Chemogenetic analysis of how receptors for short chain fatty acids regulate the gut-brain axis
Chemogenetic analysis of how receptors for short chain fatty acids regulate the gut-brain axis
复制标题
短链脂肪酸受体如何调节肠脑轴的化学遗传学分析
DOI：
10.1101/2020.01.11.902726
复制
发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Barki N
中科院分区：
文献类型：
--
作者：
Barki N
肠脑轴允许肠和中枢神经系统之间的双向交流。肠道菌群产生的短链脂肪酸（SCFAs）是这一界面的重要调节因子。然而，确定scfa的作用机制一直具有挑战性，因为在各种作用中，它们共同激活了一对密切相关且特征不明显的G蛋白偶联受体FFA2和FFA3。设计物药物特异性激活的设计物受体（DREADDs）是确定受体特异性功能的重要途径。通过筛选含有羧酸的小分子文库，我们鉴定出4-甲氧基-3-甲基苯甲酸（MOMBA）是FFA2的一种不被scfa激活的DREADD变体的特异性激动剂。用FFA2- dreadd替代FFA2的小鼠，同时保留FFA3的表达，MOMBA和现在的FFA3受体选择性SCFAs的组合确定了FFA2和FFA3在肠道转运时间、肠内分泌激素的分泌以及从肠道到每个自主神经和躯体感觉神经节细胞和脊髓的通讯中的关键但不同的作用。这些研究绘制了FFA2和FFA3连接肠道和大脑的机制和信号通路，并为进一步探索这种接口提供了动物模型和新的工具化合物。
The gut-brain axis allows bi-directional communication between the enteric and central nervous systems. Short chain fatty acids (SCFAs) generated by the gut microbiota are important regulators of this interface. However, defining mechanisms by which SCFAs do so has been challenging because, amongst various roles, they co-activate both of a pair of closely related and poorly characterized G protein-coupled receptors, FFA2 and FFA3. Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) can provide an important approach in defining receptor-specific functions. By screening a library of carboxylate-containing small molecules we identified 4-methoxy-3-methyl-benzoic acid (MOMBA) as a specific agonist of a DREADD variant of FFA2 which is not activated by SCFAs. Using mice engineered to replace FFA2 with this FFA2-DREADD, whilst retaining FFA3 expression, combinations of MOMBA and the now FFA3 receptor selective SCFAs defined key, but distinct, roles of FFA2 and FFA3 in each of gut transit time, secretion of entero-endocrine hormones, and communication from the gut to each of autonomic and somatic sensory ganglion cells and the spinal cord. These studies map mechanisms and signalling pathways by which each of FFA2 and FFA3 act to link the gut and the brain and provide both animal models and novel tool compounds to further explore this interface.
登录
查看更多内容
G 蛋白 βγ 信号传导的调节。
影响因子：
--
作者：
K. Senarath;Dinesh Kankanamge;Saroopa P. Samaradivakara;Kasun Ratnayake;M. Tennakoon;A. Karunarathne
通讯作者：
A. Karunarathne
影响因子：
--
作者：
Priyadarshini, Medha;Villa, Stephanie R.;Layden, Brian T.
通讯作者：
Layden, Brian T.
影响因子：
3.9
作者：
N. Hattori;Y. Yamashiro
通讯作者：
N. Hattori;Y. Yamashiro
定义门控有髓鞘传入输入的脊髓微电路：对触觉异常性疼痛的影响
DOI：
10.2139/ssrn.3377640
发表时间：
2019
期刊：
SSRN Electronic Journal
影响因子：
--
作者：
Boyle K
通讯作者：
Boyle K
影响因子：
13.8
作者：
Wess J;Nakajima K;Jain S
通讯作者：
Jain S