ORIGINAL ARTICLE

Effects of Prebiotic and Synbiotic Supplementation on

Inflammatory Markers and Anthropometric Indices After
Roux-en-Y Gastric Bypass
A Randomized, Triple-blind, Placebo-controlled Pilot Study
Ricardo Fernandes, MSc,* Bruna T. S. Beserra, MSc,*
Michel C. Mocellin, MSc,* Marilyn G. F. Kuntz, PhD,*
Julia S. da Rosa, MSc,w Rafaella C. D. de Miranda, BSc,z
Cristina S. O. Schreiber, PhD,z Tania S. Frode, PhD,y
Everson A. Nunes, PhD,8 and Erasmo B. S. M. Trindade, PhDz

Background: Studies have shown that prebiotics and synbiotics

modulate the intestinal microbiota and may have benecial eects
on the immune response and anthropometric indices; however, the
impact of the use of these supplements after bariatric surgery is not
yet known.
Goals: This study investigated the eects of prebiotic and synbiotic
supplementation on inammatory markers and anthropometric
indices in individuals undergoing open Roux-en-Y gastric bypass
(RYGB).
Study: In this randomized, controlled, and triple-blind trial conducted
as a pilot study, individuals undergoing RYGB (n = 9) and healthy
individuals (n = 9) were supplemented with 6 g/d of placebo (maltodextrin), prebiotic (fructo-oligosaccharide, FOS), or synbiotic
(FOS + Lactobacillus and Bidobacteria strains) for 15 days.
Results: Interleukin-1b, interleukin-6, tumor necrosis factor-a, Creactive protein, albumin, and the C-reactive protein/albumin ratio
showed no signicant changes on comparison between groups after
supplementation. The reduction in the body weight of patients
undergoing RYGB was 53.8% higher in the prebiotic group
compared with the placebo group ( 0.7 kg, P = 0.001), whereas
the reduction in the BMI and the increase in the percentage of
excess weight loss were higher in the placebo and the prebiotic
groups compared with the synbiotic group (P < 0.05).
Conclusions: Supplementation of FOS increased weight loss,
whereas both prebiotics and synbiotics were not able to promote
signicant changes in inammatory markers, although in most
analyses, there was a reduction in their absolute values. The use of
FOS may represent a potential adjunct in the treatment of obesity.
Key Words: bariatric surgery, inammatory markers, body weight,
prebiotic, synbiotic

(J Clin Gastroenterol 2016;50:208217)

Received for publication November 1, 2014; accepted March 23, 2015.
From the *Post-Graduate Program in Nutrition; wPost-Graduate
Program in Pharmacy; zPolydoro Ernani de Sao Thiago University
Hospital; Departments of yClinical Analysis and Post-Graduate
Program in Pharmacy and in Medical Sciences; 8Physiology and
Post-Graduate Program in Nutrition and in Physiological Sciences;
and zNutrition and Post-Graduate Program in Nutrition, Federal
University of Santa Catarina, Florianopolis, Brazil.
The authors declare that they have nothing to disclose.
Reprints: Erasmo B. S. M. Trindade, PhD, Post-graduate Program in
Nutrition, Federal University of Santa Catarina, Reitor Joao David
Ferreira Lima Campus, Trindade, Florianopolis, Santa Catarina
88040-900, Brazil. (e-mail: erasmotrindade@gmail.com).
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.

besity is a major public health issue, decreasing the life

expectancy and the quality of life. Evidences show that
obesity is a chronic inammatory disease, characterized by
increased plasma concentrations of proinammatory
mediators, in addition to the activation of inammatory
signaling pathways.1,2 This condition is associated with the
development of comorbidities such as diabetes mellitus type
2, hypertension, asthma, dyslipidemia, gallstones, osteoarthritis, and cancer, among others.3
Furthermore, the intestinal microbiota has been linked
with obesity and inammation. Evidence has shown that
obese individuals have an important increase in gram-positive bacteria of the phylum Firmicutes and a reduction of
gram-negative bacteria of the phylum Bacteroidetes compared with healthy individuals.4,5 The lipopolysaccharide
component of the cell wall from gram-negative bacteria is
excessively absorbed by the intestinal capillaries in the
presence of intestinal dysbiosis and failure in barrier function (conditions observed in obesity), generating metabolic
endotoxemia, which induces the secretion of proinammatory mediators by immune cells.6
In this context, there has been an increase in the
number of surgical interventions for the treatment of obesity such as Roux-en-Y gastric bypass (RYGB). A limited
number of studies have investigated the intestinal microbiota after RYGB, but it has been observed that there is a
rearrangement of the intestinal microbiota, which seems to
be related to the improvement of chronic inammation.5,7,8
However, some clinical complications may occur due to
anatomic and physiological changes, which are risk factors
for the alteration of intestinal microbiota, such as reux,
vomiting, electrolyte and nutritional abnormalities, intestinal dysmotility, lower secretion of gastric acid, and displacement of the typical bacteria from the small intestine to
the large intestine.9,10
Thus, given the changes that gut microbiota may
present both before and after RYGB, it is worth noting the
role of potential modulators of intestinal microbiota, such
as prebiotics and synbiotics.11,12 These substances exert
several benecial functions, including inhibiting the growth
of pathogenic bacteria, the preservation of the epithelial
barrier function, epithelial tissue regeneration, immunoregulation, regulation of lipid and glucose metabolism,
weight loss, and relief from constipation, vomiting, and
diarrhea.13

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J Clin Gastroenterol

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Thus, it is important to highlight the importance of

investigating the impact of prebiotic or synbiotic supplementation on inammatory markers and anthropometric
indices after RYGB, given the potential benets that these
substances can bring to individuals who undergo this surgery, such as regularization of the inammatory response
and weight loss, besides the lack of scientic evidence on the
supplementation of prebiotics or synbiotics after RYGB.
The aim of this study was to evaluate the eect of
prebiotic and synbiotic supplementation on inammatory
markers and anthropometric indices of individuals undergoing RYGB. The hypothesis is that prebiotic or synbiotic
supplementation will decrease plasma concentrations of
inammatory markers and anthropometric indices.

MATERIALS AND METHODS

Study Participants
Consecutive patients undergoing open RYGB (n = 9)
at the Polydoro Ernani de Sao Thiago University Hospital,
Federal University of Santa Catarina (Florianopolis, Brazil), and healthy individuals (n = 9) were included in this
study, from October 2013 to April 2014.
Inclusion criteria for patients undergoing RYGB were
age between 18 and 65 years, body mass index (BMI) >
40 kg/m2 or BMI > 35 kg/m2 with at least 1 comorbidity
(eg, hypertension, diabetes), previous dietary and pharmacological treatment failure, and patients scheduled to
undergo bariatric surgery by the open RYGB technique.
Exclusion criteria included the current use of anti-inammatories and/or antibiotics and/or immunosuppressive
drugs, intolerance to prebiotics and/or probiotics and/or
synbiotics, the current use of prebiotic and/or probiotic
and/or synbiotic supplements (last 3 mo), consumption of
foods fortied with prebiotic and/or probiotic and/or synbiotic, and smokers.
Patients received interdisciplinary education about
risks and changes in habits inherent in a major surgery on
the digestive tract and the need for postoperative lifestyle
changes. All patients underwent surgical, endocrinological,
psychological, and nutritional evaluations before surgery.
Inclusion criteria for healthy individuals were a BMI
between 18.5 and 24.9 kg/m2, weight stable over the past 3
months, and age between 18 and 65 years. Exclusion criteria were the presence of chronic diseases, infections, or
intolerances/food allergies, individuals who were athletes or
practitioners of intense physical activity (> 6 METs),14
smokers, those having a habitual consumption of >1
alcoholic drink per week (half a bottle or a can of beer, a
glass of wine, or a shot of liquor),15 previous or current
drug use, use of drugs that aect the appetite, intestinal
motility, and the absorption of nutrients, antibiotics, antiinammatory, immunosuppressive, lipid-lowering drugs,
oral hypoglycemic agents, insulin, antihypertensives, diuretics, laxatives, antacids, or nutritional supplements in the
past 3 months, the use of prebiotics, probiotics, or synbiotics in the last 3 months, pregnant or lactating women,
vegetarians, individuals following a diet for weight loss or
weight gain in the past 3 months, those who had previously
undergone gastrointestinal surgery, and individuals with a
personal history of gastrointestinal disorders (constipation,
diarrhea, heartburn, bloating, excessive atulence, or
abdominal pain).
Healthy individuals were instructed to maintain the
lifestyle habits and dietary intake during the
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Prebiotic and Synbiotic Effects After Gastroplasty

supplementation period, but to avoid practicing intense

physical activity, consuming alcohol, following a diet for
weight loss or weight gain, and consuming foods fortied
with prebiotics, probiotics, and/or synbiotics.

Study Design
Individuals undergoing RYGB (the surgical group)
and healthy individuals (the healthy group) were allocated
randomly into 1 of the 3 treatment arms: placebo, prebiotic,
or synbiotic. Those who received the placebo were
instructed to consume 6 g of maltodextrin daily; those who
received the prebiotic were instructed to consume 6 g of
fructo-oligosaccharide (FOS) (FiberFOS; Invictus Farmanutricao, Sao Paulo, Brazil) daily; and those who received
the synbiotic were instructed to consume 6 g of
FOS + 1 109 Lactobacillus paracasei LPC-37, 1 109
Lactobacillus rhamnosus HN001, 1 109 Lactobacillus
acidophilus NCFM, and 1 109 Bidobacteri um lactis
HN019 (LactoFOS; Invictus Farmanutricao) daily for 15
days, mixing the contents in 100 mL of water until it was
completely dissolved, in the fasting state. For the surgical
group, supplementation was initiated only after completing
30 days of surgery (baseline). It is noteworthy that the
supplementation was started after this period because the
dietary protocol of the postoperative follow-up does not
allow the consumption of gas-forming foods in the rst 30
days after surgery. After the fermentation of FOS, there
could be excessive gas production, causing complications.
For the healthy group, supplementation was initiated after
inclusion in the study (baseline).
All participants were instructed to record the intake of
the supplement on a specic form provided by the
researchers. Those who stayed for >1 day without consuming the supplement were discontinued. The researchers
maintained contact with study participants through phone
call once a week, aiming to determine the treatment adhesion. Throughout the study, all participants who underwent
RYGB were asked about compliance to the diet provided
by nutritionists and the possible adverse eects of
supplementation.
The participants were allocated randomly into the
treatment arms using a randomization list generated by the
Research Randomizer program, consisting of randomly
permuted blocks with 3 individuals each. All individuals
evaluated were assigned to the treatment arm according to
the randomization number. A copy of the randomization
sequence was kept in a locked cabinet apart from the study
personnel.
Study participants and investigators were blinded to
the consumption and the distribution of supplementation,
respectively. Laboratory technicians who performed blood
collection were blinded to the distribution of supplementation. The supplements were prepackaged by the
manufacturer with randomization codes, being identical in
physical appearance, avor, and color. The identication
codes of the supplements were revealed by the manufacturer only after data analysis.
This study was approved by the Ethics Committee on
Research with Human Beings of this institution under the
protocol number 245.650/2013, which is in accordance with
the Helsinki World Medical Declaration.16 All eligible
patients were invited to participate, and those interested
signed an informed consent form.
This trial was registered at the platform ClinicalTrials
with the identication number NCT02158676.

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Fernandes et al

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Surgical Procedure

The CRP/Albumin Ratio

All surgeries were performed by 1 surgeon with the

help of residents in a standardized manner, involving the
following components: (i) the creation of a gastric pouch
with a capacity of approximately 30 mL, which was separated from the distal stomach (gastric remnant); (ii) the
transection of the proximal jejunum 50 cm from the ligament of Treitz; (iii) anastomosis of the distal end of the
transected jejunum to the gastric pouch; (iv) anastomosis of
the proximal end of the transected jejunum to the distal
part of the jejunum at 120 cm below the site of the
transection.

The CRP/albumin ratio provides a prediction of the

nutritional and inammatory prognosis of the patient and
was calculated by dividing the serum CRP by the albumin.
The classication adopted was as follows: no risk < 0.4;
low risk = 0.4 to 1.2; medium risk = 1.2 to 2.0; and high
risk >2.0.20

Clinical Parameters
Clinical parameters such as comorbidities, medications
used, postoperative complications, surgery duration (min),
the length of hospital stay (d), uid therapy during hospitalization, the presence of edema, gastrointestinal disorders,
adverse eects, and the use of vitamin and mineral supplements were collected from medical records or directly
with the patient. Patients aected by infections were discontinued from the present study.

Blood Collection and Processing

Blood samples (10 mL) were collected in the morning,
after overnight fast of 12 hours. A cubital venipuncture was
performed in the region of the forearm by a trained professional according to a standardized technique.17 The
material was collected in vacuum tubes containing an
anticoagulant (heparin) for the determination of cytokines
or in separating gel tubes for the determination of serum Creactive protein (CRP) and albumin.
Blood samples containing the anticoagulant were
centrifuged at 400g for 7 minutes, and plasma aliquots
(500 mL) were stored at 801C. At the end of the study,
they were thawed at room temperature, homogenized, and
used immediately for analysis.
Blood samples containing a separating gel were left at
room temperature for 30 minutes to complete the coagulation, and then, centrifuged at 400g for 10 to 15 minutes to
isolate the serum, which was used immediately for the
determination of CRP and albumin.

Assessment of Biochemical Parameters

Plasma cytokines were determined by enzyme-linked
immunosorbent assay (ELISA), using specic kits for
tumor necrosis factor-a (TNF-a), interleukin-1b (IL-1b),
and interleukin-6 (IL-6) (BD OptEIATM; BD Biosciences,
San Jose, CA) according to the protocol described by the
manufacturer. The minimum threshold detection of the kits
used was 2.0 pg/mL for TNF-a, 0.8 pg/mL for IL-1b, and
2.2 pg/mL for IL-6. Intra-assay and interassay coecients
of variation were as follows: TNF-a, 4.90% 3.67% and
8.83% 6.13%; IL-1b, 2.01% 2.80% and 4.00%
4.5%; and IL-6, 7.7% 6.70% and 7.70% 9.37%. All
samples were analyzed in duplicate. Concentrations were
expressed in pg/mL.
The serum CRP was determined by immunonephelometry (Siemens Dade Behring Inc., Newark, DE)18 and
albumin was determined by the automated colorimetric
method (Siemens Healthcare Diagnostics Inc., Newark,
DE).19 The minimum threshold detection of the kits
used was 0.175 mg/L for CRP and 0.6 g/dL for albumin.
CRP concentrations were expressed as mg/L and albumin
in g/dL.

Anthropometric Indices
For the assessment of the nutritional status, anthropometric measurements of weight and height were performed by a trained professional at baseline and at the end
of the study (day 15) following standardized techniques.21
The weight was measured using a mechanical scale
platform (Welmy, Santa Barbara dOeste, Sao Paulo, Brazil), with a capacity of 150 kg and an accuracy of 0.1 kg.
The height was measured by a stadiometer coupled to
platform with a capacity of 2.00 and an accuracy of 1.0 cm.
The BMI was calculated as weight (kg)/height (m2) and
classied according to the World Health Organization.22
For individuals undergoing RYGB, the percentage of
excess weight loss was calculated [% excess weight loss =
(weight before surgery current weight/excess weight
before surgery) 100], considering excess weight as all
weight ZBMI 25.0 kg/m2.

Statistical Analysis
For analysis, the intake of the supplement was considered as the exposure variable. Concentrations of IL-1b,
TNF-a, IL-6, CRP, and albumin and the CRP/albumin
ratio were the primary outcomes assessed.
The symmetry of the data was tested by applying the
Shapiro-Wilk test. The ANOVA test followed by the
Bonferroni post hoc test or the Kruskal-Wallis test were
used to test the dierences between the 3 treatment arms
(placebo, prebiotic, and synbiotic) at the 2 time points of
the study. The Student t test or the Mann-Whitney test was
used to test the dierences between the 2 groups (the surgical group vs. the healthy group) at the 2 time points of the
study. A paired t test or the Wilcoxon sign-rank test was
used to test the dierences between the dierent time points
in the study groups. All analyses were performed with
STATA 11.0, version for Windows, considering P < 0.05
for statistical signicance.

RESULTS
Twenty-six patients underwent open RYGB between
October 2013 and April 2014. Of them, 9 were not eligible
according to the inclusion criteria or refused to participate.
Thus, 17 individuals were randomized to 1 of the 3 treatment arms (placebo, prebiotic, or synbiotic). Throughout
the study, 8 individuals were discontinued or dropped out.
Finally, 9 individuals were included (3 in each arm). With
respect to healthy individuals, 14 were recruited and
randomized to 1 of the 3 treatment arms. Four were discontinued, with no dropouts. At the end, 9 individuals were
evaluated (3 in each arm), with a total of 18 participants in
this study (Fig. 1).

Characteristics of Study Participants

Demographic, clinical, and anthropometric data of the
individuals at baseline are presented in Table 1. Characteristics of participants who underwent RYGB were not
signicantly dierent among the treatment arms. Most of
them were women (88.9%); all of them had comorbidities

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Prebiotic and Synbiotic Effects After Gastroplasty

FIGURE 1. The study flowchart.

associated with obesity and used at least 1 type of medication before surgery. Fluid replacement was necessary for
all individuals after surgery, but no one showed edema.
Two individuals reported excessive atulence and 1
reported constipation. No participants needed to use ventilatory support during hospitalization or had postoperative
complications.
At baseline, healthy individuals who received the
synbiotic showed a higher body weight compared with
those who received placebo (P = 0.045). As expected, on
comparison between the groups (surgical and healthy),
individuals in the surgical group had a higher body weight
and BMI at baseline (P < 0.001). The majority of the
healthy individuals were women (88.9%), and due to the

eligibility criteria, nobody had diseases, gastrointestinal

disorders, or used drugs.
All study participants (n = 18) complied, at least 14
days of supplementation. Adverse eects related to the
consumption of maltodextrin (placebo) were not reported.
The only adverse eect reported with the consumption of
the prebiotic and the synbiotic was excessive atulence in
the rst 3 days of supplementation, although there were no
dropouts from the study for this reason. Causes of infections in the 3 individuals who discontinued the study were
of urinary or upper respiratory tract origin, unrelated to
supplementation.
Participants who underwent RYGB reported that
they followed the prescribed diet strictly during the

TABLE 1. Baseline Characteristics of the Study Participants

Surgical Group
Characteristics

Placebo

Age (y)
32.0 2.0
Gender (male/female)
0/3
Weight (kg)
103.0 8.7
38.2 1.4
Body mass index (kg/m2)
Length of hospital stay (d)
4.7 0.6
Surgery duration (min)
186.7 20.8
Fluid replacement during hospitalization (L)
Saline 0.9%
3.7 0.6
Glucose solution 5%
4.7 1.2
Medications used [n (%)]*
Antihypertensive drugs
1 (33.3)
Diuretics
1 (33.3)
Oral hypoglycemic agents
0 (0.0)
Proton pump inhibitors
0 (0.0)
Previous comorbidities [n (%)]*
Hypertension
2 (66.7)
Type 2 diabetes mellitus
0 (0.0)
Dyslipidemia
0 (0.0)
Hepatic steatosis
1 (33.3)
Gastritis
1 (33.3)

Healthy Group

Prebiotic

Synbiotic

Placebo

Prebiotic

Synbiotic

36.7 9.1
1/2
109.5 19.3
40.2 4.5
5.3 0.6
133.3 53.5

42.0 16.5
0/3
114.1 19.9
41.6 5.2
4.7 0.6
161.7 17.5

35.0 15.7
0/3
52.1 0.7
20.9 2.5

25.6 1.5
1/2
56.8 3.0
21.3 1.7

33.0 6.2
0/3
58.2 2.2w
24.0 0.4

4.7 2.3
5.5 2.2

2.9 0.9
5.4 0.5

2 (66.7)
0 (0.0)
1 (33.3)
1 (33.3)

2 (66.7)
1 (33.3)
1 (33.3)
0 (0.0)

3 (100)
1 (33.3)
1 (33.3)
1 (33.3)
0 (0.0)

2 (66.7)
1 (33.3)
1 (33.3)
0 (0.0)
1 (33.3)

*Comorbidities and medications used in the preoperative period. The sum of the columns exceeds 100% because individuals undergoing surgery could
present >1 comorbidity or use >1 drug.
wSignicant dierence compared with the placebo in the healthy group (P < 0.05). For all other analyses, there were no signicant dierences (P > 0.05).

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Fernandes et al

supplementation period (800 kcal/d, with balanced reduction of all macronutrients and prohibition of alcoholic
drinks, carbonated drinks, and sugar) and presented no
complications related to the dietary intake. Regarding the
use of drugs and supplements after surgery, all patients
used only omeprazole 40 mg per day, a tablet of vitamin
and mineral supplement per day (Materna Pzer Canada
Inc., QC, Canada), and vitamins B1 (100 mg), B6 (100 mg),
and B12 (5000 mg) in injectable form, only on 1 occasion,
after 30 days of surgery (Citoneurin, Merck, SA de CV
Naucalpan de Juarez, Mexico, DF). Similarly, healthy
individuals reported that they did not change their dietary
intake and did not use drugs or consume alcohol
throughout the study.

Inflammatory Markers, Acute-Phase Proteins,

and the CRP/Albumin Ratio
Both in the surgical and the healthy groups, there were
no signicant dierences in the plasma concentrations of
cytokines at both time points of the study (P > 0.05). In the
intragroup analysis, there was a signicant reduction in the
concentrations of IL-1b among those who received placebo
in the healthy group (P = 0.003) (Fig. 2). When the surgical
and the healthy groups were compared (surgical vs.
healthy), no signicant dierences were observed
(P > 0.05). Likewise, changes in the values of cytokines
(nal time point baseline) were not statistically signicant
in any of the treatment arms (P > 0.05).
As observed with cytokines, there were no signicant
dierences in the serum concentrations of acute-phase
proteins at both time points of the study (P > 0.05). The
change in the values of CRP and albumin (nal time
point baseline) was not signicantly dierent in any of the
groups (P > 0.05). However, for both groups (surgical and
healthy), except for individuals supplemented with the
synbiotic in the surgical group, the absolute values of CRP
decreased after the supplementation, but without statistical
signicance. The average concentrations of albumin
showed no signicant dierence at both time points of
the study, remaining within the reference values (3.4 to
5.0 g/dL).19
With regard to the CRP/albumin ratio, no signicant
dierences were observed within the study groups (Fig. 3).
Furthermore, there were no signicant dierences between
the treatment arms at baseline (P = 0.129, surgical group;
P = 0.833, healthy group) and at the nal time point
(P = 0.945, surgical group; P = 0.690, healthy group).
When the surgical and the healthy groups were compared
(surgical vs. healthy), individuals who received placebo
in the surgical group had higher values at baseline
(P = 0.047), but not at the nal time point (P = 0.051). In
contrast, there were no signicant dierences between
individuals who were supplemented with the prebiotic or
the synbiotic at baseline (P = 0.087 and 0.603, respectively)
and at the nal time point (P = 0.053 and 0.078, respectively), although there was a tendency toward lower values
in the healthy group compared with the surgical group at
the nal time point. The change in the values of the CRP/
albumin ratio (nal time pointbaseline) was not signicantly dierent in any of the study groups (P > 0.05).

Anthropometric Indices
Among the treatment arms in the surgical group, there
were no signicant dierences in the body weight, the BMI,
and the percentage of excess weight loss at both time points

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Volume 50, Number 3, March 2016

of the study (P > 0.05). However, in the healthy group, the

body weight in those who received the synbiotic was higher
compared with the placebo at baseline (+ 6.1 kg,
P = 0.040) (Table 2). In the intragroup analysis, the body
weight, the BMI, and the percentage of excess weight loss in
the surgical group decreased signicantly in individuals
supplemented with the placebo and the prebiotic. In the
same group, the reduction in weight of those who received
the prebiotic was 53.8% higher compared with those who
received the placebo ( 0.7 kg, P = 0.001). Similarly, the
average weight reduction in the prebiotic arm was signicantly higher compared with that in the synbiotic arm
( 0.9 kg, P = 0.001). When the surgical and the healthy
groups were compared (surgical vs. healthy), individuals in
the surgical group had a higher body weight and BMI at
baseline (P < 0.001) and at the nal time point (P < 0.001).
In the surgical group, the mean reduction in BMI of
those who received the placebo and the prebiotic was signicantly higher compared with those who were supplemented with the synbiotic (0.4 kg/m2, P = 0.037 and
0.6 kg/m2, P = 0.003, respectively). Similarly, the average
increase in the percentage of excess weight loss in those who
received the placebo and the prebiotic was signicantly
higher compared with those who were supplemented with
the synbiotic (+ 2.4%, P = 0.030; + 3.2%, P = 0.007,
respectively). In the intragroup analysis, there was a signicant reduction in the body weight in individuals supplemented with the synbiotic in the healthy group (0.3 kg,
P = 0.038), but the magnitude of weight loss (nal timebaseline) was not signicantly higher compared with the
prebiotic and the placebo (P > 0.05).

DISCUSSION
To the best of our knowledge, this was the rst
randomized, triple-blind clinical trial that evaluated the
eects of prebiotic and synbiotic supplements on inammatory and anthropometric parameters of patients undergoing RYGB. The results showed that the administration
of a prebiotic (FOS) after RYGB increases weight loss
signicantly, whereas both the prebiotic and the synbiotic
supplemented did not show a signicant eect on the
cytokines and the acute-phase proteins investigated.
A limited number of studies have investigated changes
in the intestinal microbiota after RYGB and the possible
associations with anthropometric indices and immunologic
parameters in humans, presenting controversial results.5,79
Whereas some studies showed a decrease in bacteria
belonging to the phylum Firmicutes7,9 and Bacteroidetes,7
including species of Faecalibacterium prausnitzii, a group of
bacteria with anti-inammatory action,23 another study5
found that the proportion of Firmicutes and Bacteroidetes
did not change, but there was a lower abundance of Lactobacillus spp. (phylum Firmicutes) and Bidobacterium
spp. (phylum Actinobacteria), which showed an inverse
correlation with the acid a-1-acid glycoprotein, the body
weight, the body fat, and the BMI.8
Among the anatomic modications induced by
RYGB, there is the formation of a small gastric pouch
anastomosed to the jejunum, which favors the presence of
oxygen in this part of the intestine and the development of
facultative anaerobic species,5 at the expense of restricted
anaerobic organisms, such as Bidobacteria. Furthermore,
there is an increase in the pH due to low secretion of gastric
acid, which can be a disadvantage to the development of

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Prebiotic and Synbiotic Effects After Gastroplasty

FIGURE 2. Changes in inflammatory markers and acute-phase proteins over the study period. *The Wilcoxon signed-rank test. **The
paired t test. 0 indicates baseline (day 0); 15, the final time point (day 15).

Lactobacilli and Bidobacteria, which are species associated with immunoregulatory eects and the maintenance
of the barrier function (preventing the absorption of toxic
compounds, such as lipopolysaccharides).24,25 Lactobacilli
grow in slightly acidic media with an optimum pH at 5.5 to
Copyright

6.0, and Bidobacteria have an optimum pH for growth

between 6.0 and 7.0.26 Moreover, one should consider that
the use of proton pump inhibitors by study participants
may be further decrease the secretion of gastric acid and
limited the survival and the proliferation of these bacteria.

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Volume 50, Number 3, March 2016

FIGURE 3. Changes in the CRP/albumin ratio over the study period. For all analyses, the paired t test was used. Categories: 1, no risk; 2,
low risk; 3, moderate risk; 4, high risk. CRP indicates C-reactive protein.

Indeed, a recent publication showed that the use of these

drugs after RYGB increases the proportion of bacteria of
the phylum Firmicutes due to the greater abundance of the
genera Streptococcus, Clostridium, and Blautia, and not the
Lactobacillus genus.27

With regard to the role of FOS in immunomodulation,

one of the main fermentation products of this prebiotic by
fecal bacteria is acetate,28 the most abundant short-chain
fatty acid (SCFA) in the colon and it is responsible for
immunomodulatory eects29,30 and the regulation of energy

TABLE 2. Anthropometric Indices of Patients at Baseline and After the Intervention

Surgical Group
Index
Weight (kg)
Baseline
Day 15
P
Change in weight*
BMI (kg/m2)
Baseline
Day 15
P
Change in BMI*
EWL (%)*
Baseline
Day 15
P
Change in EWL*

Healthy Group

Prebiotic

Synbiotic

Placebo

Prebiotic

Synbiotic

103.0 8.7c
101.7 8.7d
0.032b
1.3 0.4

109.5 19.3c
107.4 18.8c
0.028b
 2.0 0.6ewz

114.1 19.9c
113.9 19.8c
0.121b
 0.4 0.1

0.728aa
0.685 %

0.009a

52.1 0.7
52.7 1.6
0.416b
0.5 0.9

56.8 3.0
56.3 2.3
0.369b
 0.5 0.7

58.2 2.2ey
57.9 2.3
0.038b
 0.3 0.1

0.031a
0.051a

0.183f

38.2 1.4d
37.7 1.4d
0.029b
0.5 0.1ez

40.2 4.5d
39.5 4.4d
0.014b
 0.7 0.2ez

41.6 5.2c
41.5 5.2c
0.107b
 0.1 0.1

0.607a
0.547a

0.003a

20.9 2.5
21.1 2.9
0.510b
0.1 0.3

21.3 1.7
21.3 1.8
0.667b
0.0 0.1

24.0 0.4
23.9 0.5
0.225b
 0.1 0.1

0.145a
0.244a

0.413a

19.4 5.9
22.3 6.1
0.036b
2.9 0.9ez

25.8 6.1
29.5 7.0
0.021b
3.7 1.0ez

23.2 5.3
23.7 5.1
0.092b
0.5 0.3

0.449a
0.377a

0.006a

Placebo

The ANOVA test.

The paired t test.
The Mann-Whitney test.
d
The t test.
e
The Bonferroni test.
f
The Kruskal-Wallis test.
*Calculated by subtracting the values after the intervention by the values at baseline.
wSignicant dierence compared with the placebo in the surgical group (P < 0.05).
zSignicant dierence compared with the synbiotic in the surgical group (P < 0.05).
ySignicant dierence compared with the placebo in the healthy group (P < 0.05).
BMI indicates body mass index; EWL, excess weight loss.
b
c

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J Clin Gastroenterol

Volume 50, Number 3, March 2016

homeostasis.31 G-protein-coupled receptor 43 (GPR43)

recognizes SCFA in adipose tissue and is highly expressed
on neutrophils, macrophages, and monocytes.31 Maslowski
et al32 found that the values of TNF-a and reactive oxygen
species decreased in germ-free mice with colitis after treatment with acetate, a result that was not observed in mice
with colitis GPR43  /  , suggesting that the immunomodulatory eect of acetate is mediated by this receptor.
Acetate was also able to reduce the secretion of TNF-a in
human neutrophils and inhibit the activity of the nuclear
factor kB (NF-kB) and IL-6 in a cell culture of human
colon carcinoma.29 Despite these positive eects, the dose
of FOS and the duration of supplementation required to
achieve benecial eects on inammatory markers is not
yet known; however, the small sample size in this study may
have been a factor that has not allowed us to observe signicant eects.
In relation to the energy homeostasis, Frost et al33
showed that the intraperitoneal administration of acetate in
C57BL/6 male mice resulted in reduced food intake at both
1 and 2 hours after injection, a fact explained by the
reduction in the catalytic activity of hypothalamic AMPactivated protein kinase (AMPK), stimulating the expression of anorexigenic peptides such as pro-opiomelanocortin
(POMC) and the reduction of the expression of orexigenic
peptides, such as the agouti-related peptide (AgRP).
Another mechanism of action of acetate associated with
weight reduction is mediated by carbohydrate-responsive
element-binding protein (ChREBP),34,35 responsible for
activating the transcription of enzymes involved in gluconeogenesis and lipogenesis, such as liver pyruvate kinase (LPK). Incubation of SCFA, including acetate, in a culture of
rat hepatocytes showed the inactivation of ChREBP.35 A
study showed that oral administration of acetate reduced
the accumulation of lipids in the adipose tissue by reducing
the lipogenic activity of several enzymes, including L-PK.34
With regard to synbiotics, few randomized, controlled,
and double-blind studies have investigated the eect of
these supplements on the immune and the anthropometric
parameters, especially in adults with obesity. In a recent
publication, the supplementation of synbiotics in individuals with nonalcoholic fatty liver disease and obesity
decreased plasma concentrations of CRP, TNF-a, and NFkB in nuclear extracts of peripheral blood mononuclear
cells, without aecting the BMI.36 The production of TNFa occurs as a result of the activation of NF-kB, suggesting
that the synbiotic used in the present study was not eective
in reducing the expression of this transcription factor,
which is considered as one of the main regulators of
inammatory cytokine production.37 In another study, a
signicant reduction of CRP was also observed in diabetic
patients with overweight after synbiotic supplementation,
without signicant changes in the body weight and the
BMI.38 Nevertheless, the discrepancy between the ndings
of this study and the aforementioned investigations36,38
could be attributed, in part, to the dierent synbiotics used,
the dierent health conditions of the individuals included,
the characteristics of the diet, and the dose and the duration
of supplementation.
The action of probiotic strains contained in the synbiotic used may also explain the lack of eect in reducing
inammatory markers and anthropometric indices. Studies
have shown that the dietary intake of L. rhamnosus HN001
has an immunomodulatory eect, as increased production
of interferon-g (IFN-g) and IL-4 in mice sensitized with
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Prebiotic and Synbiotic Effects After Gastroplasty

ovalbumin39 and of IL-10 in pigs with allergic lung disease.40 The specic action of this strain on body weight is
not yet known, but a meta-analysis41 did not observe signicant weight reduction with the supplementation of L.
rhamnosus species in healthy individuals and animals. L.
acidophilus NCFM has been correlated with increased
secretion of IL-12p70 in human dendritic cells42 and with
the gene expression of TNF-a, IL-6, and IL-10 in mice
epithelial cells.43 These eects are mediated by the activation of Toll-like receptor 2 (TLR-2), which activates transcription factors such as NF-kB.44 With regard to the body
weight, the specic action of L. acidophilus NCFM in this
outcome is not known, but Million et al41 observed that the
supplementation of L. acidophilus species resulted in weight
gain in healthy humans and animals. Concerning the L.
paracasei LPC-37, its eect on immunologic parameters has
been little investigated, but its eect on the immunomodulatory activity of this strain has been observed.4547
Roessler et al45 found greater phagocytic activity of
monocytes and granulocytes in healthy individuals, without modifying various subtypes of lymphocytes in
the peripheral blood (CD3 + , CD19 + , CD3 + CD8 + ,
CD3  CD16 + , CD56 + , CD3 + HLA-DR + , CD8 +
CD57 + , and CD54 + ). Similarly, Paineau et al46 and
Forssten et al47 observed no changes in the serum concentrations of immunoglobulins (IgA and IgM), acute-phase
proteins, and cytokines (CRP, IL-10, TNF-a, IL-8, IL-17,
and IL-12p70) in healthy individuals after supplementation
of L. paracasei LPC-37. Finally, studies with B. lactis
HN019 showed the ability of this strain to modulate the
immune system.4851 Gill et al48 reported the increased
phagocytic capacity of the mononuclear and the polymorphonuclear phagocytes in healthy humans, and similar
eects were reported by these authors49 and others,50,51
including increased IFN-g. Together, the action of the
supplemented strains may have minimized the eect on
reducing the concentrations of inammatory markers due
to the immunostimulatory role of these strains. It is
important to highlight that the majority of the available
studies with these strains was performed on healthy humans
and animals or on individuals with inammatory diseases,
which may have generated dierent results compared with
this study. The literature still lacks sucient studies to
clarify the eect of these strains on anthropometric indices.
Despite the above evidence, the molecular mechanisms
of action of these strains are not yet elucidated fully;
therefore, it is necessary to conduct further studies on different cell lines and on dierent experimental models, particularly in vivo, to clarify these mechanisms. However, it is
suggested that bacterial signaling in the gastrointestinal
tract requires a complex network of cell interactions,52 both
with immune cells and with intestinal epithelial cells and
other bacterial populations.
The strengths of this study are the originality of the
proposal in assessing individuals after RYGB, the study
design (randomized, controlled, triple blind), and adhesion
to supplementation (> 93%). In contrast, some limitations
should be considered when interpreting the ndings: the
sampling method (not probabilistic) may have weakened
the power and the generalizability of the results, although
this study is characterized as a pilot study; the eect of
supplementation on the intestinal microbiota was not
evaluated due to the constipation presented by most participants; intraindividual and interindividual variations in
the food intake may have occurred, leading to specic

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215

J Clin Gastroenterol

Fernandes et al

changes in the intestinal microbiota; however, individuals

who underwent RYGB received the same dietary guidelines
in the postoperative period.
In conclusion, this clinical trial supports the hypothesis that oral administration of a prebiotic (FOS) after
RYGB promotes signicant reduction in body weight,
whereas both prebiotic and synbiotic supplemented were
not sucient to promote signicant improvement in the
inammatory markers, although in most analyses there was
a reduction in their absolute values. On the basis of the
ndings, a new investigation is in progress, using a longer
treatment duration and a larger sample size.
ACKNOWLEDGMENTS
The authors are grateful to the Post-Graduate Program
in Nutrition, Federal University of Santa Catarina, Brazil, to
the Fellowship Program Social Demand/Coordination of
Improvement of Higher Education Personnel (CAPES) with
a scholarship grant for the rst 5 authors, to the University
Hospital for the assistance with patients, blood sample
logistic, and laboratory determinations, to Invictus FarmaNutricao for the donation of the dietary supplements, and to
the patients for accepting to participate in this study.
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