ArticlePDF AvailableLiterature Review

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


Abstract and Figures

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 .
This content is subject to copyright. Terms and conditions apply.
Ala‑Jaakkolaetal. Nutrition Journal (2022) 21:18‑022‑00769‑x
Role ofD‑mannose inurinary tract infections
– anarrative review
Reeta Ala‑Jaakkola, Arja Laitila, Arthur C. Ouwehand* and Liisa Lehtoranta
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
© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the
original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or
other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line
to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this
licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco
mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
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
Health & Biosciences, International Flavors & Fragrances, Sokeritehtaantie
20, FIN‑02460 Kantvik, Finland
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 2 of 16
Ala‑Jaakkolaetal. Nutrition Journal (2022) 21:18
Overview ofUTI
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.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 3 of 16
Ala‑Jaakkolaetal. Nutrition Journal (2022) 21:18
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.
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
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
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].
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
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 5 of 16
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
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 6 of 16
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
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 7 of 16
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
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
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 8 of 16
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
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
Significant improvement in the UTI symp‑
toms (dysuria, frequent voiding, urgency, and
suprapubic pain) in long‑term
No AEs mentioned
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 9 of 16
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
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‑
Long‑term: 2 sachets for 2 weeks and
one sachet for two additional weeks as
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
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
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
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
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
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 11 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)
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
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
(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
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
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 12 of 16
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
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
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.
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
(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.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 14 of 16
Ala‑Jaakkolaetal. Nutrition Journal (2022) 21:18
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
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.
This research was fully funded by Danisco Sweeteners Oy (Part of International
Flavors and Fragrances).
Availability of data and materials
Not applicable.
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
1. Beerepoot MA, ter Riet G, Nys S, van der Wal WM, de Borgie CA, de Reijke
TM, et al. Cranberries vs antibiotics to prevent urinary tract infections: a
randomized double‑blind noninferiority trial in premenopausal women.
Arch Intern Med. 2011;171(14):1270–8.
2. Khandelwal P, Abraham SN, Apodaca G. Cell biology and physiology of
the uroepithelium. Am J Physiol Ren Physiol. 2009;297(6):F1477–501.
3. Xie B, Zhou G, Chan SY, Shapiro E, Kong XP, Wu XR, et al. Distinct glycan
structures of uroplakins Ia and Ib: structural basis for the selective binding
of FimH adhesin to uroplakin Ia. J Biol Chem. 2006;281(21):14644–53.
4. Alton G, Kjaergaard S, Etchison JR, Skovby F, Freeze HH. Oral ingestion of
mannose elevates blood mannose levels: a first step toward a potential
therapy for carbohydrate‑deficient glycoprotein syndrome type I. Bio‑
chem Mol Med. 1997;60(2):127–33.
5. Scaglione F, Musazzi UM, Minghetti P. Considerations on D‑mannose
mechanism of action and consequent classification of marketed health‑
care products. Front Pharmacol. 2021;12:636377.
6. Organization. WH. Prioritization of pathogens to guide discovery, research
and development of new antibiotics for drug‑resistant bacterial infec‑
tions, including tuberculosis. 2017. Contract No.: WHO/EMP/IAU/2017.12.
7. Flores‑Mireles AL, Walker JN, Caparon M, Hultgren SJ. Urinary tract infec‑
tions: epidemiology, mechanisms of infection and treatment options. Nat
Rev Microbiol. 2015;13(5):269–84.
8. Stamm WE, Norrby SR. Urinary tract infections: disease panorama and
challenges. J Infect Dis. 2001;183(Suppl 1):S1–4.
9. Foxman B, Brown P. Epidemiology of urinary tract infections: trans‑
mission and risk factors, incidence, and costs. Infect Dis Clin N Am.
10. Foxman B. Urinary tract infection syndromes: occurrence, recurrence,
bacteriology, risk factors, and disease burden. Infect Dis Clin N Am.
11. de Lastours V, Foxman B. Urinary tract infection in diabetes: epidemio‑
logic considerations. Curr Infect Dis Rep. 2014;16(1):389.
12. Patterson JE, Andriole VT. Bacterial urinary tract infections in diabetes.
Infect Dis Clin N Am. 1997;11(3):735–50.
13. Sewify M, Nair S, Warsame S, Murad M, Alhubail A, Behbehani K, et al.
Prevalence of urinary tract infection and antimicrobial susceptibility
among diabetic patients with controlled and uncontrolled Glycemia in
Kuwait. J Diabetes Res. 2016;2016:6573215.
14. Shuman EK, Chenoweth CE. Recognition and prevention of healthcare‑
associated urinary tract infections in the intensive care unit. Crit Care
Med. 2010;38(8 Suppl):S373–9.
15. Lee EA, Malatt C. Making the hospital safer for older adult patients: a
focus on the indwelling urinary catheter. Perm J. 2011;15(1):49–52.
16. Medina M, Castillo‑Pino E. An introduction to the epidemiology and bur‑
den of urinary tract infections. Ther Adv Urol. 2019;11:1756287219832172.
17. Schmiemann G, Kniehl E, Gebhardt K, Matejczyk MM, Hummers‑Pradier E.
The diagnosis of urinary tract infection: a systematic review. Dtsch Arztebl
Int. 2010;107(21):361–7.
18. Brubaker L, Putonti C, Dong Q, Wolfe AJ. The human urobiome. Mamm
Genome. 2021;32:232–8.
19. Ceprnja M, Oros D, Melvan E, Svetlicic E, Skrlin J, Barisic K, et al. Modeling
of urinary microbiota associated with cystitis. Front Cell Infect Microbiol.
20. Price TK, Hilt EE, Thomas‑White K, Mueller ER, Wolfe AJ, Brubaker L. The
urobiome of continent adult women: a cross‑sectional study. BJOG.
21. Wolfe AJ, Brubaker L. Urobiome updates: advances in urinary microbiome
research. Nat Rev Urol. 2019;16(2):73–4.
22. Komesu YM, Dinwiddie DL, Richter HE, Lukacz ES, Sung VW, Siddiqui NY,
et al. Defining the relationship between vaginal and urinary microbi‑
omes. Am J Obstet Gynecol. 2020;222(2):154 e1‑ e10.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 15 of 16
Ala‑Jaakkolaetal. Nutrition Journal (2022) 21:18
23. Ammitzboll N, Bau BPJ, Bundgaard‑Nielsen C, Villadsen AB, Jensen AM,
Leutscher PDC, et al. Pre‑ and postmenopausal women have different
core urinary microbiota. Sci Rep. 2021;11(1):2212.
24. Stapleton AE. The vaginal microbiota and urinary tract infection. Micro‑
biol Spectr. 2016;4(6):10.1128/microbiolspec.UTI‑0025‑2016.
25. Mestrovic T, Matijasic M, Peric M, Cipcic Paljetak H, Baresic A, Verbanac D.
The role of gut, vaginal, and urinary microbiome in urinary tract infec‑
tions: from bench to bedside. Diagnostics (Basel). 2021;11:7.
26. Moreno E, Andreu A, Pérez T, Sabaté M, Johnson JR, Prats G. Relationship
between Escherichia coli strains causing urinary tract infection. Epidemiol
Infect. 2006;5(Oct):1015–23.
27. Anderson GG, Palermo JJ, Schilling JD, Roth R, Heuser J, Hultgren SJ.
Intracellular bacterial biofilm‑like pods in urinary tract infections. Science.
28. Olson PD, Hunstad DA. Subversion of host innate immunity by Uropatho‑
genic Escherichia coli. Pathogens. 2016;5:2.
29. Gupta K, Hooton TM, Miller L, Uncomplicated UTIIGC. Managing uncom‑
plicated urinary tract infection‑‑making sense out of resistance data. Clin
Infect Dis. 2011;53(10):1041–2.
30. Gupta K, Hooton TM, Naber KG, Wullt B, Colgan R, Miller LG, et al.
International clinical practice guidelines for the treatment of acute
uncomplicated cystitis and pyelonephritis in women: a 2010 update by
the Infectious Diseases Society of America and the European Society for
Microbiology and Infectious Diseases. Clin Infect Dis. 2011;52(5):e103–20.
31. Loubet P, Ranfaing J, Dinh A, Dunyach‑Remy C, Bernard L, Bruyere F, et al.
Alternative therapeutic options to antibiotics for the treatment of urinary
tract infections. Front Microbiol. 2020;11:1509.
32. Heisig P. Urinary tract infections and antibiotic resistance. Urologe A.
33. Kahlmeter G, Eco.Sens. An international survey of the antimicrobial
susceptibility of pathogens from uncomplicated urinary tract infections:
the ECO.SENS project. J Antimicrob Chemother. 2003;51(1):69–76.
34. Zhanel GG, Hisanaga TL, Laing NM, DeCorby MR, Nichol KA, Weshnoweski
B, et al. Antibiotic resistance in Escherichia coli outpatient urinary isolates:
final results from the north American urinary tract infection collaborative
Alliance (NAUTICA). Int J Antimicrob Agents. 2006;27(6):468–75.
35. Akram M, Shahid M, Khan AU. Etiology and antibiotic resistance patterns
of community‑acquired urinary tract infections in J N M C hospital
Aligarh, India. Ann Clin Microbiol Antimicrob. 2007;6:4.
36. Lu PL, Liu YC, Toh HS, Lee YL, Liu YM, Ho CM, et al. Epidemiology and
antimicrobial susceptibility profiles of gram‑negative bacteria causing
urinary tract infections in the Asia‑Pacific region: 2009‑2010 results from
the study for monitoring antimicrobial resistance trends (SMART). Int J
Antimicrob Agents. 2012;40(Suppl):S37–43.
37. de Cueto M, Aliaga L, Alos JI, Canut A, Los‑Arcos I, Martinez JA, et al. Exec‑
utive summary of the diagnosis and treatment of urinary tract infection:
guidelines of the Spanish Society of Clinical Microbiology and Infectious
Diseases (SEIMC). Enferm Infecc Microbiol Clin. 2017;35(5):314–20.
38. Gupta K, Bhadelia N. Management of urinary tract infections from
multidrug‑resistant organisms. Infect Dis Clin N Am. 2014;28(1):49–59.
39. Mickiewicz KM, Kawai Y, Drage L, Gomes MC, Davison F, Pickard R, et al.
Possible role of L‑form switching in recurrent urinary tract infection. Nat
Commun. 2019;10(1):4379.
40. Foxman B. Recurring urinary tract infection: incidence and risk factors.
Am J Public Health 1990;80(3):331–3.
41. Mabeck CE. Treatment of uncomplicated urinary tract infection in non‑
pregnant women. Postgrad Med J. 1972;48(556):69–75.
42. Ikaheimo R, Siitonen A, Heiskanen T, Karkkainen U, Kuosmanen P, Lip‑
ponen P, et al. Recurrence of urinary tract infection in a primary care
setting: analysis of a 1‑year follow‑up of 179 women. Clin Infect Dis.
43. Ballou CE, Lipke PN, Raschke WC. Structure and immunochemistry of
the cell wall mannans from Saccharomyces chevalieri, Saccharomyces
italicus, Saccharomyces diastaticus, and Saccharomyces carlsbergensis. J
Bacteriol. 1974;117(2):461–7.
44. Spencer JF, Gorin PA. Mannose‑containing polysaccharides of yeasts.
Biotechnol Bioeng. 1973;15(1):1–12.
45. Ganda OP, Soeldner JS, Gleason RE, Cleator IG, Reynolds C. Metabolic
effects of glucose, mannose, galactose, and fructose in man. J Clin
Endocrinol Metab. 1979;49(4):616–22.
46. Wood FC Jr, Cahill GF Jr. Mannose Utilization in Man. J Clin Invest.
47. Alton G, Hasilik M, Niehues R, Panneerselvam K, Etchison JR, Fana F,
et al. Direct utilization of mannose for mammalian glycoprotein bio
synthesis. Glycobiology. 1998;8(3):285–95.
48. Srivastava M, Kapoor VP. Seed galactomannans: an overview. Chem
Biodivers. 2005;2(3):295–317.
49. Yamabhai M, Sak‑Ubol S, Srila W, Haltrich D. Mannan biotechnology:
from biofuels to health. Crit Rev Biotechnol. 2016;36(1):32–42.
50. Sharma V, Ichikawa M, Freeze HH. Mannose metabolism: more than
meets the eye. Biochem Biophys Res Commun. 2014;453(2):220–8.
51. Sharma V, Smolin J, Nayak J, Ayala JE, Scott DA, Peterson SN, et al.
Mannose alters gut microbiome, prevents diet‑induced obesity, and
improves host metabolism. Cell Rep. 2018;24(12):3087–98.
52. Freeze HH, Elbein AD. Glycosylation Precursors. In: Varki A, Cummings
RD, Esko JD, Freeze HH, Stanley P, Bertozzi CR, et al., editors. Essentials
of Glycobiology. Cold Spring Harbor (NY); 2009. p. 339–72.
53. Harms HK, Zimmer KP, Kurnik K, Bertele‑Harms RM, Weidinger S, Reiter
K. Oral mannose therapy persistently corrects the severe clinical symp
toms and biochemical abnormalities of phosphomannose isomerase
deficiency. Acta Paediatr. 2002;91(10):1065–72.
54. Westphal V, Kjaergaard S, Davis JA, Peterson SM, Skovby F, Freeze
HH. Genetic and metabolic analysis of the first adult with congenital
disorder of glycosylation type Ib: long‑term outcome and effects of
mannose supplementation. Mol Genet Metab. 2001;73(1):77–85.
55. Harding VJ, Nicholson TF, Armstrong AR. Cutaneous blood‑sugar curves
after the administration of fructose, mannose and xylose. Biochem J.
56. Scribano D, Sarshar M, Prezioso C, Lucarelli M, Angeloni A, Zagaglia C,
et al. D‑mannose treatment neither affects Uropathogenic Escherichia
coli properties nor induces stable FimH modifications. Molecules.
57. Bouckaert J, Berglund J, Schembri M, De Genst E, Cools L, Wuhrer
M, et al. Receptor binding studies disclose a novel class of high‑
affinity inhibitors of the Escherichia coli FimH adhesin. Mol Microbiol.
58. Han Z, Pinkner JS, Ford B, Obermann R, Nolan W, Wildman SA, et al.
Structure‑based drug design and optimization of mannoside bacterial
FimH antagonists. J Med Chem. 2010;53(12):4779–92.
59. Hung CS, Bouckaert J, Hung D, Pinkner J, Widberg C, DeFusco A, et al.
Structural basis of tropism of Escherichia coli to the bladder during
urinary tract infection. Mol Microbiol. 2002;44(4):903–15.
60. Old DC. Inhibition of the interaction between fimbrial haemaggluti
nins and erythrocytes by D‑mannose and other carbohydrates. J Gen
Microbiol. 1972;71(1):149–57.
61. Toyota S, Fukushi Y, Katoh S, Orikasa S, Suzuki Y. Anti‑bacterial defense
mechanism of the urinary bladder. Role of mannose in urine. Nihon
Hinyokika Gakkai Zasshi. 1989;80(12):1816–23.
62. Michaels EK, Chmiel JS, Plotkin BJ, Schaeffer AJ. Effect of D‑mannose
and D‑glucose on Escherichia coli bacteriuria in rats. Urol Res.
63. Cusumano CK, Pinkner JS, Han Z, Greene SE, Ford BA, Crowley JR, et al.
Treatment and prevention of urinary tract infection with orally active
FimH inhibitors. Sci Transl Med. 2011;3(109):109ra15.
64. Klein T, Abgottspon D, Wittwer M, Rabbani S, Herold J, Jiang X, et al.
FimH antagonists for the oral treatment of urinary tract infections: from
design and synthesis to in vitro and in vivo evaluation. J Med Chem.
65. Kil KS, Darouiche RO, Hull RA, Mansouri MD, Musher DM. Identification
of a Klebsiella pneumoniae strain associated with nosocomial urinary
tract infection. J Clin Microbiol. 1997;35(9):2370–4.
66. Zhang D, Chia C, Jiao X, Jin W, Kasagi S, Wu R, et al. D‑mannose
induces regulatory T cells and suppresses immunopathology. Nat Med.
67. Domenici L, Monti M, Bracchi C, Giorgini M, Colagiovanni V, Muzii
L, et al. D‑mannose: a promising support for acute urinary tract
infections in women. A pilot study. Eur Rev Med Pharmacol Sci.
68. Kranjcec B, Papes D, Altarac S. D‑mannose powder for prophylaxis of
recurrent urinary tract infections in women: a randomized clinical trial.
World J Urol. 2014;32(1):79–84.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 16 of 16
Ala‑Jaakkolaetal. Nutrition Journal (2022) 21:18
fast, convenient online submission
thorough peer review by experienced researchers in your field
rapid publication on acceptance
support for research data, including large and complex data types
gold Open Access which fosters wider collaboration and increased citations
maximum visibility for your research: over 100M website views per year
At BMC, research is always in progress.
Learn more
Ready to submit your research
Ready to submit your research
? Choose BMC and benefit from:
? Choose BMC and benefit from:
69. Phe V, Pakzad M, Haslam C, Gonzales G, Curtis C, Porter B, et al. Open label
feasibility study evaluating D‑mannose combined with home‑based
monitoring of suspected urinary tract infections in patients with multiple
sclerosis. Neurourol Urodyn. 2017;36(7):1770–5.
70. Porru D, Parmigiani A, Tinelli C, Barletta D, Choussos D, Di Franco C, et al.
Oral D‑mannose in recurrent urinarytract infections in women: a pilot
study. J Clin Urol. 2014;7(3):208–13.
71. Del Popolo G, Nelli F. Recurrent bacterial symptomatic cystitis: a pilot
study on a new natural option for treatment. Arch Ital Urol Androl.
72. Milandri R, Maltagliati M, Bocchialini T, Del Prete C, Bianchi G, Rocco BM,
et al. Effectiveness of D‑mannose, Hibiscus sabdariffa and Lactobacillus
plantarum therapy in prevention of infectious events following urody‑
namic study. Urologia. 2019;86(3):122–5.
73. Murina F, Vicariotto F, Lubrano C. Efficacy of an orally administered
combination of Lactobacillus paracasei LC11, cranberry and D‑mannose
for the prevention of uncomplicated, recurrent urinary tract infections in
women. Urologia. 2021;88(1):64–8.
74. Vicariotto F. Effectiveness of an association of a cranberry dry extract,
D‑mannose, and the two microorganisms Lactobacillus plantarum LP01
and Lactobacillus paracasei LPC09 in women affected by cystitis: a pilot
study. J Clin Gastroenterol. 2014;48(Suppl 1):S96–101.
75. De Leo V, Cappelli V, Massaro MG, Tosti C, Morgante G. Evaluation of the
effects of a natural dietary supplement with cranberry, Noxamicina(R)
and D‑mannose in recurrent urinary infections in perimenopausal
women. Minerva Ginecol. 2017;69(4):336–41.
76. Efros M, Bromberg W, Cossu L, Nakeleski E, Katz AE. Novel concentrated
cranberry liquid blend, UTI‑STAT with Proantinox, might help prevent
recurrent urinary tract infections in women. Urology. 2010;76(4):841–5.
77. Genovese C, Davinelli S, Mangano K, Tempera G, Nicolosi D, Corsello S,
et al. Effects of a new combination of plant extracts plus d‑mannose for
the management of uncomplicated recurrent urinary tract infections. J
Chemother. 2018;30(2):107–14.
78. Manno S, Cicione A, Dell’Atti L, Capretti C, Scarcella S, Cantiello F, et al.
Effects of a new combination of cranberry extracts, D‑mannose and
GAGs for the Management of Uncomplicated Urinary Tract Infection.
Endocrinol Diabetes Metab J. 2019;3(1):1–4.
79. Marchiori D, Zanello PP. Efficacy of N‑acetylcysteine, D‑mannose and
Morinda citrifolia to treat recurrent cystitis in breast Cancer survivals.
In Vivo. 2017;31(5):931–6.
80. Palleschi G, Carbone A, Zanello PP, Mele R, Leto A, Fuschi A, et al. Prospec‑
tive study to compare antibiosis versus the association of N‑acetyl‑
cysteine, D‑mannose and Morinda citrifolia fruit extract in preventing
urinary tract infections in patients submitted to urodynamic investiga‑
tion. Arch Ital Urol Androl. 2017;89(1):45–50.
81. Panchev P, Slavov C, Mladenov D, Georgiev M, Yanev K, Paskalev E, et al. A
multicenter comparative observation on the effectiveness and the rapid‑
ness of the effect of Cystostop rapid versus antibiotic therapy in patients
with uncomplicated cystitis. Akush Ginekol (Sofiia). 2012;51(7):49–55.
82. Radulescu D, David C, Turcu FL, Spataru DM, Popescu P, Vacaroiu IA.
Combination of cranberry extract and D‑mannose ‑ possible enhancer
of uropathogen sensitivity to antibiotics in acute therapy of urinary tract
infections: results of a pilot study. Exp Ther Med. 2020;20(4):3399–406.
83. Russo E, Montt Guevara M, Giannini A, Mannella P, Palla G, Caretto M,
et al. Cranberry, D‑mannose and anti‑inflammatory agents prevent lower
urinary tract symptoms in women undergoing prolapse surgery. Climac‑
teric. 2020;23(2):201–5.
84. Salinas‑Casado J, Mendez‑Rubio S, Esteban‑Fuertes M, Gomez‑Rodriguez
A, Virseda‑Chamorro M, Lujan‑Galan M, et al. Efficacy and safety of
D‑mannose (2 g), 24h prolonged release, associated with Proanthocya‑
nidin (PAC), versus isolate PAC, in the management of a series of women
with recurrent urinary infections. Arch Esp Urol. 2018;71(2):169–77.
85. Salinas‑Casado J, Mendez‑Rubio S, Esteban‑Fuertes M, Gomez‑Rodriguez
A, Virseda‑Chamorro M, Lujan‑Galan M, et al. Large study (283 women) on
the effectiveness of Manosar(R): 2 g of d‑mannose + 140 mg of proan‑
thocyanidins (PAC), of prolonged release. Arch Esp Urol. 2020;73(6):491–8.
86. Sharma V, Nayak J, DeRossi C, Charbono A, Ichikawa M, Ng BG, et al. Man‑
nose supplements induce embryonic lethality and blindness in phospho‑
mannose isomerase hypomorphic mice. FASEB J. 2014;28(4):1854–69.
87. Lenger SM, Bradley MS, Thomas DA, Bertolet MH, Lowder JL, Sutcliffe
S. D‑mannose vs other agents for recurrent urinary tract infection
prevention in adult women: a systematic review and meta‑analysis. Am J
Obstet Gynecol. 2020;223(2):265 e1‑e13.
88. Kodner CM, Thomas Gupton EK. Recurrent urinary tract infec‑
tions in women: diagnosis and management. Am Fam Physician.
89. De Nunzio C, Bartoletti R, Tubaro A, Simonato A, Ficarra V. Role of
D‑mannose in the prevention of recurrent Uncomplicated cystitis: state
of the art and future perspectives. Antibiotics (Basel). 2021;10(4):373.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in pub‑
lished maps and institutional affiliations.
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Terms and Conditions
Springer Nature journal content, brought to you courtesy of Springer Nature Customer Service Center GmbH (“Springer Nature”).
Springer Nature supports a reasonable amount of sharing of research papers by authors, subscribers and authorised users (“Users”), for small-
scale personal, non-commercial use provided that all copyright, trade and service marks and other proprietary notices are maintained. By
accessing, sharing, receiving or otherwise using the Springer Nature journal content you agree to these terms of use (“Terms”). For these
purposes, Springer Nature considers academic use (by researchers and students) to be non-commercial.
These Terms are supplementary and will apply in addition to any applicable website terms and conditions, a relevant site licence or a personal
subscription. These Terms will prevail over any conflict or ambiguity with regards to the relevant terms, a site licence or a personal subscription
(to the extent of the conflict or ambiguity only). For Creative Commons-licensed articles, the terms of the Creative Commons license used will
We collect and use personal data to provide access to the Springer Nature journal content. We may also use these personal data internally within
ResearchGate and Springer Nature and as agreed share it, in an anonymised way, for purposes of tracking, analysis and reporting. We will not
otherwise disclose your personal data outside the ResearchGate or the Springer Nature group of companies unless we have your permission as
detailed in the Privacy Policy.
While Users may use the Springer Nature journal content for small scale, personal non-commercial use, it is important to note that Users may
use such content for the purpose of providing other users with access on a regular or large scale basis or as a means to circumvent access
use such content where to do so would be considered a criminal or statutory offence in any jurisdiction, or gives rise to civil liability, or is
otherwise unlawful;
falsely or misleadingly imply or suggest endorsement, approval , sponsorship, or association unless explicitly agreed to by Springer Nature in
use bots or other automated methods to access the content or redirect messages
override any security feature or exclusionary protocol; or
share the content in order to create substitute for Springer Nature products or services or a systematic database of Springer Nature journal
In line with the restriction against commercial use, Springer Nature does not permit the creation of a product or service that creates revenue,
royalties, rent or income from our content or its inclusion as part of a paid for service or for other commercial gain. Springer Nature journal
content cannot be used for inter-library loans and librarians may not upload Springer Nature journal content on a large scale into their, or any
other, institutional repository.
These terms of use are reviewed regularly and may be amended at any time. Springer Nature is not obligated to publish any information or
content on this website and may remove it or features or functionality at our sole discretion, at any time with or without notice. Springer Nature
may revoke this licence to you at any time and remove access to any copies of the Springer Nature journal content which have been saved.
To the fullest extent permitted by law, Springer Nature makes no warranties, representations or guarantees to Users, either express or implied
with respect to the Springer nature journal content and all parties disclaim and waive any implied warranties or warranties imposed by law,
including merchantability or fitness for any particular purpose.
Please note that these rights do not automatically extend to content, data or other material published by Springer Nature that may be licensed
from third parties.
If you would like to use or distribute our Springer Nature journal content to a wider audience or on a regular basis or in any other manner not
expressly permitted by these Terms, please contact Springer Nature at
... The concept of "disarming" bacteria, rather than outright killing them, was first proposed in the 1980s. This approach has since driven extensive research in both structural biology and clinical settings, in contrast to other small molecule strategies that aim to prevent bacterial binding to urothelial cells [2,3]. ...
... This means that it differs from glucose in only one of its chiral centers, specifically the carbon atom 2. (Fig. 1) [4]. D-mannose is one of the nine monosaccharides (D-glucose, D-galactose, D-mannose, D-xylose, L-fucose, D-glucuronic acid, N-acetyl-D-glucosamine, N-acetyl-D-galactosamine, and N-acetylneuraminic acid) commonly found in animal glycans and in vertebrate glycoconjugates [2]. D-mannose, which has a physiological blood concentration less than one-fiftieth of that of glucose, is physiologically present in the human body. ...
... Within 30-60 min, a substantial portion of D-mannose is excreted unaltered in the urine, while the remaining amount is expelled over the subsequent 8 h [9]. Roughly 20-35% of the dose of excess D-mannose infiltrates the urine from the bloodstream within an hour, presenting an opportunity to engage with the mannose-sensitive structures of uropathogenic E. coli (UPEC) and mitigate their harmful effects [2]. ...
Full-text available
The nature of alpha-D-mannose-natural aldohexose sugar, C-2 glucose epimer, whose intended use is for preventing urinary tract infections-in the interaction with E. coli is addressed in order to drive the issue of its regulatory classification as a medicinal product or medical device. PRISMA systematic review approach was applied; Delphi Panel method was used to target consensus on statements retrieved from evidence. Based on regulatory definitions and research evidence, the mechanism of D-mannose does not involve a metabolic or immunological action while there is uncertainty regarding the pharmacological action. Specific interaction between the product and the bacteria within the body occurs, but its nature is inert: it does not induce a direct response activating or inhibiting body processes. Moreover, the action of D-mannose takes place, even if inside the bladder, outside the epithelium on bacteria that have not yet invaded the urothelial tissue. Therefore, its mechanism of action is not directed to host structures but to structures (bacteria) external to the host's tissues. On the basis of current regulation, the uncertainty as regard a pharmacological action of alpha-D-mannose makes possible its medical device classification: new regulations and legal judgments can add further considerations. From a pharmacological perspective, research is driven versus synthetic mannosides: no further considerations are expected on alpha-D-mannose.
... The concept of "disarming" bacteria, rather than outright killing them, was first proposed in the 1980s. This approach has since driven extensive research in both structural biology and clinical settings, in contrast to other small molecule strategies that aim to prevent bacterial binding to urothelial cells [2,3]. ...
... Within 30-60 minutes, a substantial portion of D-mannose is excreted unaltered in the urine, while the remaining amount is expelled over the subsequent 8 hours [5]. Roughly 20-35% of the dose of excess D-mannose infiltrates the urine from the bloodstream within an hour, presenting an opportunity to engage with the mannose-sensitive structures of uropathogenic E. coli (UPEC) and mitigate their harmful effects [2]. ...
... The specific effect of D-mannose is not directly connected to a specific interaction with antibodies, immunocompetent cells or other components of the human immune system but occurs in the bladder once Dmannose is excreted into the urine. There D-mannose acts creating a chemical barrier on FimH which prevents the adhesion, i.e. chemically impeding the FimH [2,40]. D-mannose has positive immunoregulatory effects on T-cells in mice with autoimmune diabetes and airway inflammation, which however are not relevant for its effects to prevent urinary tract infections [6]. ...
Full-text available
Background: the nature of alpha-D-mannose - natural aldohexose sugar, C-2 glucose epimer, whose intended use is for preventing urinary tract infections - in the interaction with E. coli is addressed in order to drive the issue of its regulatory classification as a medicinal product or medical device. Methods: PRISMA systematic review approach was applied; Delphi Panel method used to target consensus on statements retrieved from evidence. Results: Based of regulatory definitions and research evidences, the mechanism of D-mannose does not involve a metabolic or immunological action while there is an uncertainty regarding the pharmacological action. Specific interaction between the product and the bacteria within the body occurs, but its nature is inert: it does not induce a direct response activating or inhibiting body processes. Moreover, the action of D-mannose takes place, even if inside the bladder, outside the epithelium on bacteria that have not yet invaded the urothelial tissue. Therefore, its mechanism of action is not directed to host structures but to structures (bacteria) external to the host's tissues. Conclusions: From a regulatory perspective, D-mannose maintains the current medical device classification: new regulations and legal judgments can add further considerations. From a pharmacological perspective, research is driven versus synthetic mannosides: no further considerations are expected on alpha-D-mannose.
... One meta-analysis and two systematic reviews, including four randomized controlled trials and several studies, were identified [140][141][142][143][144], which concluded that D-mannose reduced rUTI significantly in subjects, both with and without catheter and prolonged UTI-free duration. However, similar to cranberries, the dose, regime, and duration lack consistency among different clinical studies [142,143]. ...
... One meta-analysis and two systematic reviews, including four randomized controlled trials and several studies, were identified [140][141][142][143][144], which concluded that D-mannose reduced rUTI significantly in subjects, both with and without catheter and prolonged UTI-free duration. However, similar to cranberries, the dose, regime, and duration lack consistency among different clinical studies [142,143]. The other limitations were small sample sizes (less than 100 patients), non-blinded studies, and self-reported rUTIs. ...
Full-text available
Urinary tract infections (UTIs) are the most frequent bacterial infections in the clinical setting. Even without underlying anatomic or functional abnormalities, more than 40% of women experience at least one UTI in their lifetime, of which 30% develop recurrent UTIs (rUTIs) within 6 months. Conventional management with antibiotics for rUTIs may eventually lead to the development of multidrug-resistant uropathogens. Targeting of the pathogenicity of rUTIs, the evolution of uropathogenic Escherichia coli (UPEC), and inadequate host defenses by immune responses should be explored to provide non-antibiotic solutions for the management of rUTIs. The adaptive evolution of UPEC has been observed in several aspects, including colonization, attachment, invasion, and intracellular replication to invade the urothelium and survive intracellularly. Focusing on the antivirulence of UPEC and modulating the immunity of susceptible persons, researchers have provided potential alternative solutions in four categories: antiadhesive treatments (i.e., cranberries and D-mannose), immunomodulation therapies, vaccines, and prophylaxis with topical estrogen therapy and probiotics (e.g., Lactobacillus species). Combination therapies targeting multiple pathogenic mechanisms are expected to be a future trend in UTI management, although some of these treatment options have not been well established in terms of their long-term efficacy. Additional clinical trials are warranted to validate the therapeutic efficacy and durability of these techniques.
... According to the previously reported findings, chondroitin sulphate may be a valuable addition to preventive strategies for recurrent UTIs. Additionally, combining chondroitin sulphate with other compounds, such as mannose and N-acetylcysteine, has been explored for their potential synergistic effects in UTI prevention [38,39]. The combination of chondroitin sulphate with other agents may therefore enhance the overall efficacy by targeting multiple steps in the pathogenesis of UTIs, including bacterial adhesion, biofilm formation, and immune modulation [40,41]. ...
Full-text available
Urinary tract infections represent a common and significant health concern worldwide. The high rate of recurrence and the increasing antibiotic resistance of uropathogens are further worsening the current scenario. Nevertheless, novel key ingredients such as D-mannose, chondroitin sulphate, hyaluronic acid, and N-acetylcysteine could represent an important alternative or adjuvant to the prevention and treatment strategies of urinary tract infections. Several studies have indeed evaluated the efficacy and the potential use of these compounds in urinary tract health. In this review, we aimed to summarize the characteristics, the role, and the application of the previously reported compounds, alone and in combination, in urinary tract health, focusing on their potential role in urinary tract infections.
... D-mannose has been shown to have antimicrobial effects against E. coli, the commonest cause of uncomplicated UTIs. It is believed that presence of D-mannose in urine prevents the attachment of E. coli to the urothelium and, thus, prevents it from causing infection [86]. General consensus emerging in the last decade is that D-mannose, alone or in combination with other treatments, may be useful in the treatment of UTI/cystitis symptoms [87,88]. ...
Full-text available
An increasing amount of evidence implies that native microbiota is a constituent part of a healthy urinary tract (UT), making it an ecosystem on its own. What is still not clear is whether the origin of the urinary microbial community is the indirect consequence of the more abundant gut microbiota or a more distinct separation exists between these two systems. Another area of uncertainty is the existence of a link between the shifts in UT microbial composition and both the onset and persistence of cystitis symptoms. Cystitis is one of the most common reasons for 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 the majority of cystitis cases is a single pathogen overgrowth or a systemic disorder affecting the entire urinary microbiota. There is an increasing trend in studies monitoring changes and dynamics of UT microbiota, but this field of research is still in its infancy. Using NGS and bioinformatics, it is possible to obtain microbiota taxonomic profiles directly from urine samples, which can provide a window into microbial diversity (or the lack of) underlying each patient’s cystitis symptoms. However, while microbiota refers to the living collection of microorganisms, an interchangeably used term microbiome referring to the genetic material of the microbiota is more often used in conjunction with sequencing data. It is this vast amount of sequences, which are truly “Big Data”, that allow us to create models that describe interactions between different species contributing to an UT ecosystem, when coupled with machine-learning techniques. Although in a simplified predator—prey form these multi-species interaction models have the potential to further validate or disprove current beliefs; whether it is the presence or the absence of particular key players in a UT microbial ecosystem, the exact cause or consequence of the otherwise unknown etiology in the majority of cystitis cases. These insights might prove to be vital in our ongoing struggle against pathogen resistance and offer us new and promising clinical markers.
Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant cancer with limited treatment options. Mannose, a common monosaccharide taken up by cells through the same transporters as glucose, has been shown to induce growth retardation and enhance cell death in response to chemotherapy in several cancers, including PDAC. However, the molecular targets and mechanisms underlying mannose’s action against PDAC are not well understood. In this study, we used an integrative approach of network pharmacology, bioinformatics analysis, and experimental verification to investigate the pharmacological targets and mechanisms of mannose against PDAC. Our results showed that the protein Src is a key target of mannose in PDAC. Additionally, computational analysis revealed that mannose is a highly soluble compound that meets Lipinski’s rule of five and that the expression of its target molecules is correlated with survival rates and prognosis in PDAC patients. Finally, we validated our findings through in vitro and in vivo experiments. In conclusion, our study provides evidence that mannose plays a critical role in inhibiting PDAC growth by targeting Src, suggesting that it may be a promising therapeutic candidate for PDAC.
A Infecção do Trato Urinário (ITU) é uma das infecções mais prevalentes no mundo, sendo mais frequente em mulheres devido à anatomia peculiar do trato urinário inferior feminino. Estima-se que cerca de 50% a 60% das mulheres terão pelo menos um episódio de ITU ao longo da vida, sendo que a recorrência pode chegar a metade dos casos. Nesse sentido, a ITU recorrente (ITUr) é definida como 3 ou mais episódios de infecção sintomática em 12 meses, ou 2 ou mais episódios em 06 meses, afetando de 30 a 40% das mulheres. A pós-menopausa predispõe as mulheres a maiores riscos no desenvolvimento de ITUr, pois o hipoestrogenismo causa alterações no epitélio urogenital e no microbioma urogenital. O diagnóstico da ITU é baseado em evidências clínicas e laboratoriais; exames como a microscopia e cultura de urina ainda são considerados o “padrão ouro”, mas não são 100% precisos. Outrossim, diferentes organizações médicas internacionais discordam sobre a necessidade de se realizar a urocultura a cada novo episódio de ITUr. Além disso, o manejo do paciente com esta afecção inclui tratamentos curtos com antibióticos, tratamentos com D-manose para prevenção e antibioticoprofilaxia. A D-manose é um açúcar monossacarídeo que impede a aderência da bactéria à mucosa da bexiga e pode prevenir a ITUr. Estas medidas são necessárias para prevenir e tratar a doença, uma infecção comum que afeta grande parte das mulheres no mundo.
Mannose 2-epimerase (ME), a member of the acylglucosamine 2-epimerase (AGE) superfamily that catalyzes epimerization of D-mannose and D-glucose, has recently been characterized to have potential for D-mannose production. However, the substrate-recognition and catalytic mechanism of ME remains unknown. In this study, structures of Runella slithyformis ME ( Rs ME) and its D254A mutant [ Rs ME(D254A)] were determined in their apo forms and as intermediate-analog complexes [ Rs ME–D-glucitol and Rs ME(D254A)–D-glucitol]. Rs ME possesses the (α/α) 6 -barrel of the AGE superfamily members but has a unique pocket-covering long loop (loop α7–α8 ). The Rs ME–D-glucitol structure showed that loop α7–α8 moves towards D-glucitol and closes the active pocket. Trp251 and Asp254 in loop α7–α8 are only conserved in MEs and interact with D-glucitol. Kinetic analyses of the mutants confirmed the importance of these residues for Rs ME activity. Moreover, the structures of Rs ME(D254A) and Rs ME(D254A)–D-glucitol revealed that Asp254 is vital for binding the ligand in a correct conformation and for active-pocket closure. Docking calculations and structural comparison with other 2-epimerases show that the longer loop α7–α8 in Rs ME causes steric hindrance upon binding to disaccharides. A detailed substrate-recognition and catalytic mechanism for monosaccharide-specific epimerization in Rs ME has been proposed.
Urinary tract infections (UTIs) are amongst the most common microbial infections worldwide, with ∼11% of the world's population. Several plants parts are used in traditional healing systems to treat UTIs, yet the therapeutic potential of these plants against bacteria that cause UTI remains poorly explored. Approximately, 153 plant species identified and uses to treat UTIs. Several studies described toxic, carcinogenic, and mutagenic properties for extracts prepared from plants conventionally used as medicines.
Full-text available
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.
Full-text available
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.
Full-text available
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.
Full-text available
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.
Full-text available
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.
Full-text available
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.
Full-text available
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.
Full-text available
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.
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.
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.