Metformin and DPP-4 inhibitor differentially modulate the intestinal microbiota and plasma metabolome of metabolically dysfunctional mice

Background Recent evidence indicates that the gut microbiota is altered considerably by a variety of commonly prescribed medications. This study assessed the impact of two antidiabetic therapeutics on the gut microbiota and markers of cardiometabolic disease in metabolically dysfunctional mice. Materials & Methods C57BL/6 mice were fed a high-fat diet for 24-weeks while receiving one of two antidiabetic therapeutics - metformin or DPP-4 inhibitor, PKF-275-055 - for the final 12 weeks. Mice were assessed for weight gain, glucose and cholesterol metabolism, and adiposity. In addition, caecal microbiota was analysed by 16S compositional sequencing and plasma metabolome was analysed by LC-MS/MS. Results Both therapeutics had similar metabolic effects, attenuating mesenteric adiposity, improving cholesterol metabolism and insulin sensitivity. However, multivariate analyses of microbiota and metabolomics data revealed clear divergence of the therapeutic groups. While both metformin and PKF-275-055 mice displayed significantly decreased Firmicutes/Bacteroidetes ratios, only metformin harboured metabolic health-associated Akkermansia, Parabacteroides and Christensenella. Paradoxically, metformin also reduced α-diversity, a metric frequently associated with host metabolic fitness. PKF-275-055 mice displayed elevated levels of butyrate-producing Ruminococcus and acetogen Dorea, with reduced levels of certain plasma sphingomyelin, phosphatidylcholine and lysophosphatidylcholine entities. In turn, metformin reduced levels of acylcarnitines, a functional group associated with systemic metabolic dysfunction. Finally, several associations were identified between metabolites and altered taxa. Conclusions This study represents the first direct comparison of the microbiota-modifying effects of metformin and a DPP-4 inhibitor, and proposes several putative microbial targets both in terms of novel therapeutic development and adverse effect prevention

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