期刊
DIABETOLOGIA
卷 61, 期 8, 页码 1838-1848出版社
SPRINGER
DOI: 10.1007/s00125-018-4647-6
关键词
Antimicrobial peptides; DPP-4 activity; Gut microbiota; Gut-liver axis; Vildagliptin; Western diet
资金
- EU [613979]
- MOVE-IN Louvain Incoming Post-Doctoral Fellowship - Marie Curie Actions of the European Commission
- Juan de la Cierva post-doctoral contract - Spanish Ministry of Economy, Industry and Competitiveness (MINECO)
- FRFS-WELBIO [WELBIO-CGR-2017]
- Fonds Baillet-Latour
- European Research Council (ERC) Starting Grant [336452-ENIGMO]
- FSR subsidies (Fonds Special de la Recherche, Universite catholique de Louvain)
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. Conclusions/interpretation 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. 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.
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