Metformin and DPP-4 Inhibitor Differentially Modulate the Intestinal Microbiota and Plasma Metabolome of Metabolically Dysfunctional Mice

Abstract 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.