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

Abstract

Aims/hypothesisDipeptidyl 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).MethodsTwenty 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.ResultsVildagliptin 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/interpretationOur 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 availabilityThe sequences used for analysis can be found in the MG-RAST database under the project name MYNEWGUT3.Electronic supplementary materialThe online version of this article (10.1007/s00125-018-4647-6) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Saxagliptin alters bile acid profiles and yields metabolic benefits in drug‐naïve overweight or obese type 2 diabetes patient

“…Synthesis of secondary bile acids depends on a multistep 7α/β‐dehydroxylation by the gut bacteria. A previous study reported that vildagliptin, another DPP‐4 inhibitor, alters the composition of the gut microbiota . These data support the effects of saxagliptin on bile acid regulation, which may also involve effects on gut microbiota.…”

“…A previous study reported that vildagliptin, another DPP-4 inhibitor, alters the composition of the gut microbiota. 38 These data support the effects of saxagliptin on bile acid regulation, which F I G U R E 3 Scatter plots showing metabolic changes in individual subjects plotted against log-transformed concentrations of bile acids during saxagliptin treatment in A, normal weight and B-H, overweight/obese type 2 diabetes patients. Associations were calculated using a generalized estimating equation model.…”

Corrigendum: The new views on the state of the gut microbiota in obesity and diabetes mellitus type 2 (Diabetes mellitus. 2019;22(3). doi: 10.14341/DM10194)

“…Одним из недостатков является их короткий период полувыведения, поскольку они быстро расщепляются и инактивируются дипептидилпептидазой 4 типа (ДПП-4). Кроме того, уровень экспрессии ДПП-4 положительно коррелирует с массой тела, воспалением жировой ткани и инсулинорезистентностью у лиц с ожирением и СД2 [43]. Поэтому для устранения этих неблагоприятных эффектов были разработаны агонисты рецептора ГПП-1 и ингибиторы ДПП-4.…”

“…Интересно, что некоторые роды бактерий в микрофлоре кишечника, такие как Prevotella и Lactobacillus, способны оказывать ДПП-4-подобную активность, а некоторые штаммы Bifidobacterium и Lactobacillus могут синтезировать ингибиторы ДПП-4 [43]. В исследовании Zhang Q и соавт.…”

“…Обнаружено уменьшение активности ДПП-4 в содержимом слепой кишки и фекалиях, снижение экспрессии Toll-подобных рецепторов-2, -4, потенциально ответственных за выброс противовоспалительных цитокинов, а также положительные морфологические изменения в стенке кишечника в виде уменьшения глубины крипт. Таким образом, полученные результаты подтверждают положительный эффект вилдаглиптина на кишечный тракт, а также его влияние на состав микробиоты кишечника [43]. В исследовании Yan X. и соавт.…”