Probiotic Therapy and Functional Foods

for Prevention of Urinary Tract

Infections: State of the Art and Science

Gregor Reid PhD, MBA

Address
Departments of Microbiology and Immunology and Surgery,
University of Western Ontario, Lawson Health Research Institute,
268 Grosvenor Street, London, ON N6A 4V2, Canada.
E-mail: [e-mail]

Current Infectious Disease Reports 2000, 2:518–522
Current Science Inc. ISSN 1523–3847
Copyright © 2000 by Current Science Inc.

Introduction

In the past year, interest has significantly increased in the role
o f t h e u ro g e n i t a l a n d i n t e s t i n a l f l o r a t o p r e ve n t
infectious diseases, and in the potential for application of
probiotic organisms (which confer a health benefit to the
host) to restore a healthy flora and prevent disease recurrence.

Several text books have published compiling articles

from numerous authors around the world. Most of the
research has taken place in Europe, where funding for
probiotic studies has been much more available than it
has been in North America. Further, news features on
probiotics have appeared in such prestigious journals as

Lancet [1]. Although the Lancet article focused primarily on
the intestine; it, did cite the potential to use avirulent
organisms for bladder colonization of patients with spinal-
cord injuries, in which cases bacterial biofilm development
is inevitable. It also emphasized the need for a scientific
basis to select probiotic organisms.

Criteria for selection of effective urogenital probiotics

has been proposed [2••].

Rationale for the Use of Probiotics

The concept of replenishing the normal urogenital flora to
reduce the recurrence of urinary tract infections (UTIs) was
first conceived in 1974 by Dr. Andrew Bruce, a Canadian
urologist who observed, between healthy women and
those prone to UTI, differences in these flora. His rationale:
because uropathogens primarily ascend from the intestine
to the vagina and bladder, the vaginal flora could act as a
barrier against this infectious process, and if a barrier
population of “good” bacteria (predominantly lacto-
bacilli) exists, then pathogens may not so easily ascend
and infect the host. A number of studies strengthened this
concept by showing that, in an infected host, uropathogen
colonization of the vagina is heavy and lactobacilli
numbers are depleted. Subsequently, an extensive number
of in vitro and clinical studies have since supported the
concept. It is now believed that exogenous application of
probiotic lactobacilli can influence the urogenital flora
and help maintain a barrier population better able to
resist infection.

Most clinical studies have delivered the lactobacilli

directly into the vagina. In one closely studied patient with
recurrent enterococcal UTI, Lactobacillus rhamnosus GR-1
and Lactobacillus fermentum RC-14 were used to colonize
the vagina and deplete enterococcal biofilms as well as
eradicate enterococci from the bladder. Chronic symptoms
of UTI, present in this patient for four years, ceased within
weeks of therapy. The implications from this case are
exciting, but also potentially controversial.

For the purpose of discussion, we raise the idea that,

in certain patients, bladder infections require continual
seeding from the vaginal pathogen population. That
being the case, if the pathogen supply is “cut off” by re-

In the past year, interest has heightened in the potential for
probiotics to prevent urinary tract infection (UTI). Mainly,
this has been due to concerns about antibiotic resistance
and recognition of the scientific efficacy of probiotics. The
critical factors in any successful application of probiotics to
patient care are the scientific basis for selecting probiotic
strains and clinical verification that they are effective against
the recurrence of UTI. Three strains—Lactobacillus
rhamnosus GR-1 and Lactobacillus fermentum B-54 and RC-
14—have been shown to colonize the vagina and act as a
barrier to the ascension of uropathogens into the bladder.
Their ability to produce growth and adhesion antagonists
against urogenital pathogens is clinically important, because
these appear to be important mechanisms of action.
Probiotic therapy has been shown to be safe, but too few
reliable products are on the market, and none are yet
available for use against UTI. Given the right strains and
delivery system, probiotic therapy could provide the first
new UTI-prevention system in 40 years, and may help in
the management of recurrent UTI.

Probiotic Therapy and Functional Foods for Prevention of Urinary Tract Infections • Reid

519

establishment of a non-pathogen dominated vaginal
flora, then infection will subside. For more than 30 years,
it has been known that bacteriuria can resolve, in some
patients, without antibiotic intervention, but the mecha-
nism of action has been a mystery. It is also known that,
in healthy women, pathogens frequently enter the
bladder, perhaps on a daily basis, but do not become so
established that they invoke symptoms and signs of
infection. The ability of bacteria to be retained in the
bladder led to extensive studies investigating bacterial
adhesion as the main mechanism whereby pathogens are
able to stay in the bladder, multiply, and infect the host.
However, the concept of continual seeding from the
vagina, perineum and urethra has not been raised until
now. If this is proved to occur in large numbers of
patients, then the role of the lactobacilli becomes
potentially even more important, as their replenishment
could be used to prevent symptomatic UTI or treat
asymptomatic bacteriuria (Figure 1).

Factors Influencing the Urogenital Flora

A number of factors can influence a woman’s susceptibility
to UTI. These include virulence of the uropathogens;
exposure to foreign bodies, such as diaphragms and intrau-
terine devices; exposure to antibiotics and spermicidal
agents; and urinary composition and micturition habits.
With respect to probiotics, several recent publications are of
interest. Two studies show that resistance to antibiotics
commonly prescribed for UTI, particularly trimethoprim-
sulfamethoxazole, has increased significantly in the past
seven years [3••,4]. Because the standard treatment regi-
men includes daily use of trimethoprim-sulfamethoxazole
for between 6 months and 5 years, increased uropathogen
resistance is one major reason for heightened interest in
alternative ways to manage recurrent UTI.

With respect to drug resistance among lactobacilli, a

study of 46 isolates found some to be resistant to several
classes of antibiotics, suggesting that not all strains are
suitable for probiotic application [5]. However, another

Figure 1. The enhancement of Lactobacillus by oral or vaginal delivery, as a treatment for some cases of urinary tract infection and
asymptomatic bacteriuria. Lactobacillus (for example, L. rhamnosus GR-1 and L. fermentum RC-14) are ingested or delivered vaginally.
They emerge and help restore the balance of the gut and genital flora. In addition, they are antagonistic to the growth and colonization
of urogenital pathogens.

520

Urinary Tract Infections and the Female Pelvis

outcome of this study is that natural resistance of some
lactobacilli to antibiotics could enable them to be used as
combination therapy, along with antimicrobial agents, to
prevent onset of yeast infections (which are common in
women after antibiotic therapy ends) and recurrence of UTI.

Spermicidal agents—particularly nonoxynol-9, which

is commonly used to avoid pregnancy and reduce the risk
of sexually transmitted diseases—have been shown to kill
lactobacilli and support the growth of uropathogens. In
two recent studies, exposure to nonoxynol-9 caused cervi-
cal and vaginal erythema in non-human primates [6] and
transient decrease in lactobacilli concentrations and
increase in anaerobic gram-negative rods—the causative
agents of bacterial vaginosis (BV)—in humans [7].

Hormones are known to alter susceptibility to UTI. In

postmenopausal women, estrogen therapy has been shown
to reduce the risk of infection, and the associative replen-
ishment of the lactobacilli flora is believed to play a major
role. In a multicenter, randomized, open, parallel-group
study of 108 women, an estradiol-releasing silicone vaginal
ring was found to significantly (P = .008) reduce UTI [8];
vaginal pH was reduced, but vaginal flora bacterial counts
were not examined.

Studies reported in the 1970s showed that the act of

micturition itself alters the urogenital flora. Substances
such as functional foods (eg, cranberries), which alter the
composition of urine, have been tested to determine if they
can reduce the recurrence of UTI. Recently, volunteers who
ingested cranberry extracts produced urine that did not
support the adhesion of Escherichia coli to surfaces;
ingestion of vitamin C produced urine that inhibited
Enterococcus faecalis adhesion [9]. These studies implied
that risk of catheter-related UTI could be reduced by intake
of appropriate foods. Several other studies have indicated
that cranberry extracts possess anti-E. coli properties. How-
ever, a literature review by Harkins [10] claims that
evidence based upon randomized, placebo controlled
studies is insufficient to conclude, with any certainty,
that cranberry juice can prevent UTI. This may be an overly
negative a viewpoint, and time will tell the extent to which
Harkins is correct.

A randomized, double-blind, placebo-controlled inter-

vention study of 725 institutionalized elderly patients in
France showed that two years of supplemental nutrients
(zinc, selenium sulfide,

b-carotene, vitamin C, and vitamin

E) did not reduce the incidence of urogenital infections
[11]. In this case, the results would have been more
convincing if dosage studies had been done, because it is
reasonable to suspect that the levels used were insufficient
to stimulate an effect.

Other ways of manipulating the urinary composition

are worthy of investigation. Urine contains natural osmo-
regulatory substances, such as urea, organic acids and
betaines. Pathogens can adapt to high osmolarity by
activating glycine betaine and stabilizing macromolecular
structures against the toxicity of urea and low pH [12].

Clinical trials using selected dietary substances need to be
performed, to determine clinical significance. A particu-
larly interesting aspect of functional foods is that they
appear capable of changing the urogenital micro-environ-
ment. Using functional food to favor the selective growth
of lactobacilli and other normal flora members appears
feasible in vitro [13]; thus, foods and beverages might be
designed to help maintain bladder health in the future.

Selection of Probiotic Agents for UTI

A recent mini-review establishes a set of scientifically based
criteria upon which to select probiotic lactobacilli [2••]. It
also shows that only a handful of organisms have peer-
reviewed evidence supporting their effectiveness in UTIs
and proposed mechanisms of action. Some scientists place
much emphasis on lactobacilli that produce hydrogen per-
oxide [14]. While this characteristic appears to be impor-
tant, it is not the sole—or most critical—factor in getting
the urogenital flora back to normal. The blend of charac-
teristics required for a probiotic to be successful will
depend upon its site of action and delivery. Thus, if deliv-
ery is via the intestine, the ability to resist low pH and high
concentrations of bile [15] should be added to the ability
of the organisms to interfere with growth and colonization
of pathogens in the urogenital tract.

An understanding of how uropathogens cause infec-

tion may also give us a better idea of what characteristics of
probiotics could be necessary to prevent infection. E. coli
are the target of most UTI studies, as they cause the most
infections. A number of lactobacilli have been shown to
inhibit adhesion of various pathogenic E. coli [16], and
prevent intestinal infection in animals [17]. Lactobacilli
also bind to mannose, and thus can block type 1 fimbri-
ated E. coli adhesion. Studies (Reid, Unpublished data)
show that urogenital L. rhamnosus GR-1 and L. fermentum
RC-14 inhibit growth of both intestinal and urogenital
pathogens. The extent to which antagonism of uropatho-
gens by the normal flora takes place while they are in the
intestine remains to be determined fully, but it is known
that butyric acid produced by certain flora reduces the
levels of E. coli and enterococci in the gut [18••]. Other
anti-E. coli strategies are being studied. For example,
immunization is being tested using the FimH adhesin
protein on type 1 fimbriae of E. coli [19]. As yet, it is not
known to what extent systemic immunization will alter
urogenital E. coli or other bacterial populations.

Safety and Impact of Probiotics

Application of probiotics to humans has been shown to be
a safe procedure, and indeed lactobacilli are defined as
being “generally recognized as safe” [20]. Oral administra-
tion of lactic-acid bacteria to 7526 subjects, studied
between 1961 and 1998, resulted in no adverse effects
[21•]. This is remarkable, given the large number of side

Probiotic Therapy and Functional Foods for Prevention of Urinary Tract Infections • Reid

521

effects associated with antimicrobial therapy. However, this
should not cause complacency, because far too many so-
called “probiotic products” are unreliable in their content
and viable count [22•].

Physicians who want to make probiotic products avail-

able to their patients must wait until scientific evidence
about strain utility is available and has passed peer review.
Clinical evidence of product safety and reliable informa-
tion about optimal shelf-life also must be made available.
At present, no such products exist for UTI patients and, of
the scientifically proven probiotics designed for the
intestine [2••], availability is scarce for consumers in
North America.

Conclusions

A growing amount of published information strongly
suggests that probiotic therapy can be beneficial to the
host. The mechanisms of action of certain probiotic strains
are being investigated, and there is some sense of opti-
mism that well selected and characterized strains of lacto-
bacilli can prevent (and perhaps, for certain cases of
bacteriuria, even treat) UTI.

Definitive randomized, placebo-controlled trials

comparing lactobacilli with traditional antibiotic therapy
have not been performed. On the other hand, perhaps it is
antibiotic therapy for disease prevention that should no
longer be referred to as “proper therapy.”

In the next three to five years, studies will determine

the extent to which probiotic therapy and functional foods
for UTI become a major part of patient management or
prove it not to be efficacious for disease prevention. At the
very least, well selected probiotic organisms will still have a
place in the restoration and maintenance of a healthy
urogenital and intestinal flora.

Acknowledgement

The author greatly appreciates the support of the Natural
Sciences and Engineering Research Council of Canada.

References and Recommended Reading

Papers of particular interest, published recently, have been
highlighted as:
•

Of importance

••

Of major importance

1.

Larkin M: Probiotics strain for credibility. The Lancet 1999,
354:1884.

2.•• Reid G: The scientific basis for probiotic strains of Lacto-

bacillus. Appl Environ Microbiol 1999, 65:3763–3766.

This mini-review establishes a set of scientifically based criteria upon
which to select probiotic lactobacilli, and illustrates that only a
handful of organisms have “passed the litmus test” of having
supportive peer-reviewed publications on mechanisms of action and
clinical effectiveness.

3.•• Gupta K, Scholes D, Stamm WE: Increasing prevalence of

antimicrobial resistance among uropathogens causing acute
uncomplicated cystitis in women. JAMA 1999, 281:736–738.

This confirms our findings about drug-resistant uropathogens
(see reference 4) and demonstrates the major increase in resistance of
common uropathogens to trimethoprim-sulfamethoxazole.

4.

Reid G, Seidenfeld A: Drug resistance amongst uropathogens
isolated from women in a suburban population: laboratory
findings over 7 years. Can J Urol 1997, 4:432–437.

5.

Charteris WP, Kelly PM, Morelli L, Collins JK: Antibiotic
susceptibility of potentially probiotic Lactobacillus species.
J Food Protection 1998, 61:1636–1643.

6.

Patton DL, Kidder GG, Sweeney YC, et al.: Effects of multiple
applications of benzalkonium chloride and nonoxynol-9 on
the vaginal epithelium in the pigtailed macaque (Macaca
nemestrina). Am J Obstet Gynecol 1999, 180:1080–1087.

7.

Watts DH, Rabe L, Krohn MA, et al.: The effects of three
nonoxynol-9 preparations on vaginal flora and epithelium.
J Infect Dis 1999, 180:426–437.

8.

Erikson B: A randomized, open, parallel-group study on the
preventive effect of an estradiol-releasing vaginal ring
(Estring) on recurrent urinary tract infections in post-
menopausal women. Am J Obstet Gynecol 1999,
180:1072–1079.

9.

Habash M, van der Mei HC, Reid G, Busscher HJ: The effect of
water, ascorbic acid and cranberry derived supplementation
on human urine and uropathogen adhesion to silicone
rubber. Can J Microbiol 1999, 45:691–694.

10.

Harkins KJ: What’s the use of cranberry juice? A review.
Age Ageing 2000, 29:9–12.

11.

Girodon F, Galan P, Monget AL, et al.: Impact of trace elements
and vitamin supplementation on immunity and infections in
institutionalized elderly patients: a randomized controlled
trial. MIN.VIT.AOX. geriatric network. Arch Int Med 1999,
159:748–754.

12.

Chambers ST, Peddie BA, Randall K, Lever M: Inhibitors of
bacterial growth in urine: what is the role of betaines?
Int J Antimicrob Agents 1999, 11:293–296.

13.

Reid G, Bruce AW, Soboh F, Mittelman M: Effect of nutrient
composition on the in vitro growth of urogenital Lacto-
bacillus and uropathogens. Can J Microbiol 1998, 44:1–6.

14.

Ocana VS, Pesce de Ruiz Holgado AA, Nader-Macias ME:
Selection of vaginal H

2

O

2

-generating Lactobacillus species for

probiotic use. Curr Microbiol 1999, 38:279–284.

15.

Prasad J: Selection of characterisation of Lactobacillus and
Bifidobacterium strains for use as probiotics. Int Dairy J
1998, 8:993–1002.

16.

Mack DR, Michail S, Wei S, et al.: 1999. Probiotics inhibit
enteropathogenic E. coli adherence in vitro by inducing intes-
tinal mucin gene expression. Am J Physiol 1999,
276:G941–G950.

17.

Tachikawa T, Seo G, Nakazawa M, et al.: Estimation of pro-
biotics by infection model of infant rabbit with entero-
hemorrhagic Escherichia coli 0157:H7 [Japanese].
Kansenshogaku Zasshi 1998, 72:1300–1305.

18.•• Tannock GW: The bowel microflora: an important source of

urinary tract pathogens. World J Urol 1999, 17:339–344.

This is an excellent perspective on the source of uropathogens, the
intestine, and how different factors can influence their emergence to
cause urinary tract infections (UTIs). It seems critical that we
begin to understand the whole process of infection–starting at the
source–rather than just focus on the virulence of pathogens on
bladder and kidney epithelia. This review is part of an excellent issue
of World Journal of Urology completely devoted to UTI.
19.

Palaszynski S, Pinkner J, Leath S, et al.: Systemic immunization
with conserved pilus-associated adhesins protects against
mucosal infections. Dev Biol Stand 1998, 92:117–122.

20.

Salminen S: Demonstration of safety of probiotics—a review.
Int J Food Microbiol 1998, 44:93–106.

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Urinary Tract Infections and the Female Pelvis

21.• Naidu AS, Biblack WR, Clemens RA: Probiotic spectra of lactic

acid bacteria (LAB). Crit Rev Food Sci Nutr 1999, 39:13–126.

This paper reviews 143 human clinical trials of probiotics and
documents the degree to which these therapies are safe.

22.•• Hamilton-Miller JM, Shah S, Winkler JT: Public health issues

arising from microbiological and labelling quality of foods
and supplements containing probiotic microorganisms.
Public Health Nutr 1999, 2:223–229.

This papers adds to the body of information about this subject from
several other papers published during the past 10 years. The consen-
sus is that too few probiotic products contain the material that is on
the label or the viable count that is stated, and that the proof of the
“healthcare” attributes or certain products are mostly unproven. The
potential pathogen Enterococcus faecium was isolated from nine of 52
products studied.