The DPP-4 inhibitor vildagliptin impacts the gut microbiota and prevents disruption of intestinal homeostasis induced by a Western diet in mice

[Aims/hypothesis] Dipeptidyl peptidase 4 (DPP-4) inhibitors are agents designed to increase the half-life of incretins. Although they are administered orally, little is known about their effects on the gut microbiota and functions, despite the fact that some bacteria present in the gut microbiota exhibit DPP-4-like activity. Our objective was to study the impact of the DPP-4 inhibitor vildagliptin on gut functions and the intestinal ecosystem in a murine model of obesity induced by a Western diet (WD). [Methods] Twenty seven male C57BL/6J mice were randomised to receive a control diet, a WD (45% kJ from fat and 17% kJ from sucrose) or a WD + vildagliptin (0.6 mg/ml in drinking water) for 8 weeks. [Results] Vildagliptin significantly reduced DPP-4 activity in the caecal content and faeces. Vildagliptin impacted on the composition of the gut microbiota and its metabolic activity. It mainly decreased Oscillibacter spp. (a direct effect independent of DPP-4 activity was shown on cultured O. valericigenes), increased Lactobacillus spp. and propionate, and reduced the ligands of Toll-like receptors 2 and 4. Vildagliptin protected against the reductions in crypt depth and ileal expression of antimicrobial peptides induced by the WD. In the liver, the expression of immune cell populations (Cd3g and Cd11c [also known as Itgax]) and cytokines was decreased in the WD + vildagliptin-fed mice compared with the WD-fed group. Ex vivo exposure of precision-cut liver slices to vildagliptin showed that this response was not related to a direct effect of the drug on the liver tissue. [Conclusions/interpretation] Our study is the first to consider the DPP-4-like activity of the gut microbiota as a target of DPP-4 inhibition. We propose that vildagliptin exerts beneficial effects at the intestinal level in association with modulation of gut microbiota, with consequences for hepatic immunity. If relevant in humans, this could open new therapeutic uses of DPP-4 inhibition to tackle gut dysfunctions in different pathophysiological contexts. [Data availability] The sequences used for analysis can be found in the MG-RAST database under the project name MYNEWGUT3.
This work was supported by EU grant 613979 (MyNewGut). MO is a beneficiary of a MOVE-IN Louvain Incoming Post-Doctoral Fellowship co-funded by the Marie Curie Actions of the European Commission. NS benefits from a Juan de la Cierva post-doctoral contract granted by the Spanish Ministry of Economy, Industry and Competitiveness (MINECO). PDC is a senior research associate of the Fonds de la Recherche Scientifique (FRS-FNRS) and is supported by FRFS-WELBIO through grant WELBIO-CGR-2017, the Fonds Baillet-Latour (Grant for Medical Research 2015) and European Research Council (ERC) Starting Grant 2013 (grant 336452-ENIGMO). LBB is the recipient of FSR subsidies (Fonds Spécial de la Recherche, Université catholique de Louvain).