Hamada Yoji, Goto Moritaka, Nishimura Go, Nagasaki Hiroshi, Seino Yusuke, Kamiya Hideki, Nakamura Jiro
Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute, 480-1195, Japan.
Pharmaceutical Research Laboratories, Sanwa Kagaku Kenkyusho Co, Ltd, 363 Shiozaki, Hokusei-cho, Inabe, 511-0406, Japan.
Metabol Open. 2020 Jan 11;5:100024. doi: 10.1016/j.metop.2020.100024. eCollection 2020 Mar.
Bile acids (BAs) have been shown to contribute to glucose and energy homeostasis. We have recently reported that miglitol, an alpha-glucosidase inhibitor, increases fecal BA excretion and ameliorate insulin resistance and obesity in mice. The aim of this study was to clarify the mechanisms by which miglitol affects BA metabolism. The expression of genes regulating BA metabolism, gut microbiome and short-chain fatty acids (SCFA) were examined.
NSY mice, representing an obese type 2 diabetic model, were fed with a high-fat diet with or without miglitol for 4 weeks. The expression of BA-related genes in the liver and the lower intestine were measured. Alterations in fecal microbiome, fecal SCFA along with plasma lipid levels were also evaluated.
Miglitol significantly increased fecal BA secretion and markedly upregulated the mRNA expression, protein levels and enzyme activity of hepatic cholesterol 7α-hydroxylase, a rate-limiting enzyme of BA synthesis. In the intestine, miglitol treatment significantly suppressed the mRNA expression of apical sodium-dependent bile acid transporter and ATP-binding cassette transporter G5 and G8. In fecal microbiome, the prevalence of prevotella was remarkably reduced and that of clostridium subcluster XIVa was increased by miglitol. Miglitol elevated formic and n-butyric acids along with total SCFA concentration in feces, while succinic acid was decreased. There was no change in plasma total cholesterol levels.
Collectively, miglitol may affect BA metabolism via enhanced CYP7A1 activity resulting from at least in part the alterations in gut microbiome and SCFA production in obese diabetic mice.
胆汁酸（BAs）已被证明有助于葡萄糖和能量稳态。我们最近报道，α-葡萄糖苷酶抑制剂米格列醇可增加小鼠粪便中胆汁酸的排泄，并改善胰岛素抵抗和肥胖。本研究的目的是阐明米格列醇影响胆汁酸代谢的机制。研究了调节胆汁酸代谢、肠道微生物群和短链脂肪酸（SCFA）的基因表达。
将代表肥胖2型糖尿病模型的NSY小鼠喂食含或不含米格列醇的高脂饮食4周。测量肝脏和下肠道中与胆汁酸相关基因的表达。还评估了粪便微生物群、粪便短链脂肪酸以及血浆脂质水平的变化。
米格列醇显著增加粪便胆汁酸分泌，并显著上调肝脏胆固醇7α-羟化酶（胆汁酸合成的限速酶）的mRNA表达、蛋白质水平和酶活性。在肠道中，米格列醇治疗显著抑制顶端钠依赖性胆汁酸转运蛋白以及ATP结合盒转运蛋白G5和G8的mRNA表达。在粪便微生物群中，米格列醇显著降低了普氏菌的流行率，增加了梭菌属 XIVa 亚群的流行率。米格列醇提高了粪便中甲酸和正丁酸以及总短链脂肪酸的浓度，而琥珀酸则减少。血浆总胆固醇水平没有变化。
总体而言，米格列醇可能通过增强CYP7A1活性来影响胆汁酸代谢，这至少部分是由于肥胖糖尿病小鼠肠道微生物群和短链脂肪酸产生的改变所致。
