nutrients

Review
Xylitol’s Health Benefits beyond Dental Health:
A Comprehensive Review
Krista Salli, Markus J. Lehtinen, Kirsti Tiihonen and Arthur C. Ouwehand *
Global Health & Nutrition Sciences, DuPont Nutrition & Biosciences, 02460 Kantvik, Finland
* Correspondence: [email protected]; Tel.: +358-40-5956-353




Received: 24 June 2019; Accepted: 31 July 2019; Published: 6 August 2019


Abstract: Xylitol has been widely documented to have dental health benefits, such as reducing
the risk for dental caries. Here we report on other health benefits that have been investigated for
xylitol. In skin, xylitol has been reported to improve barrier function and suppress the growth of
potential skin pathogens. As a non-digestible carbohydrate, xylitol enters the colon where it is
fermented by members of the colonic microbiota; species of the genus Anaerostipes have been reported
to ferment xylitol and produce butyrate. The most common Lactobacillus and Bifidobacterium species
do not appear to be able to grow on xylitol. The non-digestible but fermentable nature of xylitol
also contributes to a constipation relieving effect and improved bone mineral density. Xylitol also
modulates the immune system, which, together with its antimicrobial activity contribute to a reduced
respiratory tract infection, sinusitis, and otitis media risk. As a low caloric sweetener, xylitol may
contribute to weight management. It has been suggested that xylitol also increases satiety, but these
results are not convincing yet. The benefit of xylitol on metabolic health, in addition to the benefit of
the mere replacement of sucrose, remains to be determined in humans. Additional health benefits
of xylitol have thus been reported and indicate further opportunities but need to be confirmed in
human studies.

Keywords: sugar alcohol; prebiotic; bowel function; immune function; respiratory tract infections;
otitis media; sinusitis; weight management; satiety; bone health

1. Introduction
Xylitol is a five-carbon sugar alcohol (C5 H12 O5 , Figure 1) with a molecular weight of 152.15 g/mol,
which is commonly used as a sweetener in sugar-free confectionery. It also naturally occurs in fruits
and vegetables (plums, strawberries, cauliflower, and pumpkin [1]). It is equisweet to sucrose and has
a very similar sweetness-time intensity to sucrose. Xylitol is the sweetest of all polyols [2]. Xylitol
is best known for its dental benefits, such as reducing the risk for dental caries [3]. This is thought
to function through three mechanisms: xylitol replaces cariogenic sucrose, xylitol may stimulate
salivation, and xylitol may have specific inhibitory effects on Streptococcus mutans—the main causative
microbe of dental caries [4]. Although a recent meta-analysis concluded that there is a need for
high-quality studies on the dental benefits of xylitol, the same study concluded nevertheless that
xylitol is an effective strategy as a self-applied caries preventive agent [3]. Furthermore, the European
Food Safety Agency has approved a health claim “xylitol chewing gum reduces the risk of caries in
children” [5]. Here, however, we want to focus on other potential health benefits of xylitol, such as
skincare, respiratory, digestive, immune health, and weight management.
Approximately half of the consumed xylitol is absorbed; the liver readily converts it to xylose by a
non-specific cytoplasmic NAD-dependent dehydrogenase. The formed xylose is phosphorylated via a
specific xylulokinase to xylulose-5-phosphate, an intermediate of the pentose-phosphate pathway before
conversion to glucose, which is only slowly released into the bloodstream or stored as glycogen [6,7].

Nutrients 2019, 11, 1813; doi:10.3390/nu11081813 www.mdpi.com/journal/nutrients

 Nutrients 2019, 11, x FOR PEER REVIEW 2 of 19

Nutrients 2019, 11, 1813 2 of 19

Nutrients 2019, 11, x FOR PEER REVIEW 2 of 19

Figure 1. Chemical structure of xylitol © DuPont Nutrition & Biosciences.

Approximately half of the consumed xylitol is absorbed; the liver readily converts it to xylose
by a non-specific cytoplasmic NAD-dependent dehydrogenase. The formed xylose is phosphorylated
via a specific xylulokinase
Figure to xylulose-5-phosphate,
1. Chemical structureofofxylitol an intermediate
xylitol ©©DuPont
DuPont Nutrition of the pentose-phosphate
& Biosciences.
Figure 1. Chemical structure Nutrition & Biosciences.
pathway before conversion to glucose, which is only slowly released into the bloodstream or stored
as glycogen
Xylitol is safe[6,7].
Approximately half of consumption
for human the consumed and xylitolin isgeneral
absorbed; wellthe liver readily
tolerated. convertsasit with
However, to xylose
all sugar
by a Xylitol is safe
non-specific for human NAD-dependent
cytoplasmic consumption anddehydrogenase.
in general well The tolerated.
formed However,
xylose is as with all sugar
phosphorylated
alcohols, overconsumption (>20 g) is associated with digestive symptoms such as bloating and loose
alcohols,
via overconsumption
a specific xylulokinase(>20 to g) is associated with digestive
xylulose-5-phosphate, symptoms of
an intermediate suchtheaspentose-phosphate
bloating and loose
stools [8]. When consumption is seized, the symptoms disappear.
stools [8].before
pathway When conversion
consumption to is seized,which
glucose, the symptoms disappear.
is only slowly released into the bloodstream or stored
as glycogen [6,7].
2. Skin
2. SkinXylitol is safe for human consumption and in general well tolerated. However, as with all sugar
alcohols,
2.1. Skin overconsumption (>20 g) is associated with digestive symptoms such as bloating and loose
Introduction
2.1. Skin
stools [8].Introduction
When consumption is seized, the symptoms disappear.
The skin actsacts
The skin as aasbarrier
a barrierbetween
between the bodyand
the body anditsits surrounding
surrounding environment.
environment. The epidermis
The epidermis is
2.
is made Skin
up of the stratum corneum (outermost layer of the skin,
made up of the stratum corneum (outermost layer of the skin, Figure 2); formed by terminally Figure 2); formed by terminally
differentiated
differentiatedepidermal
epidermal keratinocytes
keratinocytesand andlipids,
lipids, which
which play playaamain
main role
role as as a physical
a physical and and chemical
chemical
2.1. Skin Introduction
permeability barrier. Under this liesthe
thestratum
stratum granulosum,
granulosum, which forms a paracellular barrier that that
permeability barrier. Under this lies which forms a paracellular barrier
regulates
The the
skin loss
acts of
as moisture
a barrier through
between the
the skin,
body as
and shown
its in Figure
surrounding
regulates the loss of moisture through the skin, as shown in Figure 2. Below that are the stratum 2. Below
environment. that are
The the stratum
epidermis is
spinosum,
made up basal
of the cells,
stratumand melanocytes,
corneum which
(outermost are also
layer of part
theof the
skin, epidermis.
Figure
spinosum, basal cells, and melanocytes, which are also part of the epidermis. The epidermal barrier, 2); The
formedepidermal
by barrier,
terminally
which is constantly beingkeratinocytes
renewed, is characterized by its capacity
a mainto adapt
as ato changing conditions
whichdifferentiated
is constantly epidermal
being renewed, and lipids, which
is characterized by itsplay
capacity torole
adapt physical
to changing and chemical
conditions in
in the environment [9]. The dermis, the next layer, supports the epidermis and produces matrix
the environment [9]. The dermis, the next layer, supports the epidermis and produces matrix that
permeability barrier. Under this lies the stratum granulosum, which forms a paracellular barrier
proteins
proteins such as elastin and collagen, as shown in Figure 2.
regulates the loss of moisture through the skin, as shown in Figure 2. Below that are the stratum
such as elastin and collagen, as shown in Figure 2.
spinosum, basal cells, and melanocytes, which are also part of the epidermis. The epidermal barrier,
which is constantly being renewed, is characterized by its capacity to adapt to changing conditions
in the environment [9]. The dermis, the next layer, supports the epidermis and produces matrix
proteins such as elastin and collagen, as shown in Figure 2.

Figure 2. Proposed effects of xylitol on skin health. ©DuPont Nutrition & Biosciences.

2.2. Xylitol Benefits to Skin

Figure 2. Proposed effects of xylitol on skin health. © DuPont Nutrition & Biosciences.
Xylitol (100 mM) for 2 h has been observed, in an epidermal-equivalent skin model, to improve
lipid 2.2. Xylitol
fluidity in Benefits to Skin layer of the stratum granulosum. The model consisted of normal human
the uppermost
epidermal keratinocytes (NHEKs); isolated from donated skin samples; cultured ex vivo, and studied
microscopicallyFigureusing2. lipid
Proposed effectsstaining.
specific of xylitol onThe
skin improved
health. © DuPont
lipidNutrition
fluidity& accelerated
Biosciences. the release of

lipids and accelerates the exocytosis of lamellar bodies to the intercellular domain between stratum
2.2. Xylitol Benefits to Skin
granulosum and stratum corneum thereby improving the lamellar structure and accelerating epidermal
permeability barrier recovery [10]. Indeed, volunteers (n = 7) who had the inside of their forearms
mechanically irritated by repeated tape stripping, were observed to have significantly less moisture
Nutrients 2019, 11, 1813 3 of 19

loss; approximately 20%, when exposed to 100 mM xylitol for 10 min as compared to water. This was
measurable both 1.5 and 2 h after exposure [10].
Further studies with NHEKs have shown that the viability and intracellular calcium concentration
were not affected by 0.0045%–0.45% xylitol (calcium regulates keratinocyte differentiation) after 24 and
48 h as compared to the cell culture medium alone. However, xylitol up-regulated the expression
of filaggrin, loricrin, involucrin, and occludin mRNA as measured by qPCR [11]. These proteins are
involved in barrier function and tight junction (TJ) formation in the skin; occludin is the major protein
in TJs, filaggrin or filament aggregating protein is a filament associated protein that binds keratin fibers
in epithelial cells, loricrin is the major protein in cornified cells and contributes to barrier function of
the skin, involucrin is bound to loricrin [12]. Moreover, 0.45% xylitol stimulated the mitogen-activated
protein kinase (MAPK) pathway in the NHEKs and induced the activation-dependent translocation
of protein kinase Cδ, after 48h as determined by Western blotting, a key promoter of epidermal
differentiation [11]. The effect on the other cell types in the epidermis was not investigated in this
model. Twelve healthy volunteers with dry skin received topical exposure to a combination of 5%
glycerol and 5% xylitol for 14 days. This was observed to be associated with increased hydration,
reduced moisture loss and increased dermal and epidermal thickness, as measured from biopsies and
histological staining, compared to the untreated control arm of the same volunteer. In agreement with
the above-described ex vivo keratinocyte studies, increased expression of filaggrin in epidermal cells in
biopsies taken from the volunteers was also observed [13]. The separate contribution of xylitol and
glycerol in the observed effects cannot be determined from this study.
In a study with hairless mice (23/group), skin irritation induced by 3 h topical application of 5%
sodium dodecyl sulfate (SDS) was reduced with concomitant exposure to 8.26% xylitol or 5% glycerol
(same osmolarity); transepidermal water loss was reduced and in the irritated area blood flow was
reduced as well, as determined by videomicroscopy. Histological staining indicated that the epidermal
thickness was increased in response to xylitol treatment compared to SDS alone [14]. Also in healthy
adult volunteers (n = 16), the transepidermal water loss induced by experimental irritation with 0.1%
SDS could be inhibited by simultaneous exposure for 24 h to 4.5% or 15% xylitol and 2.6% or 9.0%
glycerol, but not 5.4% or 18% mannitol (same osmolarity) as compared to another site on the same arm
with 0.1% SDS alone for 24 h [15]. These results suggest a polyol-specific response.
In a study with male rats, the inclusion of 10% xylitol to basic chow for 20 months was observed
to be associated with a thicker skin and more acid-soluble collagen was observed, as determined from
biopsies. Also, less collagen fluorescence was observed, which is a marker for collagen glycosylation
and aging [16]. However, no difference in collagenase soluble and insoluble collagen was observed nor
more total collagen as compared to control animals fed the same chow without xylitol [17]. Three months
dietary supplementation with 10% xylitol in basic chow has been reported to increase the amounts of
acid-soluble and total collagen (expressed as hydroxyproline) in the skin of streptozotocin-induced
type 1 diabetic male rats (10 animals/group) as compared to type 1 diabetic animals fed unsupplemented
chow. Also here, reduced hexose concentrations of acid-soluble collagen and reduce fluorescence of
the collagenase-soluble fraction; indicating reduced glycosylation were observed. Similar observations
on increased were made for non-diabetic rats (10 animals/group) after three months on 10% xylitol
supplemented chow as compared to non-diabetic rats fed unsupplemented chow; for acid-soluble
and total collagen, as well as reduced hexose concentrations of acid-soluble collagen and reduced
fluorescence of the collagenase-soluble fraction in the skin [18].
The selective antimicrobial activity of xylitol, observed in dental health, has also been applied
to wound care. In vitro studies with a Lubbock Chronic Wound Biofilm model have shown that
the application of 2%, 10%, and 20% xylitol in water reduced growth Pseudomonas aeruginosa,
Staphylococcus aureus, and Enterococcus faecalis compared to the water control. The highest concentration
was observed to completely abolish biofilm formation [19]. Furthermore, another in vitro study
showed that the combination of 5% xylitol and 2% lactoferrin could reduce the biofilm formation of
P. aeruginosa and methicillin-resistant S. aureus after 72 h in a colony drip flow reactor, as compared to
Nutrients 2019, 11, 1813 4 of 19

base wound dressing alone [20]. The anti-S. aureus potential of xylitol has also been investigated in
human volunteers. Seventeen volunteers with atopic dermatitis received skin lotion with or without a
combination of 5% xylitol and 0.2% farnesol on either arm for seven days. Compared to the control
arm treated with unsupplemented lotion, S. aureus was significantly reduced, and skin moisture
increased [21]. The contribution of xylitol alone cannot be deduced from this study. A further potential
benefit of xylitol in wound care is the negative dissolution energy [2] which gives a cooling effect to
the tissue.

2.3. Conclusions
Topical exposure of the skin with xylitol has thus been shown to reduce skin moisture loss.
The mechanism appears to relate to increased tight junction and barrier formation in the skin. Also,
dietary exposure to xylitol has been found to improve skin thickness. The antimicrobial activity
against skin pathogens has been documented mainly in combination with other compounds and the
contribution of xylitol to the observed effects needs to be determined. Furthermore, many of these
results have been obtained in vitro and in animal models at relatively high doses (10% of the diet); their
applicability to humans thus still needs to confirmed.

3. Digestive Tract

3.1. Introduction
The digestive tract can be largely divided into the stomach, small intestine, and large intestine
(colon). Much of the digestion and nutrient absorption takes place in the stomach and small intestine.
Although the upper digestive tract harbors a microbiota [22], it is especially the colon that is host
to a diverse and extensive microbiota [23]. This colonic microbiota ferments non-digested dietary
components, mainly fiber, and other components that have escaped digestion as well as sloughed-off
cells and secretions. The colon absorbs the fermentation products together with water from the digesta;
in particular short-chain fatty acids are an important additional energy source.
Xylitol is not digested by human enzymes and approximately 50% of the consumed xylitol is
absorbed through passive diffusion in the small intestine [6]. The remaining 50% of the dietary xylitol
thus enters the colon where it can serve as an energy and carbon source for the intestinal microbiota
and leads to the formation of short-chain fatty acids which provide energy to the host and support
immune system homeostasis [24]. These properties of xylitol are very similar to what is expected from a
prebiotic; a substrate that is selectively utilized by host microorganisms conferring a health benefit [25].
The increased concentration of xylitol in the digesta leads to an increased osmotic pressure which
contributes to water retention in the digesta and thus may lead to laxative effects when consumed in
excess (>20 g) [8,24]. However, this property of xylitol can also be used to address constipation; which
is in line with the prebiotic nature of xylitol.

3.2. Prebiotic Benefits of Xylitol

Simulations of fermentation by the colonic microbiota in vitro have shown that exposure
of this microbiota to xylitol leads to a rapid disappearance of the xylitol, as determined by
enzymatic colorimetry, indicating that it is readily fermented by the simulated intestinal microbiota.
Gas chromatographic analysis of the simulated colonic digesta showed an increased formation of
butyric acid compared to the non-supplemented control simulations [26]. Strains from the genus
Anaerostipes have been observed by 16S rRNA denaturing gradient gel electrophoresis (DGGE) analyses
to be associated with the increased production of butyric acid in fecal cultures [27]. Production of
butyric acid is considered beneficial for colonic health as it is the preferred energy source for colonocytes
and is thought to be associated with a reduced risk for colorectal cancer [28]. Furthermore, butyric
acid promotes the generation of regulatory T-cells that promote immune system balance [29]. In rats
(at least 5 animals/group), early fecal microscopy studies indicated that 20% of dietary xylitol caused a
Nutrients 2019, 11, 1813 5 of 19

shift from fecal Gram-negative to Gram-positive bacteria after six weeks compared to animals fed an
unsupplemented diet; the magnitude of this change was, however, not reported. Similar observations
were made in humans; six volunteers, after an overnight fast, consumed in a cross-over design
randomly a single 30 g dose of xylitol or a single 30 g dose of glucose (control) in 200 mL water. Fecal
microscopy indicated an increase in Gram-positive bacteria from 20%–30% to 50%–55% for glucose and
xylitol, respectively, and a concomitant decrease in Gram-negative bacteria was observed. Furthermore,
a reduction in the fecal level of yeasts was reported, from Log10 9.2–9.4 colony forming units (CFU)/g
feces during the control phase to Log10 7.2–7.5 CFU/g feces after xylitol consumption [30]. The type of
yeast that was reduced was not reported, but in vitro studies have reported that xylitol can suppress
the growth of Candida with a minimal inhibitory concentration of 200 mg/mL and a 99.95% reduction
in colony-forming units at 400 mg/mL [31]. Recent mouse studies (5 animals/group) have reported
that consumption of xylitol (40 or 194 mg/kg body weight/day) for 15 weeks was associated with an
increase in the genus Prevotella, the phyla Eubacteria and Firmicutes and a reduction in the phylum
Bacteroidetes by DGGE analysis [32]. Others have made similar observations, terminal restriction
fragment length polymorphism (TRFLP) analysis indicated reduced levels of Bacteroides and Clostridium
cluster XIVa and increased levels of Prevotella in mice (7 animals/group) fed 5% xylitol for 28 days as
compared to animals fed unsupplemented chow [33]. In studies with cyclophosphamide-immune
suppressed mice, 5%–10% xylitol (12 animals) was observed to lead to significantly lower fecal counts
of Candida albicans (7.58 vs. 5.22 Log10 CFU/g, control and xylitol respectively) and significantly less
and fewer cases of C. albicans invasion of the gastric wall as compared to animals not fed xylitol
(10 animals); 80% vs. 10% of animals, control and xylitol respectively [34]. Furthermore, urinary HPLC
analysis indicated an increased metabolism of daidzein to equol when mouse diet (7 animals/group)
was supplemented with 0.05% daidzein (control) or 0.05% daidzein and 5% xylitol for 28 days [33];
this may contribute improved bone health.
These observations are in agreement with the definition of prebiotics [25]; furthermore, xylitol
is utilized only by a limited number of organisms and changes the metabolism of the microbiota;
as expected for a prebiotic, Table 1. As Table 1 also clearly shows, commercial probiotics have been
shown to be unable to grow on xylitol as sole carbon and energy source.

Table 1. Non-exhaustive list of organisms that are able to grow or not to grow in the presence of xylitol,
or that have the capacity to metabolize xylitol in vitro or not.

Organisms Reported to Organisms Reported Not to

Reference Reference
Grow on Xylitol Grow on Xylitol
Lactobacillus plantarum 299v, L. plantarum 931,
Anaerostipes hadrus
[27] L. rhamnosus GG, L. rhamnosus LB21, L. paracasei F19, [35]
(strain dependent), A. caccae
L. reuteri PTA5289
Bifidobacterium lactis 1100, B. lactis Bb-12, B. longum
913, B. lactis 420, L. acidophilus NCFM, L. casei 921,
L. casei Shirota, L. bulgaricus 365, L. johnsonii LA1,
[36]
L. paracasei F19, L. plantarum 299v, L. reuteri SD2112,
L. rhamnosus GG, L. rhamnosus, Lc-705,
Streptococcus mutans Ingbritt
L. plantarum 299v, L. reuteri DSM17938 [37]
Coprococcus catus, Eubacterium halli, E. limosum,
E. rectale, Faecalibacterium prausnitzii,
[27]
Megasphera elsedenii, Ruminococcus faecis, R. hominis,
R. intestinalis, R. inulinivoruans
S. pneumoniae
S. mutans, S. salivarius, S. sanguis
Candida albicans, S. mutans [38]
Staphylococcus epidermidis, Staphylococcus aureus,
Pseudomonas aeruginosa
Nutrients 2019, 11, 1813 6 of 19

Even though organisms may not be able to metabolize and grow on xylitol, there may still be
an opportunity for synergy with xylitol and probiotic bacteria, as was shown with the combination
of Lactobacillus plantarum Inducia in combination with 5% xylitol which was reported to completely
stop spore germination of Clostridioides (formerly Clostridium) difficile, in vitro after 48 h. In addition,
prefeeding with a single dose of 0.2 g xylitol improved the survival of hamsters in a C. difficile
challenge model (5 out of 9 survived in the xylitol test against 2 out of 15 in the unsupplemented
group). Fecal colonization with C. difficile quantified by real-time PCR was lower in the xylitol group,
3.5 vs. 4.9 Log10 gene copy number/g in the control group. Real-time PCR Lactobacillus fecal counts,
however, were highest in the xylitol group, 6.6 vs. 4.6 Log10 gene copy number/g in the control group [39].

3.3. Benefits of Xylitol on Bowel Function

Similar as other prebiotics [40], xylitol has been used to relieve constipation. To investigate
the normalization of bowel function post-laparoscopic surgery; 60 patients were randomized to
consume xylitol chewing gum (amount not reported) three times per day and 60 patients allocated to a
non-chewing gum control group. The time to first flatus (−5.7 h) and first bowel sounds (3.8 h) was
observed to be significantly reduced compared to the control group. There was, however, no influence
on time to first bowel movement [41]. This result is very similar to what was observed with xylitol
chewing gum (2.40–2.74 g xylitol/dose) every two hours until first flatus, for normalizing bowel
function after Caesarian section; 40 women in xylitol chewing gum group and 40 women in non-xylitol
chewing gum control group. Time to first bowel sounds (−1.1 h) and first flatus (−0.9 h) were
significantly reduced, but no effect was observed for time to first bowel movement compared to the
control group [42]. However, xylitol chewing gum (0.86 g xylitol/dose; 43 subjects) three times/day has
been shown to contribute to earlier normalization of bowel function after elective proctectomy; time to
first flatus (−6.9 h) and time to first stool (−12.3 h) were significantly reduced compared to the control
group (no chewing gum; 46 subjects). Interestingly, also post-operative opioid use was reduced in
the xylitol chewing group by approximately 20% as compared to the control group. No differences in
post-operative complications were observed [43].

3.4. Conclusions
Xylitol has been shown to modulate intestinal microbial composition and activity in vitro and in
animal studies. Although these data are promising, data in humans are limited. Similarly, for improving
bowel function, human data exists but are limited to specific patient groups. There is thus a need for
studies in, otherwise healthy, humans with constipation.

4. Nose, Throat and Ear

4.1. Introduction
As all the body sites that are exposed to the outside environment, also the respiratory tract is
colonized by a microbiota. An important function of this microbiota is to hamper the establishment of
exogenous microbes; in particular potential pathogens. As with the microbiota in other body sites,
the respiratory microbiota evolves from birth to an ‘adult-like’ microbiota [44]. In contrast to viral
gastrointestinal infections, it seems that during an upper respiratory tract viral infection the nasal
microbiota is relatively stable as was demonstrated in an experimental rhinovirus challenge study
in humans [45]. The microbiota composition also differs at different sites along the respiratory tract.
The anterior nares may be colonized by Staphylococcus spp., Cutibacterium (formerly Propionibacterium)
spp., Streptococcus spp. and Corynebacterium spp. [46]. The nasopharyngeal microbiota demonstrates
considerable overlap with the anterior nares and consists of Moraxella spp., Staphylococcus spp.,
Corynebacterium spp., Dolosigranulum spp., Haemophilus spp. and Streptococcus spp. [46]. The microbiota
of the oropharynx is characterized by Streptococcus spp., Neisseria spp., Rothia spp., Veillonella spp.,
Prevotella spp. and Leptotrichia spp. [46]. Some of these potential pathogens can spread from the
Nutrients 2019, 11, 1813 7 of 19

nasopharynx into the sinus cavity during viral respiratory infection and cause sinus infection; S. aureus,
Staphylococcus epidermidis, and Gram-negative bacteria such as P. aeruginosa and Klebsiella pneumoniae,
predominate in chronic rhinosinusitis [47]. Acute otitis media (AOM) is defined as the presence of
middle ear effusion (thick or sticky fluid behind the eardrum in the middle ear) and a rapid onset
of signs or symptoms of middle-ear inflammation, such as ear pain, discharge from the ear or fever.
Also here, the key step in the pathogenesis is the colonization of the upper airways with pathogenic
bacteria; in particular S. pneumoniae and H. influenzae, which move from the nasopharynx through the
eustachian tube to the middle ear [48].

4.2. Benefits of Xylitol in Respiratory Health

In vitro studies have shown that 1% and 5% xylitol markedly reduced the growth of alpha-hemolytic
streptococci, including S. pneumoniae in a dose dependent manner. The inhibitory growth pattern was
similar to that previously seen with S. mutans. Xylitol reduced slightly the growth of beta-hemolytic
streptococci but not that of H. influenzae or Moraxella catarrhalis [49]. Although in vitro inhibition of
S. pneumoniae was observed, nasal infection of rats (20 animals/group) with S. pneumoniae could not be
reduced, as evaluated by PCR, with 3 day exposure to dietary xylitol (20%) or nasal spray with 5%
xylitol compared to control animals not exposed to xylitol [50].
Furthermore, 250 µl of 5% xylitol sprayed for 4 days into each nostril of 21 healthy volunteers
significantly decreased the number of nasal coagulase-negative Staphylococcus compared with saline
control treatment in the same volunteers. Counts were reduced from 597 CFU/nasal swab during
the control treatment to 99 CFU/nasal swab during the xylitol treatment; no other organisms were
assessed [51].
A nasal spray with xylitol has been reported to improve the quality of life in patients with
non-allergic nasal congestion. Subjects were randomized to either receive xylitol spray twice daily
for 5 days (n = 14) or saline (n = 14). Objective rhinometry measures were not significantly different
from control and baseline, and subjective measures of nasal obstruction, by questionnaire, only
exhibited a trend for improvement from baseline. However, the Rhinoconjunctivitis Quality of Life
Questionnaire indicated a significant improvement from baseline for the xylitol group, but not for the
control group [52].
Despite some anti-pathogenic effects by xylitol on some potential pathogens of the upper respiratory
tract, the consumption of 5 pieces of 15% xylitol-containing chewing gum by 106 pharyngitis patients
for three months was not found to be associated with a reduction in pharyngitis and did not perform
better in reducing symptoms; difficulty in swallowing and sore throat as compared to no chewing
gum control subjects (n = 110). Data were collected by questionnaire [53]. Inhalation of xylitol
aerosol has been suggested to reduce salt concentration in airway surface liquid (ASL); increased salt
concentrations are associated with reduced antimicrobial activity of ASL and may partially explain the
pathogenesis of cystic fibrosis [51].
As will be discussed below under immune-modulatory effects of xylitol (Section 6.2) there is
substantial animal model data indicating a benefit of xylitol consumption and immune modulation
which improves resistance to experimental viral infections by the human respiratory syncytial virus
(hRSV) and influenza A virus (H1N1).

4.3. Benefits of Xylitol in Sinusitis

A reduction of the ionic composition of ASL by xylitol has been hypothesized to be beneficial not
only for respiratory tract infections but also for the treatment of sinusitis. In vitro, 5% and 10% xylitol
in saline significantly reduced S. epidermidis and S. aureus biofilm formation after 1 h, and after 24 h
also of P. aeruginosa compared to saline. After 4 h 5% and 10% xylitol significantly reduced the growth
of planktonic S. epidermidis, S. aureus, and P. aeruginosa compared to saline. There was no difference
between 5% and 10% xylitol [54]. As mentioned above, 2%, 10%, and 20% xylitol in water have also
been shown to inhibit the growth of P. aeruginosa in a biofilm model [19].
Nutrients 2019, 11, 1813 8 of 19

Indeed, in experimental sinusitis through P. aeruginosa infection of 26 rabbits, and local

pre-administration (20 min) of 0.1 mL 5% xylitol for five days, reduced the number of recovered
P. aeruginosa compared to administration with saline in the other sinus of the same rabbit (control).
Culturing showed counts of 5.37 × 106 CFU in control sinuses and 1.93 × 106 CFU in xylitol pretreated
sinuses. However, simultaneous or subsequent administration of xylitol and P. aeruginosa infection
resulted only in a non-significant reduction in P. aeruginosa [55].
A 10-day nasal irrigation with a 5% xylitol solution by 15 subjects with chronic rhinosinusitis
resulted in a significant reduction in Sino-Nasal Outcome Test 20 (SNOT-20) score compared to control
irrigation with saline. The volunteers, however, did not self-report an improvement in their sino-nasal
wellbeing. No adverse events were reported [56]. In a subsequent study with 30 patients with chronic
rhinosinusitis, nasal irrigation with a 5% xylitol solution for 30 days has indeed been found to lead
to an improvement in symptoms of chronic rhinosinusitis reported as SNOT-22 [57]. As a potential
mechanism, a reduction in the viscoelasticity of mucus has been proposed [58].

4.4. Acute Otitis Media

As noted above, S. pneumoniae is one of the main causative agents of AOM; 1% and 5% xylitol
has been shown to inhibit the growth of S. pneumoniae in vitro [49]. Ultrastructural analysis of the
pneumococci showed that the cell wall became more diffuse, the polysaccharide capsule became
ragged and the proportion of damaged pneumococci increased after exposure to 5% xylitol for 2 h,
but not after exposure to other sugars or control medium [59]. In fact, exposure to 5% xylitol lowered
pneumococcal capsular locus (cpsB) gene expression levels significantly compared with those in the
control and glucose media [60]. However, in clinical trials, xylitol did not decrease nasopharyngeal
carriage of pneumococci; even though AOM risk was reduced. Nevertheless, xylitol at 0.5% solution
has been observed to reduce the growth of 20 pneumococcal clinical isolates in vitro compared to other
carbon sources. Also in vitro pneumococcal biofilm formation was reduced and expression of genes
involved in biofilm formation—capsule, competence, and autolysin—was reduced [61].
A recent Cochrane review investigated the benefit of the prophylactic administration of xylitol to
healthy children up to 12 years of age on the risk for the development of AOM. In all, 5 clinical trials
were identified and included in the analysis, which involved 3405 children in total. Doses used ranged
from 8.4 to 10 g/day. The authors concluded that there is moderate-quality evidence that xylitol (in any
form) can reduce the risk of AOM from 30% in the control group to approximately 22%. However,
xylitol was not found to be effective in reducing AOM among healthy children during respiratory
infection or among otitis-prone healthy children [48]. Furthermore, the authors expressed the concern
that there is only a limited number of studies, mainly from the same research group. In that sense, it is
interesting to see that at least two clinical trials are on the way to investigate the effect of xylitol on
AOM (clinicaltrials.gov: NCT02950311 and NCT03055091 [62]).

4.5. Conclusions
Some subjective benefits for xylitol were observed in relieving congestion; overall these results
are not convincing. Also for sinusitis, results are inconclusive. For AOM, however, there is quite
convincing evidence on the potential benefit of xylitol in reducing its risk.

5. Bone

5.1. Introduction
Although bone may appear to be a rather static tissue, it is actually in continuous turnover.
It is, therefore, important that there is a correct balance in the resorption and reconstruction of bone
tissue. There is a continued risk for reduced reconstruction and especially with aging a risk for
osteoporosis. Dietary means to improve mineral absorption, bone mineral density, and bone strength
are thus welcome.
Nutrients 2019, 11, 1813 9 of 19

5.2. Effects of Xylitol on Bone Strength

In non-challenged animals (12 rats/group) on a diet supplemented with 10% or 20% (w/w) xylitol
for 40 days, higher levels of both serum Ca2+ (double and triple that of the control group for 10% and
20% xylitol, respectively) and 25% and 80% increase in alkaline phosphatase activity (for 10% and 20%
xylitol, respectively) were observed compared to the unsupplemented control group. Microfocus X-ray
computed tomography did not show significant differences in the three-dimensional bone structure
or trabecular bone structure of the femur. However, the histological analysis indicated an increase
in trabeculae. Furthermore, both xylitol groups showed 3% and 6% higher bone density for 10%
and 20% xylitol, respectively, than the control group fed an unsupplemented diet [63]. Xylitol has
also been shown to reduce bone resorption by 42% in tetracyclin-challenged animals (10 rats/group)
on a diet supplemented with 1 molar xylitol per kilogram dry feed for 31 days, compared to the
control animals on a non-supplemented basal diet [64]. A similar study with 5%, 10% and 20% dietary
xylitol in tetracyclin-challenged animals (10 rats/group) for 31 days noted a retarding effect on bone
resorption of about 25% in the 10% xylitol group, about 40% in the 20% xylitol group, and undetectable
in the 5% xylitol group. Furthermore, the effect was detected as early as 2 days after the beginning of
xylitol-feeding and was maintained throughout the experimental period of 31 days compared to the
unsupplemented control group [65]. This is in an agreement with observations in an ovariectomized
rat model (10 animals/group). After three months on a 10% (w/w) xylitol diet, humeral ash, calcium
and phosphorus loss was abrogated as compared to animals not supplemented with xylitol and no
significant difference compared to sham operated animals. Furthermore, there was no loss of stress and
strain resistance upon xylitol supplementation compared to sham operated animals; while elasticity
was maintained. Diets between the groups were isocaloric [66].
In an injected type II collagen-induced arthritis model with 20 rats/ group, administration of
10% dietary xylitol for 17 days led to a significant protective effect against the imbalance in bone
metabolism. This was seen in greater values of osteoid thickness, as well as in lower values of the
number of osteoclasts on bone surface, trabecular separation, and eroded surface/bone surface in the
xylitol-fed animals as compared to arthritic animals few the unsupplemented diet. In the case of
trabecular bone volume, trabecular number and trabecular separation this was not different from the
non-arthritic rats [67]. These observations can partially be explained by an increased bone formation
activity induced by xylitol and a diminished bone resorption activity. Also, in a streptozotocin-induced
type I diabetic osteoporosis model with ten rats/group, 3-month dietary supplementation with 10%
and 20% xylitol has been shown to reduce the loss of trabecular bone volume and bone strength. Tibia
density and ash weight in both xylitol groups were significantly different from diabetic rats fed the
unsupplemented diet but similar to unsupplemented healthy rats. This was similar for tibia and
femur stress tolerance and for histomorphometric assessed tibia trabecular bone volume; both xylitol
groups were significantly different from diabetic rats fed the unsupplemented diet but similar to
unsupplemented healthy rats [68].
As discussed above, in a mouse study, 28 days of 5% dietary xylitol was observed to stimulate the
conversion of daidzian to equol [33]. The conversion of isoflavones to equol has been suggested to be
responsible for their positive effects on bone health [69], whether dietary xylitol plus isoflavonoids
exert a favorable effect on bone health remains, however, to be studied [33].

5.3. Conclusions
The ability of xylitol to positively influence bone health is in line with its prebiotic properties.
Being undigestible but fermented in the colon, leads to a production of short-chain fatty acids and
a reduction in pH of the digesta. This improves the solubility and absorption of minerals such as
calcium. Furthermore, it has been shown in mice that butyrate stimulates bone formation via regulatory
T cell-dependent mechanisms [70] thus linking the butyrogenic effect of xylitol [18] to bone health.
These observations are, however, all in animals. Human studies are required to validate these benefits.
Nutrients 2019, 11, 1813 10 of 19

Furthermore, the levels of dietary xylitol in animal studies are high (up to 20%) and not feasible
for humans.

6. Immune Function

6.1. Introduction
As the first line of defense against foreign compounds and potential pathogenic micro-organisms,
the body has physicochemical barriers such as the skin and mucous membranes. As mentioned above,
xylitol may beneficially affect the skin barrier function, and as will be discussed below, xylitol also
improves mucous membrane function; especially in the oropharynx. Below these barriers, the body
relies on the immune system which can roughly be divided into a non-specific, fast-working, innate
immunity and highly specific, but slower reacting, acquired immunity [71]. Xylitol may exert its effects
on the immune system indirectly by prebiotic effect as discussed above or directly by influencing host
(e.g., immune) cell metabolism [72].

6.2. Immune Modulatory Effects of Xylitol

Xylitol has been found to potentiate immune responses mainly in animal models. A single 0.5 mL
dose of 20% xylitol within 24 h after hatching of ten female broiler chicks was found to improve
splenocyte proliferation by B-cell and T-cell mitogens (concanavalin A and pokeweed mitogen)
compared to 0.5 mL of 20% glucose. Furthermore, antibody titers to keyhole limpet hemocyanin (KHL)
and Mycobacterium butyricum injected at day 5 were higher at day 12 post-hatching compared to animals
that received glucose [73]; indicating an improved acquired immune response development in chicks.
The effect of xylitol on innate immunity has been studied in rats. Rats (20 animals/group) fed 20%
dietary xylitol exhibited a 6.7% higher increase in the percentage of activated neutrophils from baseline
than in the unsupplemented control group after 2 weeks. Likewise, the strength of the oxidative burst
per neutrophil was 13.5% higher in the xylitol group as compared to the control group [74]. When
rats (20 animals/group) were infected with an intraperitoneal inoculation of Streptococcus pneumoniae
after two weeks supplementation with 10% or 20% dietary xylitol, or no supplementation (control).
The mean survival time was 11 h longer in the 10% xylitol and 12 h longer in the 20% group compared
to the control group [74].
Anti-bacterial effects of xylitol have been well documented especially against oral [75] and
respiratory pathogens [19]; see also earlier sections. However, only a few studies have investigated
its effect on viral infections. Human respiratory syncytial virus (hRSV) is the most common cause of
bronchiolitis and pneumonia in infants. There is a need for prophylactic and therapeutic strategies to
control hRSV infection. Mice (5/group) receiving dietary xylitol (3.3–33 mg/kg/d in phosphate-buffered
saline; PBS) for 14 d prior to hRSV challenge and for a further 3 d post-challenge had significantly
lower lung virus titers compared to PBS only, control mice. In line with lower viral load, also fewer
CD3(+) and CD3(+)CD8(+) lymphocytes were found in bronchoalveolar lavage, indicating less need
for lymphocyte recruitment to control the viral infection [76]. Similar effects were observed for
the anti-viral drug ribavirin (40 mg/kg/d during the 3 days post hRSV infection) in the study [76].
The results indicate an improved innate immune response but nevertheless combined with a reduced
inflammatory response to hRSV infection. Another mouse study (five mice/group) investigated the
effect of xylitol consumption (3.3 or 33 mg/kg/d) during 5 days prior to influenza infection and three
days post-infection. Mortality in mice infected with influenza A virus (H1N1) could not be influenced
by prophylactic oral application of xylitol or red ginseng. However, combining the two remarkably
reduced mortality. With a higher dose of xylitol (33 mg/kg body weight/day) being more effective than
the lower xylitol dose (3.3 mg/kg body weight/day). Interestingly, dietary administration of 33 mg/kg/d
xylitol significantly reduced the lung viral titer compared the PBS control [77].
Nutrients 2019, 11, 1813 11 of 19

6.3. Anti-Inflammatory Effects of Xylitol

The studies discussed above indicate that xylitol may have anti-inflammatory effects on skin
by improving the epithelial tight junctions and thus limiting the leakage of microbial and other
foreign components into the host. It has been further shown that 0.0045%–0.45% xylitol exerts
direct anti-inflammatory effects after 24 and 48h on NHEKs stimulated ex vivo with toll-like receptor
agonists lipopolysaccharide (LPS), lipoteichoic acid and polyl:C, as compared to the cell culture
medium alone [11]. Although the authors noted some skin donor-dependent effect, xylitol was in
general effective in suppressing inflammatory cytokine interleukin (IL)-1α and IL-1β upregulation,
and also in decreasing tumor necrosis factor (TNF)-α after polyl:C induction. It can be hypothesized
that this reduced inflammatory response contributes to improved skin barrier function. Further
evidence on anti-inflammatory effects was observed in a hairless mouse model (23 animals/group).
Inflammatory responses induced by irritation of the skin for 3h with 5% SDS were substantially
reduced by concomitant topical xylitol administration (at 8.26% or 16.52%); normalizing the level
of lymphocytes and reducing the expression of inflammatory cytokines IL-1β and TNF-α, but not
IL-1α in skin biopsies, compared to biopsies only treated with 5% SDS [14]. On the other hand,
intraperitoneal injection of Escherichia coli LPS caused an increase in α1 acid glycoprotein in 10 and
12-day-old male broiler chicks (16 animals/group) as expected. This acute-phase inflammatory marker
protein was, however, not affected by the inclusion of 6% xylitol (+9% glucose) in the diet for 7 days [78].
Nevertheless, the LPS induced reduction in body weight gain, feed intake and feed efficiency were
partially prevented by the xylitol diet as compared to the 15% dietary glucose control; suggesting a
reduced physiological stress response to the immune challenge.

6.4. Conclusions
In animal models, xylitol has been observed to stimulate innate and acquired immunity;
mainly against bacterial infectious agents. For viral infections, results are less conclusive. Also,
the anti-inflammatory effects of xylitol are somewhat inconclusive and based on animal studies.
Information on the potential effects on human inflammatory responses is lacking.

7. Weight Management

7.1. Introduction
Overweight and obesity are an increasing health risk not only in affluent countries but increasingly
also in developing countries. Strategies to aid consumers with weight management are thus very
welcome and xylitol may play a role here. A potential mechanism by which xylitol could contribute
to weight management and reduced energy intake is through the induction of satiety. In addition to
weight management, there may also be a benefit in counteracting the consequences of overweight and
obesity, commonly referred to as metabolic syndrome; insulin resistance, high serum cholesterol and
hyperlipidemia [79].

7.2. Effects of Xylitol on Weight Management

An obvious contribution of xylitol to weight management is through the replacement of sucrose.
The caloric value of sucrose is 3.87 kcal/g and for xylitol approximately 2.4 kcal/g [2]. As xylitol is
equisweet to sucrose, replacing sucrose with xylitol will reduce the caloric value of a particular food
while maintaining taste. In confectionery, xylitol will also contribute the same bulk as sucrose. Whether
this will contribute to long-term weight loss is uncertain.
For short-term weight management, a high-fat diet animal model (6 rats/group), reported a
smaller bodyweight increase after an 8-week intervention, with less visceral (−12.9% and −15.5%)
and epididymal fat (−15.5% and −17%) was observed in rats on 1 and 2 g xylitol/100 kcal of diet,
respectively, as compared to animals fed an unsupplemented high-fat diet. This may be explained by
the observation that adipose tissue of the xylitol-fed rats exhibited significantly higher levels of mRNAs
Nutrients 2019, 11, 1813 12 of 19

encoding peroxisome proliferator-activated receptor (PPAR)γ, adiponectin, hormone-sensitive lipase

(HSL) and adipose triglyceride lipase (ATGL). These factors regulate lipid metabolism and storage
and may have caused a miniaturization of adipocytes, lipolysis, and liver fatty acid oxidation [7].
Further animal studies (12 rats/group) have also reported lower weight for animals consuming 10%
or 20% dietary xylitol for 40 days; with 10% xylitol approximately 5% lower body weight and with
20% approximately 15% lower body weight [63]. In a fructose-streptozotocin-induced type 2 diabetic
rat model, 7 animals/group, were fed 0 (control), 2.5%, 5% and 10% dietary xylitol for 4 weeks.
A dose-dependent reduction in food and fluid intake was noted compared to diabetic control animals,
where 10% xylitol was not different from non-diabetic animals. Bodyweight gain was, however, similar
to the control animals but less than the healthy animals [80].
A one-year study with 91 obese subjects suggests an inverse relation between xylitol consumption
and weight loss; a high intake of xylitol would predict for a small weight loss. People in the two lower
quartiles had a 5.5-fold greater chance of losing more than 10% weight, while subjects in the highest
quartile and a 14 chance of losing less than 10% weight [81]. Whether this is just a correlation or an
actual causality remains to be determined.

7.3. Benefits of Xylitol on Satiety

Nasogastric administration of 50 g xylitol in 300 mL water to 10 obese and 10 lean volunteers
after an 8 h fasting, induced an increase in cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1)
compared to water alone [82]; both are indicated as satiation hormones. This was associated with
an increased time to gastric emptying in both groups as compared to the control (water). However,
subjective feelings of appetite were not influenced compared to the water control [82]. Similarly,
an earlier study indicated that 25 g xylitol in yogurt for 10 days had no influence on reported fullness in
16 healthy lean adults. However, the combination of 12.5 g xylitol and 12.5 g polydextrose resulted in
an increased subjective feeling of fullness [83]. Interestingly, clinical studies have reported that a single
dose of 30 g xylitol in 200 mL water resulted in a change in gastric emptying half-time from 39.8 min
during the glucose control to 77.5 min during the xylitol test with 5 healthy volunteers in a cross
over design study. This delay in gastric emptying was associated with increased plasma motilin [84].
Motilin is involved in the regulation of small intestinal motility [85]. After ingestion of 25 g of xylitol
in 50 mL water by ten healthy volunteers, the gastric emptying halftime was increased from 58 min to
91 min compared to the water only control as well as the 25 g glucose comparator in a crossover study.
Food intake after xylitol preloading was reduced from 920 (water control) to 690 kcal [86]. Similar
observations were made by King and co-workers [83] who observed that during a ten-day ingestion of
yogurt containing 25 g of xylitol, 90 min prior to lunch, reduced the combined caloric intake by 11.9%.
This difference did, however, not reach statistical significance compared to control.

7.4. Benefits of Xylitol on Metabolic Health

Xylitol, although having a similar sweetness as sucrose and glucose, has different molecular
properties and thus does not lead to an increase in blood glucose or insulin levels [83]. Xylitol has a
glycemic index of 7 ± 7 compared to a value of 100 for glucose; not surprisingly, the serum insulin and
C-peptide responses to xylitol are negligible [87]. Carbohydrate and lipid oxidation were not observed
to be influenced when eight healthy non-obese males consumed a single dose of 25 g xylitol after an
overnight fast [87].
In animal models of type-2 diabetes (7 rats/group), induced through high-fructose feeding and
injection of streptozotocin, administration of xylitol at 2.5%, 5% and 10% in drinking water during 4,
respectively 5 weeks has been observed to improve serum insulin concentration at all tested xylitol
concentration and glucose tolerance at 10% but not 2.5% and 5% xylitol [80,88]. In a study with 10 obese
and 10 lean, non-diabetic volunteers; nasogastric administration of 50 g xylitol in 300 mL water after an
8 h fasting, resulted in a small but significant increase in serum glucose after administrations of xylitol
compared with placebo. The authors hypothesized that this could be due to a decrease in plasma
Nutrients 2019, 11, 1813 13 of 19

glucose over time after placebo intake rather than an increase in plasma glucose after xylitol intake [82].
However, the small increase is in line with earlier reports [87] and can be explained by the normal
metabolism of absorbed xylitol to glucose by the liver [7].
In a non-diabetic non-high-fat diet rat model, total cholesterol and low-density lipoprotein
(LDL)-cholesterol were significantly reduced (approximately 50% and 75%, respectively) after
three weeks in the 10% xylitol drinking water group (6 animals) compared to water only control
(5 animals) [89]. In a fructose-streptozotocin-induced type 2 diabetic rat model, 7 animals/group,
were fed 0 (control), 2.5%, 5%, and 10% dietary xylitol for 4 weeks a dose-dependent reduction in
serum cholesterol was observed. This was in particular driven by a dose-dependent reduction in
LDL-cholesterol, where 10% xylitol reached a level lower than the non-diabetic control animals [80].
A similar trend has been reported for humans as well, but only with high doses (40–100 g/day) of
xylitol [90].
In a high-fructose streptozotocin-induced, diabetes animal model (7 rats/group), administration of
10% xylitol in drinking water was not found to improve serum triglycerides after 5 weeks as compared to
diabetic animals in the unsupplemented control group [88]. However, a fructose-streptozotocin-induced
type 2 diabetic rat model, 7 animals/group, were fed 0 (control), 2.5%, 5%, and 10% dietary xylitol
for 4 weeks observed a dose-dependent increase in serum triglycerides [80]. A differential lipidemic
response between healthy and type 2 diabetic animal models and humans has been suggested [91].

7.5. Conclusions
While there is some indication for improved short-term weight loss in animal models, the long-term
data in humans is inconclusive. There is some indication that xylitol may influence satiety hormones
and gastric emptying in humans. Whether this translates into an effect on weight management remains
to be determined. The benefit of xylitol on metabolic health; in addition to the benefit of the mere
replacement of sucrose, remains to be determined in humans. Although there are indications for
reduced LDL-cholesterol with xylitol consumption, this would need to be confirmed with lower dietary
doses in humans as well as the effect of xylitol on serum triglycerides.

8. Discussion
The dental health benefits of xylitol are well established [3]. Here, we have highlighted that xylitol
also has other potential health benefits, Figure 3. Many of these are related to oral-pharyngeal health.
Changes in the respiratory microbiota are associated with positive effects on respiratory infections,
sinusitis, and acute otitis media. Also, the immune function modulating effects of xylitol may
contribute to the reduction in respiratory-related infections. Furthermore, topical or oral administration
of xylitol seems to have anti-inflammatory effects on immune function and could be beneficial in
controlling for example skin inflammation. As a non-digestible, non-absorbed, selectively fermentable
carbohydrate, xylitol also exhibits the characteristics of prebiotics. Xylitol consumption is associated
with changes in microbiota composition and metabolic activity, and influences bowel and immune
function, and positively influences bone health. Being a low caloric sweetener, xylitol may contribute
to weight management; but also by stimulating satiety and contributing to improved serum cholesterol
levels. Finally, the topical application of xylitol is associated with improved skin moisture and improved
skin barrier.
There are thus many opportunities for additional health benefits of xylitol. However, a limitation is
that many of these novel health end-points are mainly based on in vitro and animal studies, and limited
human intervention studies. This is helpful for the exploration of new health targets and for their
mechanistic understanding. Furthermore, it should be observed that animal studies often used 6%–20%
of xylitol in the diet, which obviously is beyond what is feasible for human consumption. There is,
therefore, a rationale and especially a need to investigate the feasibility of these potential health benefits
in humans.
Nutrients 2019, 11, 1813 14 of 19
Nutrients 2019, 11, x FOR PEER REVIEW 14 of 19

Figure
Figure 3.3. Summary of non-dental
non-dental health
health benefits
benefits of
of xylitol.
xylitol. Arrow thickness indicates the level
level of
of
documentation. Thin arrows indicate only in vitro or
documentation. or animal
animal data,
data, while
while thick
thick arrows
arrows indicate
indicate some
some
level
level of
of human
human data.
data.

The
Therepurpose
are thusofmany
the current review was
opportunities to focus on
for additional xylitol.
health However,
benefits it may
of xylitol. be relevant
However, to place
a limitation
this into the perspective of other sugar alcohols; without embarking on an in-depth
is that many of these novel health end-points are mainly based on in vitro and animal studies, and review. In addition
to 4 g/day
limited xylitol,
human one month
intervention of 4 g/day
studies. This issorbitol
helpfulandfor to
theaexploration
lesser degree 4 g/day
of new mannitol
health targets but
andnot
for
3their
g/day erythritol reduced tetracycline induced bone resorption in rats [64].
mechanistic understanding. Furthermore, it should be observed that animal studies often usedInhaled mannitol may
improve
6%–20% some lunginfunctions
of xylitol the diet,in cysticobviously
which fibrosis patients
is beyondas indicated in a recent
what is feasible for Cochrane review [92].
human consumption.
Some
Therepolyols, such e.g.,
is, therefore, lactitol [93]
a rationale and and sorbitola [94],
especially needhave been suggested
to investigate to have prebiotic
the feasibility of these potential.
potential
For improving bowel
health benefits in humans. function, lactitol appears to be the sugar alcohol of choice [95]. Mannitol can
workThe as an antioxidant
purpose of the and protect
current hyaluronic
review acidon
was to focus in xylitol.
the skinHowever,
[96]. Lactitol
it may hasbebeen reported
relevant to
to place
stimulate
this into secretory IgA production
the perspective of other[97]. Erythritol
sugar alcohols;causes
withoutno increase in blood
embarking on serum glucosereview.
an in-depth level [82].
In
While
addition to 4 g/day xylitol, one month of 4 g/day sorbitol and to a lesser degree 4 g/day mannitoland
sorbitol and erythritol have been shown to reduce glucose absorption from the intestine but
improve
not 3 g/daymuscular glucose
erythritol absorption
reduced ex vivo induced
tetracycline [98–100]. bone
Thus,resorption
while otherinsugar alcohols
rats [64]. have mannitol
Inhaled multiple
potential
may improve some lung functions in cystic fibrosis patients as indicated in a recent Cochraneone.
beneficial health effects, xylitol seems to be the more versatile or more investigated review
[92]. Some polyols, such e.g. lactitol [93] and sorbitol [94], have been suggested to have prebiotic
Author Contributions: Conceptualization, A.C.O.; resources, K.S.; writing—original draft preparation, A.C.O.;
potential. For improving
writing—review bowel
and editing, K.S., function,
M.J.L., lactitol
K.T., and A.C.O.appears to be the sugar alcohol of choice [95].
Mannitol can work as an antioxidant and protect hyaluronic acid in the skin [96]. Lactitol has been
Funding: This research received no external funding.
reported to stimulate secretory IgA production [97]. Erythritol causes no increase in blood serum
Conflicts of Interest: All authors are employees of DuPont Nutrition & Biosciences. DuPont Nutrition &
glucose level
Biosciences [82]. While
manufactures sorbitol
and marketsand erythritol
xylitol. have been
The authors shown
declare to conflict
no other reduce ofglucose
interest.absorption from
the intestine and improve muscular glucose absorption ex vivo [98–100]. Thus, while other sugar
alcohols have multiple potential beneficial health effects, xylitol seems to be the more versatile or
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