Lactobacillus reuteri

Taxobox
color = lightgrey
name = "Lactobacillus reuteri"
regnum = Bacteria
divisio = Firmicutes
classis = Bacilli
ordo = Lactobacillales
familia = Lactobacillaceae
genus = "Lactobacillus"
species = "L. reuteri"
binomial = "Lactobacillus reuteri"
binomial_authority = N/A

"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. "L. reuteri" is a trademark of Biogaia, Inc., a Sweden-based company devoted to the bacterium's commercial prospects.

History

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 [Orla-Jensen, S. 1919. The lactic acid Bacteria. Det Kongelige Danske Videnskasbernes Selskab. Naturvidenskabelige mathematiske Afdeling, NS 8.5.2 ] , 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 re-classified the species as "Lactobacillus fermentum" biotype II".Reuter G. Das vorkommen von laktobazillen in lebensmitteln und ihr verhalten im menschlichen intestinaltrakt. Zbl Bak Parasit Infec Hyg I Orig 1965; 197 S: 468–87.]

"L. reuteri" was eventually identified as a distinct species in 1980 by Kandler et al. [Kandler O., Stetter K., Kohl R. 1980. Lactobacillus reuteri sp. nov. a new species of heterofermentative lactobacilli. Zbl. Bakt. Hyg. Abt. Orig. C1:264-269.] This group found significant differences between "L. reuteri" and other biotypes of "L. fermentum", and thus proposed that 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. "L. reuteri" has been isolated from many foods, especially meat and milk products [Lerche M, Reuter G. Das vorkommen aerob wachsender grampositiver stabchen des genus Lactobacuillus beijerinck im darminhalt erwachsener menchen. Zbl Bak Parasit Infec Hyg I Orig 1965; 185 S: 446–81.] [Dellaglio F, Arrizza FS, Leda A. Classification of citratefermenting lactobacilli isolated from lamb stomach, sheep milk, and pecorino romano cheese. Zbl Bakt Hyg Abt Orig 1981; C2: 349–56.] .

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 [Molin G, Jeppsson B, Johansson M-L, et al. Numerical taxonomy of Lactobacillus spp. associated to healthy and diseased mucosa of the human intestines. J Appl Microbiol 1993; 74: 314–23. Entrez Pubmed|8468264] . The same experiments – attempting to isolate "L. reuteri" from feces and intestine of healthy animals – were also done for non-human 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 [Sarra PG, Dellaglio F, Bottazzi V. Taxonomy of lactobacilli isolated from the alimentary tract of chickens. Syst Appl Microbiol 1985; 6: 86–9.] , pigs [Naito S, Hayashidani H, Kaneko K, Ogawa M, Benno Y. Development of intestinal lactobacilli in normal piglets. J Appl Bacteriol 1995; 79: 230–6. Entrez Pubmed|7592119] , and rodentsMolin G, Johansson M-L, Stahl M, et al. Systematics of the Lactobacillus population on rat mucosa with special reference to Lactobacillus reuteri. Antonie Van Leeuwenhoek 1992a; 61: 175–83. Entrez Pubmed|1325752] .

Furthermore, a study searching for 18 major species of gut flora, including "Lactobacillus acidophilus", in a variety of animals found that "L. reuteri" was the only bacterium that constituted a "major component" of the "Lactobacillus" species present in the gut of each of the host animals tested. [Mitsuoka T. The human gastrointestinal tract. In: Wood BJB, ed. The lactic acid bacteria. v. 1. The lactic acid bacteria in health and disease. New York: Elsevier Applied Science, 1992: 69–114.] "L. reuteri" is now well-established as one of the most ubiquitous members of the naturally-occurring gut bacteria.

A related discovery is that 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. [Casas IA, Dobrogosz WJ. Lactobacillus reuteri: An overview of a new probiotic for humans and animals. Microecol Therap 1997; 25: 221–31.] 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 organismIvan A. Casas, Walter J. Dobrogosz. "Validation of the Probiotic Concept: Lactobacillus reuteri Confers Broad-spectrum Protection against Disease in Humans and Animals", Microbial Ecology in Health and Disease, December 1 2000, Volume 12, Number 4. [http://taylorandfrancis.metapress.com/link.asp?id=th7818k39wgjuwfd (link to article)] ] .

"L. reuteri" as an anti-microbial agent

In the late 1980s, Walter Dobrogosz, Ivan Casas, and their colleagues discovered that "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. [Talarico TL, Casas IA, Chung TC, Dobrogosz WJ. Production and isolation of reuterin, a growth inhibitor produced by Lactobacillus reuteri. Antimicrob Agents Chemother. 1988 Dec;32(12):1854-8. Entrez Pubmed|3245697] Reuterin is a multi-compound dynamic equilibrium (HPA system, HPA) consisting of 3-hydroxypropionaldehyde, its hydrate, and its dimer. [Hall RH, Stern ES. Acid-catalysed hydration of acrylalde. Kinetics of the reaction and isolation of β-hydroxypropionaldehyde. J Chem Soc. 1950, 490-498.] [Nielsen AT, Moore DW, Schuetze Jr. A ¹³C and ¹H NMR study of formaldehyde reactions with acetaldehyde and acrolein. Synthesis of 2-(hydroxymethyl)-1,3-propanediol. Pol J Chem 55:1393–1403.] 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. [Vollenweider S, Grassi G, König I, Puhan Z. Purification and structural characterization of 3-hydroxypropionaldehyde and its derivatives. J Agric Food Chem. 2003 May 21;51(11):3287-93.Entrez Pubmed|12744656]

Reuterin, it was found, inhibits the growth of some harmful Gram-negative and Gram-positive bacteria, along with yeasts, fungi, and protozoa [Talarico TL, Dobrogosz WJ. Chemical characterization of an antimicrobial substance produced by Lactobacillus reuteri. Antimicrob Agents Chemother. 1989 May;33(5):674-9. Entrez Pubmed|2751282] . Naturally, a gut organism capable of fighting off other, harmful gut organisms was of great interest. Researchers found that "L. reuteri" can indeed secrete sufficient amounts of reuterin to cause the desired anti-microbial effects. Furthermore, since about 4-5 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.

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 on "L. reuteri". In fact, in early 2008 it was confirmed that "L. reuteri" is capable of producing reuterin in the gastrointestinal tract, and that this improves its ability to inhibit the growth of "E. coli". [ Cleusix V, Lacroix C, Vollenweider S, Le Blay G. Glycerol induces reuterin production and decreases "Escherichia coli" population in an in vitro model of colonic fermentation with immobilized human feces. FEMS Microbiol Ecol. 2008 Jan;63(1):56-64. Entrez Pubmed|18028400]

The gene cluster controlling the biosynthesis of reuterin and cobalamin in the "L. reuteri" genome is a genomic island acquired from an anomalous source. [ Morita H, Toh H, Fukuda S, Horikawa H, Oshima K, Suzuki T, Murakami M, Hisamatsu S, Kato Y, Takizawa T, Fukuoka H, Yoshimura T, Itoh K, O'Sullivan DJ, McKay LL, Ohno H, Kikuchi J, Masaoka T, Hattori M. Comparative genome analysis of Lactobacillus reuteri and Lactobacillus fermentum reveal a genomic island for reuterin and cobalamin production. DNA Res. 2008 Jun;15(3):151-161. Entrez Pubmed| 18487258]

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 "L. reuteri" in most 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 amount of the bacterium present in the body returns to low levels within several months after intake is stopped [Wolf BW, Garleb KA, Ataya DG, Casas IA. Safety and tolerance of Lactobacillus reuteri in healthy adult male subjects. Microbial Ecol Health Dis 1995; 8: 41–50.] . Furthermore, "L. reuteri" is found in breast milk [Sinkiewicz G, Nordström EA. Occurrence of Lactobacillus reuteri, lactobacilli and bifidobacteria in human breast milk. Pediatr Res 58:415, abstract 353.] , 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 [Abrahamsson T, Jakobsson T, Sinkiewicz G, Fredriksson M, Björkstén B. Intestinal microbiota in infants supplemented with the probiotic bacterium Lactobacillus reuteri. J Ped Gastroenterol Nutr 40(5):692, abstract PN 1-17.] .

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.

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 [Shornikova AV, Casas IA, Mykkanen H, Salo E, Vesikari T. Bacteriotherapy with Lactobacillus reuteri in rotavirus gastroenteritis. Pediatr Infect Dis J 1997; 16: 1103-7. Entrez Pubmed|9427453] . "L. reuteri" is also effective as a prophylactic for this illness; children fed "L. reuteri" while healthy are less likely to fall ill with diarrhea in the first place [Ruiz-Palacios G, Guerrero ML, Hilty M. Feeding of a probiotic for the prevention of community-acquired diarrhea in young Mexican children. (1996) Pediatr Res 39(4) part 2:184A, abstract 1089.] . With regard to prevention of gut infections, comparative research has found "L. reuteri" to be more potent than other probiotic organisms [Romeo MG, Betta P, Oliveri S. (2006) Presented at the 5th Annual meeting of the Italian Society of Perinatal Medicine, Parma, Italy, 15-17 June 2006. Abstract published in J Perinat Med 34(Suppl 1): A9, abstract MSL_24.] [Guerrero M, Dohnalek M, Newton P, Kuznetsova O, Ruiz-Palacios G, Murphy T, Calva J, Hilty M, Costigan T., 1st World Congress of Pediatric Infectious Diseases, Dec. 1996, abstract no. 610:45-2.] .

"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 L. reuteri was much better in decreasing the infants' crying time than the standard therapy of simethicone treatment [cite journal | author = Savino F., Pelle E., Palumeri E., Oggero R. and Miniero R. | title = "Lactobacillus reuteri" (ATCC strain 55730) versus simethicone in the treatment of infantile colic: a prospective randomized study | journal = Pediatrics | volume = 119 | issue = 1 |pages = 124–130 | year = 2007 | pmid = 17200238 | doi = 10.1542/peds.2006-1222] . However, colic is still poorly understood, and it is not clear why or through what mechanism "L. reuteri" ameliorates its symptoms. [colic] One theory of colic, though, holds that affected infants cry because of severe gastro-intestinal 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.

"L. reuteri" is capable of eradicating the gut pathogen "Helicobacter pylori", which causes peptic ulcers and is endemic in parts of the developing world. In one study, none of "H. pylori"-infected patients treated with omeprazole were cured, while those given "L. reuteri" in addition to omeprazole had a cure rate of 60% [Saggioro A, Caroli M, Pasini M, Bortoluzzi F, Girardi L, Pilone G. Helicobacter pylori eradication with Lactobacillus reuteri. A double blind placebo-controlled study. (2005) Dig Liver Dis 37(suppl 1): S88, abstr. PO1.49.] .

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 that "L. reuteri" was the only species of those tested able to block "S. mutants". Before testing in humans was begun, another study showed that "L. reuteri" had no harmful effects on teeth. Clinical trials have since proven that those people whose mouths are colonized with "L. reuteri" (via dietary supplementation) have significantly less of the harmful "S. mutans" [Nikawa H, Makihira S, Fukushima H, Nishimura H, Ozaki Y, Ishida K, Darmawan S, Hamada T, Hara K, Matsumoto A, Takemoto T, Objectivei R. Lactobacillus reuteri in fermented bovine milk decreases the oral carriage of mutans streptococci. (2004) Int J Food Microbiol 95:219-223. Entrez Pubmed|15282133] . Since these studies have been short-term, it is not yet known whether "L. reuteri" prevents tooth decay. However, since "L. reuteri" 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 gingivitis-associated symptoms compared with placebo after chewing gum containing "L. reuteri" [Krasse P, Carlsson B, Dahl C, Paulsson A, Nilsson Å, Sinkiewicz G. Decreased gum bleeding and reduced gingivitis by the probiotic Lactobacillus reuteri. (2006) Swed Dent J 30:55-60. Entrez Pubmed|16878680] .

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 that "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" [Weizman Z, Asli G, Alsheikh A. Effect of a probiotic infant formula on infections in child care centers: Comparison of two probiotic agents. (2005) Pediatrics 115:5-9. Entrez Pubmed|15629974] .

Similar results have been found in adults; adults consuming "L. reuteri" daily end up falling ill 50% less often, as measured by their decrease use of sick leave [Tubelius P, Stan V, Zachrisson A. Increasing work-place healthiness with the probiotic Lactobacillus reuteri: A randomised, double blind placebo-controlled study. (2005) Environmental Health 4:25. Entrez Pubmed|16274475] .

Results in animal models

Scientific studies that require harming the subjects (for example, exposing them to a dangerous virus) may obviously not 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 [Carbajal N, Sriburi A, Carter P, Dobrogosz W, Casas, I. Probiotic administrations of Lactobacillus reuteri protect mice from Salmonella typhimurium infection. Proceedings of the 36th Annual Meeting of the Association for Gnotobiotics. 1998 Jun 14–16; Bethesda (MD): Association for Gnotobiotics; 1998.] . The same is true for chickens [Casas IA, Edens FW, Dobrogosz WJ. Lactobacillus reuteri: an effective probiotic for poultry and other animals. Lactic acid bacteria, 2nd ed. New York: Marcel Dekker, 1998: 475–518.] 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 its host. A study performed in chickens showed that "L. reuteri" was as potent as the antibiotic gentamicin in preventing "E. coli"-related deaths [Edens FW, Parkhurst CR, Casas IA, Dobrogosz WJ. Principles of ex ovo competitive exclusion and in ovo administration of Lactobacillus reuteri. Poult Sci 1997; 76: 179–96. Entrez Pubmed|9037704] .

The protozoal 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" in mice [Alak JI, Wolf BW, Mdurvwa EG, Pimentel-Smith GE, Adeyemo O. Effect of Lactobacillus reuteri on intestinal resistance to Cryptosporidium parvum infection in a murine model of acquired immunodeficiency syndrome. J Infect Dis 1997; 175: 218–21. Entrez Pubmed|8985225] and pigs. Given that there is no known direct treatment for "C. parvum" (the antibiotic Paromomycin has limited effect) [Cryptosporidium parvum] , "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" [Wagner RD, Pierson C, Warner T, et al. Biotherapeutic effects of probiotic bacteria on candidiasis in immunodeficient mice. Infect Immun 1997; 65: 4165–72. Entrez Pubmed|9317023] .

General health

In young commercial livestock such as turkey chicks 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 [Barnes JH. Evaluating poult growth and productivity during brooding. Turkeys 1993; 41: 23–4.] .

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 [Casas IA, Edens FW, Parkhurst CR, Dobrogosz WJ. Probiotic treatment with "Lactobacillus reuteri" protects commercial turkeys from avian growth depression. Biosci Microflora 1998; 17: 141–7.] . A similar study on piglets showed that "L. reuteri" is at least as effective as synthetic antibiotics in improving body weight under crowded conditions [Blanchard P, Gill P, Schulze H. Efficacy of "Lactobacillus reuteri" 1063-IA in pre and post-weaning pigs. Hertfordshire SG5 4JG (UK): MLC Stotfold Pig Development Unit; 1998. Study Reference No. FF9801.] .

The mechanism by which "L. reuteri" is able to support the healthy growth of these animals is not entirely understood. It is possible that "L. reuteri" simply 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 that "L. reuteri" can also help when the growth depression is caused entirely by a lack of dietary protein, and not by contageous disease [Dunham HJ, Casas IA, Edens FW, Parkhurst CR, Garlich JD, Dobrogosz WJ. Avian growth depression in chickens induced by environmental, microbiological, or nutritional stress is moderated by probiotic administrations of "Lactobacillus reuteri". Biosci Microflora 1998; 17: 133–9.] . This raises the possibility that "L. reuteri" somehow improves the intestines' ability to absorb and process nutrients .

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 [Fabia R, Ar’Rajab A, Johansson ML, et al. The effect of exogenous administration of "Lactobacillus reuteri" R2LC and oat fiber on acetic acid-induced colitis in the rat. Scandinavian J Gastroenterol 1993; 28: 155–62. Entrez Pubmed|8382837] , 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 injestion 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 [Wang XD, Soltesz V, Molin G, Anderson R. The role of oral administration of oatmeal fermented by "Lactobacillus reuteri" R2LC on bacterial translocation after acute liverfailure induced by subtotal liver resection in the rat. Scandinavian J Gastroenterol 1995; 30: 180–5.Entrez Pubmed|7732342] or injection with D-galactosamine [Adawi D, Kasravi B, Molin G, Jeppsson B. Effect of Lactobacillus supplementation with and without arginine on liver damage and bacterial translocation in an acute liver injury model in the rat. Hepatology 1997; 25: 642–7. Entrez Pubmed|9049212] , a chemical which also causes liver damage.

The anti-cancer 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 [Mao Y, Nobaek S, Kasravi B, et al. The effects of Lactobacillus strains and oat fiber on methotrexate-induced enterocolitis in rats. Gastroenterol 1996; 111: 334–44. Entrez Pubmed|8690198] .

Sources

External links

* [http://www.jgi.doe.gov/sequencing/why/CSP2005/lactobacillusreut.html Joint Genome Institute on "L. reuteri"]
* [http://pediatrics.aappublications.org/cgi/content/full/119/1/e124 "L. reuteri" in colicky infants]