Potential benefits of metformin and pioglitazone combination therapy via gut microbiota and metabolites in high-fat diet-fed mice

Abstract

Metformin and pioglitazone monotherapy have been proven to alter gut microbiota in diabetes and obesity. The present study aimed to investigated whether the combined administration of pioglitazone and metformin achieved superior protective effects on high-fat diet (HFD)-fed obese mice and elucidated its molecular mechanism via the gut microbiota and its metabolites. C57BL/6 males were randomly divided into five groups: the control group, fed a normal control diet; the HFD group, fed an HFD; the metformin monotherapy group, fed an HFD and treated with metformin; the pioglitazone monotherapy group, fed an HFD and treated with pioglitazone; and the combination therapy group, fed an HFD and treated with metformin and pioglitazone combination therapy. The cecal contents were collected for 16S rDNA amplicon sequencing and untargeted metabolomics analysis. The results showed that the combination therapy of metformin and pioglitazone significantly improved insulin sensitivity and glucolipid metabolism in HFD-fed mice. Combination therapy markedly altered gut microbiota by increasing beneficial bacteria, such as Bifidobacterium, Christensenellaceae_R-7_group, Faecalibacterium and Roseburia, and decreasing harmful bacteria, such as Oscillibacter and Eubacterium_xylanophilum_group. Fecal metabolites were significantly changed in the combination therapy group, including a reduction in amino acid metabolism and augmentation of lipid metabolism, such as citrulline, sarcosine, D-glutamine, lipoxin A4, prostaglandin E2, stearidonic acid and lucidenic acid A. These results revealed that combined metformin and pioglitazone therapy had synergistic effects or at least have an additive effect on modifying gut microbiota and metabolites, closely associated with improved glucolipid metabolic parameters in HFD-fed mice, which provides novel evidence and promising targets for metformin and pioglitazone combination therapy in type 2 diabetes.

Combination of Pioglitazone and Metformin Actions on Liver Lipid Metabolism in Obese Mice

“…As shown in Figure 1 and Table 1 , an HFD significantly induced obesity and the IR phenotype of the mice after a total of 18 weeks of HFD treatment, in line with previous results [ 24 ]. As expected, eight weeks of combined treatment with metformin and pioglitazone (HFD + Met + Pio group) had synergistic effects or at least additive effects on body weight reduction and ITT improvement compared with monotherapy intervention ( p < 0.05).…”

“…The experimental animal models were described in our previous study and we repeated the experimental protocol in this study [ 24 ]. Seven-week-old male C57BL/6 mice were obtained from Beijing Vital River Laboratory Animal Technology Co., Ltd. (Beijing, China, SCXK-2021-0011).…”

“…The glucose levels were evaluated using a glucometer (FreeStyle Optium™, Abbott, Chicago, IL, USA) after blood samples were taken from the tail vein at six separate time periods for OGTT and five separate time periods for ITT (0, 15, 30, 60, 90 or 120 min). The areas under the curve (AUCs) for the OGTT and ITT were calculated as previously described [ 24 ].…”

“…Therefore, the above-mentioned insulin sensitizers, that is, fixed-dose pioglitazone/metformin tablets, are approved for the treatment of T2DM patients who have inadequate maintenance of glucose homeostasis with monotherapy [ 23 ]. In our previous study, we found that the combined effect of metformin and pioglitazone significantly improved glucolipid metabolic parameters as well as modified gut microbiota and metabolites compared with monotherapy in high-fat diet (HFD)-induced obese mice [ 24 ]. Based on previous evidence, we hypothesized that metformin and pioglitazone combined therapy would play a synergetic role in the improvement of liver steatosis in HFD-fed mice.…”

Rosiglitazone Does Not Affect the Risk of Inflammatory Bowel Disease: A Retrospective Cohort Study in Taiwanese Type 2 Diabetes Patients

“…Second, patients with IBD show a reduced relative abundance of Akkermansia muciniphila, and administration of this bacterial species has shown some promising results in the treatment of IBD [ 75 , 76 , 77 ]. A recent study suggests that metformin significantly increases the relative abundance of Akkermansia but pioglitazone fails to do so [ 78 ]. Another study shows that rosiglitazone treatment cannot restore the microbiota composition in mice fed with a high-fat diet [ 72 ].…”