Nine studies reported the effect of probiotics on lipid profiles among 508 subjects. Probiotic agent increased HDL-C (SMD 0.42 mmol/L, 95% CI [0.08, 0.76], P = 0.01). The forest plot of this effect is presented in Fig. 4A. Significant evidence of interstudy heterogeneity was observed (I2 = 71%; P = 0.0005), so the random-effect model was used. These heterogeneities may be due to design difference among the studies, including the difference of probiotic agent and duration of intervention. As shown in Figs. 4B–D, 5, and 6, there were no significant differences in LDL-C, TC, TG, HbA1c, and HOMA-IR between treatment group and control group. Sensitivity analysis was performed by removing the trials one by one to evaluate the reliability of the pooled mean difference, results remained consistent after removing the trials. No significant effects were observed in single species and multispecies. Probiotic use for ≤8 weeks revealed mild increase of HDL-C. However, there is no significant effect on HDL-C in probiotic use for >8 weeks. Subgroup analysis is presented in Table 2.
The publication bias of this meta-analysis was assessed using funnel plot and Egger's test. As shown in Fig. 7A and B, no evidence of significant publication was found by inspection of statistical test (Egger's test, P = 0.161).
In our study, probiotics reduced FBG by 0.61 mmol/L, indicating a modest effect on glycemic control. Abnormal glucose metabolism in T2DM brings risks for many complications, such as nephropathy, retinopathy, and cardiovascular disease. However, even a small reduction in FBG could have important public health consequences. The beneficial effect of probiotics on glucose is not fully understood. The hypothesis that probiotics might be involved in maintenance of normal gut flora and glucose metabolism has received much attention. The gut microbial profiles show reductions in Lactobacillus spp and Bifidobacterium spp with increased plasma “Lipopolysaccharides”(LPS), which accelerate the apoptosis of pancreatic beta cells and cause the molecular onset of insulin resistance and hyperglycemia via “Nuclear Factor kappa B” (NF-κB).[37,38] Chronic systemic inflammation is common in T2DM and metabolism syndrome (MS) and is considered as a risk factor for arteriosclerosis and infarction. Probiotics could affect the structure of gut flora, increase GLP-1 secretion from enteroendocrine L-cells to improve carbohydrate metabolism, and enhance insulin sensitivity of target cells. Improving of intestinal epithelial integrity and permeability, regulation of immune system, and reduction of Toll-like receptor (TLR)-4 signaling are likely to illustrate the hypoglycemic effect of probiotics. Probiotic dairy products demonstrate the beneficial effect on inflammatory factors by influencing the gut microbiota, inhibition of ascorbic acid autoxidation, metal ion chelation, reduction activity and scavenging of superoxide anion free radicals, hydrogen peroxide.[43,44]
In our meta-analysis, probiotics could increase HDL-C by 0.42mmol/L, whereas there were no significant differences in LDL-C, TC and TG between treatment group and control group. Generally, an elevated HDL-C level is regarded as a protective factor reducing the risk of cardiovascular disease. Some studies observed significant effect on blood lipid profiles by using dairy products.[45–47] The beneficial effect of probiotics on blood lipid might be due to the inhibition of dietary cholesterol absorption and the suppression of bile acid reabsorption in the small intestine. Fermentation of food-derived indigestible carbohydrates by probiotics could cause increased production of short-chain fatty acids, which decrease cholesterol concentrations either by inhibiting hepatic cholesterol synthesis or by redistributing cholesterol from plasma to the liver. However, the composition of fermented milk is very complex, the exact role of certain substance should be further investigated. The protective effect of fermented milk on lipid profiles might be explained by the fatty acid and sphingolipids or other ingredient in dairy products rather than probiotics. Moreover, the calcium and protein content of dairy products might play a role. It was reported that some probiotic-free dairy products could decrease serum lipid. Inverse association between the consumption of milk products and the LDL-C/HDL-C ratio was showed.
In order to minimize the risk of confounding factor, all the included studies were randomized controlled trials in this meta-analysis. By using the method of meta-analysis, we increased the sample size and the statistical power. However, there are still some shortcomings. First, we only included studies published in English, causing the risk of publication bias. However, Egger's test showed no significant publication bias, indicating that the unpublished evidence did not affect the results of the meta-analysis. Second, the validity of meta-analysis depended on the quality of included studies. Although all trials selected were randomized and controlled, the quality of included study varied, for instance, the lack of double-blinding increased the risk of expectation bias. Third, all trials had a relatively small sample size and short treatment duration, so the validity of the results was limited. Due to short duration, whether the result of this meta-analysis could be translated into a long-term treatment effect or not is uncertain.
In conclusion, this meta-analysis of available RCTs suggests that probiotics has beneficial effect on FBG and HDL-C in T2DM. Probiotic agents might become a new method for management of T2DM. However, before they can be recommended for use in supportive treatment of T2DM, large-scale and long duration multicenter randomized controlled trials are still required.
1. Guariguata L, Whiting DR, Hambleton I, et al Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract
2. Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res
3. Lefèbvre P, Pierson A. The global challenge of diabetes. World Hosp & Health Serv the Official Journal of the International Hospital Federation
4. Hansen AK, Hansen CHF, Krych L, et al Impact of the gut microbiota on rodent models of human disease. World J Gastroenterol
5. Qin J, Li R, Raes J, et al A human gut microbial gene catalogue established by metagenomic sequencing. Nature
6. Bienenstock J, Kunze W, Forsythe P. Microbiota and the gut-brain axis. Nutr Rev
2015; 73 (suppl 1):28–31.
7. Panwar H, Rashmi HM, Batish VK, et al Probiotics as potential biotherapeutics in the management of type 2 diabetes—prospects and perspectives. Diabetes Metab Res Rev
8. Delzenne NM, Cani PD. Gut microflora is a key player in host energy homeostasis. Med Sci
9. Larsen N, Vogensen FK, van den Berg FWJ, et al Gut microbiota in human adults with type 2 diabetes differs from non-diabetic adults. PloS One
10. Lê K-A, Li Y, Xu X, et al Alterations in fecal Lactobacillus and Bifidobacterium species in type 2 diabetic patients in Southern China population. Front Physiol
11. Joint FAO. WHO Working Group Report on Drafting Guidelines for the Evaluation of Probiotics in Food London, Ontario, Canada, April 30 and May 1, 2002. 2014.
12. Szajewska H, Skórka a, Ruszczyński M, et al Meta-analysis: lactobacillus GG for treating acute diarrhoea in children. Aliment Pharmacol Thers
13. St-Onge M-P, Farnworth ER, Savard T, et al Kefir consumption does not alter plasma lipid levels or cholesterol fractional synthesis rates relative to milk in hyperlipidemic men: a randomized controlled trial [ISRCTN10820810]. BMC Complement Altern Med
14. Ooi L-G, Liong M-T. Cholesterol-lowering effects of probiotics and prebiotics: a review of in vivo and in vitro findings. Int J Mol Sci
15. Begley M, Hill C, Gahan CGM. Bile salt hydrolase activity in probiotics. Appl Environ Microbiol
16. Patel AK, Singhania RR, Pandey A, et al Probiotic bile salt hydrolase: current developments and perspectives. Appl Biochem Biotechnol
17. Guo Z, Liu XM, Zhang QX, et al Influence of consumption of probiotics on the plasma lipid profile: a meta-analysis of randomised controlled trials. Nutr Metab Cardiovasc Dis
18. Li Z, Yang S, Lin H, et al Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology
19. Tabuchi M, Ozaki M, Tamura A, et al Antidiabetic effect of Lactobacillus GG in streptozotocin-induced diabetic rats. Biosci Biotechnol Biochem
20. Kootte RS, Vrieze A, Holleman F, et al The therapeutic potential of manipulating gut microbiota in obesity and type 2 diabetes mellitus. Diabetes Obesity Metab
21. Moher D, Liberati A, Tetzlaff J, et al Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Int Med
22. John Wiley & Sons, Higgins JPT, Green S. Higgins JP, Green S. Cochrane Handbook for Systematic Reviews of Interventions. Vol 4. 2011.
24. Tajadadi-Ebrahimi M, Bahmani F, Shakeri H, et al Effects of daily consumption of synbiotic bread on insulin metabolism and serum high-sensitivity C-reactive protein among diabetic patients: a double-blind, randomized, controlled clinical trial. Ann Nutr Metab
25. Hove KD, Brons C, Faerch K, et al Effects of 12 weeks of treatment with fermented milk on blood pressure, glucose metabolism and markers of cardiovascular risk in patients with type 2 diabetes: a randomised double-blind placebo-controlled study. Eur J Endocrinol
26. Firouzi S, Majid HA, Ismail A, et al Effect of multi-strain probiotics (multi-strain microbial cell preparation) on glycemic control and other diabetes-related outcomes in people with type 2 diabetes: a randomized controlled trial. Eur J Nutr
2016; [Epub ahead of print].
27. Ejtahed HS, Mohtadi-Nia J, Homayouni-Rad S A., et al Effect of probiotic yogurt containing Lactobacillus acidophilus
and Bifidobacterium lactis
on lipid profile in individuals with type 2 diabetes mellitus. J Dairy Sci
28. Ejtahed HS, Mohtadi-Nia J, Homayouni-Rad A, et al Probiotic yogurt improves antioxidant status in type 2 diabetic patients. Nutrition
29. Hosseinzadeh P, Javanbakht MH, Mostafavi S-A, et al Brewer's yeast improves glycemic indices in type 2 diabetes mellitus. Int J Prev Med
30. Asemi Z, Zare Z, Shakeri H, et al Effect of multispecies probiotic supplements on metabolic profiles, hs-CRP, and oxidative stress in patients with type 2 diabetes. Ann Nutr Metab
31. Shakeri H, Hadaegh H, Abedi F, et al Consumption of synbiotic bread decreases triacylglycerol and VLDL levels while increasing HDL levels in serum from patients with type-2 diabetes. Lipids
32. Mohamadshahi M, Veissi M, Haidari F, et al Effects of probiotic yogurt consumption on lipid profile in type 2 diabetic patients: a randomized controlled clinical trial. J Res Med Sci
33. Bayat A, Azizi-Soleiman F, Heidari-Beni M, et al Effect of cucurbita ficifolia and probiotic yogurt consumption on blood glucose, lipid profile, and inflammatory marker in type 2 diabetes. Int J Prev Med
34. Mazloom Z, Yousefinejad A, Dabbaghmanesh MH. Effect of probiotics on lipid profile, glycemic control, insulin action, oxidative stress, and inflammatory markers in patients with type 2 diabetes: a clinical trial. Iran J Med Sci
35. Seino Y, Nanjo K, Tajima N, et al Report of the committee on the classification and diagnostic criteria of diabetes mellitus. J Diabetes Invest
36. Toth PP, Zarotsky V, Sullivan JM, et al Dyslipidemia treatment of patients with diabetes mellitus in a US managed care plan: a retrospective database analysis. Cardiovasc Diabetol
37. Cani PD, Amar J, Iglesias MA, et al Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes
38. Amyot J, Semache M, Ferdaoussi M, et al Lipopolysaccharides impair insulin gene expression in isolated islets of Langerhans via Toll-Like Receptor-4 and NF-κB signalling. PloS One
39. Festa a, D’Agostino R, Howard G, et al Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). Circulation
40. Tremaroli V, Bäckhed F. Functional interactions between the gut microbiota and host metabolism. Nature
41. Konstantinov SR, Smidt H, de Vos WM, et al S layer protein A of Lactobacillus acidophilus
NCFM regulates immature dendritic cell and T cell functions. Proc Natl Acad Sci USA
42. Ouwehand AC, Tiihonen K, Saarinen M, et al Influence of a combination of Lactobacillus acidophilus
NCFM and lactitol on healthy elderly: intestinal and immune parameters. Br J Nutr
43. Wang YC, Yu RC, Chou CC. Antioxidative activities of soymilk fermented with lactic acid bacteria and bifidobacteria. Food Microbiol
44. Lin MY, Chang FJ. Antioxidative effect of intestinal bacteria Bifidobacterium longum ATCC 15708 and Lactobacillus acidophilus
ATCC 4356. Dig Dis Sci
45. Rumbak I, Bituh M, Keser I, et al The relationship between milk and milk products consumption and blood lipid profile in women. J Hygienic Eng Design V 8
46. Agerbaek M, Gerdes LU, Richelsen B. Hypocholesterolaemic effect of a new fermented milk product in healthy middle-aged men. Eur J Clin Nutr
47. St-Onge MP, Farnworth ER, Jones PJ. Consumption of fermented and nonfermented dairy products: effects on cholesterol concentrations and metabolism. Am J Clin Nutr
48. Zhuang G, Liu X-M, Zhang Q-X, et al Research advances with regards to clinical outcome and potential mechanisms of the cholesterol-lowering effects of probiotics. Clin Lipidol
49. Kiessling G, Schneider J, Jahreis G. Long-term consumption of fermented dairy products over 6 months increases HDL cholesterol. Eur J Clin Nutr
50. Smedman aE, Gustafsson IB, Berglund LG, et al Pentadecanoic acid in serum as a marker for intake of milk fat: relations between intake of milk fat and metabolic risk factors. Am J Clin Nutr
51. Ruan Y, Sun J, He J, et al Effect of probiotics on glycemic control: a systematic review and meta-analysis of randomized, controlled trials. Plos One
2015; 10: e0132121.
52. Sun J, Buys NJ. Glucose- and glycaemic factor-lowering effects of probiotics on diabetes: a meta-analysis of randomised placebo-controlled trials. Brit J Nutr
53. Kasińska MA, Drzewoski J. Effectiveness of probiotics in type 2 diabetes: a meta-analysis. Polskie Archiwum Medycyny Wewnetrznej