Metformin and a DPP-4-inhibitor differentially modulate the microbiome and metabolome of Metabolic Syndrome mice

This study assessed the impact of 2 anti-diabetic therapies on the gut microbiome and markers of cardiometabolic disease risk in mice. We employed a metabolic syndrome model in which C57BL/6 mice were fed a high-fat diet for 25 weeks while receiving 1 of 2 antidiabetic therapeutics—metformin or a DPP-4 inhibitor (PKF-275- 055)—for the final 12 weeks. Animals were monitored for weight gain, as well as glucose/cholesterol metabolism. In addition, adiposity was investigated at dissection, cecal microbiome was analyzed by 16S compositional sequencing and serum was analyzed by liquid chromatography-tandem mass spectrometry. Both therapeutics significantly improved glucose/cholesterol metabolism, attenuated weight gain and mesenteric adipose accumulation. However, multivariate analyses of microbiome and metabolomics data revealed clear profile separation of the therapeutic groups. While both metformin (0.78; p<0.05) and PKF-275-055 (1.00; p<0.05) mice displayed significantly decreased Firmicutes/Bacteroidetes ratios, only metformin animals harboured metabolic health-promoting Akkermansia (3.4%; p<0.0001). Intriguingly, PKF-275-055 mice displayed elevated levels of the butyrate-producing Rumminococcus (2.0%; p<0.05) and the acetogen Dorea (0.95%; p<0.05). We identified reduced levels of certain sphingomyelin, phosphatidylcholine and lysophosphatidylcholine entities within serum of the PKF-275- 055 group when compared to metformin and control. Conversely, metformin mice presented primarily with reduced levels of acylcarnitines, a functional group that has correlated with obesity, insulin resistance and systemic metabolic dysfunction in humans. This study adds weight to the hypothesis that some anti-diabetic therapeutics act in part through manipulation of the gut microbiome. Additionally, we identify several metabolites that may be of central importance in the mechanisms of metformin and PKF-275-055.