Probiotic

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

Probiotics are micro-organisms that have claimed health benefits when consumed.[1]

Lactic acid bacteria (LAB) and bifidobacteria are the most common types of microbes used as probiotics, but certain yeasts and bacilli may also be used. Probiotics are commonly consumed as part of fermented foods with specially added active live cultures, such as in yogurt, soy yogurt, or as dietary supplements.

Studies are examining whether probiotics affect mechanisms of intestinal inflammation,[2] diarrhea,[3] urogenital infections[4] or allergies.[5] 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.[6]

When a person takes antibiotics, both the harmful bacteria and the beneficial bacteria are killed. A reduction of beneficial bacteria can lead to digestive problems, such as diarrhea, yeast infections and urinary tract infections. The possibility that supplemental probiotics affect such digestive issues is unknown, and remains under study.[7]

Definition[edit]

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".[8] This definition, although widely adopted, is not acceptable to the European Food Safety Authority because it embeds a health claim which is not measurable.[1]

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").[9]

History[edit]

The original observation of the positive role played by certain bacteria was first introduced by Russian scientist and Nobel laureate Élie Metchnikoff, who in the beginning of the 20th century suggested that it would be possible to modify the gut flora and to replace harmful microbes with useful microbes.[10] 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 flora, 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 auto-intoxication", which would cause the physical changes associated with old age.[citation needed]

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 facts, 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.[11]

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[12] 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.[citation needed]

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.[13] 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.[citation needed]

In 1920, Rettger demonstrated that Metchnikoff's "Bulgarian Bacillus", later called Lactobacillus delbrueckii subsp. bulgaricus, could not live in the human intestine,[14] and the fermented food phenomenon petered out. Metchnikoff's theory was disputable (at this stage), and people doubted his theory of longevity.[citation needed]

After Metchnikoff's death in 1916, the centre of activity moved to the United States. It was reasoned that bacteria originating from the gut were more likely to produce the desired effect in the gut, and in 1935 certain strains of Lactobacillus acidophilus were found to be very active when implanted in the human digestive tract.[15] Trials were carried out using this organism, and encouraging results were obtained especially in the relief of chronic constipation.[citation needed]

The term "probiotics" was first introduced in 1953 by Werner Kollath (see Hamilton-Miller et al. 2003). 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".[16] Fuller's definition emphasizes the requirement of viability for probiotics and introduces the aspect of a beneficial effect on the host.[citation needed]

The term "probiotic" originally referred to microorganisms that have effects on other microorganisms, a usage credited to Lilly and Stilwell (1965).[17] 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 [18] to describe tissue extracts which stimulated microbial growth. The term probiotics was taken up by Parker in 1974 [19] 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,[20] 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.

In the following decades, intestinal lactic acid bacterial species with alleged health beneficial properties have been introduced as probiotics, including Lactobacillus rhamnosus, Lactobacillus casei, and Lactobacillus johnsonii.[21]

Research and effectiveness[edit]

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.[22] Testing of a probiotic applies to a specific strain under study.[23] The scientific community cautions against extrapolating an effect from a tested strain to an untested strain.[24][25]

In general, only preliminary evidence exists for the health effects stated below. Few of the strains have been sufficiently developed in basic and clinical research to warrant approval for health claim status by a regulatory agency such as the Food and Drug Administration or European Food Safety Authority, and to date no single health effect has been proven to warrant a health claim[26]

Infectious disease specialist Mark Crislip has written that while some promising clinical data exists for some applications, such as treating diarrhea, the 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. In Crislips view, "the alleged health benefits of probiotics are often an example of spin".[27]

There is very little evidence to support claims that probiotic dietary supplements have any health benefits.[28]

Allergies[edit]

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.[29]

Diarrhea[edit]

Some probiotics have been shown in preliminary research to possibly treat various forms of gastroenteritis.[30] 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.[31][32]

Antibiotic-associated diarrhea

Some of the best evidence in support of probiotic health benefits is in the treatment of Antibiotic-associated diarrhea (AAD).[27] 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. Another consequence of antibiotic therapy leading to diarrhea is overgrowth of potentially pathogenic organisms such as Clostridium difficile.[33]

Probiotic treatment might reduce the incidence and severity of AAD as indicated in several meta-analyses.[34] 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.[35] 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.[36][37]

A further meta-analysis indicated that probiotics may inhibit C. difficile associated diarrhea (CDAD) without increasing the incidence of clinically significant side effects.[38]

Lactose intolerance[edit]

Ingestion of certain active strains may help lactose-intolerant individuals tolerate more lactose than they would otherwise have tolerated.[39]

Cholesterol[edit]

Animal studies have demonstrated the efficacy of some strains of LAB at being able to lower serum cholesterol levels, presumably by breaking down bile in the gut, thus inhibiting its reabsorption (which enters the blood as cholesterol).[39]

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.[40]

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.[41]

Studies specifically on hyper-lipidemic subjects are still needed.

Blood pressure[edit]

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.[39]

Immune function and infections[edit]

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.[42][43] Clinical trials have demonstrated that probiotics may decrease the incidence of respiratory tract infections[44] and dental caries in children.[45] LAB products might aid in the treatment of acute diarrhea, and possibly affect rotavirus infections in children and travelers' diarrhea in adults,[42][43] 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.[46]

Helicobacter pylori[edit]

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.[47]

Inflammation[edit]

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.[42] Clinical studies suggest that they can prevent reoccurrences of inflammatory bowel disease in adults,[42] as well as improve milk allergies.[48] They are not effective for treating eczema, a persistent skin inflammation.[49] 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.[50]

Bacterial growth under stress[edit]

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.[51]

Irritable bowel syndrome and colitis[edit]

In one study, a commercial strain of Bifidobacterium infantis improved some symptoms of irritable bowel syndrome in women.[52] A separate small study showed that a strain of Lactobacillus plantarum may also be effective in reducing IBS symptoms.[53] A study focused on Bifidobacterium animalis showed a reduction in discomfort and bloating in individuals with constipation-predominant IBS, as well as helping to normalize stool frequency in said individuals.[54] For maintenance of remission of ulcerative colitis, Mutaflor (E.coli Nissle 1917) randomized clinical studies showed equivalence of Mutaflor and mesalazine (5-ASAs).[55]

Necrotizing enterocolitis (NEC)[edit]

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.[56]

Vitamin production[edit]

Probiotics synthesize vitamins. For example, they produce vitamin K,[57] folic acid,[58] and vitamin B12.[59]

Eczema[edit]

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.[60] 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%).[61]

Bacterial Vaginosis[edit]

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 re-balance vaginal flora, preventing and alleviating bacterial vaginosis.[62]

Other[edit]

A study in 2004 testing the immune system of students given either milk or Actimel over a 6-week exam period (3 weeks of studying, 3 weeks of exams) tested 19 different biomarkers. Of these 19 biomarkers, only 2 were shown to be different between the two groups: increased production of lymphocytes and increased production of CD56 cells. The tests were not blind and show that certain probiotic strains may have no overall effect on the immune system or on its ability.[63]

A 2007 study at University College Cork in Ireland showed that a diet including milk fermented with Lactobacillus bacteria prevented Salmonella infection in pigs.[64]

A 2007 preliminary study at Imperial College London showed that a commercially available probiotic drink containing Lactobacillus casei DN-114001 and yoghurt bacteria might reduce the incidence of antibiotic-associated diarrhea (AAD) and C difficile-associated diarrhea.[65]

The efficacy and safety of a daily dose of Lactobacillus acidophilus CL1285 in affecting antibiotic-associated diarrhea (AAD) was demonstrated in one preliminary study of hospitalized patients.[66]

A 2011 study found that mice given Lactobacillus rhamnosus JB-1 showed lower levels of stress and anxiety than controls.[67]

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.[68][69]

Side effects[edit]

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.[70]

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.[71]

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.[71][72][unreliable medical source?]

There is no published evidence that probiotic supplements are able to replace the body's natural flora when these have been killed off; indeed bacterial levels in feces disappear within days when supplementation ceases.[73]

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.[74]

One 2009 study causally linked probiotic products such as yogurts with obesity trends.[75] However, this is contested as the link to obesity, and other health related issues with yogurt may link to its dairy and calorie attributes.[76][77]

Some experts are skeptical on the efficacy of many strains and believe not all subjects will benefit from the use of probiotics.[78]

Strains[edit]

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.

Probiotic Research[79]
StrainClaimed potential effect in humans
Bacillus coagulans GBI-30, 6086May improve abdominal pain and bloating in IBS patients.[80] May increase immune response to a viral challenge.[81]
Bifidobacterium animalis subsp. lactis BB-12May have an effect on the gastrointestinal system.[82]
Bifidobacterium longum subsp. infantis 35624Possible relief from abdominal pain/discomfort, bloating and constipation.[83]
Lactobacillus acidophilus NCFMShown in one study to reduce the side effects of antibiotic therapy.[84]
Lactobacillus paracasei St11 (or NCC2461)One study indicated reduction of diarrhea in children[85]
Lactobacillus johnsonii La1 (= Lactobacillus LC1, Lactobacillus johnsonii NCC533)May reduce incidence of H. pylori-caused gastritis and may reduce inflammation [86]
Lactobacillus plantarum 299vMay affect symptoms of IBS.[87]
Lactobacillus reuteri ATCC 55730 (Lactobacillus reuteri SD2112)Evidence for diarrhea mitigation in children,[88][89] decreased crying in infantile colic,[90] H. pylori infection,[91] antibiotic-associated side-effects,[92][93] fever and diarrhea in children[94] and number of sick days in adults.[95]
Lactobacillus reuteri Protectis (DSM 17938, daughter strain of ATCC 55730)[96]Evidence for shortened duration of diarrhea in children,[97] decreased crying in infantile colic,[98][99] reduced risk of diarrhea in children,[100] may affect constipation [101] and functional abdominal pain in children.[102]
Lactobacillus reuteri Prodentis (DSM 17938/ATCC 55730 and ATCC PTA 5289 in combination) for oral healthEvidence for effect on gingivitis and periodontitis,[103][104][105][106] preliminary evidence for reduction of oral malodor,[107] evidence for reduction of risk factors for caries [108][109][110]
Saccharomyces boulardiiGood evidence for treatment and prevention of antibiotic-associated diarrhea[111] and acute diarrhea.[112][113]
tested as mixture:
Lactobacillus rhamnosus GR-1 & Lactobacillus reuteri RC-14
In one study, oral ingestion resulted in vaginal colonisation and reduced vaginitis.[114]
tested as mixture:
Lactobacillus acidophilus NCFM & Bifidobacterium bifidum BB-12
Preliminary evidence for reduced C. difficile–associated disease.[115]
tested as mixture:
Lactobacillus acidophilus CL1285 & Lactobacillus casei LBC80R
May affect digestive health.[66]

In vitro inhibition of Listeria monocytogenes and L. innocua, Escherichia coli, Staphylococcus aureus, Enterococcus faecalis and Enterococcus faecium.[116]
May reduce symptoms of lactose intolerance and immune stimulation.[117]

Lactobacillus plantarum HEAL 9 & Lactobacillus paracasei 8700:2Under study for common cold infections.[118]

Some additional forms of lactic acid bacteria include:

Some fermented products containing similar lactic acid bacteria include:

EFSA scientific review of probiotics[edit]

The European Food Safety Authority has so far rejected 260 claims[130] 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:

Multi-probiotic[edit]

Preliminary research is evaluating the potential physiological effects of multiple probiotic strains, as opposed to a single strain.[132][133] 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.

See also[edit]

References[edit]

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