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
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α-葡萄糖苷酶抑制剂的降血糖作用需要小鼠胆汁酸信号
DOI：
10.1007/s00125-020-05095-7
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发表时间：
2020-02-08
期刊：
影响因子：
8.2
通讯作者：
Gu, Yanyun
中科院分区：
文献类型：
--
作者：
Qiu, Yixuan;Shen, Linyan;Gu, Yanyun
目的/假设胆汁酸（BA）信号传导在代谢稳态中至关重要，最近发现其介导降糖治疗（包括α-葡萄糖苷酶抑制剂（AGI））的治疗作用。然而，其基本机制尚待澄清。我们假设BA信号可能是AGI的降糖作用和代谢益处所必需的。方法用AGI处理瘦素受体（Leptin receptor，Lepr）基因敲除（KO）db/db小鼠和高脂高糖（HFHS）喂养的Fxr（也称为Nr 1h 4）基因敲除小鼠。评估了不同隔室（包括肝脏、肠道和内分泌胰腺）中的代谢表型和BA信号传导。通过质谱法分析BA合并液图谱。通过RNA测序分析胰岛转录谱。通过16 S核糖体RNA基因测序分析肠道微生物组。结果AGI通过改变肠道微生物组降低了体内不同隔室BA池中的微生物BA水平，并增加了db/db和HFHS喂养小鼠模型的肠道BA重吸收。AGI诱导的BA信号传导的变化（包括肝脏中法尼醇X受体[FXR]的激活增加和回肠中FXR的抑制）与不同器官中BA池大小和组成的变化相呼应。在Fxr-KO小鼠中，AGI的降糖和降脂作用被部分消除，这可能是由于AGI对减缓β细胞复制、缓解胰岛素分泌过多和改善肝脏脂质和葡萄糖代谢的Fxr依赖性作用。结论/解释通过调节微生物BA代谢，AGI引起不同宿主隔室中BA池组成的不同变化，以协调全身的BA信号传导。AGI诱导的BA信号转导的变化可能部分是其降糖作用所必需的。因此，我们的研究揭示了调节微生物BA和宿主FXR信号传导用于治疗2型糖尿病的前景。数据可用性测序数据可从BioProject数据库（登录号PRJNA 600345;）获得。
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 alpha-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; ).