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Role of D-mannose in urinary tract infections – a narrative review

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Urinary tract infections (UTIs) are one of the most prevalent bacterial diseases worldwide. Despite the efficacy of antibiotics targeted against UTI, the recurrence rates remain significant among the patients. Furthermore, the development of antibiotic resistance is a major concern and creates a demand for alternative treatment options. D-mannose, a monosaccharide naturally found in fruits, is commonly marketed as a dietary supplement for reducing the risk for UTIs. Research suggests that supplemented D-mannose could be a promising alternative or complementary remedy especially as a prophylaxis for recurrent UTIs. When excreted in urine, D-mannose potentially inhibits Escherichia coli , the main causative organism of UTIs, from attaching to urothelium and causing infection. In this review, we provide an overview of UTIs, E. coli pathogenesis and D-mannose and outline the existing clinical evidence of D-mannose in reducing the risk of UTI and its recurrence. Furthermore, we discuss the potential effect mechanisms of D-mannose against uropathogenic E.coli .
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Ala‑Jaakkolaetal. Nutrition Journal (2022) 21:18
https://doi.org/10.1186/s12937‑022‑00769‑x
REVIEW
Role ofD‑mannose inurinary tract infections
– anarrative review
Reeta Ala‑Jaakkola, Arja Laitila, Arthur C. Ouwehand* and Liisa Lehtoranta
Abstract
Urinary tract infections (UTIs) are one of the most prevalent bacterial diseases worldwide. Despite the efficacy of anti‑
biotics targeted against UTI, the recurrence rates remain significant among the patients. Furthermore, the develop‑
ment of antibiotic resistance is a major concern and creates a demand for alternative treatment options. D‑mannose,
a monosaccharide naturally found in fruits, is commonly marketed as a dietary supplement for reducing the risk for
UTIs. Research suggests that supplemented D‑mannose could be a promising alternative or complementary remedy
especially as a prophylaxis for recurrent UTIs. When excreted in urine, D‑mannose potentially inhibits Escherichia coli,
the main causative organism of UTIs, from attaching to urothelium and causing infection. In this review, we provide
an overview of UTIs, E. coli pathogenesis and D‑mannose and outline the existing clinical evidence of D‑mannose in
reducing the risk of UTI and its recurrence. Furthermore, we discuss the potential effect mechanisms of D‑mannose
against uropathogenic E.coli.
Keywords: D‑mannose, UTI, Urinary tract infection, Escherichia coli
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Introduction
Urinary tract infections (UTIs) are among the lead-
ing infectious diseases globally. UTIs are highly preva-
lent in women, especially after menopause. Despite the
short-term impact of antibiotics on acute UTIs, a long-
term risk of recurrence still exists. Furthermore, anti-
biotic resistance of UTI pathogens to many commonly
used antimicrobial drugs is alarmingly increasing. For
instance, 90% of the UTI causing Escherichia coli strains
in patients treated with trimethoprim-sulfamethoxazole
for a month were resistant to the antibiotic, whereas in
the control group, subject to cranberry juice, the inci-
dence was 28% [1]. E. coli is the causative organism in
85% of UTI cases. e adhesion of E. coli in the urinary
tract is mainly based on mannose-sensitive mechanism,
where E.coli type I pili adhere to mannose structures on
the uroepithelial cell surfaces [2, 3].
D-mannose is a monosaccharide, naturally found in
various plants, and fruits/berries, for instance in cranber-
ries. It is also known to be synthesized in the body from
glucose for the synthesis of glycoproteins [4]. D-mannose
is commonly marketed as a dietary supplement for uri-
nary tract health. Research suggests that free D-mannose
in urine has the potential to saturate E. coli FimH struc-
tures, and subsequently block E. coli adhesion to urinary
tract epithelial cells. is so-called competitive inhibition
is considered as one of the potential mechanisms for pre-
venting UTI development [5].
e aim of this review was to examine the current
evidence on the role of D-mannose against UTI. Earlier
reviews have focused on various aspects of this topic.
Here, we integrate these parts into one comprehen-
sive narrative; presenting an overview of UTIs, urethral
microbiota, current treatments and E. coli pathogenesis
followed by D-mannose and its potential effect mecha-
nisms against uropathogenic E. coli (UPEC). Finally, we
review existing preclinical and clinical studies which have
investigated D-mannose in UTIs.
Open Access
*Correspondence: arthur.ouwehand@iff.com
Health & Biosciences, International Flavors & Fragrances, Sokeritehtaantie
20, FIN‑02460 Kantvik, Finland
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Ala‑Jaakkolaetal. Nutrition Journal (2022) 21:18
Overview ofUTI
Prevalence
A WHO report from 2017 listed E. coli as the main spe-
cies responsible for community- and hospital- acquired
UTIs [6]. e WHO has recognized the matter as a high
community and health-care burden. More than 150
million people are affected by UTIs annually [7, 8]. It
is considered as one of the most common infections in
communities as well as within healthcare settings. e
prevalence of UTIs are especially high among women. An
estimated 11% of women over the age of 18 suffer from
UTI annually [9]. Approximately 50% of all women will
have at least one UTI episode during their lifetime [10].
Women are at risk for UTI due to a short urethra located
close to the rectum, which allows easier access for bac-
teria to the urinary tract as compared to men. Changes
in the sexual activity, pregnancy, and menopausal status
have a high impact on the risk for UTI occurrence since
all of them affect the urogenital bacterial composition.
Higher prevalence to UTI is also seen among specific
populations such as people with structural changes (e.g.
prostate enlargement) and diabetics (up to 35% of the
patients) [1113]. Moreover, healthcare-associated UTIs
are the most common infections occurring in intensive-
care units, especially among patients needing catheteri-
zation [14]. Furthermore, UTI is listed among the 10
most common reasons for unplanned readmission to
medical care [15]. erefore, the societal and healthcare
costs caused by hospitalizations and medical expenses
associated with UTI are high.
Diagnosis andetiology
UTIs can be categorized into several sub-classes based
on their complexity, acuteness, and location [16]. Clini-
cally, UTIs are classified as uncomplicated or compli-
cated, where the first often considers otherwise healthy
individuals and the latter is associated with structural or
functional challenges e.g. pregnancy, male gender, young
age (children), catheterization, or diabetes, which com-
plicate the condition. UTI diagnosis can also be a recur-
rent UTI (rUTI) defined by the occurrence of more than
2 symptomatic UTIs within the last 6 months or more
than 3 within the last 12 months. UTIs can be local-
ized either in the upper urinary tract, including kidneys
(upper UTI a.k.a. pyelonephritis), or on the lower urinary
tract, affecting the bladder (lower UTI a.k.a. cystitis) [16].
e gold standard for UTI diagnosis is based on patho-
gen detection and identification from a midstream urine
sample (103–105 or more colony forming units (CFU)/
ml urine) combined with clinical symptoms (dysuria, fre-
quency, urgency, suprapubic pain, nocturia, and hema-
turia). In case the clinical symptoms are absent, and the
number of bacteria counts exceed 105 CFU/ml, the diag-
nosis is asymptomatic bacteriuria and treatment is only
rarely prescribed [17].
UPEC is the main causative organism of UTIs, in both
uncomplicated and complicated infections, being the
responsible pathogen in up to 85% of the cases. Other
pathogenic microbes associated with uncomplicated
UTIs are, starting from the most likely pathogen, Kleb-
siella pneumoniae, Staphylococcus saprophyticus, Ente-
rococcus faecalis, Group B Streptococcus (GBS), Proteus
mirabilis, Pseudomonas aeruginosa, Staphylococcus
aureus as well as Candida species. Common pathogens
associated with complicated UTIs are Enterococcus spp.,
K. pneumoniae, Candida spp., S. aureus, P. mirabilis, P.
aeruginosa, and GBS [7].
Urinary microbiota andUTI
Advancements in molecular techniques have increased
the understanding of the microbial community in the uri-
nary tract, which has been previously regarded as sterile
[18]. Overall, in contrast to the gut, urine contains very
few microbes and is dominated by one or two species
(also called as urotypes) [18, 19]. Research implies that
the urinary microbiota is gender specific, likely due to
anatomical and hormonal differences [20, 21]. As women
are more at risk of UTI, we mainly focus on providing an
overview of the urinary microbiota of women and asso-
ciation with UTI.
e most common bacteria in the urinary microbiota of
healthy women are the same species of Lactobacillus that
exists in the vagina [18, 22]. Other predominating species
are from the genera Gardnerella, Streptococcus, Staphy-
lococcus, Corynebacterium, and Escherichia. Research
suggests that urotype changes with age and for instance
a Lactobacillus- or Gardnerella-dominated urotype is in
some cases reported to be more common in pre-meno-
pausal women, whereas the Escherichia-dominated uro-
type and more diverse microbiota seem to predominate
in postmenopausal women [18, 23].
Urinary microbiota is associated with rUTIs [24]. Espe-
cially changes resulting in the loss of normally protective
Lactobacillus spp. seem to increase the risk of UTI. e
vaginal tract is suggested to play a role in UTI pathogen-
esis by serving as a potential reservoir for uropathogenic
bacteria ascending from the gastrointestinal tract. Stud-
ies show that women with rUTI have lower abundance of
lactobacilli and are more commonly colonized with vagi-
nal E. coli [24, 25]. Indigenous vaginal lactobacilli pro-
duce H2O2 and lactic acid which contributes to lowering
vaginal pH which thus inhibits the growth of pathogenic
bacteria, such as E. coli, and may ultimately reduce the
risk of such organisms colonizing the urinary tract.
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Ala‑Jaakkolaetal. Nutrition Journal (2022) 21:18
Pathogenesis
e pathogenicity of UTI associated bacteria is based on
their ability to attach, colonize, and survive in the urinary
tract environment. UPEC strains, the most common path-
ogens for UTI, mainly enter the urogenital tract from the
gut via fecal–perineal–urethral route [26]. UPEC strains
possess several virulence factors, such as adhesins, tox-
ins, iron acquisition factors, lipopolysacharide and cap-
sules, that contribute to UTI pathogenesis. One of the
main disease-causing mechanisms for UPEC is based on
its adherence to mannosylated protein components called
uroplakins on the bladder epithelium (Fig.1) [2, 3]. is
binding occurs via the FimH tip of the type I pili adhesin
of E. coli. e attachment activates signal cascades causing
actin rearrangement, which ultimately leads to an inter-
nalization of the bacteria into the umbrella cells of the epi-
thelium [7]. e vesicular UPECs can be recognized by the
innate immune system within the cells and exported via
exocytosis back to the bladder where they are exposed to
neutrophils and destroyed. However, UPEC strains employ
several strategies to evade the host immune system, which
facilitates formation of intracellular bacterial communities
(IBCs); this enables bacteria to multiply, mature and infect
other cells [27, 28]. Furthermore, this can potentially lead
to more severe infection or risk for recurrence as the path-
ogen might remain hidden inside the uroepithelial cells.
Treatment
UTIs are commonly treated with antibiotics but due
to increasing development of multidrug resistant
strains, there is a need for alternative and comple-
mentary remedies [2931]. The most commonly pre-
scribed antibiotics are sulfonamides, trimethoprim,
fluoroquinolones, fosfomycin, and beta-lactams, but
resistance to these drugs varies between 15 and 50%
in Europe, limiting their use for severe infections [32].
The use of some antibiotics, such as amoxicillin, has
been restricted for UTI owing to the development
of antibiotic resistance [17]. An international study
on antibiotic susceptibility patterns performed in 17
European countries including 4734 women with acute
uncomplicated UTI showed that 42% of the E. coli
associated UTIs were resistant to one or more antibi-
otics. From the 12 used antimicrobials, the resistance
was the highest for ampicillin (29.8%) and sulfameth-
oxazole (29.1%). Antibiotic resistance was relatively
common also to trimethoprim (14.8%), trimethoprim/
sulfamethoxazole (14.1%) and nalidixic acid (5.4%).
Regional differences existed as in Spain and Portugal,
antibiotic resistance was higher compared with the
Nordic countries and Austria [33]. Another study per-
formed in the US/Canada involving 40 clinical centers
showed that E. coli resistance to ampicillin was 37.7,
21.3% to trimethoprim/sulfamethoxazole, 5.5% to
ciprofloxacin, 5.1% to levofloxacin and 1.1% to nitro-
furantoin [34]. Antibiotic resistance of UPEC has also
been shown to be a prominent threat in Asia-Pacific
regions [35, 36].
e family of Enterobacteriaceae (incl. E. coli) has
acquired plasmids containing genes for extended-spectrum
Fig. 1 Schematic representation of E. coli attachment by FimH tips of the type 1 pili adhesins to mannosylated uroplakins on the surface of
uroepithelium
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Page 4 of 16
Ala‑Jaakkolaetal. Nutrition Journal (2022) 21:18
of β-lactamases (ESBL). β-lactamases cleave the
amide bonds of β-lactams, thus the ability to produce
β-lactamases compromises the antibiotic treatments mak-
ing β-lactams ineffective in both uncomplicated and com-
plicated UTIs [37, 38]. Research shows that UPEC strains
isolated from the elderly who suffer from rUTIs, are cell-
wall deficient i.e. providing to these strains resistance to
antibiotics targeting the bacterial cell walls [39]. e WHO
has listed Enterobacteriaceae as one of the pathogen groups
that should be prioritized for research owing to its resist-
ance patterns specifically to the third generation cephalo-
sporin (β-lactam) that affects UTI treatments [6].
In addition to the development of multi-resistant
strains the use of antibiotics for UTI has other disadvan-
tages. For instance, in 25–35% of the cases rUTI occurred
within 6 months of the first antibiotic treatment [40,
41] and in 44% of the cases within 12 months [10, 42].
Furthermore, repetitive use of antibiotics disturbs the
indigenous microbiota especially in the gastrointestinal
tract and vagina, and their use is often associated with
unpleasant side effects such as nausea, vomiting, diar-
rhea, headaches, and skin rash. us, a search for alterna-
tive approaches to be used especially as a prophylactic in
rUTIs is necessitated. Among the most commonly pro-
posed natural alternatives is the daily intake of cranber-
ries and/or D-mannose [31].
D‑mannose
The interest towards D-mannose and UTIs dates back
to the 1970s [43, 44]. The emergence of antibiotic
resistance related to uropathogens, especially UPEC,
has maintained this interest. D-mannose is marketed
globally as a dietary supplement and it is mainly tar-
geted for supporting urinary tract health either as
a standalone product or combined with cranberry
extract or probiotics.
D-mannose (C6H12O6) (mannose) is one of the nine
monosaccharides (D-glucose, D-galactose, D-mannose,
D-xylose, L-fucose, D-glucuronic acid, N-acetyl-D-glu-
cosamine, N-acetyl-D-galactosamine, and N-acetylneu-
raminic acid) commonly found in animal glycans and
abundant in vertebrate glycoconjugates.
In the human body, D-mannose is primarily syn-
thesized from glucose or is derived from the break-
down of endogenous glycoconjugates. Catabolism
of D-mannose occurs via glycolysis after which it is
used for energy or incorporated into glycans [45, 46].
D-mannose contributes to the glycoprotein synthe-
sis, more specifically to the glycosylation of certain
proteins (post-translational modifications). Many cell
types have mannose-specific receptors, hence, stable
blood mannose levels are important for facilitating effi-
cient/constant mannose uptake to different cells [47].
Physiological blood D-mannose level varies between 50
to 100 μM [4].
Fruits such as oranges, apples and peaches contain free
D-mannose in relatively small amounts. Furthermore,
mannose can be found in the form of galactomannans
(undigestible plant polysaccharides) in coffee beans, fen-
ugreek and guar gums [48]. However, the bioavailability
of mannose for glycan synthesis in these dietary sources
is poor, and likely only partially improved by anaerobic
bacteria in the colon [49]. erefore, dietary mannose is
not considered as a significant source of D-mannose for
humans. Neverthless, undigestable plant polysaccha-
rides in the colon could lead to other health benefits, for
instance via short chain fatty acid production [49], a topic
not in the scope of this review. Also yeast cell walls con-
sist of mannans that are undigestible [50]. Further, ani-
mal-derived mannose would require specific transport
mechanisms. Interestingly, in an animal model of obesity,
addition of D-mannose to the diet (at 2%) reduced weight
gain, adiposity and liver steatosis and glucose sensitivity.
It also led to a change in fecal microbiota with increases
in putative beneficial microbes such as Faecalibaculum
and Akkermansia [51]. D-mannose is absorbed into the
bloodstream from the gastrointestinal tract after inges-
tion, the absorption rate being 10% of that of glucose. It
is absorbed mainly by passive diffusion across the intes-
tinal barrier, but also active transport molecules have
been identified [52]. D-mannose can be administered in
dietary supplements in biologically usable forms. Studies
indicate that a dose level of 0.2 g/kg of body weight seems
to be the upper limit for daily consumption of mannose
for a long-term use, as higher doses may cause gastro-
intestinal disturbances (diarrhea, bloating) [4]. Dietary
ingestion increases the blood D-mannose levels 3 to
10-fold from the normal levels in a dose dependent man-
ner [4]. e peak values are reached approximately 60 to
90 min after oral ingestion and return to normal physi-
ological levels after 6 to 8 h the half time being approxi-
mately 4 h [4, 53, 54]. A rat study by Alton etal. [47]
showed that mannose is relatively fast absorbed (within
an hour) from the intestine to the blood, the half time
in blood being half an hour. Furthermore, less than 1%
of the labeled mannose remained in the intestine, feces
and urine after 4–8 h of the gavage, demonstrating the
efficacy of mannose uptake from the intestine. Despite
the relatively fast increase of D-mannose concentra-
tions in the blood, D-mannose is not fully metabolized in
humans. Excess D-mannose (20–35% of the dose) enters
urine from the blood circulation within 60 min [45, 46],
where it has the potential to interact with mannose-sen-
sitive structures of UPEC and further lowering patho-
genic effect of the bacterium. e low renal threshold
for mannose (and high for glucose) was demonstrated
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Ala‑Jaakkolaetal. Nutrition Journal (2022) 21:18
already by Harding etal. [55] in 1933 in a study where
participants were getting a single oral dose of 25 or 50 g
of mannose. Mannose supplementation was shown not
to affect blood glucose or mannose levels, however, man-
nose was detected in the urine sample taken 2 h after oral
ingestion. Figure2 describes D-mannose supplementa-
tion and its route to urine.
D‑mannose & uropathogenic E. coli
In vitro / preclinical evidence
In vitro and preclinical studies conducted with D-man-
nose provide insight on potential mechanism of action of
D-Mannose against UPEC strains.
As an assumption, sugars like D-mannose, could
potentially serve as a carbon source for bacteria and
hence induce their growth. However, Scribano and co-
workers [56] demonstrated in vitro that D-mannose is
not inducing effects on the UPEC metabolism/bacterial
growth nor does it interfere with the antibiotic activity.
ese findings support the suitability of D-mannose in
UTI management. Several studies have demonstrated
that the binding of E. coli FimH to the high-mannose
glycoproteins on the surface of urinary tract cells can be
inhibited by naturally occurring mannose or designed
mannose-derivatives, referred as mannosides [5760].
e structural analysis by Hung etal. [59] revealed that
FimH can envelope mannose molecules in a deep pocket
where primarily hydrogen bonds are affecting the com-
plex. Bouckaert etal. [57] demonstrated that the affinity
of mannose to FimH is very high, especially compared
to other monosaccharides (fructose 15-fold less, glu-
cose 4000-fold less). Animal trials have shown that free
D-mannose in urine, even in low concentrations (< 20 μg/
ml) can inhibit bacterial adherence mediated by type 1
pili to urinary tract mucosa of pigs [61]. A rat study by
Michaels etal., [62] demonstrated that beneficial effects
on bacteriuria can be reached already after one day of
saccharide injection (D-mannose or D-glucose), the effi-
cacy being dependent on both the injected dose and the
amount of E. coli. Studies performed in mice, have inves-
tigated the potential of small molecular weight FimH
antagonists, mannosides, to be used in UTI treatments
[63, 64]. Klein etal. [64] demonstrated that orally supple-
mented FimH antagonist reduced CFU counts of UPEC
in the urine by 2 folds and in the bladder of the animals
by 4 -fold. Cusumano et al. [63] showed in a murine
model of chronic cystitis that orally given active FimH
antagonists reduced UPEC colonization in the urethra
after 6 h when compared with the control group (phos-
phate buffered saline). UPEC concentration in the mice
treated with antibiotics seemed to be higher than in the
mice subject to FimH antagonist. is finding potentially
indicates shorter and more effective UTI treatment time
by FimH antagonist than with trimethoprim-sulfameth-
oxazole, an antibiotic. Furthermore, the study showed
that IBC formation in the uroepithelium was prevented,
supporting the prophylactic potential of the studied man-
noside. Although, most of the research has focused on E.
coli and type 1 pili, it is worthwhile to note that type 1
pili are also found on other bacteria in the Enterobacte-
riaceae family, such as K. pneumoniae. Indeed, in vitro
D-mannose has shown potential to inhibit adhesion of a
clinical isolate of K. pneumoniae [65].
us far, immunological effects of D-mannose in the
context of UTI are largely unknown. However, a study
by Zhang and coworkers [66] suggested that D-mannose
Fig. 2 D‑mannose, from supplementation to urine. Roughly one third of supplemented D‑mannose ends up into urine where it has the potential
to block pathogenic Escherichia coli from adhering to uroepithelial cells. Some of the D‑mannose can be detected in the feces and some is utilized
within the target tissues
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Ala‑Jaakkolaetal. Nutrition Journal (2022) 21:18
has positive immunoregulatory effects on T-cells in mice
with autoimmune diabetes and airway inflammation. e
role of regulatory T-cells, UTI and D-mannose are worth
exploring in further studies.
e affinity between FimH and mannosides shown
invitro and animal models will presumably prevent the
bacterial entry and infection of the urinary tract cells and
thus provide therapeutic value and scientific rationale for
mannose supplementation as a prophylactic treatment
for UTIs in humans. In the next section we review and
discuss the existing evidence from clinical trials including
UTI patients and D-mannose supplementation.
Clinical evidence ofD‑mannose inUTI
To identify clinical trials conducted with D-Mannose
in UTI, we performed a literature search with terms of
“UTI” and “D-mannose” from common databases such as
Pubmed, Scopus andWeb of Science until January 2021.
Original articles were included in this review. e stud-
ies meeting the criteria are discussed below and details of
the studies are provided in the Tables1, 2 and 3.
Acute andlong‑term eects ofD‑mannose inUTI
Several studies have investigated both acute and pro-
phylactic effects of D-mannose, or more often, D-man-
nose combined with antibiotic or other alternative
supplements, in UTI. ese studies have focused mostly
on females suffering from acute or rUTIs.
To date, four studies have assessed the effect of supple-
mentation, including D-mannose only, in UTIs (Table1).
A pilot study by Domenici and co-authors showed that
D-mannose could be used for acute UTI (13 days treat-
ment) but also has potential as a prophylaxis (6 months
treatment) in women with symptomatic (dysuria, fre-
quency, urgency, supra-pubic pain, nocturia, and hema-
turia) or asymptomatic UTI (diagnosed as 103 CFU/
mL of urine) [67]. Most of the symptoms were shown to
decrease significantly compared to control group. ere
was also a statistically significant difference in the rUTI
percentages between the active and control groups (4.5
and 33.3%, respectively). In an open-label clinical trial
by Kranjčec etal. [68], adult women with acute UTI and
tendency for recurrence consumed either D-mannose,
nitrofurantoin or no prophylaxis for 6 months after acute
antibiotic treatment. e risk for rUTIs decreased sig-
nificantly in both prophylactic treatments. ere were
no differences between the study groups receiving either
D-mannose or antibiotic, suggesting that D-mannose
is as effective as antibiotics to be used as an alternative
treatment in preventing rUTIs. An open-label, feasibil-
ity study including multiple sclerosis patients demon-
strated that a 16-weeks daily oral supplementation with
D-mannose significantly reduced the number of UTIs
(by 75% in patients without urinary catheter and by 63%
in those with catheter) [69]. A cross-over study in adult
women demonstrated that D-mannose supplementation
delays significantly the onset of rUTI compared to anti-
biotics [70]. In the study, the recurrence of UTI occurred
on average in 200 days with daily oral supplementation
of D-mannose, whereas for used antibiotic the time to
recurrent infection was on average 52.7 days.
D-mannose’s effect on UTI/rUTIs has also been stud-
ied in combination with probiotics (Table2). Del Popolo
et al. [71] demonstrated in a pilot, open-label study in
women (n = 68) and men (n = 17) including both non-
neurological and neurological patients, that an oral
combination of D-mannose and salicin, for acute UTI,
together with Lactobacillus acidophilus La-14 for main-
tenance/prevention, is a promising approach for rUTIs.
e acute treatment consisted of 5-day supplemen-
tation of D-mannose + salicin 3 times a day and the
maintenance treatment 7-days with D-mannose + L.
acidophilus La-14 (1 × 109 CFU) twice a day. e UTI
symptoms improved significantly after the acute treat-
ment (2 weeks), long-term treatment (12 weeks = end
of treatment) and also 1 month after the supplementa-
tion had ended, compared to the baseline symptoms. An
observational study by Milandri etal. [72] demonstrated
that 14-day phytotherapeutic supplementation includ-
ing D-mannose, Hibiscus sabdariffa, and Lactiplantiba-
cillus plantarum Lp-115 after urodynamic procedure
can reduce the risk of bacteriuria and UTI in women. A
study by Murina etal. [73] investigated UTI patients in a
controlled trial. After a 2-day treatment with antibiotics
and confirming that patients were free of symptoms, they
received Lacticaseibacillus paracasei LC11, cranberry
and D-mannose for the 10 first days of 3 months (Group
1) or once a day for 90 days (Group 2) or no treatment at
all (Group 3). In the study 87.7% of patients in the Group
1 remained free of UTI until day 90 and 65.8% of patients
were not diagnosed with UTI at day 150. In the Group 2
the 84.9% were UTI free at day 90 and 68.8% at day 150,
whereas in the Group 3 (control) 42% at day 90 and 36.9%
at day 150 were UTI free. ese results showed that in
both active treatment groups, UTI recurrence was sig-
nificantly lower compared to the control group during
the 150 days trial. ere was no significant difference in
the recurrence frequencies between the two treatment
types i.e. whether the treatment was continuous or hap-
pened only for 10 days each month. Another study sug-
gested that the supplementation including cranberry,
D-mannose and tara gum in addition with probiotic
strains L. plantarum LP01 (2.5 × 109 CFU), L. paracasei
LPC09 (109 CFU) and Streptococcus thermophilus ST10
(109 CFU) relieved the symptoms of acute UTI [74]. e
symptom relief was detectable1 month after starting the
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Ala‑Jaakkolaetal. Nutrition Journal (2022) 21:18
Table 1 Clinical trials in acute UTI/rUTIs with treatment supplementations including D‑mannose only
UTI urinary tract infection, rUTI recurrent urinary tract infection, AE adverse event, MS multiple sclerosis
Reference Study Design Subjects and groups Supplementation Main Findings (including safety)
Domenici 2016 [67] Pilot study, randomized for long‑term
prophylactic effect 18–65 year old women with acute cystitis
and/or history of rUTIs
n = 43
Acute: 13 days; 1.5 g D‑mannose twice
daily for 3 days and then once a day for
10 days.
Long‑term: 6 months; once a day for a
week every other month
D‑mannose has potential as an effective
agent for both acute UTI and as prophylac‑
tic for rUTI in a specific population
No AEs
Kranjčec 2014 [68] Prospective, randomized, open‑label,
controlled study 18 + years old women with acute cystitis
and a history of recurrent cystitis in 3
groups:
1. (n = 103) D‑mannose
2. (n = 103) Nitrofurantoin
3. (n = 102) no prophylaxis
n = 308
Long‑term: 6 months once a day
D‑mannose: 2 g in 200 ml water Nitro‑
furantoin: 50 mg
D‑mannose may be beneficial for UTI
prevention. The decreased recurrence rate
did not differ between patients who took
Nitrofurantoin and D‑mannose
Mild AEs in 7.8% (diarrhea) of D‑mannose
group compared to 27.2% (various AEs) in
Nitrofurantoin group
Phe 2017 [69] A single‑center, open‑label, feasibility
study 46–59 year old MS patients using and not
using urinary catheters, experiencing rUTIs
n = 22
Long‑term: 16 weeks, 1.5 g D‑mannose
twice a day D‑mannose is safe and feasible supplemen‑
tation for patients having MS. For efficacy,
further studies are needed.
No AEs
Porru 2014 [70] Pilot study, randomized, cross‑over trial 22–54 years old female patients with acute
symptomatic UTI and 3rUTIs during the
preceding 12 months
n = 60
Long‑term cross‑over design:
Group 1: 1 g D‑mannose 3 times a day,
every 8 h for 2 weeks, and subsequently
1 g twice a day for 22 weeks.
Group 2: 5‑day antibiotic therapy
with trimethoprim/sulfamethoxazole
160 mg/800 mg twice a day, followed by
a single dose at bedtime for 1 week each
month in the following 23 weeks
Cross‑over point at week 24
D‑mannose was shown to be effective and
safe in preventing rUTIs in women. The
proportion of infection free women was
greater in D‑mannose group compared to
antibiotic group.
No AEs mentioned
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Ala‑Jaakkolaetal. Nutrition Journal (2022) 21:18
Table 2 Clinical trials in acute UTI/rUTIs with treatment supplementations including D‑mannose and probiotics
UTI urinary tract infection, rUTI recurrent urinary tract infection, AEs adverse events, CFU colony forming units, bid two times a day
Reference Study Design Subjects and groups Supplementation Main Findings (including safety)
Del Popolo 2018 [71] Pilot study, non‑randomized 68 women and 17 men affected by recurrent
symptomatic cystitis. Of those, 33 women and
13 men suffered from neurogenic bladder
n = 85
Acute: 5‑days bid 1000 mg of D‑mannose,
200 mg of dry willow extract (salicin) (attack
phase), followed by 7‑days bid with 700 mg of
D‑mannose plus 50 mg (109 CFU) of L. acido-
philus La‑14 (maintenance treatment).
Long term: The maintenance treatment was
repeated for 15 days every month for the next
two months.
Combination treatment was effective in acute
UTI and as prophylaxis
No significant AEs reported
Milandri 2018 [72] Single‑center, single‑arm,
uncontrolled observational
study
19–87‑year‑old female patients who under‑
went urodynamic invasive procedure
n = 100
Long‑term: After invasive surgery, 14‑days
bid 1000 mg D‑mannose, 200 mg H. sabdariffa,
and 109 CFU L. plantarum Lp‑115
Risk of bacteriuria and UTI in women could be
reduced with the studied product
No AEs
Murina 2020 [73] Single‑center Premenopausal women aged 18–50 years
with an acute UTI and a history of recurrent
uncomplicated UTIs
n = 55
After 2 days Fosfomycin (3 g once a day) the
following combination treatment: Lactoflor‑
ene Cist® including 109 CFU L. paracasei LC11,
cranberry extract and 1000 mg D‑mannose:
Group 1: once a day for 10 days/month for
90 days (n = 19)
Group 2: once a day for 90 days (n = 19)
Group 3: No treatment (n = 17)
Both treatments efficient and safe as prophy‑
laxis for rUTIs.
No AEs
Vicariotto 2014 [74] A pilot prospective study Premenopausal, nonpregnant women diag‑
nosed with acute uncomplicated cystitis
n = 33
Acute: For 30 days 2 doses a day
Long‑term: after 30 days acute phase, 1 dose
a day until day 60
Dose: 2.5 × 109L. plantarum LP01 and 1 billion
L. paracasei LPC09 and S. thermophilus ST10,
250 mg of tara gum, 500 mg of a high proan‑
thocyanidins cranberry extract and 250 mg of
D‑mannose
Significant improvement in the UTI symp‑
toms (dysuria, frequent voiding, urgency, and
suprapubic pain) in long‑term
No AEs mentioned
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Ala‑Jaakkolaetal. Nutrition Journal (2022) 21:18
Table 3 Clinical trials in acute UTI/rUTIs with treatment supplementations including D‑mannose in combination with other supplements
Reference Study Design Subjects and groups Supplementation Main Findings (including safety)
De Leo 2017 [75]
Article in Italian Multicenter, Randomized, controlled trial 40 to 50 year old women suffering from
recurrent episodes of cystitis;
n = 150
1 Kistinox® Forte sachet per day includ‑
ing cranberry (Vaccinium macrocarpon),
Noxamicina® (propolis extract) and
500 mg D‑mannose during the first
10 days of the month, for 3 months
(n = 100).
No treatment in the control group
(n = 50)
Product efficient and well‑tolerated in
treatment of acute UTI and reducing rUTI
No AEs
Efros 2010 [76] Prospective, dose‑escalation study 18 to 75 years old women with history of
recurrent UTIs (no acute infection)
n = 28 (planned)
n = 23 (actual)
6 per dose group
12 weeks daily dose of 15 ml, 30 ml, 45 ml,
60 ml, 75 ml or 90 ml of UTI‑STAT with
Proantinox
3875 mg Proantinox (cranberry concen‑
trate [4:1], ascorbic acid, D‑mannose,
fructo‑oligosaccharides, and bromelain)
per 30 ml
D‑mannose dose not indicated
Safe and well tolerated. Efficient in reduc‑
ing rUTI incidence and increasing quality
of life.
AES: 9 reported (nausea, heartburn, head‑
ache, dyspepsia (4), diarrhea, back pain)
Max tolerated dose set for 60 ml/day.
Genovese 2018 [77] A randomized three‑arm parallel group
intervention trial Adult Caucasian females with acute
uncomplicated cystitis history of recur‑
rent UTIs
n = 72
12 weeks with follow‑up at 24 weeks.
group A: D‑mannose 420 mg + berber‑
ine, arbutin and birch (n = 24)
group B: D‑mannose 420 mg + berber‑
ine, arbutin, birch and forskolin (n = 24)
group C: D‑mannose 500 mg + proan‑
thocyanidins (n = 24)
Plant‑based supplements reduce the
risk for UTI but no specific benefits for
D‑mannose alone
No AEs
Manno 2019 [78] Prospective comparative study Women with acute cystitis and history of
recurrent cystitis
n = 40
12 weeks including follow‑up time
Acute: Fosfomycin Tromethamine (3 g)
single dose (UROFOS®) for all partici‑
pants
Long‑term: 2 sachets for 2 weeks and
one sachet for two additional weeks as
follows:
group A: UROIAL containing S&R PACs
(250 mg) with type‑A proanthocya‑
nidins (72 mg), D‑mannose (1000 mg),
chondroitin sulfate (200 mg), vitamin C
(120 mg) and hyaluronic acid (100 mg)
(n = 20)
group B: no treatment (n = 20)
Complete remission in 37 participants after
fosfomycin. Lower UTI episodes and symp‑
toms in treatment group after 4 week’s
intervention and follow‑up time.
No AES mentioned
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Page 10 of 16
Ala‑Jaakkolaetal. Nutrition Journal (2022) 21:18
Table 3 (continued)
Reference Study Design Subjects and groups Supplementation Main Findings (including safety)
Marchiori 2017 [79] Observational, retrospective study Pre‑ and postmenopausal women who
had survived breast cancer and had
recurrent cystitis
n = 60 (50 had reached menopause)
Long‑term: Group 1 ‑ antibiotic therapy
associated with NDM (n = 40) given
12 h after emptying bladder for 60 days
followed by dose 24 h after emptying
bladder for 4 months,
Group 2 ‑ antibiotics alone (n = 20)
NDM dose: D‑mannose 500 mg, N‑ace‑
tylcysteine 100 mg and Morinda citrifolia
fruit extract 200 mg (NDM)
Antibiotic options depending on
microbial sensitivity: fosfomycin ‑ 3 g per
day for two days every 15 days for three
cycles, nitrofurantoin ‑ 1cps 100 mg tid
for 6 days and ciprofloxacin ‑ 1000 RM
or prulifloxacin ‑ 600 mg 1 cps/day for
6 days
Greater efficacy in NDM combined with
antibiotic in reducing UTIs and urinary
discomfort compared to antibiotics only
No AEs related to IP usage specified
Palleschi 2017 [80] Prospective, randomized study ~ 65.4 years old male [42] and female
[38] patients eligible for urodynamic
examination.
n = 80
Acute preventive Group A: antibiotic
Prulifloxacine 400 mg/day for 5 days
(n = 40),
Group B: D‑mannose 500 mg, N‑acetyl‑
cysteine 100 mg and Morinda citrifolia
fruit extract 300 mg, twice a day for
7 days (n = 40)
D‑mannose and NAC therapy resulted
similar results to the antibiotic therapy in
preventing UTIs in patients submitted to
urodynamic examination. Considered as
usable alternative treatment
No AEs
Panchev 2012 [81]
Article in Bulgarian Multicenter, comparative, observational
study Female patients with acute uncompli‑
cated urinary bladder infections (Age not
reported)
n = 158
Acute: Group 1: Product containing
D‑mannose 1000 mg, standardized dry
birch leaf extract 50 mg, standardized
dry cranberry extract 50 mg according to
manufacturer’s instructions (n = 86)
Group 2: Ciprofloxacin 500 mg twice
daily for 3 days (n = 72)
Better effectiveness related to symptoms
and clinical outcomes with the product
compared to antibiotic was reported
No AEs
Rădulescu 2020 [82] a pilot, randomized study non‑pregnant, healthy women with
uncomplicated lower UTI
Age range 18–60 years
n = 93
First phase/Acute:
1) Antibiotic (TMP‑SMX) (n = 45) or
2) Antibiotic + D‑mannose
(1000 mg) + cranberry (400 mg) (Uro‑
Care with CranActin®)(n = 48) for 7 days
Second phase/ prophylaxis:
For cured participants either 1) D‑man‑
nose + cranberry (n = 47) or 2) placebo
(n = 46) for 21 days
Higher cure rate after acute phase in the
combined group especially in the resistant
strains. No significant differences between
the active and the placebo in the second
phase of the study
No AEs related to IP usage specified
Russo 2020 [83] A prospective, randomized, no‑placebo,
controlled study ~ 67.2 years old postmenopausal women
undergoing surgery for cystocele
n = 40
Active: cranberry, D‑mannose, Boswellia,
Curcuma and Noxamicine VR (Kistinox
ActVR) twice a day for 2 weeks starting
from surgery (n = 20)
Control: only surgery (n = 20)
Symptom relief was reported in the active
group compared to control. No differences
in UTI incidences
No AEs
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Ala‑Jaakkolaetal. Nutrition Journal (2022) 21:18
Table 3 (continued)
Reference Study Design Subjects and groups Supplementation Main Findings (including safety)
Salinas‑Casado 2018 [84]
Article in Spanish A multicenter, double‑blind, randomized,
experimental study ~ 48 years old women with non‑compli‑
cated UTI
n = 95
Long‑term:
Group 1: 2 g of D‑mannose, 140 mg of
PAC and 7.98 mg of ursolic acid together
with vitamins A, C and E, and the Zinc
trace element (Manosar®) (n = 44) once
a day for 24 weeks
Group 2: 240 mg proanthocyanidins
(n = 51) as a single dose/day
Product was reported to be more efficient
for preventing rUTI than single dose of PAC
AEs: 21.4% in Group 1 and 21.6% in Group
2
(diarrhea, headache, vaginal discomfort,
nausea rash)
Salinas‑Casado 2020 [85]
Article in Spanish A multicenter, randomized and double‑
blind experimental study ~ 49.5 years old women with a history of
recurrent UTIs
n = 184
Group1: 2 g of D‑mannose, 140 mg of
PAC and 7.98 mg of ursolic acid together
with vitamins A, C and E, and the Zinc
trace element (Manosar®) (n = 90) once
a day for 24 weeks
Group 2: 240 mg proanthocyanidins
(n = 94) as a single dose
Product was reported to be more efficient
for preventing rUTI than single dose of PAC
AEs:
16.8% of participants experienced AEs (12
in Group 1 and 19 in Group 2)
(diarrhea, headache, vaginal discomfort,
nausea rash)
UTI urinary tract infection, rUTI recurrent urinary tract infection, AEs adverse events, cps capsule, tid three times a day, IP investigational product, NDM N‑acetylcysteine D‑mannose Morinda citrifolia, PAC proanthocyanidin
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Ala‑Jaakkolaetal. Nutrition Journal (2022) 21:18
treatment (2 doses daily) and remained when supple-
menting one dose daily for an additional month (Day 60)
and 1 month after the treatment had ended (Day 90).
Most commonly in UTI studies, D-mannose is com-
bined with other plant-based supplements (Table3). A
randomized study on peri- and postmenopausal women
with rUTI showed that oral supplementation of a prod-
uct containing cranberry, propolis extract and D-man-
nose, was well-tolerated and effective in UTI treatment
and in reducing risk for rUTIs [75]. In the studied treat-
ment group, the product was administered for 10 days
at the beginning of each month for 3 months, whereas
control group did not receive any treatment. e uri-
nary symptoms were shown to be completely alleviated
from 92 of the studied women. A randomized study
by Genovese et al. [77] in UTI patients investigated
the effects of oral D-mannose and different botanicals
for 12 weeks on UTI recurrence. rUTI diagnosis was
assessed by microbial analyses from urine samples, vagi-
nal swabs and vaginal smear. e study demonstrated
that either D-mannose together with berberin, arbutin,
birch or D-mannose together with berberin, arbutin,
birch, and forskolin were more effective in preventing
rUTIs than D-mannose in combination with proantho-
cyanidin emphasizing the beneficial effects of combi-
nation of various plant-based supplements in lowering
the risk for rUTIs. Manno et al. [78] hypothesized that
efficacy of D-mannose + cranberry as a prophylaxis for
rUTI could be enhanced by adding hyaluronic acid, and
chondroitin sulfate into the study product. Adults with
acute cystitis were treated with single dose of antibiot-
ics after which they were randomized to either treatment
or control group. Patients consumed daily 2 sachets of
the study product for 2 weeks followed by one sachet for
another two weeks. After 12 weeks of follow-up, symp-
toms were relieved in 85% of participants who had con-
sumed the combination product, whereas the symptoms
were relieved only in 10% of participants in the control
group. Bacterial counts revealed that E. coli was detected
from the urine of 1 patient in the treatment group after
12 weeks, compared to that of 10 in the control (Baseline
numbers 15/20 and 16/19, respectively). An observa-
tional study performed on 60 female breast cancer survi-
vors indicated, that a combination of oral antibiotic with
D-mannose, N-acetylcysteine and Morinda citrifolia fruit
extract provided more benefits by reducing UTIs and uri-
nary discomfort when compared to antibiotics-only in a
study which lasted for 6 months [79]. e same product
was used in a larger population including 42 men and
38 women submitted to urodynamic investigation [80].
is randomized study showed that there were no dif-
ferences in UTI recurrences between the group using
antibiotics and the group using nutraceutical agents,
indicating that a product containing D-mannose, N-ace-
tylcysteine and Morinda citrifolia fruit extract could be
a potential prophylaxis alternative for UTI in this group
of patients. Panchev et al. [81] assessed the efficacy of
an oral combination product containing D-mannose,
birch leaf, and cranberry extract on acute UTI in an
observational study. e study results showed that after
3-day supplementation the clinical - and symptomatic
improvements were faster with the D-mannose contain-
ing investigational product (IP) compared to antibiotics
(mean time being 24 h and 46 h, respectively). At 48 h,
97% of the IP group had improved symptoms, whereas
only 65.3% in the antibiotic group. A pilot study by Rad-
ulesku etal., [82] showed that cure rate in acute UTI was
higher when combining 7 days antibiotic treatment with
an oral IP containing D-mannose and cranberry (84.44%
in the antibiotic alone and 91.66% in the antibiotic + IP)
– though not reaching statistically significant difference
between the groups. When looking at only the patients
with antibiotic resistant strains, the cure rate was signifi-
cantly better in the combined group. e cure rate was
also assessed after 21 days prophylactic treatment with
the IP (no antibiotic involved), showing no significant dif-
ferences between the IP and placebo. e potential ben-
eficial effect of 2 weeks cranberry, D-mannose, Boswellia,
Curcuma and Noxamicine supplementation on perceived
lower urinary tract symptoms after cystocele operation
was assessed by Russo et al. [83] in a randomized trial.
In the study, postmenopausal women received sup-
plementation twice a day for two weeks starting on the
operation day or operation only. Specific symptom scores
from the used questionnaire were reported to be lower
in the group receiving the supplementation. However, no
differences in the perioperative outcomes or UTI inci-
dences were detected between the study groups during
the follow-up. e recurrence of UTIs was also assessed
in a randomized double-blind study in adult women [84].
e study products were 1) a food supplement contain-
ing D-mannose, proanthocyanidins, ursolic acid and vita-
mins A, C and E, and zinc and 2) a compound containing
proanthocyanidins (polyphenols). In the study, once a day
consumption for 24 weeks of the investigational product
containing D-mannose was more effective in lowering
the risk for UTI than a single daily dose of proanthocya-
nidin. A similar study with a larger study population was
performed with similar results [85].
Safety ofsupplemented D‑mannose
Despite the potential benefits of D-mannose in UTI,
some mice studies have shown that prenatal mannose
supplementation causes embryonic lethality and eye
defects among the mice who survived [86]. In this trial,
the dose ranged from 1 to 5% in the drinking water. In
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Page 13 of 16
Ala‑Jaakkolaetal. Nutrition Journal (2022) 21:18
humans, safety and tolerability of a D-mannose contain-
ing product has been tested in a so called maximal tol-
erated dose design study [76]. is study showed that
the product containing D-mannose was well-tolerated
up to 90 ml of study product (D-mannose amount not
specified). Of note, the main ingredient in the product
was cranberry liquid. In the above reviewed clinical tri-
als where D-mannose was investigated as a single active
ingredient with a daily dose between 2 and 3 g [6770],
no serious adverse events were associated with the use of
D-mannose. In addition, a systematic review and meta-
analysis by Lenger etal. [87] concluded that D-mannose
was well tolerated with minimal side effects—only a
small percentage experiencing diarrhea. e occurrence
of adverse events is likely to be dose-depended as daily
doses exceeding 0.2 g/kg of body weight may cause diar-
rhea and bloating [4]. Of note, in human diabetics, blood
glucose balance could potentially be disturbed by man-
nose supplementation [50]. is should be taken into
account when considering D-mannose supplementation
among diabetics and pregnant women.
Discussion
While antibiotics are still the mainstay for treatment of
acute UTI, their use as prophylaxis has already led to the
development of resistant bacterial strains; compromising
treatments, and accumulating challenges over time. Fur-
thermore, the antibiotic side effects can cause discomfort
and predispose patients to other infections.
It has been demonstrated in both animal and human
studies that the renal threshold for D-mannose is low
i.e. excess D-mannose is secreted into urine [45, 46,
55]. In addition, good affinity of mannose and manno-
sides to E.coli type 1 pilus structures has been shown
by several invitro experiments [5760]. Furthermore,
based on an animal trial even at concentrations as low
as 20 μg/ml, D-mannose can efficiently block uropatho-
genic E. coli adhesion to the urinary tract, subsequently
lowering the risk for UTI [61]. Several clinical trials
have assessed the potential of D-mannose supplemen-
tation to improve either acute clinical and symptomatic
outcome of UTI or/and shorten the time-to-relapse in
rUTIs. To date, altogether 19 peer-reviewed clinical tri-
als have been published (Tables1, 2 and 3). However,
only four studies were conducted with D-mannose
alone, from which 2 trials [67, 70] assessed both acute
and long-term preventive effect of D-mannose on UTI
and 2 trials [68, 69] only the preventive effect. In most
of the studies (n = 15) a combined effect of D-mannose
and other “nutraceutical(s)”, such as cranberry extract
or probiotic, was studied. In addition, there are few
studies comparing the efficacy of D-mannose supple-
mentation and antibiotics on treatment of acute UTI
or as prophylaxis. From the 19 studies reported here,
18 indicate that D-mannose supplementation, alone or
combined with other products, could be beneficial in
the management of UTI; one study [69] reported on
feasibility and not efficacy. Of these 18 studies, seven
report on treatment of acute UTI; six report on ben-
eficial effects and one [83] did not observe a difference
in UTI with the control group but did nevertheless
observe a reduction in symptoms. Further, 14 of the 18
studies reported on prophylaxis in the management of
rUTI. Of these 14 studies, 13 reported on reductions
in rUTI, one study [82] did not report a difference in
recurrence compared to the antibiotic control. us,
D-mannose may help to improve clinical/symptomatic
recovery rate from UTI - sometimes even faster than
some of the used antibiotics – and/or may especially
have potential as a prophylactic by decreasing the risk
for rUTIs. However, to date no common guidelines for
the D-mannose treatment duration, dose and combina-
tion exist. Furthermore, no health claims thus far have
been approved for the use of D-mannose in UTI in any
jurisdiction. Such claim would protect the consumer
seeking self-help and provide health-care professionals
with confidence to recommend D-mannose as an alter-
native or complementary treatment.
rUTI is a common challenge especially among women
[88]. Imbalance of the urogenital bacteria caused by
frequent intercourse (especially younger women) or
postmenopausal age are risk factors for UTI occur-
rence. Frequent infections and the use of antibiotics
lead to changes in the microbiota in the urogenital area.
Especially antibiotic use may affect the dominance of
indigenous lactobacilli, and potentially creating suitable
environment for the uropathogens to thrive. erefore,
also the use of probiotic lactobacilli to reduce the risk
of rUTIs by supporting vaginal and urinary micro-
biota has gained attention. Currently (mid-2021), four
clinical trials including both D-mannose and probiotics
(one had also cranberry) have been conducted showing
promising outcomes related UTI symptoms and reoc-
currence rates.
Of the eight studies registered in clinicaltrials.gov
(accessed 3rd February 2022) investigating the effect of
D-mannose on UTI, only one has results, but these seem
not to have been published in the scientific literature
while another study has an ‘unknown’ status. Further, one
study was terminated and the remaining five studies are
in various stages of recruitment. us, although more
results are to be expected in the future, it also highlights
the challenge of potential reporting bias. is is espe-
cially challenging when only a limited number of studies
are available as in the case of D-mannose and UTI.
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Page 14 of 16
Ala‑Jaakkolaetal. Nutrition Journal (2022) 21:18
Conclusions
In addition to female gender, sexual activity at young
age and higher age in general, specific conditions such
as diabetes, neurologic conditions, chronic institu-
tional residence, and chronic urinary catheterization
might predispose to rUTIs. erefore, individuals in
need of repetitive antibiotic treatments, going through
urogenital procedures or women with changed bacte-
rial environment in the urogenital area would ben-
efit the most from a non-antibiotic alternative. Due to
increasing antibiotic resistance among UTI pathogens,
the burden caused by UTIs is expected to increase
creating a high demand for alternative options. For
the treatment of acute UTI, antibiotics are likely to
remain the first choice. Supplementing antibiotics with
D-mannose may increase treatment success. However,
for prophylaxis in reducing rUTI, D-mannose appears
to have great potential with minimal side effects. e
overall picture of preclinical and clinical studies with
D-mannose in the management of UTI is favorable, as
discussed here and in a recent narrative review by De
Nunzio etal. [89]. D-mannose has also been shown to
be relatively safe and well-tolerated. Yet, the quality
of these studies leaves something to be desired; they
are mostly confounded with other active ingredients,
have small numbers of participants, are open label or
uncontrolled. What is first and foremost needed are
sufficiently powered, well-designed double-blinded,
randomized, and placebo-controlled clinical trials with
solely D-mannose in the active product; distinguishing
between treatment and prophylaxis. Such studies are
registered in clini caltr ials. gov; we look forward to their
results.
Acknowledgements
The authors would like to acknowledge Kati Kousa for providing expertise
on the manufacturing, commercialization, and regulation of D‑Mannose as a
dietary supplement.
Authors’ contributions
“Conceptualization, R. A‑J., A.L., A.C.O., and L.L.; methodology, R. A‑J., A.L., L.L.;
investigation, R. A‑J.; writing—original draft preparation, R.A‑J., L.L.; writing—
review and editing, R.A‑J. L.L., A.L., A.C.O. visualization, R.A‑J.; All authors have
read and agreed to the published version of the manuscript.
Funding
This research was fully funded by Danisco Sweeteners Oy (Part of International
Flavors and Fragrances).
Availability of data and materials
Not applicable.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
All authors were employed by Danisco Sweeteners Oy (Part of International
Flavors and Fragrances) at the time the study was conducted.
Received: 11 November 2021 Accepted: 4 March 2022
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... In addition, cranberries have fructose, which inhibits the adhesins of E. coli that are sensitive to mannose [98]. Fructose has an affinity to FimH, which allows the factor of virulence type I pili of E. coli to connect to the urinary cells of the host [100][101][102]. There are unfortunately no studies that directly link fructose to UTIs, and there are no studies yet that link cranberry's fructose to the beneficial effects that this fruit has on UTIs. ...
... Another important compound of cranberries is D-mannose. This is a basic sugar that is present in several fruits, and has been linked to methods of preventing UTIs since the 1970s [100,[103][104][105]. Studies involving this monosaccharide have suggested that it can bind with E. coli bacteria and promote their elimination through the urine, which is called competitive inhibition [106]. ...
... This is a basic sugar that is present in several fruits, and has been linked to methods of preventing UTIs since the 1970s [100,[103][104][105]. Studies involving this monosaccharide have suggested that it can bind with E. coli bacteria and promote their elimination through the urine, which is called competitive inhibition [106]. Free D-mannose saturates the E. coli FimH structure, which blocks its linkage with urinary cells [89,90,100]. E. coli bacteria remain in the urinary tract due to their connection to type I pili via their adhesion component FimH, which is a virulence factor, through a mannose-sensitive mechanism [89,90,100]. ...
Article
Full-text available
Urinary tract infections (UTIs) are a prevalent global health issue, often requiring antibiotic treatment, which contributes to antimicrobial resistance. This narrative review explores the potential of probiotics and plant-based foods as alternative or complementary preventive strategies against UTIs. Fermented foods, such as yogurt, kefir, and kombucha, contain probiotic strains that can modulate the gut and urogenital microbiota, enhancing resistance to uropathogens. Likewise, plant-based foods, including cranberry, garlic, bearberry, juniper, and nettle, possess bioactive compounds with antimicrobial, anti-inflammatory, and diuretic properties. Laboratory and clinical studies suggest that these natural interventions may reduce the incidence of UTIs by inhibiting pathogen adhesion, modulating immune responses, and promoting urinary tract health. However, despite promising findings, inconsistencies in study methodologies, dosage standardization, and long-term efficacy warrant further investigation. Future research should focus on optimizing probiotic formulations, standardizing plant-based supplement dosages, and assessing potential food–drug interactions to establish evidence-based guidelines for UTI prevention.
... Therefore, D-mannose reduces the risk of rUTIs [42]. Studies showed that D-mannose can block the uropathogenic E. coli adhesion and invasion of the urothelium, thus preventing urinary tract infection [41][42][43]. However, a Cochrane systematic review that included 719 patients could not determine whether D-mannose compared to other treatments, other supplements, or antibiotics significantly reduced the number of rUTI episodes [42]. ...
... Low-dose antibiotic therapy Bacteriostatic Bactericidal [17][18][19][20][21]25] Immunoprophylaxis Bacteriostatic [35][36][37][38][39] Probiotics Bacteriostatic [31] Methenamine Bactericidal [40] D-mannose Bacteriostatic [41][42][43] Cranberry extract Bacteriostatic [12,28] Intravesical instillations of hyaluronic acid (HA) or chondroitin sulfate (CS) temporarily replace the deficient glycosaminoglycan (GAG) layer and have proved to be effective in the treatment of interstitial cystitis, overactive bladder, and post-radiation cystitis, as well as in rUTI prevention. A meta-analysis of two randomized control trials (RCTs) and six non-RCTs including 800 patients showed that intravesical treatment with HA, associated or not with CS, determined a low incidence of rUTIs and a significantly longer disease-free interval of time between the episodes of infection [44]. ...
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Worldwide, urinary tract infections (UTIs) have an increased incidence, especially in women. Recurrent UTIs (rUTIs) appear in less than three months in 80% of the cases, being associated with age, sexual activity, or diabetes mellitus. Antibiotics represent the first line of treatment for rUTIs after the diagnosis based on a positive mid-stream urine (MSU) culture. Alternative therapies including low-dose antibiotic treatment, immunoprophylaxis, cranberry extracts, probiotics, D-mannose, intravesical instillations, methenamine, and estrogens may reduce the recurrence of UTIs in female patients. Multimodal therapy seems to be the future in preventing and treating rUTIs. The main aim of this narrative review is to present the actual therapeutic challenges and the most efficient prophylaxis options in women diagnosed with rUTIs.
... In published clinical trials, D-mannose as a single active ingredient exhibits efficacy at daily doses between 2 and 3 g. Moreover, no serious adverse event was described, except for bloating and diarrhea at high doses, or hyperglycemia among diabetics [28]. Recently, results from a Cochrane systematic review including 7 RCTs (719 patients) showed that the overall quality of the evidence was low, mainly due to the lack of high-quality trials [29]. ...
... In published clinical trials, Dmannose as a single active ingredient exhibits efficacy at daily doses between 2 and 3 g. Moreover, no serious adverse event was described, except for bloating and diarrhea at high doses, or hyperglycemia among diabetics [28]. Recently, results from a Cochrane systematic review including 7 RCTs (719 patients) showed that the overall quality of the evidence was low, mainly due to the lack of high-quality trials [29]. ...
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Urinary tract infections (UTIs) are among the most common bacterial infections worldwide. They occur in the urinary system when a microorganism, commonly present on the perineal skin or rectum, reaches the bladder through the urethra, and adheres to the luminal surface of uroepithelial cells, forming biofilms. The treatment of UTIs includes antibiotics, but their indiscriminate use has favored the development of multidrug-resistant bacteria strains, which represent a serious challenge to today’s microbiology. The pathogenesis of the infection and antibiotic resistance synergistically contribute to hindering the eradication of the disease while favoring the establishment of persistent infections. The repeated requirement for antibiotic treatment and the limited therapeutic options have further contributed to the increase in antibiotic resistance and the occurrence of potential relapses by therapeutic failure. To limit antimicrobial resistance and broaden the choice of non-antibiotic preventive approaches, this review reports studies focused on the bacteriostatic/bactericidal activity, inhibition of bacterial adhesion and quorum sensing, restoration of uroepithelial integrity and immune response of molecules, vitamins, and compounds obtained from plants. To date, different supplementations are recommended by the European Association of Urology for the management of UTIs as an alternative approach to antibiotic treatment, while a variety of bioactive compounds are under investigation, mostly at the level of in vitro and preclinical studies. Although the evidence is promising, they are far from being included in the clinical practice of UTIs.
... Ефекти манози, що були доведені in vivo, включали: запобігання колонізації та інвазії уропатогенів сечового міхура, ефективність проти мультирезистентної кишкової палички, посилення ефекту антибіотиків і можливість лікування ІХСШ та катетер-асоційованих ІХСШ [63]. ...
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Urinary tract infections are one of the most common infectious diseases in the world. Pregnancy contributes to both the manifestation and recurrence of urinary tract diseases. Urinary tract infections occur in approximately 2-15% pregnant women and increase the frequency of obstetric complications, such as premature birth and low birth weight.This article pays special attention to the prevention of urinary tract infections in pregnant women. For this purpose, bacteriological examination of urine is recommended in most countries of the world, including European ones, which is also regulated by the order of the Ministry of Health of Ukraine. If asymptomatic bacteriuria is detected, a pregnant woman will be prescribed the so-called antibiotic prophylaxis of urinary tract infections. This publication considers the issue of choosing an antibacterial drug and pays special attention to antibiotic resistance. Urinary tract infections are the most common reason for prescribing antibiotics to pregnant women. The development of antibiotic resistance poses a danger to both the mother and the child. In addition to the development of resistance, problems associated with the use of antimicrobial drugs include patient non-compliance with the treatment regimen, side effects for both the mother and the child, and the overall effectiveness of treatment. All of this potentiates alternative methods of preventing both recurrent bacteriuria and urinary tract infections.The prescription of D-mannose-forming drugs, cranberries, their combination with other uro- or immunoprotective agents is an alternative to a re-prescribed antibiotic in order to prevent the recurrence or in case of persistent bacteriuria and recurrent urinary tract infections, especially if Escherichia coli is isolated from the urine (80-85% of all uropathogens).
... Approximately 150 million urinary tract infections (UTIs) are diagnosed worldwide annually (Flores-Mireles et al., 2015). A 2017 report showed that the WHO considered E. coli to be the main strain causing community-and hospital-acquired UTIs (Ala-Jaakkola et al., 2022). UTIs acquire nosocomial infections, which are associated with ESBL-PE. ...
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... Globally urinary tract infections (UTIs) affect both inpatient and outpatient individuals however patients with structural abnormalities or comorbidities including diabetes, advanced age, pregnancy, or immunocompromised condition are more likely to have complicated infections (Medina et al., 2015). Women are more likely to have urinary tract infections because of pathogenic organisms indigenous to the rectum and perineum (Ala-Jaakkola et al., 2022). Additionally, women's urethras are shorter than men's, which increases their vulnerability to UTIs (Zare et al., 2022). ...
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One of the most frequently acquired infections is urinary tract infection and Escherichia coli is a major causative pathogen. This study aims to determine the prevalence and antibiotic susceptibility of E. coli and extended-spectrum beta-lactamases (ESBLs) producing E. coli in urine samples of antenatal pregnant women attending Ajikobi Hospital in Ilorin, Nigeria. The study was conducted on urine samples from 117 consented pregnant women attending the antenatal clinic between January and October 2022. They were screened for Escherichia coli and Extended-spectrum β-lactamase producing E. coli using standard microbiological procedures such as growth on Eosin methylene blue, Gram staining, and biochemical tests. Antibiotic susceptibility testing was done by the modified Kirby-Bauer protocol while ESBL production was determined by the Double Disk Synergy Test (DDST). A total of 117 samples were screened, 26 (22.2%) showed significant bacteriuria, and 18 (69%) E coli was isolated. The age distribution shows that 15- 20 years has a prevalence rate of 23.1%, 21- 25 years (24.1%), 26- 30 years (25%), 31-35 (21.6%), and women above 35 years (27.3%). Antibiotic sensitivity profile shows that 16.7% were resistant to gentamicin, 66.7% to cefuroxime, 27.8% to meropenem, 11.1 % to ceftriaxone, ceftazidime (33.3%), 16.7% to amoxicillin/clavulanic, 22.2 % to ciprofloxacin and 100% susceptibility to both ofloxacin and nitrofurantoin. The study shows the prevalence of ESBLproducing E. coli and the high susceptibility of nitrofurantoin and ofloxacin.
... The PEG-lipid content of LNP 496 was 2 mol% DSPE-PEG-mannose (molecular weight 5000 (MW 5K), indicating that mannose is exposed on the surface of LNP 496. Previously, mannose was reported to attach to a mannose specific lectin protein FimH on the surface of E. coli, [26] suggesting that mannose on the surface of LNPs could enhance LNP-mediated plasmid delivery into bacteria. Indeed, the plasmid delivery efficiency of LNP 496 was significantly increased compared to that of LNP 470 at a PMB concentration of 1.5 μg mL −1 ( Figure 3D). ...
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Urinary tract infections (UTIs) are a considerable global concern and are among the most prevalent types of microbial infection globally. Young and sexually active women are disproportionately affected, with over 60% of females being diagnosed with UTIs at some point in their lives. Staphylococcus saprophyticus is a significant pathogen that causes UTIs in the community. The pathophysiology of coagulase-negative staphylococcal UTIs relies significantly on virulence factors and their expression. The main goal of the current investigation was to ascertain the occurrence of uropathogenic genes in S. saprophyticus isolated from urine samples of women who had suspected UTIs in Baghdad hospitals in Baghdad, Iraq. The prevalence of S. saprophyticus in urine samples was identified with the microscopic patterns, cultural and biochemical characteristics, Vitek 2 Compact System and S. saprophyticus-specific primers. Nine virulence genes, including Ssp, UafA, Aas, sarA, sdrl, rot, dsdA, capD and agr were screened using multiplex polymerase chain reaction. Out of the 300 samples, 31.66% harbored S. saprophyticus pathogens, confirmed by the existence of S. saprophyticus-specific primers in all isolates. The current data indicated that all isolates tested positive for the UafA, sarA, rot, and agr genes. Moreover, the results revealed that 94.74% of isolates tested carried the Aas gene, followed by Ssp (84.2%) and lastly dsdA (20%). However, SdrI and CapD genes were not detected in any of the isolates. These findings demonstrate that S. saprophyticus is a major contributor to UTIs in women in this specific region with the prevalence of certain virulence genes for this bacterium.
Chapter
Threat of drug resistance and superbugs is not new, but the stride with which it is increasing is worrisome. Non-conventional traditional therapies which have been in use since ancient times signify the remedial curative practices. In the modern era of medicine and “omics” biology, the traditional medicine has again emerged supplementary therapies to control various diseases. These therapies are still used either alone or along with standard remedies. The therapies practiced with traditional medicine are named as “complementary,” and those used alone are considered as “alternative.” These therapies are classified into different categories based on nutritional, physiological, and physical approaches.
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Background: Urinary tract infections (UTI) are highly frequent in women, with a significant impact on healthcare resources. Although antibiotics still represent the standard treatment to manage recurrent UTI (rUTI), D-mannose, an inert monosaccharide that is metabolized and excreted in urine and acts by inhibiting bacterial adhesion to the urothelium, represents a promising nonantibiotic prevention strategy. The aim of this narrative review is to critically analyze clinical studies reporting data concerning the efficacy and safety of D-mannose in the management of rUTIs. Methods: A non-systematic literature search, using the Pubmed, EMBASE, Scopus, Web of science, Cochrane Central Register of Controlled Trials, and Cochrane Central Database of Systematic Reviews databases, was performed for relevant articles published between January 2010 and January 2021. The following Medical Subjects Heading were used: “female/woman”, “urinary tract infection”, and “D-mannose”. Only clinical studies, systematic reviews, and meta-analyses reporting efficacy or safety data on D-mannose versus placebo or other competitors were selected for the present review. Evidence was limited to human data. The selected studies were organized in two categories according to the presence or not of a competitor to D-mannose. Results: After exclusion of non-pertinent studies/articles, 13 studies were analyzed. In detail, six were randomized controlled trials (RCTs), one a randomized cross-over trial, five prospective cohort studies, and one a retrospective analysis. Seven studies compared D-mannose to placebo or others drugs/dietary supplements. Six studies evaluated the efficacy of D-mannose comparing follow-up data with the baseline. D-mannose is well tolerated, with few reported adverse events (diarrhea was reported in about 8% of patients receiving 2 g of D-mannose for at least 6 months). Most of the studies also showed D-mannose can play a role in the prevention or rUTI or urodynamics-associated UTI and can overlap antibiotic treatments in some cases. The possibility to combine D-mannose with polyphenols or Lactobacillus seems another important option for UTI prophylaxis. However, the quality of the collected studies was very low, generating, consequently, a weak grade of recommendations as suggested by international guidelines. Data on D-mannose dose, frequency, and duration of treatment are still lacking. Conclusion: D-mannose alone or in combination with several dietary supplements or Lactobacillus has a potential role in the non antimicrobial prophylaxis or recurrent UTI in women. Despite its frequent prescription in real-life practice, we believe that further well-designed studies are urgently needed to definitively support the role of D-mannose in the management of recurrent UTIs in women.
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A decade ago, when the Human Microbiome Project was starting, urinary tract (UT) was not included because the bladder and urine were considered to be sterile. Today, we are presented with evidence that healthy UT possesses native microbiota and any major event disrupting its “equilibrium” can impact the host also. This dysbiosis often leads to cystitis symptoms, which is the most frequent lower UT complaint, especially among women. Cystitis is one of the most common causes of antimicrobial drugs prescriptions in primary and secondary care and an important contributor to the problem of antimicrobial resistance. Despite this fact, we still have trouble distinguishing whether the primary cause of majority of cystitis cases is a single pathogen overgrowth, or a systemic disorder affecting entire UT microbiota. There are relatively few studies monitoring changes and dynamics of UT microbiota in cystitis patients, making this field of research still an unknown. In this study variations to the UT microbiota of cystitis patients were identified and microbial dynamics has been modeled. The microbial genetic profile of urine samples from 28 patients was analyzed by 16S rDNA Illumina sequencing and bioinformatics analysis. One patient with bacterial cystitis symptoms was prescribed therapy based on national guideline recommendations on antibacterial treatment of urinary tract infections (UTI) and UT microbiota change was monitored by 16S rDNA sequencing on 24 h basis during the entire therapy duration. The results of sequencing implied that a particular class of bacteria is associated with majority of cystitis cases in this study. The contributing role of this class of bacteria – Gammaproteobacteria, was further predicted by generalized Lotka-Volterra modeling (gLVM). Longitudinal microbiota insight obtained from a single patient under prescribed antimicrobial therapy revealed rapid and extensive changes in microbial composition and emphasized the need for current guidelines revision in regards to therapy duration. Models based on gLVM indicated protective role of two taxonomic classes of bacteria, Actinobacteria and Bacteroidia class, which appear to actively suppress pathogen overgrowth.
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Traditionally, the healthy urinary bladder has been considered to be sterile. Several teams have used metagenomic (DNA-dependent) and metaculturomic (culture-dependent) methods to debunk this longstanding dogma. In fact, resident microbial communities (urobiome) have been detected in both adult females and males. Although the field is young, several observations have been made. For example, the urobiome differs between men and women, likely due to anatomical and hormonal differences. Importantly, the urobiome has been associated with a variety of lower urinary tract disorders, including overactive bladder and post-operative urinary tract infection, raising the possibility that clinicians might one day treat symptoms by modifying the urobiome instead of killing the suspected uropathogen. Little is known concerning the relationship between the urobiome and host genetics; so far, only a single paper has reported such a study. However, major efforts have gone into understanding the genomics of the urobiome itself, a process facilitated by the fact that many urobiome studies have used metaculturomic methods to detect and identify microbes. In this narrative review, we will introduce the urobiome with separate sections on the female and male urobiomes, discuss challenges specific to the urobiome, describe newly discovered associations between the urobiome and lower urinary tract symptoms, and highlight the one study that has attempted to relate host genetics and the urobiome. We will finish with a section on how metagenomic surveys and whole genome sequencing of bacterial isolates are improving our understanding of the urobiome and its relationship to lower urinary tract health and disorders.
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Urinary tract infections (UTIs) are very common disorders that affect adult women. Indeed, 50% of all women suffer from UTIs at least one time in their lifetime; 20–40% of them experience recurrent episodes. The majority of UTIs seems to be due to uropathogenic Escherichia coli that invades urothelial cells and forms quiescent bacterial reservoirs. Recurrences of UTIs are often treated with non-prescribed antibiotics by the patients, with increased issues connected to antibiotics resistance. D-mannose, a monosaccharide that is absorbed but not metabolized by the human body, has been proposed as an alternative approach for managing UTIs since it can inhibit the bacterial adhesion to the urothelium. This manuscript discusses the mechanisms through which D-mannose acts to highlight the regulatory aspects relevant for determining the administrative category of healthcare products placed on the market. The existing literature permits to conclude that the anti-adhesive effect of D-mannose cannot be considered as a pharmacological effect and, therefore, D-mannose-based products should be classified as medical devices composed of substances.
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Recent studies suggest that alterations in the female urinary microbiota is associated to development of bladder disease. However, the normal microbiota composition and variation in healthy women are poorly described. Moreover, the effects of hormonal changes on microbiota during menopause is not well understood. The aim of our study was to investigate the urinary microbiota in healthy pre- and postmenopausal women without urinary tract symptoms. Microbiota composition in catheterized urine samples was mapped using 16S rRNA gene sequencing. In total, 41 premenopausal and 42 postmenopausal women were initially included. Samples with first PCR amplification concentration below level of the negative control were excluded, resulting in 34 premenopausal and 20 postmenopausal women included in data analysis. Urine from postmenopausal women showed significantly higher alpha diversity compared to premenopausal women. Lactobacillus was the most abundant bacteria in both groups, however the relative abundance of Lactobacillus accounted for 77.8% in premenopausal versus 42.0% in postmenopausal women. In conclusion, urine from premenopausal mostly presented with Lactobacillus dominated urotypes, whereas urine from postmenopausal women presented a more diverse urinary microbiota with higher abundance of the genera Gardnerella and Prevotella. The clinical and pathophysiological implications of this difference remain to be elucidated.
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The current paradigm of urinary tract infection (UTI) pathogenesis takes into account the contamination of the periurethral space by specific uropathogens residing in the gut, which is followed by urethral colonization and pathogen ascension to the urinary bladder. Consequently, studying the relationship between gut microbiota and the subsequent development of bacteriuria and UTI represents an important field of research. However, the well-established diagnostic and therapeutic paradigm for urinary tract infections (UTIs) has come into question with the discovery of a multifaceted, symbiotic microbiome in the healthy urogenital tract. More specifically, emerging data suggest that vaginal dysbiosis may result in Escherichia coli colonization and prompt recurrent UTIs, while urinary microbiome perturbations may precede the development of UTIs and other pathologic conditions of the urinary system. The question is whether these findings can be exploited for risk reduction and treatment purposes. This review aimed to appraise the three aforementioned specific microbiomes regarding their potential influence on UTI development by focusing on the recent studies in the field and assessing the potential linkages between these different niches, as well as evaluating the state of translational research for novel therapeutic and preventative approaches.
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Objective: To compare the efficacy and safety in the prophylasis of urinary tract infections (UTIs) with a food supplement that contains D-mannose like active ingredient (Manosar®), in comparison to another preparation in which the active ingredient are the proanthocyanidins (PAC), both of them, in prolonged released, after, they was administered for 24 weeks. Methods: A multicenter, randomized and double blind experimental study was carried out. 283 women with a history of recurrent UTIs without evidence of complication were included. They were randomized 1: 1 in two groups. In one group, 1 oral sachet of Manosar® a day was administered, and in the other group 1 oral sachet of a compound of 240 mg of continuous-release PAC. Prior to inclusion in the study, the episode of UTI was confirmed at least by the clinical symptoms and positivity of the Combur test. Results: Valid data were obtained from 184 patients with an average age of 49.5 years: 90 received Manosar® and 94 isolated PAC. A total of 72 patients suffered an UTI due to E.coli: 25 patients in the arm with Manosar® versus 47 patients in the isolated PAC group, this difference being statistically significant (p=0.002). The free time of new UTI recurrences was 98.6 days in the group treated with Manosar® and 84.6 days in the group with isolated PAC. Conclusion: The oral taking of a daily sachet of Manosar® is effective and safe in preventing recurrent UTIs in women, being superior to the oral taking of isolated PAC.
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Urinary tract infections (UTIs) mainly caused by Uropathogenic Escherichia coli (UPEC), are common bacterial infections. Many individuals suffer from chronically recurring UTIs, sometimes requiring long-term prophylactic antibiotic regimens. The global emergence of multi-drug resistant uropathogens in the last decade underlines the need for alternative non-antibiotic therapeutic and preventative strategies against UTIs. The research on non-antibiotic therapeutic options in UTIs has focused on the following phases of the pathogenesis: colonization, adherence of pathogens to uroepithelial cell receptors and invasion. In this review, we discuss vaccines, small compounds, nutraceuticals, immunomodulating agents, probiotics and bacteriophages, highlighting the challenges each of these approaches face. Most of these treatments show interesting but only preliminary results. Lactobacillus-containing products and cranberry products in conjunction with propolis have shown the most robust results to date and appear to be the most promising new alternative to currently used antibiotics. Larger efficacy clinical trials as well as studies on the interplay between non-antibiotic therapies, uropathogens and the host immune system are warranted.
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Background: Most women experience a urinary tract infection (UTI) at least once in their lifetime. The present study determined the efficacy and safety of a combination of Lactobacillus paracasei LC11, cranberry and D-mannose (Lactoflorene Cist®) in the prophylaxis of recurrent uncomplicated UTIs in premenopausal women. Methods: This single-centre study enrolled premenopausal women aged 18-50 years with an acute UTI and a history of recurrent uncomplicated UTIs. Patients were first treated with fosfomycin (3 g once a day for 2 days) to eliminate any underlying infection, followed by treatment with Lactoflorene Cist® once a day for 10 days/month for 90 days (Group 1), Lactoflorene Cist® once daily for 90 days (Group 2) or no treatment (Group 3; control). The main study endpoint was the rate of UTI recurrence during the study period. Any adverse events with treatment were also recorded. Results: A total of 55 women (mean age 39.3 years; range: 20-46) were enrolled in the study. A significantly higher proportion of patients in the control group experienced UTIs during the study period compared with the two treatment groups (52.9% vs 16.0% in Group 1 and 15.5% in group 2; p < 0.01). Similarly, a higher proportion of patients in Group 1 (65.8%) and Group 2 (68.7%) remained UTI-free during the study versus the control group. No adverse events were reported in the treated patients. Conclusion: Prophylactic treatment with Lactoflorene Cist® was effective and safe in the management of recurrent uncomplicated UTIs in premenopausal women.
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Uncomplicated lower urinary tract infections are extremely common in women. Antibiotic treatment for acute episodes and for recurrence prophylaxis has its drawbacks and alternative therapies are sought in order to reduce the antimicrobial resistance phenomenon and the intestinal dismicrobism expansion. There are few studies on the effect of combination of cranberry extract with D-mannose in acute urinary tract infection management. In a pilot, randomized study 93 non-pregnant, otherwise healthy women, were enrolled with mean age of 39.77±10.36, diagnosed with uncomplicated lower urinary tract infection. Medical history, clinical examination, urine culture and a list of complaints were noted at the baseline visit. In a first phase of the study, treatment with either guideline recommended antibiotic alone or in association with the investigated product (cranberry extract plus D-mannose) was prescribed and all patients were clinically examined at day 7. All ameliorated and cured patients received in a second phase of the study, in a double-blind manner, prophylaxis with the investigated product or placebo for another 21 days, then a second clinical examination and a check of the list of complaints were performed. The cure rates were higher at day 7 when investigated product was added to antibiotic (91.6 vs. 84.4%). In resistant strains, a significantly higher cure rate was shown when the investigated product was added to antibiotic prescribed (88.8 vs. 37.5%, P<0.0001). The effect of cranberry extract plus D-mannose combination in acute urinary tract infection episodes seems to be promising. The significant cure rate registered in the patients with antibiotic-resistant urine cultures may be explained by a beneficial influence of the product on the antimicrobial sensitivity. Further studies are needed on this subject.