The genus Lactobacillus contains a number of phenotypically and genotypically diverse species. Lactobacilli are Gram-positive, nonsporulating rods that produce lactic acid as their primary byproduct of carbohydrate metabolism. Some species of Lactobacillus are utilized by the food industry for their ability to ferment foods, and others are recognized for their proposed probiotic benefits. Some species of lactobacilli are natural inhabitants of the gastrointestinal tract, skin, and vagina of humans and other mammals.
Relevance to Humans and Ecosystems
- Saada, N., C. Delattreb, M. Urdacic, J.M. Schmitterd, and P. Bressollier. 2013. An overview of the last advances in probiotic and prebiotic field. LWT - Food Science and Technology 50(1): 1-16.
Lactobacillus, also called Döderlein's bacillus, is a genus of Gram-positive facultative anaerobic or microaerophilic rod-shaped bacteria. They are a major part of the lactic acid bacteria group, named as such because most of its members convert lactose and other sugars to lactic acid. In humans they are present in the vagina and the gastrointestinal tract, where they make up a small portion of the gut flora. They are usually benign, except in the mouth where they have been associated with cavities and tooth decay (dental caries). Many species are prominent in decaying plant material. The production of lactic acid makes its environment acidic, which inhibits the growth of some harmful bacteria. Several members of the genus have had their genome sequenced.
Sourdough bread is made using a "starter culture," which is a symbiotic culture of yeast and lactic acid bacteria growing in a water and flour medium. The bacteria metabolize sugars into lactic acid, which lowers the pH of their environment, creating a signature "sourness" associated with yogurt, sauerkraut, etc.
In many traditional pickling processes, vegetables are submerged in brine, and salt-tolerant lactobacillus species feed on natural sugars found in the vegetables. The resulting mix of salt and lactic acid is a hostile environment for other microbes, such as fungi, and the vegetables are thus preserved -- remaining edible for long periods.
Probiotics and biotherapeutics
Some strains of Lactobacillus spp. and other lactic acid bacteria may possess potential therapeutic properties including anti-inflammatory and anti-cancer activities, as well as other features of interest. A study by researchers from the Beth Israel Deaconess Medical Center and UCLA in 2009 demonstrated the protective effects of some strains of these bacteria for anti-tumor and anti-cancer effects in mice.
Lactobacilli can also be used to restore particular physiological balance such as in the vaginal eco-system. Their role is (1) to physically protect the vaginal epithelium by building a thick layer separating the epithelium from pathogens, (2) to physiologically keep the balance of the vaginal ecosystem in maintaining the pH at ~4.5, and (3) generating hydrogen peroxide against pathogens. Lactobacilli are highly tolerant to low pH and can easily maintain low pH and protect the vaginal eco-system from Gram-negative and Gram-positive bacteria.
The genus Lactobacillus currently consists of over 180 species and encompasses a wide variety of organisms. The genus is polyphyletic, with the genus Pediococcus dividing the L. casei group, and the species L. acidophilus, L. salivarius, and L. reuteri being representatives of three distinct subclades. The genus Paralactobacillus falls within the L. salivarius group. In recent years, other members of the genus Lactobacillus (formerly known as the Leuconostoc branch of Lactobacillus) have been reclassified into the genera Atopobium, Carnobacterium, Weissella, Oenococcus, and Leuconostoc. More recently, the Pediococcus species P. dextrinicus has been reclassified as a Lactobacillus species (IJSEM, Paper in Press).
While streptococci family bacteria (e.g. Streptococcus mutans) are the main cause of tooth decay, other varieties of microbes can cause dental caries, but to a lesser extent. For example, although considered beneficial, some Lactobacillus species have been associated with dental caries. The Lactobacillus count in saliva has been used as a "caries test" for many years. This is one of the arguments used in support of the use of fluoride in toothpaste. Lactobacilli characteristically cause existing carious lesions to progress, especially those in coronal caries. The issue is, however, complex as recent studies show probiotics can allow beneficial lactobacilli to populate sites on teeth, preventing streptococci pathogens from taking hold and inducing dental decay.
Many lactobacilli are unusual in that they operate using homofermentative metabolism (that is, they produce only lactic acid from sugars in contrast to heterofermentative lactobacilli which can produce either alcohol or lactic acid from sugars) and are aerotolerant despite the complete absence of a respiratory chain. This aerotolerance is manganese-dependent and has been explored (and explained) in Lactobacillus plantarum. Many lactobacilli do not require iron for growth and have an extremely high hydrogen peroxide tolerance.
According to metabolism, Lactobacillus species can be divided into three groups:
- Obligately homofermentative (Group I) including:
- Facultatively heterofermentative (Group II) including:
- Obligately heterofermentative (Group III) including:
- Lactic acid bacteria
- Lactic acid fermentation
- MRS agar
- Makarova, K.; Slesarev, A.; Wolf, Y.; Sorokin, A.; Mirkin, B.; Koonin, E.; Pavlov, A.; Pavlova, N. et al. (Oct 2006). "Comparative genomics of the lactic acid bacteria". Proc Natl Acad Sci U S A 103 (42): 15611–6. doi:10.1073/pnas.0607117103. PMC 1622870. PMID 17030793.
- Dicks, LMT; M. Silvester; PA Lawson; MD Collins (2000). "Lactobacillus fornicalis sp. nov., isolated from the posterior fornix of the human vagina". International Journal of Systematic and Evolutionary Microbiology (Society for General Microbiology) 50 (3): 1253–8. doi:10.1099/00207713-50-3-1253. ISSN 1466-5034. PMID 10843070. Retrieved February 14, 2010.
- Ljungh, Åsa; Wadström, Torkel, eds. (2009). Lactobacillus Molecular Biology: From Genomics to Probiotics. Caister Academic Press. ISBN 978-1-904455-41-7.
- Chen, X.; Fruehauf, J.; Goldsmith, J. D.; Xu, H.; Katchar, K. K.; Koon, H. W.; Zhao, D.; Kokkotou, E. G.; Pothoulakis, C.; Kelly, C. N. P. (2009). "Saccharomyces boulardii Inhibits EGF Receptor Signaling and Intestinal Tumor Growth in Apcmin Mice". Gastroenterology 137 (3): 914–923. doi:10.1053/j.gastro.2009.05.050. PMC 2777664. PMID 19482027.
- Reid, G.; Dols, J.; Miller, W. (2009). "Targeting the vaginal microbiota with probiotics as a means to counteract infections". Current Opinion in Clinical Nutrition and Metabolic Care 12 (6): 583–587. doi:10.1097/MCO.0b013e328331b611. PMID 19741517.
- Osset, J.; Bartolomé, R. M.; García, E.; Andreu, A. N. (2001). "Assessment of the Capacity ofLactobacillusto Inhibit the Growth of Uropathogens and Block Their Adhesion to Vaginal Epithelial Cells". The Journal of Infectious Diseases 183 (3): 485–491. doi:10.1086/318070. PMID 11133381.
- Pascual, L. M.; Daniele, M. B.; Ruiz, F.; Giordano, W.; Pájaro, C.; Barberis, L. (2008). "Lactobacillus rhamnosus L60, a potential probiotic isolated from the human vagina". The Journal of general and applied microbiology 54 (3): 141–148. PMID 18654035.
Lactobacillus bulgaricus GLB44
Lactobacillus delbrueckii subsp. bulgaricus is a bacterial subspecies traditionally isolated from European yogurts. Lactobacillus bulgaricus GLB44 differs from the rest of the L. bulgaricus strains as it was isolated from the leaves of Galanthus nivalis (snowdrop flower) in Bulgaria, becoming the only known strain of this subspecies that has vegan origin (not from yogurt) available as a commercial probiotic. Probiotics are health promoting bacteria which, when consumed in adequate amounts, confer a benefit on the host, normally associated with positive effects on the digestive and immune systems, and are usually prescribed during or after antibiotic treatment to alleviate the symptoms of antibiotic-associated diarrhea. Probiotics are also associated with decreasing of the risk of traveler’s diarrhea. The natural habitat of the snowdrop flower are European mountainous regions. Thus, GLB44 is capable of surviving in freezing temperatures, as the snowdrop flowers between January and May in nature, when the temperatures can fall below freezing in this region. These characteristics of its natural habitat allows for GLB44 to survive in foods that are plant based and remain unaffected when stored in refrigerator temperatures.
GLB44 has inhibitory qualities against bad bacteria such as E. Coli and Salmonella spp. A research study was completed by a Harvard Medical School Professor at Brigham and Women's Hospital, Andrew B. Onderdonk, PhD. The study has revealed GLB44’s strength and effectiveness against bacterial pathogens. GLB44 has patent pending status in the US for its pathogen inhibitory qualities in vegan foods.
All other commercially available strains of L. bulgaricus are isolated from traditional yogurts and are grown in milk. Distinctly from the other L. bulgaricus, GLB44 grows very well in vegetable juices, given its natural plant habitat. Since all probiotics carry some of the organic matter in which they are grown, GLB44 carries traces of vegetable juice. GLB44 is currently grown in the European Union, in vegetable juice sourced from European farms that are GMO free.
Sourced originally from the leaves of the snowdrop flower, GLB44 differs significantly from other probiotics such as L. plantarum 299v or L. rhamnosus GG which are originally extracted from the human mouth. Others like Bifidobacterium are extracted from the feces of newborns14, while others such as some strains of L. brevis come from the human vaginal canal. GLB44 does not have any interface with mammalian organs, only flower leaves and juice. This is important for multiple reasons such as the fact that there is some scientific evidence that if a probiotic grows in the human mouth naturally it could accelerate tooth decay.
Also while many probiotics have major allergens in the growth solution, GLB44 has no major allergens as part of its growth medium. For example the growth medium for L. plantarum 299v includes barley that has small content of gluten, and L. rhamnosus GG has small content of casein. The fact that GLB44 is grown in vegetable juice means GLB44 does not contain any of the seven major allergens for which the U.S. Food and Drug Administration requires additional labeling: lactose, gluten, soya, peanuts, tree nuts, fish or crustacean shellfish.
It is estimated that 30 to 50 million Americans have some degree of lactose intolerance. Certain populations are more affected than others, including 75% of African American, Jewish, Mexican and Native American, and 90% of Asian populations. Thus, having probiotic bacteria such as GLB44 without any lactose is especially important for the lactose sensitive population.
Another major difference is the safety tract record of L. bulgaricus is now over 109 years since it was scientifically isolated. Even well established probiotics such as L. rhamnosus and L. plantarum 299v have only a fraction of the safety record with 31 years and 21 years, respectively., On the other hand, there are certain similarities between L. bulgaricus GLB44 and some of the other probiotics. For example L. bulgaricus, L. rhamnosus GG and L. plantarum 299v all have scientific records of their ability to pass successfully through the gastrointestinal tract, Also they all have records to inhibit to a degree pathogenic bacteria.,
Finally, all three example probiotics in this comparison have all research tests performed by reputable academic professionals, for the case of GLB44, the research was performed by a Harvard Medical School professor, for the case of L. rhamnosus GG by two Tufts University professors, and for L. plantarum 299v by a professor at the Lund University. All three probiotics have commercial brand names in the United States. GLB44 is commercially available under the brand name ProViotic as a probiotic food supplement, L. rhamnosus GG as Culturelle, and L. plantarum 299v as the ingredient in GoodBelly.
History of discovery: the bacillus of long life
The first L. bulgaricus was discovered more than a century ago, the result of a study into the unusual longevity of mountain villagers in Bulgaria (thus called L. bulgaricus) by Dr. Stamen Grigorov in 1905. In 1912, the New York Times wrote an overview article about the new discovery and the use of fermented yogurts with L. bulgaricus in Bulgaria titled “Metchnikoff Confirmed in His Theory of Long Life,” highlighting villager baba Vasilka, age 126, as the longest living person in the world. In fact, in these Bulgarian communities there were 3,000 centenarians from a population of 3 million – six times higher than the number of centenarians per capita in the United States today. In the article the author described the discovery as follows: "In Bulgaria, the home of this bacillus, the majority of the natives live to age considerably in excess of what is recognized as the term of life among Western nations, an inquiry has shown that in the Eastern part of Southern Europe, among a population of about 3,000,000, there were more than 3,000 centenarians found performing duties which would not be assigned to a man of 65 years of age elsewhere. It is quite common to find among the peasants who live to such a large extent upon soured milk individuals of 110 and 120 years of age."
The article continues in the explanation of these facts: "Prof. Élie Metchnikoff gave to the world the result of his investigation on the subject of longevity in which he held that the chief enemy to long life in the human species the large intestine, or colon. This organ by becoming the breeding place for poisonous microbes, the fertile cause for the debility that comes with old age, and the death that cuts off many a career of normal course is not nearly run." "Acids are the best antiseptics; they have been used from time immemorial as preservatives; pickles are persevered with vinegar, acidic acid, and when milk is allowed to sour under proper conditions, the germs of putrefaction are destroyed or their activity inhibited, and it keeps a considerable time. How can acids be applied so as to control the bacterial flora of the large intestine? Not in the ordinary way because, when administered through the mouth, they are used up long before they can penetrate the colon. The brilliant idea occurred to Prof. Metchnikoff of the administering acid-producing germs which might work their way through the digestive system, and, reaching the large intestine, produce the acid required. After much experimenting, the bacillus of Massol, Bacillus Bulgaricus was adopted as the most suitable."
Since Metchnikoff, advances in science have uncovered that the process of pathogenic inhibition is more complex than simply increasing the acidity in the colon, as the probiotic bacteria produce bacteriocins, bacterial synthesized proteins that inhibit pathogenic bacteria. In the case of L. bulgaricus this bacteriocin is called bulgaricin. Also there is a complex interplay between the probiotic bacteria and the body’s immune system in the large intestine, where the good bacteria stimulate the body’s own immune system to inhibit the pathogenic bacteria. For example, in a controlled study, 61 elderly volunteers, after 6 months of a daily dose of L. bulgaricus, responded to the intake of probiotic with an increase in the percentage of NK cells, an improvement in the parameters defining the immune risk profile (IRP), and an increase in the T cell subsets that are less differentiated. The probiotic group also showed decreased concentrations of the pro-inflammatory cytokine IL-8 but increased antimicrobial peptide hBD-2.
GLB44 studies at Brigham and Women’s Hospital
Dr. Andrew Onderdonk, a Pathology Professor at Harvard Medical School and a Director of the Clinical Microbiology Laboratory at Brigham and Women’s hospital has published one of his research tests on the following website: www.glb44.org, where GLB44 is tested against bacterial pathogens such as Salmonella sp. and E. Coli. In his study, both Salmonella sp. and E. Coli are inhibited when mixed with GLB44 in vegetable juice. The study confirms that GLB44 is a specific strain of the L. bulgaricus subspecies, and that its inhibitory power surpasses other L. bulgaricus strains.
Scientific studies on effects
These studies do not involve significant human trials sufficient for the U.S. Food and Drug Administration to allow representative health claims, nevertheless, these studies, performed in reputable academic institutions, provide an insight on some of the properties of this bacteria:
- The scientific study “In Vitro Cholesterol Uptake by Lactobacillus delbrueckii subsp. bulgaricus Isolates” performed at the University of Warsaw proved that L. bulgaricus has the ability to uptake cholesterol from its environment.
- Helicobacter pylori bacterial infection is associated with chronic gastritis, peptic ulcer disease, and gastric cancer. The scientific study “Anti-Helicobacter pylori activity of Lactobacillus delbrueckii subsp. bulgaricus strains” performed by the Medical University of Sofia concluded that all tested L. bulgaricus strains inhibited a number of H. pylori strains.
- In 2010, the British Journal of Nutrition reported a study that included fifty-seven elderly individuals (mean age 74) and eighty five healthy individuals (mean age 67), who consumed L. bulgaricus every day over 12 week period. The result of the study clearly showed that people who consumed L. bulgaricus daily had 2.6 times lower incidence of catching a cold. The study concluded that the consumption of yogurt fermented with L. bulgaricus augmented natural killer cell activity and reduced the risk of catching the common cold in elderly individuals.
- The Federal Research Centre for Nutrition in Germany reported that consuming L. bulgaricus on regular basis is associated with anticarcinogenic effects, one mechanism of which is the detoxification of genotoxins in the gut. This mechanism was shown experimentally in animals with use of the rat colon carcinogen, with endpoints that ranging from tumorigenesis to induction of DNA damage.
- The Journal of Dairy Science reports that L. bulgaricus can act as a suppressant of allergic inflammation. Allergic inflammation is an important pathophysiological feature of several disabilities or medical conditions including allergic asthma, atopic dermatitis, allergic rhinitis and several ocular allergic diseases.,
- Clostridium difficile is the most common cause of Antibiotic-associated diarrhea, and the resulting C. difficile mediated infection (CDI) is potentially deadly. C. difficile associated diarrhea (CDAD) is manifested by severe inflammation and colitis, mostly due to the release of two exotoxins by C. difficile that cause destruction of epithelial cells in the intestine. The study “Lactobacillus delbrueckii ssp. bulgaricus B-30892 can inhibit cytotoxic effects and adhesion of pathogenic Clostridium difficile to Caco-2 cells“ demonstrates that L. bulgaricus can reduce the colonization of C. difficile cells in colorectal cells, and thus prevent Antibiotic Associated Diarrhea.
Safety of use
Due to more than a century of safe use, the FDA has granted L. bulgaricus a “grandfather” status, with an automatic GRAS status (Generally Recognized as Safe). Moreover, the Code of Federal Regulations mandates that in the US, for a product to be called “yogurt”, it must contain two specific strains of lactic acid bacteria: Lactobacillus bulgaricus and Streptococcus thermophilus, as regulated by the FDA.
Even as a direct supplement, L. bulgaricus has a track record of safe use for more than 60 years in the United States. For example, the supplement Lactinex with a different strain of L. bulgaricus has been marketed as a commercial product in the US market since 1952. Despite not being vegan, and grown in milk, Lactinex shows a long history of L. bulgaricus as a food supplement in the United States.
For the last 100 years there has been not a case of overdose on probiotics, which substantiates L. bulgaricus GLB44 as an extremely safe product, without limitations of the quantity consumed. It is also recommendable for the elderly as it helps reduce infections such as the common cold, as well as for young children (i.e. when they suffer from acute diarrhea). Harvard Women’s Health Watch, published by Harvard Medical School, recommends a GLB44 dose range of between 1 to 10 billion colony forming units (CFU) per day, the amount contained in a capsule or two several days a week.
GLB44 is not a bacteria that can live naturally in the human mouth, as presented by the Human Oral Microbiome Database. A study conducted by the University of Texas uncovered that while a bacteria called S. mutans is the biggest culprit for tooth decay, various lactobacilli are also associated with the progression of lesions. GLB44 does not increase the risk of tooth decay due to its inability to live in the human mouth, an advantage versus other probiotics that contain any of the following lactobacilli that live naturally in the human mouth and could contribute to the tooth decay: L. acidophilus, L. brevis, L. casei, L. fermentum, L. gasseri, L. paracasei, L plantarum, L. reuteri, L. rhamnosus, L. salivarius
L. bulgaricus GLB44 and the definition of probioitics
The U.S. Food and Drug Administration (FDA) has presented on their website the following guideline: “Guidance for Industry on Complementary and Alternative Medicine Products and Their Regulation by the Food and Drug Administration” In this article, the definition of “Probiotics” is twofold: 1) live microbial food supplements that beneficially affect the host by improving its intestinal microbial; 2) live microorganisms which, when consumed in adequate amounts of food, confer a health benefit on the host.
Another guideline presented on the FDA website “Guidelines for Evaluation of Probiotics in Food” has outlined more specific criteria for the definition of effective probiotic based on the following criteria:
- Resistance to gastric acidity
- Bile acid resistance
- Adherence to mucus and/or human epithelial cells and cell lines
- Antimicrobial activity against potentially pathogenic bacteria
- Ability to reduce pathogen adhesion to surfaces
- Bile salt hydrolase activity
Of note, the authors of this guideline specifically outline L. bulgaricus as an example of an effective probiotic with suitable scientific substantiation of health benefits.
Resistance to gastric acid and bile acid are scientifically presented in the following studies where L. bulgaricus successfully passes through the human intestinal tract, maintaining its viability: “Survival of Yogurt Bacteria in the Human Gut” and “Lactobacillus delbrueckii subsp. bulgaricus Collection to select a strain able to survive to the human intestinal tract.”. Adherence to mucus and human epithelial cells and cell lines and the ability to reduce pathogen adhesion to surfaces is scientifically proven by the research “Influence of Gastrointestinal System Conditions on Adhesion of xopolysaccharide-producing Lactobacillus delbrueckii subsp. bulgaricus strains to Caco-2 Cells”
There are also numerous studies that outline the antimicrobial activity of L. bulgaricus against potentially pathogenic bacteria such as E. Coli, Salmonella sp., S. aureus, V. cholera, B. subtilis, C. difficile and others.
Thus, the L. bulgaricus meets all the criteria of the FDA probiotic guideline, with scientific evidence supporting the strain as the clearest example of a safe and effective probiotic food supplement.
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