Wageningen Academic

Beneficial Microbes, 2018

2016;online
##(##): 1-10 ARTICLE IN PRESS P u b l i s h e r s

Oral administration of Simbioflora® (synbiotic) attenuates intestinal damage in a

mouse model of 5-fluorouracil-induced mucositis
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L.M. Trindade2#, V.D. Martins3#, N.M. Rodrigues2, E.L.S. Souza4, F.S. Martins4, G.M.F. Costa5, C.M. Almeida-Leite5,
A.M.C. Faria2, V.N. Cardoso3, T.U. Maioli1# and S.V. Generoso1#*

1Departamento de Nutrição, Escola de Enfermagem, Universidade Federal de Minas Gerais, Av Alfredo Balena 190, Belo
Horizonte, MG 30130-100, Brazil; 2Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade
Federal de Minas Gerais, Av. Pres. Antônio Carlos 6627, Belo Horizonte, MG 31270-901, Brazil; 3Departamento de Análises
Clínicas e Toxicológicas, Escola de Farmácia, Universidade Federal de Minas Gerais, Av. Pres. Antônio Carlos 6627, Belo
Horizonte, MG 31270-901, Brazil; 4Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal
de Minas Gerais, Av. Pres. Antônio Carlos 6627, Belo Horizonte, MG 31270-901, Brazil; 5Departamento de Morfologia,
Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av. Pres. Antônio Carlos 6627, Belo Horizonte,
MG 31270-901, Brazil; simonenutufmg@gmail.com; #These authors contributed equally to this work

Received: 25 June 2017 / Accepted: 15 November 2017

© 2018 Wageningen Academic Publishers

RESEARCH ARTICLE
Abstract

The use of probiotics to prevent or treat mucosal inflammation has been studied; however, the combined effect
of probiotics and prebiotics is unclear. The aim of this study was to test whether oral administration of a synbiotic
(Simbioflora®) preparation containing Lactobacillus paracasei, Lactobacillus rhamnosus, Lactobacillus acidophilus
and Bifidobacterium lactis plus fructooligosaccharide could help control mucosal inflammation in experimental
mucositis induced by 5-fluorouracil (5-FU). Male BALB/c mice were randomly divided into six groups: control (CTL),
control + prebiotic (CTL+P), control + synbiotic (CTL+S), mucositis (MUC), mucositis + prebiotic (MUC+P), and
mucositis + synbiotic (MUC+S). Mice from the CTL+S, MUC+S, CTL+P, and MUC+P groups received synbiotic or
prebiotic daily by oral gavage for 13 days. Mice in the CTL and MUC groups received the same volume of saline. On
day 11, mice in the MUC, MUC+P, and MUC+S groups received an intraperitoneal injection of 300 mg/kg 5-FU to
induce mucositis. After 72 h, all mice were euthanised. Intestinal permeability, intestinal histology, and biochemical
parameters were analysed. Group MUC showed a greater weight loss and increased intestinal permeability (0.020
counts per min [cpm]/g) compared to the CTL group (0.01 cpm/g) P<0.05. Both treatments attenuated weight
loss compared to the MUC group. Nonetheless, the synbiotic caused a greater reduction in intestinal permeability
(0.012 cpm/g) compared to the MUC (0.020 cpm/g) and MUC+P (0.016 cpm/g) groups P<0.05. Mice in groups
MUC+P and MUC+S displayed significant recovery of lesions and maintenance of the mucus layer. There were no
differences in the short-chain fatty acid concentrations in the faeces between the MUC and CTL groups (P>0.05).
Increased acetate and propionate concentrations were evidenced in the faeces of the MUC+P and MUC+S groups.
Only the synbiotic treatment increased the butyrate concentration (P<0.05). The results indicate that administration
of synbiotic can decrease mucosal damage caused by mucositis.

Keywords: synbiotic, prebiotic, mucositis, short-chain fatty acid

1. Background expectancy (Ahmad et al., 2015). This scenario has

influenced many studies, which have resulted in new
Cancer is one of the leading causes of death worldwide treatments and drugs, including 5-fluorouracil (5-FU),
(Fitzmaurice et al., 2015). This in part reflects the unhealthy which are improving the survival of cancer patients (Keefe,
lifestyle of the global population and the increasing life 2007; Longley et al., 2003; Sonis, 1998). Antineoplastic

ISSN 1876-2883 print, ISSN 1876-2891 online, DOI 10.3920/BM2017.00821

 L.M. Trindade et al.
drugs like 5-FU are widely used for cancer treatment and
are efficacious in the treatment of breast and lung cancer
(Longley et al., 2003). Yet, 5-FU has adverse effects that
include nausea, vomiting, neutropenia, infections, and
mucositis (Sonis, 1998). These side effects can result in
the reduction in the dose of 5-FU, which can compromise
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treatment and lead to higher mortality (Blijlevens et al.,
2000; Van Vliet et al., 2010).
5-FU acts on S-phase cells by inhibiting transcription of
DNA to RNA and suppressing the proliferation of cancer
cells. However, healthy cells are also affected, particularly
those with a high proliferation rate, such as gastrointestinal
mucosal cells (Longley et al., 2003). The resulting mucosal
inflammation is termed mucositis. Mucositis is followed by
a cytotoxic effect, increased inflammation, and disruption
of the intestinal barrier (Li et al., 2009), and can cause pain,
diarrhoea, weight loss, and increased intestinal permeability
(IP), and can be fatal (Keefe, 2007).
Mucositis induced by 5-FU involves the destruction of the
gastrointestinal mucosa, and there is growing evidence
that the microbiota is involved in the development of
mucositis (Pedroso et al., 2015). The balance between the
gastrointestinal tract and the resident microbiota is critical
in maintaining the homeostatic environment of the intestine
(Touchefeu et al., 2014; Wang et al., 2016). Therefore, it is
reasonable to suppose that the disruption of this interaction
is important for the development of intestinal diseases.
Thus, new approaches are needed to improve mucositis
treatment and prevention. Accordingly, administration of
prebiotics, probiotics, or synbiotic (a combination of the
first two) appears to be an alternative therapy to treat or
prevent mucositis (Lalla et al., 2014).
Dietary prebiotics are indigestible compounds that result
in specific changes in the composition and/or activity
of the gastrointestinal microbiota, thus benefitting host
health (Bindels et al., 2015). A synbiotic supplement is a
combination of a probiotic supplement (live microorganisms
that confer a health benefit to the host) and a prebiotic
supplement (Roberfroid, 1998). Benefits related to synbiotic
use include the possible restoration of the gut microbiota
diversity and activity, stimulation of the production
of compounds that participate in the defence against
pathogens, stimulation of an immune response favouring
the balance between inflammation and regulation, and
fermentation of indigestible carbohydrates that leads to
the production of short-chain fatty acids (SCFA) (Kolida
and Gibson, 2011).
In a recent study, we showed that the probiotic
Saccharomyces boulardii cannot prevent the effects of
experimental mucositis induced by 5-FU (Maioli et
al., 2014). However, some studies have indicated that
combination of probiotics and prebiotics can improve the
Please
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results when compared to the use of probiotics alone by
inducing a regulatory immune response and health benefits
(Morelli et al., 2003; Rastall et al., 2005). Additionally,
probiotics in combination with prebiotics can promote
intestinal microbiota balance (Sattler et al., 2015; Wang
et al., 2016). However, only two studies have analysed the
impact of synbiotic on intestinal inflammation (Smith et
al., 2008; Spyropoulos et al., 2013).
The aim of this study was to evaluate the effects of oral
administration of a synbiotic in the maintenance of the
intestinal barrier integrity during mucositis induced by
5-FU.
2. Material and methods
Synbiotic and prebiotic
The commercial synbiotic used was Simbioflora® (FQM, Rio
de Janeiro, Brazil). It contains 5.5 g fructooligosaccharide
(FOS) as a prebiotic plus four strains of probiotic
microorganisms (Lactobacillus paracasei LPC-31,
Lactobacillus rhamnosus HN001, Lactobacillus acidophilus
NCFM, Bifidobacterium lactis HN019). The total quantity
of bacteria was 109 colony-forming units (cfu) per package.
The synbiotic package was diluted in 1 ml of saline, with 0.1
ml of the diluted preparation administered daily by intra-
gastric injection (gavage) to each mouse. The prebiotic was
Fosvita® (FOS; Vitafor, São Paulo, Brazil); 5.5 g FOS was
diluted in 1 ml of saline and 0.1 ml of the diluted preparation
was administered by gavage to each mouse. The mice in the
control group received the same volume of saline.
Mice and the experimental design
Male, 6-week-old BALB/c mice weighing approximately
25 g were provided by the animal facility of the Institute of
Biological Sciences (CEBIO, UFMG, Brazil). Mice were kept
in an open cage, with water and standard chow available ad
libitum. This study protocol (366/2012) was approved by
the Ethics Committee for Animal Experimentation of the
Universidade Federal de Minas Gerais (CETEA/UFMG).
The protocol complied with the guidelines recommended
by the Institute of Laboratory Animal Resources for the
care and use of laboratory animals.
The animals were distributed into six groups (n=6 in
each group): control (CTL), control + prebiotic (CTL+P),
control + synbiotic (CTL+S), mucositis (MUC), mucositis
+ prebiotic (MUC+P), and mucositis + synbiotic (MUC+S).
For 10 days before mucositis induction and 03 days after,
mice in the CTL+P and MUC+P groups received 0.1 ml
of the prebiotic suspension by gavage. Mice in groups
CTL+ S and MUC+S received 0.1 ml of the diluted synbiotic
suspension. The CTL and MUC groups of mice received
the same volume of saline. The bodyweight of each animal
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  Synbiotic and prebiotic in mucositis treatment
was measured every day on a semi-analytical balance. The
bodyweight variation was calculated as the difference
between the weight of mice at the beginning and end of
mucositis induction.
Mucositis induction with 5-fluorouracil
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After 10 days of treatment, animals from the MUC, MUC+P,
and MUC+S groups received an intraperitoneal injection
containing 300 mg/kg 5-FU to induce mucositis. Mice in
groups CTL, CTL+P, and CTL+S received an intraperitoneal
injection of the same volume of sterile saline (Maioli et
al., 2014). At 72 h after 5-FU injection, the animals were
euthanised and blood, intestines, and faeces were collected
for analyses.
Determination of intestinal permeability
IP was determined by measuring the diffusion of
radioactivity in blood after the oral administration of
diethylenetriaminepentaacetic acid (DTPA) labelled with
technetium-99m (99mTc). After 13 days of treatment, all the
mice received 0.1 ml of 99mTc-DTPA containing 18.5 MBq
99mTc by gavage. 4 h later, all the mice were anesthetised and
their blood was collected and placed in appropriate tubes for
radioactivity determination using a Wallac Wizard 1470-020
automated gamma counter (Perkin Elmer, Waltham, MA,
USA). Data are expressed as a % dose calculated as [(counts
per min [cpm of blood/cpm of administered dose)]×100.
Histopathological and mucus analyses
After euthanasia, intestines were excised and opened
longitudinally, and luminal content was gently removed.
The tissue was prefixed in Bouin’s fixative for 30 min, rolled
up to form ‘Swiss rolls’, and fixed for an additional 18 to
20 h in 4% buffered formaldehyde as previously described
(Arantes et al., 2004). The material was processed for
paraffin embedding, and 4 µm thick slices of each sample
were prepared and stained with haematoxylin and eosin
(H&E) or 3% Alcian blue (Merck, Darmstadt, Germany)
in acetic acid (pH 2.5) and periodic acid Schiff (PAS).
Microscopic slides were reviewed by a pathologist. Lesions
in the mucosa and muscles were evaluated on H&E-stained
slides using a histopathological grading system described
elsewhere (Soares et al., 2008). For morphometrical
examination, 10 images per specimen were captured with
a BX51 microscope (Olympus, Tokyo, Japan) and the
digital images were processed using Image-Pro Express
4.0 software (Media Cybernetics, Rockville, MD, USA). For
each image, villus length and mucus areas were measured
by means of the ImageJ 1.45S software (NIH, Bethesda,
MD, USA).
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Short-chain fatty acids analysis
To analyse SCFA, gas chromatography (GC) was performed
to determine acetate, butyrate, and propionate in the
faeces. Briefly, suspensions were prepared from fresh
faeces by mixing with water (material/water 1:5; w/v).
Each suspension was homogenised and dry matter was
determined. After centrifugation, 50 μl of isobutyrate
(internal standard), 280 μl of a 0.36 mol/l perchloric acid
solution, and 270 μl of a 1 mol/l potassium hydroxide
solution were added to 100 μl of the supernatant. The
freeze-dried samples were homogenised in a mixture of
200 μl of 5 mol/l formic acid and 800 μl of acetone. One
microliter of the supernatant after centrifugation was
assayed on a 25 m ×0.32 mm (internal diameter) Carbowax
20M column using a temperature program. The GC system
(Hewlett-Packard, Waldbronn, Germany) consisted of
an HP gas-chromatograph 5890 Series II, HP 7673 GC/
SFC Injector, HP GC Auto Sampler Controller, Detector
FID, and Software-HP Chemstation. Helium served as
the carrier.
Eosinophil peroxidase and myeloperoxidase activity
assays
These assays were used to measure eosinophilic and
neutrophilic activities in the small intestine. Briefly,
100 mg of tissue was homogenised in 1.9 ml phosphate
buffered saline (PBS, pH 7.4 here and hereafter) using
a tissue homogeniser. The homogenate was centrifuged
(3,000×g for 10 min), then the pellets were subjected to
hypotonic lysis (1.5 ml of 0.2% NaCl) and the osmolarity
was restored with 1.5 ml of a 1.6% NaCl solution containing
5% glucose. After further centrifugation (3,000×g for 10
min), the pellet was resuspended in PBS containing 0.5%
hexadecyltrimethylammonium bromide (PBS-HTAB).
The tissue suspension was homogenised again and the
homogenates were freeze-thawed three times in liquid
nitrogen and centrifuged for 15 min at 3000×g. The resulting
supernatant was used to measure eosinophil peroxidase
(EPO) and myeloperoxidase (MPO) activities.
For the EPO assay, 75 μl of each experimental sample
obtained from different tissues was incubated with 75 μl
of substrate (1.5 mM o-phenylenediamine [OPD] in 0.075
mM Tris-HCl buffer, pH 8.0, containing 6.6 mM hydrogen
peroxide) for 30 min at room temperature in the dark. The
reaction was stopped by addition of 50 μl of 1 M H2SO4.
The reaction intensity was measured as optical density at
492 nm on a microplate reader. The results are shown as
absorbance units.
The extent of neutrophilic activity was indirectly estimated
using the MPO assay. Tissue samples were homogenised
in extraction buffer (0.1 M NaCl, 0.02 M NaH2PO4, 0.015
M Na2EDTA; pH 4.7) and the pellets were subjected to
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 L.M. Trindade et al.

hypotonic/hypertonic lysis as described in the EPO assay.

After further centrifugation (3,000×g for 10 min) the pellet 2
was resuspended and homogenised in 0.05 M sodium a
1 a
phosphate buffer, pH 5.4, containing 0.5% HTAB, followed a
by three freeze-thaw cycles using liquid nitrogen. The

Weight variation (g)

resultant solution was centrifuged for 15 min at 10,000×g, 0
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and the supernatant was used in the colorimetric assay. In

-1
this assay, 75 μl of the supernatant was incubated with 75 μl
of a substrate (1.6 mM tetramethylbenzidine and 0.5 mM -2
hydrogen peroxide [H2O2] in 0.05 M sodium phosphate b
b
buffer, pH 5.4) for 30 min at room temperature in the dark. -3
The reaction was stopped by addition of 50 μl of 1 M H2SO4. c
MPO activity in the sample was measured as optical density -4
CTL MUC CTL+P MUC+P CTL+S MUC+S
at 450 nm on a microplate reader (Leonel et al., 2013).

Statistical analyses Figure 1. Synbiotic attenuates weight loss caused by mucositis.

Differences among groups were evaluated by one-way
analysis of variance ANOVA using GraphPad Instat
software® (GraphPad, La Jolla, CA, USA) followed by the
Newman-Keuls test. Differences with probability values
≤0.05 were considered significant.
3. Results
Weight variation was calculated as the difference between the
weight on day 10 and day 13. Data are expressed as average
and standard deviation. Different letters indicate statistically
significant differences (P<0.05) according to ANOVA. Data are
representative of three independent experiments with 8 mice
in each group. CTL = control; P = prebiotic; S = synbiotic;
MUC = mucositis.

Treatment with synbiotic attenuates weight loss

0.04
To check whether the treatment with synbiotic and prebiotic b
can decrease the symptoms of mucositis, weight loss was
0.03
% dose of 99m-DTPA

assessed. Mice in the MUC group had greater weight loss ab

(-2.5 g) compared to the CTL group (P<0.05) (Figure 1).
The synbiotic and prebiotic treatment-related weight loss
was smaller (-1.4 and -1.6 g, respectively) compared to mice
from the MUC group (P<0.05) (Figure 1).
Synbiotic prevents intestinal damage induced by
mucositis
Increased intestinal permeability (IP) is due to the
disruption in the intestinal mucosa, with increased
numbers of inflammatory cells, decreased villus height,
and decreased mucus layer. To test whether the treatments
could prevent such damage, IP was measured. Mice in the
MUC group had higher IP (0.020 cpm/g) compared to the
CTL group (0.010 cpm/g) (P<0.05). Synbiotic (MUC+S)
treatment decreased the IP (0.012 cpm /g) compared to
the MUC group (P<0.05) (Figure 2). In contrast, prebiotic
treatment (MUC+P) did not prevent the increase in IP
(0.016 cpm /g) (P>0.05) (Figure 2).
a
0.02
a a
a
0.01
0.00
CTL MUC CTL+P MUC+P CTL+S MUC+S
Figure 2. Synbiotic prevents increased intestinal permeability
caused by mucositis. For permeability analyses, blood was
collected and the % dose of diethylenetriaminepentaacetic
acid (DTPA) (counts per min of blood/counts per min of the
administered dose) was measured. Data are expressed as
average and standard deviation. Different letters denote
statistically significant differences (P<0.05) according
to ANOVA. Data are representative of three independent
experiments with 8 mice in each group. CTL = control; P =
prebiotic; S = synbiotic; MUC = mucositis.

To confirm the alteration in the intestinal mucosa,

histological analyses were performed. The CTL group
displayed integrity villus and crypts (Figures 3A and 3G).
There was no infiltration of inflammatory cells and the
submucosal layer was not damaged. The treatments did
not alter the mucosa without disease induction (Figures 3C
and E). Conversely, 5-FU induced the complete alteration
in mucosal integrity. Villus shortening and crypt atrophy
were evident with copious inflammatory infiltrate (Figures
3B, 3G, and 3H). Mice with induced mucositis developed
histological lesions characterised by shortened villi with

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  Synbiotic and prebiotic in mucositis treatment

flattened and vacuolated cells, increased cell infiltration
in the lamina propria (LP) and loss of normal crypt
architecture (Figure 3B). The histological score (Soares
et al., 2008) in the MUC group was higher than in the
other groups (P<0.05) (Figure 3G). Mice with induced
mucositis treated with the synbiotic (MUC+S) showed
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Synbiotic decreases eosinophil peroxidase activity
EPO and MPO are related to infiltration of eosinophils
and neutrophils, respectively, in the gut. To verify whether
the treatments could reduce the infiltration of those cells
in the gut mucosal layer, the activity of the EPO and MPO

significant maintenance of the villus and crypt height, and
the inflammatory infiltration was similar to the CTL group
(Figures 3F, 3G, and 3H). Prebiotic treatment partially
preserved gut mucosal integrity, with villus and crypt
heights maintained, although the inflammatory infiltrate
was not decreased (Figures 3D, 3G, and 3H).
The mucus layer is an important barrier of the intestine.
Therefore, it was quantified by PAS coloration. Staining
of the mucus layer staining (Figures 4A-4F) indicated that
mice with mucositis treated with the synbiotic or prebiotic
had a larger mucus layer compared to mice from the MUC
group (P<0.05) (Figure 4G).
enzymes was measured. Mucositis increased MPO activity
in the small intestine of mice however, both treatments
were not able to reduce it (P>0.05) (Figure 5A). In contrast,
EPO activity was reduced by both treatments (P<0.05)
(Figure 5B).
Production of short-chain fatty acids is improved by
synbiotic treatment
SCFA are products of bacterial metabolism of indigestible
carbohydrates in the mammalian gut. To determine the
possible products generated by the treatments with the
synbiotic or prebiotic, concentration of SCFA (acetate,
butyrate, and propionate) were measured in mouse faeces.

A B G 4
b
3
Microscopic score
Mucositis
Control

2 c
ac

1 a
C D a a
Mucositis + Prebiotic
Control + Prebiotic

0
L

P
C

S
CT

L+

C+

L+

C+
MU

CT

CT
MU

MU
H 150
a
Villus height (×1000 µm)

a a
c
100 bc
E F b
Mucositis + Synbiotic
Control + Synbiotic

50

0
L

P
C

S
CT

L+

C+

L+

C+
MU

CT

CT
MU

MU

Figure 3. Synbiotic improves microscopic characteristics of the small intestine. (A-F) Histological features of mucositis in the gut
mucosa analysed (inflammatory cells infiltration, villus shortening, and ulceration in the lamina propria and submucosal layer)
in 5 μm-thick slices stained with H&E and examined at 100× magnification. Scale bar = 50 μm. Shortened villi with flattened and
vacuolated cells are indicated with arrow; inflammatory cell infiltration in the lamina propria is indicated with an arrowhead. Mice
with induced mucositis and treated by prebiotic showed partial preservation of the villi (D, arrow) and crypts (D, asterisk), but
with sparse inflammatory cell infiltration in the lamina propria (D, arrowhead). Bar = 50 μm. (G) The microscopic score calculated
according to aspects described for A-F. (H) Morphometrical analyses of the small intestine. Data represent the mean villus height
(μm) and are expressed as average and standard deviation. Different letters denote statistically significant differences (P<0.05)
according to ANOVA. Data are representative of three independent experiments with 8 mice in each group. CTL = control; P =
prebiotic; S = synbiotic; MUC = mucositis.

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 L.M. Trindade et al.

A B
G 400
b
b

small intestine area

300

Mucositis
Control

Mucus/(104 µm2)
200
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ab a a
100 a
C D
0

Mucositis + Prebiotic
Control + Prebiotic

P
C

S
CT

L+

C+

L+

C+
MU

CT

CT
MU

MU
E F

Mucositis + Synbiotic
Control + Synbiotic

Figure 4. Synbiotic increases the mucus layer in the small intestine. (A-F) Mucous production was measured by PSA colour staining.
The mucous layer and the mucus producer cells are in black. (G) Data are expressed as average and standard deviation. Different
letters denote statistically significant differences according to ANOVA (P<0.05). Data are representative of three independent
experiments with 5 mice in each group each. CTL = control; P = prebiotic; S = synbiotic; MUC = mucositis.

A B
b b
1.75 1.75
b
1.50 1.50
(arbitrary unit)

(arbitrary unit)

1.25 1.25
b
MPO

EPO

1.00 1.00
0.75 a 0.75 a a
a a
a a
0.50 0.50
0.25 0.25 a
0.00 0.00
CTL MUC CTL+P MUC+P CTL+S MUC+S CTL MUC CTL+P MUC+P CTL+S MUC+S

Figure 5. Treatment with the synbiotic decreases eosinophil peroxidase (EPO). (A) Myeloperoxidase (MPO) and (B) EPO assays
were used to measure neutrophilic and eosinophilic activity in the small intestine. Data are expressed as average and standard
deviation. Different letters indicate statistically significant differences (P<0.05) according to ANOVA. Data are representative of
three independent experiments with 8 mice in each group. CTL = control; P = prebiotic; S = synbiotic; MUC = mucositis.

No differences in the concentrations of the three SCFA
in the faeces were evident in mice from the MUC and
CTL groups (P>0.05). However, there was an increase in
the concentration of acetate in the faeces of mice with
mucositis treated with the prebiotic or symbiotic (P<0.05)
(Figure 6A). Increased levels of butyrate were evident only
after treatment with the synbiotic (Figure 6B). Treatment
with the synbiotic and prebiotic increased the production
of propionate, with no difference between groups CTL+P
and MUC+P, or groups CTL+S and MUC+S (P>0.05)
(Figure 6C).

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  Synbiotic and prebiotic in mucositis treatment

A 10,000 B 2,500 C 2,000

c c c c
(µmol/g of faeces)

(µmol/g of faeces)
c

(µmol/g of faeces)
8,000 c 2,000 1,500 bc
Acetic acid

Propionate
6,000 b 1,500

Butirate
a b 1000
a a
4,000 a 1000 a
a a
2,000 500 a a 500
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0 0 0

L
L

L
MU P
P

MU P
P

MU P
P
C
C

MU S
S

MU S
S

MU S
S
CT
CT

CT
L+
C+

L+
C+

L+
C+
L+
C+

L+
C+

L+
C+
MU
MU

MU
CT

CT

CT
CT

CT

CT
Figure 6. Treatment with the synbiotic increases acetate and butyrate production. Mouse faeces were collected on day 13 and analysed
for the presence of short-chain fatty acids (acetate, butyrate, and propionate). (A) Acetic acid analysis by gas chromatography. (B)
Butyrate analysis by gas chromatography. (C) Propionate analysis by gas chromatography. Data are expressed as average and
standard deviation. Different letters denote statistically significant differences (P<0.05) according to ANOVA. Data are representative
of three independent experiments with 8 CTL = control; P = prebiotic; S = synbiotic; MUC = mucositis.

4. Discussion authors observed that the treatment with this probiotic

This study assessed the effects of treatment with synbiotic
and prebiotic using a mouse model of 5-FU-induced
mucositis. Attenuations of weight loss, IP, and mucosal
ulceration were evident in the synbiotic treated mice with
mucositis. These observations are amenable with the
increase in the intestinal mucus layer and production of
SCFA, and with the decreased EPO activity observed in
these mice. The effects of the synbiotic seemed superior
to those of the prebiotic.
Studies on mucositis using the 5-FU model have described
the 5-FU-mediated induction of intestinal cell apoptosis
(Generoso et al., 2015; Li et al., 2009), with villus shortening
and loss of crypt cell function. These alterations lead to
decreased nutrient absorption, which can cause weight
loss and increased IP (Generoso et al., 2015; Maioli et al.,
2014). The effects of 5-FU were observed in mice with
induced mucositis in the present study. Weight loss and
destruction of the intestinal barrier were also reported
recently (Hamouda et al., 2017). The authors observed
severe intestinal mucositis accompanied by diarrhoea, body
weight loss, and crypt apoptosis in the mice subjected to
mucositis.
Synbiotic and prebiotic decreased the IP. This led to
greater preservation of the intestinal mucosa architecture,
and consequently to lower weight loss. A few studies
evaluated the impact of synbiotic treatment on mucositis.
(Spyropoulos et al., 2013) evaluated the effects of
administration of six species of probiotics plus gluco-
oligosaccharides as prebiotic on a model of acute radiation.
The authors found that the synbiotic attenuated weight loss
and significantly improved the histological profile. Others
studies evaluated the use of different probiotic strains
on mucositis effects and the results were contradictory.
Whitford et al. (2009) evaluated the effect of Streptococcus
thermophilus in rats with mucositis induced by 5-FU. The
partially normalised the histological severity score of the
intestinal mucosa. Another study showed that treatment
with S. thermophilus did not improve bodyweight, MPO
activity, and histological damage score (Tooley et al.,
2011). However, a more recent study documented higher
villus height, increased cellular proliferation, and reduced
expression of pro-inflammatory factors in the intestines of
rats treated with the probiotic Bifidobacterium infantis in
the same mucositis model (Yuan et al., 2015).
Another important characteristic of intestinal homeostasis
is the maintenance of the mucus layer. This layer is
important in the mucosa-associated microbiota population
(Lugea et al., 2000). The use of probiotics to prevent
intestinal inflammation has been shown (Elian et al., 2015;
Souza et al., 2016; Tiago et al., 2015). Natural or genetically
modified probiotics can decrease intestinal inflammation
and increase the number of Paneth cells and the mucus
layer in the intestine (Carvalho et al., 2017; Kumar et al.,
2017). The effect of dietary fibre on the mucus layer is also
positive (Desai et al., 2016). Mucus glycans can interact with
bacteria and serve as an adhesion substrate for bacterial
adhesins, thereby decreasing bacterial translocation (Desai
et al., 2016). In the present study, we tested the efficacy
of prebiotic or synbiotic in protecting the intestine from
mucosa disruption. The results agree with reports that
both treatments increase the mucus layer (Ahl et al., 2016;
Kumar et al., 2017).
Mucositis inflammation is also associated with increased
activity of enzymes produced by activated innate-immunity
cells, such as MPO and EPO (Pedroso et al., 2015). To
evaluate the efficacy of prebiotic and synbiotic in decreasing
infiltration of the intestinal mucosa by neutrophils and
eosinophils, MPO and EPO activities were measured. There
was no difference in MPO activity in the groups of mice,
but there was a reduction in EPO activity after prebiotic
or synbiotic treatment.

Beneficial Microbes ##(##) Please cite this article as 'in press'7

 L.M. Trindade et al.
The action of a chemotherapeutic drug on the intestinal
barrier exposes subepithelial layers, allowing infiltration
of interstitial tissues by eosinophils from the intestinal
mucosa (Longley et al., 2003). Presently, the synbiotic and
prebiotic preserved the intestinal barrier, so it is likely that
the inflammatory process characterised by the presence of
http://www.wageningenacademic.com/doi/pdf/10.3920/BM2017.0082 - Sunday, April 22, 2018 6:36:02 AM - Gothenburg University Library IP Address:130.241.16.16
eosinophils in the cell infiltrate was attenuated.
Homeostasis of the intestinal mucosa is also related to the
fermentation of fibre by the microbiota, which produces
SCFA (mainly acetate, propionate, and butyrate). Butyrate
is used as energetic substrate by colonocytes. Propionate
is metabolised in the liver while acetate is absorbed and
can be used by several cells. In addition, they have anti-
inflammatory actions and reduce IP (Peng et al., 2007).
These SCFA are related to the tropism of intestinal cells
and control of inflammation because SCFA can induce
differentiation of both effector and regulatory immune
cells, depending on the immunological milieu (Park et al.,
2015). Presently, the prebiotic treatment increased the
production of acetic acid and propionate, while treatment
with the synbiotic increased concentrations of the three
SCFA. Treatment with synbiotic may be more effective at
inducing the production of these SCFA. This is important
because these compounds have a direct influence on
regulatory cells and inflammation when the compounds
bind to their receptor, GPR43 (Ferreira et al., 2012). In
one study (Ferreira et al., 2012), animals with mucositis
treated orally with butyrate showed less weight loss, less
tissue damage, preserved villus length in all segments of
the small intestine, and the absence of mucosal ulceration,
relative to control animals with mucositis.
Taken together, the beneficial effects of prebiotic and
synbiotic are related to different mechanisms of action.
Bacteria that are defined as probiotics are able to regulate
inflammation by induction of mucous layer, regulatory
T cells, production of interleukin (IL)-10, and especially
by decreasing the activation of nuclear factor (NF)-κB.
These events are reflected by the decreased number of
inflammatory cells activity and production of IL-4 and
tumour necrosis factor(TNF)-α, and secretion of IL-1β.
Conversely, the metabolism of prebiotic in SCFA induces
the stimulation of GPR43 receptor, which by downstream
signalling induces peroxisome proliferator-activated
receptor-γ activation, which leads to blocked NF-κB
translocation to the nucleus and maintains homeostasis
of the mucosal tissue (Alexander et al., 2017; Wasilewski
et al., 2015).
In summary, treatment with synbiotic prevented the mucosal
damage induced by 5-FU. It was observed attenuation in
weight loss, IP, mucosal tissue inflammation, and decreased
activation of eosinophils, as well as increases in the mucus
layer and production of SCFA. These outcomes might
involve different mechanisms that together can increase the
Please
8 cite this article as 'in press' 
gut mucosal homeostasis. These findings provide insights
into new therapeutic targets and mechanisms that can help
to prevent side effects of chemotherapy.
Acknowledgements
This work was supported by grants provided by the
Conselho Nacional para o Desenvolvimento Cientifico
e Tecnológico from Brazil (CNPq), by the Fundação
de Amparo a Pesquisa de Minas Gerais (FAPEMIG-
APQ-00593-14, and others) and by the Pro Reitoria de
Pesquisa da Universidade Federal de Minas Gerais (PRPq/
UFMG).
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