This paper is part of NMJ's 2018 Microbiome Special Issue. Download the full issue here.
Samimi M, Dadkhah A, Haddad Kashani H, et al. The effects of synbiotic supplementation on metabolic status in women with polycystic ovary syndrome: a randomized double-blind clinical trial [published online ahead of print March 12, 2018]. Probiotics Antimicrob Proteins.
A 12-week randomized double-blind placebo-controlled clinical trial
To determine the effect of synbiotic supplementation on markers of glycemic control and cardiometabolic risk in women with polycystic ovary syndrome (PCOS).
Sixty women, aged 18 to 40 years, with PCOS diagnosis based on the Rotterdam criteria; women who reported use of probiotic or synbiotic supplementation within 3 months of the trial were excluded. Further exclusion criteria included smoking, pregnancy, and hyperandrogenism and/or anovulation due to other causes (eg, Cushing syndrome, androgen-secreting tumors, hyperprolactinemia, thyroid dysfunction).
Participants in the experimental group (n=30) received capsules containing Lactobacillus acidophilus strain T16, Lactobacillus casei strain T2, and Bifidobacterium bifidum strain T1 (2 x 109 CFU/g of each) plus 800 mg inulin. The control group (n=30) received capsules containing inulin only. Dosing was 1 capsule taken orally once a day for 12 weeks. Compliance was determined upon return of the medication container at the end of the trial.
All participants were advised to maintain their routine dietary and lifestyle habits throughout the study. A 3-day food record and 3 physical activity records were completed during weeks 0, 3, 6, 9, and 12.
Study Parameters Assessed
Labs were obtained at weeks 0 and 12 to assess markers of glycemic control, including fasting plasma glucose (FPG), serum insulin, homeostatic model assessment for insulin resistance (HOMA-IR), and the quantitative insulin sensitivity check index (QUICKI), and measures of cardiometabolic risk, including serum triglycerides, total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), very low-density lipoprotein cholesterol (VLDL-C), and atherogenic index of plasma (AIP).
Primary Outcome Measures
Change in markers of glycemic control (FPG, serum insulin, HOMA-IR, and QUICKI) from baseline following 12 weeks of synbiotic supplementation.
Of the 60 women enrolled, 2 from each group withdrew for unspecified reasons. In keeping with the intention-to-treat principle, all participants were included in the final analysis.
Significant improvements in serum insulin levels (P=0.002), HOMA-IR (P=0.002), QUICKI (P<0.001), triglycerides (P=0.003), VLDL-C (P=0.003), and AIP (P=0.03) were observed in the experimental group only. Neither group experienced significant changes in mean weight or BMI. When controlled for age and baseline BMI, FPG levels became significant (P=0.04) and AIP nonsignificant (P=0.06).
Polycystic ovary syndrome has become an increasingly prevalent endocrine disorder, affecting up to 18% of reproductive-aged women.1 Diagnosis, according to the Rotterdam Criteria, requires that 2 of the following criteria are met: chronic oligoovulation/anovulation; hyperandrogenism; and/or polycystic ovarian morphology. However, symptom presentation and severity are highly variable.2 Dysglycemia and dyslipidemia are common findings among many, though not all, women with PCOS. Because PCOS is associated with an increased risk of type 2 diabetes and cardiovascular disease, primary treatment goals include improved insulin sensitivity and normalization of lipid levels.3
Metformin, a first-line conventional intervention for type 2 diabetes and PCOS, is primarily used to regulate serum glucose and insulin levels. As a secondary effect, it may aid in weight loss by lowering serum lipid levels and/or improving PCOS symptomology.4 Metformin-induced alterations in gut microbiota have been shown to contribute to its antidiabetic effects.5 A correlation between gut dysbiosis and diabetes has been documented in several papers.6,7 The same has been reported in PCOS patients: Atypical findings of lower diversity and altered phylogenetic composition have been observed in women with PCOS when compared to controls.8,9
Atypical findings of lower diversity and altered phylogenetic composition have been observed in women with PCOS when compared to controls.
Two studies evaluating the effect of probiotics on hormonal and metabolic markers in PCOS have been conducted. The first, published by Shoaei et al in 2015, reported improvements, though mostly nonsignificant, in markers of glycemic control after 8 weeks of probiotic supplementation.10 A randomized controlled trial published in January 2018 revealed beneficial effects of supplementation on total testosterone, sex hormone–binding globulin (SHBG), modified Ferriman-Gallwey (mFG) scores, high-sensitivity C-reactive protein (hs-CRP), total antioxidant capacity (TAC), and malondialdehyde (MDA) after a 12-week intervention.11
Use of synbiotic supplementation to modulate the microbiome has been of recent interest among researchers. Pairing probiotics with prebiotics to create synbiotics is thought to increase increase survivability of probiotics as they pass through the upper intestinal tract, allowing for more effective delivery into the colon.12 Since 2004, numerous papers have been published with the hope to elucidate the role that synbiotics have on conditions such as metabolic syndrome,13 type 2 diabetes,14,15 gestational diabetes,16 rheumatoid arthritis,17 and nonalcoholic fatty liver disease.18
A total of 3 papers on synbiotics and PCOS have been published, all within this year. The first was a randomized controlled trial aiming to determine the effect of synbiotics on metabolic parameters and apelin-36, a potential marker of insulin sensitivity.19 After 12 weeks of intervention, there was a marked reduction in apelin levels, though no significant improvements in markers of dysglycemia (FBG, 2-hour fasting plasma glucose, hemoglobin A1c [HbA1c], HOMA-IR, QUICKI) or C-reactive protein (CRP) were observed.20 There are inconsistencies in the literature about whether PCOS patients present with low or high apelin levels compared to controls, so the implications of these findings are unclear.21
The present study revealed significant beneficial changes to markers of glycemic control, changes that could possibly reduce overall risk of type 2 diabetes. Improvements were seen in triglycerides, AIP, and VLDL-C; however, other lipid parameters were not significantly impacted. Given that the atherosclerotic cardiovascular disease (ASCVD) risk estimator takes into consideration total cholesterol, LDL-C, and HDL-C, it is unlikely that a direct reduction in cardiovascular risk would be achieved from synbiotic supplementation alone.
Several of this study’s investigators went on to conduct a second study looking at the effect of synbiotic supplementation on hormonal status and biomarkers of inflammation and oxidative stress. The study design was nearly identical to their first. Following 12 weeks of supplementation, levels of SHBG and nitric oxide (NO) increased from baseline, while mFG scores, hs-CRP, free androgen index (FAI), serum insulin, and HOMA-IR fell significantly. There were no significant changes in total testosterone, dehydroepiandrosterone sulfate (DHEA-S), total antioxidant capacity (TAC), glutathione (GSH), or malondialdehyde (MDA).22
It is evident that dysbiosis is a common finding in PCOS, and that interventions that alter gut microbiota composition have the potential to positively impact metabolic, inflammatory, and/or hormonal markers.8,9 Further research to determine the effects of different probiotic strains and dosing would be helpful. Studies comparing probiotics to synbiotics would also provide valuable information. Because the studies thus far have involved women with elevated BMIs, it would be beneficial to conduct a study on women with lean PCOS. In the meantime, addressing gut health, with synbiotic supplementation or other microbiota-modulating therapy, appears to be a worthwhile consideration for our patients with PCOS.
While probiotics and supplements alike are generally considered safe, they may not be safe for all individuals. According to a 2014 systematic review on probiotic safety, populations at risk for adverse effects include critically ill patients in intensive care units, critically ill infants, postoperative and hospitalized patients, and those with immunodeficiency disorders. Probiotics are not necessarily contraindicated in these patients; however, the risk-benefit ratio should be considered.23 In all cases, probiotic/synbiotic quality should be ensured.
A paper written by Lise Alschuler, ND, FABNO, in 2011 outlines quality standards that may be helpful to consider when selecting a probiotic supplement.
- March WA, Moore VM, Willson KJ, Phillips DI, Norman RJ, Davies MJ. The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum Reprod. 2010;25(2):544-551.
- Moran LJ, Norman RJ, Teede HJ. Metabolic risk in PCOS: phenotype and adiposity impact. Trends Endocrinol Metab. 2015;26(3):136-143.
- Bajuk Studen K, Pfeifer M. Cardiometabolic risk in polycystic ovary syndrome [published online ahead of print May 29, 2018]. Endocr Connect.
- Gong L, Goswami S, Giacomini KM, et al. Metformin pathways: pharmacokinetics and pharmacodynamics. Pharmacogenet Genomics. 2012;22(11):820-827.
- Rodriguez J, Hiel S, Delzenne NM. Metformin: old friend, new ways of action-implication of the gut microbiome? Curr Opin Clin Nutr Metab Care. 2018;21(4):294-301.
- Karlsson FH, Tremaroli V, Nookaew I, et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature. 2013;498(7452):99-103.
- Qin J, Li Y, Cai Z, et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature. 2012;490(7418):55-60.
- Lindheim L, Bashir M, J Münzker, et al. Alterations in gut microbiome composition and barrier function are associated with reproductive and metabolic defects in women with polycystic ovary syndrome (PCOS): a pilot study. PLoS One. 2017;12(1).
- Torres PJ, Siakowska M, Banaszewska B, et al. Gut microbial diversity in women with polycystic ovary syndrome correlates with hyperandrogenism. J Clin Endocrinol Metab. 2018;103(4):1502-1511.
- Shoaei T, Heidari-Beni M, Tehrani HG, et al. Effects of probiotic supplementation on pancreatic β-cell function and C-reactive protein in women with polycystic ovary syndrome: a randomized double-blind placebo-controlled clinical trial. Int J Prev Med. 2015;6:27.
- Karamali M, Eghbalpour S, Rajabi S, et al. Effects of probiotic supplementation on hormonal profiles, biomarkers of inflammation and oxidative stress in women with polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial. Arch Iran Med. 2018;21(1):1-7.
- Pandey KR, Naik SR, Vakil BV. Probiotics, prebiotics and synbiotics- a review. J Food Sci Technol. 2015;52(12):7577-7587.
- Rabiei S, Hedayati M, Rashidkhani B, et al. The effects of synbiotic supplementation on body mass index, metabolic and inflammatory biomarkers, and appetite in patients with metabolic syndrome: a triple-blind randomized controlled trial [published online ahead of print April 19, 2018]. J Diet Suppl.
- Akram Kooshki A, Tofighiyan T, Rakhshani MH. Effects of synbiotics on inflammatory markers in patients with type 2 diabetes mellitus. Glob J Health Sci. 2015;7(7 Spec No):1-5.
- Tajabadi-Ebrahimi M, Sharifi N, Farrokhian A, et al. A randomized controlled clinical trial investigating the effect of synbiotic administration on markers of insulin metabolism and lipid profiles in overweight type 2 diabetic patients with coronary heart disease. Exp Clin Endocrinol Diabetes. 2017;125(1):21-27.
- Nabhani Z, Hezaveh SJG, Razmpoosh E, Asghari-Jafarabadi M, Gargari BP. The effects of synbiotic supplementation on insulin resistance/sensitivity, lipid profile and total antioxidant capacity in women with gestational diabetes mellitus: a randomized double blind placebo controlled clinical trial. Diabetes Res Clin Pract. 2018;138:149-157.
- Zamani B, Farshbaf S, Golkar HR, et al. Synbiotic supplementation and the effects on clinical and metabolic responses in patients with rheumatoid arthritis: a randomised, double-blind, placebo-controlled trial. Br J Nutr. 2017;117(8):1095-1102.
- Mofidi F, Poustchi H, Yari Z, et al. Synbiotic supplementation in lean patients with non-alcoholic fatty liver disease: a pilot, randomised, double-blind, placebo-controlled, clinical trial. Br J Nutr. 2017;117(5):662-668.
- Saedii AAF, Kamal AM, Naeem EA, et al. Apelin-36 and copeptin levels in polycystic ovary syndrome. J Infec Dis Treat. 2017;3:1.
- Karimi E, Moini A, Yaseri M, et al. Effects of synbiotic supplementation on metabolic parameters and apelin in women with polycystic ovary syndrome: a randomised double-blind placebo-controlled trial. Br J Nutr. 2018 Feb;119(4):398-406.
- Polak K, Czyzyk A, Simoncini T, et al. New markers of insulin resistance in polycystic ovary syndrome. J Endocrinol Invest. 2017;40(1):1-8.
- Nasri K, Jamilian M, Rahmani E, et al. The effects of synbiotic supplementation on hormonal status, biomarkers of inflammation and oxidative stress in subjects with polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial. BMC Endocr Disord. 2018;18(1):21.
- Didari T, Solki S, Mozaffari S, et al. A systematic review of the safety of probiotics. Expert Opin Drug Saf. 2014;13(2):227-239.