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

      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 dipeptidyl peptidase-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.

      Résumé

      Objectifs

      Des données probantes récentes montrent qu'un grand nombre de médicaments souvent prescrits modifient considérablement le microbiote intestinal. La présente étude a permis d’évaluer les effets de 2 traitements antidiabétiques sur le microbiote intestinal et les marqueurs de maladies cardiométaboliques chez des souris ayant un dysfonctionnement métabolique.

      Méthodes

      Les souris C57BL/6 ont été soumises à un régime riche en matières grasses durant 24 semaines, et ont reçu 1 ou 2 traitements antidiabétiques (metformine ou inhibiteur de la dipeptidyl peptidase-4 [DPP-4], PKF-275-055) durant les 12 dernières semaines. Nous avons évalué le gain de poids, le métabolisme du glucose et du cholestérol, et l'adiposité des souris. De plus, nous avons analysé la composition du microbiote cæcal par séquençage compositionnel du 16S et le métabolome plasmatique par chromatographie en phase liquide couplée à un spectromètre de masse en tandem.

      Résultats

      Les 2 traitements ont montré des effets métaboliques similaires, qui atténuaient l'adiposité du mésentère et amélioraient le métabolisme du cholestérol et la sensibilité à l'insuline. Toutefois, les analyses multivariées des données sur le microbiote et le métabolisme ont révélé une divergence nette entre les groupes selon le traitement. Bien que les souris qui recevaient de la metformine ou du PKF-275-055 aient montré une diminution significative des rapports Firmicutes/Bacteroidetes, seule la metformine a permis d'abriter les bactéries Akkermansia, Parabacteroides et Christensenella associées à la santé métabolique. Paradoxalement, la metformine a aussi réduit la diversité α, un indicateur fréquemment associé à l'activité métabolique de l'hôte. Les souris qui recevaient le PKF-275-055 ont montré des concentrations élevées de bactéries Ruminococcus produisant du butyrate et de bactéries acétogènes Dorea, et des concentrations réduites de certaines entités plasmatiques de sphingomyéline, de phosphatidylcholine et de lysophosphatidylcholine. Pour sa part, la metformine a permis de réduire les concentrations d'acylcarnitines, un groupe fonctionnel associé au dysfonctionnement du métabolisme systémique. Finalement, nous avons déterminé plusieurs associations entre les métabolites et les taxons modifiés.

      Conclusions

      Cette étude représente la première comparaison directe sur les effets de la metformine et d'un inhibiteur de la DPP-4 qui modifient le microbiote, et propose plusieurs cibles microbiennes présumées tant pour la mise au point de nouveaux traitements que pour la prévention des effets indésirables.

      Keywords

      Mots clés

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