Bacteria An Important Part of Urological Health
Overview
Bacteria can be good for your health? When was the last time this was stated as part of the Urology curriculum? A glance through classical urology text books and you would be hard pushed to find anything on this topic. On the contrary, reference to bacteria is essentially focused on those that infect the urinary tract and prostate. Yet, as more research emerges from various centers, it appears that indeed we need to look differently at how we view bacteria.
Urinary tract infection and prostatitis are major reasons for urologic visits, yet the management of these conditions has changed little in the past two decades. This might in part be due to a decline in the already small number of urologists doing research on the pathogenesis, prevention and treatment of infection. In essence, the main approach has been to use antibiotic for treatment and prophylaxis. The elegant work of Scott Hultgren at Washington University in St. Louis, has recently brought into question the whole process of detecting and managing infections in the bladder. Indeed, his work suggests that in some cases the use of antibiotics only drives the invading bacteria deeper into the epithelium in dense biofilms that are recalcitrant to eradication [1]. Not only would such biofilms not be detected by routine microbiological cultures, but their ability to sense and resist chemotherapeutic intervention makes them particularly difficult to clear.
Rather than continue to try and kill the E. coli, using a process that also kills many commensal organisms, another approach could be to entice them away from their niche, or make it more difficult for them to colonize. One such concept is to avirulent E. coli implanted into the bladder. Scientists in Houston, Texas have indeed shown that in some spinal cord injured patients the administration of avirulent E. coli and their subsequent colonization of the bladder can reduce symptomatic infections. If these friendly E. coli could also entice biofilm-encased pathogens to emerge from their intracellular domain, it might provide a means to cure patients with chronic infections. Thus, in addition to Hultgrens work suggesting we take a whole different look at infection, so too we need to reconsider how we prevent and treat infection, and utilize non-pathogenic bacteria for those outcomes.
Probiotics
The direct application of beneficial microbes to the host is termed probiotics, meaning for life. Some of the applications of probiotics have origins in urology. In 1915, Newman reported the insertion of lactic acid bacteria into the bladder to treat infections. He reported a degree of success at a time when Elie Metchnikoff reported a correlation between longevity and lactic acid bacteria. Unfortunately, there is no peer-reviewed publications thereafter, so it is difficult to know if and how well this concept worked, or why it failed. Preliminary efforts to repeat the concept using lactobacilli failed in a pilot study performed in Sweden in 1989 [2]. That study was not the ideal method of using lactobacilli, as there is no record of them living in the normal bladder. Thus, their direct administration into the bladder did not lead to colonization. The observations of Bruce et al. in 1973 [3] that infection was an ascending process from the gut, and women with no history of UTI had lactobacilli in the vagina, led to the hypothesis that these organisms might be able to interfere with pathogens and prevent UTI. However, this interference would be best at the vaginal level rather than by intravesical implantation.
The 2007 International Dairy Foundation Elie Metchnikoff Prize for Nutrition and Health, named after the Russian scientists awarded the Nobel Prize in 1908, was awarded to
Dr. Bruce and colleague Dr Reid (shown above, Dr. Bruce on left), for their discovery that orally administered lactobacilli probiotics could indeed interfere with ascendancy of uropathogens and help prevent infection. They showed that the lactobacilli, as with pathogens, can ascend from the rectum and perineal skin into the vagina and reduce uropathogen ascension. Not only that, intravaginally administered Lactobacillus rhamnosus GR-1 and L. reuteri RC-14 were shown to reduce the UTI recurrence rate [4] and cure bacteria vaginosis (BV) [5] a condition that involves a major disruption of the vaginal flora and one that can predispose the patient to UTI. A recent prospective randomized controlled study using a strain of Lactobacillus acidophilus in 120 children with persistent primary vesicoureteral reflux (VUR) showed equivalent UTI prevention to trimethoprim/sulfamethoxazole 2/10 mg/kg h.s (incidence of recurrent UTI was 18.3% (11/60) in the probiotics group and 21.6%(13/60) in the antibiotic group; P = 0.926) [6]. More studies are warranted, but these findings are encouraging.
Given the drying up of new antibiotic pipelines, emergence of major problems with resistance, and ongoing side effects with these agents, another approach is to enhance the efficacy of antibiotics by conjointly using probiotics. In a randomized, placebo-controlled study of 106 women with bacterial vaginosis, the efficacy of metronidazole was significantly improved and antibiotic side effects negated by conjoint use of probiotics [7]. This finding has now been repeated in a 64 patient study (unpublished). The mechanism may involve replenishment of the vaginal flora with lactobacilli at the expense of pathogens, immune modulation that helps eradicate the infecting organisms, or improved bioavailability of the drug at the site, but it is too early to know.
An unlikely correlation between regular use of probiotics and urology, comes from studies in Japan which showed that ingestion of L. casei Shirota in fermented milk correlated with a reduction in the recurrence of bladder cancer [8]. There are several theories as to why this might have occurred, albeit none of them explored by the authors themselves. Firstly, studies by various researchers in the 1980s showed a correlation between UTI and early death, as well as increased production of carcinogens in the bladder. It is feasible that L. casei Shirota reduced the presence of pathogens in the bladder, and therefore lowered carcinogen exposure. Alternatively, the anti-cancer effects might occur in the gut, and in doing so reduce the availability of these compounds being absorbed and secreted in urine. Such gut-urinary tract effects are also noted in stone disease as will be mentioned later. Other anti-cancer effects could be due to immune modulation in the mucosa, beginning in the gut and then affecting distant sites. Inflammation is often associated with cancer and the immuno-modulatory effects of probiotics have been well documented. Another option that is feasible is that molecules with anti-tumour effects are released by the lactobacilli into the bloodstream, thereby affecting the bladder directly or through modulation of another biomechanical pathway. These concepts certainly warrant further investigation and the clinical trial should be repeated at other sites.
An estimated 80% of calculi are in the form of oxalate. This substance is present in the gut and absorbed into the blood stream where it is deposited with calcium in the kidney, ureter or bladder. Researchers in Florida hypothesized that when an anaerobic bacterium Oxalobacter formigenes is present in the gut, oxalates are degraded and risk of oxaluria and calculi reduced. They have since generated some evidence that this is correct in animal and human studies [9] and are now moving towards commercial development of this probiotic technology.
Bacterial by-products
Further to studies by Morales, Bruce and others, bacteria such as Mycobacterium, have been used in urologic practice for over 30 years to treat superficial bladder cancer. The mechanism is presumed to be an immune effect, and in recent times by-products (namely the glycocalyx) of the organism have been isolated with the hope of boosting the hosts response without inducing side effects associated with the live bacteria.
Lactobacilli can also be potent adjuvants under the right circumstances, but the primary mechanism of action was long believed to be through production of bacteriocins. The isolation of bacteriocins has, for the most part, not led to the development of commercial products to fight infection. The discovery of signaling molecules produced by lactobacilli [10] has led to studies showing that secreted products do have immuno-modulatory activity as well as being able to down-regulate toxin secretion in E. coli and S. aureus. This raises the potential for beneficial bacterial by-products to be used to negate the infectivity of pathogens, not necessarily by having to kill them, but rather to disable their ability to infect the host and/or induce symptomatic conditions.
Such compounds also show potential for application to biomedical devices, such as urinary and peritoneal catheters, in the hope of either preventing or delaying infection. This is not an easily proven concept as urinary mucins and other host substances alter the properties of surfaces rapidly, or mask the compounds, while leaching out of molecules from catheters and stents affects shelf-life of products. So far, industry has not shown an interest in using bacterial products for anti-infective or anti-inflammatory applications in urology, but this could well change as more compounds are identified and shown to work in vivo.
In Conclusion Take home message
The following are the main points of this article.
--- Article by Gregor Reid
Tel: 519-646-6100 x65256
Fax: 519-646-6031
Email: gregor@uwo.ca
Canadian R&D Centre for Probiotics
Room F2-116, Lawson Health Research Institute
268 Grosvenor Street, London, Ontario N6A 4V2, Canada
References
1. Mysorekar IU, Hultgren SJ. Mechanisms of uropathogenic Escherichia coli persistence and eradication from the urinary tract. Proceedings of the National Academy of Science U S A. 2006;103(38):14170-5.
2. Hagberg L, Bruce AW, Reid G, Svanborg Eden C, Lincoln K, Lidin-Janson G. Colonization of the urinary tract with live bacteria from the normal fecal and urethral flora in patients with recurrent symptomatic urinary tract infections. In, Host-parasite interactions in urinary tract infections. E. H. Kass, and C. Svanborg Eden (Eds), University of Chicago Press 1989, pp. 194-197
3. Bruce AW, Chadwick P, Hassan A, VanCott GF. Recurrent urethritis in women. Canadian Medical Association Journal. 1973; 108:973-6.
4. Reid G, Bruce AW, Taylor M. Instillation of Lactobacillus and stimulation of indigenous organisms to prevent recurrence of urinary tract infections. Microecology and Therapy. 1995; 23: 32-45.
5. Anukam KC, Osazuwa E, Osemene GI, Ehigiagbe F, Bruce AW, Reid G. Clinical study comparing probiotic Lactobacillus GR-1 and RC-14 with metronidazole vaginal gel to treat symptomatic bacterial vaginosis. Microbes and Infection. 2006; 8(12-13):2772-2776.
6. Lee SJ, Shim YH, Cho SJ, Lee JW. Probiotics prophylaxis in children with persistent primary vesicoureteral reflux. Pediatric Nephrology. 2007;22(9):1315-20.
7. Anukam K, Osazuwa E, Ahonkhai I, Ngwu M, Osemene G, Bruce AW, Reid G. Augmentation of antimicrobial metronidazole therapy of bacterial vaginosis with oral probiotic Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14: randomized, double-blind, placebo controlled trial. Microbes and Infection. 2006; 8(6):1450-4.
8. Ohashi Y, Nakai S, Tsukamoto T, Masumori N, Akaza H, Miyanaga N, Kitamura T, Kawabe K, Kotake T, Kuroda M, Naito S, Koga H, Saito Y, Nomata K, Kitagawa M, Aso Y. Habitual intake of lactic acid bacteria and risk reduction of bladder cancer. Urology International. 2002;68(4):273-80.
9. Hoppe B, Beck B, Gatter N, von Unruh G, Tischer A, Hesse A, Laube N, Kaul P, Sidhu H. Oxalobacter formigenes: a potential tool for the treatment of primary hyperoxaluria type 1. Kidney International. 2006;70(7):1305-11.
10. Laughton J, Devillard E, Heinrichs D, Reid G, McCormick J. Inhibition of expression of a staphylococcal superantigen-like protein by a secreted signaling factor from Lactobacillus reuteri. Microbiology 2006;152: 1155-1167.
Bacteria can be good for your health? When was the last time this was stated as part of the Urology curriculum? A glance through classical urology text books and you would be hard pushed to find anything on this topic. On the contrary, reference to bacteria is essentially focused on those that infect the urinary tract and prostate. Yet, as more research emerges from various centers, it appears that indeed we need to look differently at how we view bacteria.
Urinary tract infection and prostatitis are major reasons for urologic visits, yet the management of these conditions has changed little in the past two decades. This might in part be due to a decline in the already small number of urologists doing research on the pathogenesis, prevention and treatment of infection. In essence, the main approach has been to use antibiotic for treatment and prophylaxis. The elegant work of Scott Hultgren at Washington University in St. Louis, has recently brought into question the whole process of detecting and managing infections in the bladder. Indeed, his work suggests that in some cases the use of antibiotics only drives the invading bacteria deeper into the epithelium in dense biofilms that are recalcitrant to eradication [1]. Not only would such biofilms not be detected by routine microbiological cultures, but their ability to sense and resist chemotherapeutic intervention makes them particularly difficult to clear.
Rather than continue to try and kill the E. coli, using a process that also kills many commensal organisms, another approach could be to entice them away from their niche, or make it more difficult for them to colonize. One such concept is to avirulent E. coli implanted into the bladder. Scientists in Houston, Texas have indeed shown that in some spinal cord injured patients the administration of avirulent E. coli and their subsequent colonization of the bladder can reduce symptomatic infections. If these friendly E. coli could also entice biofilm-encased pathogens to emerge from their intracellular domain, it might provide a means to cure patients with chronic infections. Thus, in addition to Hultgrens work suggesting we take a whole different look at infection, so too we need to reconsider how we prevent and treat infection, and utilize non-pathogenic bacteria for those outcomes.
Probiotics
The direct application of beneficial microbes to the host is termed probiotics, meaning for life. Some of the applications of probiotics have origins in urology. In 1915, Newman reported the insertion of lactic acid bacteria into the bladder to treat infections. He reported a degree of success at a time when Elie Metchnikoff reported a correlation between longevity and lactic acid bacteria. Unfortunately, there is no peer-reviewed publications thereafter, so it is difficult to know if and how well this concept worked, or why it failed. Preliminary efforts to repeat the concept using lactobacilli failed in a pilot study performed in Sweden in 1989 [2]. That study was not the ideal method of using lactobacilli, as there is no record of them living in the normal bladder. Thus, their direct administration into the bladder did not lead to colonization. The observations of Bruce et al. in 1973 [3] that infection was an ascending process from the gut, and women with no history of UTI had lactobacilli in the vagina, led to the hypothesis that these organisms might be able to interfere with pathogens and prevent UTI. However, this interference would be best at the vaginal level rather than by intravesical implantation.
The 2007 International Dairy Foundation Elie Metchnikoff Prize for Nutrition and Health, named after the Russian scientists awarded the Nobel Prize in 1908, was awarded to
Dr. Bruce and colleague Dr Reid (shown above, Dr. Bruce on left), for their discovery that orally administered lactobacilli probiotics could indeed interfere with ascendancy of uropathogens and help prevent infection. They showed that the lactobacilli, as with pathogens, can ascend from the rectum and perineal skin into the vagina and reduce uropathogen ascension. Not only that, intravaginally administered Lactobacillus rhamnosus GR-1 and L. reuteri RC-14 were shown to reduce the UTI recurrence rate [4] and cure bacteria vaginosis (BV) [5] a condition that involves a major disruption of the vaginal flora and one that can predispose the patient to UTI. A recent prospective randomized controlled study using a strain of Lactobacillus acidophilus in 120 children with persistent primary vesicoureteral reflux (VUR) showed equivalent UTI prevention to trimethoprim/sulfamethoxazole 2/10 mg/kg h.s (incidence of recurrent UTI was 18.3% (11/60) in the probiotics group and 21.6%(13/60) in the antibiotic group; P = 0.926) [6]. More studies are warranted, but these findings are encouraging.
Given the drying up of new antibiotic pipelines, emergence of major problems with resistance, and ongoing side effects with these agents, another approach is to enhance the efficacy of antibiotics by conjointly using probiotics. In a randomized, placebo-controlled study of 106 women with bacterial vaginosis, the efficacy of metronidazole was significantly improved and antibiotic side effects negated by conjoint use of probiotics [7]. This finding has now been repeated in a 64 patient study (unpublished). The mechanism may involve replenishment of the vaginal flora with lactobacilli at the expense of pathogens, immune modulation that helps eradicate the infecting organisms, or improved bioavailability of the drug at the site, but it is too early to know.
An unlikely correlation between regular use of probiotics and urology, comes from studies in Japan which showed that ingestion of L. casei Shirota in fermented milk correlated with a reduction in the recurrence of bladder cancer [8]. There are several theories as to why this might have occurred, albeit none of them explored by the authors themselves. Firstly, studies by various researchers in the 1980s showed a correlation between UTI and early death, as well as increased production of carcinogens in the bladder. It is feasible that L. casei Shirota reduced the presence of pathogens in the bladder, and therefore lowered carcinogen exposure. Alternatively, the anti-cancer effects might occur in the gut, and in doing so reduce the availability of these compounds being absorbed and secreted in urine. Such gut-urinary tract effects are also noted in stone disease as will be mentioned later. Other anti-cancer effects could be due to immune modulation in the mucosa, beginning in the gut and then affecting distant sites. Inflammation is often associated with cancer and the immuno-modulatory effects of probiotics have been well documented. Another option that is feasible is that molecules with anti-tumour effects are released by the lactobacilli into the bloodstream, thereby affecting the bladder directly or through modulation of another biomechanical pathway. These concepts certainly warrant further investigation and the clinical trial should be repeated at other sites.
An estimated 80% of calculi are in the form of oxalate. This substance is present in the gut and absorbed into the blood stream where it is deposited with calcium in the kidney, ureter or bladder. Researchers in Florida hypothesized that when an anaerobic bacterium Oxalobacter formigenes is present in the gut, oxalates are degraded and risk of oxaluria and calculi reduced. They have since generated some evidence that this is correct in animal and human studies [9] and are now moving towards commercial development of this probiotic technology.
Bacterial by-products
Further to studies by Morales, Bruce and others, bacteria such as Mycobacterium, have been used in urologic practice for over 30 years to treat superficial bladder cancer. The mechanism is presumed to be an immune effect, and in recent times by-products (namely the glycocalyx) of the organism have been isolated with the hope of boosting the hosts response without inducing side effects associated with the live bacteria.
Lactobacilli can also be potent adjuvants under the right circumstances, but the primary mechanism of action was long believed to be through production of bacteriocins. The isolation of bacteriocins has, for the most part, not led to the development of commercial products to fight infection. The discovery of signaling molecules produced by lactobacilli [10] has led to studies showing that secreted products do have immuno-modulatory activity as well as being able to down-regulate toxin secretion in E. coli and S. aureus. This raises the potential for beneficial bacterial by-products to be used to negate the infectivity of pathogens, not necessarily by having to kill them, but rather to disable their ability to infect the host and/or induce symptomatic conditions.
Such compounds also show potential for application to biomedical devices, such as urinary and peritoneal catheters, in the hope of either preventing or delaying infection. This is not an easily proven concept as urinary mucins and other host substances alter the properties of surfaces rapidly, or mask the compounds, while leaching out of molecules from catheters and stents affects shelf-life of products. So far, industry has not shown an interest in using bacterial products for anti-infective or anti-inflammatory applications in urology, but this could well change as more compounds are identified and shown to work in vivo.
In Conclusion Take home message
The following are the main points of this article.
- Bacteria perform a number of functions in the body that are beneficial, and utilization of certain strains can help to prevent or even treat some urologic conditions, including infection, oxaluria and cancer.
- Lactobacilli are the primary probiotic organisms for application to the intestine and urogenital tract. Studies show great promise in reducing the burden of infection either by prophylactic use of lactobacilli or by their combined use with antibiotics.
- By-products of beneficial bacteria can also play a role in urology, through immune modulation, cell-cell signaling, and down regulation of virulence of pathogens.
- Great opportunities exist for young urologists to investigate the role of bacteria in health, and to not only do the clinical studies that are needed to determine if and how probiotics work, but also to uncover new methods by which commensal bacteria restore and maintain urinary health.
--- Article by Gregor Reid
Tel: 519-646-6100 x65256
Fax: 519-646-6031
Email: gregor@uwo.ca
Canadian R&D Centre for Probiotics
Room F2-116, Lawson Health Research Institute
268 Grosvenor Street, London, Ontario N6A 4V2, Canada
References
1. Mysorekar IU, Hultgren SJ. Mechanisms of uropathogenic Escherichia coli persistence and eradication from the urinary tract. Proceedings of the National Academy of Science U S A. 2006;103(38):14170-5.
2. Hagberg L, Bruce AW, Reid G, Svanborg Eden C, Lincoln K, Lidin-Janson G. Colonization of the urinary tract with live bacteria from the normal fecal and urethral flora in patients with recurrent symptomatic urinary tract infections. In, Host-parasite interactions in urinary tract infections. E. H. Kass, and C. Svanborg Eden (Eds), University of Chicago Press 1989, pp. 194-197
3. Bruce AW, Chadwick P, Hassan A, VanCott GF. Recurrent urethritis in women. Canadian Medical Association Journal. 1973; 108:973-6.
4. Reid G, Bruce AW, Taylor M. Instillation of Lactobacillus and stimulation of indigenous organisms to prevent recurrence of urinary tract infections. Microecology and Therapy. 1995; 23: 32-45.
5. Anukam KC, Osazuwa E, Osemene GI, Ehigiagbe F, Bruce AW, Reid G. Clinical study comparing probiotic Lactobacillus GR-1 and RC-14 with metronidazole vaginal gel to treat symptomatic bacterial vaginosis. Microbes and Infection. 2006; 8(12-13):2772-2776.
6. Lee SJ, Shim YH, Cho SJ, Lee JW. Probiotics prophylaxis in children with persistent primary vesicoureteral reflux. Pediatric Nephrology. 2007;22(9):1315-20.
7. Anukam K, Osazuwa E, Ahonkhai I, Ngwu M, Osemene G, Bruce AW, Reid G. Augmentation of antimicrobial metronidazole therapy of bacterial vaginosis with oral probiotic Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14: randomized, double-blind, placebo controlled trial. Microbes and Infection. 2006; 8(6):1450-4.
8. Ohashi Y, Nakai S, Tsukamoto T, Masumori N, Akaza H, Miyanaga N, Kitamura T, Kawabe K, Kotake T, Kuroda M, Naito S, Koga H, Saito Y, Nomata K, Kitagawa M, Aso Y. Habitual intake of lactic acid bacteria and risk reduction of bladder cancer. Urology International. 2002;68(4):273-80.
9. Hoppe B, Beck B, Gatter N, von Unruh G, Tischer A, Hesse A, Laube N, Kaul P, Sidhu H. Oxalobacter formigenes: a potential tool for the treatment of primary hyperoxaluria type 1. Kidney International. 2006;70(7):1305-11.
10. Laughton J, Devillard E, Heinrichs D, Reid G, McCormick J. Inhibition of expression of a staphylococcal superantigen-like protein by a secreted signaling factor from Lactobacillus reuteri. Microbiology 2006;152: 1155-1167.
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