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Abstract
BackgroundGut microbiota is now known to control glucose metabolism. Previous studies have shown that probiotics and prebiotics may improve glucose metabolism, but their effects have not been studied in combination with drug therapy. The aim of this study was to investigate whether probiotics and prebiotics combined with drug therapy affect diabetic outcomes.MethodsTwo different study designs were used to test gut microbiota modulating treatments with metformin (MET) or sitagliptin (SITA) in male C57Bl/6J mice. In Design 1, diabetes was induced with four-week feeding with a ketogenic, 72 kcal% fat diet with virtually no carbohydrates. Mice were then randomly divided into four groups (n = 10 in each group): (1) vehicle, (2) Bifidobacterium animalis ssp. lactis 420 (B420) (109 CFU/day), (3) MET (2 mg/mL in drinking water), or (4) MET + B420 (same doses as in the MET and B420 groups). After another 4 weeks, glucose metabolism was assessed with a glucose tolerance test. Fasting glucose, fasting insulin and HOMA-IR were also assessed. In Design 2, mice were fed the same 72 kcal% fat diet to induce diabetes, but they were simultaneously treated within their respective groups (n = 8 in each group): (1) non-diabetic healthy control, (2) vehicle, (3) SITA [3 mg/(kg*day)] (4) SITA with prebiotic polydextrose (PDX) (0.25 g/day), (5) SITA with B420 (109 CFU/day), and (6) SITA + PDX + B420. Glucose metabolism was assessed at 4 weeks, and weight development was monitored for 6 weeks.ResultsIn Design 1, with low-dose metformin, mice treated with B420 had a significantly lower glycemic response (area under the curve) (factorial experiment, P = 0.002) and plasma glucose concentration (P = 0.02) compared to mice not treated with B420. In Design 2, SITA + PDX reduced glycaemia in the oral glucose tolerance test significantly more than SITA only (area under the curve reduced 28 %, P < 0.0001). In addition, B420, PDX or B420+PDX, together with SITA, further decreased fasting glucose concentrations compared to SITA only (−19.5, −40 and −49 %, respectively, P < 0.01 for each comparison). The effect of PDX may be due to its ability to increase portal vein GLP-1 concentrations together with SITA (P = 0.0001 compared to vehicle) whereas SITA alone had no statistically significant effect compared to vehicle (P = 0.14).ConclusionsThis study proposes that combining probiotics and/or prebiotics with antidiabetic drugs improves glycemic control and insulin sensitivity in mice. Mechanisms could be related to incretin secretion.Electronic supplementary materialThe online version of this article (doi:10.1186/s13098-015-0075-7) contains supplementary material, which is available to authorized users.
Highlights
Gut microbiota is known to control glucose metabolism
We have previously shown that Bifidobacterium animalis ssp. lactis 420 improves insulin sensitivity and glucose tolerance while decreasing fat mass in dietary mouse models of diabetes and obesity [6, 24]
Pro‐ and prebiotics improve glucose regulation during anti‐diabetic treatment At the dose used in this design metformin demonstrated no effect on glucose tolerance in mice on a ketogenic diet (Fig. 1A, B) (P = 0.18)
Summary
Gut microbiota is known to control glucose metabolism. Previous studies have shown that probiotics and prebiotics may improve glucose metabolism, but their effects have not been studied in combination with drug therapy. Various metabolic disorders have been linked to the gut microbiota through a common mechanism: metabolic endotoxaemia-induced inflammation [1] In both animals [2,3,4] and humans [5] glucose metabolism disorders have been related to increased permeability of the gut barrier, which leads to increased translocation of endotoxins and even translocation of commensal bacteria [6]. These translocated bacteria form a so-called tissue microbiota [7], which evokes tissue inflammation [8] and, eventually, metabolic disorders [7, 9]. Feces were transferred from healthy lean donors to male recipients with metabolic syndrome and, strikingly, the treatment improved the insulin sensitivity of the recipients
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