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).

中文翻译：

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α-葡萄糖苷酶抑制剂的降糖作用需要在小鼠体内产生胆汁酸信号。

目的/假设胆汁酸（BA）信号在代谢稳态中至关重要，最近发现它可以介导包括α-葡萄糖苷酶抑制剂（AGI）在内的降糖疗法的治疗作用。但是，尚需阐明其基本机制。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（Lepr）敲除（KO）db / db小鼠和高脂高蔗糖（HFHS）喂养的Fxr（也称为Nr1h4）-KO小鼠。评价了包括肝，肠和内分泌胰腺在内的不同区室的代谢表型和BA信号。通过质谱分析BA池概况。通过RNA测序测定胰岛转录谱。通过16S核糖体RNA基因测序来测定肠道微生物组。结果AGI降低了人体不同隔间的BA池中的微生物BA水平，并通过改变肠道微生物组提高了db / db和HFHS喂养的小鼠模型中肠道BA的重吸收。AGI诱导的BA信号变化（包括肝脏中的法呢素X受体[FXR]活化增强和回肠中的FXR抑制）改变了不同器官中BA池大小和组成的变化。在Fxr-KO小鼠中，AGI的葡萄糖和脂质降低作用被部分废除，这可能是由于AGI对Fxr的依赖作用对β细胞复制的减速，减轻了胰岛素的过度分泌并改善了肝脂质和葡萄糖的代谢。结论/解释通过调节微生物BA的代谢，AGI引发了不同宿主区室中BA池组成的各种变化，以协调整个体内的BA信号传导。AGI诱导的BA信号传导变化可能是其降糖作用的部分原因。因此，我们的研究揭示了调节微生物BA和宿主FXR信号转导用于治疗2型糖尿病的潜在潜力。数据可用性测序数据可从BioProject数据库中获取（登录号PRJNA600345； www.ncbi.nlm.nih.gov/bioproject/600345）。