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

Ryan, Paul M.; Patterson, Elaine; Carafa, Ilaria; Mandal, Rupasri; Wishart, David S.; Dinan, Timothy G.; Cryan, John F.; Tuohy, Kieran M.; Stanton, Catherine; Ross, R. Paul

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

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Accepted version

Date

2019-05-27

Authors

Ryan, Paul M.

Patterson, Elaine

Carafa, Ilaria

Mandal, Rupasri

Wishart, David S.

Dinan, Timothy G.

Cryan, John F.

Tuohy, Kieran M.

Stanton, Catherine

Ross, R. Paul

Publisher

Elsevier

Published Version

10.1016/j.jcjd.2019.05.008

Abstract

Objectives: Recent evidence indicates that gut microbiota is altered considerably by a variety of commonly prescribed medications. This study assessed the impact of 2 antidiabetic therapeutics on gut microbiota and markers of cardiometabolic disease in metabolically dysfunctional mice. Methods: C57BL/6 mice were fed a high-fat diet for 24 weeks while receiving 1 of 2 antidiabetic therapeutics—metformin or dipeptidase peptidyl-4 (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, cecal microbiota was analyzed by 16S compositional sequencing, and plasma metabolome was analyzed by liquid chromatography with tandem mass spectrometry. Results: Both therapeutics had similar metabolic effects, attenuating mesenteric adiposity and improving cholesterol metabolism and insulin sensitivity. However, multivariate analyses of microbiota and metabolomics data revealed clear divergence of the therapeutic groups. Although 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.

Keywords

Diabetes , DPP-4 , Metformin , Microbiota , PKF-275-055 , Metformine , Microbiote , Diabetes

Citation

Ryan, P. M., Patterson, E., Carafa, I., Mandal, R., Wishart, D. S., Dinan, T. G., Cryan, J. F., Tuohy, K. M., Stanton, C. and Ross, R. P. (2019) 'Metformin and Dipeptidase Peptidyl-4 Inhibitor Differentially Modulate the Intestinal Microbiota and Plasma Metabolome of Metabolically Dysfunctional Mice', Canadian Journal of Diabetes, doi: 10.1016/j.jcjd.2019.05.008