Clinical Nutrition 38 (2019) 1594e1598

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Clinical Nutrition
journal homepage: http://www.elsevier.com/locate/clnu

Randomized Control Trials

The effects of probiotic and selenium co-supplementation on mental

health parameters and metabolic profiles in type 2 diabetic patients
with coronary heart disease: A randomized, double-blind,
placebo-controlled trial
Fariba Raygan a, Vahidreza Ostadmohammadi b, Zatollah Asemi b, *
a
Department of Cardiology, School of Medicine, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran
b
Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran

a r t i c l e i n f o s u m m a r y

Article history: Background and aims: The objective of this investigation was to assess the effects of probiotic and se-
Received 3 June 2018 lenium co-supplementation on indicators of mental health and metabolic profiles in diabetic people with
Accepted 4 July 2018 coronary heart disease (CHD).
Methods: This randomized, double-blind, placebo-controlled trial was conducted among 54 diabetic
Keywords: people with CHD. Patients were randomly allocated into two groups to receive either 200 mg/day sele-
Selenium
nium plus 8
109 CFU/day probiotic (n ¼ 27) or placebo (n ¼ 27) for 12 weeks.
Probiotic
Results: Probiotic and selenium co-supplementation significantly decreased Beck Depression Inventory
Mental health
Metabolic profiles
index (b 1.46; 95% CI, 2.61, 0.31; P ¼ 0.01) and Beck Anxiety Inventory index (b 1.23; 95%
Diabetes mellitus CI, 2.33, 0.12; P ¼ 0.02) compared with the placebo. Consuming probiotic plus selenium lowered
fasting plasma glucose (b 10.80 mg/dL; 95% CI, 17.68, 3.92; P ¼ 0.003), serum insulin levels (b 3.42
mIU/mL; 95% CI, 4.93, 1.90; P < 0.001), insulin resistance (b 0.96; 95% CI, 1.45, 0.47; P < 0.001),
and enhanced insulin sensitivity (b 0.01; 95% CI, 0.007, 0.01; P < 0.001) compared with the placebo.
Additionally, co-supplementation reduced triglycerides (b 34.45 mg/dL; 95% CI, 56.18, 12.72;
P ¼ 0.003), VLDL- (b 6.89 mg/dL; 95% CI, 11.23, 2.54; P ¼ 0.003), total cholesterol (b 18.13 mg/dL;
95% CI, 23.42, 2.83; P ¼ 0.02) and high sensitivity C-reactive protein (b 1043.28 ng/mL; 95%
CI, 1929.67, 156.89; P ¼ 0.02), and increased nitric oxide (b 7.86 mmol/L; 95% CI, 5.63, 10.09; P < 0.001),
total antioxidant capacity (b 119.30 mmol/L; 95% CI, 63.04, 175.57; P < 0.001) and total glutathione (b
154.16 mmol/L; 95% CI, 82.57, 225.74; P < 0.001) compared with the placebo.
Conclusions: Probiotic and selenium co-supplementation to diabetic people with CHD improved in-
dicators of mental health and metabolic profiles.
Registered under Clinical Trials.gov Identifier no. http://www.irct.ir: IRCT20170513033941N28.
© 2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

1. Introduction depression, and T2DM and CHD occur together and this status can
cause a vicious circle [4]. Approximately, 30% of the people with
Type 2 diabetes mellitus (T2DM) and obesity are risk factors for T2DM and/or CHD has subthreshold depression and higher than
coronary heart disease (CHD) and stroke [1]. Diabetic patients 40% of those will develop major depressive disorder within two
compared with nondiabetic people bear up to six-fold higher risk of years [5]. Moreover, increased inflammatory markers and oxidative
future CHD [2]. Various factors including obesity, insulin resistance, damage play important roles in the progress of diabetes and
dyslipidemia and hypertension in diabetic patients may affect atherosclerosis [6].
vascular risk [3]. Disorders related to mental health such as It was reported that selenium levels were low in diabetic pa-
tients with peripheral artery disease [7]. In addition, the gut
microbiota plays an important function in host metabolism and has
* Corresponding author. Fax: þ98 31 55463377.
been associated with metabolic disorders and mental health [8].
E-mail address: asemi_r@yahoo.com (Z. Asemi). However, the beneficial effects of only selenium or probiotic

https://doi.org/10.1016/j.clnu.2018.07.017
0261-5614/© 2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
 F. Raygan et al. / Clinical Nutrition 38 (2019) 1594e1598 1595

supplementation on metabolic profiles in patients with T2DM and/ 2.3. Assessment of outcomes
or CHD were previously reported, data on combined selenium and
probiotic supplementation on metabolic profiles in these patients The homeostasis model of assessment-insulin resistance
are limited. In two meta-analyses studies, the beneficial effects of (HOMA-IR) was considered as the primary outcome, but in-
selenium on inflammation and oxidative damage [9] and probiotic dicators of mental health and other metabolic parameters were
on lipid profiles among people with CHD [10] were reported. considered as secondary results. Fasting blood (10 mL) were taken
Combined selenium and probiotic administration may reduce at baseline and after the 12-week intervention. ELISA kits were
complications of people with T2DM and CHD by improving their used to determine insulin (DiaMetra, Milano, Italy) and high
metabolic profiles and attenuating oxidative stress and inflamma- sensitivity C-reactive protein (hs-CRP) (LDN, Nordhorn, Ger-
tion. Nido et al. [11] demonstrated that selenium-enriched pro- many). HOMA-IR and the quantitative insulin sensitivity check
biotic than only selenium or probiotic improved metabolic profiles index (QUICKI) were assessed in accordance with the standard
in an animal study. formulas. Enzymatic kits (Pars Azmun, Tehran, Iran) were applied
Both probiotics and selenium have antidiabetic, antioxidant and to estimate fasting plasma glucose (FPG) and lipid profiles. Nitric
anti-inflammatory effects, therefore we hypothesized that co- oxide (NO) [12], total antioxidant capacity (TAC) [13], total
administration of probiotic and selenium might benefit diabetic glutathione (GSH) [14] and malondialdehyde (MDA) levels [15]
patients diagnosed with CHD. To address the hypotheses, this study were determined by the spectrophotometric test. Inter-assay
was aimed to determine the effects of probiotic and selenium co- and intra-assay coefficient variances (CVs) of metabolic profiles
supplementation on mental health and metabolic status of dia- were lower than 7%
betic patients with CHD.
2.4. Clinical assessment
2. Methods
Beck Depression Inventory (BDI) and Beck Anxiety Inventory
(BAI) developed by Beck et al. were assessed. Quality of sleep was
2.1. Trial design and participants
determined using Pittsburgh Sleep Quality Index (PSQI).
This study was a randomized, double-blinded, placebo-
2.5. Statistical methods and sample size
controlled trial registered with Iranian Clinical Trials website
(http://www.irct.ir: IRCT20170513033941N28). Study participants
Sample size formula for randomized clinical trial were used,
aged 45e85 years old had been diagnosed with both T2DM and
where type one (a) and type two errors (b) were 0.05, and 0.20
CHD. The criteria of the American Diabetes Association and Amer-
(power ¼ 80%), respectively. In a previous study [16], 1.61 as the SD
ican Heart Association were used to diagnose T2DM and 2- and 3-
and 2.30 as the change in mean (d) of HOMA-IR were used. Ac-
vessel CHD, respectively. Study protocol was approved by the
cording to the formula, in each group 25 individuals were required;
research ethics committee of Kashan University of Medical Sciences
after the attrition rate 20% in every group, the sample size was 30
(KAUMS) and informed consent was signed by all participants. The
persons in each group.
study was conducted from December 2017 through March 2018.
The KolmogoroveSmirnov test was used for checking the
Participants reported selenium, probiotic and/or synbiotic con-
normality of data. Differences in anthropometric measures and
sumption within the last 3 months, patients with thyroid disorders,
dietary intakes between the two groups were tested using the
severe renal insufficiency and hepatic failure, and those experi-
independent-samples t-test. To evaluate treatment impacts on
encing an acute myocardial infarction and cardiac surgery within
study variables, we used multiple linear regression models. Dif-
the past 3 months were excluded from the study.
ferences in proportions were evaluated by Chi square test. Statis-
tical significance was set at P-value <0.05. The Statistical Package
2.2. Study procedures for Social Science version 18 (SPSS Inc., Chicago, Illinois, USA) was
used for statistical analyses of this trial.
Initially, study participants were stratified according to their age
and BMI. Then, they were randomly allocated into intervention 3. Results
groups to receive either 200 mg/day selenium as selenium yeast
(Webber Naturals Company, Coquitlam, Canada) plus 8
109 CFU/ Three subjects in the supplements (n ¼ 3) and placebo (n ¼ 3)
day probiotic (LactoCare®, Zisttakhmir Company, Tehran, Iran) groups dropped out for personal reasons (Fig. 1). Finally, 54 patients
containing Lactobacillus acidophilus, Lactobacillus reuteri, Lactoba- [selenium plus probiotic (n ¼ 27) and placebo (n ¼ 27)] finished the
cillus fermentum and Bifidobacterium bifidum (2
109 CFU/g each) trial. Overall, the compliance rate was high, such that more than
or placebo (Barij Essence, Kashan, Iran) (n ¼ 27 each group) for 12 90% of capsules were consumed throughout the study in both
weeks. Computer-generated random numbers were used for groups. No adverse effects were recorded in diabetic patients with
randomization. Randomization and allocation were concealed from CHD after the intake of selenium and probiotic.
both researchers and participants until the completion of final No difference in mean age, anthropometric parameters and
analyses. All process of randomization, enrollment, and partici- METs was seen between the two groups (Table 1).
pants' assignment into the intervention groups were conducted by We observed no significant changes in dietary intake of macro-
a trained nutritionist. Compliance rate was estimated by counting and micronutrients between the two groups (Data not shown).
the pills of placebo, selenium and probiotics in the returned con- Probiotic and selenium co-supplementation decreased BDI
tainers. A 3-day dietary intake record was completed by study (b 1.46; 95% CI, 2.61, 0.31; P ¼ 0.01) and BAI (b 1.23; 95%
participants at week 1, 4, 8 and 12. Nutritionist IV software (First CI, 2.33, 0.12; P ¼ 0.02) compared with the placebo (Table 2).
Databank, San Bruno, CA), adopted for Iranian food pattern, was Consuming probiotic plus selenium lowered FPG (b 10.80 mg/dL;
applied to determine participants' macro- and micro-nutrient in- 95% CI, 17.68, 3.92; P ¼ 0.003), insulin levels (b 3.42 mIU/mL;
takes. The same nutritionist also measured anthropometric pa- 95% CI, 4.93, 1.90; P < 0.001), HOMA-IR (b 0.96; 95%
rameters (Seca, Hamburg, Germany) at the beginning and end of CI, 1.45, 0.47; P < 0.001), and enhanced QUICKI (b 0.01; 95% CI,
the intervention in cardiology clinic. 0.007, 0.01; P < 0.001) compared with the placebo. Additionally, co-
1596 F. Raygan et al. / Clinical Nutrition 38 (2019) 1594e1598

Assessed for eligibility (n=65)

Enrollment
Excluded (n=5)
- Not living in Kashan (n=5)

Randomized (n=60)
Allocation

Allocated to placebo (n=30) Allocated to intervention (n=30)

Lost to follow-up due to Lost to follow-up due to

Follow-up

personal reasons (n=3) personal reasons (n=3)

Analysis

Analyzed (n=27) Analyzed (n=27)

Fig. 1. Summary of patient flow diagram.

4.1. Effect on clinical symptoms

Table 1
General characteristics of study participants.
We demonstrated that consuming probiotic plus selenium by
Placebo group Probiotic plus Pa diabetic people with CHD significantly improved BDI and BAI
(n ¼ 27) selenium group scores, but did not affect PSQI. Intervention studies of selenium
(n ¼ 27)
administration in humans and its effects on depression have pro-
Age (y) 62.4 ± 13.1 64.8 ± 8.3 0.45 posed inconsistent findings. In a study by Mokhber et al. [17],
Gender
100 mg/day selenium administration for 2 months to pregnant
Female 17 (63.0) 16 (59.3) 0.78b
Male 10 (37.0) 11 (40.7)
women prevented postpartum depression. Moreover, probiotic
Height (m) 160.7 ± 8.8 158.9 ± 10.4 0.46 administration for 12 weeks to people with multiple sclerosis
Weight at study baseline (kg) 77.1 ± 13.1 78.7 ± 12.7 0.65 improved mental health parameters [18]. Selenium intake may
Weight at end-of-trial (kg) 77.3 ± 13.0 78.7 ± 12.7 0.68 affect mental health parameters through modulating thyroid
Body weight change (kg) 0.2 ± 1.3 0.1 ± 0.6 0.61
function, which in turn play a role in the reduction of depression
BMI at study baseline (kg/m2) 29.9 ± 5.0 31.4 ± 5.8 0.31
BMI at end-of-trial (kg/m2) 30.0 ± 5.0 31.4 ± 5.7 0.33 [19]. The main mechanisms by which probiotic intake may improve
BMI change (kg/m2) 0.1 ± 0.5 0.02 ± 0.3 0.56 metal health symptoms include the modulation of neurotrans-
Data are means± SDs. mitters and inflammation [20].
BMI, body mass index.
a
Obtained from independent samples t-test. 4.2. Effect on metabolic parameters
b
Obtained from Pearson Chi-square test.

In a study by Wang et al. [21], higher dietary selenium intake

significantly reduced insulin resistance. We have previously showed
supplementation reduced triglycerides (b 34.45 mg/dL; 95% that 200 mg/day selenium intake for 2 months to women with poly-
CI, 56.18, 12.72; P ¼ 0.003), VLDL- (b 6.89 mg/dL; 95% cystic ovary syndrome improved insulin resistance, triglycerides and
CI, 11.23, 2.54; P ¼ 0.003), total cholesterol (b 18.13 mg/dL; 95% VLDL-cholesterol levels, while did not affect other metabolic profiles
CI, 23.42, 2.83; P ¼ 0.02) and hs-CRP (b 1043.28 ng/mL; 95% [22]. Insulin resistance and dyslipidemia lead to peripheral arterial
CI, 1929.67, 156.89; P ¼ 0.02), and increased NO (b 7.86 mmol/L; disorder and endothelial cell dysfunctions, thus increasing risk fac-
95% CI, 5.63, 10.09; P < 0.001), TAC (b 119.30 mmol/L; 95% CI, 63.04, tors for heart failure [23]. Selenium intake may improve glycemic
175.57; P < 0.001) and GSH (b 154.16 mmol/L; 95% CI, 82.57, 225.74; status and lipid profiles through enhancing gene expression of very
P < 0.001) compared with the placebo. Probiotic and selenium co- long chain dehydrogenase and enzymes related to b-oxidation [24].
supplementation did not affect PSQI, other metabolic profiles and In addition, probiotic intake by increasing b-oxidation of long-chain
blood pressures. fatty acids in liver and muscle tissues and decreasing lipid synthesis
in liver may decrease insulin resistance and dyslipidemia [25].
4. Discussion
4.3. Effect on inflammation and oxidative stress
We found that co-supplementation with probiotic and selenium
to diabetic people with CHD improved indicators of mental health This study documented that taking probiotic plus selenium
and metabolic profiles. decreased hs-CRP, and increased NO, TAC and GSH levels, but did
 F. Raygan et al. / Clinical Nutrition 38 (2019) 1594e1598 1597

Table 2
The effect of probiotic and selenium co-supplementation on mental health parameters, cardio-metabolic risk and biomarkers of oxidative stress in type 2 diabetic patients with
coronary heart disease.

Variables Placebo group (n ¼ 27) Probiotic plus selenium group Difference in outcome measures between probiotic plus
(n ¼ 27) selenium and placebo treatment groupsa

Baseline Week 12 Baseline Week 12 b (95% CI) Pb

BDI 24.5 ± 4.1 23.5 ± 3.6 24.9 ± 4.5 22.2 ± 3.8 1.46 (2.61, 0.31) 0.01
BAI 17.9 ± 4.5 16.8 ± 4.7 18.1 ± 4.8 15.7 ± 4.3 1.23 (2.33, 0.12) 0.02
PSQI 8.2 ± 1.9 8.3 ± 2.2 7.9 ± 1.8 7.7 ± 2.1 0.47 (1.56, 0.61) 0.38
FPG (mg/dL) 134.7 ± 43.9 132.6 ± 43.1 142.0 ± 41.9 129.5 ± 45.5 10.80 (17.68, 3.92) 0.003
Insulin (mIU/mL) 11.5 ± 4.8 12.7 ± 4.9 12.9 ± 2.5 10.3 ± 2.7 3.42 (4.93, 1.90) <0.001
HOMA-IR 3.8 ± 2.1 4.1 ± 1.9 4.5 ± 1.4 3.6 ± 1.4 0.96 (1.45, 0.47) <0.001
QUICKI 0.32 ± 0.02 0.31 ± 0.01 0.30 ± 0.01 0.32 ± 0.01 0.01 (0.007, 0.01) <0.001
Triglycerides (mg/dL) 179.9 ± 68.2 179.1 ± 67.9 176.8 ± 76.4 143.7 ± 62.8 34.45 (56.18, 12.72) 0.003
VLDL-cholesterol (mg/dL) 36.0 ± 13.6 35.8 ± 13.6 35.3 ± 15.3 28.7 ± 12.6 6.89 (11.23, 2.54) 0.003
Total cholesterol (mg/dL) 171.6 ± 41.4 174.9 ± 49.3 169.6 ± 29.8 154.6 ± 24.3 18.13 (23.42, 2.83) 0.02
LDL-cholesterol (mg/dL) 90.0 ± 42.7 91.9 ± 50.5 87.5 ± 24.5 79.7 ± 17.6 8.69 (22.09, 4.70) 0.19
HDL-cholesterol (mg/dL) 45.7 ± 8.3 47.3 ± 8.7 46.7 ± 10.7 46.2 ± 9.4 2.22 (5.20, 0.75) 0.14
Total-/HDL-cholesterol ratio 3.8 ± 1.0 3.8 ± 1.4 3.8 ± 0.9 3.4 ± 0.6 1.48 (0.68, 0.12) 0.17
hs-CRP (ng/mL) 2683.9 ± 1812.5 3321.6 ± 2667.4 2618.5 ± 1395.9 2133.3 ± 1127.6 1043.28 (1929.67, 156.89) 0.02
NO (mmol/L) 36.0 ± 8.7 35.4 ± 8.3 36.6 ± 5.7 43.6 ± 6.1 7.86 (5.63, 10.09) <0.001
TAC (mmol/L) 959.6 ± 204.7 944.5 ± 194.0 1062.2 ± 98.3 1141.8 ± 102.9 119.30 (63.04, 175.57) <0.001
GSH (mmol/L) 511.7 ± 117.7 491.9 ± 167.8 542.3 ± 73.9 669.5 ± 149.9 154.16 (82.57, 225.74) <0.001
MDA (mmol/L) 2.4 ± 0.4 2.5 ± 0.4 2.7 ± 0.3 2.7 ± 0.2 0.10 (0.04, 0.25) 0.17
SBP (mmHg) 136.7 ± 9.3 135.9 ± 7.6 134.2 ± 12.6 132.4 ± 9.6 2.64 (6.32, 1.02) 0.15
DBP (mmHg) 78.2 ± 5.1 78.5 ± 5.7 76.8 ± 6.1 77.5 ± 6.8 0.11 (2.54, 2.77) 0.93

Data are mean ±SDs.

BDI, beck depression inventory; BAI, beck anxiety inventory; DBP, diastolic blood pressure; FPG, fasting plasma glucose; GSH, total glutathione; HOMA-IR, homeostasis model
of assessment-estimated insulin resistance; hs-CRP, high-sensitivity C-reactive protein; MDA, malondialdehyde; NO, nitric oxide; PSQI, Pittsburgh Sleep Quality Index;
QUICKI, quantitative insulin sensitivity check index; SBP, systolic blood pressure; TAC, total antioxidant capacity.
a
“Outcome measures” refers to the change in values of measures of interest between baseline and week 12. b [difference in the mean outcomes measures between
treatment groups (probiotic plus selenium group ¼ 1 and placebo group ¼ 0)].
b
Obtained from multiple regression model (adjusted for baseline values of each biochemical variables, age and baseline BMI).

not affect MDA and blood pressures. Selenium-enriched probiotics Acknowledgments

intake for 42 days in an animal model significantly decreased bio-
markers of oxidative stress [26]. Probiotic supplementation for 8 The present study was supported by a grant (no. 96178) from the
weeks to people with rheumatoid arthritis also decreased inflam- Vice-chancellor for Research, KAUMS, Kashan, and Iran.
matory cytokines [27]. Tissue inflammation and oxidative damage
are main pathogenic factors for the progress of diabetic complica- Appendix A. Supplementary data
tions [28]. Therefore, selenium and probiotic intake due to their
anti-inflammatory and antioxidative effects may reduce compli- Supplementary data related to this article can be found at
cations related to diabetes and CHD events. The anti-inflammatory https://doi.org/10.1016/j.clnu.2018.07.017.
and antioxidative effects of selenium may be due to blocking acti-
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