Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

ACC 2024 Congress

Catch up on all the top stories and latest evidence in cardiology research with our ACC 2024 Congress hub page.
ADVANCED SEARCH
Log in
Top
Diabetologia
Published in: Diabetologia 8/2018

Open Access 01-08-2018 | Article

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

Authors: Marta Olivares, Audrey M. Neyrinck, Sarah A. Pötgens, Martin Beaumont, Nuria Salazar, Patrice D. Cani, Laure B. Bindels, Nathalie M. Delzenne

Published in: Diabetologia | Issue 8/2018

Login to get access

Abstract

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.
Appendix
Available only for authorised users
Literature
1.
2.
Mulvihill EE, Drucker DJ (2014) Pharmacology, physiology, and mechanisms of action of dipeptidyl peptidase-4 inhibitors. Endocr Rev 35:992–1019CrossRefPubMed
3.
Lee SA, Kim YR, Yang EJ et al (2013) CD26/DPP4 levels in peripheral blood and T cells in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 98:2553–2561CrossRefPubMed
4.
Stengel A, Goebel-Stengel M, Teuffel P et al (2014) Obese patients have higher circulating protein levels of dipeptidyl peptidase IV. Peptides 61:75–82CrossRefPubMed
5.
Sell H, Bluher M, Kloting N et al (2013) Adipose dipeptidyl peptidase-4 and obesity: correlation with insulin resistance and depot-specific release from adipose tissue in vivo and in vitro. Diabetes Care 36:4083–4090CrossRefPubMedPubMedCentral
6.
Kushwaha RN, Haq W, Katti SB (2014) Sixteen-years of clinically relevant dipeptidyl peptidase-IV (DPP-IV) inhibitors for treatment of type-2 diabetes: a perspective. Curr Med Chem 21:4013–4045CrossRefPubMed
7.
Waget A, Cabou C, Masseboeuf M et al (2011) Physiological and pharmacological mechanisms through which the DPP-4 inhibitor sitagliptin regulates glycemia in mice. Endocrinology 152:3018–3029CrossRefPubMed
8.
Mulvihill EE, Varin EM, Gladanac B et al (2017) Cellular sites and mechanisms linking reduction of dipeptidyl peptidase-4 activity to control of incretin hormone action and glucose homeostasis. Cell Metab 25:152–165CrossRefPubMed
9.
Mortier A, Gouwy M, Van Damme J, Proost P, Struyf S (2016) CD26/dipeptidylpeptidase IV-chemokine interactions: double-edged regulation of inflammation and tumor biology. J Leukoc Biol 99:955–969CrossRefPubMed
10.
Yazbeck R, Howarth GS, Abbott CA (2009) Dipeptidyl peptidase inhibitors, an emerging drug class for inflammatory disease? Trends Pharmacol Sci 30:600–607CrossRefPubMed
11.
Hartmann B, Thulesen J, Kissow H et al (2000) Dipeptidyl peptidase IV inhibition enhances the intestinotrophic effect of glucagon-like peptide-2 in rats and mice. Endocrinology 141:4013–4020CrossRefPubMed
12.
Wronkowitz N, Gorgens SW, Romacho T et al (2014) Soluble DPP4 induces inflammation and proliferation of human smooth muscle cells via protease-activated receptor 2. Biochim Biophys Acta 1842:1613–1621CrossRefPubMed
13.
Lee DS, Lee ES, Alam MM et al (2016) Soluble DPP-4 up-regulates toll-like receptors and augments inflammatory reactions, which are ameliorated by vildagliptin or mannose-6-phosphate. Metabolism 65:89–101CrossRefPubMed
14.
15.
Ta NN, Li Y, Schuyler CA, Lopes-Virella MF, Huang Y (2010) DPP-4 (CD26) inhibitor alogliptin inhibits TLR4-mediated ERK activation and ERK-dependent MMP-1 expression by U937 histiocytes. Atherosclerosis 213:429–435CrossRefPubMed
16.
Ervinna N, Mita T, Yasunari E et al (2013) Anagliptin, a DPP-4 inhibitor, suppresses proliferation of vascular smooth muscles and monocyte inflammatory reaction and attenuates atherosclerosis in male apo E-deficient mice. Endocrinology 154:1260–1270CrossRefPubMed
17.
18.
He YL (2012) Clinical pharmacokinetics and pharmacodynamics of vildagliptin. Clin Pharmacokinet 51:147–162CrossRefPubMed
19.
Delzenne NM, Neyrinck AM, Backhed F, Cani PD (2011) Targeting gut microbiota in obesity: effects of prebiotics and probiotics. Nat Rev Endocrinol 7:639–646CrossRefPubMed
20.
Shin NR, Lee JC, Lee HY et al (2014) An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut 63:727–735CrossRefPubMed
21.
Walker ND, McEwan NR, Wallace RJ (2003) Cloning and functional expression of dipeptidyl peptidase IV from the ruminal bacterium Prevotella albensis M384(T). Microbiology 149:2227–2234CrossRefPubMed
22.
Stressler T, Eisele T, Schlayer M, Lutz-Wahl S, Fischer L (2013) Characterization of the recombinant exopeptidases PepX and PepN from Lactobacillus helveticus ATCC 12046 important for food protein hydrolysis. PLoS One 8:e70055CrossRefPubMedPubMedCentral
23.
Sanz Y, Toldra F (2001) Purification and characterization of an X-prolyl-dipeptidyl peptidase from Lactobacillus sakei. Appl Environ Microbiol 67:1815–1820CrossRefPubMedPubMedCentral
24.
Zeng Z, Luo JY, Zuo FL et al (2016) Bifidobacteria possess inhibitory activity against dipeptidyl peptidase-IV. Lett Appl Microbiol 62:250–255CrossRefPubMed
25.
Zhu Zeng JL, Zuo F, Chen S Screening for potential novel probiotic Lactobacillus strains based on high dipeptidyl peptidase IV and α-glucosidase inhibitory activity. J Funct Foods 20:486–495
26.
27.
Grasset E, Puel A, Charpentier J et al (2017) A specific gut microbiota dysbiosis of type 2 diabetic mice induces GLP-1 resistance through an enteric NO-dependent and gut–brain axis mechanism. Cell Metab 25:e1075CrossRef
28.
Bindels LB, Neyrinck AM, Claus SP et al (2016) Synbiotic approach restores intestinal homeostasis and prolongs survival in leukaemic mice with cachexia. ISME J 10:1456–1470CrossRefPubMed
29.
Bindels LB, Segura Munoz RR, Gomes-Neto JC et al (2017) Resistant starch can improve insulin sensitivity independently of the gut microbiota. Microbiome 5:12CrossRefPubMedPubMedCentral
30.
Salazar N, Dewulf EM, Neyrinck AM et al (2015) Inulin-type fructans modulate intestinal Bifidobacterium species populations and decrease fecal short-chain fatty acids in obese women. Clin Nutr 34:501–507CrossRefPubMed
31.
Neyrinck AM, Taminiau B, Walgrave H et al (2017) Spirulina protects against hepatic inflammation in aging: an effect related to the modulation of the gut microbiota? Nutrients 9
32.
Neyrinck AM, Alexiou H, Delzenne NM (2004) Kupffer cell activity is involved in the hepatoprotective effect of dietary oligofructose in rats with endotoxic shock. J Nutr 134:1124–1129CrossRefPubMed
33.
Neyrinck AM, Gomez C, Delzenne NM (2004) Precision-cut liver slices in culture as a tool to assess the physiological involvement of Kupffer cells in hepatic metabolism. Comp Hepatol 3(Suppl 1):S45CrossRefPubMedPubMedCentral
34.
Suriano F, Bindels LB, Verspreet J et al (2017) Fat binding capacity and modulation of the gut microbiota both determine the effect of wheat bran fractions on adiposity. Sci Rep 7:5621CrossRefPubMedPubMedCentral
35.
Reichardt N, Duncan SH, Young P et al (2014) Phylogenetic distribution of three pathways for propionate production within the human gut microbiota. ISME J 8:1323–1335CrossRefPubMedPubMedCentral
36.
Cani PD, Possemiers S, Van de Wiele T et al (2009) Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut 58:1091–1103CrossRefPubMedPubMedCentral
37.
38.
Psichas A, Sleeth ML, Murphy KG et al (2015) The short chain fatty acid propionate stimulates GLP-1 and PYY secretion via free fatty acid receptor 2 in rodents. Int J Obes 39:424–429CrossRef
39.
Vaishnava S, Behrendt CL, Ismail AS, Eckmann L, Hooper LV (2008) Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host–microbial interface. Proc Natl Acad Sci U S A 105:20858–20863CrossRefPubMedPubMedCentral
40.
De A, Pompilio A, Francis J et al (2018) Antidiabetic drugs ‘gliptins’ affect biofilm formation by Streptococcus mutans. Microbiol Res 209:79–85
41.
Lam YY, Ha CW, Campbell CR et al (2012) Increased gut permeability and microbiota change associate with mesenteric fat inflammation and metabolic dysfunction in diet-induced obese mice. PLoS One 7:e34233CrossRefPubMedPubMedCentral
42.
Moya-Perez A, Neef A, Sanz Y (2015) Bifidobacterium pseudocatenulatum CECT 7765 reduces obesity-associated inflammation by restoring the lymphocyte–macrophage balance and gut microbiota structure in high-fat diet-fed mice. PLoS One 10:e0126976CrossRefPubMedPubMedCentral
43.
Geurts L, Lazarevic V, Derrien M et al (2011) Altered gut microbiota and endocannabinoid system tone in obese and diabetic leptin-resistant mice: impact on apelin regulation in adipose tissue. Front Microbiol 2:149CrossRefPubMedPubMedCentral
44.
Scaldaferri F, Pizzoferrato M, Gerardi V, Lopetuso L, Gasbarrini A (2012) The gut barrier: new acquisitions and therapeutic approaches. J Clin Gastroenterol 46(Suppl):S12–S17CrossRefPubMed
45.
Everard A, Lazarevic V, Gaia N et al (2014) Microbiome of prebiotic-treated mice reveals novel targets involved in host response during obesity. ISME J 8:2116–2130CrossRefPubMedPubMedCentral
46.
Lee SJ, Lee J, Li KK et al (2012) Disruption of the murine Glp2r impairs Paneth cell function and increases susceptibility to small bowel enteritis. Endocrinology 153:1141–1151CrossRefPubMedPubMedCentral
47.
Drucker DJ, Erlich P, Asa SL, Brubaker PL (1996) Induction of intestinal epithelial proliferation by glucagon-like peptide 2. Proc Natl Acad Sci U S A 93:7911–7916CrossRefPubMedPubMedCentral
48.
Briand F, Brousseau E, Quinsat M, Burcelin R, Sulpice T (2018) Obeticholic acid raises LDL-cholesterol and reduces HDL-cholesterol in the diet-induced NASH (DIN) hamster model. Eur J Pharmacol 818:449–456CrossRefPubMed
49.
Sheng L, Jena PK, Hu Y et al (2017) Hepatic inflammation caused by dysregulated bile acid synthesis is reversible by butyrate supplementation. J Pathol 243:431–441CrossRefPubMedPubMedCentral
50.
Scheen AJ (2010) Pharmacokinetics of dipeptidylpeptidase-4 inhibitors. Diabetes Obes Metab 12:648–658CrossRefPubMed
Metadata
Title
The DPP-4 inhibitor vildagliptin impacts the gut microbiota and prevents disruption of intestinal homeostasis induced by a Western diet in mice
Authors
Marta Olivares
Audrey M. Neyrinck
Sarah A. Pötgens
Martin Beaumont
Nuria Salazar
Patrice D. Cani
Laure B. Bindels
Nathalie M. Delzenne
Publication date
01-08-2018
Publisher
Springer Berlin Heidelberg
Published in
Diabetologia / Issue 8/2018
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-018-4647-6

Other articles of this Issue 8/2018

Diabetologia 8/2018 Go to the issue

Up Front

Up front

Letter

Medicalising pregnancy with new diagnostic criteria for gestational diabetes mellitus: do we need more evidence? Reply to Venkataraman H and Saravanan P [letter]

Letter

Flash glucose monitoring: objective, not self-referential, outcomes are needed

Article

Nuts as a replacement for carbohydrates in the diabetic diet: a reanalysis of a randomised controlled trial

Short Communication

A selective CD28 antagonist and rapamycin synergise to protect against spontaneous autoimmune diabetes in NOD mice

Short Communication

Corneal confocal microscopy for identification of diabetic sensorimotor polyneuropathy: a pooled multinational consortium study

ACC 2024 Congress Coverage

Cardiology Video

Highlights from the ACC 2024 Congress

Watch now

Watch official videos from the ACC congress summarizing key highlights from the last year in heart failure, cardiomyopathies, valvular disease, pulmonary vascular disease, and pediatric cardiology.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits