Selecting, testing and understanding probiotic microorganisms (original) (raw)
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Canadian R&D Centre for Probiotics, Lawson Health Research Institute
University of Western Ontario, London, Canada
Correspondence: Gregor Reid, Lawson Health Research Institute, Rm H214, 268 Grosvenor Street, London, Ontario N6A 4V2 Canada. Tel.:+1 519 6466100 x65256; fax:+1 519 6466031; e-mail: gregor@uwo.ca
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Canadian R&D Centre for Probiotics, Lawson Health Research Institute
University of Western Ontario, London, Canada
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Department of Cell and Tissue Biology (CTB), University of California San Francisco, CA, USA
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Gregor Reid, Sung O. Kim, Gerwald A. Köhler, Selecting, testing and understanding probiotic microorganisms, FEMS Immunology & Medical Microbiology, Volume 46, Issue 2, March 2006, Pages 149–157, https://doi.org/10.1111/j.1574-695X.2005.00026.x
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Abstract
The interest in probiotics and the modulation of microbiota for restoring and maintaining health continues to gain momentum. Research is fueled by a need to develop alternatives to antibiotics and drugs that have severe side effects. It is recognised that bacteria play a major role in human and animal health, and how scientific advances help to explain how and when probiotics work. This minireview provides an update on critical studies, particularly since 2002, that are helping to explain the mechanisms of action of probiotic organisms.
Probiotics
A PubMed literature search demonstrates the rapid growth of research in probiotics, with half of the cited papers being published since 2003. Defined as ‘Live microorganisms which when administered in adequate amounts confer a health benefit on the host’ (Reid et al., 2003a, b), the concept is undergoing a resurgence as scientists rediscover events taking place at the interface between mucosal surfaces and microbiota. The logical rationale is that having emerged from bacteria hundreds of millions of years ago, and being colonized by so many organisms, much of human life is influenced by microorganisms. Probiotics simply represents a means, in some case quite elementary, to replenish microorganisms that are excreted or die within us, and thereby help to restore and maintain health.
The present minireview will focus on new information emerging about probiotic strains and products, particularly since 2002.
Climate change
There are a number of reasons why probiotic research has become a hot topic. Despite over 50 years of antibiotics, infectious diseases remain a major cause of death, with gastroenteritis killing a child every 15 s. Hospital infection rates are not declining, multi-drug resistant bacteria continue to emerge as the antibiotic pipeline dries up, and pathogenic microorganisms are being linked with induction or worsening of many chronic diseases. Add to this the alarming spread of HIV and the complications of AIDS, plus the pending threat of a deadly flu pandemic, and worried consumers, governments, scientists and industries are looking for new approaches to health restoration and retention.
Science itself is playing a major role, with an ever-growing number of studies providing tangible evidence that probiotics can alleviate some disease processes. Meanwhile, the market for probiotic products continues to increase rapidly, resulting in better availability of different formulations, albeit not yet in many cases aligned to proper FAO/WHO Guidelines (Reid, 2005c).
Strain selection process
Since the discovery and documentation of probiotic properties of Lactobacillus rhamnosus (formerly casei) GR-1 and Lactobacillus reuteri (formerly acidophilus then fermentum) between 1980 and 1986, our understanding of how these and other probiotic organisms confer health benefits on the host has grown substantially. Over 20 years ago, the production of substances that inhibited pathogen growth on agar plates or the ability to reduce adherence of pathogens in vitro defined a probiotic (Chan et al., 1984). Now, the bar has been raised significantly higher, and use of the term ‘probiotic’ necessitates that bacteria be properly speciated, shown in appropriate formulations to be safe and effective at conferring health benefits on mammalian hosts, and manufactured and sold in a way that accurately reflects what benefits a consumer can derive (Reid, 2005b). Sadly, governments and industry have not yet taken these requirements to heart, and whereas many so-called probiotic products are available, relatively few true probiotic products exist (Table 1).
Table 1
A selection of probiotic strains fulfilling the FAO/WHO Guidelines (as can be determined from known peer-reviewed literature)
Strain (company licensed to sell the organism) | An example of clinical evidence showing probiotic effect |
---|---|
Lactobacillus casei Shirota (Yakult, Japan) | Improvement in treatment of constipation (Koebnick et al., 2003). |
L. casei DN114 001 (Danone, France) | Reduced duration of winter infections in elderly subjects (Turchet et al., 2003). |
Lactobacillus rhamnosus GG (Valio, Finland) | Various benefits including improved treatment of diarrhea and management of atopy (Szajewska et al., 2001; Kirjavainen et al., 2003). |
L. rhamnosus HN001 (Danisco, Denmark) | Enhanced immunity in the elderly, as measured by in vitro phagocytic capacity of peripheral blood polymorphonuclear leukocytes and tumoricidal activity of natural killer cells, following 3 weeks intake of probiotic (Sheih et al., 2001). |
L. rhamnosus 19070-2 and Lactobacillus reuteri DSM 12246 (Chr. Hansen, Denmark) | Reduction in acute diarrhea in children following twice daily treatment (Rosenfeldt et al., 2002). |
L. rhamnosus GR-1 and L. reuteri RC-14 (Chr. Hansen, Denmark) | Reduction in, and better treatment of, urogenital infections in women taking oral lactobacilli daily for 2 months (Reid et al., 2004). |
L. reuteri ATCC 55730 (BioGaia, Sweden) | For treatment of diarrhea and to produce CD4-positive T-lymphocytes in the ileal epithelium (Valeur et al., 2004). |
Lactobacillus plantarum 299V (Probi, Sweden) | Decreased incidence of infections in liver transplant patients (Rayes et al., 2002). |
Lactobacillus acidophilus La5 (Chr. Hansen, Denmark) | Suppression of Helicobacter pylori with use of La5 and B. lactis BB12 yogurt given twice daily after a meal for 6 wks (Wang et al., 2004). |
L. acidophilus L1 (Campina Melkunie, Holland) | Fermented milk containing this organism was found to lower serum cholesterol — this would translate to 6–10% reduction in risk for coronary heart disease (Anderson & Gilliland, 1999) |
Lactobacillus johnsonii La1 (Nestle, Switzerland) | A moderate but significant difference in H. pylori colonization was detected in children receiving live La1 (Cruchet et al., 2003). |
Lactobacillus paracasei LP-33 | Effectively and safely improved the quality of life of patients with allergic rhinitis (Wang et al., 2004b). |
(Uni-President Enterprise Corp., Tainan, Taiwan) | |
Lactobacillus brevis CD2 (VSL Pharmaceuticals, Inc., Fort Lauderdale, FL). | Decreases Helicobacter pylori colonization, thus reducing polyamine biosynthesis (Linsalata et al., 2004). |
Lactobacillus gasseri OLL 2716 (Meiji Milk Products, Tokyo, Japan). | Yogurt containing this organism suppressed H. pylori and reduced gastric mucosal inflammation (Sakamoto et al., 2001). |
VSL#3 (VSL Pharmaceuticals, Inc., Fort Lauderdale, FL). | Effective for the management of remission of pouchitis and colitis (Mimura et al., 2004). |
Saccharomyces cerevisiae boulardii lyo (Biocodex, France) | 250 mg treatment for 5 days reduced the duration of acute diarrhea and the duration of hospital stay (Kurugol & Koturoglu, 2005). |
Bifobacterium animalis/lactis BB12 (Chr. Hansen, Denmark/Nestle, Switzerland) | Various effects including prevention and treatment of diarrhea (Weizman et al., 2005) |
B. animalis/lactis DN-173 010 (Danone, France) | Two to three servings per day helps with regularity (Marteau et al., 2002). |
Bifidobacterium longum BL1 (Morinaga, Japan) | 3 × 100 mL per day low-fat drinking yogurt prepared with the two starter cultures plus B. longum BL1 resulted in some evidence of lower serum cholesterol (Xiao et al., 2003). |
Bifidobacterium lactis HN019 | The ex vivo phagocytic capacity of mononuclear and polymorphonuclear phagocytes and the tumoricidal activity of natural killer cells were elevated (Gill et al., 2001) |
Bifobacterium infantis 35624 (Ardeypharm, Germany) | Taken in a malted milk drink for 8 weeks, shown to relieve abdominal pain/discomfort, bloating/distention, and bowel movement difficulty (O'Mahony et al., 2005). |
Escherichia coli Nissle 1917 | Possible use in treatment of colitis (Tromm et al., 2004). |
Strain (company licensed to sell the organism) | An example of clinical evidence showing probiotic effect |
---|---|
Lactobacillus casei Shirota (Yakult, Japan) | Improvement in treatment of constipation (Koebnick et al., 2003). |
L. casei DN114 001 (Danone, France) | Reduced duration of winter infections in elderly subjects (Turchet et al., 2003). |
Lactobacillus rhamnosus GG (Valio, Finland) | Various benefits including improved treatment of diarrhea and management of atopy (Szajewska et al., 2001; Kirjavainen et al., 2003). |
L. rhamnosus HN001 (Danisco, Denmark) | Enhanced immunity in the elderly, as measured by in vitro phagocytic capacity of peripheral blood polymorphonuclear leukocytes and tumoricidal activity of natural killer cells, following 3 weeks intake of probiotic (Sheih et al., 2001). |
L. rhamnosus 19070-2 and Lactobacillus reuteri DSM 12246 (Chr. Hansen, Denmark) | Reduction in acute diarrhea in children following twice daily treatment (Rosenfeldt et al., 2002). |
L. rhamnosus GR-1 and L. reuteri RC-14 (Chr. Hansen, Denmark) | Reduction in, and better treatment of, urogenital infections in women taking oral lactobacilli daily for 2 months (Reid et al., 2004). |
L. reuteri ATCC 55730 (BioGaia, Sweden) | For treatment of diarrhea and to produce CD4-positive T-lymphocytes in the ileal epithelium (Valeur et al., 2004). |
Lactobacillus plantarum 299V (Probi, Sweden) | Decreased incidence of infections in liver transplant patients (Rayes et al., 2002). |
Lactobacillus acidophilus La5 (Chr. Hansen, Denmark) | Suppression of Helicobacter pylori with use of La5 and B. lactis BB12 yogurt given twice daily after a meal for 6 wks (Wang et al., 2004). |
L. acidophilus L1 (Campina Melkunie, Holland) | Fermented milk containing this organism was found to lower serum cholesterol — this would translate to 6–10% reduction in risk for coronary heart disease (Anderson & Gilliland, 1999) |
Lactobacillus johnsonii La1 (Nestle, Switzerland) | A moderate but significant difference in H. pylori colonization was detected in children receiving live La1 (Cruchet et al., 2003). |
Lactobacillus paracasei LP-33 | Effectively and safely improved the quality of life of patients with allergic rhinitis (Wang et al., 2004b). |
(Uni-President Enterprise Corp., Tainan, Taiwan) | |
Lactobacillus brevis CD2 (VSL Pharmaceuticals, Inc., Fort Lauderdale, FL). | Decreases Helicobacter pylori colonization, thus reducing polyamine biosynthesis (Linsalata et al., 2004). |
Lactobacillus gasseri OLL 2716 (Meiji Milk Products, Tokyo, Japan). | Yogurt containing this organism suppressed H. pylori and reduced gastric mucosal inflammation (Sakamoto et al., 2001). |
VSL#3 (VSL Pharmaceuticals, Inc., Fort Lauderdale, FL). | Effective for the management of remission of pouchitis and colitis (Mimura et al., 2004). |
Saccharomyces cerevisiae boulardii lyo (Biocodex, France) | 250 mg treatment for 5 days reduced the duration of acute diarrhea and the duration of hospital stay (Kurugol & Koturoglu, 2005). |
Bifobacterium animalis/lactis BB12 (Chr. Hansen, Denmark/Nestle, Switzerland) | Various effects including prevention and treatment of diarrhea (Weizman et al., 2005) |
B. animalis/lactis DN-173 010 (Danone, France) | Two to three servings per day helps with regularity (Marteau et al., 2002). |
Bifidobacterium longum BL1 (Morinaga, Japan) | 3 × 100 mL per day low-fat drinking yogurt prepared with the two starter cultures plus B. longum BL1 resulted in some evidence of lower serum cholesterol (Xiao et al., 2003). |
Bifidobacterium lactis HN019 | The ex vivo phagocytic capacity of mononuclear and polymorphonuclear phagocytes and the tumoricidal activity of natural killer cells were elevated (Gill et al., 2001) |
Bifobacterium infantis 35624 (Ardeypharm, Germany) | Taken in a malted milk drink for 8 weeks, shown to relieve abdominal pain/discomfort, bloating/distention, and bowel movement difficulty (O'Mahony et al., 2005). |
Escherichia coli Nissle 1917 | Possible use in treatment of colitis (Tromm et al., 2004). |
Product is classified Saccharomyces boulardii lyo but the microbiol classification is currently considered invalid and should be Saccharomyces cerevisiae boulardii.
Table 1
A selection of probiotic strains fulfilling the FAO/WHO Guidelines (as can be determined from known peer-reviewed literature)
Strain (company licensed to sell the organism) | An example of clinical evidence showing probiotic effect |
---|---|
Lactobacillus casei Shirota (Yakult, Japan) | Improvement in treatment of constipation (Koebnick et al., 2003). |
L. casei DN114 001 (Danone, France) | Reduced duration of winter infections in elderly subjects (Turchet et al., 2003). |
Lactobacillus rhamnosus GG (Valio, Finland) | Various benefits including improved treatment of diarrhea and management of atopy (Szajewska et al., 2001; Kirjavainen et al., 2003). |
L. rhamnosus HN001 (Danisco, Denmark) | Enhanced immunity in the elderly, as measured by in vitro phagocytic capacity of peripheral blood polymorphonuclear leukocytes and tumoricidal activity of natural killer cells, following 3 weeks intake of probiotic (Sheih et al., 2001). |
L. rhamnosus 19070-2 and Lactobacillus reuteri DSM 12246 (Chr. Hansen, Denmark) | Reduction in acute diarrhea in children following twice daily treatment (Rosenfeldt et al., 2002). |
L. rhamnosus GR-1 and L. reuteri RC-14 (Chr. Hansen, Denmark) | Reduction in, and better treatment of, urogenital infections in women taking oral lactobacilli daily for 2 months (Reid et al., 2004). |
L. reuteri ATCC 55730 (BioGaia, Sweden) | For treatment of diarrhea and to produce CD4-positive T-lymphocytes in the ileal epithelium (Valeur et al., 2004). |
Lactobacillus plantarum 299V (Probi, Sweden) | Decreased incidence of infections in liver transplant patients (Rayes et al., 2002). |
Lactobacillus acidophilus La5 (Chr. Hansen, Denmark) | Suppression of Helicobacter pylori with use of La5 and B. lactis BB12 yogurt given twice daily after a meal for 6 wks (Wang et al., 2004). |
L. acidophilus L1 (Campina Melkunie, Holland) | Fermented milk containing this organism was found to lower serum cholesterol — this would translate to 6–10% reduction in risk for coronary heart disease (Anderson & Gilliland, 1999) |
Lactobacillus johnsonii La1 (Nestle, Switzerland) | A moderate but significant difference in H. pylori colonization was detected in children receiving live La1 (Cruchet et al., 2003). |
Lactobacillus paracasei LP-33 | Effectively and safely improved the quality of life of patients with allergic rhinitis (Wang et al., 2004b). |
(Uni-President Enterprise Corp., Tainan, Taiwan) | |
Lactobacillus brevis CD2 (VSL Pharmaceuticals, Inc., Fort Lauderdale, FL). | Decreases Helicobacter pylori colonization, thus reducing polyamine biosynthesis (Linsalata et al., 2004). |
Lactobacillus gasseri OLL 2716 (Meiji Milk Products, Tokyo, Japan). | Yogurt containing this organism suppressed H. pylori and reduced gastric mucosal inflammation (Sakamoto et al., 2001). |
VSL#3 (VSL Pharmaceuticals, Inc., Fort Lauderdale, FL). | Effective for the management of remission of pouchitis and colitis (Mimura et al., 2004). |
Saccharomyces cerevisiae boulardii lyo (Biocodex, France) | 250 mg treatment for 5 days reduced the duration of acute diarrhea and the duration of hospital stay (Kurugol & Koturoglu, 2005). |
Bifobacterium animalis/lactis BB12 (Chr. Hansen, Denmark/Nestle, Switzerland) | Various effects including prevention and treatment of diarrhea (Weizman et al., 2005) |
B. animalis/lactis DN-173 010 (Danone, France) | Two to three servings per day helps with regularity (Marteau et al., 2002). |
Bifidobacterium longum BL1 (Morinaga, Japan) | 3 × 100 mL per day low-fat drinking yogurt prepared with the two starter cultures plus B. longum BL1 resulted in some evidence of lower serum cholesterol (Xiao et al., 2003). |
Bifidobacterium lactis HN019 | The ex vivo phagocytic capacity of mononuclear and polymorphonuclear phagocytes and the tumoricidal activity of natural killer cells were elevated (Gill et al., 2001) |
Bifobacterium infantis 35624 (Ardeypharm, Germany) | Taken in a malted milk drink for 8 weeks, shown to relieve abdominal pain/discomfort, bloating/distention, and bowel movement difficulty (O'Mahony et al., 2005). |
Escherichia coli Nissle 1917 | Possible use in treatment of colitis (Tromm et al., 2004). |
Strain (company licensed to sell the organism) | An example of clinical evidence showing probiotic effect |
---|---|
Lactobacillus casei Shirota (Yakult, Japan) | Improvement in treatment of constipation (Koebnick et al., 2003). |
L. casei DN114 001 (Danone, France) | Reduced duration of winter infections in elderly subjects (Turchet et al., 2003). |
Lactobacillus rhamnosus GG (Valio, Finland) | Various benefits including improved treatment of diarrhea and management of atopy (Szajewska et al., 2001; Kirjavainen et al., 2003). |
L. rhamnosus HN001 (Danisco, Denmark) | Enhanced immunity in the elderly, as measured by in vitro phagocytic capacity of peripheral blood polymorphonuclear leukocytes and tumoricidal activity of natural killer cells, following 3 weeks intake of probiotic (Sheih et al., 2001). |
L. rhamnosus 19070-2 and Lactobacillus reuteri DSM 12246 (Chr. Hansen, Denmark) | Reduction in acute diarrhea in children following twice daily treatment (Rosenfeldt et al., 2002). |
L. rhamnosus GR-1 and L. reuteri RC-14 (Chr. Hansen, Denmark) | Reduction in, and better treatment of, urogenital infections in women taking oral lactobacilli daily for 2 months (Reid et al., 2004). |
L. reuteri ATCC 55730 (BioGaia, Sweden) | For treatment of diarrhea and to produce CD4-positive T-lymphocytes in the ileal epithelium (Valeur et al., 2004). |
Lactobacillus plantarum 299V (Probi, Sweden) | Decreased incidence of infections in liver transplant patients (Rayes et al., 2002). |
Lactobacillus acidophilus La5 (Chr. Hansen, Denmark) | Suppression of Helicobacter pylori with use of La5 and B. lactis BB12 yogurt given twice daily after a meal for 6 wks (Wang et al., 2004). |
L. acidophilus L1 (Campina Melkunie, Holland) | Fermented milk containing this organism was found to lower serum cholesterol — this would translate to 6–10% reduction in risk for coronary heart disease (Anderson & Gilliland, 1999) |
Lactobacillus johnsonii La1 (Nestle, Switzerland) | A moderate but significant difference in H. pylori colonization was detected in children receiving live La1 (Cruchet et al., 2003). |
Lactobacillus paracasei LP-33 | Effectively and safely improved the quality of life of patients with allergic rhinitis (Wang et al., 2004b). |
(Uni-President Enterprise Corp., Tainan, Taiwan) | |
Lactobacillus brevis CD2 (VSL Pharmaceuticals, Inc., Fort Lauderdale, FL). | Decreases Helicobacter pylori colonization, thus reducing polyamine biosynthesis (Linsalata et al., 2004). |
Lactobacillus gasseri OLL 2716 (Meiji Milk Products, Tokyo, Japan). | Yogurt containing this organism suppressed H. pylori and reduced gastric mucosal inflammation (Sakamoto et al., 2001). |
VSL#3 (VSL Pharmaceuticals, Inc., Fort Lauderdale, FL). | Effective for the management of remission of pouchitis and colitis (Mimura et al., 2004). |
Saccharomyces cerevisiae boulardii lyo (Biocodex, France) | 250 mg treatment for 5 days reduced the duration of acute diarrhea and the duration of hospital stay (Kurugol & Koturoglu, 2005). |
Bifobacterium animalis/lactis BB12 (Chr. Hansen, Denmark/Nestle, Switzerland) | Various effects including prevention and treatment of diarrhea (Weizman et al., 2005) |
B. animalis/lactis DN-173 010 (Danone, France) | Two to three servings per day helps with regularity (Marteau et al., 2002). |
Bifidobacterium longum BL1 (Morinaga, Japan) | 3 × 100 mL per day low-fat drinking yogurt prepared with the two starter cultures plus B. longum BL1 resulted in some evidence of lower serum cholesterol (Xiao et al., 2003). |
Bifidobacterium lactis HN019 | The ex vivo phagocytic capacity of mononuclear and polymorphonuclear phagocytes and the tumoricidal activity of natural killer cells were elevated (Gill et al., 2001) |
Bifobacterium infantis 35624 (Ardeypharm, Germany) | Taken in a malted milk drink for 8 weeks, shown to relieve abdominal pain/discomfort, bloating/distention, and bowel movement difficulty (O'Mahony et al., 2005). |
Escherichia coli Nissle 1917 | Possible use in treatment of colitis (Tromm et al., 2004). |
Product is classified Saccharomyces boulardii lyo but the microbiol classification is currently considered invalid and should be Saccharomyces cerevisiae boulardii.
With a market potential growing, more and more probiotic strains are being selected. Some are created by the mere addition of different strains to a formulation in the hope that it will benefit the host. This was the case with VSL#3, where Italian scientists believed that an eight strain formulation would be beneficial. Without studying the organisms individually or knowing their mechanisms of action, clinical trials were undertaken. Fortunately, positive clinical outcomes have been obtained in patients with inflammatory bowel disease (IBD) with VSL#3, helping keep the condition in remission (Bibiloni et al., 2005). A recent animal study showed that VSL#3 could prevent onset of diabetes, ostensibly by reduced insulitis and a decreased rate of beta cell destruction due to increased production of interleukin (IL)-10 from Peyer's patches, the spleen and the pancreas (Calcinaro et al., 2005). Various other multispecies so-called probiotic products are available, but none have this level of clinical documentation, and indeed the contents of most are of questionable repute (Elliot & Teversham, 2004; Huff, 2004).
In other cases, the same, or an extremely similar, probiotic strain may be being used by different companies (Masco et al., 2005). This may be the case with Bifidobacterium animalis BB12, an organism sold by Chr. Hansen and Nestle, and similar to one sold by Danone. Studies using B. animalis or Bifidobacterium lactis (Masco et al., 2004) indicate that it can alleviate diarrhea, shorten colonic transit time, lower cholesterol and enhance host immunity (Fukushima et al., 1998; Marteau et al., 2002; Chouraqui et al., 2004; Lepercq et al., 2004; Weizman et al., 2005). The use of strains of the same species, or indeed the use of someone else's strain, presents an interesting situation. In the case of Bifidobacterium, some strains may be patent protected for particular use, and some companies may have specific probes to identify their organism, but for the most part the key is for any given group/company to document properly what their strain can do. Difference between strains of the same species clearly do exist, for example L. rhamnosus GR-1 adheres to intestinal and vaginal cells in vitro and colonizes the gut and vagina, unlike the strain GG, which is well documented for intestinal benefits (Szajewska et al., 2001) and possible management of atopy (Kirjavainen et al., 2003) but poorly colonizes the vagina (Cadieux et al., 2002), for reasons that are not yet clear. Differences also exist between strains of L. reuteri such as RC-14 and the commercial strain DSM 20016 (Reid, 2005a). Lactobacillus reuteri RC-14 was recently classified using DNA–DNA hybridization techniques, having initially been termed Lactobacillus acidophilus (based upon crude biochemical typing) in 1986, and then Lactobacillus fermentum (ribotyping). The organism adheres to intestinal and urogenital cells in vitro (Reid et al., 1987, 1993), has been recovered from human stool and vaginal samples several days after instillation (Gardiner et al., 2002; Morelli et al., 2004), and has been shown to express important probiotic effects (Heinemann et al. 2001) that have no relationship to the antibiotic reuterin that forms the basis of patents associated with strain DSM 20016. As the genome sequence of L. reuteri becomes available (http://www.jgi.doe.gov/sequencing/cspseqplans.html) it will be possible to further distinguish strain activity, determine in vivo functionality with respect to antidisease effects, and compare animal and human strains isolated from different sites. Indeed, there is already one study showing that the ability of L. reuteri to produce reuterin is not exclusive to this species, and Lactobacillus coryniformis produces this antibiotic (Martin et al., 2005).
A common trend, stimulated in part by the interest of physicians, is for probiotics to be used to treat medical problems rather than as natural supplements to enhance health. By necessity, this has led to studies designed to identify strains with specific antidisease properties, or the creation of recombinant strains that act in precise ways. Nine examples are provided.
- A rat study has shown that L. rhamnosus and not L. fermentum could reduce levels of plasma endotoxin, bacterial translocation, and disruption of F-actin distribution following hemorrhagic shock compared with nontreated control rats (Luyer et al., 2005). This is interesting, but it would be helpful to know what functional component of one species of Lactobacillus is critical for the effect and lacking in another species.
- A localized use of Lactobacillus plantarum in a burn model showed an improvement in tissue repair, enhanced phagocytosis of Pseudomonas aeruginosa by tissue phagocytes, and a decrease in apoptosis at 10 days (Valdez et al., 2005). Physicians will be reluctant to apply living lactobacilli to infected wounds, so the risk of bacteremia needs to be assessed and nonviable lactobacilli tested to allay fears.
- In an attempt to protect against colon cancer, a symbiotic combination of resistant starch and a strain of B. lactis has been shown to facilitate significantly the apoptotic response to a genotoxic carcinogen in the distal colon of rats (Le Leu et al., 2005). This study raises the question of how important it is to include a food for the probiotic, and to ask if ingestion of high numbers of bifidobacteria are needed or if indigenous strains are able to also prevent carcinogen damage.
- Lactobacillus acidophilus L1 has been shown to reduce cholesterol levels in humans by 3%, which translates to a 10% lowering of risk for coronary heart disease (Anderson & Gilliland, 1999). The life-threatening side effects of statins make probiotics an interesting option for cholesterol lowering. It would be useful to determine whether probiotic dosage and time of consumption plays any role in reducing cholesterol, and whether levels beyond 3% can be achieved in humans.
- Strains of Lactobacillus helveticus are currently being tested for their ability to affect breast cancer cells (de Moreno de LeBlanc et al., 2005). This again is a major and potentially deadly illness, but the extent to which ingested lactobacilli can impact a disease that occurs at such a distant site as the breast remains to be determined.
- Several recombinant approaches have shown promise in animal studies. Pretreatment of animals with a noncolonizing recombinant Lactococcus lactis expressing bovine beta-lactoglobulin (BLG) showed induction of BLG-specific T-helper type 1 (Th1) response, and abrogated the oral tolerance induced by BLG alone (Adel-Patient et al., 2005).
- A food grade L. lactis has been engineered to express co-protective trefoil factors that help promote epithelial wound healing and potentially aid in the treatment of chronic and acute colitis (Vandenbroucke et al., 2004).
- The same research group had previously shown that lactococci expressing IL-10 could provide a 50% reduction in colitis in mice and prevent onset of colitis in IL-10−/− mice (Steidler et al., 2000).
- A final example is the work of Lee's group, which has engineered a natural human vaginal isolate of Lactobacillus jensenii to secrete two-domain CD4 (2D CD4) proteins that recognized a conformation-dependent anti-CD4 antibody and bound HIV type 1 (HIV-1) gp120 (Chang et al., 2003). A modest decrease in HIV infectivity resulted. Human testing of such recombinant approaches are needed, after which regulatory hurdles must be overcome.
The recent outbreak of Clostridium difficile infections resulting in many deaths in Canadian hospitals (Valiquette et al., 2004) has led to consideration of probiotics as a counter-measure. Although very few proven probiotics are available in Canada, primarily due to regulatory inefficiencies, strains such as Lactobacillus GG have been tested, so far without success. A systematic review of clinical studies designed to prevent or treat _C. difficile_-associated diarrhea showed some evidence of benefits with Saccharomyces cerevisiae boulardii but the data overall were inconclusive (Dendukuri et al., 2005). Even though this paper was published on July 19, the authors did not cite the Kotowska study of March 2005, in which a study of 269 children concluded that 250 mg S. boulardii given twice daily for as long as antibiotics were used, could lower antibiotic-associated diarrhoea (AAD) rates [4/119 (3.4%) vs. 22/127 (17.3%), relative risk: 0.2; 95% confidence interval: 0.07–0.5]. At best it may be ascertained that S. boulardii may have some effect in recurrent AAD. A hesitancy to use S. boulardii therapy is due to the sparsity of efficacy data, the fact that products have not followed FAO/WHO Guidelines so it is impossible to know which strains have been tested clinically, and the fact that some cases of fungemia have been reported (Munoz et al., 2005). Further studies are underway to select appropriate S. boulardii strains for probiotic consideration, but testing their survival in acid and bile or their adhesiveness to epithelial cells in vitro is not sufficient to classify strains as probiotic (van der Aa Kuhle et al., 2005). Interestingly, a poorly adhesive strain inhibited pro-inflammatory cytokine IL-1α in cells exposed to toxin-producing Escherichia coli, suggesting that other attributes are important for antipathogen effects.
The selection of probiotic candidates has widened considerably to the extent that avirulent E. coli are being tested to prevent symptomatic UTI in spinal cord injured patients (Darouiche et al., 2001). The apparent success of E. coli Nissle 1917 to maintain remission of colitis (Kruis et al., 2004), and reduction in visceral hyperalgesia associated with gut disorders (Liebregts et al., 2005) makes this organism worthy of further study. Genomic studies show that it lacks defined virulence factors such as alpha-hemolysin, P-fimbriae, and semirough lipopolysaccharide phenotype, but possesses fitness factors such as microcins, different iron uptake systems, adhesins and proteases to support its survival and successful colonization of the human gut, thereby providing a rationale for using E. coli Nissle 1917 as a probiotic (Grozdanov et al., 2004).
Mechanisms of action
In terms of probiotic effects, the ultimate evidence must come from human studies, and therefore while production of antimicrobial substances shown in vitro suggests a means to prevent infection, bacteriocins and antibiotics may be degraded in the stomach and intestine and thereby may have little chance of conferring health benefits. On the contrary, acid and hydrogen peroxide production may help protect the vagina from pathogenic bacteria and viruses (Cadieux et al., 2002; Beigi et al., 2005; Strus et al., 2005), and an ability to signal the host's own defenses, such as mucins in the gut (Mack et al., 2003), defensins and antimicrobial immune factors in the gut and vagina, is likely to be very important.
Acid production has long been known to be detrimental to some microorganisms, not only killing viruses such as HIV, rotavirus and even influenza virus (Reid, 2005b), but also displacing some pathogens from surfaces (Reid et al., 2005). Some microorganisms in the vagina, such as yeast and enterococci, can tolerate acids and resist hydrogen peroxide action (Strus et al., 2005). This may be due to cell wall structures and biofilm formation. The end result is that very few probiotic strains are effective against Candida and enterococci in the vagina. Microarray studies (Kohler & Reid, 2005) have shown that exposure of Candida albicans to L. rhamnosus GR-1 during co-cultivation results in expression of stress genes in the fungi and downregulation of genes involved in filamentation, an important factor for candidal virulence and biofilm formation. Consequently, the probiotic bacteria are able to suppress generation of Candida biofilms (Fig. 1). It is hoped these studies will uncover the mechanism of interference and shed light on which lactobacilli can reduce fungal infections and how.
Figure 1
Inhibition of biofilm (BF) formation of Candida albicans by Lactobacillus GR-1. C. albicans forms a biofilm at the liquid–air interface in MRS broth at 37°C. Co-culture of C. albicans with GR-1 abolishes biofilm formation (the culture medium was removed for photography) (courtesy of Dr G. Köhler, UCSF).
Anti-enterococcal activity is also being studied. In addition to hospital infections, there is some evidence to suggest that enterococci can invade bladder cells and cause urinary tract infection (UTI) as well as a portion of cases known loosely under the condition interstitial cystitis (IC). The perception that intracellular bacteria may cause IC comes from E. coli UTI studies showing uropathogenic bacterial invasion of bladder cells (Anderson et al., 2003), studies showing enterococci can bind to glycosaminoglycans and invade macrophages (Baldassarri et al., 2005), and clinical studies in IC patients showing ‘cure’ following antibiotic use (Burkhard et al., 2004). Research by Jass (unpublished) at our Canadian Centre has shown that low levels of enterococcal bacteria do occur in IC patients, and some intracellularization also appears to occur. The study by Burkhard (2004) showed that eradication of enterococci from the vagina and from the partner's penis was necessary to establish cure. Thus, if probiotics could displace and deplete enterococci from the vaginal origin of IC and UTI, it could be possible to prevent these conditions. To achieve this, strains like L. reuteri RC-14 which inhibit growth of enterococci and produce biosurfactants that form a barrier to pathogen colonization (Velraeds et al., 1996), could prove useful. Two recurrent UTI patients have been successfully treated at our Canadian Centre using this approach, one of which is illustrated in Fig. 2. No such studies have been undertaken for IC patients, but, in principle, it may benefit some women.
The ability of Lactobacillus GR-1 and RC-14 to colonize the vagina may involve lipoteichoic acids, various binding proteins, electrostatic and hydrophobic interactions, proteinaceous S-layers or perhaps even specific receptors whose availability is modulated by estrogen (Chan et al., 1985; Reid et al., 1992; Raz & Stamm, 1993; Vall-Jaaskelainen & Palva, 2005). The extent to which adhesion to epithelial cells is critical to probiotic effects is not clear, as the presence of few lactobacilli can displace or inhibit adhesion of relatively large numbers of pathogens (Reid & Tieszer, 1993). This supports the concept that the lactobacilli function through signaling and biosurfactant molecules and create an environment less supportive of pathogen survival. This could explain why so few microbial species inhabit the vagina out of the 500 or more that emerge in the stool.
Cross-talk between uropathogens and lactobacilli can occur in several ways. In vitro studies have shown that strains of L. plantarum 299V and L. rhamnosus GG signal the host to produce MUC2 and MUC3 intestinal mucins, which in turn inhibit enteropathogenic E. coli adhesion and invasion (Mack et al., 1999). Interestingly, preliminary studies suggest that L. rhamnosus GR-1 is not as efficient as GG in this regard, but L. reuteri RC-14 does induce MUC 3 expression (Mack et al., unpublished). In human genome microarray studies, intravaginal instillation of L. rhamnosus GR-1 has been found to induce over 700 gene expression changes, in particular innate antimicrobial defenses (Kirjavainen et al., submitted), emphasizing that probiotic effects involve host as well as microbial components. An exploration of GR-1 signaling has shown that it produces factors which induce macrophage-secreted inhibitory factors suppressing _E. coli_-induced inflammatory cytokines (Kim et al., submitted; see Fig. 3). Thus, immune modulation is clearly a part of L. rhamnosus GR-1′s probiotic armamentarium.
Figure 3
One of the proposed mechanisms of anti-inflammatory effects of Lactobacillus (courtesy of Dr. Sung Kim, Canadian R&D Centre for Probiotics). Lactobacillus rhamnosus GR-1 releases a signaling compound that primes macrophage-secreted inhibitory factors to suppress TNF and IL-6 production (induced by pathogens) in an IL-10-dependent and independent pathway. This also up-regulates antibacterial responses (e.g. NO, H2O2).
Exploration of signaling factors produced by L. reuteri RC-14 has also proved revealing. Whilst the actual factor or factors remain to be fully identified, studies have shown that this organism transfers a signal that results in a dramatic decrease in expression of Staphylococcus aureus superantigen-like protein 11 (SSL11) (Laughton et al., Submitted). This coincides with animal studies showing that RC-14 could prevent S. aureus infection (Gan et al., 2002), probably by blocking collagen binding receptors, producing anti-infective signaling and modulation of immunity.
Linkage between mucosal systems
Studies using Lactobacillus casei Shirota to reduce the incidence of recurrent bladder cancer (Ohashi et al., 2002) and Lactobacillus GG to lower respiratory tract infections (Hatakka et al., 2001) illustrate the link between probiotic use and effects at distant body sites. The primary mechanism is probably related to immune function, whether through enhancement of sIgA (Perdigon et al., 1999) or through increases in the proportions of total, helper (CD4+), and activated (CD25+) T lymphocytes and natural killer cells (Gill & Rutherfurd, 2001; Gill et al., 2001). Clearly, such linkages express themselves in allergic reactions, with Th2 cells typically infiltrating the affected tissue and producing cytokines such as IL-4, -5, -9 and -13, which then promote the production of IgE antibodies, the development and accumulation of mast cells, eosinophils and basophils (the primary effector cells in allergic inflammation) and overproduction of mucus, with airway hyper-responsiveness in asthma. The mast cells and basophils trigger release of pre- and newly formed proinflammatory and vasoactive molecules (e.g. histamine) that may cause tissue damage and other detrimental effects (Kay, 2001). Probiotic therapy might reduce the adverse effects of allergy and atopy through anti-inflammatory adaptive responses elicited by TGF-β-secreting Th3 cells, IL-10-secreting TR1 cells, and CD4+CD25+ regulatory T cells (Rautava et al., 2005), as well as induce higher C-reactive protein, IL-6 and soluble E-selectin levels (Viljanen et al., 2005).
The ability of Lactobacillus GR-1 and RC-14 to promote vaginal health following oral consumption (Reid et al., 2004) is less likely to be due to distant immune effects, but rather through an increase in lactobacilli transfer and reduction in the number of pathogens that emerge from the rectum and ascend to the vagina and bladder (Reid et al., 2003a, b; Morelli et al., 2004). Nevertheless, all these studies emphasize that one cannot simply separate probiotic effects merely by site of administration.
Conclusion
Much progress has been made in understanding the breadth, depth and limitations of probiotics. Many strains, including species outwith the traditional Lactobacillus and Bifidobacterium genera are being examined for probiotic effects. Functionality and human testing will be vital not only to fulfill the requirements for strains to be called probiotic, but to increase our understanding of how products work. Applications in the fields of cancer, cardiovascular disease, inflammation, allergy and infection are currently the main target areas with potential to benefit large numbers of people. With more emphasis on therapy than health retention and augmentation, the parameters within which probiotics operate or fail to provide benefits must be delineated. The emergence of new molecular, microscopic, nanoscale and imaging technologies will make it feasible to see in real time how probiotic (and indeed indigenous) bacteria influence the host. This will help both humans and animals regain their health when adversely affected by pathogenic microbial damage, antimicrobial treatment and other threats.
Acknowledgements
The assistance of NSERC Canada is appreciated. This research was supported partially by funds from the Universitywide AIDS Research Program (UARP) of the University of California, grant ID04-SF-030 to G. Köhler.
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