If UPEC get into the bladder or the urethra, the body has ways of fighting them off - including the obvious method of simply flushing them out with the urine. But these bacteria have evolved ways of anchoring themselves to the cells of the urinary tract. The invading UPEC take advantage of receptors naturally found on the cells of the mucosal lining of the urinary tract. Receptors are like molecular "docking bays" for substances that the cells need for their normal growth and development. Like pirates in an old movie, UPEC use "grappling hooks" called type I pili to first hook on to these receptors, and then to invade the cell.
Once inside the cell, these pathogens can live and reproduce in safety, shielded from many of the body's defensive immune responses. In fact, they are so sophisticated that when the body detects that cells have been infected and activates the cell suicide program to destroy the bacteria, UPEC can actually flee the dying host cell before it is flushed out, and look for new cells to invade!
Pathogenic E. coli bacteria's pili "grappling hooks" are composed of long, fibrous chains of a molecular "glue" called adhesin. The effective binding of these adhesin molecules depends on the chemical attraction that exists between them and the residues of a simple carbohydrate called D-Mannose on the cell surface receptors of the urinary tract host cells.
The chemical attraction between UPEC adhesins and D-Mannose is their strength - but it also provides a point of vulnerability. If you can interfere with the binding of adhesins to the D-Mannose residues in the receptors of your urinary tract cells, then you can also prevent UPEC from getting a foothold for adherence and infection. One way to do this, long known to work in a test tube, is by using D-Mannose itself. When isolated urinary tract cells are bathed in D-Mannose, it acts as a molecular "chaff." The bacterial adhesins bind to the D-Mannose in their environment instead of to the D-Mannose residues on the cells. This gums up their pili and prevents them from hooking onto urinary tract cells.
It was discovered in the late 1980s that a small amount of D-Mannose is present in the urine normally, apparently acting as a defensive mechanism against pathogenic bacteria. When D-Mannose is taken as a supplement, much more of the carbohydrate passes through the urinary tract, strengthening this natural defense.
A decade after this discovery, Dr. Jonathan V. Wright of the Tahoma Clinic pioneered the use of D-Mannose supplements to fight off UTIs. For some years, he has been reporting the successful results that his patients have experienced in using D-Mannose to rid themselves of infection. Even patients who had remained infected after having been subjected to a wide range of potent, side-effect-inducing antibiotics have successfully rid themselves of chronic or acute infections using D-Mannose. Other nutritionally oriented physicians and health practitioners have since adopted Dr. Wright's protocols, and the feedback is uniformly excellent from UTI sufferers and their caregivers alike.
Again, not all UTIs are caused by UPEC. So if you try a course of D-Mannose and infection persists, it is likely not caused by these E. coli bacteria but by some other pathogen. In that case, don't just keep going on with the supplement in hopes that it will eventually "kick in:" discontinue use of D-Mannose and consult a physician for treatment appropriate to your case. But for the great majority of urinary tract infections, D-Mannose offers a safe, natural option with a simple, ingenious rationale, no known side-effects, and a great reported success rate.
References
Martinez JJ, Mulvey MA, Schilling JD, Pinkner JS, Hultgren SJ. Type 1 pilus-mediated bacterial invasion of bladder epithelial cells. EMBO J. 2000 Jun 15; 19(12): 2803-12.
Sauer FG, Mulvey MA, Schilling JD, Martinez JJ, Hultgren SJ. Bacterial pili: molecular mechanisms of pathogenesis.Curr Opin Microbiol. 2000 Feb; 3(1): 65-72.
Toyota S, Fukushi Y, Katoh S, Orikasa S, Suzuki Y. Anti-bacterial defense mechanism of the urinary bladder. Role of mannose in urine. Nippon Hinyokika Gakkai Zasshi. 1989 Dec; 80(12): 1816-23.
Wright JV. D-Mannose for bladder and kidney infections. Townsend Letter for Doctors and Patients. 1999 Jul; 192: 96-8.
Virulence of Escherichia coli in ascending urinary-tract infection in mice.
J Med Microbiol. 1982 Aug;15(3):303-16.
Iwahi T, Abe Y, Tsuchiya K.
The virulence of Escherichia coli strains in ascending urinary-tract infection was studied in mice drinking a 5% glucose solution; factors determining the virulence were examined. Of 33 strains, 8 (group I) infected the bladder and kidney, 10 (group II) infected only the bladder, while the remaining 15 strains (group III) did not cause infection. The adherence of group-I and group-II strains to bladder epithelial cells in vitro was inhibited by D-mannose. In group III, 13 strains barely adhered to the epithelial cells, while two strains showed an adherence unaffected by D-mannose. Most strains in groups I and II agglutinated erythrocytes of guinea-pig, chicken, and horse, and cells of Candida albicans in a mannose-sensitive manner. All strains in groups I and II had fimbriae. Virulence for the urinary tract was not directly related with O-serotype, intraperitoneal virulence, ability to grow in mouse urine, ability to ferment dulcitol, production of haemolysin, susceptibility to serum bactericidal activity, or susceptibility to antibiotics. These results suggest that the adherence of the E. coli to mouse-bladder epithelial cells in a mannose-sensitive manner plays an important role in the development of urinary-tract infection in mice and that the adherence is probably mediated by type-1 or closely related fimbriae.
Effect of D-mannose and D-glucose on Escherichia coli bacteriuria in rats.
Urol Res. 1983;11(2):97-102.
Michaels EK, Chmiel JS, Plotkin BJ, Schaeffer AJ.
The effect of D-mannose and D-glucose on bacteriuria due to Escherichia coli with mannose-sensitive adhesins was investigated in adult male Sprague-Dawley rats undergoing diuresis. Inocula of 10(5), 10(7), or 10(8) bacteria in 0.1 ml of normal saline or 2.5% or 10% D-mannose or D-glucose were injected intravesically and urine was cultured 1, 3, 5, 7 and 9 days later. The levels of bacteriuria on days 1 and 5 were significantly lower in rats inoculated with 10(5) E coli and 10% D-mannose than in controls (p less than 0.05 and 0.01 respectively) and the percentages of rats with less than 100 bacteria/ml were higher on days 1 and 3 (p = 0.05 and 0.02 respectively). Bacteriuria was significantly lower in rats inoculated with 10(7) bacteria and 10% D-mannose than in controls on days 5 and 7 (p less than 0.01 for each day) and the percentage of rats with less than 100 bacteria/ml was higher on day 7 (p = 0.01). D-glucose reduced bacteriuria significantly only with a concentration of 10% after instillation of 10(5) E. coli (p less than 0.05, day 1). The results indicate that D-mannose and D-glucose can significantly reduce bacteriuria within 1 day and that their efficacy is dependent upon the concentration of both saccharide and bacteria.
Influence of urological irrigation fluids on urothelial bacterial adherence.
Urol Res. 1993;21(6):401-5.
Gasser TC, Madsen PO.
The influence of various urological irrigation solutions on bacterial growth and adherence to urothelium was investigated in in vitro and guinea pig models. The irrigation solutions glycine 1.5%, glycine 1.5% and ethanol 1%, glycerol 3%, mannose 6%, sorbitol 2.7% and mannitol 0.54% all inhibited bacterial growth compared with normal saline. In guinea pigs, the influence on bacterial adherence of four irrigation solutions (glycine 1.5%, glycine 1.5% and ethanol 1%, mannose 6%, povidone-iodine) was investigated using two different strains of E. coli. After cauterizing one side of the bladder and inoculation with 2.7 x 10(8) colony forming units under high or low pressure, the bladder was irrigated with the irrigation solutions. There was a stronger adherence of E. coli O6 (with type I pili) than of E. coli ATCC 25922 (without type I pili) to bladder urothelium, particularly to the injured side. There was no significant difference between the high- and low-pressure groups. None of the various irrigation solutions was clearly superior. As mannose 6% effectively inhibited type I pili and also had some antibacterial activity it may reduce urinary tract infection if used as irrigation solution.
Quantitation of Tamm-Horsfall protein binding to uropathogenic Escherichia coli and lectins.
J Infect Dis. 1990 Dec;162(6):1335-40.
Reinhart HH, Obedeanu N, Sobel JD.
In quantitative experiments using ELISA, binding of Tamm-Horsfall protein (THP) to uropathogenic Escherichia coli was studied with monoclonal antibody to THP. Adherence to E. coli bearing type 1 fimbriae was proportional to THP concentration and size of the bacterial inoculum. Type 1 fimbriae-bearing E. coli bound 50 times more THP than did non-type 1-fimbriated or P-fimbriated strains. Concanavalin A and wheat germ agglutinin bound THP in a dose-dependent fashion, whereas pokeweed mitogen and Vicia villosa B4 isolectin did not. Addition of mannose and N-acetylglucosamine reduced adherence of THP to concanavalin A and wheat germ agglutinin by 50%-80%. Sugar inhibition studies suggested that the fimbrial receptor site for THP has lectin-like properties and that THP binds to fimbriae via its mannose side chains. This quantitative assay is useful for studying the interaction between THP, uroepithelial cells, and bacteria in vitro.
Environmental alteration and two distinct mechanisms of E. coli adherence to bladder epithelial cells.
Invest Urol. 1981 Mar;18(5):364-70.
Avots-Avotins AE, Fader RC, Davis CP.
We used an in vitro model to investigate Escherichia coli attachment to transitional epithelial cells obtained from bladders of female rats. Adhesive abilities and sensitivity to mannose inhibition differed among the isolates for both epithelial cells and erythrocytes. Adherence of some strains could be modulated by bacterial washes and growth media. Variations in adhesiveness were related to bacterial piliation as determined by transmission electron microscopy. With two strains, mannose inhibition of adherence to epithelial cells was dose-related; however, with a maximal inhibitory dose, adherence was reduced by approximately 80 per cent even when the bacteria-to-epithelial cell ratio was varied. These studies show that adhesiveness and piliation of certain adhesive E. coli strains are either reduced or enhanced by environmental alterations. We conclude that E. coli strains adhere to epithelial cells by at least two distinct mechanisms and that a single isolate may utilize both mechanisms. The more efficient process is pili-mediated and inhibited by mannose whereas undetermined surface components mediate the less efficient but mannose-resistant mechanism.
Mannose inhibition of Escherichia coli adherence to urinary bladder epithelium: comparison with yeast agglutination.
Urol Res. 1985;13(2):79-84.
Ruggieri MR, Hanno PM, Levin RM.
The adherence of piliated strains of Escherichia coli (E. coli) to mammalian epithelial cells has been reported by several investigators to be specifically inhibited by D(+)-mannose or its derivatives. Much of this work utilized mannose type compounds to inhibit agglutination of mannan containing yeast cells by E. coli to demonstrate mannose sensitivity. This report investigates the ability of the neotype strain of E. coli (which is sensitive to mannose inhibition of yeast cell agglutination) to bind and metabolize radiolabeled D(+)-mannose. In addition the relative efficacy of D(+)-mannose and heparin to inhibit the adherence of E. coli to rabbit bladder mucosa was compared. Results showed that although D(+)-mannose did block E. coli--yeast cell agglutination in a reversible manner, radiolabeled D(+)-mannose binding by E. coli could not be displaced by 1,000 fold excess unlabeled D(+)-mannose. This suggests uptake of the sugar as opposed to a surface binding phenomenon which was confirmed by the demonstration of significant metabolism of mannose by E. coli. The same concentration of D(+)-mannose which prevented E. coli--yeast cell agglutination was not particularly effective in preventing E. coli adherence to the acid denuded rabbit bladder. Heparin treatment of the acid denuded bladder was very effective in preventing E. coli adherence but was ineffective in preventing E. coli--yeast cell agglutination. This indicates that E. coli--yeast cell agglutination should not be correlated with E. coli adherence to mammalian epithelial tissue.
Sub-MIC ciprofloxacin effect on fimbrial production by uropathogenic Escherichia coli strains.
J Chemother. 1999 Oct;11(5):357-62.
Lo Bue AM, Geremia E, Castagna C, Chisari G, Nicoletti G.
The urine from 210 patients with acute urinary tract infection (UTI) was examined to study the in vitro effect of ciprofloxacin on fimbriae production by uropathogenic Escherichia coli isolates. Forty-nine bacterial samples of density 10(5) CFU/ml were not considered. From the resulting 161 samples, E. coli was the major strain found, present in 54 samples. Other microoganisms found were: Enterococcus sp. (34 samples), Staphylococcus epidermis (22), yeasts (11), Proteus sp. (11), Pseudomonas sp. (11), Klebsiella sp. (8), Enterobacter sp. (6), Citrobacter sp. (3), and Acinetobacter sp. (1). The uropathogenic E. coli strains found were P-fimbriated, as demonstrated by hemoagglutination activity against human erythrocytes with and without mannose, SDS-PAGE of fimbrial proteins and transmission electron microscopy (TEM). All E. coli strains found were exposed in vitro to sub-inhibitory concentrations of ciprofloxacin (1/8 MIC). Our results showed that: 1) P-fimbriated E. coli is the most prevalent microorganism in acute UTI (34%); 2) exposure to sub-MICs of ciprofloxacin inhibits fimbrial production in 79% of E. coli strains; 3) the pattern of SDS-PAGE fimbrial proteins is modified after exposure; in particular, the most affected synthesis involves the protein at 18 kD known as P-fimbriae.
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