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Lactobacillus reuteri Lactobacillus reuteri is a Gram-positive bacterium that naturally inhabits the gut of mammals and birds. First described in the early 1980s, some strains of L. reuteri are used as probiotics. BioGaia AB in Sweden owns several commercially important strains and a large number of different patents for commercial usage of L. reuteri. Discovery Though the species Lactobacillus reuteri has been recognized for some time, knowledge of its probiotic properties did not come until much later. As early as the turn of the 20th century, L. reuteri was recorded in scientific classifications of lactic acid bacteria,[1] though at this time it was mistakenly grouped as a member of Lactobacillus fermentum. In the 1960s, further work by German microbiologist Gerhard Reuter – for whom the species eventually would be named – began to distinguish L. reuteri from L. fermentum. Reuter reclassified the species as "Lactobacillus fermentum biotype II".[2] L. reuteri was eventually identified as a distinct species in 1980 by Kandler et al.[3] This group found significant differences between L. reuteri and other biotypes of L. fermentum, and thus proposed it be given formal species identity. They chose the species name "reuteri", after discoverer Gerhard Reuter, and L. reuteri has since been recognized as a separate species within the Lactobacillus genus.

L. reuteri as a "universal" gut organism In the early 1980s, shortly after its recognition as a distinct species, scientists began to find L. reuteri in many natural environments; it has been isolated from many foods, especially meat and milk products.[2][4][5] Interest in L. reuteri began to increase as scientists began to find it colonizing the intestines of healthy animals. Gerhard Reuter first isolated L. reuteri from human fecal and intestinal samples in the 1960s, and this work was later repeated by other researchers.[6] The same experiments – attempting to isolate L. reuteri from feces and intestine of healthy animals – were also done for nonhuman species, proving that L. reuteri seems to be present almost universally throughout the animal kingdom. For example, L. reuteri was discovered to be present naturally in the intestines of healthy sheep, chickens,[7] pigs,[8] and rodents.[9] Furthermore, a study searching for 18 major species of gut flora, including Lactobacillus acidophilus, in a variety of animals found L. reuteri was the only bacterium to constitute a "major component" of the Lactobacillus species present in the gut of each of the host animals tested.[10] It is now well-established as one of the most ubiquitous members of the naturally occurring gut bacteria. In a related discovery, each animal host seems to have a host-specific strain of L. reuteri, e.g. a rat strain for rats, a pig strain for pigs, etc.[9][11] The universality of L. reuteri, in conjunction with this evolved host-specificity, has led scientists to make inferences about its importance in promoting the health of the host organism.[12]

L. reuteri as an antimicrobial agent In the late 1980s, Walter Dobrogosz, Ivan Casas, and their colleagues discovered L. reuteri produced a novel broad-spectrum antibiotic substance via the organism's fermentation of glycerol. They named this substance "reuterin", also after Gerhard Reuter.[13] Reuterin is a multiple-compound dynamic equilibrium (HPA system, HPA) consisting of 3hydroxypropionaldehyde, its hydrate, and its dimer.[14][15] At concentrations above 1.4 M, the HPA dimer was predominant. However, at concentrations relevant for biological systems, HPA hydrate was the most abundant, followed by the aldehyde form.[16] Reuterin was found to inhibit the growth of some harmful Gram-negative and Gram-positive bacteria, along with yeasts, fungi, and protozoa.[17] Naturally, a gut organism capable of

fighting off other, harmful gut organisms was of great interest. Researchers found L. reuteri can indeed secrete sufficient amounts of reuterin to cause the desired antimicrobial effects. Furthermore, since about four to five times the amount of reuterin is needed to kill "good" gut bacteria (i.e. L. reuteri and other Lactobacillus species) as "bad", this would allow L. reuteri to remove gut invaders while keeping normal gut flora intact.[12] Some studies have called into question whether or not reuterin production is essential for L. reuteri 's health-promoting activity. However, the discovery that it naturally produces an antibiotic substance was nevertheless important, as it has led to a great deal of further research. In fact, in early 2008, L. reuteri was confirmed to be capable of producing reuterin in the gastrointestinal tract, and this improves its ability to inhibit the growth of E. coli.[18] The gene cluster controlling the biosynthesis of reuterin and cobalamin in the L. reuteri genome is a genomic island acquired from an anomalous source.[19]

Benefits Clinical results in humans Although L. reuteri occurs naturally in humans, it is not found in all individuals. Therefore, dietary supplementation is needed to introduce and maintain high levels of it in some people. Oral intake of L. reuteri has been shown to effectively colonize the intestine of healthy people; colonization begins rapidly within days of ingestion, although the levels in the body drop within several months after intake is stopped.[20] Furthermore, L. reuteri is found in breast milk,[21] and oral intake on the mother's part likewise increases the amount of L. reuteri present in her milk, and the likelihood that it will be transferred to the child's body.[22] Once present in the body, L. reuteri benefits its host in a variety of ways, particularly by fighting off harmful infections and mediating the body's immune system. Safety L. reuteri has been tested for host tolerance in children,[23] healthy adults,[24] and the immunosuppressed (HIV patients).[25] No adverse serious medical consequences have been observed up to the maximum tested dosage of 1010 colony-forming units per day, and no significant differences in standard medical laboratory tests were found, including complete blood count, urinalysis, complete metabolic panel, and liver function tests between those subjects given L. reuteri and those given placebo. Intestinal effects One of the most well-documented effects of L. reuteri is in the treatment of rotavirus-induced diarrhea, especially in children. Treatment of rotaviral diarrhea by consumption of L. reuteri significantly shortens the duration of the illness as compared to placebo. Furthermore, this effect is dose-dependent: the more L. reuteri consumed, the faster the diarrhea stops.[26] L. reuteri is also effective as a prophylactic for this illness; children fed it while healthy are less likely to fall ill with diarrhea in the first place.[27] With regard to prevention of gut infections, comparative research has found L. reuteri to be more potent than other probiotic organisms. [28][29]

L. reuteri is also an effective treatment against infant colic. Over a period of several weeks, infants who are given L. reuteri steadily decrease the amount of time each day spent crying – the defining symptom of colic. In fact, it was much better in decreasing the infants' crying time than the standard therapy of simethicone treatment.[30] A randomized, double-blind, placebo-controlled trial of 50 exclusively breast-fed, colicky infants found a significant decrease in daily crying time amounts when treated with L. reuteri DSM 17 938 compared with placebo. It further found a significant increase in lactobacilli colonization, a decrease in fecal Escherichia coli and ammonia when compared with placebo.[31] However, colic is still poorly understood, and it is not clear why or how L. reuteri ameliorates its symptoms.[32] One

theory of colic, though, holds that affected infants cry because of severe gastrointestinal discomfort; if this is indeed the case, it is quite plausible that L. reuteri somehow acts to lessen this discomfort, since its primary residence is inside the gut. Growing evidence indicates L. reuteri is capable of fighting the gut pathogen Helicobacter pylori, which causes peptic ulcers and is endemic in parts of the developing world. One study showed dietary supplementation of L. reuteri alone reduces, but does not fully eradicate, H. pylori in the gut.[33] Another study found the addition of L. reuteri to omeprazole therapy dramatically increased (from 0% to 60%) the cure rate of H. pylori-infected patients compared to the drug alone.[34] Yet another study showed L. reuteri effectively suppressed H. pylori infection and decreased the occurrence of dyspeptic symptoms, although it did not improve the outcome of antibiotic therapy.[35] Oral health L. reuteri may also be capable of promoting dental health, as it has been proven to kill Streptococcus mutans, a bacterium responsible for tooth decay. A screen of several probiotic bacteria found L. reuteri was the only species of those tested able to block S. mutans. Before testing in humans was begun, another study showed L. reuteri had no harmful effects on teeth. Clinical trials have since proven those people whose mouths are colonized with L. reuteri (via dietary supplementation) have significantly less of the harmful S. mutans.[36] Since these studies have been short-term, it is not yet known whether L. reuteri prevents tooth decay. However, since it is able to reduce the numbers of an important decay-causing bacterium, this would be expected. Gingivitis also may be ameliorated by consumption of L. reuteri. Patients afflicted with severe gingivitis showed decreased gum bleeding, plaque formation, and other gingivitisassociated symptoms compared with placebo after chewing gum containing L. reuteri.[37] General health By protecting against many common infections, L. reuteri promotes overall wellness in both children and adults. Double-blind, randomized studies in child care centers have found L. reuteri-fed infants fall sick less often, require fewer doctor visits, and are absent fewer days from the day care center compared to placebo and to the competing probiotic Bifidobacterium lactis.[38] Similar results have been found in adults; those consuming L. reuteri daily end up falling ill 50% less often, as measured by their decrease use of sick leave.[39]

Results in animal models Scientific studies that require harming the subjects (for example, exposing them to a dangerous virus) obviously cannot be conducted in humans. Therefore, many of the benefits of L. reuteri have been studied only in different animal species, such as pigs and mice. Given the similarity of mammalian species, however, it is likely – though not scientifically proven – that these benefits hold true for humans, as well. In general, animal studies on L. reuteri are done using the species-specific strain of the bacterium (see above). Protection against pathogens L. reuteri confers a high level of resistance to the pathogen Salmonella typhimurium, halving mortality rates in mice.[40] The same is true for chickens[41] and turkeys; L. reuteri greatly moderates the morbidity and mortality caused by this dangerous food-bourne pathogen. L. reuteri is also effective in stopping harmful strains of E. coli from affecting their hosts. A study performed in chickens showed L. reuteri was as potent as the antibiotic gentamicin in preventing E. coli-related deaths.[42] The protozoic parasite Cryptosporidium parvum causes severe watery diarrhea, which can become life-threatening if the patient is immunocompromised (as in individuals infected with

HIV). L. reuteri is known to lessen the symptoms of C. parvum infection in mice[43] and pigs. [12] With no known direct treatment for C. parvum (the antibiotic paromomycin has limited effect),[44] L. reuteri may prove valuable in protecting patients suffering from this disease. Some protective effect against the yeast Candida albicans has been found in mice, but in this case, L. reuteri did not work as well as other probiotic organisms, such as L. acidophilus and L. casei.[45] General health In young commercial livestock, such as turkey poults and piglets, body weight and growth rate are good indicators of the health of the animal. Animals raised in the dirty, crowded environments of commercial farms are generally less healthy (and therefore weigh less) than their counterparts born and bred in cleaner homes. In turkeys, for example, this phenomenon is known as "poult growth depression", or PGD.[46] Supplementing the diets of these young farm animals with L. reuteri helps them to largely overcome the stresses imposed by their unhealthy habitats. Commercial turkeys fed L. reuteri from birth had nearly a 10% higher adult body weight than their peers raised in the same conditions.[47] A similar study on piglets showed L. reuteri is at least as effective as synthetic antibiotics in improving body weight under crowded conditions.[48] The mechanism by which L. reuteri is able to support the healthy growth of these animals is not entirely understood. It possibly serves to protect livestock against illness caused by Salmonella typhimurium and other pathogens (see above), which are much more common in crowded commercial farms. However, other studies have revealed it can also help when the growth depression is caused entirely by a lack of dietary protein, and not by contagious disease.[49] This raises the possibility that L. reuteri somehow improves the intestines' ability to absorb and process nutrients.[12] Effect on chemical and trauma-induced injury Treating colonic tissue from rats with acetic acid causes an injury similar to the human condition ulcerative colitis. Treating the injured tissue with L. reuteri immediately after removing the acid almost completely reverses any ill effects,[50] leading to the possibility that L. reuteri may be beneficial in the treatment of human colitis patients. In addition to its role in digestion, the intestinal wall is also vital in preventing harmful bacteria, endotoxins, etc., from "leaking" into the bloodstream. This leaking, known as bacterial "translocation", is very dangerous and can lead to lethal conditions such as sepsis. In humans, translocation is more likely to occur following such events as liver injury and ingestion of some poisons. In rodent studies, L. reuteri was found to greatly reduce the amount of bacterial translocation following either the surgical removal of the liver[51] or injection with D-galactosamine,[52] a chemical which also causes liver damage. The anticancer drug methotrexate causes severe enterocolitis in high doses. L. reuteri greatly mitigates the symptoms of methotrexate-induced enterocolitis in rats, one of which is bacterial translocation.[53]

Lactobacillus reuteri