The Effects of Probiotic Supplementation on Genetic and Metabolic Profiles in Patients with Gestational Diabetes Mellitus: a Randomized, Double-Blind, Placebo-Controlled Trial

Abstract

This study was carried out to evaluate the effects of probiotic supplementation on genetic and metabolic profiles in patients with gestational diabetes mellitus (GDM) who were not on oral hypoglycemic agents. This randomized, double-blind, placebo-controlled clinical trial was conducted in 48 patients with GDM. Participants were randomly divided into two groups to intake either probiotic capsule containing Lactobacillus acidophilus, Lactobacillus casei, Bifidobacterium bifidum, Lactobacillus fermentum (2 × 109 CFU/g each) (n = 24) or placebo (n = 24) for 6 weeks. Probiotic intake upregulated peroxisome proliferator-activated receptor gamma (P = 0.01), transforming growth factor beta (P = 0.002) and vascular endothelial growth factor (P = 0.006), and downregulated gene expression of tumor necrosis factor alpha (P = 0.03) in peripheral blood mononuclear cells of subjects with GDM. In addition, probiotic supplementation significantly decreased fasting plasma glucose (β, − 3.43 mg/dL; 95% CI, − 6.48, − 0.38; P = 0.02), serum insulin levels (β, − 2.29 μIU/mL; 95% CI, − 3.60, − 0.99; P = 0.001), and insulin resistance (β, − 0.67; 95% CI, − 1.05, − 0.29; P = 0.001) and significantly increased insulin sensitivity (β, 0.009; 95% CI, 0.004, 0.01; P = 0.001) compared with the placebo. Additionally, consuming probiotic significantly decreased triglycerides (P = 0.02), VLDL-cholesterol (P = 0.02), and total-/HDL-cholesterol ratio (P = 0.006) and significantly increased HDL-cholesterol levels (P = 0.03) compared with the placebo. Finally, probiotic administration led to a significant reduction in plasma malondialdehyde (P < 0.001), and a significant elevation in plasma nitric oxide (P = 0.01) and total antioxidant capacity (P = 0.01) was observed compared with the placebo. Overall, probiotic supplementation for 6 weeks to patients with GDM had beneficial effects on gene expression related to insulin and inflammation, glycemic control, few lipid profiles, inflammatory markers, and oxidative stress.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3

References

  1. 1.

    Patti AM, Giglio RV, Pafili K, Rizzo M, Papanas N (2018) Pharmacotherapy for gestational diabetes. Expert Opin Pharmacother 19:1407–1414. https://doi.org/10.1080/14656566.2018.1509955

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    American Diabetes Association (2009) Standards of medical care in diabetes. Diabetes Care 32(Suppl 1):S13–S61. https://doi.org/10.2337/dc09-S013.

    Article  PubMed Central  Google Scholar 

  3. 3.

    Hossein-Nezhad A, Maghbooli Z, Vassigh AR, Larijani B (2007) Prevalence of gestational diabetes mellitus and pregnancy outcomes in Iranian women. Taiwan J Obstet Gynecol 46:236–241

    Article  Google Scholar 

  4. 4.

    Gao Y, She R, Sha W (2017) Gestational diabetes mellitus is associated with decreased adipose and placenta peroxisome proliferator-activator receptor gamma expression in a Chinese population. Oncotarget 8:113928–113937. https://doi.org/10.18632/oncotarget.23043

    Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Zhao Q, Yang D, Gao L, Zhao M, He X, Zhu M, Tian C, Liu G, Li L, Hu C (2018) Down-regulation of peroxisome proliferator activated receptor gamma (PPARgamma) in placenta correlates to hyperglycemia in offspring at young adulthood following exposure to gestational diabetes mellitus. J Diabetes Investig. https://doi.org/10.1111/jdi.12928

  6. 6.

    Rueangdetnarong H, Sekararithi R, Jaiwongkam T, Kumfu S, Chattipakorn N, Tongsong T, Jatavan P (2018) Comparisons of the oxidative stress biomarkers levels in gestational diabetes mellitus (GDM) and non-GDM among Thai population: cohort study. Endocr Connect 7:681–687. https://doi.org/10.1530/EC-18-0093

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Roca-Rodriguez MM, Lopez-Tinoco C, Fernandez-Deudero A, Murri M, García-Palacios MV, García-Valero MA, Tinahones-Madueño FJ, Aguilar-Diosdado M (2012) Adipokines and metabolic syndrome risk factors in women with previous gestational diabetes mellitus. Diabetes Metab Res Rev 28:542–548. https://doi.org/10.1002/dmrr.2313

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Dolatkhah N, Hajifaraji M, Abbasalizadeh F, Aghamohammadzadeh N, Mehrabi Y, Abbasi MM (2015) Is there a value for probiotic supplements in gestational diabetes mellitus? A randomized clinical trial. J Health Popul Nutr 33:25. https://doi.org/10.1186/s41043-015-0034-9

    Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Karamali M, Dadkhah F, Sadrkhanlou M, Jamilian M, Ahmadi S, Tajabadi-Ebrahimi M, Jafari P, Asemi Z (2016) Effects of probiotic supplementation on glycaemic control and lipid profiles in gestational diabetes: a randomized, double-blind, placebo-controlled trial. Diabetes Metab 42:234–241. https://doi.org/10.1016/j.diabet.2016.04.009

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Taylor BL, Woodfall GE, Sheedy KE, O'Riley ML, Rainbow KA, Bramwell EL, Kellow NJ (2017) Effect of probiotics on metabolic outcomes in pregnant women with gestational diabetes: a systematic review and meta-analysis of randomized controlled trials. Nutrients 9. https://doi.org/10.3390/nu9050461

  11. 11.

    Lindsay KL, Kennelly M, Culliton M, Smith T, Maguire OC, Shanahan F, Brennan L, McAuliffe FM (2014) Probiotics in obese pregnancy do not reduce maternal fasting glucose: a double-blind, placebo-controlled, randomized trial (Probiotics in Pregnancy Study). Am J Clin Nutr 99:1432–1439. https://doi.org/10.3945/ajcn.113.079723

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Zheng J, Feng Q, Zheng S, Xiao X (2018) The effects of probiotics supplementation on metabolic health in pregnant women: an evidence based meta-analysis. PLoS One 13:e0197771. https://doi.org/10.1371/journal.pone.0197771

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    American Diabetes Association (2014) Diagnosis and classification of diabetes mellitus. Diabetes Care 37(Suppl 1):S81–S90. https://doi.org/10.2337/dc14-S081

    Article  Google Scholar 

  14. 14.

    Ainsworth BE, Haskell WL, Whitt MC, Irwin ML, Swartz AM, Strath SJ, O'Brien WL, Bassett DR Jr, Schmitz KH, Emplaincourt PO, Jacobs DR Jr, Leon AS (2000) Compendium of physical activities: an update of activity codes and MET intensities. Med Sci Sports Exerc 32:S498–S504

    CAS  Article  Google Scholar 

  15. 15.

    Pisprasert V, Ingram KH, Lopez-Davila MF, Munoz AJ, Garvey WT (2013) Limitations in the use of indices using glucose and insulin levels to predict insulin sensitivity: impact of race and gender and superiority of the indices derived from oral glucose tolerance test in African Americans. Diabetes Care 36:845–853. https://doi.org/10.2337/dc12-0840

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Tatsch E, Bochi GV, Pereira Rda S, Kober H, Agertt VA, de Campos MM, Gomes P, Duarte MM, Moresco RN (2011) A simple and inexpensive automated technique for measurement of serum nitrite/nitrate. Clin Biochem 44:348–350. https://doi.org/10.1016/j.clinbiochem.2010.12.011

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Benzie IF, Strain JJ (1996) The ferric reducing ability of plasma (FRAP) as a measure of "antioxidant power": the FRAP assay. Anal Biochem 239:70–76

    CAS  Article  Google Scholar 

  18. 18.

    Beutler E, Gelbart T (1985) Plasma glutathione in health and in patients with malignant disease. J Lab Clin Med 105:581–584

    CAS  PubMed  Google Scholar 

  19. 19.

    Janero DR (1990) Malondialdehyde and thiobarbituric acid-reactivity as diagnostic indices of lipid peroxidation and peroxidative tissue injury. Free Radic Biol Med 9:515–540

    CAS  Article  Google Scholar 

  20. 20.

    Gmelig-Meyling F, Waldmann TA (1980) Separation of human blood monocytes and lymphocytes on a continuous Percoll gradient. J Immunol Methods 33:1–9

    CAS  Article  Google Scholar 

  21. 21.

    Tamtaji OR, Kouchaki E, Salami M, Aghadavod E, Akbari E, Tajabadi-Ebrahimi M, Asemi Z (2017) The effects of probiotic supplementation on gene expression related to inflammation, insulin, and lipids in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled trial. J Am Coll Nutr 36:660–665

    CAS  Article  Google Scholar 

  22. 22.

    Borzabadi S, Oryan S, Eidi A, Aghadavod E, Daneshvar Kakhaki R, Tamtaji OR, Taghizadeh M, Asemi Z (2018) The effects of probiotic supplementation on gene expression related to inflammation, insulin and lipid in patients with Parkinson's disease: a randomized, double-blind, placebo controlled trial. Arch Iran Med 21:289–295

    PubMed  Google Scholar 

  23. 23.

    Huang L, Luo L, Zhang Y, Wang Z, Xia Z (2018) Effects of the dietary probiotic, Enterococcus faecium NCIMB11181, on the intestinal barrier and system immune status in Escherichia coli O78-challenged broiler chickens. Probiotics Antimicrob Proteins. https://doi.org/10.1007/s12602-018-9434-7

  24. 24.

    Liu H, Hou C, Wang G, Jia H, Yu H, Zeng X, Thacker PA, Zhang G, Qiao S (2017) Lactobacillus reuteri I5007 modulates intestinal host defense peptide expression in the model of IPEC-J2 cells and neonatal piglets. Nutrients 9. https://doi.org/10.3390/nu9060559

  25. 25.

    Wang Y, Xie J, Li Y, Dong S, Liu H, Chen J, Wang Y, Zhao S, Zhang Y, Zhang H (2016) Probiotic Lactobacillus casei Zhang reduces pro-inflammatory cytokine production and hepatic inflammation in a rat model of acute liver failure. Eur J Nutr 55:821–831. https://doi.org/10.1007/s00394-015-0904-3

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Olijhoek JK, van der Graaf Y, Banga JD, Algra A, Rabelink TJ, Visseren FL (2004) The metabolic syndrome is associated with advanced vascular damage in patients with coronary heart disease, stroke, peripheral arterial disease or abdominal aortic aneurysm. Eur Heart J 25:342–348

    Article  Google Scholar 

  27. 27.

    Yang YS, Su YF, Yang HW, Lee YH, Chou JI, Ueng KC (2014) Lipid-lowering effects of curcumin in patients with metabolic syndrome: a randomized, double-blind, placebo-controlled trial. Phytother Res 28:1770–1777. https://doi.org/10.1002/ptr.5197

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Kuzmicki M, Telejko B, Wawrusiewicz-Kurylonek N, Lipinska D, Pliszka J, Wilk J, Zielinska A, Skibicka J, Szamatowicz J, Kretowski A, Gorska M (2013) The expression of genes involved in NF-kappaB activation in peripheral blood mononuclear cells of patients with gestational diabetes. Eur J Endocrinol 168:419–427. https://doi.org/10.1530/EJE-12-0654

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Chon SJ, Kim SY, Cho NR, Min DL, Hwang YJ, Mamura M (2013) Association of variants in PPARgamma(2), IGF2BP2, and KCNQ1 with a susceptibility to gestational diabetes mellitus in a Korean population. Yonsei Med J 54:352–357. https://doi.org/10.3349/ymj.2013.54.2.352

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Dallanora S, Medeiros de Souza Y, Deon RG, Tracey CA, Freitas-Vilela AA, Wurdig Roesch LF, Hack Mendes R (2018) Do probiotics effectively ameliorate glycemic control during gestational diabetes? A systematic review. Arch Gynecol Obstet 298:477–485. https://doi.org/10.1007/s00404-018-4809-2

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Hyronimus B, Le Marrec C, Urdaci MC (1998) Coagulin, a bacteriocin-like inhibitory substance produced by Bacillus coagulans I4. J Appl Microbiol 85:42–50

    CAS  Article  Google Scholar 

  32. 32.

    Feng Y, Jiang CD, Chang AM, Shi Y, Gao J, Zhu L, Zhang Z (2019) Interactions among insulin resistance, inflammation factors, obesity-related gene polymorphisms, environmental risk factors, and diet in the development of gestational diabetes mellitus. J Matern Fetal Neonatal Med 32:339–347. https://doi.org/10.1080/14767058.2018.1446207

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Roesch LF, Silveira RC, Corso AL, Dobbler PT, Mai V, Rojas BS, Laureano ÁM, Procianoy RS (2017) Diversity and composition of vaginal microbiota of pregnant women at risk for transmitting group B Streptococcus treated with intrapartum penicillin. PLoS One 12:e0169916. https://doi.org/10.1371/journal.pone.0169916

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Blaser M (2011) Antibiotic overuse: stop the killing of beneficial bacteria. Nature 476:393–394. https://doi.org/10.1038/476393a.

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    McNabney SM, Henagan TM (2017) Short chain fatty acids in the colon and peripheral tissues: a focus on butyrate, colon cancer, obesity and insulin resistance. Nutrients 9. https://doi.org/10.3390/nu9121348

  36. 36.

    Miraghajani M, Dehsoukhteh SS, Rafie N, Hamedani SG, Sabihi S, Ghiasvand R (2017) Potential mechanisms linking probiotics to diabetes: a narrative review of the literature. Sao Paulo Med J 135:169–178. https://doi.org/10.1590/1516-3180.2016.0311271216

    Article  PubMed  Google Scholar 

  37. 37.

    Hommelberg PP, Langen RC, Schols AM, Mensink RP, Plat J (2010) Inflammatory signaling in skeletal muscle insulin resistance: green signal for nutritional intervention? Current opinion in clinical nutrition and metabolic care 13:647–655. https://doi.org/10.1097/MCO.0b013e32833f1acd

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Hsu TC, Huang CY, Liu CH, Hsu KC, Chen YH, Tzang BS (2017) Lactobacillus paracasei GMNL-32, Lactobacillus reuteri GMNL-89 and L. reuteri GMNL-263 ameliorate hepatic injuries in lupus-prone mice. Br J Nutr 117:1066–1074. https://doi.org/10.1017/S0007114517001039

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Liu C, Zhu Q, Chang J, Yin Q, Song A, Li Z, Wang E, Lu F (2017) Effects of Lactobacillus casei and Enterococcus faecalis on growth performance, immune function and gut microbiota of suckling piglets. Arch Anim Nutr 71:120–133. https://doi.org/10.1080/1745039X.2017.1283824

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Indrio F, Riezzo G, Tafuri S, Ficarella M, Carlucci B, Bisceglia M, Polimeno L, Francavilla R (2017) Probiotic supplementation in preterm: feeding intolerance and hospital cost. Nutrients 9. https://doi.org/10.3390/nu9090965

  41. 41.

    Ganguli K, Collado MC, Rautava J, Lu L, Satokari R, von Ossowski I, Reunanen J, de Vos WM, Palva A, Isolauri E, Salminen S, Walker WA, Rautava S (2015) Lactobacillus rhamnosus GG and its SpaC pilus adhesin modulate inflammatory responsiveness and TLR-related gene expression in the fetal human gut. Pediatr Res 77:528–535. https://doi.org/10.1038/pr.2015.5

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Aqaeinezhad Rudbane SM, Rahmdel S, Abdollahzadeh SM, Zare M, Bazrafshan A, Mazloomi SM (2018) The efficacy of probiotic supplementation in rheumatoid arthritis: a meta-analysis of randomized, controlled trials. Inflammopharmacology 26:67–76. https://doi.org/10.1007/s10787-017-0436-y

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Lekva T, Bollerslev J, Norwitz ER, Aukrust P, Henriksen T, Ueland T (2015) Aortic stiffness and cardiovascular risk in women with previous gestational diabetes mellitus. PLoS One 10:e0136892. https://doi.org/10.1371/journal.pone.0136892

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Moreli JB, Santos JH, Lorenzon-Ojea AR, Corrêa-Silva S, Fortunato RS, Rocha CR, Rudge MV, Damasceno DC, Bevilacqua E, Calderon IM (2016) Hyperglycemia differentially affects maternal and fetal DNA integrity and DNA damage response. Int J Biol Sci 12:466–477. https://doi.org/10.7150/ijbs.12815

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Tozour J, Delahaye F, Suzuki M, Praiss A, Zhao Y, Cai L, Heo HJ, Greally JM, Hughes F (2018) Intrauterine hyperglycemia is associated with an impaired postnatal response to oxidative damage. Stem Cells Dev 15:683–691. https://doi.org/10.1089/scd.2017.0232

    CAS  Article  Google Scholar 

  46. 46.

    Kalina U, Koyama N, Hosoda T, Nuernberger H, Sato K, Hoelzer D, Herweck F, Manigold T, Singer MV, Rossol S, Böcker U (2002) Enhanced production of IL-18 in butyrate-treated intestinal epithelium by stimulation of the proximal promoter region. Eur J Immunol 32:2635–2643

    CAS  Article  Google Scholar 

  47. 47.

    Vitali B, Ndagijimana M, Cruciani F, Carnevali P, Candela M, Guerzoni ME, Brigidi P (2010) Impact of a synbiotic food on the gut microbial ecology and metabolic profiles. BMC Microbiol 10:4. https://doi.org/10.1186/1471-2180-10-4

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors would like to thank the staff of Naghavi Clinic (Kashan, Iran) for their assistance in this project. We are grateful to thank LactoCare®, Zisttakhmir Company, in Tehran that provided probiotic capsules for the present study.

Funding

This study was supported by the research grant provided by the Research Deputy of Kashan University of Medical Sciences (KAUMS).

Author information

Affiliations

Authors

Contributions

ZA: conception, design, and statistical analysis, drafting of the manuscript, and supervised the study.

MB, AK, EA, FB, AM, RS, and MS: data collection and manuscript drafting.

Corresponding authors

Correspondence to Ahmad Khorshidi or Zatollah Asemi.

Ethics declarations

Competing Interests

The authors declare no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Clinical trial registration number

http://www.irct.ir: IRCT20171010036697N1

This study was registered in the Iranian website (www.irct.ir) for registration of clinical trials (http://www.irct.ir: IRCT20171010036697N1).

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Babadi, M., Khorshidi, A., Aghadavood, E. et al. The Effects of Probiotic Supplementation on Genetic and Metabolic Profiles in Patients with Gestational Diabetes Mellitus: a Randomized, Double-Blind, Placebo-Controlled Trial. Probiotics & Antimicro. Prot. 11, 1227–1235 (2019). https://doi.org/10.1007/s12602-018-9490-z

Download citation

Keywords

  • Probiotic supplementation
  • Gestational diabetes mellitus
  • Metabolic status
  • Insulin resistance
  • Inflammation