The Potential of Probiotics
November 1, 1999
The Potential of Probiotics
November 1999; Volume 1: 91-94
By Gregor Reid, PhD, MBA
More than 100 years ago, elie metchnikoff recognized that certain lactic acid-producing bacteria could be harmful to pathogens. So the concept that "good bugs" could interfere with "bad bugs" was born. Indigenous to human intestines and the female urogenital tract, lactobacilli are added to many food substances (especially dairy-based products). Approximately 400 species of bacteria live in the intestines, and about 50 species live in the female genital tract.
Background
The term "probiotics" refers to the use of viable organisms that benefit the host by improving the microbial balance. The term is thus the opposite of "antibiotics," which kill or inhibit the growth of bacteria. A number of probiotic products, especially lactobacilli and bifidobacteria, are sold commercially, generally advertised to "promote intestinal health." In Europe, many lactobacilli-containing products are available; in France, probiotic yogurt is a $400 million yearly business. In Japan, a multibillion dollar company has built its core business on the use of one organism, Lactobacillus casei Shirota, in a sweet milky drink and various other products. It is estimated that 30 million people worldwide take this product each day.
Bifidobacterium species have been quite well studied and there is some evidence that certain strains can be effective at colonizing the intestine. Other organisms also are used as probiotics. Streptococcus faecium or Enterococcus faecium often are incorporated into dairy drinks or yogurt; this has raised concerns because these species may have pathogenic properties or could acquire virulence factors, including drug resistance genes. Further work needs to be done to delineate both the benefits and the risks of these organisms.
Despite their popularity elsewhere, probiotics have been slow to catch on in North America. There probably are several reasons for this, including a research emphasis on antibiotics; antipathy toward purposely introducing bacteria into people; and fear that bacteria could mutate and become virulent.
Antibiotics and Probiotics
Although antibiotics have saved many lives, overuse and misuse have had public health ramifications. Hardly a week goes by without some press article on bacterial drug resistance. Hospital outbreaks of methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant enterococci (VRE), statistics on drug over-usage, and epidemiological findings on drug resistance patterns have attracted the attention and concern of consumers as well as physicians. Several other factors also contribute to this problem: using broad-spectrum antibiotics rather than a narrower-spectrum antibiotic; the use of antibiotics for prophylaxis (for example, large numbers of women worldwide take low-dose antibiotics chronically to prevent the recurrence of bladder infections); and the use of systemic antibiotics when local wound treatment or vaginal application of antibiotics may work just as well. There is relatively little research on systemic vs. local antibiotic treatment but the latter may well be adequate; for example, a recent study found that metronidazole vaginal gel was as effective as oral metronidazole for the treatment of trichomoniasis.1
The response to drug resistance has been mainly unidimensional: Find new antibiotics. (New data also exist on peptides, vaccines, and receptor blockage strategies, which may provide alternative approaches in time, but good human studies are a long way off.) In the meantime, infectious disease conferences are filled with papers on new drugs that are essentially variations of existing chemicals. The strategy is basically the same—kill the offending bugs at all costs. Not only are antibiotics often expensive, they can cause serious adverse effects. We know little about the effects of destruction of normal flora.
Regulatory agencies and physicians in North America have been consistently reluctant to introduce live organisms into people. There are only a few exceptions, such as the use of Bacillus Calmette-Guerin (BCG) for bladder cancer. It is interesting that this use of BCG is more accepted in the United States than its primary use. Despite a growing tuberculosis problem in the United States and Canada, and the proven efficacy of BCG vaccine in reducing the risk of TB acquisition, this use has never garnered widespread support. There is some support for the use of BCG vaccine in high-risk tuberculin-negative children. North Americans are notoriously phobic about germs, and although drugs are perceived as clean and pure, microorganisms are perceived as dirty. However, the human environment (both external and internal) is dominated by microorganisms and more work is needed to educate the public to this reality and to find ways to maintain and restore health within this microbial soup.
The possibility that introduced organisms could acquire virulence properties is a reasonable fear. In the 1960s, there was an attempt to propagate "good bugs" for oropharyngeal infections using alpha-streptococci, but apparant mishandling of alpha-streptococci by some laboratories resulted in treatment failures and acquisition of virulence properties by the organisms. However, modern manufacturing and handling techniques should reduce this fear.
Probiotic Potential
Probiotics hold promise in several areas of women’s health, including reducing the risk of sexually transmitted diseases, recurrent candidal vaginitis, urinary tract infections, and preterm labor. (Clinical trials in these areas will be discussed in a future issue of Alternative Therapies in Women’s Health.)
Often, infections arise when microorganisms form biofilms—dense clumps adherent to the cells and mucus. These biofilms are difficult to eradicate by antibiotic therapy. In situations requiring indwelling catheters (such as chronic neurogenic bladder disease or peritoneal dialysis), biofilms that do not necessarily infect the host can form. It may be possible to actually create "good" biofilms on devices, perhaps using lactobacilli probiotic strains, to prevent infectious biofilms from taking hold.
Most probiotic usage has been for diarrheal and other intestinal ailments, but the potential for probiotics is broadening. There is intriguing preliminary evidence that probiotics may also have potential in reducing the effects of Crohn’s disease, and the risk of bowel cancer, bladder cancer, allergies, kidney stone formation, tonsillitis, and even dermatitis.2-4
Very few laboratories around the world study probiotics and funding for this research is difficult to obtain. Since bacteria cannot be patented (although formulations containing them may be patented), the interest of pharmaceutical companies in this area is limited. Government agencies, such as National Institutes of Health (NIH) and Canada’s Medical Research Council (MRC), have also been slow to fund this research. In Canada, in the last three years the MRC has funded only one small grant on cystitis and none on probiotics. This is hard to justify when 20% of antibiotics are prescribed for cystitis, which afflicts several hundred thousand Canadian women each year. Although cystitis itself is not life-threatening, it may lead to kidney infections and sepsis.
Lactobacilli and Vaginal Health
In the United States, there has been some limited research on the role of lactobacilli in maintaining a healthy balance of vaginal flora. Bacterial vaginosis (BV) is an imbalance of vaginal flora in which lactobacilli are decreased or absent, gram-negative anaerobes predominate, and the pH of the vagina increases to above 4.5. BV appears to increase the risk of male to female transmission of STDs, including HIV,5 and is also a risk factor for preterm birth.6 The presence of lactobacilli is a marker for healthy vaginal flora. All Lactobacillus organisms produce lactic acid and some strains produce hydrogen peroxide. Although some researchers regard hydrogen peroxide production as key to the role of vaginal lactobacilli in vaginal resistance to infection, studies have shown this is too simplistic an explanation. Hydrogen peroxide-producing lactobacilli can be found in women prone to urogenital infections, and non-H2O2 producing strains, such as L. rhamnosus GR-1, can colonize the vagina and express antipathogen properties including bacteriocins and biosurfactants.7
If one is to use probiotics successfully for treatment, one must select an organism shown to be effective for that disease or condition. Any strain of lactobacilli would probably be inadequate to cure candidal vaginitis (Candida species are, after all, part of the normal flora and are found in the vaginas of 40-60% of healthy women). However, several strains could potentially reduce the risk of recurrent candidiasis by maintaining microbial balance in the vagina and thereby preventing candidal overgrowth.
Disruption of normal vaginal flora can occur as a result of exposure to antibiotics and spermicides. By introducing the proper lactobacilli, a good biofilm (like a community of organisms) could be created, which should prevent overgrowth of uropathogens, Candida, and BV organisms, by interfering with their growth and adhesion. Indeed, studies have shown that introduced lactobacilli can flourish, reducing recurrences of cystitis and yeast vaginitis.7
Availability/Formulation
In North America, probiotics are currently considered alternative therapies, available primarily through health food stores and on the Internet. However, labeling may not accurately reflect contents. Although a label may state, for example, that a product contains greater than 109 viable L. acidophilus per capsule, analysis has shown that the organisms present are not necessarily those stated on the label, and the number of viable organisms at the time of purchase may have fallen significantly since the time of packaging.8,9 Furthermore, very few strains contained in current product lines have undergone rigorous examination or have proven mechanisms of action and efficacy (as shown by peer-reviewed scientific publications) for the ailment that is being treated or prevented.10
It should be noted that it is not an easy process to ensure viable lactobacilli in a product. Lactobacilli have fastidious growth requirements, and there are numerous problems associated with freezing and storing them. Also, the speciation of lactobacilli has not been as accurate as that of pathogens. Thus, the reliability and experience of the manufacturer with these cultures is critical to a high-quality product.
Conclusion
More research is necessary to ensure the efficacy of marketed products (for example by comparing probiotics directly with prophylactic antimicrobial therapy for the prevention of recurrent infection). There is currently research being done in at least two labs in Canada and the United States to bring reliable probiotic products to market for urogenital health.
Still, I remain optimistic. My own prediction is that many North Americans will ingest probiotics daily within the next 10 years.
Dr. Reid is Associate Scientific Director of the Lawson Research Institute and Professor of Microbiology and Immunology at the University of Western Ontario, London, ON, Canada. Dr. Reid has an interest in Urex Biotech Inc., a company with patents on lactobacilli probiotics.
References
1. Ransom SB, et al. Oral metronidazole vs. Metrogel Vaginal for treating bacterial vaginosis. Cost-effectiveness evaluation. J Reprod Med 1999;44:359-362.
2. Tano K, et al. In vitro inhibition of S. pneumoniae, nontypable H. influenzae and M. catharralis by alpha-hemolytic streptococci from healthy children. Int J Pediatr Otorhinolaryngol 1999;47:49-56.
3. Brook I, Gober AE. Interference by aerobic and anaerobic bacteria in children with recurrent group A beta-hemolytic streptococcal tonsillitis. Arch Otolaryngol Head Neck Surg 1999;125:552-554.
4. Sidhu H, et al. Identification and classification of Oxalobacter formigenes strains by using oligonucleotide probes and primers. J Clin Microbiol 1997;35:350-353.
5. Sewankambo N, et al. HIV-1 infection associated with abnormal vaginal flora morphology and bacterial vaginosis. Lancet 1997;350:546-550.
6. Hay PE, et al. Abnormal bacterial colonisation of the genital tract and subsequent preterm delivery and late miscarriage. BMJ 1994;308:295-298.
7. Reid G, et al. Instillation of Lactobacillus and stimulation of indigenous organisms to prevent recurrence of urinary tract infections. Microecol Ther 1995;65:3763-3766.
8. Hughes VL, Hillier SL. Microbiologic characteristics of Lactobacillus products used for colonization of the vagina. Obstet Gynecol 1990;75:244-248.
9. Zhong W, et al. Differentiation of Lactobacillus species by molecular typing. Appl Environ Microbiol 1998;64:2418-2423.
10. Reid G. The scientific basis for probiotic strains of lactobacillus. Appl Environ Microbiol 1999;65:3763-3766.
Editor’s Note
The editor would like to thank the following people for their valuable input in preparing articles that appeared in previous issues of Alternative Therapies in Women’s Health: Laneta Dorflinger, PhD; David Grimes, MD; Ted Kaptchuk, OMD; Godfrey Oakley Jr., MD; and Fred Vogel, PhD.
November 1999; Volume 1: 91-94
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