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Ala‑Jaakkolaetal. Nutrition Journal (2022) 21:18
https://doi.org/10.1186/s12937‑022‑00769‑x
REVIEW
Role ofD‑mannose inurinary tract infections
– anarrative review
Reeta Ala‑Jaakkola, Arja Laitila, Arthur C. Ouwehand* and Liisa Lehtoranta
Abstract
Urinary tract infections (UTIs) are one of the most prevalent bacterial diseases worldwide. Despite the efficacy of anti‑
biotics targeted against UTI, the recurrence rates remain significant among the patients. Furthermore, the develop‑
ment of antibiotic resistance is a major concern and creates a demand for alternative treatment options. D‑mannose,
a monosaccharide naturally found in fruits, is commonly marketed as a dietary supplement for reducing the risk for
UTIs. Research suggests that supplemented D‑mannose could be a promising alternative or complementary remedy
especially as a prophylaxis for recurrent UTIs. When excreted in urine, D‑mannose potentially inhibits Escherichia coli,
the main causative organism of UTIs, from attaching to urothelium and causing infection. In this review, we provide
an overview of UTIs, E. coli pathogenesis and D‑mannose and outline the existing clinical evidence of D‑mannose in
reducing the risk of UTI and its recurrence. Furthermore, we discuss the potential effect mechanisms of D‑mannose
against uropathogenic E.coli.
Keywords: D‑mannose, UTI, Urinary tract infection, Escherichia coli
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Introduction
Urinary tract infections (UTIs) are among the lead-
ing infectious diseases globally. UTIs are highly preva-
lent in women, especially after menopause. Despite the
short-term impact of antibiotics on acute UTIs, a long-
term risk of recurrence still exists. Furthermore, anti-
biotic resistance of UTI pathogens to many commonly
used antimicrobial drugs is alarmingly increasing. For
instance, 90% of the UTI causing Escherichia coli strains
in patients treated with trimethoprim-sulfamethoxazole
for a month were resistant to the antibiotic, whereas in
the control group, subject to cranberry juice, the inci-
dence was 28% [1]. E. coli is the causative organism in
85% of UTI cases. e adhesion of E. coli in the urinary
tract is mainly based on mannose-sensitive mechanism,
where E.coli type I pili adhere to mannose structures on
the uroepithelial cell surfaces [2, 3].
D-mannose is a monosaccharide, naturally found in
various plants, and fruits/berries, for instance in cranber-
ries. It is also known to be synthesized in the body from
glucose for the synthesis of glycoproteins [4]. D-mannose
is commonly marketed as a dietary supplement for uri-
nary tract health. Research suggests that free D-mannose
in urine has the potential to saturate E. coli FimH struc-
tures, and subsequently block E. coli adhesion to urinary
tract epithelial cells. is so-called competitive inhibition
is considered as one of the potential mechanisms for pre-
venting UTI development [5].
e aim of this review was to examine the current
evidence on the role of D-mannose against UTI. Earlier
reviews have focused on various aspects of this topic.
Here, we integrate these parts into one comprehen-
sive narrative; presenting an overview of UTIs, urethral
microbiota, current treatments and E. coli pathogenesis
followed by D-mannose and its potential effect mecha-
nisms against uropathogenic E. coli (UPEC). Finally, we
review existing preclinical and clinical studies which have
investigated D-mannose in UTIs.
Open Access
*Correspondence: arthur.ouwehand@iff.com
Health & Biosciences, International Flavors & Fragrances, Sokeritehtaantie
20, FIN‑02460 Kantvik, Finland
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Ala‑Jaakkolaetal. Nutrition Journal (2022) 21:18
Overview ofUTI
Prevalence
A WHO report from 2017 listed E. coli as the main spe-
cies responsible for community- and hospital- acquired
UTIs [6]. e WHO has recognized the matter as a high
community and health-care burden. More than 150
million people are affected by UTIs annually [7, 8]. It
is considered as one of the most common infections in
communities as well as within healthcare settings. e
prevalence of UTIs are especially high among women. An
estimated 11% of women over the age of 18 suffer from
UTI annually [9]. Approximately 50% of all women will
have at least one UTI episode during their lifetime [10].
Women are at risk for UTI due to a short urethra located
close to the rectum, which allows easier access for bac-
teria to the urinary tract as compared to men. Changes
in the sexual activity, pregnancy, and menopausal status
have a high impact on the risk for UTI occurrence since
all of them affect the urogenital bacterial composition.
Higher prevalence to UTI is also seen among specific
populations such as people with structural changes (e.g.
prostate enlargement) and diabetics (up to 35% of the
patients) [11–13]. 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 andetiology
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 andUTI
Advancements in molecular techniques have increased
the understanding of the microbial community in the uri-
nary tract, which has been previously regarded as sterile
[18]. Overall, in contrast to the gut, urine contains very
few microbes and is dominated by one or two species
(also called as urotypes) [18, 19]. Research implies that
the urinary microbiota is gender specific, likely due to
anatomical and hormonal differences [20, 21]. As women
are more at risk of UTI, we mainly focus on providing an
overview of the urinary microbiota of women and asso-
ciation with UTI.
e most common bacteria in the urinary microbiota of
healthy women are the same species of Lactobacillus that
exists in the vagina [18, 22]. Other predominating species
are from the genera Gardnerella, Streptococcus, Staphy-
lococcus, Corynebacterium, and Escherichia. Research
suggests that urotype changes with age and for instance
a Lactobacillus- or Gardnerella-dominated urotype is in
some cases reported to be more common in pre-meno-
pausal women, whereas the Escherichia-dominated uro-
type and more diverse microbiota seem to predominate
in postmenopausal women [18, 23].
Urinary microbiota is associated with rUTIs [24]. Espe-
cially changes resulting in the loss of normally protective
Lactobacillus spp. seem to increase the risk of UTI. e
vaginal tract is suggested to play a role in UTI pathogen-
esis by serving as a potential reservoir for uropathogenic
bacteria ascending from the gastrointestinal tract. Stud-
ies show that women with rUTI have lower abundance of
lactobacilli and are more commonly colonized with vagi-
nal E. coli [24, 25]. Indigenous vaginal lactobacilli pro-
duce H2O2 and lactic acid which contributes to lowering
vaginal pH which thus inhibits the growth of pathogenic
bacteria, such as E. coli, and may ultimately reduce the
risk of such organisms colonizing the urinary tract.
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Ala‑Jaakkolaetal. Nutrition Journal (2022) 21:18
Pathogenesis
e pathogenicity of UTI associated bacteria is based on
their ability to attach, colonize, and survive in the urinary
tract environment. UPEC strains, the most common path-
ogens for UTI, mainly enter the urogenital tract from the
gut via fecal–perineal–urethral route [26]. UPEC strains
possess several virulence factors, such as adhesins, tox-
ins, iron acquisition factors, lipopolysacharide and cap-
sules, that contribute to UTI pathogenesis. One of the
main disease-causing mechanisms for UPEC is based on
its adherence to mannosylated protein components called
uroplakins on the bladder epithelium (Fig.1) [2, 3]. is
binding occurs via the FimH tip of the type I pili adhesin
of E. coli. e attachment activates signal cascades causing
actin rearrangement, which ultimately leads to an inter-
nalization of the bacteria into the umbrella cells of the epi-
thelium [7]. e vesicular UPECs can be recognized by the
innate immune system within the cells and exported via
exocytosis back to the bladder where they are exposed to
neutrophils and destroyed. However, UPEC strains employ
several strategies to evade the host immune system, which
facilitates formation of intracellular bacterial communities
(IBCs); this enables bacteria to multiply, mature and infect
other cells [27, 28]. Furthermore, this can potentially lead
to more severe infection or risk for recurrence as the path-
ogen might remain hidden inside the uroepithelial cells.
Treatment
UTIs are commonly treated with antibiotics but due
to increasing development of multidrug resistant
strains, there is a need for alternative and comple-
mentary remedies [29–31]. The most commonly pre-
scribed antibiotics are sulfonamides, trimethoprim,
fluoroquinolones, fosfomycin, and beta-lactams, but
resistance to these drugs varies between 15 and 50%
in Europe, limiting their use for severe infections [32].
The use of some antibiotics, such as amoxicillin, has
been restricted for UTI owing to the development
of antibiotic resistance [17]. An international study
on antibiotic susceptibility patterns performed in 17
European countries including 4734 women with acute
uncomplicated UTI showed that 42% of the E. coli
associated UTIs were resistant to one or more antibi-
otics. From the 12 used antimicrobials, the resistance
was the highest for ampicillin (29.8%) and sulfameth-
oxazole (29.1%). Antibiotic resistance was relatively
common also to trimethoprim (14.8%), trimethoprim/
sulfamethoxazole (14.1%) and nalidixic acid (5.4%).
Regional differences existed as in Spain and Portugal,
antibiotic resistance was higher compared with the
Nordic countries and Austria [33]. Another study per-
formed in the US/Canada involving 40 clinical centers
showed that E. coli resistance to ampicillin was 37.7,
21.3% to trimethoprim/sulfamethoxazole, 5.5% to
ciprofloxacin, 5.1% to levofloxacin and 1.1% to nitro-
furantoin [34]. Antibiotic resistance of UPEC has also
been shown to be a prominent threat in Asia-Pacific
regions [35, 36].
e family of Enterobacteriaceae (incl. E. coli) has
acquired plasmids containing genes for extended-spectrum
Fig. 1 Schematic representation of E. coli attachment by FimH tips of the type 1 pili adhesins to mannosylated uroplakins on the surface of
uroepithelium
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Page 4 of 16
Ala‑Jaakkolaetal. Nutrition Journal (2022) 21:18
of β-lactamases (ESBL). β-lactamases cleave the
amide bonds of β-lactams, thus the ability to produce
β-lactamases compromises the antibiotic treatments mak-
ing β-lactams ineffective in both uncomplicated and com-
plicated UTIs [37, 38]. Research shows that UPEC strains
isolated from the elderly who suffer from rUTIs, are cell-
wall deficient i.e. providing to these strains resistance to
antibiotics targeting the bacterial cell walls [39]. e WHO
has listed Enterobacteriaceae as one of the pathogen groups
that should be prioritized for research owing to its resist-
ance patterns specifically to the third generation cephalo-
sporin (β-lactam) that affects UTI treatments [6].
In addition to the development of multi-resistant
strains the use of antibiotics for UTI has other disadvan-
tages. For instance, in 25–35% of the cases rUTI occurred
within 6 months of the first antibiotic treatment [40,
41] and in 44% of the cases within 12 months [10, 42].
Furthermore, repetitive use of antibiotics disturbs the
indigenous microbiota especially in the gastrointestinal
tract and vagina, and their use is often associated with
unpleasant side effects such as nausea, vomiting, diar-
rhea, headaches, and skin rash. us, a search for alterna-
tive approaches to be used especially as a prophylactic in
rUTIs is necessitated. Among the most commonly pro-
posed natural alternatives is the daily intake of cranber-
ries and/or D-mannose [31].
D‑mannose
The interest towards D-mannose and UTIs dates back
to the 1970s [43, 44]. The emergence of antibiotic
resistance related to uropathogens, especially UPEC,
has maintained this interest. D-mannose is marketed
globally as a dietary supplement and it is mainly tar-
geted for supporting urinary tract health either as
a standalone product or combined with cranberry
extract or probiotics.
D-mannose (C6H12O6) (mannose) is one of the nine
monosaccharides (D-glucose, D-galactose, D-mannose,
D-xylose, L-fucose, D-glucuronic acid, N-acetyl-D-glu-
cosamine, N-acetyl-D-galactosamine, and N-acetylneu-
raminic acid) commonly found in animal glycans and
abundant in vertebrate glycoconjugates.
In the human body, D-mannose is primarily syn-
thesized from glucose or is derived from the break-
down of endogenous glycoconjugates. Catabolism
of D-mannose occurs via glycolysis after which it is
used for energy or incorporated into glycans [45, 46].
D-mannose contributes to the glycoprotein synthe-
sis, more specifically to the glycosylation of certain
proteins (post-translational modifications). Many cell
types have mannose-specific receptors, hence, stable
blood mannose levels are important for facilitating effi-
cient/constant mannose uptake to different cells [47].
Physiological blood D-mannose level varies between 50
to 100 μM [4].
Fruits such as oranges, apples and peaches contain free
D-mannose in relatively small amounts. Furthermore,
mannose can be found in the form of galactomannans
(undigestible plant polysaccharides) in coffee beans, fen-
ugreek and guar gums [48]. However, the bioavailability
of mannose for glycan synthesis in these dietary sources
is poor, and likely only partially improved by anaerobic
bacteria in the colon [49]. erefore, dietary mannose is
not considered as a significant source of D-mannose for
humans. Neverthless, undigestable plant polysaccha-
rides in the colon could lead to other health benefits, for
instance via short chain fatty acid production [49], a topic
not in the scope of this review. Also yeast cell walls con-
sist of mannans that are undigestible [50]. Further, ani-
mal-derived mannose would require specific transport
mechanisms. Interestingly, in an animal model of obesity,
addition of D-mannose to the diet (at 2%) reduced weight
gain, adiposity and liver steatosis and glucose sensitivity.
It also led to a change in fecal microbiota with increases
in putative beneficial microbes such as Faecalibaculum
and Akkermansia [51]. D-mannose is absorbed into the
bloodstream from the gastrointestinal tract after inges-
tion, the absorption rate being 10% of that of glucose. It
is absorbed mainly by passive diffusion across the intes-
tinal barrier, but also active transport molecules have
been identified [52]. D-mannose can be administered in
dietary supplements in biologically usable forms. Studies
indicate that a dose level of 0.2 g/kg of body weight seems
to be the upper limit for daily consumption of mannose
for a long-term use, as higher doses may cause gastro-
intestinal disturbances (diarrhea, bloating) [4]. Dietary
ingestion increases the blood D-mannose levels 3 to
10-fold from the normal levels in a dose dependent man-
ner [4]. e peak values are reached approximately 60 to
90 min after oral ingestion and return to normal physi-
ological levels after 6 to 8 h the half time being approxi-
mately 4 h [4, 53, 54]. A rat study by Alton etal. [47]
showed that mannose is relatively fast absorbed (within
an hour) from the intestine to the blood, the half time
in blood being half an hour. Furthermore, less than 1%
of the labeled mannose remained in the intestine, feces
and urine after 4–8 h of the gavage, demonstrating the
efficacy of mannose uptake from the intestine. Despite
the relatively fast increase of D-mannose concentra-
tions in the blood, D-mannose is not fully metabolized in
humans. Excess D-mannose (20–35% of the dose) enters
urine from the blood circulation within 60 min [45, 46],
where it has the potential to interact with mannose-sen-
sitive structures of UPEC and further lowering patho-
genic effect of the bacterium. e low renal threshold
for mannose (and high for glucose) was demonstrated
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Ala‑Jaakkolaetal. Nutrition Journal (2022) 21:18
already by Harding etal. [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. Figure2 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 [57–60].
e structural analysis by Hung etal. [59] revealed that
FimH can envelope mannose molecules in a deep pocket
where primarily hydrogen bonds are affecting the com-
plex. Bouckaert etal. [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 etal., [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 etal. [64] demonstrated that orally supple-
mented FimH antagonist reduced CFU counts of UPEC
in the urine by 2 folds and in the bladder of the animals
by 4 -fold. Cusumano et al. [63] showed in a murine
model of chronic cystitis that orally given active FimH
antagonists reduced UPEC colonization in the urethra
after 6 h when compared with the control group (phos-
phate buffered saline). UPEC concentration in the mice
treated with antibiotics seemed to be higher than in the
mice subject to FimH antagonist. is finding potentially
indicates shorter and more effective UTI treatment time
by FimH antagonist than with trimethoprim-sulfameth-
oxazole, an antibiotic. Furthermore, the study showed
that IBC formation in the uroepithelium was prevented,
supporting the prophylactic potential of the studied man-
noside. Although, most of the research has focused on E.
coli and type 1 pili, it is worthwhile to note that type 1
pili are also found on other bacteria in the Enterobacte-
riaceae family, such as K. pneumoniae. Indeed, in vitro
D-mannose has shown potential to inhibit adhesion of a
clinical isolate of K. pneumoniae [65].
us far, immunological effects of D-mannose in the
context of UTI are largely unknown. However, a study
by Zhang and coworkers [66] suggested that D-mannose
Fig. 2 D‑mannose, from supplementation to urine. Roughly one third of supplemented D‑mannose ends up into urine where it has the potential
to block pathogenic Escherichia coli from adhering to uroepithelial cells. Some of the D‑mannose can be detected in the feces and some is utilized
within the target tissues
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Ala‑Jaakkolaetal. 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
invitro 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 ofD‑mannose inUTI
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 andWeb 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 Tables1, 2 and 3.
Acute andlong‑term eects ofD‑mannose inUTI
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 (Table1).
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 etal. [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 (Table2). 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 etal. [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 etal. [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 detectable1 month after starting the
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Ala‑Jaakkolaetal. Nutrition Journal (2022) 21:18
Table 1 Clinical trials in acute UTI/rUTIs with treatment supplementations including D‑mannose only
UTI urinary tract infection, rUTI recurrent urinary tract infection, AE adverse event, MS multiple sclerosis
Reference Study Design Subjects and groups Supplementation Main Findings (including safety)
Domenici 2016 [67] Pilot study, randomized for long‑term
prophylactic effect 18–65 year old women with acute cystitis
and/or history of rUTIs
n = 43
Acute: 13 days; 1.5 g D‑mannose twice
daily for 3 days and then once a day for
10 days.
Long‑term: 6 months; once a day for a
week every other month
D‑mannose has potential as an effective
agent for both acute UTI and as prophylac‑
tic for rUTI in a specific population
No AEs
Kranjčec 2014 [68] Prospective, randomized, open‑label,
controlled study 18 + years old women with acute cystitis
and a history of recurrent cystitis in 3
groups:
1. (n = 103) D‑mannose
2. (n = 103) Nitrofurantoin
3. (n = 102) no prophylaxis
n = 308
Long‑term: 6 months once a day
D‑mannose: 2 g in 200 ml water Nitro‑
furantoin: 50 mg
D‑mannose may be beneficial for UTI
prevention. The decreased recurrence rate
did not differ between patients who took
Nitrofurantoin and D‑mannose
Mild AEs in 7.8% (diarrhea) of D‑mannose
group compared to 27.2% (various AEs) in
Nitrofurantoin group
Phe 2017 [69] A single‑center, open‑label, feasibility
study 46–59 year old MS patients using and not
using urinary catheters, experiencing rUTIs
n = 22
Long‑term: 16 weeks, 1.5 g D‑mannose
twice a day D‑mannose is safe and feasible supplemen‑
tation for patients having MS. For efficacy,
further studies are needed.
No AEs
Porru 2014 [70] Pilot study, randomized, cross‑over trial 22–54 years old female patients with acute
symptomatic UTI and ≥ 3rUTIs during the
preceding 12 months
n = 60
Long‑term cross‑over design:
Group 1: 1 g D‑mannose 3 times a day,
every 8 h for 2 weeks, and subsequently
1 g twice a day for 22 weeks.
Group 2: 5‑day antibiotic therapy
with trimethoprim/sulfamethoxazole
160 mg/800 mg twice a day, followed by
a single dose at bedtime for 1 week each
month in the following 23 weeks
Cross‑over point at week 24
D‑mannose was shown to be effective and
safe in preventing rUTIs in women. The
proportion of infection free women was
greater in D‑mannose group compared to
antibiotic group.
No AEs mentioned
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Ala‑Jaakkolaetal. Nutrition Journal (2022) 21:18
Table 2 Clinical trials in acute UTI/rUTIs with treatment supplementations including D‑mannose and probiotics
UTI urinary tract infection, rUTI recurrent urinary tract infection, AEs adverse events, CFU colony forming units, bid two times a day
Reference Study Design Subjects and groups Supplementation Main Findings (including safety)
Del Popolo 2018 [71] Pilot study, non‑randomized 68 women and 17 men affected by recurrent
symptomatic cystitis. Of those, 33 women and
13 men suffered from neurogenic bladder
n = 85
Acute: 5‑days bid 1000 mg of D‑mannose,
200 mg of dry willow extract (salicin) (attack
phase), followed by 7‑days bid with 700 mg of
D‑mannose plus 50 mg (109 CFU) of L. acido-
philus La‑14 (maintenance treatment).
Long term: The maintenance treatment was
repeated for 15 days every month for the next
two months.
Combination treatment was effective in acute
UTI and as prophylaxis
No significant AEs reported
Milandri 2018 [72] Single‑center, single‑arm,
uncontrolled observational
study
19–87‑year‑old female patients who under‑
went urodynamic invasive procedure
n = 100
Long‑term: After invasive surgery, 14‑days
bid 1000 mg D‑mannose, 200 mg H. sabdariffa,
and 109 CFU L. plantarum Lp‑115
Risk of bacteriuria and UTI in women could be
reduced with the studied product
No AEs
Murina 2020 [73] Single‑center Premenopausal women aged 18–50 years
with an acute UTI and a history of recurrent
uncomplicated UTIs
n = 55
After 2 days Fosfomycin (3 g once a day) the
following combination treatment: Lactoflor‑
ene Cist® including 109 CFU L. paracasei LC11,
cranberry extract and 1000 mg D‑mannose:
Group 1: once a day for 10 days/month for
90 days (n = 19)
Group 2: once a day for 90 days (n = 19)
Group 3: No treatment (n = 17)
Both treatments efficient and safe as prophy‑
laxis for rUTIs.
No AEs
Vicariotto 2014 [74] A pilot prospective study Premenopausal, nonpregnant women diag‑
nosed with acute uncomplicated cystitis
n = 33
Acute: For 30 days 2 doses a day
Long‑term: after 30 days acute phase, 1 dose
a day until day 60
Dose: 2.5 × 109L. plantarum LP01 and 1 billion
L. paracasei LPC09 and S. thermophilus ST10,
250 mg of tara gum, 500 mg of a high proan‑
thocyanidins cranberry extract and 250 mg of
D‑mannose
Significant improvement in the UTI symp‑
toms (dysuria, frequent voiding, urgency, and
suprapubic pain) in long‑term
No AEs mentioned
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Ala‑Jaakkolaetal. Nutrition Journal (2022) 21:18
Table 3 Clinical trials in acute UTI/rUTIs with treatment supplementations including D‑mannose in combination with other supplements
Reference Study Design Subjects and groups Supplementation Main Findings (including safety)
De Leo 2017 [75]
Article in Italian Multicenter, Randomized, controlled trial 40 to 50 year old women suffering from
recurrent episodes of cystitis;
n = 150
1 Kistinox® Forte sachet per day includ‑
ing cranberry (Vaccinium macrocarpon),
Noxamicina® (propolis extract) and
500 mg D‑mannose during the first
10 days of the month, for 3 months
(n = 100).
No treatment in the control group
(n = 50)
Product efficient and well‑tolerated in
treatment of acute UTI and reducing rUTI
No AEs
Efros 2010 [76] Prospective, dose‑escalation study 18 to 75 years old women with history of
recurrent UTIs (no acute infection)
n = 28 (planned)
n = 23 (actual)
− 6 per dose group
12 weeks daily dose of 15 ml, 30 ml, 45 ml,
60 ml, 75 ml or 90 ml of UTI‑STAT with
Proantinox
3875 mg Proantinox (cranberry concen‑
trate [4:1], ascorbic acid, D‑mannose,
fructo‑oligosaccharides, and bromelain)
per 30 ml
D‑mannose dose not indicated
Safe and well tolerated. Efficient in reduc‑
ing rUTI incidence and increasing quality
of life.
AES: 9 reported (nausea, heartburn, head‑
ache, dyspepsia (4), diarrhea, back pain)
Max tolerated dose set for 60 ml/day.
Genovese 2018 [77] A randomized three‑arm parallel group
intervention trial Adult Caucasian females with acute
uncomplicated cystitis history of recur‑
rent UTIs
n = 72
12 weeks with follow‑up at 24 weeks.
group A: D‑mannose 420 mg + berber‑
ine, arbutin and birch (n = 24)
group B: D‑mannose 420 mg + berber‑
ine, arbutin, birch and forskolin (n = 24)
group C: D‑mannose 500 mg + proan‑
thocyanidins (n = 24)
Plant‑based supplements reduce the
risk for UTI but no specific benefits for
D‑mannose alone
No AEs
Manno 2019 [78] Prospective comparative study Women with acute cystitis and history of
recurrent cystitis
n = 40
12 weeks including follow‑up time
Acute: Fosfomycin Tromethamine (3 g)
single dose (UROFOS®) for all partici‑
pants
Long‑term: 2 sachets for 2 weeks and
one sachet for two additional weeks as
follows:
group A: UROIAL containing S&R PACs
(250 mg) with type‑A proanthocya‑
nidins (72 mg), D‑mannose (1000 mg),
chondroitin sulfate (200 mg), vitamin C
(120 mg) and hyaluronic acid (100 mg)
(n = 20)
group B: no treatment (n = 20)
Complete remission in 37 participants after
fosfomycin. Lower UTI episodes and symp‑
toms in treatment group after 4 week’s
intervention and follow‑up time.
No AES mentioned
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Ala‑Jaakkolaetal. Nutrition Journal (2022) 21:18
Table 3 (continued)
Reference Study Design Subjects and groups Supplementation Main Findings (including safety)
Marchiori 2017 [79] Observational, retrospective study Pre‑ and postmenopausal women who
had survived breast cancer and had
recurrent cystitis
n = 60 (50 had reached menopause)
Long‑term: Group 1 ‑ antibiotic therapy
associated with NDM (n = 40) given
12 h after emptying bladder for 60 days
followed by dose 24 h after emptying
bladder for 4 months,
Group 2 ‑ antibiotics alone (n = 20)
NDM dose: D‑mannose 500 mg, N‑ace‑
tylcysteine 100 mg and Morinda citrifolia
fruit extract 200 mg (NDM)
Antibiotic options depending on
microbial sensitivity: fosfomycin ‑ 3 g per
day for two days every 15 days for three
cycles, nitrofurantoin ‑ 1cps 100 mg tid
for 6 days and ciprofloxacin ‑ 1000 RM
or prulifloxacin ‑ 600 mg 1 cps/day for
6 days
Greater efficacy in NDM combined with
antibiotic in reducing UTIs and urinary
discomfort compared to antibiotics only
No AEs related to IP usage specified
Palleschi 2017 [80] Prospective, randomized study ~ 65.4 years old male [42] and female
[38] patients eligible for urodynamic
examination.
n = 80
Acute preventive Group A: antibiotic
Prulifloxacine 400 mg/day for 5 days
(n = 40),
Group B: D‑mannose 500 mg, N‑acetyl‑
cysteine 100 mg and Morinda citrifolia
fruit extract 300 mg, twice a day for
7 days (n = 40)
D‑mannose and NAC therapy resulted
similar results to the antibiotic therapy in
preventing UTIs in patients submitted to
urodynamic examination. Considered as
usable alternative treatment
No AEs
Panchev 2012 [81]
Article in Bulgarian Multicenter, comparative, observational
study Female patients with acute uncompli‑
cated urinary bladder infections (Age not
reported)
n = 158
Acute: Group 1: Product containing
D‑mannose 1000 mg, standardized dry
birch leaf extract 50 mg, standardized
dry cranberry extract 50 mg according to
manufacturer’s instructions (n = 86)
Group 2: Ciprofloxacin 500 mg twice
daily for 3 days (n = 72)
Better effectiveness related to symptoms
and clinical outcomes with the product
compared to antibiotic was reported
No AEs
Rădulescu 2020 [82] a pilot, randomized study non‑pregnant, healthy women with
uncomplicated lower UTI
Age range 18–60 years
n = 93
First phase/Acute:
1) Antibiotic (TMP‑SMX) (n = 45) or
2) Antibiotic + D‑mannose
(1000 mg) + cranberry (400 mg) (Uro‑
Care with CranActin®)(n = 48) for 7 days
Second phase/ prophylaxis:
For cured participants either 1) D‑man‑
nose + cranberry (n = 47) or 2) placebo
(n = 46) for 21 days
Higher cure rate after acute phase in the
combined group especially in the resistant
strains. No significant differences between
the active and the placebo in the second
phase of the study
No AEs related to IP usage specified
Russo 2020 [83] A prospective, randomized, no‑placebo,
controlled study ~ 67.2 years old postmenopausal women
undergoing surgery for cystocele
n = 40
Active: cranberry, D‑mannose, Boswellia,
Curcuma and Noxamicine VR (Kistinox
ActVR) twice a day for 2 weeks starting
from surgery (n = 20)
Control: only surgery (n = 20)
Symptom relief was reported in the active
group compared to control. No differences
in UTI incidences
No AEs
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Ala‑Jaakkolaetal. Nutrition Journal (2022) 21:18
Table 3 (continued)
Reference Study Design Subjects and groups Supplementation Main Findings (including safety)
Salinas‑Casado 2018 [84]
Article in Spanish A multicenter, double‑blind, randomized,
experimental study ~ 48 years old women with non‑compli‑
cated UTI
n = 95
Long‑term:
Group 1: 2 g of D‑mannose, 140 mg of
PAC and 7.98 mg of ursolic acid together
with vitamins A, C and E, and the Zinc
trace element (Manosar®) (n = 44) once
a day for 24 weeks
Group 2: 240 mg proanthocyanidins
(n = 51) as a single dose/day
Product was reported to be more efficient
for preventing rUTI than single dose of PAC
AEs: 21.4% in Group 1 and 21.6% in Group
2
(diarrhea, headache, vaginal discomfort,
nausea rash)
Salinas‑Casado 2020 [85]
Article in Spanish A multicenter, randomized and double‑
blind experimental study ~ 49.5 years old women with a history of
recurrent UTIs
n = 184
Group1: 2 g of D‑mannose, 140 mg of
PAC and 7.98 mg of ursolic acid together
with vitamins A, C and E, and the Zinc
trace element (Manosar®) (n = 90) once
a day for 24 weeks
Group 2: 240 mg proanthocyanidins
(n = 94) as a single dose
Product was reported to be more efficient
for preventing rUTI than single dose of PAC
AEs:
16.8% of participants experienced AEs (12
in Group 1 and 19 in Group 2)
(diarrhea, headache, vaginal discomfort,
nausea rash)
UTI urinary tract infection, rUTI recurrent urinary tract infection, AEs adverse events, cps capsule, tid three times a day, IP investigational product, NDM N‑acetylcysteine D‑mannose Morinda citrifolia, PAC proanthocyanidin
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Ala‑Jaakkolaetal. 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 (Table3). 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 etal., [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 ofsupplemented D‑mannose
Despite the potential benefits of D-mannose in UTI,
some mice studies have shown that prenatal mannose
supplementation causes embryonic lethality and eye
defects among the mice who survived [86]. In this trial,
the dose ranged from 1 to 5% in the drinking water. In
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Page 13 of 16
Ala‑Jaakkolaetal. 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 [67–70],
no serious adverse events were associated with the use of
D-mannose. In addition, a systematic review and meta-
analysis by Lenger etal. [87] concluded that D-mannose
was well tolerated with minimal side effects—only a
small percentage experiencing diarrhea. e occurrence
of adverse events is likely to be dose-depended as daily
doses exceeding 0.2 g/kg of body weight may cause diar-
rhea and bloating [4]. Of note, in human diabetics, blood
glucose balance could potentially be disturbed by man-
nose supplementation [50]. is should be taken into
account when considering D-mannose supplementation
among diabetics and pregnant women.
Discussion
While antibiotics are still the mainstay for treatment of
acute UTI, their use as prophylaxis has already led to the
development of resistant bacterial strains; compromising
treatments, and accumulating challenges over time. Fur-
thermore, the antibiotic side effects can cause discomfort
and predispose patients to other infections.
It has been demonstrated in both animal and human
studies that the renal threshold for D-mannose is low
i.e. excess D-mannose is secreted into urine [45, 46,
55]. In addition, good affinity of mannose and manno-
sides to E.coli type 1 pilus structures has been shown
by several invitro experiments [57–60]. 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 (Tables1, 2 and 3). However,
only four studies were conducted with D-mannose
alone, from which 2 trials [67, 70] assessed both acute
and long-term preventive effect of D-mannose on UTI
and 2 trials [68, 69] only the preventive effect. In most
of the studies (n = 15) a combined effect of D-mannose
and other “nutraceutical(s)”, such as cranberry extract
or probiotic, was studied. In addition, there are few
studies comparing the efficacy of D-mannose supple-
mentation and antibiotics on treatment of acute UTI
or as prophylaxis. From the 19 studies reported here,
18 indicate that D-mannose supplementation, alone or
combined with other products, could be beneficial in
the management of UTI; one study [69] reported on
feasibility and not efficacy. Of these 18 studies, seven
report on treatment of acute UTI; six report on ben-
eficial effects and one [83] did not observe a difference
in UTI with the control group but did nevertheless
observe a reduction in symptoms. Further, 14 of the 18
studies reported on prophylaxis in the management of
rUTI. Of these 14 studies, 13 reported on reductions
in rUTI, one study [82] did not report a difference in
recurrence compared to the antibiotic control. us,
D-mannose may help to improve clinical/symptomatic
recovery rate from UTI - sometimes even faster than
some of the used antibiotics – and/or may especially
have potential as a prophylactic by decreasing the risk
for rUTIs. However, to date no common guidelines for
the D-mannose treatment duration, dose and combina-
tion exist. Furthermore, no health claims thus far have
been approved for the use of D-mannose in UTI in any
jurisdiction. Such claim would protect the consumer
seeking self-help and provide health-care professionals
with confidence to recommend D-mannose as an alter-
native or complementary treatment.
rUTI is a common challenge especially among women
[88]. Imbalance of the urogenital bacteria caused by
frequent intercourse (especially younger women) or
postmenopausal age are risk factors for UTI occur-
rence. Frequent infections and the use of antibiotics
lead to changes in the microbiota in the urogenital area.
Especially antibiotic use may affect the dominance of
indigenous lactobacilli, and potentially creating suitable
environment for the uropathogens to thrive. erefore,
also the use of probiotic lactobacilli to reduce the risk
of rUTIs by supporting vaginal and urinary micro-
biota has gained attention. Currently (mid-2021), four
clinical trials including both D-mannose and probiotics
(one had also cranberry) have been conducted showing
promising outcomes related UTI symptoms and reoc-
currence rates.
Of the eight studies registered in clinicaltrials.gov
(accessed 3rd February 2022) investigating the effect of
D-mannose on UTI, only one has results, but these seem
not to have been published in the scientific literature
while another study has an ‘unknown’ status. Further, one
study was terminated and the remaining five studies are
in various stages of recruitment. us, although more
results are to be expected in the future, it also highlights
the challenge of potential reporting bias. is is espe-
cially challenging when only a limited number of studies
are available as in the case of D-mannose and UTI.
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Page 14 of 16
Ala‑Jaakkolaetal. Nutrition Journal (2022) 21:18
Conclusions
In addition to female gender, sexual activity at young
age and higher age in general, specific conditions such
as diabetes, neurologic conditions, chronic institu-
tional residence, and chronic urinary catheterization
might predispose to rUTIs. erefore, individuals in
need of repetitive antibiotic treatments, going through
urogenital procedures or women with changed bacte-
rial environment in the urogenital area would ben-
efit the most from a non-antibiotic alternative. Due to
increasing antibiotic resistance among UTI pathogens,
the burden caused by UTIs is expected to increase
creating a high demand for alternative options. For
the treatment of acute UTI, antibiotics are likely to
remain the first choice. Supplementing antibiotics with
D-mannose may increase treatment success. However,
for prophylaxis in reducing rUTI, D-mannose appears
to have great potential with minimal side effects. e
overall picture of preclinical and clinical studies with
D-mannose in the management of UTI is favorable, as
discussed here and in a recent narrative review by De
Nunzio etal. [89]. D-mannose has also been shown to
be relatively safe and well-tolerated. Yet, the quality
of these studies leaves something to be desired; they
are mostly confounded with other active ingredients,
have small numbers of participants, are open label or
uncontrolled. What is first and foremost needed are
sufficiently powered, well-designed double-blinded,
randomized, and placebo-controlled clinical trials with
solely D-mannose in the active product; distinguishing
between treatment and prophylaxis. Such studies are
registered in clini caltr ials. gov; we look forward to their
results.
Acknowledgements
The authors would like to acknowledge Kati Kousa for providing expertise
on the manufacturing, commercialization, and regulation of D‑Mannose as a
dietary supplement.
Authors’ contributions
“Conceptualization, R. A‑J., A.L., A.C.O., and L.L.; methodology, R. A‑J., A.L., L.L.;
investigation, R. A‑J.; writing—original draft preparation, R.A‑J., L.L.; writing—
review and editing, R.A‑J. L.L., A.L., A.C.O. visualization, R.A‑J.; All authors have
read and agreed to the published version of the manuscript.
Funding
This research was fully funded by Danisco Sweeteners Oy (Part of International
Flavors and Fragrances).
Availability of data and materials
Not applicable.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
All authors were employed by Danisco Sweeteners Oy (Part of International
Flavors and Fragrances) at the time the study was conducted.
Received: 11 November 2021 Accepted: 4 March 2022
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