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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Article info
Publication history
Published online: May 27, 2019
Accepted:
May 22,
2019
Received in revised form:
March 31,
2019
Received:
January 4,
2019
Identification
Copyright
© 2019 Canadian Diabetes Association.
