Soluble DPP-4 up-regulates toll-like receptors and augments inflammatory reactions, which are ameliorated by vildagliptin or mannose-6-phosphate

Lee, Dong-Sung; Lee, Eun-Sol; Alam, Md. Morshedul; Jang, Jun‐Hyeog; Lee, Ho-Sub; Oh, Hyuncheol; Kim, Youn‐Chul; Manzoor, Zahid; Koh, Young‐Sang; Kang, Dae‐Gil; Lee, Dong Hoon

doi:10.1016/j.metabol.2015.10.002

Cited by 54 publications

(32 citation statements)

References 36 publications

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“…Here, on the one hand, we have shown that vildagliptin reduces levels of TLR-2 and TLR-4 agonists in the caecal content. Previously, it has been reported that vildagliptin suppresses TLR-2 and TLR-4 content in macrophages stimulated with soluble DPP-4 and lipopolysaccharide [13]. This observation is in agreement with the reduction in TLR-4 agonist activity (such as lipopolysaccharide) in the caecal content of mice treated with vildagliptin and demonstrates that vildagliptin impacts the crosstalk between the gut microbiota and the host.…”

Section: Discussionsupporting

confidence: 86%

“…No blinding procedure was followed. The groups ( n = 9) were: (1) group-fed a control diet (D12450K; Research Diets, New Brunswick, NJ, USA) containing 10% kJ fat; (2) group-fed a WD (D12451; Research Diets) containing 45% kJ fat and 17% kJ sucrose; and (3) group-fed a WD plus vildagliptin (Cayman, Ann Arbor, MI, USA [supplied by Sanbio, Uden, the Netherlands]) in the drinking water (0.6 mg/ml according to previous studies [13], corresponding to approximately 50 mg kg −1 day −1 ). To discriminate the effect of vildagliptin from the effect of the WD on DPP-4 activity, we pretreated with vildagliptin for 2 weeks.…”

Section: Methodsmentioning

confidence: 99%

“…These effects can be reduced by DPP-4 inhibitors [14–16]. For instance, in macrophages vildagliptin counteracts the production of cytokines and expression of TLR-2 and TLR-4 induced by soluble DPP-4 and lipopolysaccharide [13]. As TLRs are part of the innate immune response and play a crucial role in the maintenance of gut homeostasis, investigating the effect of vildagliptin in the context of intestinal health may produce particularly relevant results [17].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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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.

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Section: Discussionsupporting

confidence: 86%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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“…Soluble DPP-4 increases the expression of TLR-4 and amplified inflammatory cytokine production in murine macrophage cells and these effects could be inhibited by vildagliptin 84 . Linagliptin decreases M1 macrophages and increases M2 macrophages in adipose tissue and liver in mice on HFD 85 .…”

Section: Macrophage Functions In Lean Tissuementioning

confidence: 99%

Macrophage functions in lean and obese adipose tissue

2017

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Summary Interactions between macrophages and adipocytes influence both metabolism and inflammation. Obesity-induced changes to macrophages and adipocytes lead to chronic inflammation and insulin resistance. This paper reviews the various functions of macrophages in lean and obese adipose tissue and how obesity alters adipose tissue macrophage phenotypes. Metabolic disease and insulin resistance shift the balance between numerous pro- and anti-inflammatory regulators of macrophages and create a feed-forward loop of increasing inflammatory macrophage activation and worsening adipocyte dysfunction. This ultimately leads to adipose tissue fibrosis and diabetes. The molecular mechanisms underlying these processes have therapeutic implications for obesity, metabolic syndrome, and diabetes.

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“…sDPP4 has been shown to demonstrate multiple cellular effects including T cell activation, induction of insulin resistance, inflammation in smooth muscle cells, reactive oxygen species (ROS) generation and CD86 up-regulation in antigen presenting cells [41–44]. Lee et al investigated the effects of sDPP-4 and DPP-4 inhibition with vildagliptin on inflammatory reactions in a murine macrophage cell line (RAW264.7), as well as the in vivo effects of intravenously administered sDPP4 in mice [36]. sDPP4 increased the expression of iNOS, NO and the production of proinflammatory cytokines in lipopolysaccharide (LPS)-stimulated RAW264.7.…”

Section: Basic Research Studiesmentioning

confidence: 99%