A live microbial feed supplement which beneficially affects the host animal by improving its intestinal microbial balance." Fuller's definition emphasizes the requirement of viability for probiotics and introduces the aspect of a beneficial effect on the host.
The term "probiotic" originally referred to microorganisms that have effects on other microorganisms. The concept of probiotics involved the notion that substances secreted by one microorganism stimulated the growth of another microorganism. The term was used again to describe tissue extracts that stimulated microbial growth. The term probiotics was taken up by Parker, who defined the concept as, "Organisms and substances that have a beneficial effect on the host animal by contributing to its intestinal microbial balance." Later, the definition was greatly improved by Fuller, whose explanation was very close to the definition used today. Fuller described probiotics as a "live microbial feed supplement which beneficially affects the host animal by improving its intestinal microbial balance." He stressed two important claims for probiotics: the viable nature of probiotics and the capacity to help with intestinal balance.
Some literature gives the word a full Greek etymology, 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', the latter deriving from the noun βίος (bios), meaning 'life'. The term contrasts etymologically with the term antibiotic, although it is not a complete antonym. The related term prebiotic comes from the Latin prae, meaning 'before', and refers to a substance that is not digested, but rather may be fermented to promote the growth of beneficial intestinal microorganisms.
As food products or dietary supplements, probiotics are under preliminary research to evaluate if they provide any effect on health. In all cases proposed as health claims to the European Food Safety Authority, the scientific evidence remains insufficient to prove a cause-and-effect relationship between consumption of probiotic products and any health benefit. There is no scientific basis for extrapolating an effect from a tested strain to an untested strain. Improved health through gut flora modulation appears to be directly related to long-term dietary changes. Claims that some lactobacilli may contribute to weight gain in some humans remain controversial.
Acute otitis media
There is inconsistency in the results of different groups of 3488 children as reported in a cochrane review. Also, it shows no significant difference regading the adverse effects between probiotic and the other comparators.
Only limited, low-quality evidence exists to indicate that probiotics are helpful for treating people with milk allergy. 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.
It is unclear whether probiotic supplementation helps with childhood asthma, as the quality of research evidence is low.
Antibiotics are a common treatment for children, with 11% to 40% of antibiotic-treated children developing diarrhea.Antibiotic-associated diarrhea (AAD) results from an imbalance in the colonic microbiota caused by antibiotic therapy. These microbial community alterations result in changes in carbohydrate metabolism, with decreased short-chain fatty acid absorption and osmotic diarrhea as a result. A 2015 Cochrane review concluded that a protective effect of some probiotics existed for AAD in children. In adults, some probiotics showed a beneficial role in reducing the occurrence of AAD and treating Clostridium difficile disease.
Probiotic treatment might reduce the incidence and severity of AAD as indicated in several meta-analyses. For example, treatment with probiotic formulations including L. rhamnosus may reduce the risk of AAD, improve stool consistency during antibiotic therapy, and enhance the immune response after vaccination.
The potential efficacy of probiotics to treat AAD depends on the probiotic strains and dosage. One review recommended for children L. rhamnosus or Saccharomyces boulardii at 5 to 40 billion colony-forming units/day, given the modest number needed to treat and the likelihood that adverse events are very rare. The same review stated that probiotic use should be avoided in pediatric populations at risk for adverse events, such as severely debilitated or immune-compromised children.
Probiotic treatment of bacterial vaginosis is the application or ingestion of bacterial species found in the healthy vagina to cure the infection of bacteria causing bacterial vaginosis. This treatment is based on the observation that 70% of healthy females have a group of bacteria in the genus Lactobacillus that dominate the population of organisms in the vagina. Currently, the success of such treatment has been mixed, since the use of probiotics to restore healthy populations of Lactobacillus has not been standardized. Often, standard antibiotic treatment is used at the same time that probiotics are being tested. In addition, some groups of women respond to treatment based upon ethnicity, age, number of sexual partners, pregnancy, and the pathogens causing bacterial vaginosis. In 2013, researchers found that administration of hydrogen peroxide-producing strains, such as L. acidophilus and L. rhamnosus, were able to normalize vaginal pH and rebalance the vaginal microbiota, preventing and alleviating bacterial vaginosis.
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.
There is a lack of consistent evidence to support the use of probiotics to treat atopic dermatitis (AD), and some risk of adverse effects. The American Academy of Dermatology state "The use of probiotics/prebiotics for the treatment of patients with established AD is not recommended due to inconsistent evidence".
Some probiotics are suggested as a possible treatment for various forms of gastroenteritis, and a Cochrane Collaboration meta-analysis on the use of probiotics to treat acute infectious diarrhea based on a comprehensive review of medical literature through 2010 (35 relevant studies, >4500 participants) reported that use of any of the various tested probiotic formulations appeared to reduce the duration of diarrhea by a mean of 25 hours (vs. control groups, 95% confidence interval, 16–34 hours), also noting, however, that "the differences between the studies may be related to other unmeasured and unexplored environmental and host factors" and that further research was needed to confirm reported benefits.
Probiotics are commonly given to breast-feeding mothers and their young children to prevent eczema, but no good evidence shows they are effective for this purpose.
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. The only peer-reviewed treatments for H. pylori to date all include various Antibiotic Regimes.
Immune function and infections
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. LAB products might aid in the treatment of acute diarrhea, and possibly affect rotavirus infections in children and travelers' diarrhea in adults, but no products are approved for such indications. There is weak evidence probiotics might lower the incidence of acute upper respiratory-tract infections in adults.
Probiotics do not appear to change the risk of infection in older people.
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.
Several clinical studies provide evidence for the potential of probiotics to lower the risk of necrotizing enterocolitis and mortality in premature infants. One meta-analysis indicated that probiotics reduce these risks by more than 50% compared with controls.
Recurrent abdominal pain
A 2017 review based on moderate to low-quality 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.
No good evidence indicates probiotics are of benefit in the management of infection or inflammation of the urinary tract.
Supplements such as tablets, capsules, powders, and sachets containing the bacteria have been studied. However, probiotics taken orally can be destroyed by the acidic conditions of the stomach. As of 2010, a number of microencapsulation techniques were being developed to address this problem.
Preliminary research is evaluating the potential physiological effects of multiple probiotic strains, as opposed to a single strain. As the human gut may contain several hundred microbial species, one theory indicates that this diverse environment may benefit from consuming multiple probiotic strains, an effect that remains scientifically unconfirmed.
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[update], no claims had been approved by those two agencies. Some experts are skeptical about the efficacy of different probiotic strains and believe that not all subjects benefit from probiotics.
Scientific guidelines for testing
First, probiotics must be alive when administered. One of the concerns throughout the scientific literature resides in the viability and reproducibility on a large scale of observed results for specific studies, as well as the viability and stability during use and storage, and finally the ability to survive in stomach acids and then in the intestinal ecosystem.
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. 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.
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. This calls for a precise identification of the strain, i.e. genotypic and phenotypic characterization of the tested microorganism.
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:
Determination of antibiotic resistance patterns
Assessment of certain metabolic activities (e.g. D-lactate production, bile salt deconjugation)
Assessment of side effects in human studies
Epidemiological surveillance of adverse incidents in consumers (after market)
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.
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 safety assessment of microbial species used in food and feed productions to set priorities for the need of risk assessment. The assessment is made for certain microorganisms; if the result is favorable, it leads to “Qualified Presumption of Safety” status.
^ abcdefghijklRijkers GT, de Vos WM, Brummer RJ, Morelli L, Corthier G, Marteau P (2011). "Health benefits and health claims of probiotics: Bridging science and marketing". British Journal of Nutrition. 106 (9): 1291–6. doi:10.1017/S000711451100287X. PMID21861940.
^ abcTurck, Dominique; Castenmiller, Jacqueline; De Henauw, Stefaan; Hirsch‐Ernst, Karen Ildico; Kearney, John; Knutsen, Helle Katrine; MacIuk, Alexandre; Mangelsdorf, Inge; McArdle, Harry J.; Naska, Androniki; Pelaez, Carmen; Pentieva, Kristina; Thies, Frank; Tsabouri, Sophia; Vinceti, Marco; Bresson, Jean‐Louis; Siani, Alfonso (15 April 2019). "Nutrimune and immune defence against pathogens in the gastrointestinal and upper respiratory tracts: evaluation of a health claim pursuant to Article 14 of Regulation (EC) No 1924/2006". EFSA Journal. European Food Safety Authority, Panel on Nutrition, Novel Foods and Food Allergens. 17 (4). doi:10.2903/j.efsa.2019.5656.
^ abcEngle MK, Roosevelt MW, Waltrip EA (22 November 2011). "Warning letter to CocoKefir LLC". Compliance Branch, Inspections, Compliance, Enforcement, and Criminal Investigations, US Food and Drug Administration and Federal Trade Commission. Archived from the original on 23 October 2016. Retrieved 4 June 2016.CS1 maint: BOT: original-url status unknown (link)
^Magdalena Araya, Catherine Stanton, Lorenzo Morelli, Gregor Reid, Maya Pineiro, et al., 2006, "Probiotics in food: health and nutritional properties and guidelines for evaluation," Combined Report of a Joint FAO/WHO Expert Consultation on Evaluation of Health and Nutritional Properties of Probiotics in Food Including Powder Milk with Live Lactic Acid Bacteria, Cordoba, Argentina, 1–4 October 2001, and Report of a Joint FAO/WHO Working Group on Drafting Guidelines for the Evaluation of Probiotics in Food, London, Ontario, Canada, 30 April–1 May 2002 [FAO Food and Nutrition paper 85], pp. 1–50, Rome, Italy:World Health Organization (WHO), Food and Agriculture Organization (FAO) [of the United Nations], ISBN9251055130, see [permanent dead link], accessed 11 June 2015.
^ abRijkers GT, Bengmark S, Enck P, Haller D, Herz U, Kalliomaki M, Kudo S, Lenoir-Wijnkoop I, Mercenier A, Myllyluoma E, Rabot S, Rafter J, Szajewska H, Watzl B, Wells J, Wolvers D, Antoine JM (2010). "Guidance for substantiating the evidence for beneficial effects of probiotics: current status and recommendations for future research". J. Nutr. 140 (3): 671S–6S. doi:10.3945/jn.109.113779. PMID20130080.
^Hill, C; Guarner, F; Reid, G; Gibson, GR; Merenstein, DJ; Pot, B; Morelli, L; Canani, RB; Flint, HJ; Salminen, S; Calder, PC; Sanders, ME (August 2014). "Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic". Nature Reviews. Gastroenterology & Hepatology. 11 (8): 506–14. doi:10.1038/nrgastro.2014.66. PMID24912386.
^Moreno MR, Leisner JJ, Tee LK, Ley C, Radu S, Rusul G, Vancanneyt M, De Vuyst L (2002). "Microbial analysis of Malaysian tempeh, and characterization of two bacteriocins produced by isolates of Enterococcus faecium". Journal of Applied Microbiology. 92 (1): 147–157. doi:10.1046/j.1365-2672.2002.01509.x. PMID11849339.
^Tanasupawat S, Thongsanit J, Okada S, Komagata K (2002). "Lactic acid bacteria isolated from soy sauce mash in Thailand". Journal of General and Applied Microbiology. 48 (4): 201–209. doi:10.2323/jgam.48.201. PMID12469319.
^Plessas S, Alexopoulos A, Voidarou C, Stavropoulou E, Bezirtzoglou E (2011). "Microbial ecology and quality assurance in food fermentation systems. The case of kefir grains application". Anaerobe. 17 (6): 483–5. doi:10.1016/j.anaerobe.2011.03.014. PMID21497663.
^ abSchmidt, Nancy, Acting Director (30 July 2014). "Warning letter to Plexus Worldwide Inc". Compliance Branch, Inspections, Compliance, Enforcement, and Criminal Investigations, US Food and Drug Administration. Archived from the original on 8 May 2017. Retrieved 9 May 2017.CS1 maint: multiple names: authors list (link)
^Élie [Ilya Ilyich] Metchnikoff, 2004 , The prolongation of life: Optimistic studies, p. 116. Springer Classics in Longevity and Aging, New York, NY:Springer, ISBN0826118771, reprint of 1908 English edition by É.M., same title (P. Chalmers Mitchell, Ed.), New York, NY:Putnam, ISBN0826118763, itself a translation of 1907 French edition by I.I.M., Essais optimistes, Paris:Heinemann, Retrieved 12 November 2015.
^Arteriosclerosis and intestinal poisons. [a contemporary review of Metchnikoff's work] JAMA 1910, 55:2311-12.
^Parker, R. B. (1974). "Probiotics, the other half of the antibiotic story". Animal Nutrition and Health. 29: 4–8.
^Tannock GW (September 2003). "Probiotics: time for a dose of realism". Current Issues in Intestinal Microbiology. 4 (2): 33–42. PMID14503687.
^Fuller, R., ed. (1992) Probiotics. The Scientific Basis. Chapman & Hall, London, U.K
^Alvarez-Olmos MI, Oberhelman RA (2001). "Probiotic agents and infectious diseases: a modern perspective on a traditional therapy". Clin. Infect. Dis. 32 (11): 1567–76. doi:10.1086/320518. PMID11340528.
^"Scientific Opinion on the substantiation of a health claim related to a combination of Bifidobacterium longum LA 101, Lactobacillus helveticus LA 102, Lactococcus lactis LA 103 and Streptococcus thermophillus LA 104 and reducing intestinal discomfort pursuant to Article 13(5) of Regulation (EC) No 1924/2006 (example, search EFSA for other opinion reports on probiotics". EFSA Journal. 11 (2): 3085. 2013. doi:10.2903/j.efsa.2013.3085.
^Million M, Angelakis E, Paul M, Armougom F, Leibovici L, Raoult D (August 2012). "Comparative meta-analysis of the effect of Lactobacillus species on weight gain in humans and animals". Microbial Pathogenesis. 53 (2): 100–8. doi:10.1016/j.micpath.2012.05.007. PMID22634320.
^Lin J, Zhang Y, He C, Dai J (September 2018). "Probiotics supplementation in children with asthma: A systematic review and meta-analysis". J Paediatr Child Health (Systematic review). 54 (9): 953–961. doi:10.1111/jpc.14126. PMID30051941. S2CID51723667.
^Szajewska H, Ruszczyński M, Radzikowski A (September 2006). "Probiotics in the prevention of antibiotic-associated diarrhea in children: a meta-analysis of randomized controlled trials". J Pediatr. 149 (3): 367–372. doi:10.1016/j.jpeds.2006.04.053. PMID16939749.
^Sazawal S, Hiremath G, Dhingra U, Malik P, Deb S, Black RE (June 2006). "Efficacy of probiotics in prevention of acute diarrhoea: a meta-analysis of masked, randomised, placebo-controlled trials". Lancet Infect Dis. 6 (6): 374–82. doi:10.1016/S1473-3099(06)70495-9. PMID16728323.
^Arvola T, Laiho K, Torkkeli S, Mykkänen H, Salminen S, Maunula L, Isolauri E (1999). "Prophylactic Lactobacillus GG reduces antibiotic-associated diarrhea in children with respiratory infections: A randomized study". Pediatrics. 104 (5): e64. doi:10.1542/peds.104.5.e64. PMID10545590.
^Agerholm-Larsen L, Bell ML, Grunwald GK, Astrup A (2002). "The effect of a probiotic milk product on plasma cholesterol: a meta-analysis of short term intervention studies". European Journal of Clinical Nutrition. 54 (11): 856–860. doi:10.1038/sj.ejcn.1601104. PMID11114681.
^Cuello-Garcia CA, Brożek JL, Fiocchi A, Pawankar R, Yepes-Nuñez JJ, Terracciano L, Gandhi S, Agarwal A, Zhang Y, Schünemann HJ (2015). "Probiotics for the prevention of allergy: A systematic review and meta-analysis of randomized controlled trials". J. Allergy Clin. Immunol. (Systematic review & meta-analysis). 136 (4): 952–61. doi:10.1016/j.jaci.2015.04.031. PMID26044853.
^Hamilton-Miller JM (October 2003). "The role of probiotics in the treatment and prevention of Helicobacter pylori infection". International Journal of Antimicrobial Agents. 22 (4): 360–6. doi:10.1016/S0924-8579(03)00153-5. PMID14522098.
^Wachholz, PA; Nunes, VDS; Polachini do Valle, A; Jacinto, AF; Villas-Boas, PJF (3 February 2018). "Effectiveness of probiotics on the occurrence of infections in older people: systematic review and meta-analysis". Age and Ageing. 47 (4): 527–536. doi:10.1093/ageing/afy006. hdl:11449/164454. PMID29415116.
^Moayyedi P, Ford AC, Talley NJ, Cremonini F, Foxx-Orenstein AE, Brandt LJ, Quigley EM (March 2010). "The efficacy of probiotics in the treatment of irritable bowel syndrome: a systematic review". Gut (Systematic review). 59 (3): 325–32. doi:10.1136/gut.2008.167270. PMID19091823. S2CID18281136.
^Newlove-Delgado TV, Martin AE, Abbott RA, Bethel A, Thompson-Coon J, Whear R, et al. (2017). "Dietary interventions for recurrent abdominal pain in childhood". Cochrane Database Syst Rev. 3: CD010972. doi:10.1002/14651858.CD010972.pub2. PMC6464236. PMID28334433. Overall, there is some evidence to suggest that probiotics may be effective in the treatment of RAP, in terms of improving pain in the shorter term. Clinicians may therefore consider probiotic interventions as part of themanagement strategy for children with RAP (Recurrent Abdominal Pain). However, we were unable to recommend the optimum strain and dosage of probiotic based on this review. The evidence for the effectiveness of probiotics was based largely on shorter-term outcomes. Further trials are required to assess whether improvements in pain are maintained over the longer term; these trials should also consider the importance of using validated and consistent scales to measure pain and other outcomes.
^Shortliffe LMD (2013). Wein AJ (ed.). Chapter 116: Infection and Inflammation of the Pediatric Genitourinary Tract. Urology. 4 (10th ed.). Saunders Elsevier. p. 3121.
^Opinion of the Scientific Committee, European Food Safety Authority (2007). "Introduction of a Qualified Presumption of Safety (QPS) approach for assessment of selected microorganisms referred to EFSA". EFSA Journal. 587 (12): 1–16. doi:10.2903/j.efsa.2007.587.