Élie Metchnikoff first suggested the possibility of colonizing the gut with beneficial flora in the early 20th century.
Probiotics are microorganisms that some have claimed provide health benefits when consumed. The term probiotic is currently used to name ingested microorganisms associated with beneficial effects to humans and animals. Introduction of the concept is generally attributed to Nobel Prize recipient Eli Metchnikoff, who in 1907 suggested that "the dependence of the intestinal microbes on the food makes it possible to adopt measures to modify the flora in our bodies and to replace the harmful microbes by useful microbes". A significant expansion of the potential market for probiotics has led to higher requirements for scientific substantiation of putative beneficial effects conferred by the microorganisms.
Etymologically, the term appears to be a composite of the Latin preposition pro ("for") and the Greek adjective βιωτικός (biotic), the latter deriving from the noun βίος (bios, "life").
Most of the literature gives it a full Greek etymology, but the word is actually composed of a Latin prefix “pro” and the Ancient Greek word “bios”, a linguistic hybrid, which means “life”.
The World Health Organization's 2001 definition of probiotics is "live micro-organisms which, when administered in adequate amounts, confer a health beneﬁt on the host". Following this definition, a working group convened by the FAO/WHO in May 2002 issued the “Guidelines for the Evaluation of Probiotics in Food”. This 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 claim. The same principles emerged from those groups as the ones expressed in the Guidelines of FAO/WHO in 2002. This definition, although widely adopted, is not acceptable to the European Food Safety Authority because it embeds a health claim which is not measurable.
A consensus definition of the term “probiotics”, based on the available information and scientific evidence, was adopted after a joint Food and Agricultural Organization of the United Nations and World Health Organization expert consultation. In October 2001, this expert consultation defined probiotics as: “live micro-organisms which, when administered in adequate amounts, confer a health benefit on the host”. The FAO/WHO consultation was also a first effort towards the assessment of probiotics efficacy and resulted in May 2002 in a document named “Guidelines for the Evaluation of Probiotics in Food”. This effort is accompanied by local governmental and supra-governmental regulatory bodies requirements to better characterize health claims substantiations.
Probiotics have to be alive when administered. One of the concerns throughout the scientific literature resides in the viability and reproducibility on a large scale of the observed results, as well as the viability and stability during use and storage and finally the ability to survive in the intestinal ecosystem.
Probiotics must have undergone controlled evaluation to document health benefits in the target host. Only products containing live organisms shown in reproducible human studies to confer a health benefit can actually claim to be a probiotic. The correct definition of health benefit, backed with solid scientific evidence, is a strong element for the proper identification and assessment of the effect of a probiotic. This aspect represents a major challenge for scientific and industrial investigations because several difficulties arise, such as variability in the site for probiotic use (oral, vaginal, intestinal) and mode of application.
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 probiotic 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.
Probiotics must be safe for their intended use. The 2002 FAO/WHO guidelines recommend that, though bacteria may be Generally Recognized as Safe (GRAS), the safety of the potential probiotic should be assessed by the minimum required tests:
Determination of antibiotic resistance patterns
Assessment of certain metabolic activities (e.g., D-lactate production, bile salt deconjugation)
Assessment of side-effects during human studies
Epidemiological surveillance of adverse incidents in consumers (post-market)
If the strain under evaluation belongs to a species that is a known mammalian toxin producer, 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 (SCAN, 2000)
If the strain under evaluation belongs to a species with known hemolytic potential, determination of hemolytic activity is required
In Europe, EFSA has adopted a pre-market system for safety assessment of microbial species used in food and feed productions, in order to set priorities for the need of risk assessment. The assessment is made for a selected group of microorganisms, which if favorable, leads to the “Qualified Presumption of Safety” (QPS) status.
Finally probiotics have to be supplied in adequate amounts which may be defined as the amount able to trigger the targeted effect on the host. It depends on strain specificity, process and matrix, as well as the targeted effect. Most of reported benefits demonstrated with the traditional probiotics have been observed after ingestion of a concentration around 107 to 108 probiotics per gram, with serving size around 100 to 200 grams per day.
Though probiotics have received renewed attention recently from product manufacturers, research studies and consumers, the idea of health benefits through food starts with the history of mankind. The history of probiotics can be traced back 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.
It was at that time known that milk fermented with lactic-acid bacteria inhibits the growth of proteolytic bacteria because of the low pH produced by the fermentation of lactose. Metchnikoff had also observed that certain rural populations in Europe, for example in Bulgaria and the Russian steppes who lived largely on milk fermented by lactic-acid bacteria were exceptionally long lived. Based on these observations, Metchnikoff proposed that consumption of fermented milk would "seed" the intestine with harmless lactic-acid bacteria and decrease the intestinal pH and that this would suppress the growth of proteolytic bacteria. Metchnikoff himself introduced in his diet sour milk fermented with the bacteria he called "Bulgarian Bacillus" and found 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 flora of breast-fed babies and he observed clinical benefits from treating diarrhea in infants with bifidobacteria. The claimed effect was bifidobacterial displacement of proteolytic bacteria causing the disease.
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 Escherichia 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, by feeding them with Lactobacilus acidophilus. They observed changes in composition of fecal microbiota, which they described as “transformation of the intestinal flora”. Rettger further explored the possibilities of Lactobacilus 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 Lactobacillus acidophilus were found to be 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.
According to Hamilton-Miller et al., in a letter in which they call for the oldest known citation of the word, the term "probiotics" was first introduced in 1953 by Werner Kollath (see Hamilton-Miller et al. 2003) to describe organic and inorganic food supplements applied to restore health to patients suffering from manlnutrition. 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, a usage credited to Lilly and Stilwell (1965). Their conception of probiotics involved the notion that substances secreted by one microorganism stimulated the growth of another microorganism. The term was used again in 1971 by Sperti  to describe tissue extracts which stimulated microbial growth. The term probiotics was taken up by Parker in 1974  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 in 1989, whose explanation was very close to the definition used today. Fuller in 1989 described probiotics as a "live microbial feed supplement which beneficially affects the host animal by improving its intestinal microbial balance". He stressed two important facts of probiotics: the viable nature of probiotics and the capacity to help with intestinal balance.
Probiotics are under considerable research, as the concept holds promise for human health and well-being, and corresponding commercial opportunities. Protection of consumers requires health claims to be confirmed with sufficient scientific evidence. Overall scientific demonstration of probiotic effects requires defining a healthy microbiota and interactions between microbiota and host, and the difficulty to characterize probiotic effectiveness in health and disease. Recent developments of high-throughput sequencing technology and the consequent progresses of metagenomics represent a new approach for the future of probiotics research.
Studies are examining whether probiotics affect mechanisms of intestinal inflammation,diarrhea, urogenital infections or allergies. Through 2012, however, 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.
Research into the potential health effects of supplemental probiotics has included the molecular biology and genomics of Lactobacillus in immune function, cancer, and antibiotic-associated diarrhea, travellers' diarrhea, pediatric diarrhea, inflammatory bowel disease and irritable bowel syndrome. Testing of a probiotic applies to a specific strain under study. The scientific community cautions against extrapolating an effect from a tested strain to an untested strain.
One expert reasoned that preliminary clinical results exist for some applications, such as treating diarrhea, but wider health benefits claimed by probiotic proponents lack plausibility since the body's "ecosystem" is sufficiently complex that adding a few bacteria is unlikely to have the claimed effect. Accordingly, "the alleged health benefits of probiotics are often an example of spin".
A 2013 meta-analysis of 25 trials found that probiotic supplementation in pregnancy and early life might help with atopic sensitivity in infants but probably not with asthma or wheezing.
Some probiotics have been shown in preliminary research to possibly treat various forms of gastroenteritis. A Cochrane Collaboration systematic review of the use of probiotics to treat acute infectious diarrhoea found encouraging results, but said further research was necessary to confirm the reported benefits.
Some of the best evidence in support of probiotic health benefits is in the treatment of Antibiotic-associated diarrhea (AAD). Antibiotics are a common treatment for children, and 20% of antibiotic-treated children develop diarrhea. AAD results from an imbalance in the colonic microbiota caused by antibiotic therapy. Microbiota alteration changes carbohydrate metabolism with decreased short-chain fatty acid absorption and an osmotic diarrhea as a result. The preventive role of some probiotics has been correctly assessed in randomly clinical trials. A review, assessing the work of 16 different studies representing more than 3400 patients’ evaluation, concluded that the evidence gathered suggested a protective effect of some probiotics in this condition. In adults, some probiotics showed a beneficial role in reducing the occurrence of antibiotic associated diarrhea. Another consequence of antibiotic therapy leading to diarrhea is overgrowth of potentially pathogenic organisms such as Clostridium difficile.
Probiotic treatment might reduce the incidence and severity of AAD as indicated in several meta-analyses. For example, treatment with probiotic formulations including Lactobacillus rhamnosus may reduce the risk of antibiotic-associated diarrhea, improve stool consistency during antibiotic therapy, and enhance the immune response after vaccination. However, further documentation of these findings through randomized, double blind, placebo-controlled trials is required to confirm specific effects and obtain regulatory approval, which currently does not exist.
Potential efficacy of probiotic AAD prevention is dependent on the probiotic strain(s) used and on the dosage. A Cochrane Collaboration systematic review, in which 16 randomized clinical trials (n=3432 participants) were analyzed, concluded that treatments with less than 5000 million of CFU/day did not show a significant decrease of AAD. On the other hand, patients treated with ≥5000 million of CFU/day (including Lactobacillus rhamnosus and Saccharomyces boulardii) had 60% lower relative risk (95%CI: 44%-71%) of experiencing AAD than non-treated patients.
Ingestion of certain active strains may help lactose-intolerant individuals tolerate more lactose than they would otherwise have tolerated.
Preliminary human and animal studies have demonstrated the efficacy of some strains of lactic acid bacteria for reducing serum cholesterol levels, presumably by breaking down bile in the gut, thus inhibiting its reabsorption (where it enters the blood as cholesterol).
A meta-analysis that included five double blind trials examining the short term (2-8weeks) effects of a yogurt with probiotic strains on serum cholesterol levels found a minor change of 8.5 mg/dL (0.22 mmol/L) (~4% decrease) in total cholesterol concentration, and a decrease of 7.7 mg/dL (0.2 mmol/L) (~5% decrease) in serum LDL concentration.
A slightly longer study evaluating the effect of a yogurt with probiotic strains on twenty-nine subjects over six months found no statistically significant differences in total serum cholesterol or LDL values. However, the study did note a significant increase in serum HDL from, 50 mg/dL (1.28 mmol/L) to 62 mg/dL (1.6 mmol/L) following treatment. This corresponds to a possible improvement of LDL/HDL ratio.
Studies specifically on hyper-lipidemic subjects are still needed.
Although not a confirmed effect, some studies have indicated that consumption of milk fermented with various strains of LAB may result in modest reductions in blood pressure, an effect possibly related to the ACE inhibitor-like peptides produced during fermentation.
Immune function and infections
Some strains of LAB may affect pathogens by means of competitive inhibition (i.e., by competing for growth) and there is evidence to suggest that they may improve immune function by increasing the number of IgA-producing plasma cells, increasing or improving phagocytosis as well as increasing the proportion of T lymphocytes and Natural Killer cells.Clinical trials have demonstrated that probiotics may decrease the incidence of respiratory tract infections and dental caries in children. LAB products might aid in the treatment of acute diarrhea, and possibly affect rotavirus infections in children and travelers' diarrhea in adults, but no products are approved for such indications.
A 2010 study suggested that probiotics, by introducing "good" bacteria into the gut, may help maintain immune system activity, which in turn helps the body react more quickly to new infections. Antibiotics seem to reduce immune system activity as a result of killing off the normal gut bacteria.
Some strains of LAB may affect Helicobacter pylori infections (which may cause peptic ulcers) in adults when used in combination with standard medical treatments, but there is no standard in medical practice or regulatory approval for such treatment.
Some strains of LAB may modulate inflammatory and hypersensitivity responses, an observation thought to be at least in part due to the regulation of cytokine function. Clinical studies suggest that they can prevent reoccurrences of inflammatory bowel disease in adults, as well as improve milk allergies. They are not effective for treating eczema, a persistent skin inflammation. How probiotics may influence the immune system remains unclear, but a potential mechanism under research concerns the response of T lymphocytes to pro-inflammatory stimuli.
Bacterial growth under stress
In a study done to see the effects of stress on intestinal flora, rats that were fed probiotics had little occurrence of harmful bacteria adhering to their intestines compared to rats that were fed sterile water.
Irritable bowel syndrome and colitis
There is some evidence probiotics may help people with irritable bowel syndrome, although uncertainty remains around which type of priobiotic works best, and around the size of the effect.
Several clinical studies provide evidence for the potential of probiotics to lower the risk of NEC and mortality in premature infants. One meta-analysis indicated that probiotics reduce all-cause mortality and risk of having NEC by more than 50% compared with controls.
In 2003, researchers found that a combination of L rhamnosus 19070-2 and L reuteri DSM 122460 was beneficial in the management of Atopic Dermatitis.The effect was more pronounced in patients with increased IgE levels. In 14 trials, most done between 2007 and 2011, researchers found a roughly 20% reduction in the rate of atopic dermatitis (from around 34% in the children in these trials to 26%).
Current research is focusing on the molecular biology and genomics of Lactobacillus strains and bifidobacteria. The application of modern whole genome approaches is providing insights into bifidobacterial evolution, while also revealing genetic functions that may explain their presence in the particular ecological environment of the gastrointestinal tract.
In some situations, such as where the person consuming probiotics is critically ill, probiotics could be harmful. In a therapeutic clinical trial conducted by the Dutch Pancreatitis Study Group, the consumption of a mixture of six probiotic bacteria increased the death rate of patients with predicted severe acute pancreatitis.
In a clinical trial conducted at the University of Western Australia, aimed at showing the effectiveness of probiotics in reducing childhood allergies, researchers gave 178 children either a probiotic or a placebo for the first six months of their life. Those given the probiotic were more likely to develop a sensitivity to allergens.
Some hospitals have reported treating lactobacillus septicaemia, which is a potentially fatal disease caused by the consumption of probiotics by people with lowered immune systems or who are already very ill.[unreliable medical source?]
Probiotics taken orally can be destroyed by the acidic conditions of the stomach. A number of micro-encapsulation techniques are being developed to address this problem.
One 2009 study causally linked probiotic products such as yogurts with obesity trends. However, this is contested as the link to obesity, and other health related issues with yogurt may link to its dairy and calorie attributes.
Some experts are skeptical on the efficacy of many strains and believe not all subjects will benefit from the use of probiotics.
Live probiotic cultures are available in fermented dairy products and probiotic fortified foods. However, tablets, capsules, powders and sachets containing the bacteria in freeze dried form are also available.
Only preliminary evidence exists for most probiotic health claims. Even of the most researched strains, few have been sufficiently developed in basic and clinical research to warrant approval for health claim status to a regulatory agency such as the Food and Drug Administration or European Food Safety Authority, and to date no claims have been approved by those two agencies.
Lactobacillus reuteri Protectis (DSM 17938, daughter strain of ATCC 55730)
Evidence for shortened duration of diarrhea in children, decreased crying in infantile colic, reduced risk of diarrhea in children, may affect constipation  and functional abdominal pain in children.
Lactobacillus reuteri Prodentis (DSM 17938/ATCC 55730 and ATCC PTA 5289 in combination) for oral health
In vitro inhibition of Listeria monocytogenes and L. innocua, Escherichia coli, Staphylococcus aureus, Enterococcus faecalis and Enterococcus faecium. May reduce symptoms of lactose intolerance and immune stimulation.
Lactobacillus plantarum HEAL 9 & Lactobacillus paracasei 8700:2
The European Food Safety Authority has so far rejected 260 claims on probiotics in Europe due to insufficient research and thus inconclusive proof. The review did not refute the potential for effectiveness, but rather that a cause-effect relationship had not been sufficiently established in studies to date. The claims rejected include:
Lactobacillus paracasei LMG P 22043 decreases potentially pathogenic gastro-intestinal microorganisms or reduce gastro-intestinal discomfort.
Lactobacillus johnsonii BFE 6128 . Immunity and skin claims (all too general for consideration).
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 microbe species, one theory indicates that this diverse environment may benefit from consuming multiple probiotic strains, an effect that remains scientifically unconfirmed.
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