Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder characterized by islet beta cell failure and insulin resistance [1
]. It is the most prevalent type of diabetes patients [2
]. Based on previous studies, T2DM is considered as a multifactorial disease, with genetic predisposition, environmental factors and behavioral changes contributing to disease incidence [3
]. T2DM can lead to a series of severe complications, which include cardiovascular disease, neuropathy and nephropathy [5
], making it a serious threat to human health. Recently, it has been considered as a major global public health concern due to the increasing number of affected patients and the reducing age of disease onset [6
Previously, some studies have shown that more than 50% of T2DM patients present with dyslipidemia [7
]. Dyslipidemia is characterized by an increase in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) concentrations, and a decrease in high-density lipoprotein cholesterol (HDL-C) concentrations, either occurring individually or in various combinations [9
]. Some previous studies have confirmed the relationship between dyslipidemia and T2DM [10
]. They have shown that dyslipidemia is highly prevalent (>75%) in T2DM patients [12
], which manifested as the elevated plasma concentrations of LDL-C particles, and low concentrations of HDL-C in T2DM patients [13
]. In another study, 108 adult T2DM patients were recruited by the Nnamdi Azikiwe University Teaching Hospital Nnewi to evaluate the potential pattern of dyslipidemia among T2DM patients [7
]. The results showed that 24.1% of the patients had single dyslipidemia and 66.6% had combined dyslipidemia [7
]. Therefore, the influence of dyslipidemia on the development and progression of T2DM should not be overlooked. Given the close relationship between T2DM and dyslipidemia, ongoing research has focused on searching for effective methods to relieve T2DM.
The results of clinical trials indicate that probiotics may have potential therapeutic effects on T2DM. It was found that probiotic consumption could be helpful in alleviating the dysregulation of blood lipids and blood pressure [15
], and decreasing cholesterolemia [16
]. After that, several meta-analyses have attempted to elucidate the effects of probiotics on T2DM. One study [17
] found that probiotics intake could markedly increase HDL-C concentrations, but had no significant effects on LDL-C, TC or TG levels compared with the control groups. In contrast, another meta-analysis [18
], which included 11 eligible RCTs, suggested that probiotic consumption remarkably decreased TC, TG and LDL-C concentrations in the T2DM groups, compared with the placebo groups. The variable results reported by these meta-analyses have led to controversy. These variable results may be attributable to the variabilities in eligibility criteria, study selection, number of studies included and targeted outcomes.
Thus, a meta-analysis with a larger sample size and more recent reports is necessary to clarify the potential effects of probiotic intake on dyslipidemia in T2DM patients. We aim to analyze all recent (up to February 2020) eligible RCTs and determine the clinical benefits of probiotic intake in T2DM patients, including changes in TC, TG, LDL-C and HDL-C concentrations. Subgroup analyses were performed to clarify the effects of numbers of probiotic species, body mass index (BMI), intervention type and supplementation duration on controlling dyslipidemia in T2DM patients. Notably, our meta-analysis differs from previous studies, particularly with respect to the major clinical endpoints and the participant characteristics. Our analysis included more RCTs (n
= 15, 884 participants) than previous studies. Additionally, two recent clinical studies by Sabico et al. [19
] and Razmpoosh et al. [20
] that were not analyzed in previous meta-analyses were also included in our study.
Dyslipidemia, a large range of lipid abnormalities, may involve a combination of increased TC, LDL-C and TG levels, or decreased HDL-C level [42
]. It is considered as a main risk factor for the occurrence and development of cardiovascular disease (CVD) in T2DM patients [42
]. Notably, insulin resistance is a main factor for atherosclerotic CVD, cerebrovascular accident, and peripheral arterial disease [43
], which could increase concentrations of plasma TG and LDL-C and reduce concentrations of HDL-C [44
]. Previous studies have shown that the severe impairment of HDL function could further increase the risk of CVD [45
]. In addition, the nature of LDL particles in patients with diabetes is more atherogenic than in those patients who are nondiabetic [46
]. Based on these results, some studies considered that the reduction in HDL-C [45
] and increase in LDL-C [47
] indicate an increasing risk of CVD. Thus, regulating plasma lipid concentrations could be helpful in alleviating T2DM. Recently, increasing attention has been paid to probiotics due to their potential role in alleviating dyslipidemia in T2DM patients. Some studies have demonstrated that probiotics intake could inhibit the host absorption of dietary cholesterol and suppress the reabsorption of bile acid in the small intestine [48
]. Probiotics may help break down food-derived indigestible carbohydrates and increase the production of short-chain fatty acids (SCFAs) [49
]. The resultant SCFAs could contribute to decreasing the cholesterol concentrations, either by inhibiting hepatic cholesterol synthesis or redistributing cholesterol from plasma to the liver [49
In this meta-analysis, 2 [30
] of the included studies were omitted because of high heterogeneity, leaving 13 eligible studies for analysis. The results demonstrated that probiotic intake could reduce TG and TC concentrations. This finding is in line with those of another one meta-analysis [50
]. They included 11 RCTs in their study, 7 of which were also included in our meta-analysis. These similar results confirm the role of probiotics in reducing TC and TG concentrations in T2DM patients. A published meta-analysis by Li et al. [17
] demonstrated that probiotic intake could significantly increase HDL-C levels, but showed no significant effect on the TC, TG and LDL-C concentrations. Our study showed that the effects of probiotics intake on LDL-C and HDL-C concentrations were not statistically significant. High risks of bias were found in most of the RCTs included in the study by Li et al. [17
], along with high heterogeneity between the individual analyses, which may explain this discrepancy. Notably, 2 of the 12 studies from the meta-analysis by Li et al. [17
], which were of high-quality, and two recently published RCTs were also included in this study.
The results of the subgroup analysis based on the type of probiotic intervention revealed that probiotic intake in powder form, but not liquid form, could significantly reduce TC and TG concentrations. A similar result was reported by Ivey et al. [51
], who found that probiotic intake via capsules, but not via yoghurt, could significantly increase the fasting glucose concentration. These results support the finding that the powder form could be a better choice for probiotic supplementation. However, as the composition of probiotic products is very complex, the benefits may be attributable to ingredients other than the probiotics themselves. Therefore, more trials with specified ingredients of probiotic products are needed to verify the exact roles of those ingredients.
Several previous studies have demonstrated that Lactobacillus plantarum PH04 intake reduces TC (7%) and TG (10%) concentrations [52
]. Enterococcus faecium
CRL 183 and L. helveticus
416 consumption were found to reduce TC, non-HDL-C (LDL + IDL + VLDL cholesterol fractions) and electronegative LDL levels [53
]. This phenomenon may be attributable to the deconjugation of bile via a complex process, which includes bile salt hydrolysis, the binding of cholesterol to cellular surfaces and the coprecipitation of cholesterol with deconjugated bile [54
]. These studies confirmed the role of probiotics in regulating blood lipid profiles, but also suggested that this role varies depending on the probiotic strains used. In our study, multispecies probiotic supplementation was found to be more effective than single-species probiotic treatment. A similar result was found in the meta-analysis by Hu et al. [50
], which demonstrated that multiple species of probiotics and longer interventions (≥8 weeks) had a greater beneficial impact in terms of alleviating lipid profiles. The superiority of multispecies probiotics may result from synergistic interactions between individual species with different therapeutic activities [55
A series of studies have demonstrated that probiotic consumption may decrease the LDL-C concentrations [16
] and increase HDL-C concentrations [17
]. However, our meta-analysis demonstrated that probiotic intake was not beneficial in regulating the LDL-C and HDL-C concentrations. This contradictory conclusion may result from the variations in experimental design and participant characteristics between the included studies. All of the results from our meta-analysis indicate that more well-designed RCTs are needed to conclusively determine which probiotic strains are more effective in alleviating dyslipidemia in T2DM.
This meta-analysis has some strengths. To date, there are some published meta-analysis studies on the topic of probiotics supplementation against T2DM. Some of these studies are focused on symptoms indicators such as HbA1c (Glycated hemoglobin A1c) [17
], HOMA-IR (homeostasis model assessment of insulin resistance) [50
], FBG (fasting blood glucose) [50
] and FBS (fasting blood sugar) [58
] et al. Compared to these studies, our manuscript pays more attention to the effects of probiotics against dyslipidemia in T2DM. The parameters including TC, TG, LDL-C and HDL-C were specifically analyzed in our study. Five of the published meta-analyses discussed indicators of dyslipidemia [17
], but all of these were published before 2017. In our study, we have searched for relevant RCTs up to 2020 to provide an update analysis of the effects of probiotic supplementation against dyslipidemia in T2DM. Interestingly, we noticed that there are two recent RCTs [19
] that have not been included in all the previous meta-analysis studies. These two studies revealed that multi-strain probiotic supplementation could significantly decrease HDL-C levels compared with baseline, which conflicts with the results of previous meta-analyses [17
]. Therefore, we think these two references provide updated information in our present meta-analysis.
This meta-analysis has some limitations. Firstly, the funnel plots of TC, TG, LDL-C and HDL-C concentrations were not completely symmetrical, suggesting a risk of publication bias. There were variations in both experimental design and statistical methods between the included studies, which possibly led to selection bias. Furthermore, few studies performed microbiological experiments to test the viability of the probiotic species. Only four studies [37
] performed fecal analyses to quantify the changes in intestinal microbial composition before and after the supplementation. Lastly, the observation period of some of the included RCTs was short, which was insufficient to evaluate changes in dyslipidemia in T2DM patients.
In summary, probiotic supplementation could be helpful in regulating blood lipid profiles, particularly with respect to reducing TC and TG concentrations. However, it is likely not helpful in regulating LDL-C and HDL-C concentrations. This result suggests that probiotics could be a non-pharmacological alternative for the treatment of T2DM. However, more RCTs with a larger sample size, longer research periods and a rigorous experimental design are needed in the future. Furthermore, more indicators should be included in RCTs to develop clinical practice guidelines.