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

Liao, Xiaoyu; Song, Lingyu; Zeng, Benhua; Liu, Bingyao; Qiu, Yuyang; Qu, Hua; Zheng, Yi; Long, Min; Zhou, Huifang; Wang, Yuan; Du, Yingxuan; Xu, Jing; Shen, Rufei; Tong, Qiang; Cai, Leiqin; Li, Xing; Guo, Shaodong; Yang, Gangyi; Zhu, Zhiming; Pu, Ximing; Wei, Hong; Wang, Cong-Yi

doi:10.1016/j.ebiom.2019.03.057

Cited by 59 publications

(64 citation statements)

References 71 publications

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“…Of note, a recent study showed that transplanting faeces from AGI-treated individuals with diabetes did not lower blood glucose levels in high-fat-diet (HFD)-fed germ-free mice [56]. Consistently, we found that pre-treatment of mice with an antibiotic mix as a proxy for germ-free status did not attenuate the glucose-lowering and bodyweight-reducing effects of AGI (ESM Fig.…”

Section: Discussionsupporting

confidence: 84%

The glucose-lowering effects of α-glucosidase inhibitor require a bile acid signal in mice

Qiu

Shen

et al. 2020

Diabetologia

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Aims/hypothesis Bile-acid (BA) signalling is crucial in metabolism homeostasis and has recently been found to mediate the therapeutic effects of glucose-lowering treatments, including α-glucosidase inhibitor (AGI). However, the underlying mechanisms are yet to be clarified. We hypothesised that BA signalling may be required for the glucose-lowering effects and metabolic benefits of AGI. Methods Leptin receptor (Lepr)-knockout (KO) db/db mice and high-fat high-sucrose (HFHS)-fed Fxr (also known as Nr1h4)-KO mice were treated with AGI. Metabolic phenotypes and BA signalling in different compartments, including the liver, gut and endocrine pancreas, were evaluated. BA pool profiles were analysed by mass spectrometry. The islet transcription profile was assayed by RNA sequencing. The gut microbiome were assayed by 16S ribosomal RNA gene sequencing. Results AGI lowered microbial BA levels in BA pools of different compartments in the body, and increased gut BA reabsorption in both db/db and HFHS-fed mouse models via altering the gut microbiome. The AGI-induced changes in BA signalling (including increased activation of farnesoid X receptor [FXR] in the liver and inhibition of FXR in the ileum) echoed the alterations in BA pool size and composition in different organs. In Fxr-KO mice, the glucose-and lipid-lowering effects of AGI were partially abrogated, possibly due to the Fxr-dependent effects of AGI on decelerating beta cell replication, alleviating insulin hypersecretion and improving hepatic lipid and glucose metabolism. Conclusions/interpretation By regulating microbial BA metabolism, AGI elicited diverse changes in BA pool composition in different host compartments to orchestrate BA signalling in the whole body. The AGI-induced changes in BA signalling may be partly required for its glucose-lowering effects. Our study, hence, sheds light on the promising potential of regulating microbial BA and host FXR signalling for the treatment of type 2 diabetes. Data availability Sequencing data are available from the BioProject Database (accession no. PRJNA600345; www.ncbi.nlm.nih. gov/bioproject/600345).

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Section: Discussionsupporting

confidence: 84%

The glucose-lowering effects of α-glucosidase inhibitor require a bile acid signal in mice

Qiu

Shen

et al. 2020

Diabetologia

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“…Moreover, the results were inconsistent among those studies treated with liraglutide, sitagliptin, vildagliptin, and saxagliptin. In terms of β-diversity, there was higher cumulative evidence of significant difference after using metformin (5, 36-39, 41, 43-50, 54-56), and similar results were consistently reported among those studies treated with acarbose (5, 58-61), liraglutide (60,65,66,69,70), sitagliptin (5,60,73), and vildagliptin (6,74) across different mouse models. Evidence for the effects of other drugs was limited ( Table 9).…”

Section: Diversitysupporting

confidence: 68%

Effects of Non-insulin Anti-hyperglycemic Agents on Gut Microbiota: A Systematic Review on Human and Animal Studies

Cao

Hsu

et al. 2020

Front. Endocrinol.

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Background: As growing evidence links gut microbiota with the therapeutic efficacy and side effects of anti-hyperglycemic drugs, this article aims to provide a systematic review of the reciprocal interactions between anti-hyperglycemic drugs and gut microbiota taxa, which underlie the effect of the gut microbiome on diabetic control via bug-host interactions. Method: We followed the PRISMA requirements to perform a systematic review on human vs. animal gut microbiota data in PubMed, SCOPUS, and EMBASE databases, and used Cochrane, ROBIN-I, and SYRCLE tools to assess potential bias risks. The outcomes of assessment were trends on gut microbiota taxa, diversity, and associations with metabolic control (e.g., glucose, lipid) following anti-hyperglycemic treatment. Results: Of 2,804 citations, 64 studies (17/humans; 47/mice) were included. In human studies, seven were randomized trials using metformin or acarbose in obese, pre-diabetes, and type 2 diabetes (T2D) patients. Treatment of pre-diabetes and newly diagnosed T2D patients with metformin or acarbose was associated with decreases in genus of Bacteroides, accompanied by increases in both Bifidobacterium and Lactobacillus. Additionally, T2D patients receiving metformin showed increases in various taxa of the order Enterobacteriales and the species Akkermansia muciniphila. Of seven studies with significant differences in beta-diversity, the incremental specific taxa were associated with the improvement of glucose and lipid profiles. In mice, the effects of metformin on A. muciniphila were similar, but an inverse association with Bacteroides was reported. Animal studies on other anti-hyperglycemic drugs, however, showed substantial variations in results. Cao et al. Anti-hyperglycemic Drugs and Gut Microbiota Conclusions: The changes in specific taxa and β-diversity of gut microbiota were associated with metformin and acarbose in humans while pertinent information for other anti-hyperglycemic drugs could only be obtained in rodent studies. Further human studies on anti-hyperglycemic drugs other than metformin and acarbose are needed to explore gut microbiota's role in their therapeutic efficacies and side effects.

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“…SCFAs could alter the metabolic state via activation of nuclear receptors such as PPARs (Hasan, et al, 2019) or specific GPRs such as GPR41 and GPR43 that are involved in the release of the entero hormone PYY (Samuel, et al, 2008), fat accumulation reduction, energy expenditure (Kimura, et al, 2013) and insulin secretion (Tolhurst, et al, 2012). Several molecules, including GLP-1, MyD88, dipeptidyl peptidase-4 (DPP-4) and sodium glucose cotransporter 2 (SGLT2), interact closely with the gut microbiota to modulate insulin secretion (Grasset, et al, 2017), diabetes-related metabolic effects (Duparc, et al, 2017;Liao, et al, 2019) and diabetes-induced vascular dysfunction (Lee, et al, 2018).…”

Section: Diabetesmentioning

confidence: 99%

The gut microbiota and its interactions with cardiovascular disease

Wang

Feng

et al. 2020

Microbial Biotechnology

104

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Summary The intestine is colonized by a considerable community of microorganisms that cohabits within the host and plays a critical role in maintaining host homeostasis. Recently, accumulating evidence has revealed that the gut microbial ecology plays a pivotal role in the occurrence and development of cardiovascular disease (CVD). Moreover, the effects of imbalances in microbe–host interactions on homeostasis can lead to the progression of CVD. Alterations in the composition of gut flora and disruptions in gut microbial metabolism are implicated in the pathogenesis of CVD. Furthermore, the gut microbiota functions like an endocrine organ that produces bioactive metabolites, including trimethylamine/trimethylamine N‐oxide, short‐chain fatty acids and bile acids, which are also involved in host health and disease via numerous pathways. Thus, the gut microbiota and its metabolic pathways have attracted growing attention as a therapeutic target for CVD treatment. The fundamental purpose of this review was to summarize recent studies that have illustrated the complex interactions between the gut microbiota, their metabolites and the development of common CVD, as well as the effects of gut dysbiosis on CVD risk factors. Moreover, we systematically discuss the normal physiology of gut microbiota and potential therapeutic strategies targeting gut microbiota to prevent and treat CVD.

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

Cited by 59 publications

References 71 publications

The glucose-lowering effects of α-glucosidase inhibitor require a bile acid signal in mice

The glucose-lowering effects of α-glucosidase inhibitor require a bile acid signal in mice

Effects of Non-insulin Anti-hyperglycemic Agents on Gut Microbiota: A Systematic Review on Human and Animal Studies

The gut microbiota and its interactions with cardiovascular disease

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