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Alteration of gut microbiota induced by DPP-4i treatment improves glucose homeostasis.

ABSTRACT: BACKGROUND:Increasing evidence indicates that the gut microbiota contributes to the occurrence and development of metabolic diseases. However, little is known about the effects of commonly used antidiabetic agents on the gut microbiota. In this study, we investigated the roles of dipeptidyl peptidase-4 inhibitors (DPP-4i) and ?-glucosidase inhibitor in modulating the gut microbiota. METHODS:16S-rDNA sequencing was performed to analyse the effects of DPP-4i and acarbose on the gut microbiota in mice fed a high-fat diet (HFD). Fecal microbiota transplantation (FMT) from type 2 diabetes patients to germ-free mice was performed to investigate the contribution of the altered microbiome to antidiabetic effects of the drugs. Fecal metabolomics was also analysed by untargeted and targeted GC-MS systems. FINDINGS:Although DPP-4i and ?-glucosidase inhibitor both altered the gut microbial composition, only the microbiome modulation of DPP-4i contributed to its hypoglycemic effect. Specifically, the changes of 68.6% genera induced by HFD were rescued by DPP-4i. FMT showed that the DPP-4i-altered microbiome improved glucose tolerance in colonized mice, while acarbose did not. Moreover, DPP-4i increased the abundance of Bacteroidetes, and also promoted a functional shift in the gut microbiome, especially increasing the production of succinate. INTERPRETATION:Our findings demonstrate an important effect of DPP-4i on the gut microbiota, revealing a new hypoglycemic mechanism and an additional benefit of it. Furthermore, modulating the microbial composition, and the functional shift arising from changes in the microbiome, might be a potential strategy for improving glucose homeostasis. FUND: This work was supported by grants from the National Natural Science Foundation of China (No. 81700757, No. 81471039, No. 81700714 and No. 81770434), the National Key R&D Program of China (No. 2017YFC1309602, No. 2016YFC1101100, No. 2017YFD0500503 and No. 2017YFD0501001), and the Natural Science Foundation of Chongqing (No. cstc2014jcyjjq10006, No. cstc2016jcyjA0093 and No. cstc2016jcyjA0518).

SUBMITTER: Liao X

PROVIDER: S-EPMC6603491 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Alteration of gut microbiota induced by DPP-4i treatment improves glucose homeostasis.

Liao Xiaoyu X Song Lingyu L Zeng Benhua B Liu Bingyao B Qiu Yuyang Y Qu Hua H Zheng Yi Y Long Min M Zhou Houdi H Wang Yuan Y Du Yingxuan Y Xu Jing J Shen Rufei R Tong Qiang Q Cai Leiqin L Li Xing X Guo Shaodong S Yang Gangyi G Zhu Zhiming Z Pu Xiaoyun X Wei Hong H Zheng Hongting H

EBioMedicine 20190326

<h4>Background</h4>Increasing evidence indicates that the gut microbiota contributes to the occurrence and development of metabolic diseases. However, little is known about the effects of commonly used antidiabetic agents on the gut microbiota. In this study, we investigated the roles of dipeptidyl peptidase-4 inhibitors (DPP-4i) and α-glucosidase inhibitor in modulating the gut microbiota.<h4>Methods</h4>16S-rDNA sequencing was performed to analyse the effects of DPP-4i and acarbose on the gut ...[more]

PMID: 30922964

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Project description: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.

Project description:Disturbed homeostasis of gut microbiota has been suggested to be closely associated with 5-fluorouracil (5-Fu) induced mucositis. However, current knowledge of the overall profiles of 5-Fu-disturbed gut microbiota is limited, and so far there is no direct convincing evidence proving the causality between 5-Fu-disturbed microbiota and colonic mucositis. In mice, in agreement with previous reports, 5-Fu resulted in severe colonic mucositis indicated by weight loss, diarrhea, bloody stool, shortened colon, and infiltration of inflammatory cells. It significantly changed the profiles of inflammatory cytokines/chemokines in serum and colon. Adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and VE-Cadherin were increased. While tight junction protein occludin was reduced, however, zonula occludens-1 (ZO-1) and junctional adhesion molecule-A (JAM-A) were increased in colonic tissues of 5-Fu treated mice. Meanwhile, inflammation related signaling pathways including NF-?B and mitogen activated protein kinase (MAPKs) in the colon were activated. Further study disclosed that 5-Fu diminished bacterial community richness and diversity, leading to the relative lower abundance of Firmicutes and decreased Firmicutes/Bacteroidetes (F/B) ratio in feces and cecum contents. 5-Fu also reduced the proportion of Proteobacteria, Tenericutes, Cyanobacteria, and Candidate division TM7, but increased that of Verrucomicrobia and Actinobacteria in feces and/or cecum contents. The fecal transplant from healthy mice prevented body weight loss and colon shortening of 5-Fu treated mice. In addition, the fecal transplant from 5-Fu treated mice reduced body weight and colon length of vancomycin-pretreated mice. Taken together, our study demonstrated that gut microbiota was actively involved in the pathological process of 5-Fu induced intestinal mucositis, suggesting potential attenuation of 5-Fu induced intestinal mucositis by manipulating gut microbiota homeostasis.

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Alteration of gut microbiota induced by DPP-4i treatment improves glucose homeostasis.

Publications

Alteration of gut microbiota induced by DPP-4i treatment improves glucose homeostasis.

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