Department of Biological and Biomedical Sciences, Glasgow Caledonian University, Glasgow, United Kingdom; Department of Biology, Faculty of Science, University of Zakho, Kurdistan Region, Iraq.
Department of Biological and Biomedical Sciences, Glasgow Caledonian University, Glasgow, United Kingdom.
Biochem Pharmacol. 2020 Oct;180:114151. doi: 10.1016/j.bcp.2020.114151. Epub 2020 Jul 15.
Obesity is intimately associated with diet and dysbiosis of gut microorganisms but anxiolytics, widely used in treatment of psychiatric conditions, frequently result in weight gain and associated metabolic disorders. We are interested in effects of the anxiolytic etifoxine, which has not been studied with respect to weight gain or effects on gut microorganisms. Here we induced obesity in mice by feeding a high-fat diet but found that intraperitoneal administration of etifoxine resulted in weight loss and decreased serum cholesterol and triglycerides. Obese mice had increased hepatic transcripts associated with lipid metabolism (cyp7a1, cyp27a1, abcg1 and LXRα) and inflammatory factors (TNFα and IL18) but these effects were reversed after etifoxine treatment other than cyp7a1. Taxonomic profiles of the organisms from the caecum were generated by 16S rRNA gene sequencing and Obese and etifoxine mice show differences by diversity metrics, Differential Abundance and functional metagenomics. Organisms in genus Oscillospira and genera from Lachnospiraceae family and Clostridiales order are higher in Control than Obese and at intermediate levels with etifoxine treatment. With respect to community metabolic potential, etifoxine mice have characteristics similar to Control and particularly with respect to metabolism of butanoate, sphingolipid, lipid biosynthesis and xenobiotic metabolism. We suggest mechanisms where-by etifoxine influences processes of host, such as on bile acid synthesis, and microbiota, such as signalling from production of butanoate and sphingosine, resulting in decreased cholesterol, lipids and inflammatory factors. We speculate that the indirect effect of etifoxine on microbial composition is mediated by microbial β-glucuronidases that metabolise excreted etifoxine glucuronides.
肥胖与饮食和肠道微生物失调密切相关，但广泛用于治疗精神疾病的抗焦虑药常常导致体重增加和相关代谢紊乱。我们对具有镇静作用的乙非他嗪的影响很感兴趣，该药物尚未研究其与体重增加或对肠道微生物的影响。在这里，我们通过喂食高脂肪饮食诱导肥胖，但发现腹腔内给予乙非他嗪会导致体重减轻和血清胆固醇和甘油三酯降低。肥胖小鼠肝脏中与脂质代谢（cyp7a1、cyp27a1、abcg1 和 LXRα）和炎症因子（TNFα 和 IL18）相关的转录物增加，但这些作用在乙非他嗪治疗后除了 cyp7a1 之外都得到了逆转。通过 16S rRNA 基因测序生成盲肠中生物体的分类群图谱，肥胖和乙非他嗪小鼠的多样性指标、差异丰度和功能宏基因组学显示出差异。属 Oscillospira 和 Lachnospiraceae 科的属中的生物体在对照中高于肥胖，而在乙非他嗪治疗中处于中间水平。就群落代谢潜能而言，乙非他嗪小鼠具有与对照相似的特征，特别是在丁酸、鞘脂、脂质生物合成和外来化合物代谢方面。我们提出了乙非他嗪影响宿主（如胆汁酸合成）和微生物群（如丁酸和鞘氨醇产生的信号）的机制，导致胆固醇、脂质和炎症因子减少。我们推测乙非他嗪对微生物组成的间接影响是由微生物β-葡糖苷酸酶介导的，这些酶代谢排泄的乙非他嗪葡萄糖醛酸苷。
