Aim
Low-grade chronic inflammation in patients with type 2 diabetes mellitus (T2DM) may be influenced by circulating endotoxin levels, acting as an inflammatory stimulus. Health- promoting live microorganisms, such as probiotics, may influence circulating endotoxin levels and reduce inflammation. Limited information is available whether or not probiotics do so in patients with T2DM. The aim of this study was to characterize the beneficial effects of probiotics on circulating endotoxin levels and other biomarkers related to systemic low-grade inflammation and cardiometabolic status in patients with T2DM.
Methods
A total of 150 adult Saudi T2DM patients (naïve and without co-morbidities, aged 40-60 years) were initially recruited, 96 of whom were randomized, 78 completed 3 months, and 61 completed the entire clinical trial. They were randomized to receive twice daily placebo or probiotics [(2.5×109cfu/gram) containing the following bacterial strains: Bifidobacterium bifidum W23, Bifidobacterium lactis W52, Lactobacillus acidophilus W37, Lactobacillus brevis W63, Lactobacillus casei W56, Lactobacillus salivarius W24, Lactococcus lactis W19 and Lactococcus lactis W58 (Ecologic®Barrier)]  in a double-blind manner over a 6 month period. Anthropometrics, glycemic and lipid profiles, as well as inflammatory and other markers, including adipocytokines, were measured. Measurements/samples were obtained at baseline and after 3 and 6 months of treatment.
Results
After 6 months of intervention, significant improvements were observed in endotoxin levels, glycemic, lipid, inflammatory and adipocytokine profiles in the probiotics group, which were not seen in the placebo group. Between group analyses, however, revealed that only HOMA-IR demonstrated a clinically significant reduction in favor of the probiotics group after adjusting for baseline covariates [Placebo % change: 0.80 vs. Probiotics % change: -3.40 (CI: -0.59 - -0.17); p=0.001]. 
Discussion

Our study is, to our knowledge, the first to demonstrate the effects of a multi-strain probiotics supplementation in several adipocytokines, such as leptin, adiponectin and resistin in T2DM patients. Previous observations have shown that endotoxins from noncommensal bacteria may affect adipocytokine levels secondary to translocation induction of several intestinal microbial antigens into the circulation, creating an altered adipokine profile and intestinal dysbiosis [1]. Certain probiotics, specifically lactic acid bacteria strains, have demonstrated in vitro that they can differentially modulate adipokine expression and the inflammatory response [2]. Similar to their findings, we demonstrated improved levels of adipocytokines, as well as decreased levels of inflammatory markers, in the probiotics group but not in the placebo, even though interaction effects overall pointed to no clinically significant difference. It is noteworthy that 6 of the 8 probiotic strains used belong to the lactic acid bacteria class. How probiotics directly or indirectly influence adipocytokine levels need further evaluation, as the effects may be secondary to improved insulin sensitivity and stronger intestinal barrier function.

Conclusion
Daily multi-strain probiotic supplementation over 6 months significantly decreased HOMA-IR in T2DM patients and is a promising adjuvant anti-diabetes therapy. Larger trials may causally confirm the beneficial effects of probiotics in reducing endotoxin levels and improving glycemic, lipid, inflammatory, and adipocytokine profiles. 
Trial Registration: ClinicalTrials.gov Identifier: NCT01765517
Funding
This project is funded by the National Plan for Science and Technology (NPST) (Grant Number: 11-MED2114-02) and supported by the Dean of Scientific Research Chairs, PMCO, KSU, Riyadh, Saudi Arabia.

A 26-week, randomized, double-blind clinical trial on the cardiometabolic effects of probiotics in T2DM patients