ORIGINAL ARTICLE

Consumption of Synbiotic Bread Decreases Triacylglyceroland VLDL Levels While Increasing HDL Levels in Serumfrom Patients with Type-2 Diabetes

Hossein Shakeri • Haleh Hadaegh • Fatemeh Abedi •

Maryam Tajabadi-Ebrahimi • Navid Mazroii •

Yaser Ghandi • Zatollah Asemi

Received: 11 February 2014 / Accepted: 20 March 2014

� AOCS 2014

Abstract To our knowledge, no reports are available

indicating the favorable effects of synbiotic bread con-

sumption on blood lipid profiles among patients with type 2

diabetes mellitus (T2DM). This study was conducted to

evaluate the effects of the daily consumption of synbiotic

bread on blood lipid profiles of patients with T2DM. This

randomized double-blinded controlled clinical trial was

performed with 78 diabetic patients, aged 35–70 years. After

a 2-week run-in period, subjects were randomly assigned to

consume either synbiotic (n = 26), probiotic (n = 26) or

control bread (n = 26) for 8 weeks. The synbiotic bread

contained viable and heat-resistant probiotic Lactobacillus

sporogenes (1 9 108 CFU) and 0.07 g inulin (HPX) as

prebiotic per 1 g. The probiotic bread contained L. sporog-

enes (1 9 108 CFU) per 1 g. Patients were asked to consume

the synbiotic, probiotic and control breads three times a day

in a 40 g package for a total of 120 g/day. Biochemical

measurements including blood lipid profiles were conducted

before and after 8 weeks of intervention. Consumption of the

synbiotic bread, compared to the probiotic and control

breads, led to a significant decrease in serum TAG (P =

0.005), VLDL-C (P = 0.005), TC/HDL-C (P = 0.002) and

a significant increase in serum HDL-C levels (P = 0.01). No

significant effect of synbiotic bread consumption on FPG,

TC, LDL-C and non-HDL-C levels was seen compared to the

probiotic and control breads (P [ 0.05). Trial registry code:

http://www.irct.ir IRCT201311215623N13.

Keywords Synbiotic � Probiotic � Lipid profiles � Type 2

diabetes mellitus

Abbreviations

HDL-C High density lipoprotein-cholesterol

LDL-C Low density lipoprotein-cholesterol

MUFA Monounsaturated fatty acid(s)

PUFA Polyunsaturated fatty acid(s)

SFA Saturated fatty acid(s)

TAG Triacylglycerol(s)

TC Total cholesterol

VLDL-C Very low density lipoprotein-cholesterol

Introduction

Type 2 diabetes mellitus (T2DM), which accounts for

90–95 % of those with diabetes, encompasses individuals

who have insulin resistance and usually have relative

(rather than absolute) insulin deficiency [1]. It has been

estimated that 8.3 % of the adult population in the world

[2] and 8 % in Iran are affected [3]. Due to hyperinsuli-

nemia, insulin resistance and obesity, T2DM is associated

with debilitating consequences including dyslipidemia [4].

Increased lipid profiles among diabetic patients may result

in cardiovascular diseases (CVD)-related morbidity and

mortality [5], fatty liver [6] and kidney failures [7].

H. Shakeri � F. Abedi � N. Mazroii � Y. Ghandi � Z. Asemi (&)

Research Center for Biochemistry and Nutrition in Metabolic

Diseases, Kashan University of Medical Sciences, Kashan,

Islamic Republic of Iran

e-mail: asemi_r@yahoo.com

H. Hadaegh

Department of Research and Development of Sahar Bread

Company, Tehran, Islamic Republic of Iran

M. Tajabadi-Ebrahimi

Faculty Member of Science Department, Science Faculty,

Islamic Azad University, Tehran Central Branch, Tehran,

Islamic Republic of Iran

123

Lipids

DOI 10.1007/s11745-014-3901-z

Weight loss via hypocaloric and low-glycemic index

diets as well as increased physical activity are first-line

treatments in the management of T2DM [8, 9]. Further-

more, other strategies for the management of lipid profiles

in diabetic patients have been suggested including the use

of cholesterol-lowering drugs, antioxidant and mineral

supplementation [10, 11]. Recently, a few studies have also

reported that consumption of probiotics and synbiotics can

result in improved metabolic profiles [12–14]. However,

such effects have mainly been observed in animal models

or non-diabetic patients. In addition, data on the effects of

probiotics and synbiotics on serum lipid profiles are con-

flicting. Intake of a synbiotic containing Lactobacillus

acidophilus, fructo-oligosaccharide, inulin and mannitol

for 8 weeks resulted in decreased serum triglycerides

(TAG), total cholesterol (TC) and LDL-C levels as well as

increased HDL-C concentrations in hypercholesterolemic

pigs [15]. Our previous study with healthy pregnant women

showed decreased serum TAG and VLDL-C levels fol-

lowing consumption of synbiotic food containing heat-

resistant Lactobacillus sporogenes (1 9 107 CFU) and

0.04 g inulin as prebiotic per 1 g after 9 weeks [14].

The beneficial effects of probiotics and synbiotics on

lipid profiles might be explained by the production of short

chain fatty acids (SCFA) [16] as well as carbon disulfide

and methyl acetate [17], assimilation of cholesterol in the

gastrointestinal tract, enzymatic deconjugation of bile acids

[18, 19] and conversion of cholesterol into coprostanol in

the gut [20]. We are unaware of any study evaluating the

effects of daily consumption of probiotic and synbiotic

breads on lipid profiles among patients with T2DM. The

aim of the current study was, therefore, to investigate the

effects of daily consumption of synbiotic bread on lipid

profiles in T2DM patients.

Participants

This randomized, double-blinded, controlled, clinical trial

was conducted in Kashan, Iran, during October 2013–

December 2013. To estimate the required sample size, we

used the appropriate formula, where the type 1 (a) and

type 2 errors (b) were considered as 0.05 and 0.20

(power = 80 %), respectively. In addition, serum HDL-C

levels was defined as the key variable and based on earlier

studies [21], the standard deviation of this variable was

14.16 mg/dL. We considered 11.21 mg/dL as the signifi-

cant difference in mean HDL-C between the two groups.

Therefore, the estimated sample size was 25 subjects in

each group. Diagnosis of T2DM was based on the criteria

of the American Diabetes Association [22]: those with one

of the following criteria were considered as having T2DM:

fasting plasma glucose (FPG) C 126 mg/dL, blood sugar

(BS) 2-h pp C 200 mg/dL and HbA1C C 6.5 %. Individ-

uals with the above-mentioned inclusion criteria were

called in for participation in the study from those that

attended Golabchi Diabetes Clinic affiliated to Kashan

University of Medical Sciences, Kashan, Iran. Subjects

were not included if they were pregnant, using insulin or

vitamin supplements, or had chronic kidney, liver, lung and

chronic or acute inflammatory disease, heart valve disease,

short bowel syndrome or allergies. The study was con-

ducted according to the guidelines laid down in the Dec-

laration of Helsinki. The ethical committee of Kashan

University of Medical Sciences approved the study and

informed written consent was obtained from all

participants.

Study Procedure

To obtain detailed information about the dietary intakes of

study participants, all patients entered into a 2-week run-in

period; during which they were advised to refrain from

taking any other synbiotic and probiotic foods. During the

run-in period, participants were asked to record their

dietary intakes for three non-consecutive days. At the end

of the run-in period, subjects were randomly assigned to

the initial arm of the study to receive either probiotic,

synbiotic or control breads for 8 weeks. Participants were

asked not to alter their routine physical activity or usual

diets and to not consume any synbiotic, probiotic and

fermented products other than those provided for them.

Probiotic, synbiotic or control breads were supplied to

participants every 3 days. Compliance with the con-

sumption of foods was monitored once a week through

phone interviews and by the use of 3-day dietary records

completed in each phase of intervention. The dietary

records were based on estimated values in household

measurements. To obtain nutrient intakes of participants

based on these three-day food diaries in each phase, we

used Nutritionist IV software (First Databank, San Bruno,

CA) modified for Iranian foods.

Assessment of Variables

Anthropometric measurements were performed at baseline

and after 8 weeks of intervention in each arm. Body weight

was measured in an overnight fasting state, without shoes

and in minimal clothing with a digital scale (Seca, Ham-

burg, Germany) to the nearest 0.1 kg. Height was measured

using a non-stretched tape measure (Seca, Hamburg, Ger-

many) to the nearest 0.1 cm. The BMI was calculated as

weight in kg divided by the height in meters squared.

Lipids

123

Biochemical Assessment

Fasting blood samples (10 mL) were taken at baseline and

after the 8-week intervention at Kashan reference labo-

ratory after an overnight fast. Fasting plasma glucose

(FPG), serum TAG, TC, HDL-C and LDL-C concentra-

tions were assayed using the standard enzymatic methods

with commercial kits (Parsazmun, Tehran, Iran). Serum

VLDL-C concentration was assessed by photometric

methods in which LDL-C, HDL-C and chylomicrons were

blocked by antibodies and finally the VLDL-C concen-

tration was evaluated by enzymatic measurement and with

available kits (Zistshimi, Tehran, Iran). All inter- and

intra-assay CV for lipid profile measurements were less

than 5 %.

Synbiotic, Probiotic and Control Breads

The synbiotic bread contained a viable and heat-resistant

probiotic, L. sporogenes (1 9 108 CFU) and 0.07 g inulin

(HPX) as prebiotic per 1 g. The probiotic bread containing

L. sporogenes (1 9 108 CFU) per 1 g. The control bread

(the same substance without probiotic bacteria and prebi-

otic inulin) was packed in identical packages and coded by

the producer to guarantee blinding. Patients were asked to

consume the synbiotic, probiotic and control breads three

times a day for a total of 120 g/day. Due to viability against

the high temperature, acidity of the stomach, bile acids and

growth at physiological conditions as well as beneficial

effects on the intestinal environment, stool frequency and

characteristics [23], we selected L. sporogenes over other

Lactobacillus species. The synbiotic, probiotic and control

breads were provided by the Sahar Bread Company, Teh-

ran, Iran.

Statistical Analysis

To ensure the normal distribution of variables, the Kol-

mogorov–Smirnov test were applied. Log transformation

was performed for non-normally distributed variables. The

analyses were done based on the intention-to-treat

approach. Missing values were treated based on the Last-

Observation-Carried-Forward (LOCF) method. LOCF

ignores whether the participant’s condition was improving

or deteriorating at the time of dropout but instead freezes

outcomes at the value observed before dropout (i.e., last

observation). One-way analysis of variance (ANOVA) was

used to detect differences in general characteristics and

dietary intakes between the three groups. To determine

the effect of probiotic, synbiotic and control breads on

lipid profiles, we applied repeated measures analysis of

variance. In these analyses, the treatments (probiotic,

synbiotic and control breads) were regarded as between-

subject factors and time was considered as within-subject

factor. The changes across three groups were compared

using one-way analysis of variance with Bonferoni post-

hoc pair-wise comparisons. To assess if the magnitude of

the change depended on the baseline values, age and

baseline BMI, we conditioned all analyses on baseline

values, age and baseline BMI to avoid potential bias. These

adjustments were done using analysis of covariance

(ANCOVA). All statistical analyses were done using the

Statistical Package for Social Science version 17 (SPSS

Inc., Chicago, IL, USA).

Results

A total of 78 patients (15 males and 63 females) with

T2DM were recruited in the study. After matching for age,

sex, BMI, type and dosage of oral hypoglycemic medica-

tions, and dosage of lowering lipid medications, partici-

pants were randomly assigned to receive either synbiotic

(n = 26) or probiotic (n = 26) or control breads (n = 26)

for 8 weeks. The exclusions in the control bread were two

patients [insulin therapy (n = 1) and supplement therapy

(n = 1)]. Among individuals in the probiotic bread group,

two persons [antibiotic treatment (n = 1) and withdrawal

(n = 1)] and in synbiotic bread group, two persons [with-

drawal (n = 1) and supplement therapy (n = 1)] dropped

out. Finally, 72 participants [synbiotic bread (n = 24),

probiotic bread (n = 24) and control bread (n = 24)]

completed the trial (Fig. 1). Therefore, 24/26 persons of

each group were available for follow-up measures. How-

ever, as the analysis was done based on intention-to-treat

approach, all 78 patients (26 in each group) were included

in the final analysis.

No serious adverse events were reported throughout

the study. Comparing the anthropometric measures at

baseline and after intervention, we found no significant

differences in weight and BMI between the three groups

(Table 1).

No statistically significant difference was seen between

the three groups in dietary intake of energy, carbohydrate,

protein, fat, saturated fatty acids (SFA), polyunsaturated

fatty acids (PUFA), monounsaturated fatty acids (MUFA),

cholesterol or total dietary fiber (TDF) (Table 2).

Consumption of the synbiotic bread, compared to the

probiotic and control breads, led to a significant decrease in

serum TAG (-26.7 ± 60.3 vs. -31.6 ± 80.0 and

33.0 ± 85.9 mg/dL, respectively, P = 0.005), VLDL-C

(-5.3 ± 12.1 vs. -6.3 ± 16.0 and 6.6 ± 17.2 mg/dL,

Lipids

123

respectively, P = 0.005), TC/HDL-C (-0.5 ± 0.8 vs.

-0.6 ± 1.1 and 4.1 ± 1.1, respectively, P = 0.002) and a

significant increase in serum HDL-C levels (2.2 ± 6.8 vs.

2.2 ± 8.0 and -3.1 ± 7.5 mg/dL, respectively, P = 0.01)

(Table 3). No significant effect of synbiotic bread con-

sumption on FPG, TC, LDL-C and non-HDL-C levels was

seen. In addition, in a pair-wise comparison between

synbiotic and probiotic groups, no significant differences

was seen.

When we adjusted the analysis for baseline values, the

above-mentioned findings remained significant, except for

TC (P = 0.01), HDL-C (P = 0.07) and non-HDL-C

(P = 0.003) (Table 4). Adjustment for age and baseline

BMI did not affect our findings.

Lost to follow-up (n=2)Insulin therapy (n=1)Supplement use (n=1)

Analyzed (n=26)

Fol

low

-up

Ana

lysi

s

Lost to follow-up (n=2)Antibiotic use (n=1)Withdraw (n=1)

Lost to follow-up (n=2)Withdraw (n=1)

Supplement use (n=1)

Analyzed (n=26) Analyzed (n=26)

Randomized (n=78)

Assessed for eligibility (n= 100)

Excluded (n=22) Not living in Kashan (n=6) Taking excluded insulin therapy

(n=16)

Enr

ollm

ent

Allo

cati

on

Allocated to probiotic bread(n=26)

Allocated to synbiotic bread(n=26)

Allocated to control bread (n=26)

Fig. 1 Summary of patient

flow diagram

Table 1 General

characteristics of study

participants

a P values were computed by

the ANOVA testb Values are presented as

means ± SD

Control bread

(n = 26)

Probiotic bread

(n = 26)

Synbiotic bread

(n = 26)

P valuea

Age (years) 53.1 ± 7.5b 52.3 ± 8.2 52.3 ± 10.8 0.93

Height (cm) 158.5 ± 7.7 159.1 ± 8.8 161.8 ± 10.6 0.37

Weight at study baseline (kg) 76.9 ± 12.3 74.4 ± 14.3 80.8 ± 15.5 0.26

Weight at end-of-trial (kg) 76.9 ± 12.1 74.2 ± 14.4 80.8 ± 15.6 0.24

Weight change (kg) -0.05 ± 1.6 -0.2 ± 1.4 0.03 ± 1.9 0.92

BMI at study baseline (kg/m2) 30.6 ± 4.1 29.5 ± 5.7 30.9 ± 6.0 0.57

BMI at end-of-trial (kg/m2) 30.6 ± 4.1 29.4 ± 5.9 30.9 ± 5.9 0.56

BMI change (kg/m2) -0.02 ± 0.6 -0.04 ± 0.6 0.02 ± 0.8 0.97

Metformin use (number/day) 2.1 ± 0.9 2.0 ± 1.1 2.1 ± 1.2 0.92

Glibenclamide use (number/day) 2.1 ± 0.8 1.9 ± 1.1 2.0 ± 1.3 0.74

Gemfibrozil use (number/day) 0.1 ± 0.4 0.1 ± 0.3 0.1 ± 0.3 0.97

Atorvastatin use (number/day) 0.5 ± 0.6 0.5 ± 0.5 0.5 ± 0.5 0.90

Lipids

123

However, when we carried out analysis without the

intention-to-treat approach (excluding subjects with insulin

and supplement therapy, antibiotic use and withdraw), no

significant change was seen in our findings.

Discussion

The current study demonstrated that consumption of syn-

biotic bread for 8 weeks among diabetic patients has ben-

eficial effects on serum TAG, VLDL-C, TC/HDL-C and

HDL-C levels; however, no change was observed in FPG,

serum TC, LDL-C and non-HDL-C levels. To the best of

our knowledge, this is the first study to examine the effect

of synbiotic and probiotic breads on lipid profiles of dia-

betic patients.

Patients with T2DM are susceptible to metabolic

complications and dyslipidemia [5]. In line with our study,

Liong et al. [15] reported decreased serum TAG, TC and

LDL-C levels as well as increased concentrations of HDL-

C in hypercholesterolemic pigs after 8 weeks following

the consumption of a synbiotic food containing L. aci-

dophilus, fructo-oligosaccharide, inulin and mannitol.

Furthermore, our previous study involving healthy preg-

nant women showed decreased serum TAG and VLDL-C

after consumption of synbiotic food containing heat-

resistant L. sporogenes (1 9 107 CFU) and 0.04 g inulin

as a prebiotic per 1 g for 9 weeks [14]. The same results

were seen among pregnant women who received probiotic

yogurt containing L. acidophilus LA5 and Bifidobacterium

animalis BB12 with a total of min 1 9 107 CFU after

9 weeks [24] and among young healthy subjects who

received a diet with inulin-enriched pasta after 5 weeks

[25]. In contrast, some investigators did not find a sig-

nificant effect of synbiotic and probiotic supplementation

on lipid profiles. For instance, our previous study among

patients with T2DM did not show any significant differ-

ence in lipid profiles following the consumption of a

synbiotic food containing L. sporogenes (1 9 107 CFU)

and 0.04 g inulin as prebiotic per 1 g after 6 weeks [21].

Consumption of Kefir did not show any effect on serum

lipid profiles among hyperlipidemic men after 4 weeks

[26]. Similar findings were seen with consumption of a

combination of L. acidophilus and B. animalis among

healthy women for 4 weeks [27].

The TAG and VLDL-C decreasing effects as well as the

HDL-C increasing effect of the synbiotic and probiotic

breads may be due to SCFA production especially propi-

onate, which in turn could inhibit the synthesis of fatty

acids in the liver, thereby decreasing the TAG and VLDL-

C secretion rate and serum TAG and VLDL-C levels [28].

Furthermore, inulin has been shown to be a determining

factor in decreased expression of the enzymes involved in

fatty acid synthesis [29] and suppressed gene expression of

lipogenic enzymes [30]. Synbiotics and probiotics may also

affect serum lipid profiles through their immune-modula-

tory effects [31], TLR4 signaling and pro-inflammatory

cytokines [32].

Limitations

Several limitations must be considered in the interpreta-

tion of our findings. Firstly, we did not assess the effects

of synbiotic and probiotic breads on fecal SCFA. Sec-

ondly, we did not assess the effects of synbiotic and

probiotic breads on inflammatory factors such as TNF-aand IL6.

In conclusion, consumption of the synbiotic bread for

8 weeks among patients with T2DM resulted in a signifi-

cant decrease in serum TAG, VLDL-C, TC/HDL-C and a

significant rise in serum HDL-C levels compared with

probiotic and control breads, but did not affect FPG, TC,

LDL-C and non-HDL-C levels. Further studies are needed

to determination the mechanisms responsible for these

effects.

Table 2 Dietary intakes of

study participants throughout

the study

SFA saturated fatty acids, PUFA

polyunsaturated fatty acids,

MUFA monounsaturated fatty

acids, TDF total dietary fibera P values were computed by

the ANOVA testb Values are presented as

means ± SD

Control bread

(n = 26)

Probiotic bread

(n = 26)

Synbiotic bread

(n = 26)

P valuea

Energy (kcal/day) 2,202 ± 234b 2,197 ± 294 2,281 ± 226 0.41

Carbohydrates (g/day) 246.7 ± 50.7 261.8 ± 46.9 273.5 ± 41.9 0.12

Protein (g/day) 72.0 ± 10.8 73.9 ± 10.9 76.8 ± 11.7 0.30

Fat (g/day) 106.2 ± 20.1 98.7 ± 19.9 101.8 ± 21.2 0.41

SFA (g/day) 23.1 ± 5.7 22.3 ± 4.7 24.3 ± 5.3 0.39

PUFA (g/day) 45.8 ± 12.5 42.8 ± 12.7 39.6 ± 13.1 0.22

MUFA (g/day) 27.5 ± 7.3 26.5 ± 7.4 30.2 ± 11.1 0.29

Cholesterol (mg/day) 179.4 ± 98.3 179.5 ± 81.1 186.9 ± 84.9 0.94

TDF (g/day) 16.0 ± 3.4 16.7 ± 4.6 17.6 ± 3.9 0.35

Lipids

123

Acknowledgments The present study was supported by a Grant

(No. 92107) from the Vice-Chancellor for Research, KUMS, Kashan,

Iran. The authors would like to thank the staff of Gholabchi Clinic

(Kashan, Iran) for their assistance in this project. We are grateful to

the Research and Development Department of Sahar Bread Company,

Tehran, Iran that provided probiotic and synbiotic products for the

present study. Furthermore, we are grateful to the Research and

Development Department of Tak Gene Zist Company, Tehran, Iran

that provided Lactobacillus sporogenes for this study.

Conflict of interest None of the authors had any personal or

financial conflict of interest.

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2. Ruggiero L, Castillo A, Quinn L, Hochwert M (2012) Translation

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of community health workers. Curr Diab Rep 12:127–137Ta

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Table 4 Adjusted changes in lipid profiles in diabetic patients that

received either probiotic or synbiotic or control breads

Controlbread(n = 26)

Probioticbread(n = 26)

Synbioticbread(n = 26)

P valuea

FPG (mg/dL)

Model 1b 10.5 ± 10.1d -14.2 ± 10.0 -17.6 ± 9.9 0.10

Model 2c 0.2 ± 11.4 -6.4 ± 11.5 -15.0 ± 11.4 0.64

TAG (mg/dL)

Model 1 27.7 ± 12.4 -34.3 ± 12.4 -18.7 ± 12.5 0.002

Model 2 33.9 ± 15.0 -33.0 ± 15.1 -26.3 ± 15.0 0.004

VLDL-C (mg/dL)

Model 1 5.5 ± 2.5 -6.9 ± 2.5 -3.7 ± 2.5 0.002

Model 2 6.8 ± 3.0 -6.6 ± 3.0 -5.3 ± 3.0 0.004

TC (mg/dL)

Model 1 6.5 ± 6.4 -14.8 ± 6.3 -18.6 ± 6.4 0.01

Model 2 -0.2 ± 8.0 -16.6 ± 8.0 -10.1 ± 8.0 0.35

LDL-C (mg/dL)

Model 1 3.1 ± 5.5 -10.1 ± 5.4 -16.1 ± 5.5 0.05

Model 2 -3.9 ± 7.4 -12.5 ± 7.5 -6.7 ± 7.4 0.70

HDL-C (mg/dL)

Model 1 -2.1 ± 1.4 2.2 ± 1.4 1.2 ± 1.4 0.07

Model 2 -3.1 ± 1.4 2.5 ± 1.4 1.9 ± 1.4 0.01

TC/HDL-C

Model 1 0.3 ± 0.1 -0.6 ± 0.1 -0.5 ± 0.1 \0.001

Model 2 0.3 ± 0.2 -0.6 ± 0.2 -0.5 ± 0.2 0.001

Non-HDL-C (mg/dL)

Model 1 7.7 ± 5.9 -17.1 ± 5.8 -18.8 ± 5.9 0.003

Model 2 2.9 ± 7.5 -19.1 ± 7.5 -11.9 ± 7.5 0.11

FPG fasting plasma glucose, TAG triacylglycerols, TC total cholesterol,HDL-C high density lipoprotein-cholesterol, VLDL-C very low densitylipoprotein-cholesterol, LDL-C low density lipoprotein-cholesterola P values were computed by ANCOVA testb Adjusted for baseline valuesc Adjusted for age and baseline BMId Values are presented as means ± SE

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